Vinyl epoxides in organic synthesis.

Review pubs.acs.org/CR

Vinyl Epoxides in Organic Synthesis Jiayun He, Jesse Ling, and Pauline Chiu* Department of Chemistry and State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong 3.3.2. Meinwald Rearrangements 3.3.3. Ring Expansion Rearrangements 3.3.4. Other Rearrangement Reactions 3.4. Radical Reactions 3.4.1. Reactions of Alkoxy Radicals Derived from Vinyl Epoxides 3.4.2. Reactions of Carbon Radicals Derived from Vinyl Epoxides 3.4.3. Reactions of Allylic Radicals Derived from Vinyl Epoxides 3.5. Cycloadditions and Formal Cycloadditions 3.5.1. (3 + 2) Cycloadditions of Vinyl Epoxides 3.5.2. (4 + 2) Cycloadditions of Vinyl Epoxides 3.5.3. (4 + 3) Cycloadditions of Vinyl Epoxides 3.5.4. (5 + 2) Cycloadditions of Vinyl Epoxides 4. Conclusion Author Information Corresponding Author Notes Biographies Acknowledgments References

CONTENTS 1. Introduction 2. Synthesis of Vinyl Epoxides 2.1. Strategy A: From Dienes 2.1.1. Epoxidation of the More ElectronDeficient Double Bond 2.1.2. Epoxidation of the More Electron-Rich Carbon−Carbon Double Bond 2.1.3. Directed Monoepoxidation of Dienes 2.1.4. Epoxide Formation from Enediols 2.2. Strategy B: From Epoxy Aldehydes/Ketones 2.2.1. Olefination by Wittig-Type Reactions 2.2.2. Olefination by Aldol-Type Condensations 2.2.3. Other Olefinations 2.3. Strategy C: From Enone/Enal 2.3.1. Corey−Chaykovsky Epoxidation 2.3.2. Using diazomethane 2.3.3. Darzen-Type Reactions 2.4. Strategy D: From Aldehydes 2.4.1. Corey−Chaykovsky Epoxidation 2.4.2. Synthesis via Halohydrin-Type Intermediates 2.5. Strategy E: Kinetic Resolutions 2.6. Miscellaneous Strategies 3. Reactions of Vinyl Epoxides 3.1. Nucleophilic Openings 3.1.1. Nitrogen Nucleophiles 3.1.2. Oxygen Nucleophiles 3.1.3. Sulfur Nucleophiles 3.1.4. Halide Nucleophiles 3.1.5. Reductive Ring-Opening Reactions 3.1.6. Carbon Nucleophiles 3.1.7. Other Nucleophiles 3.2. Eliminative Ring-Opening Reactions 3.3. Rearrangements 3.3.1. Pericyclic Reactions © 2014 American Chemical Society

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1. INTRODUCTION Vinyl epoxides are molecules with a rich chemistry because of the strained oxirane, already a reactive moiety on its own, in proximity with a carbon−carbon double bond. The chemistry of vinyl epoxides is uniquely characterized by the conjugated reactivity of these two functional groups, which is not offered by either one of them separately. Moreover, in spite of the reactivity that vinyl epoxides exhibit, they are easily procured via simple synthetic routes. Hence, they are important building blocks having a vast potential for organic synthesis. The chemistry of the vinyl epoxides has attracted many to investigate their reactions and applications, and efforts have already been made to summarize the results that have appeared in the literature over the years. The synthesis and reactions of vinyl epoxides have been reviewed up to 2005 by Olofsson and Somfai.1 In the present review, results from the literature appearing since 2005 on the synthesis and reactions of vinyl epoxides are presented as a continuation of the coverage from the previous review. Reactions developed prior to 2005 will not be extensively discussed, except those that have been recently reported with new developments or applications. During the preparation of this review, we became aware of an updated

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Special Issue: 2014 Small Heterocycles in Synthesis Received: December 13, 2013 Published: April 29, 2014 8037

dx.doi.org/10.1021/cr400709j | Chem. Rev. 2014, 114, 8037−8128

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epoxide 5 from a diactivated diene using the same catalyst 2 in good yield and good ee (Scheme 2).7

review by Pineschi et al. in 2013 on nucleophilic reactions of vinyl epoxides.2 Hopefully, our review will provide a complementary resource that, together with the Pineschi update, could cover the entire body of literature more completely.

Scheme 2

2. SYNTHESIS OF VINYL EPOXIDES In this section, classical strategies for the synthesis of vinyl epoxides are cited but emphasis will be on the more recent diastereoselective and enantioselective syntheses of vinyl epoxides that have been reported since the last review,1 organized according to their precursors as depicted in Figure 1. Kinetic resolution and other synthetic methods resulting in optically enriched vinyl epoxides will also be discussed.

For cross-conjugated dienes, the chemoselectivity issue is trivial due to the electronic difference between the two double bonds. In Danishefsky’s total synthesis of peribysin E (Scheme 3),8 nucleophilic epoxidation occurred at the electron-deficient alkene chemo- and diastereoselectively on the convex face of the bicyclic system 6 to yield vinyl epoxide 7. Scheme 3

Figure 1. Retrosynthesis of vinyl epoxides.

2.1. Strategy A: From Dienes

Vinyl epoxides have been obtained from the monoepoxidation of dienes. Selective monoepoxidation without overoxidation can be controlled by electronic factors and reactivity as well as by directing groups. 2.1.1. Epoxidation of the More Electron-Deficient Double Bond. For electron-deficient conjugated dienes, nucleophilic epoxidation with peroxide (Weitz−Scheffer epoxidation) occurs with chemoselectivity at the double bond more proximate to the electron-withdrawing group. Enantioselective epoxidation of dienones has been achieved using polyleucine3 or a lanthanum−BINOL complex as catalysts.4 More recently, chemoselective and enantioselective epoxidation of α,β,γ,δ-bisunsaturated trichloroketones has been achieved with prolinol catalysts5 such as 2 by Zhao and coworkers. Monoepoxidation of 1 to yield 4 was achieved with excellent enantioselectivity (Scheme 1).6 The proposed mechanism is depicted in Scheme 1, in which the prolinol catalyst acts as both a Brønsted acid to activate the ketone and a Brønsted base to direct the peroxide to the dienone in the conjugate addition. Similarly, De Fusco et al. prepared vinyl

Patonay et al. prepared 2,3-epoxy-3-styrylchromones from 3styrylchromones such as 8 in the presence of NaOH/H2O2. However, attempts to prepare optically enriched 10 using cinchona alkaloid derivative 9 developed by Wynberg as catalyst9 generated the vinyl epoxide with a low ee (Scheme 4).10 Scheme 4

Scheme 1

2.1.2. Epoxidation of the More Electron-Rich Carbon− Carbon Double Bond. The majority of epoxidations are electrophilic; therefore, there are more literature examples in which the more electron-rich double bond of dienes have been selectively monoepoxidized. Monoepoxidation has been achieved using common oxidants such as mCPBA.11 In the synthesis of liphagal, AlvarezManzaneda clearly demonstrated the chemoselectivity of mCPBA to oxidize the more hindered but also the more electron-rich alkene, regardless of the steric hindrance.12 8038


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Epoxidation occurred anti with respect to the axial methyl group (Scheme 5).

Scheme 9

Scheme 5

Diastereoselective synthesis of vinyl epoxide 12 by Bellomo et al. from an enantiomerically pure bromodiene 1113 relied on selective oxidation of the more electron-rich alkene, anti with respect to the acetonide (Scheme 6).

synthesis of (−)-balanol (Scheme 10)18 and members of the labdane family (Scheme 11).19 Scheme 10

Scheme 6

Scheme 11 Beller et al. developed an epoxidation that attempted to mimic biochemical oxidation by iron-based oxygenases.14 Monoepoxidation of 1,3-cyclooctadiene catalyzed by a Fe(III) complex was realized in 65% yield (Scheme 7). Scheme 7

Fuchs and co-workers investigated extensively the complementary epoxidations of cross-conjugated sulfonyl dienes 19 and their applications.20 Either double bond of the diene has been chemoselectively epoxidized using suitable oxidants (Scheme 12).21

Metal-catalyzed asymmetric epoxidation using a molybdenum−chiral bishydroxamic acid complex generated vinyl epoxide (R,S)-14 in moderate ee from cyclohexadiene 13 (Scheme 8).15

Scheme 12

Scheme 8

The more electron-rich double bonds of cyclic sulfonyl dienes 20 and 22 were epoxidized using Jacobsen’s catalyst (24) with excellent enantiomeric excesses (Scheme 13).20a The reaction was successful on a 350 g scale.20f Related substrates such as triflyl dienes have also been similarly epoxidized under these conditions. Asymmetric epoxidation of acyclic sulfonyl dienes and cyclic dienes of ring sizes other than six and seven were less successful. Jacobsen epoxidation has been applied to many total syntheses, including the syntheses of the scaffolds of aplyronine A, apoptolidin, (+)-pretazettine, and vitamin D3.20b−g Terry and Stack developed a silica-bound manganese(II) bisPhen complex 27 as a catalyst for oxidation of alkenes and dienes (Scheme 14).22 Conjugated diene 25 was oxidized preferentially at the less electron-deficient double bond, giving racemic vinyl epoxide 26 in quantitative yield.

Another asymmetric oxidation, the Shi epoxidation, employing chiral dioxiranes derived from sugars,16 has been employed to effectively distinguish the difference in the reactivity between (Z)- and (E)-alkenes. Epoxidation was selective for the (Z)double bond of the electronically similar double bonds of diene 16 to give 17 in good ee (Scheme 9).17 This asymmetric reaction has been employed in several total syntheses having vinyl epoxide intermediates, including the 8039


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Scheme 13

Scheme 16

2.1.3. Directed Monoepoxidation of Dienes. Epoxidation by peracids and metal complexes such as VO(acac)2/ tBuOOH are directed by functional groups.11,26 This directing effect has been used to control the selectivity of diene monoepoxidation to effectively enhance the yield in the synthesis of vinyl epoxides. The diastereoselectivity in the epoxidation of an acyclic substrate is derived by reaction from the most favored conformation with minimization of allylic strain. Some recent examples of directed epoxidations in the context of dienes have been reported by Kobayashi and co-workers in the synthesis of decarestrictine D, where a series of vinyl epoxides 33 was prepared in good yields by diastereoselective mCPBA oxidations of dienols 32 (Scheme 17).27 Morken and Zhang

Scheme 14

Scheme 17

While dioxiranes are powerful enough to oxidize electrondeficient alkenes, epoxidation of electron-rich olefins is still preferred (Scheme 15).23 Epoxidation under the Shi conditions oxidized the less electron-deficient double bond of conjugated dienoate 25 to yield vinyl epoxide (R,R)-26 with high enantioselectivity.

reported a highly diastereoselective monoepoxidation of trienol 34 using a similar protocol, as depicted in Scheme 18.28 In the Scheme 18

Scheme 15

case of dienol 35, Sharpless epoxidation yielded vinyl epoxide 36 with a low de, probably because there is not a particularly favored conformational isomer of 36 (Scheme 19).29 Zhang et al. demonstrated in their synthesis of montabuphine stereocontrolled preparation of diastereomeric vinyl epoxides 39 and 41, starting from dienone 37 (Scheme 20).30 Diastereoselective reduction of 37 from the less hindered α-face generated β-alcohol 38, in which directed epoxidation yielded vinyl epoxide 39. On the other hand, nucleophilic epoxidation Scheme 19 Studies by Fernández de la Pradilla on the epoxidation of dienyl sulfones 30 showed that the terminal double bond, which was both more electron-rich and less hindered, was selectively epoxidized using the Jacobsen−Katsuki reaction24 (Scheme 16).25 8040


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Scheme 20

Scheme 23

Scheme 24

of 37 from the α-face generated epoxide 40, which was then reduced from the less hindered β-face as defined by the newly installed α-epoxide to yield diastereomeric vinyl epoxide 41. In the synthesis of sulfonyl vinyl epoxide 43 the hydroxyl group of dienol 42 directed the epoxidation, and this effect was suggestd to have been enhanced by additional chelation with the sulfone that was concomitantly formed under the oxidizing conditions (Scheme 21).31 However, there was overoxidation of 43 to ketone 44, which complicated the reaction outcome.

the carbamate, to provide vinyl epoxide 49 in excellent yield (Scheme 25).35 Scheme 25

Scheme 21

2.1.4. Epoxide Formation from Enediols. Alkenediols have been selectively monoactivated and cyclized to yield vinyl epoxides readily. A number of naturally occurring polyols have been used as starting materials for the synthesis of vinyl epoxides by this strategy, including tartrates,36 derivatives of mannitol,37 xylose,38 and mannose.39 Crotti and his group reported the preparation of cyclic vinyl epoxides from commercially available tri-O-acetyl-D-glucal 50 (Scheme 26).40 After a series of protections, deprotections, and activations, mesylated glycals 51 were obtained. Upon treatment with base, vinyl epoxides 52 were generated, although they were not isolable due to their instability. Their formation was inferred by the reaction products 53−55, derived from attack of 52 by a range of nucleophiles.41 From the high yields of the ring-opened products, however, 52 appeared to have been formed quantitatively from 51. With recent developments in the desymmetrization of polyols, substrates other than those from the chiral pool can also be used in the synthesis of optically active vinyl epoxides. Kang realized this asymmetric synthetic strategy and applied it to the total synthesis of azithromycin.42 Triol 56 was desymmetrized by an optimized chiral copper catalyst 57, which can activate the benzoyl chloride by chelation,43 to give diol 58 in 91% ee. Selective activation of the primary alcohol and base-induced cyclization yielded the enantiomerically enriched vinyl epoxide 59 (Scheme 27). Boyd et al. made use of tetraols derived from oxidation of aromatic compounds in their preparation of vinyl epoxides.44 The tetraols 62 were prepared in enantiomerically enriched

The Sharpless asymmetric epoxidation32 also relies on the directing effect by a hydroxyl group, has been applied to the regio- and enantioselective monoepoxidation of dienols, and is an excellent strategy to obtain enantiomerically and diastereomerically pure vinyl epoxides. For example, in Fujiwara’s model studies on the synthesis of goniodomin A, vinyl epoxide intermediates 45 and 46 were prepared by Sharpless asymmetric epoxidations in high yields (Schemes 22 and 23).33 Takamura et al. also applied the same reaction to procure 47 for their synthesis of gummiferol (Scheme 24).34 Direction of epoxidation has also been realized with aminesubstituted dienes. Kann’s synthesis of oseltamivir involved dienoate 48, which was epoxidized stereoselectively, directed by Scheme 22

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cyclized in the presence of methoxide to give unsaturated epoxides 64 in good yields and with retention of enantiomeric excess. Oxidation of toluene, however, also generated isomer 66 in a significant amount in addition to 65 (Scheme 29); 66 was subjected to the same protocol to produce toluene dioxide 67.

Scheme 26

Scheme 29

Scheme 27

In the formal synthesis of oseltamivir (Tamiflu), Kamimura and Nakano prepared a vinyl epoxide starting from the strained ring system 68 (Scheme 30).45 Saponfication resulted in Scheme 30 form from the corresponding monosubstituted benzenes 60 by treatment with toluene dioxygenase (TDO) from bacterium P. putida UV4 and then by further oxidation with osmium tetroxide (Scheme 28). The cyclohexene tetraols 62 underwent bromoacetylation to give dibromodiacetates 63, which were Scheme 28

epoxide formation via elimination of mesylate. Deprotonation with aza bridge opening generated the vinyl group. A similar preparation of an unsaturated epoxide is found in the synthesis of acosamine by Bagal et al.46 2.2. Strategy B: From Epoxy Aldehydes/Ketones

Starting from an epoxy ketone or an epoxy aldehyde, transformation of the carbonyl group to an olefin yields a vinyl epoxide. Epoxy ketones and aldehydes are readily 8042


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obtained from the many diastereoselective and enantioselective epoxidation reactions of enones and enals.47 Alternatively, epoxy ketones and aldehydes have also been obtained from epoxidation of allylic alcohols and subsequent alcohol oxidation. There are many and oxidizing agents and protocols that oxidize epoxy alcohols, while the oxirane remains inert, including the Swern oxidation,48 the Parikh-Doering oxidation,49 IBX,50 DMP,51 TPAP,52 and TEMPO oxidations.53 Because of the availability of starting materials and robust olefination protocols for carbonyl groups, this strategy is among the most used for the synthesis of vinyl epoxides. 2.2.1. Olefination by Wittig-Type Reactions. The Wittig reaction has been commonly employed to convert epoxy aldehydes to vinyl epoxides. Both the Wittig and the Horner− Wadsworth−Emmons olefinations have been applied successfully,54 as illustrated in Schemes 31,50b 32,49d and 33.48e The olefination is usually performed immediately after oxidation of the epoxy alcohol to avoid isolation of epoxy aldehyde intermediates that tend to decompose.

Scheme 34

Scheme 35

Scheme 31

Scheme 32

Scheme 33

Scheme 36

2.2.2. Olefination by Aldol-Type Condensations. The aldol condensation has been another effective way to olefinate an epoxy aldehyde, and the Kobayashi group used this strategy to prepare vinyl epoxides 73 for synthesis of prostaglandin derivatives (Scheme 34). Epoxy aldehydes (1R,2S)-69 and (1S,2R)-69 were treated with lithium enolate 70; then dehydration yielded exclusively (E)-vinyl epoxides (S,S)-72 and (R,R)-72, respectively.55 A related addition−elimination sequence using 73 as nucleophile was reported by Jung et al. to afford vinyl epoxides 74 and 75 in good yields (Scheme 35).56 2.2.3. Other Olefinations. Vinyl epoxides have been prepared from the reduction of propargylic epoxides, which in turn have been obtained from epoxy aldehydes. Vaz et al. designed the synthesis of a stannylated vinyl epoxide from epoxy aldehyde 76 (Scheme 36).57 Alkynyl epoxide 77 was obtained from 76 via a Colvin rearrangement,58

whereupon a palladium-catalyzed hydrostannation afforded vinyltin 78 as product. This protocol was also applied to synthesis of carotenoids by Brückner’s group.59 In the course of the synthesis of eupomatilone-6, McIntosh and co-workers prepared a vinyl epoxide from an epoxy ketone via an Ireland−Claisen rearrangement (Scheme 37).60 Nucleophilic addition of (E)-propenyllithium to epoxy ketone 79 followed by acylation of the resulting alcohol yielded 80, the precursor of the Ireland−Claisen rearrangement. After enolsilane formation, rearrangement was induced upon warming and afforded vinyl epoxide 81 as product with high diastereoselectivity. 8043


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Scheme 37

Scheme 40

cinnamaldehyde via an in-situ-generated sulfonium salt formed from a catalytic amount of thiophane (Scheme 41).65 Scheme 41

Epoxy ketones have been converted to epoxy enolsilanes, which can be regarded as functionalized, substituted vinyl epoxides. Epoxy enolsilanes can be readily synthesized from epoxy ketones by low-temperature deprotonation and silylation (Scheme 38) but not by silylation using silyl triflate and amine which typically require higher reaction temperatures.61

Accordingly, synthesis of optically enriched vinyl epoxide (R)86 was achieved using chiral sulfonium salt 87 to induce asymmetric epoxidation (Scheme 42).66 While good enantioselectivity was observed, the reaction required a stoichiometric amount of the chiral sulfonium species, 87.

Scheme 38

Scheme 42

Yoshida et al. provided an alternative strategy for synthesis of cyclic epoxy enol ethers.62 Starting from a series of propargylic epoxides 83, a range of phenols added to the carbon−carbon triple bond under palladium catalysis to give 84 (Scheme 39). The yield and regioselectivity were generally very good; however, the reaction has only been demonstrated in the context of six-membered ring substrates. Scheme 39 2.3.2. Using diazomethane. Vinyl epoxides have been synthesized from the reaction of enones with diazomethane. Ferreira et al. prepared racemic bis-vinyl epoxides 89 from quinones 88 in moderate to good yields (Scheme 43).67 The authors reported that competitive cyclopropanation of the carbon−carbon double bonds resulted in decreased yields of some vinyl epoxides. 2.3.3. Darzen-Type Reactions. The Darzens reaction of an enone or an enal produces a vinyl epoxide.68 Vinyl epoxides 90 were prepared in this manner by Krafft and co-workers (Scheme 44) using a bromoester enolate.69 A similar reaction

Substituted vinyl epoxides have also been prepared by enol triflation of epoxy ketones; a typical procedure is shown in Scheme 40.63 These procedures are well established and usually employ strong bulky bases and low temperatures for enolate formation and trapping.

Scheme 43

2.3. Strategy C: From Enone/Enal

Addition of a carbon nucleophile to convert the carbonyl groups in enones or enals to epoxides represents another strategy to prepare vinyl epoxides. 2.3.1. Corey−Chaykovsky Epoxidation. The classical reaction to transform a carbonyl group to an epoxide is the Corey−Chaykovsky reaction via sulfur ylides.64 For example, Piccinini et al. reported the synthesis of racemic 86 from 8044


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Scheme 44

Scheme 47

was reported by Kowalkowska and Jończyk employing the enolate of a chloroester generated in situ (Scheme 45).70 Use of Scheme 45

a phase-transfer catalyst resulted in better yields for some substrates.71 Jończyk’s group also used chloronitriles 91 instead of haloesters to react with both enals and enones to give cyanosubstituted vinyl epoxides 92 (Scheme 46).70 Generally, the stereochemistry of the epoxide was quite difficult to control under these reaction conditions.

Scheme 48

Scheme 46

Metzner’s group reported a diastereoselective synthesis of vinyl epoxides from aldehydes via this strategy.73 The sulfur ylide was formed in situ from allylation of a catalytic amount of tetrahydrothiophene by bromide 98 and deprotonation. Reaction with aldehydes yielded 99 selectively as trans-epoxides (Table 1). The asymmetric version of this reaction mediated by Lautens’s group demonstrated a related strategy to synthesize optically enriched vinyl epoxides from enals and enones. Addition of chloromethyllithium produced racemic chlorohydrins 93, followed by an enzymatic kinetic resolution generated optically enriched 94 and 95. Subsequent treatment of each compound under basic conditions produced the enantiomeric vinyl epoxides 96 and ent-96 (Scheme 47).72 Epoxide formation from the chlorohydrins 94 showed perfect ee retention, but cyclization starting from the acylated chlorohydrins 95 showed some ee leakage, possibly due to equilibration and racemization via a tetrahedral intermediate such as 97 for a particular substrate (Scheme 48).

Table 1. Corey−Chaykovsky Reactions73

2.4. Strategy D: From Aldehydes

Aldehydes can undergo homologation to generate vinyl epoxide derivatives. Several protocols have been developed for this type of transformation. 2.4.1. Corey−Chaykovsky Epoxidation. There has been a resurgence of interest and activity in employing sulfide derivatives as mediators and organocatalysts in sulfur−ylide chemistry. As noted by Olofsson and Somfai.1 only stabilized ylides such as allyl react with high diastereoselectivity. However, this is sufficient for reaction with aldehydes to achieve a vinyl epoxide synthesis.

a

entry

R

dr (trans:cis)

yield (%)a

1 2 3 4 5 6

4-CF3C6H4 4-NO2C6H4 4-MeOC6H4 2-furyl cinnamyl n-butyl

93:7 94:6 >95:5 95:5 92:8 77:23

92 83 33 75b 67 78

Isolated yield. bNMR conversion.

a stoichiometric amount of chiral thiophane (R,R)-100 afforded enantiomerically enriched 101 in modest yield and ee (Scheme 49). Chiral sulfide 102 was designed by Aggarwal as a more effective mediator of the Corey−Chaykovsky reaction (Table 2).74 Chiral sulfide (−)-102 could be prepared practically from limonene in bulk, in contrast to the long, multistep synthesis of 8045


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range of aldehydes to trans-epoxides 104 with excellent enantiomeric excesses. The authors demonstrated the synthetic potential of this asymmetric reaction in the total synthesis of quinine and quinidine. Scheme 50 depicts the synthesis of quinine from allylic alcohol 105. Reaction of triflated 105 and chiral sulfide (−)-102 generated sulfonium salt 106, which was deprotonated and used in a Corey−Chaykovsky reaction with chiral aldehyde 107. Vinyl epoxide 108 was obtained in high yield and diastereoselectivity. Ring opening and oxidation of 108 yielded quinine 109. Synthesis of the pseudoenantiomer, quinidine, followed the same strategy but employed (+)-102 instead.74 Tang’s group reported a novel synthesis of cyclic vinyl epoxides using a diastereoselective intramolecular Corey− Chaykovsky epoxidation.76 Treatment of enones with the sulfur−ylide-derived 110 resulted in a domino conjugate addition−Corey−Chaykovsky epoxidation via the mechanism shown in Scheme 51 to furnish cyclohexene oxides 111 in good

Scheme 49

Table 2. Asymmetric Corey−Chaykovsky Reactions74

Scheme 51

entry

R1

R2

R3

X

yield (%)a

dr (trans:cis)

ee

1 2 3 4 5

H Me Me Me Me

Ph Ph H Ph H

Ph Ph Ph Cy Cy

BF4 BF4 OTf BF4 OTf

65 97 80 77 77

80:20 >95:5 >95:5 >95:5 >95:5

70% 98% 98% 96% 94%

a

yields. Moreover, carrying out the same reaction using the enantiomerically pure camphor-derived sulfonium salt 112 generated the cyclohexene oxide products 115 and 116 with excellent enantiomeric purities (Scheme 52). The intramolecular version of this reaction is equally successful, and substrates 119−121 were transformed to fused bicyclic vinyl epoxides 122−124 and with high ee as well (Scheme 53).

NMR yield.

chiral sulfides previously reported.75 After allylation, sulfonium salt 103 in the presence of base stoichiometrically converted a Scheme 50

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The nucleophilic addition was diastereoselective and furnished the corresponding chlorohydrins 127, which cyclized upon treatment with base to afford vinyl epoxides 128 in good yields. Marino et al. provided an account on the preparation of some sulfonyl vinyl epoxides by a similar strategy.78 Treatment of chloroaldehyde 129 with nonracemic sulfonyl vinyllithium reagents 130 afforded diastereomeric chlorohydrins 131 and 132, each of which underwent base-induced cyclization to generate vinyl epoxides 133 and 134, respectively, in high yields (Scheme 55). A related protocol involves addition of vinyl nucleophiles to α-siloxyaldehydes. Optically enriched siloxyaldehydes 135 were treated with nonracemic sulfone-substituted vinyllithium 136 to afford diastereomeric mixtures of siloxyalcohols 137 and 138. These intermediates were activated and then desilylated to induce cyclization to generate vinyl epoxides 139 and 140, respectively (Scheme 56). The dr of the epoxides thus obtained

Scheme 52

Scheme 53

Scheme 56

2.4.2. Synthesis via Halohydrin-Type Intermediates. Addition of a vinyl nucleophile to an α-haloaldehyde gives rise to a vinyl halohydrin, which is a precursor to a vinyl epoxide. Kang and Britton subjected chiral chloroaldehyde 125 to reaction with various vinyllithium reagents 126 (Scheme 54).77 Scheme 54

were low due to the poor diastereoselectivity in the vinyllithium addition to 135. An alternative diastereomeric vinyl epoxide can be obtained from siloxyalcohol 141 by exploiting its silyl group migration upon treatment with base and heat to yield 142 as Scheme 55

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the precursor to 143 (Scheme 57). The authors also reported the preparation of vinyl epoxy sulfides 148 and 149 by the same protocol using vinyllithium 145 as nucleophile (Scheme 58).

Scheme 59

Scheme 57

Scheme 60

Scheme 58

Scheme 61

2.5. Strategy E: Kinetic Resolutions

A novel preparation of optically enriched and highly functionalized vinyl epoxides has been reported by Evans and Aye (Scheme 59).79 N-Phenyl glyoxamide 150 was treated with propargylsilane 151 under catalysis by a chiral aluminum complex 152 to generate 153. The proposed mechanism is illustrated in Scheme 60. The vinylic cation 155 undergoes [1,2]-silyl migration to produce allyl cation 156, which cyclizes to afford epoxy vinylsilane 153. This reaction is high yielding, highly (E)-selective, and enantioselective. The product is contiguously functionalized with vinylsilane, epoxide, and amide functional groups and has great potential to undergo further functional group elaborations. Doyle and co-workers have shown that vinyl carbenes reacted with aldehydes to yield vinyl epoxides. Aldehyde 157 reacted with the rhodium carbene generated from diazoester 158 to give vinyl epoxide 159 in excellent yield (Scheme 61).80 The group later employed this reaction in a one-pot epoxidation−Cope rearrangement strategy (Scheme 62) to synthesize oxepines 160.81

Kinetic resolution of a racemic mixture of vinyl epoxides is a practical protocol to obtain these compounds in bulk in enantiomerically enriched form. Jacobsen’s hydrolytic kinetic resolution82 is an efficient nonenzymatic resolution for epoxides, which has been applied to vinyl epoxides as well.83 Although the vinyl epoxide enantiomer can only be obtained at most in 50% yield, the hydrolysis product, i.e., the vinyl diol, can be readily converted back to the vinyl epoxide having the opposite configuration. Hence, both enantiomers of the vinyl epoxide can be obtained from the racemic mixture. An example is illustrated in Scheme 63,84 in which (R)-86 was resolved, and the hydrolyzed product 162 was converted to the enantiomer (S)-86 under Mitsunobu conditions. Enzymes have been used for kinetic resolutions of vinyl epoxides. Halohydrin dehalogenase is an enzyme that catalyzes the ring opening of epoxides by various nucleophiles, including azide, cyanide, and thiocyanide. Halohydrin dehalogenase from Agrobacterium radiobacter AD1 (HheC) has been employed by Elenkov et al. to catalyze the ring opening of vinyl epoxides 163 8048


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Scheme 62

Scheme 63

Scheme 65

2.6. Miscellaneous Strategies

Adler et al. reported the sodium periodate oxidation of ohydroxyalkylphenol 169 to give spiroepoxide 170 (Scheme Scheme 66

and 164 by sodium cyanide (Scheme 64).85 The unreacted vinyl epoxides (S)-163 and (S)-164 were recovered with good to excellent ee.

66),87 a highly functionalized vinyl epoxide that has been used as a starting material for many reactions. For instance, Singh et al. oxidized hydroxyindane 171 and tetrahydronaphthenols 172 to yield epoxy dienones (Scheme 67).88 When the oxidation is performed in the presence of a dienophile, an in-situ Diels−

Scheme 64

Scheme 67

Alder reaction ensues (Scheme 68), leading to formation of cycloadducts 177−180. In their studies to synthesize vinigrol, Njardarson’s group prepared a series of vinyl epoxides using this dearomatization reaction.89 The reaction was successful even when the alkyl chains contain ester functional groups (Schemes 69 and 70) and terminal double bonds (Schemes 70 and 71).

Enzymatic hydrolysis to achieve kinetic resolution of vinyl epoxides has been realized by Shoji’s group using an engineered enzyme from Bacillus subtilis (BSEH) (Scheme 65).86 While the conversion is low and the unreacted vinyl epoxide 167 is recovered with poor ee, the hydrolyzed product 168 is obtained with much higher enantiomeric purity and can be readily converted to enantiomerically enriched vinyl epoxide 167. 8049


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Scheme 68

Figure 2. Nucleophilic ring-opening pathways of vinyl epoxides.

Scheme 69 While these are the general trends, vinyl epoxides belonging to complex, sterically hindered, conformationally rigid, or polyfunctionalized molecules display peculiar reactivity due to participation or interference by such neighboring structures. In addition, reagent control could also induce atypical reactivity patterns. The following sections will discuss the nucleophilic ring opening of vinyl epoxides based on the type of nucleophiles in turn. 3.1.1. Nitrogen Nucleophiles. 3.1.1.1. Intermolecular Reactions with Nitrogen Nucleophiles. Addition of amines to vinyl epoxides has been promoted by acids as well as by heating and microwave irradiation. Amine nucleophiles are hard nucleophiles, and addition typically occurs in an SN2 rather than an SN2′ manner. Therefore, aminolysis of vinyl epoxides is a good method to synthesize vinyl amino alcohols. For unsubstituted vinyl epoxides such as butadiene monoxide (163), the hard nucleophilic amine prefers to attack at the less

Scheme 70

Scheme 71

Scheme 72

3. REACTIONS OF VINYL EPOXIDES Reactions of vinyl epoxides have been reviewed previously as a subcategory under a reaction type as well as a topic on its own. As set out previously, this review aimed to cover the literature since the last review in 2005.1 However, in the course of our literature survey, we noted that radical and cycloaddition reactions of vinyl epoxides have never been covered comprehensively in any previous review. Hence, for these reactions (sections 3.4 and 3.5), the coverage of this review extends to relevant literature prior to 2005. 3.1. Nucleophilic Openings

Nucleophilic ring opening is a major reaction type for vinyl epoxides due to the strain of the oxirane, and intermolecular attacks have been observed at all four sites (Figure 2). Generally, soft nucleophiles tend to attack vinyl epoxides via an SN2′ process (pathway a), while hard nucleophiles prefer SN2 attack (pathway b).1 Attack via pathway c is an alternative SN2 attack that occurs when this reaction site is particularly unhindered compared to attack by pathway b, or if the nucleophile is internal and the ring size disfavors pathway b, or when there are directing groups. Nucleophilic addition via pathway d has been observed only for the substrates where R is an electron-withdrawing group that competes with the reactivity of the epoxide.

hindered SN2 site (Figure 2, pathway c) and treatment of 163 with a large excess of allylamine followed by protection provided allylic alcohol 181 as the major regioisomer (Scheme 72). A major application of this reaction has been in the synthesis of azasugars via intermediate 182, which was obtained from the ring-closing metathesis of 181.90 More recently, Takahata’s group reported a similar synthetic strategy toward (+)-isofagomine that involved aminolysis of 163 with propargylamine to obtain 183 and then its enyne metathesis to yield 184 (Scheme 73).91 8050


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nucleophiles.92 For example, as shown in Scheme 76, under microwave irradiation94 and activation by Brønsted95 or Lewis acid,95c,96 with both acyclic and cyclic vinyl epoxides, it is the allylamines, rather than allylic alcohols, that are obtained as the major products diastereoselectively. In the ring opening of vinyl epoxy alcohol 187 with allylamine, activation using LiClO4 provided a moderate yield of ring-opened product as a mixture of regioisomers. The regioselectivity was greatly enhanced by activation using titanium(IV) isopropoxide, which could chelate with both the

Scheme 73

Scheme 77 Lindsay’s group reported the nucleophilic ring opening of isoprene oxide (164) by stoichiometric amounts of amines with Scheme 74

hydroxyl group and the epoxide,97 and led exclusively to amine addition at the allylic position of 187 to generate 188 after protection (Scheme 77).98

Scheme 75

Scheme 78

assistance by microwave irradiation to yield allylic alcohols 185 as the major regioisomer with up to 50:1 selectivity (Scheme 74).92 Cossy also reported that the amine ring opening of 164 yielded the allylic alcohol as the major product (Scheme 75).93 However, when the terminal carbon of the epoxide is substituted, as in the more complex vinyl epoxide substrates, in the absence of additional and overwhelming electronic biases, the selectivity is for attack at the allylic SN2 position by amine Scheme 76

Several protocols for aminolysis of in-situ-generated D-glucalderived vinyl oxiranes have been examined by the Crotti group (Scheme 78). Ring opening of 53 did not occur when treated with 3 equiv of Et2NH but proceeded only when the amine was used as solvent.99 Alternatively, Lewis acid catalysis by Yb(OTf)3 promoted reaction of a stoichiometric amount of the amine with 53 and provided the same anti-1,2-adduct 190.41a The exclusive 1,2-anti selectivity was attributed to the1,2-anti-adducts being thermodynamically more stable than the 1,4-adducts. Careful monitoring of the reaction progress by NMR found that 1,4-adducts such as 189 did form as kinetic products at the early stages of the reaction but appeared to have isomerized to 190 over the course of the reaction. Ring-opening reactions of more substituted vinyl epoxides are not very diastereoselective. As shown in Somfai’s studies, nucleophilic attack at both the allylic and homoallylic positions 8051


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allylamine 197. The effect of methanol was to accelerate the retro-Michael process that facilitated formation of 197. As a nitrogen nucleophile, a hydrazine is less basic than an amine, and after addition to vinyl epoxides, interesting tandem reactions and rearrangements have been observed. In a concise synthesis of the Ziegler intermediate en route to the total synthesis of forskolin, Ye et al. employed an acid-promoted hydrazine addition to vinyl epoxide 199, followed by treatment

Scheme 79

Scheme 81

occurred in such substituted cyclic94a and acyclic94b vinyl epoxides (Scheme 79). Nucleophilic addition to α,β-unsaturated γ,δ-epoxy carbonyl compounds are faced with competitive reactivities. A substrate such as α,β-unsaturated γ,δ-epoxy ester 195 (Scheme 80) could conceivably react as a Michael acceptor without ring opening Scheme 80

with aqueous sulfuric acid, to give allylic alcohol 204 as the only product (Scheme 81).101 The reaction is rationalized by the expected S N 2 ring opening of the vinyl epoxide by tosylhydrazine to give 200, which eliminated sulfinic acid upon heating to yield allylic diazine 201. Allylic alcohol 202 was then formed by a sigmatropic rearrangement with loss of nitrogen. 1,3-Transposition of the hydroxyl group to generate 204 was facilitated under acidic conditions for formation of the more stable cyclohexene. A similar strategy was employed by Sarpong’s group to complete the synthesis of icetexone.102 Treatment of endocyclic vinyl epoxide 205 with tosylhydrazine under acidic conditions resulted in 207 as an epimeric mixture, presumably because the usual allylic substitution was disfavored due to steric congestion and an SN1 pathway was followed instead (Scheme 82). In-situ lactonization and allylic diazene rearrangement resulted in icetexone and epi-icetexone 208. Sodium azide is a good nucleophile that can undergo SN2 reaction, without the aid of catalysts, to a subset of vinyl epoxides to provide 1,2-addition products (Scheme 83).103 Nucleophilic ring opening of vinyl epoxides 209 and 211 with sodium azide occurred at the silylated carbon of the epoxides, rather than at the usual allylic position (Scheme 84),104 an example of nucleophilic attack via pathway c (Figure 2). This regioselectivity was due to the activating effect of the silyl substituent, whose activation has been reported to be greater than that of a vinyl group or even an electron-deficient olefin for vinyl epoxides, according to Courillon and Malacria. Both cis- and trans-epoxides reacted with the same regioselectivity and stereospecificity. However, the stereochemistry of the alkene appeared to be crucial, since the corresponding (E)-vinyl epoxides reacted, but the (Z)-vinyl epoxides were inert under the same conditions. Except for

(Figure 2, pathway d) or as a vinyloxirane system (Figure 2, pathway a or b). Saotome et al. investigated the reaction of ester 195 with amine nucleophiles.100 Treatment of 195 with neat amine provided conjugate addition product 196 and SN2 ring-opening product 197 in a ratio of about 3:1. However, the ratio was reversed to 1:2 in favor of 197 when methanol was used as solvent. The role of methanol in changing the product distribution was elucidated by treating each compound with methanol separately (Scheme 80). Conjugate addition was found to be the kinetic and reversible reaction, yielding 196 as the more stable product rather than its diastereomer 198, and the two could be interconverted via 195. Ring opening of the epoxide was the thermodynamic and irreversible pathway to yield 8052


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Scheme 82

Scheme 85

are alkyl groups shows no selectivity.105 When R2 is an electron-withdrawing group, the electrophilicity at C3 is enhanced and nucleophilic attack at the allylic position is favored. Scheme 86

Scheme 83

Scheme 84

As shown in Scheme 86, azidolysis of the D-glucal derived vinyl oxirane 52a with TMGA proceeded via 1,2-addition to give 215 with complete anti selectivity.41a This observed regioselectivity was analogous to that of amine additions under Lewis acid catalysis (Scheme 78). However, reaction of 52a with TMSN3 was neither regio- nor stereoselective, yielding a mixture of three addition products. In addition to SN2 and SN2′ additions that gave rise to 215 and 216, syn-1,4-adduct 216 further underwent [3,3]-sigmatropic rearrangement to generate syn-1,2-adduct 217.106 The palladium-catalyzed Tsuij−Trost reaction of vinyl epoxides provides an alternative reaction manifold which results in nucleophilic attack at the allylic positions. Reaction of a vinyl epoxide with Pd(0) complexes by a backside attack results in a π-allylpalladium(II) complex such as 218, which has been isolated by column chromatography and characterized by 1 H NMR by Szabó’s group (Scheme 87).107 Subsequently, the π-allyl complex 219 reacted with nucleophiles to form substitution products (Scheme 88).108

sodium azide, no other nitrogen nucleophiles promoted the ring opening of 209 and 211. As sodium azide is somewhat limited in its synthetic applications due to its low solubility in organic solvents, other azides, such as TMSN3 and tetramethylguanidinium azide (TMGA), have been employed in nucleophilic reactions of vinyl epoxides. The Lewis acid-promoted vinyl epoxide ring opening with TMSN3 presents competitive sites of SN2 attack depending on the electronic factors of the substituents (Scheme 85). The Lewis acid-promoted azidolysis of vinyl epoxides when R1 = R2 8053


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Scheme 87

221 as substrate generated SN2 nucleophilic ring-opened product 222 instead (Scheme 91),111 This was due to the deactivation of the brominated vinyl epoxide toward πallylpalladium(II) complex formation, and an uncatalyzed amine ring opening of the epoxide preceded the Suzuki coupling to give rise to exo-arylidene glycal derivatives 222.

Scheme 88

Scheme 92

In the absence of any directing effects, external nucleophiles tend to attack at the least hindered position (Scheme 88, Scheme 89

Azidolysis reactions via π-allylpalladium as intermediates also show 1,4-selectivity (Scheme 92), which distinguish them from nucleophilic reactions in the absence of palladium catalysts (Scheme 83).103 Movassaghi reported a diastereoselective allylic reduction of vinyl epoxides 223 through a palladium-catalyzed hydrazine addition and the intermediacy of an allylic diazene. Treatment of allylic epoxide (Z)-223 with palladium resulted in the πallylpalladium(II) complex 224, which was converted to the more favored π-allyl 225 prior to 1,4-addition of N-

pathway a) to give rise to allylic alcohols as products. Examples of this overall SN2′ addition of amines include the key step in Scheme 90

Scheme 93 Bäckvall’s synthesis of (+)-pseudoconhydrine (Scheme 89)109 and the aminations of furanose derivative 220, as reported by Gómez and López (Scheme 90).110 In this case, further attempts by Gómez and López to combine a Suzuki coupling with the nucleophilic ring opening using bromovinyl epoxide Scheme 91

isoprop ylid ene-N′-2-nitrobenzenesulfonylhydrazine (IPNBSH). Decomposition of the sulfonyl hydrazine yielded allylic diazene 226. A sigmatropic rearrangement with loss of N2 afforded reduction product (4S,5R)-227 (Scheme 93).112 On the other hand, the analogous reaction of (E)-223 that proceeded without π-allylpalladium(II) complex isomerization 8054


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yields (Scheme 95).113 Both cis- and trans-epoxide substrates undergo similar transformations. Chandrasekharand and Muthyala applied this reaction in their syntheses of hyacinthacine A1 (Scheme 96)50b and (−)-balanol (Scheme 97).18 Preference toward 1,2-addition is also observed in reactions catalyzed by imposing palladium complexes bearing sterically demanding ligands.114 Furthermore, enabled by equilibration between π−σ−π allylpalladium(II) intermediates, dynamic kinetic resolutions in the presence of palladium catalysts bearing chiral ligands have been realized and extensively applied. A review of dynamic kinetic palladium-catalyzed asymmetric allylic alkylation (Pd-AAA) reactions using diphenylphosphino benzoic acid (DPPBA) ligands based on the chiral 1,2-diaminocyclohexane scaffold has been published by Trost and Fandrick.115

Scheme 94

resulted in the double-bond geometry-retained, diastereomeric 1,2-reduction product 228 (Scheme 94). If nucleophilic attack were directed by the alkoxide in the πallylpalladium(II) complex 219, a configurationally retained syn-1,2-addition occurs (Scheme 88, pathway b). Many stereospecific palladium-catalyzed 1,2-additions demonstrate this regio- and stereoselectivity. Scheme 95

Scheme 98

Miyashita et al. developed a palladium-catalyzed reaction of α,β-unsaturated γ,δ-epoxy esters with TMSN3 that takes place via directed SN2 delivery with regioselectivity to produce azido alcohols with double inversion of configuration in excellent Scheme 96

Scheme 97 The mechanism of these asymmetric reactions has been extensively studied and reviewed by Trost.115,116 A prerequisite for an effective dynamic kinetic resolution relies on a rapid π−σ−π interconversion of allylpalladium intermediates (large kπ−σ) and a chiral ligand effective at inducing enantioselective reaction with one intermediate (Scheme 98), i.e., Curtin− Hammett conditions. It was found that these conditions were favored by having identical geminal substituents on the olefin terminus of the vinyl epoxide.115 Halide additives, such as tetran-butylammonium chloride (TBACl) and tetra-n-butylammonium triphenyldifluorosilicate (TBAT), also accelerate the equilibration process. The dynamic kinetic resolution process takes place by selective addition (k1 ≫ k2) to the matched π-allylpalladium(II) intermediate which is interconverting with the mismatched 8055


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intermediate. The regioselectivity for 1,2-addition is due to the favored, nucleophilic attack of the sterically matched πallylpalladium(II) complex, which can be visualized by the “nun’s hat” model (Scheme 98).116b,117 However, nitrogen nucleophiles present more challenges than other nucleophiles in palladium-catalyzed allylation reactions. With primary amines as nucleophiles, double alkylation could occur. In addition, nitrogen nucleophiles have a wide range of pKa, as low as imide (pKa ≈ 8) or as high as amine (pKa ≈ 35), and therefore, optimization of the substituents or protecting groups on the amine is an additional parameter of investigation.118 According to studies by Trost, neither carbamate-protected amines nor secondary amines are particularly effective in Pd-AAA reactions.119 Nucleophilic attack of the sterically demanding palladium π-allyl intermediate formed from isoprene oxide 164 is challenging. Only

Scheme 101

generated alkoxide, are superior nucleophiles for the Trost reactions. An enantioselective synthetic strategy toward a series Scheme 102

Scheme 99

the less hindered primary amines react to give allylamines 230 in acceptable yields and high enantiomeric excesses in this dynamic kinetic resolution. Therefore, in many applications, PMBNH2 (PMB = p-methoxybenzyl) has often been used as nucleophile, because it is a primary amine that could be selectively deprotected for further manipulations (Scheme 99). of 2,5-dihydropyrroles was thus devised by Trost based on imide Pd-AAA reactions.118 In this synthesis, two stereocenters were established by dynamic kinetic Pd-AAA reactions of butadiene monoxide 163 with phthalimide and oxazolidinone successively (Scheme 102) and controlled by the chiral DPPBA ligands used in each Pd-AAA step. Therefore, by varying the chiral ligands, both trans- and cis-2,5-dihydropyrroles were synthesized in optically pure forms. Using this method, the Trost group successfully accomplished the total syntheses of (+)-DMDP (2,5-dideoxy-2,5-imino-D-mannitol), (−)-bulgecinine, and (+)-broussonetine G.

Scheme 100

More recently, Trost reported a Pd(0)-catalyzed asymmetric allylic amination of butadiene monoxide 163 with sulfamate diamine 231 (Mbs = p-MeOC6H4SO2−), which gave 232 with a high enantiomeric enrichment, Scheme 100.120 The amination process occurred exclusively at the more substituted nitrogen because of its higher acidity. Mangion extended the scope of the nitrogen nucleophiles for dynamic kinetic Pd-AAA to hydrazines and hydroxylamines (Scheme 101).121 The dynamic kinetic resolution of 163 produced allylic hydrazines and allylic aminoxy compounds in high yields and with very good enantiomeric excesses. While a rather limited number of protected amines are good nitrogen nucleophiles for dynamic kinetic Pd-AAA reactions, imides, whose anionic forms have comparable nucleophilicity to amines122 but are more readily deprotonated by the in-situ-

Scheme 103

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the key reaction in the total synthesis of securinine123 and

equilibrating allylic azides 237 and 238 as previously recognized, but only the less hindered primary azide 238

(−)-norsecurinine,124 in which racemic butadiene monoxide

Scheme 107

The palladium-catalyzed dynamic kinetic resolution was also

Scheme 104

underwent a “click” reaction with the alkyne and thus gave rise to allylic 1,2,3-triazoles 239 predominantly. A related cascade reaction was reported by Pale’s group under catalysis by a copper(I) zeolite complex (Cu(I)-USY),128 in which the “click” reaction occurred with the allylic azide derived from overall SN2 substitution, presumably due to its relative stability over the alternative unconjugated regioisomer, to generate allylic 1,2,3-triazole 240 as product (Scheme 107). Other metal-mediated ring-opening reactions showing results complementary to those of the palladium-catalyzed additions have been reported. A different reactivity profile was offered by zirconium imido complexes to promote amine additions to vinyl epoxides, as reported by Bergman (Scheme 108). Butadiene monoxide 163 reacted with Cp2(THF)ZrNtBu to give 1,2- and 1,4-amination products 244 and 245 as a 1:1 mixture.129 Notably, 244 was obtained exclusively as the (Z)geometric isomer. Monitoring of the reaction by 1H NMR revealed that two stable metallacycle intermediates 242 and 243 were formed as a 1:1 mixture in the reaction, presumably through equally favorable ring closures of cationic complex 241, and the metallacycles were subsequently protonolyzed to form 244 and 245 in the same ratio. Alternatively, treatment of the same substrate with the related silylated imido complex, Cp2(THF)ZrNTBS, generated exclusively the 1,4-addition product 246 in excellent yield and with exclusive (E)stereoselectivity.130 As supported by calculations, the mechanism of this reaction did not involve any metallacyclic intermediates but was a concerted asynchronous [3,3]sigmatropic rearrangement related to the allylic imidate rearrangement,131 giving rise to 246. Harman reported the amination reactions of vinyl epoxide tungsten complexes 248, which were obtained from oxidation of the m-cresol tungsten complex 247.132 Treatment of 248 with the less basic nucleophiles, such as PhNH2, yielded allylic amine 249 from attack at the allylic position, but the products were exclusively cis-amino alcohols, a stereochemistry complementary to that obtained from palladium-mediated substitutions. However, reactions of 248 with more basic nucleophiles, like morpholine, resulted in 251 as product. The stronger bases induced elimination and epoxide cleavage in situ to give 250, Scheme 109, before substitution via the allyltungsten intermediate 252. The dienone complex 250 has been isolated by treatment of 248 with KHMDS under a nitrogen atmosphere in a glovebox. 3.1.1.2. Intramolecular Reactions with Nitrogen Nucleophiles. Tanimoto and Kakiuchi designed a synthetic strategy toward α,β-unsaturated cycloimines via acid-promoted allyl cation formation from a vinyl epoxide and capturing the reactive intermediate intramolecularly with azide (Scheme 110).133 Trisubstituted vinyl epoxide 253 was treated with acid to generate allyl cation 254, whereupon azide added

163 reacted with succinimide under chiral catalysis to afford alcohol 234 in 87% ee (Scheme 103). In addition to the Trost DPPBA ligands, Cn-TunePhos, developed by Zhang’s group, is another series of chiral ligands Scheme 105

that have been applied to the palladium-catalyzed dynamic kinetic resolution of vinyl epoxides (Scheme 104).125 This family of ligands allows systematic variation of the length of the tether in order to tune the bite angle of the bisphosphine. For epoxides such as isoprene oxide 164 substituted at the allylic positions, the regioselectivity of azide addition is low under both uncatalyzed or palladium-catalyzed reaction Scheme 106

conditions (Scheme 105).103 This may be due to a lack of selectivity in the addition as well as the tendency for allylic azides to equilibrate via a [3,3]-sigmatropic rearrangement.126 However, Alonso and Yus reported a three-component reaction of vinyl epoxides, azides, and alkynes catalyzed by copper nanoparticles on carbon (CuNPs/C) that provided 1,2,3triazoles 239 as the ultimate products selectively (Scheme 106).127 Presumably, 1,4-addition of azide to 164 generated the 8057


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Scheme 108

Scheme 109

Scheme 111

isomer was the major product, and the ratio of 258 to 259 was a direct result of the stereoselectivity of the diene monoepoxidation (Scheme 111).134 Scheme 112 Scheme 110

intramolecularly. Deprotonation and elimination of nitrogen yielded the cycloimine 255. Viso et al. reported the in-situ bis-oxidation of dienyl sulfoxide 256 to tosyl vinyl epoxide 257, which underwent an acid-promoted 5-endo-cyclization with the tosylated amine to provide 3-sulfinyl-2,5-dihydropyrroles in moderate yields as mixtures of cis and trans isomers (258 and 259). The cis

Isocyanates are synthetically useful reagents for oxazolidinone synthesis. Treatment of vinyl epoxy alcohol 187 with allyl isocyanate yielded carbamate 260, which, after deprotonation, added intramolecularly in an SN2 manner to give hydroxy oxazolidinone 261 in excellent yield (Scheme 112).135 Similarly, reaction of 187 with benzoyl isocyanate yielded 8058


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the cis-epoxide substrate 267, because the bis-coordinated rhodium complex 273 was destabilized by unfavorable

Table 3. Intramolecular Ring Opening with Nitrogen Nucleophiles

Scheme 114

interactions (Scheme 113). On the other hand, the analogous complexes 274 of trans-epoxides 264 and 265 were favored and resulted in formation of either rhodium enyl or π-allylrhodium species that terminated with selective endo cyclization to give 268 and 269, respectively. An intramolecular version of the Tsuji−-Trost reaction involving nitrogen nucleophiles was reported by Hatakeyama to construct enantioselectively tetrahydropyrroles 275 and 276 bearing tertiary stereocenters (Scheme 114).139 Only one cyclization product (E)-278 was obtained even though substrate 276 was a mixture of geometric isomers, indicating

a Conditions: 1 equiv of BF3·Et2O, DCM bConditions: 2 mol % [Rh(CO)2Cl]2, THF

carbamate 262, which underwent cyclization and benzoyl group migration to afford 263.136 Ha and Chung investigated the BF3·Et2O-catalyzed ring opening of vinyl epoxides by internal nitrogen nucleophiles, leading to piperidine and pyrrolidine ring systems.137 The results are summarized in Table 3. Endo ring closures disfavored by Baldwin’s rules were observed, in competition with the favored exo cyclizations. Endo cyclization was exclusive when the alternative exo mode produced azetidine derivatives (Table 3, entry 1) and when the allylic position was particularly activated (Table 3, entry 3). cis-Epoxides only

Scheme 115

Scheme 113

that isomerization of the olefin had occurred, probably via the π−σ−π interconversion of the π-allylpalladium intermediate. 3.1.2. Oxygen Nucleophiles. 3.1.2.1. Intermolecular Reactions with Oxygen Nucleophiles. Cleavage of epoxides by water or other oxygen nucleophiles is facilitated by protic acids,86,140 Lewis acids,48h,141 or bases.86,142 Under acidic conditions, protonation of the epoxide facilitates ring opening at the allylic position, so that alcoholysis of vinyl epoxides

underwent the exo-ring closures due to geometric constraints (Table 3, entry 4). When [Rh(CO)2Cl]2 was used as catalyst in the same ringclosure reactions, the results paralleled those obtained with BF3·Et2O, except for the higher selectivity in the reaction of substrate 265.138 The intermediacy of a rhodium enyl or πallylrhodium species was invoked. No reaction occurred with 8059


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with anchimeric assistance from the pyran oxygen (Scheme 118).47e Brière and Metzner observed that when epoxide 283 (R1 = Bu) was treated with acid, a one-pot ring-opening−lactonization occurred stereospecifically, presumably by an SN2 hydrolysis directed by the carbonyl group, to generate γlactone 284 with the same stereoisomeric ratio.144 However, the same reaction of 284 (R1 = Ph) to produce γ-lactone 286 was not stereospecific (Scheme 119). This was rationalized by an SN1 epoxide cleavage at the homoallylic position of 284, which was stabilized by the phenyl group that could undergo bond rotation prior to lactone formation. Nucleophilic additions of alcohols to vinyl epoxides usually require activation by Brønsted acids, Lewis acids, or the intermediacy of transition metal π-allyl complexes. The previous review by Somfai and Olofsson has showcased examples of BF3·Et2O-catalyzed alcoholysis.1 In addition to BF3·Et2O, Cu(OTf)2 has been reported to be an effective catalyst and offered improved yields in the SN2 opening of vinyl epoxides 288 with inversion of configuration at the site of attack (Scheme 120).50a In order to minimize competitive hydrolysis, Brønsted acidmediated alcoholysis of vinyl epoxides is performed using the alcohols as solvent in the presence catalytic amounts of strong acids (Scheme 121), such as TsOH, 145 concentrated H2SO4,145,146 and HCl.147 Interestingly, Pineschi et al. reported a metal-free stereoselective ring opening of cyclic vinyl epoxides using (ArO)3B without any other additives that yielded syn-1,2-addition products.148 Presumably the borate activated the epoxide for ring opening and also intramolecularly delivered the aryloxy nucleophile from the same face to give syn addition products stereoselectively (Scheme 122). Retention of configuration in the hydrolysis of vinyl epoxides is more generally and reliably obtained through palladium chemistry, and the stereoselectivity is typically high. Miyashita reported that under Pd(0) catalysis treatment of vinyl epoxides 290 with B(OH)3 achieved overall hydrolysis smoothly to give syn-1,2-diols 291 (Scheme 123).149 Both cis- and trans-epoxide substrates were hydrolyzed with excellent stereospecificity, with double inversions of configuration resulting from anti attack of palladium with respect to the epoxide, followed by intramolecular nucleophilic addition of boronate. The selectivity of this method was demonstrated by the interconversion of diastereomeric trisubstituted epoxy α,β-unsaturated esters 292 to 294 and vice versa (Scheme 124).150 A recent application of a vinyl epoxide ring opening by a substituted phenol via a π-allylpalladium(II) complex was in Fukuyama’s total synthesis of (±)-morphine (Scheme 125).151 Alcohols are more effective nucleophiles for additions to πallylpalladium(II) in the form of ate species (route a, X = B(OR)2, Scheme 88). Use of B2O3/pinacol or alkoxide exchange between (PhO)3B and alcohols facilitated in-situ generation of the alkoxyboronate, which intramolecularly delivered alkoxide to give the syn-addition product 296 by double inversion of configuration in good yields and excellent diastereoselectivities (Scheme 126).152 Miyashita’s Pd(0)-catalyzed stereospecific alkoxy substitution reaction facilitated interconversion of disubstituted cis- and trans-epoxy α,β-unsaturated esters without scrambling (Scheme 127).150 This reaction has been applied to the synthesis of target molecules, including 2,5-anhydro-D-glucitol,50d and (±)-noviose.153

Scheme 116

usually give regio- and stereoselective 1,2-addition products with inversion of configuration (Scheme 115). Scheme 117

Base-mediated additions to vinyl epoxides provide 1,2addition products by SN2 substitution. Malik et al. reported a regioselective ring-opening reaction of vinyl epoxide 164 with oxime as nucleophile (Scheme 116). Nucleophilic attack occurred at the less hindered SN2 reaction site (i.e., pathway c, Figure 2). Subsequently, reduction converted oxime 279 to a hydroxylamine 280.143 Base-mediated hydrolysis of vinyl epoxides provides diols via an SN2 substitution that also occurs with inversion of configuration (Scheme 117).142a Scheme 118

However, in more complex systems, retention of stereochemistry has also been observed. In the synthesis of (±)-phomactin A, Hsung observed exclusive formation of diol 282 with unexpected retention of configuration in the hydrolysis of 281. This stereochemical outcome was rationalized by compound 281 undergoing either an SN1-type of reaction via formation of the allyl cationic intermediate and nucleophilic attack from the less hindered face or hydrolysis 8060


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Scheme 119

Scheme 120

Scheme 124

Scheme 121

Scheme 122 Scheme 125

Scheme 123

Scheme 126

Epoxide ring opening by phenoxide was observed to be more effective using pinacol as a non-nucleophilic boron tether than directly using (PhO)3B (Scheme 128).152 In Trost’s dynamic kinetic Pd-AAA reactions, when alcohols are used as nucleophiles (Scheme 129),154 borane is usually used as a cocatalyst for achieving higher yields and enantioselectivities.115 Enols have been used as nucleophiles in this reaction as well (Scheme 130).155 The presence of the chloride additive accelerated the π−σ−π interconversion of the 8061


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Scheme 127

Scheme 131

Scheme 128

Scheme 132


Scheme 130

π-allylpalladium species and thus enhanced the enantioselectivity of the allylation reaction.156 A further application was the development of a one-pot sequence involving the Pd-AAA reaction, alkene isomerization, and Claisen rearrangement (Scheme 131).157 The chirality generated by the asymmetric palladium-catalyzed ring opening of the vinyl epoxide by the allylic alcohol 305 was perfectly transferred to a carbon−carbon bond via the Claisen rearrangement, so that enantiomerically enriched unsaturated aldehydes 307 were obtained in moderate to good yields. Although 1,2-addition products are typically favored, the structure and electronic and steric demands of the vinyl epoxide could alter the typical regioselectivity to yield 1,4-addition products as major products. As shown in Scheme 132, methanolysis reactions of isoprene monoxide and cyclohexadiene monoxide generated predominantly the expected

SN2 products. However, Hanna reported a Yb(OTf)3-catalyzed alcoholysis of some bicyclic vinyl epoxides, where SN2′ products were obtained in all cases, as mixtures of anti and syn diastereomers (Scheme 133).158 Presumably in these fused ring systems, due to the steric hindrance at the allylic position, SN2′ nucleophilic attack became more favorable over SN2. In the formal total synthesis of (±)-cortistatin A, methanolysis of a bicyclic vinyl epoxide occurred by selective 1,4-addition under CSA catalysis due to assistance by the enol ether (Scheme 134).159 Acid-catalyzed alcoholysis of the carba-analogues of D-glucalderived β-vinyl epoxide, 311, proceeded exclusively in an SN2 manner, as anticipated (Scheme 135).145 In contrast, addition of alcohols to D-glucal-derived β- and α-vinyl oxiranes 52b and 314 was highly syn-1,4 diastereoselective (Scheme 136). 8062


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Scheme 134

Scheme 137

Scheme 135

Scheme 138

Scheme 136

Nucleophilic ring opening by 1,4-addition of alcohol was promoted by the electron-rich enol ether and directed by the oxirane. Crotti’s group reported comprehensive studies on the nucleophilic reactions of such substrates and their derivatives.40,41,106,160 The contrasting outcomes of the alcoholysis reactions shown in Schemes 135 and 136 underscored the effect exerted by the pyran oxygen on the reactivity and regioselectivity of nucleophilic ring opening.145 Directed epoxide ring opening has also been observed with metal alkoxides to provide syn-1,4-adducts (Scheme 137).41a In contrast, alkoxides with the ammonium counterion or metal alkoxides in the presence of crown ethers reacted with 52b to give anti-1,2-adducts via an undirected SN2 process. More recently, Vankar reported an alternative palladiumcatalyzed alcoholysis of 52b and 314 which offered higher

yields and efficiencies than Crotti’s uncatalyzed reactions, particularly when hindered alcohols were nucleophiles (Scheme 138).161 The authors suggested, however, that the palladium catalyst acted as a Lewis acid rather than promoting formation of a π-allylpalladium(II) complex, based on the fact that both the regio- and stereoselectivity of the catalyzed and uncatalyzed reactions remained unchanged and was largely dependent on the stereochemistry of the substrates. Palladium(0)-catalyzed ring opening of vinyl epoxides with AcOH is usually 1,4-selective, as the acetate anion is a weaker nucleophile and base, and its addition is not usually directed by hydrogen bonding (route b, Scheme 88). Kobayashi reported a 8063


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Scheme 139

induced cyclizations effectively by promoting a more SN1-like mechanism via an electrophilic intermediate with allyl cation character, resulting in endocyclization being more favored than 5-exo-tet cyclization (Scheme 141).164 Some elegant syntheses that employed this synthetic strategy include Nicolaou’s studies toward maitotoxin, a highly toxic polyether marine natural product (Scheme 142)165 Sasaki’s total synthesis of gambieric acids A and C (Scheme 143),49c and Shiina’s asymmetric total synthesis of botcinins C, D, and F (Scheme 144).49d In Nicolaou’s synthetic studies of the QRSTU domain of maitotoxin, attempts to cyclize epoxy alcohol 330 under the usual Brønsted acid conditions failed. Finally, the desired transformation was achieved remarkably under Jamison’s conditions163 by simply heating 329 in water, a reaction presumably promoted by extensive hydrogen bonding in aqueous medium (Scheme 145).166 An epoxide has also acted as the nucleophile in an intramolecular ring opening of a vinyl epoxide. Vatèle’s group reported formation of 334 upon treatment of 331 with phosphomolybdic acid (PMA) and H2O2 (Scheme 146). Under acid catalysis, an epoxide at an optimal proximity induced SN2 ring opening of the vinyl epoxide, with the resulting epoxonium intermediate being quenched by hydrogen peroxide.167 Recently, the same group reported an unusual 5-exocyclization of a peroxy vinyl epoxide (Scheme 147).168 The acidic resin Amberlyst-15 promoted desilylation and the concomitant cyclization of 335 to give 1,2-dioxolane 336 in moderate yield. The author accounted for the preference for 5exo-cyclization by the difficulties of the peroxy (3S*,4R*)-vinyl epoxide to proceed to the coplanar transition state required for 6-endo-cyclization. Intramolecular 5-exo or 6-exo reactions of (Z)-vinyl epoxides 337, which are favored by Baldwin’s rules, occur readily and provide dihydrofurans or dihydropyrans as products (Scheme 148). For example, in the total synthesis of (+)-varitriol, treatment of vinyl epoxy alcohol 339 with a catalytic amount of CSA generated 5-exo-cyclization products 340 and 341 (Scheme 149).169 Hewitt and Harvey reported the base-induced 6-exocyclization of vinyl epoxy alcohol 342. Treatment of a stereoisomeric mixture 342 with NaH offered a low yield of

Scheme 140

synthetic strategy for 3-alkene-1,2,5-triol derivatives which utilized this transformation.27,162 The stereochemistry of the products at C5 depended on the configuration of the double bond of the vinyl epoxide (Scheme 139). For (E)-320, acetate attack with double inversion yielded 322. The π-allylpalladium(II) complex derived from (Z)-320, however, underwent an isomerization via π−σ−π interconversion to finally give 325 selectively. A similar Pd(0)-catalyzed AcOH addition was used in Micalizio’s total synthesis of (+)-phorbasin C (Scheme 140).48d 3.1.2.2. Intramolecular Reactions with Oxygen Nucleophiles. Many marine natural products have been found to consist of “ladder” polyether systems.163 One efficient strategy toward these fused O-heterocyclic systems has been the intramolecular ring opening of vinyl epoxides by oxygen nucleophiles. Cyclization of 326 featuring exocyclic vinyl groups, via 6endo-tet or 7-endo-tet would yield the desired products 327 that are precursors for polyether formation. However, according to Baldwin’s rules, these cyclization modes are disfavored. However, in the presence of pyridinium p-toluenesulfonate (PPTS) or camphorsulfonic acid (CSA), these acidic conditions Scheme 141

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Scheme 142

Scheme 143

Scheme 144

Scheme 145

Scheme 149


Scheme 147

dihydropyran 343 having the same diastereomeric ratio as 343. Using NaOMe afforded a higher yield of 343 accompanied by epimerization at C2 (Scheme 150).170 Fernández de la Pradilla’s group reported a Jacobsen epoxidation of acyclic α-siloxy sulfinyl dienes 344 that generated epoxy vinyl sulfone 346, which upon treatment with acid further cyclized to 2,5-trans-sulfonyl dihydrofurans 348 with good selectivities (Scheme 151).25 Under acidic conditions, γ,δ-epoxy-(Z)-acrylate 349 was poised to undergo a 5-exo-cyclization by an SN2 ring opening to give hydroxybutenolide 352 (Scheme 152).171 The epoxide could conceivably be ring opened either via the carboxylate 350 or by the ester carbonyl 351 to afford the observed product.172 On the other hand, Miyashita found that the related ethyl ester derivatives 353 and 356 not only underwent 5-exo-

Scheme 148

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Scheme 151

Scheme 154

studies toward galbonolide B, an intramolecular SN2′ ring opening of an epoxy allylsilane by a carboxylic acid generated lactone 361, which was further transformed to dienol 362 by desilylation under acidic conditions (Scheme 154).174 Another intramolecular SN2′ ring opening of a vinyl epoxide 363 by a carboxylic acid group yielded 365 selectively. The outcome was rationalized by a transition state resembling conformation 364 that experienced less allylic strain than 364′ (Scheme 155).60 Elimination of methanol and aromatization afforded 366. Harvey et al. noted that Pd-catalyzed reactions of α,βunsaturated γ,δ-epoxy ester (E)-367 and (Z)-367 were stereospecific SN2 reactions that afforded C-furanosides 368α and 368β, respectively (Scheme 156).175 The stereochemistry of 368α at C4 is as expected from formation of the πallylpalladium(II) complex and overall retention of configuration in the substitution, but the stereochemistry of C4 in 368β probably resulted from a π−σ−π rearrangement of the π−allylpalladium(II) intermediate accompanied by Z/E isomerization of the double bond prior to cyclization. On the other hand, nucleophilic cyclization under basic conditions engaged the enoate instead of the epoxide and underwent an oxaMichael reaction to generate epoxy C-pyranoside products 369α and 369β from (E)-367 and (Z)-367, respectively, which are examples of reactivity by pathway d (Figure 2).175 Shishido reported a similar intramolecular oxa-Michael cyclization of electron-deficient vinyl epoxides.176 Due to the overriding reactivity of the electron-deficient olefin, reaction of 370 (R = Et) with base resulted in an excellent yield of antipyran 372 as the sole diastereomer (Scheme 157). The cyclization process was understood to have occurred prior to hydrolysis of the ester, because carboxylic acid 371 (R = H) did not undergo reaction under the same conditions. The anti selectivity could be rationalized by the relatively more stable chair-like chelated transition state 374. 3.1.3. Sulfur Nucleophiles. Terminal vinyl epoxides such as 164 and 375 have been ring opened by anhydrous sodium hydrosulfide (Scheme 158) to afford mercapto allylic alcohols 376 and 377, respectively, from attack via pathway c (Figure 2).177 This reaction was used by Overman in the stereocontrolled synthesis of substituted tetrahydrothiophenes. Degl’Innocenti employed hexamethyldisilathiane as a masked H2S equivalent in the nucleophilic SN2 ring opening of butadiene monoxide (Scheme 159).178 A catalytic amount of TBAF was used to initiate desilylation to reveal the thiol nucleophile. Various terminal epoxides including 163 were attacked exclusively at the less hindered site. Ring opening of butadiene monoxide with allyl mercaptan proceeded predominantly by attack at the terminal homoallylic position to provide homoallylic sulfide 378. However, this

Scheme 152

Scheme 153

cyclization and opening but in the presence of Me3Al proceeded to generate functionalized furans instead of butenolides (Scheme 153).173 The benzyloxy group may have remained in coordination with the aluminum and attenuated its acidity, because the same reaction with vinyl epoxide 358 resulted in dehydration to generate butenolide 359. Vinyl epoxide ring opening by carboxylate groups produces lactones. However, the regio- and stereoselectivities of these cyclizations are quite substrate dependent. In the synthetic 8066


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Scheme 155

Scheme 156

Scheme 157

Scheme 160

Table 4. Addition of Thiols and Thiolates to D-GlucalDerived Vinyl Oxiranes

epoxide

EtSH %/yielda (382:383)

PhSH %/yielda (382:383)

MeSNa %/yielda (382:383)

380 381 52a

89 (90:10) 71 (100:0)

76 (100:0) 98 (92:8) 79 (85:15)

97 (90:10) 71 (100:0)

Scheme 158

a

Crude yield.


stereochemical inversion and yielded anti-1,2-adducts 382 as products (Table 4).40,41,106,145 This was rationalized by the addition proceeding in an undirected manner via 384 instead of 385 (Scheme 161) due to the inferior hydrogen-bonding ability

reaction required the use of allylthiol as solvent (Scheme 160).90,179 Ring opening of cyclic vinyl oxiranes by both thiols and thiolates was predominantly a SN2 process that resulted in 8067


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Scheme 162

Scheme 164

Scheme 165

of RSH and the weak basicity of thiolate, in contrast to the evidently substrate-directed additions of alcohols which resulted in products of 1,4-addition (vide infra). Acid-promoted addition of thiophenol to cyclohexadiene monoxide 386 generated 1,2-addition products anti- and syn387, where the use of Yb(OTf)3 as catalyst can achieve a dr of anti:syn at 7.5:1 (Scheme 162).180 The authors surmised that anti-387 was from the SN2 ring opening of 386, while syn-387 probably arose from SN1 substitution induced by acidpromoted epoxide cleavage.180 Without assistance by acid, nucleophilic ring opening with thiocyanate provided only anti-

Optically pure (R)-163 activated by acid was attacked at the allylic position with SN2 inversion by various nonenolizable Scheme 166

Scheme 163

thioketones (Scheme 165). Cleavage of the epoxide is followed by cyclization back to the thiocarbonyl to yield 1,3-oxathiolanes 393 as products in moderate to good yields and with conservation of ee.184 Dormann and Brückner reported a short asymmetric synthesis of thiolactomycin and its analogues 396 in which a key step was the SN2′ ring opening of vinyl epoxide 394 with thiocarboxylic acid (Scheme 166).185 This was a challenging transformation because C1, C2, C3, C4, and C5 are all potentially electrophilic reaction sites. Indeed, side reactions were observed under unoptimized reaction conditions. Finally, 5 equiv of Me3Al was employed to provide SN2′ product 395 from syn addition in acceptable yield as a single diastereomer with perfectly retained ee. Subsequently, diene formation and Dieckmann condensation provided thiolactomycins 396. 1,4-Addition of thiols to vinyl epoxides could be achieved under transition metal catalysis. Kang et al. developed a

388 from SN2 ring opening.181 In the presence of 18-crown-6, the alkoxide from oxirane cleavage was activated to undergo further reactions with the thiocyanate, terminating in the episulfide 389. Treatment of 388 with base induced the same transformation. An inseparable mixture of 390α and 390β was subjected to thiolysis under catalysis by BF3·Et2O. Only the α-epoxide, which could undergo a transdiaxial ring opening, reacted, while the β-epoxide remained inert (Scheme 163).182 Thioketones react with vinyl epoxides under Lewis acid catalysis to produce 1,3-oxathiolanes 393 (Scheme 164).183 With unhindered thioketones, even weak Lewis acids like SiO2 are able to promote nucleophilic attack, but stronger Lewis acids are needed for reactions of hindered thioketones. 8068


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Scheme 167

Scheme 171

Scheme 168

Scheme 172

palladium-catalyzed addition of bismuth thiolate to vinyl epoxides.186 Good regioselectivity for 1,4-addition was observed. The selectivity for the (E)-isomer was high in the reaction with butadiene monoxide (Scheme 167). Koo’s group reported the use of Cu(I) salts as catalyst for addition of thiol.187 Catalyzed by CuI, nucleophilic ring opening of isoprene oxide occurred predominantly by a 1,4addition of thiophenol, generating 397 in good yield and also good (E)-stereoselectivity (Scheme 168). 3.1.4. Halide Nucleophiles. Halide nucleophiles exhibit the typical reactivities expected from reactions of hard/soft nucleophiles with vinyl epoxides. Excluding the cases of very special substrates, fluorides typically undergo 1,2-addition, while 1,4-addition is generally observed for iodides. Both

other nucleophiles, TMSCl can act as a chlorinating agent. For example, Tanino and Miyashita reported the high-yielding synthesis of a series of chlorohydrins from treatment of epoxy acrylates 404 with TMSCl (Scheme 171).190 Scheme 173

Scheme 169

Usami and co-workers used HCl in ether to react with vinyl epoxide 406 to generate the anti-chlorohydrin as the sole product.191 The authors suggested that the top face of 406 was blocked by the 3,4-O-cyclohexylidene moiety, leaving only the SN2 pathway for chloride anion attack from the bottom face (Scheme 172).

modes of addition have been observed for chloride and bromide. Scheme 170

Scheme 174

3.1.4.1. Chlorination and Bromination. LiBr or LiCl in combination with an acid catalyst to activate the epoxide are effective conditions for halide-induced ring opening with good regioselectivity for SN2 attack at the allylic position. For example, in the presence of Amberlyst-15, LiBr accomplished the overall regioselective 1,2-addition of HBr to a range of vinyl epoxides 399 (Scheme 169).188 Use of TMSCl as Lewis acid promoter accomplished the concomitant silylation of the newly generated alcohol and prevented the product from reverting back to epoxide (Scheme 170).189 It should be noted that under the reaction conditions, even when TMSCl was used in stoichiometric amounts and LiCl was generated as a byproduct, 403 was not contaminated by 402. However, in the absence of

MgX2 salts have been found to be effective for halogenations of electron-deficient vinyl epoxides. Ha’s group reported regioselective and high-yielding MgBr2-induced bromination of a number of epoxy acrylates 408 in acetonitrile (Scheme 173).192 Righi et al. found that the same reaction using the more environmentally friendly solvent dimethyl carbonate also proceeded smoothly.193 Substrates bearing many functional groups are compatible and reactive, except for very sterically hindered epoxides, such as that derived from β-ionone.192 Yoshimura et al. reported the corresponding MgCl2-induced chlorination of epoxy enones 411 (Scheme 174).194 8069


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Scheme 175

Scheme 178

Scheme 176

but compounds 422 and 424 as the major products, indicating that chloride underwent addition in an SN2′ manner (Scheme 178). Interestingly, using Ph2PCl instead of PPh3, the authors successfully reversed the product ratio and 1,2-dichlorination Scheme 179

Vinyl epoxides can be brominated or chlorinated under the Appel reaction conditions. Martiń reported the regioselective synthesis of halohydrins from vinyl epoxides 413 using Ph3P/ X2 or Ph3P/CBr4 (Scheme 175).195 The epoxide is activated by phosphonium, and subsequent SN2 attack by halide at the allylic Scheme 177 products 421 and 424 became the major products again. This result was probably due to intramolecular delivery of chloride by the phosphenium species activating the epoxide.196 Chlorosulpholipids 426 are a family of natural products bearing stereochemically defined, polychlorinated skeletons. One challenge faced in their total synthesis has been installation Scheme 180

position ultimately furnished anti-halohydrins 414−416 in good yields. Yoshimitsu et al. reported a dichlorination reaction of vinyl epoxides under related reaction conditions (Scheme 176).196 Reaction of cis-vinyl epoxide 417 with NCS/PPh3 provided vicinal dichloride 418 along with diene 419. The reaction was initiated as in the previous sequence, except that the oxaphosphonium intermediate 420 underwent a second SN2 substitution with chloride to yield 418 (Scheme 177). The stereochemistry of 419 indicated that it was the elimination product of 420. On the other hand, subjecting trans-vinyl epoxide 420 to the same conditions provided SN2 products only as minor products 8070


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of the syn-chlorohydrin array. Direct intermolecular ring opening of cis-427 by TMSCl to yield syn-428 was compromised by anchimeric participation from a vicinal chloride residue, resulting in double inversion and anti-428 as the major ring-opened product (Scheme 179).197 As a solution to the synthesis of syn-428, Carreira’s group used trans-epoxide (trans-427) as substrate, exploiting the favorable anchimerically assisted ring opening to generate syn-428 as the major product (Scheme 180).197 An alternative solution devised by Vanderwal’s group consisted of treating epoxide cis-427 with a large excess of BF3·Et2O and Et4NCl (Scheme 180). These conditions provided a high concentration of external chloride for the intermolecular reaction to overtake neighboring group participation and successfully resulted in the desired syn-428 in 48% yield. This method was applied to synthesis of the chlorosulfolipids danicallpin A198 and malhamensilipin A.199

Scheme 183

Various chlorination/bromination products of gem-difluorinated vinyl epoxides can be obtained in a controlled manner using appropriate reagents and conditions, which are summarized in Scheme 183.204 Epoxide activation and intermolecular SN2 halide ring opening, typified by 435, produced anti-vicinal halohydrins 436. Activation and intramolecular delivery of halides using reagents such as HBr, via

Scheme 181

Scheme 184

Matsuda and Umezawa provided yet another strategy to solve this problem.200 They established the problematic doublet prior to installation of the chloride that could interfere through anchimeric assistance. Therefore, chlorination of cis-vinyloxirane 429 using SOCl2−Et2O generated syn-β-chlorohydrin 430, the typical SN2 product, in excellent yield and stereoselectivity (Scheme 180). The adjacent chlorides were then introduced through subsequent transformations. Scheme 182

438, generated syn-vicinal halohydrins 439. 1,4-Addition products 437 were obtained under thermodynamic conditions by conducting the reactions at higher temperatures and extending the reaction times. 3.1.4.2. Fluorination. Hedhli and Baklouti used Et3N·3HF for 1,2-hydrofluorination of vinyl epoxides and suggested that the reaction proceeded by an S N 1-like mechanism.205 O’Hagan’s attempt to hydrofluorinate enantiomerically pure (R)-163 yielded (S)-440 with eroded ee, which verified that Scheme 185 To achieve 1,4-hydrochlorination, TiCl4 in CH2Cl2 at low temperatures has been applied, but the yields vary significantly across different reports (Scheme 181) .49a,201 Poli provided an alternative two-step procedure to achieve the 1,4-hydrohalogenation of vinyl epoxide 164 involving oxidative chlorination of 164 by CuCl2 to chloroenal 431 and then reduction of 431 to alcohol 432.201a The mechanism proposed by Eletti-Bianchi et al. in 1976 was that CuCl2 was both the chlorinating and the oxidizing agent (Scheme 182).202 The role of LiCl was unclear, although in its absence the reaction became much slower. Similarly, CuBr2 combined with Li2CO3 induces oxidative bromination of 164 to yield 433.203 8071


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ring opening showed partial SN1 character.206 However, using MeCN as solvent, the fluorination reaction of epoxide 441 proceeded strictly via an SN2 pathway and yielded 442 with retention of ee (Scheme 184).207 Kitazume and co-workers found that HF−pyridine reacted with 443 to provide the trifluoromethylated allylic alcohols 444

Scheme 190

Scheme 186 Ring opening by iodide is aided by Lewis acids. For example, treatment of 164 with Bu4NI and TBSCl, as reported by Williams, provided 449 as a mixture of E/Z isomers (Scheme 187).210 Using Sc(OTf)3 and LiI in THF, Myers optimized the selective iodide ring opening of vinyl epoxide 450 in the presence of an enone to provide 451 in excellent yield (Scheme 188).211 Hsung also accomplished the challenging SN2′ ring Scheme 191

by 1,4-hydrofluorination (Scheme 185).208 Unfluorinated vinyl epoxide 445 only underwent a Friedel−Crafts cyclization under the same conditions, indicating that HF served mainly to activate the epoxide, and SN2′ addition of fluoride was due to the exceptional electrophilicity of the gem-difluorinated olefin. 3.1.4.3. Iodination. The only reports on iodide-induced nucleophilic ring opening of vinyl epoxides have been of 1,4-

opening of vinyl epoxide 452 under similar conditions (Scheme 189).47e 3.1.5. Reductive Ring-Opening Reactions. Reduction of vinyl epoxides could generate three types of reductively ringopened products (Scheme 190). Allylic alcohols (453) are

Scheme 187

Scheme 192 additions, probably due to the softness of this nucleophile compared with other halides. Furthermore, any 1,2-additions that occur would result in vicinal iodohydrin products, which undergo dehydration readily under acidic conditions. This overall deoxygenation reaction of vinyl epoxides was reported

obtained from an SN2′ reductive ring opening. Homoallylic alcohols 454 and 455 are derived from reduction at the allylic and homoallylic sites, respectively. There is some control of the regio- and stereoselectivity of the reduction using different reducing agents. Palladium-catalyzed hydrogen transfer selectively reduces vinyl epoxides at the allylic position and affords homoallylic

Scheme 188


alcohols in high yields. This method has been reviewed1 and remains widely used in organic synthesis as its conditions are comparatively mild (Scheme 191).48e,50e,f,212 With strong reducing agents such as LiAlH4/ether there is a preference for reduction at the more activated allylic position in the absence of a strong steric bias. Reductions of a series of cyclic vinyl epoxides of a range of ring sizes all yielded homoallylic alcohols as products (Scheme 192).213 Vinyl epoxides with distinctly different steric demands at the two sites of SN2 attack tend to be reduced by LiAlH4 selectively

by Righi in 2000 (Scheme 186).188 Under treatment with LiI and Amberlyst 15, deoxygenation of epoxide 447 was achieved, and it was suggested that the mechanism involved iodination at allylic position followed by elimination to give diene 448.209 8072


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Scheme 194

Table 6. Reduction of Spirocyclic Vinyl Epoxide 467

reductant

solvent/T

yield

468:cis-469:trans-469:470

NaBH4 DIBAL DIBAL

MeOH/0 °C to rt hexane/−78 °C DCM/−78 °C

83% 95% 60%

73:23:1:4 8:87:5:0 10:40:50:0

On the other hand, reduction using the more Lewis-acidic reducing agent DIBAL in hexane yielded the same regioisomeric alcohol but with (Z)-olefin geometry preferentially. In nonpolar solvents like hexane and benzene, DIBAL chelated effectively to the epoxide (as in 465, Scheme 195) and then delivered hydride intramolecularly to yield the (Z)-allylic alcohol. When coordinating solvents such as THF were used instead, chelation of DIBAL to the epoxide was weakened.

Table 5. Reduction of Vinyl Epoxides

Scheme 196

a

Isolated yields were 59−85%.

Scheme 195 Consequently, hydride was delivered without any directing effects to generate 1,2-reduction products predominantly.214f Tomooka studied the reductions of spirocyclic vinyl epoxide 467 and found that only NaBH4 in MeOH induced 1,4reduction regioselectively (Table 6).216 Even in nonpolar Scheme 197

at less hindered position. For example, terminal vinyl epoxides are selectively reduced at the homoallylic position (Scheme 193).214 Trisubstituted vinyl epoxides are also reduced at the less hindered site to generate allylic alcohols as products (Scheme 194).49a,215 In 1973, Lenox and Katzenellenbogen reported reductions of vinyl epoxides with complementary stereoselectivity using a metal−liquid ammonia system and DIBAL (Table 5).214f The dissolving metal reducing system selectively produced 1,4-reduction products (461) with (E)-olefin stereochemistry. The stereoselectivity can be explained by the preference of the allylic anion to be in an extended conformation 464 rather than 463 (Scheme 195).

solvents, DIBAL did not deliver hydride intramolecularly in an SN2′ manner presumably because of the conformational restrictions of the spirocyclic system. Instead chelation activated the epoxide and facilitated an intermolecular SN2 reduction to give 469 stereoselectively as the cis isomer. In the more polar but noncoordinating CH2Cl2 as solvent, however, DIBAL reduction was still highly regioselective for allylic reduction to give 469, but the stereoselectivity was lost. This was explained by the polar solvent facilitating a more carbocation-like transition state 472, which allowed reduction to occur from both faces (Scheme 196). 8073


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as a side reaction, even when hindered boranes such as 9-BBN were used. The regioselectivity in the reduction of epoxy vinylsulfonates was controlled by the reductant employed. Fuchs reported that DIBAL selectively reduced at the allylic position, while borane induced 1,4-reduction (Scheme 199).220

Scheme 198

Scheme 202

Scheme 199

NaBH3CN is unable to reduce vinyl epoxides unless catalysts are employed. Vankar reported a regioselective 1,2-reduction of terminal vinyl epoxides to homoallylic alcohols using Scheme 203

Suzuki utilized the modified ate complex,217 generated in situ from DIBAL and nBuLi, to induce 1,2-reductions of vinyl epoxides. 218 For example, in the synthetic studies of obtusenyne and its derivatives, reduction of 473 occurred at the allylic position and yielded 474 (Scheme 197).

NaBH3CN in the presence of a zeolite (H-ZSM-5) (Scheme 200). The reduction is limited, however, to terminal epoxides.221 Scheme 204

Scheme 200

ZnI2 has also mediated the selective 1,2-reduction of vinyl epoxides by NaBH3CN. Shindo’s group utilized this reducing system in the final step of the total synthesis of sundiversifolide and showed that the delivery of hydride was selective for the allylic position (Scheme 201).222 Red-Al is often used for reductive ring opening of epoxy alcohols via hydroxyl-directed hydride delivery. In the context of vinyl epoxides, Krishna et al. successfully obtained 1,3-diol 480 in high yield by treating 478 with Red-Al. Homoallylic delivery of hydride occurred presumably via transition state 479 (Scheme 202).223 Similarly, vinyl epoxide 481 was reduced at the unhindered homoallylic carbon to yield diol 482, which was not isolated but subjected to protection and epoxidation in the same pot (Scheme 203).42 SN2 reduction at the allylic position was observed by Takamura et al. in the Red-Al reduction of 484 (Scheme 204).34

Like DIBAL, the Lewis-acidic borane reacted with vinyl epoxides 475 also via chelation and intramolecular hydride delivery (476), resulting in 1,4-reduction, to afford homoallylic alcohols 477 with high (Z)-selectivity (Scheme 198).219 It is noteworthy that hydroboration on the alkene did not take place Scheme 201

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Scheme 205

products due to activation of the allylic position by the electron-withdrawing group.224

Kitazume conducted a thorough study of the reduction of the rather special subclass of substrates, the gem-difluorinated vinyl epoxides such as 491 (Scheme 205).208,224 The strong electronwithdrawing effects of fluorine increased the electrophilicity at the allylic SN2 and the SN2′ reaction sites. Whereas DIBAL reduction of typical trans vinyl epoxides such as 447 favored delivery of hydride at the allylic position, the gem-difluorinated vinyl epoxides 491 underwent 1,4-reduction to yield (E)-493. Borane reduction of 491 also showed excellent selectivity for

Scheme 208

Scheme 206

It should be noted that by controlling the reaction conditions, such as using lower reaction temperatures or Scheme 209

1,4-reduction products but was (Z)-selective. The authors suggested that DIBAL reduction may proceed through transition state 495 that permitted both intra- and intermolecular hydride delivery. Borane reduction occurred through an alternative chair-like transition state 494 that delivered hydride intramolecularly and led to formation of (Z)-isomers. Reduction of 491 with LiAlH4 with comparatively attenuated Lewis-acidic character regioselectively yielded allylic reduction

decreasing the reactivity of the reducing agent, the carbonyl functional groups in a substrate can usually be chemoselectively reduced in the presence of vinyl epoxides. Hatakeyama reported a series of reductions on epoxy acrylate 496 (Scheme 206).225 When 496 was treated with DIBAL in THF at −78 °C, chemoselective ester reduction was observed. When 496 was

Scheme 207

Scheme 210

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3.1.6.1. Friedel−Crafts-Type Reactions. Electron-rich π systems react as nucleophiles toward vinyl epoxides activated by Lewis and Brønsted acids. The Friedel−Crafts type of reaction has been reviewed briefly in the previous literature.1 In intermolecular reactions, acidic conditions generally promoted attack at the allylic site of the vinyl epoxide, due to development of substantial carbocation character in the transition state. However, in practice, such reactions are not clean. Taylor’s group investigated the Friedel−Crafts alkylation of toluene by butadiene monoxide 163 using SnCl4 and BF3· OEt2 as the Lewis acid catalysts (Scheme 212).231 Both SN2

treated with LiEt3BH at 0 °C, both the ester and the vinyl epoxide were reduced quantitatively. Similarly, an excess of DIBAL induced the reduction of both functional groups to furnish diols (Scheme 207).49f,226 Scheme 211

Scheme 213 In the reduction of 499, LiAlH4 in ether induced the chemoselective reduction of the ester (Scheme 208).227 Treatment with 1 equiv of LiAlH4 selectively generated the desired epoxy dienol, which was then oxidized to the dienyl aldehyde 500 in overall excellent yield. Takamura et al. reported that slow addition of DIBAL to 501 resulted in chemoselective ester reduction (Scheme 209).34,228 Pitsinos and Negishi showed that the trichloroacetyl group could be reductively removed in the presence of the vinyl epoxide by a DIBAL reduction at low temperatures (Scheme 210).229 Epoxides are usually inert under typical alkene catalytic hydrogenation conditions. However, in the synthesis of (+)-aconitine, Conrad and Bios reported that epoxide cleavage occurred under conditions for hydrogenation such as H2 and Pd/C, Pt/C, or PtO2 in a range of solvents. Only the use of Rh/C in benzene was found to minimize the competing hydrogenolysis of the epoxide (Scheme 211).230 In summary, many reagents have been able to achieve the reduction of vinyl epoxides, varying in steric demand, Lewis acidity, mechanism of reduction, and directed/undirected modes of delivery. Due to the wide range of reagents available, not only have regio- and stereoselective reductions have been demonstrated for a wide variety of vinyl epoxide substrates but also in some cases complementary modes and stereochemistries of reduction have been found for the same substrate by optimization of the reaction conditions.

products (505) and SN2′ products (506) were observed, and each was obtained as mixtures of ortho and para regioisomers. The product mixture was also complicated by bisarylated products 507, generated from a second alkylation of either 505 and 506. The ratio of products obtained also varied with the reaction conditions. Scheme 214

Scheme 212

Recent reports demonstrate better control over the regioand stereoselectivity of this type of reaction by selecting substrates and reaction conditions judiciously. Ono et al. investigated the intermolecular reaction of vinyl epoxides 508 with electron-rich arenes catalyzed by boron trifluoride etherate, which was regioselective for alkylation at the allylic carbon to give the SN2 product only. This reaction was a synthetically useful preparation of hydroxylated aryl pentenoates.232 Arenes with one or more electron-donating substituents (i.e., methoxy or methyl group) were found to be sufficiently nucleophilic for aromatic substitution. This reaction was also observed to be stereoselective, generating the product from backside attack of the epoxide (Scheme 213).233 The ester group contributed to the stereoselectivity by decreasing the nucleophilicity of the double bond in conjugation and suppressed formation of an open carbocation.

3.1.6. Carbon Nucleophiles. In this section, nucleophilic additions to vinyl epoxides by carbon nucleophiles are broadly organized by mechanism types: Friedel−Crafts type of reactions, alkene additions, ring opening by stabilized nucleophiles and cyanide, addition of stoichiometric organometallic nucleophiles, and catalytic activation by transition metal catalysis followed by addition of carbon nucleophiles. 8076


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Nagumo and co-workers investigated the intramolecular version of this Friedel−Crafts reaction using various electronrich arenes with tethered vinyl epoxides.235 Upon treatment

Table 7. Friedel−Crafts Cyclizations To Form SevenMembered Rings

Table 8. Friedel−Crafts Cyclization of Substrates with NTethers

entry

R1

R2

R3

yield/%

1 2 3 4 5

H H OMe H OMe

H CO2Me CO2Me CO2Me CO2Me

H H H Me Me

85a 97 95 48b 87

a

Mixture of trans/cis isomers. substituent on the benzene ring.

b

Regioisomers of the methoxy

Scheme 215 entry

R1

R2

1 2 3 4 5

−OCHH2O− −OCHH2O− OMe OMe H

BF3·Et2O TMSOTf OMe OMe OMe

a

Lewis acid

T (°C)

yield of 516

BF3·Et2O TMSOTf BF3·Et2O

−30 0 −30 0 −30

51% 15% 91% 83%a

yield of 517 79% 18% 79% 17%

Mixture of regioisomers of the methoxyarene.

with Lewis acid, tethered arenes 509 cyclized to give sevenmembered ring homoallylic alcohols 510 as products.235a The ester substituent was again essential for good stereoselectivity in the alkylation reaction (Table 7, entries 1 and 2). Electrondonating substituents on the arene improved the yields. The extra methoxy groups served not only to increase the electron density of the arenes but to promote ipso attack, resulting in

Scheme 216

Scheme 218

Accordingly, substituted epoxy esters such as 195 also underwent the Friedel−Crafts reaction with excellent diastereoselectivity (Scheme 214).234 This reaction was employed in the formal total synthesis of (−)-anisomycin (Scheme 213).233 Scheme 217

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formation of spirocyclic intermediate 511, which then

Scheme 221

rearranged to finally afford 512 (Scheme 215). This was confirmed by isolation of the spirocycles 514 and 515 in the reaction of another substrate, 513 (Scheme 216).235c,d Scheme 219

been derived from 518 from initial ipso attack (Scheme 218). However, the nitrogen in the tether-directed fragmentation via an alternative pathway to generate iminium 519, which was quenched by a Friedel−Crafts cyclization by pathway a to give benzazepine type products 516 or captured by the alkoxy group by pathway b, to yield 517. The ratio of 516 and 517 was influenced by Lewis acids and substituents on the aromatic ring.

Scheme 220

Scheme 222

Similarly, cyclizations to yield six-membered rings with diastereoselectivity have also been accomplished. The yields of the reactions were also higher for electron-rich methoxyarenes (Scheme 217).235d Substrates with a nitrogen atom in the tether have also been investigated.235c Although benzazepines 516 were obtained predominantly as the Friedel−Crafts cyclization products in most cases, another rearrangement product 517 was also observed (Table 8). Both products were postulated to have

Scheme 223

Table 9. Friedel−Crafts Cyclizations To Form EightMembered Rings

entry

R1

R2

R3

R4

R5

yield of 524

1 2 3 4 5 6

H OMe OMe OMe OMe OMe

OMe H OMe H OMe OMe

H H H OMe H H

H H H H Me H

H H H H H Me

0% 39% 95% 99% 83% 91%

The homologous substrate 520 afforded the eight-membered azacycle 521 as the major product (Scheme 219). The authors also made use of the iminium oxa-cyclization to prepare oxazolidine 522 in the context of a 10-membered ring (Scheme 220). Construction of eight-membered rings using this Friedel− Crafts cyclization was achieved diastereoselectively using homologous substrates 523 which were rigidified as cobalt− alkyne complexes. Decomplexation of 524 has been achieved by acids or reducing agents (Table 9).235c Recently, Bertolini et al. investigated the intermolecular Friedel−Crafts reaction of vinyl epoxides with aromatic borates.236 The general reaction, illustrated in Scheme 221, proceeded without additional Lewis acid. Aromatic borates 526 8078


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Scheme 224

Scheme 227

Scheme 225

added to vinyl epoxides 536, forming Friedel−Crafts products 537 and 538 via SN2 and SN2′ attack, respectively. Takikawa reported that simply heating alone was sufficient to initiate alkylation of pyrone 540 by a reactive vinyl epoxide 539 (Scheme 226).239 SN2′ alkylation followed by a nonfacial selective intramolecular SN2′ displacement yielded diastereomeric oxaspirocyclic compounds 541/542 and 543/544 in moderate yield, where 541 and 543 are intermediates in the synthesis of brevione B and decaturin D, respectively. This method was also applied to generate 545 for the synthesis of decaturin C (Scheme 227).240 3.1.6.2. Alkenes. In addition to electron-rich aromatics, alkenes and enol ethers have undergone the mechanistically related electrophilic alkylation with activated vinyl epoxides. In contrast to the Friedel−Crafts reaction, alkylation of an alkene generates an intermediate with carbocation character that can promulgate cascade processes with polyene substrates. Such domino reactions allow multiple bonds to be formed in a single step and have been applied to build up the scaffolds of polycyclic natural products efficiently. Recent examples of applications of this strategy include synthetic studies on the macrocyclic natural products terpestacin and fusaproliferin by Myers et al.241 Enolsilane 547 reacted via a cationic cyclization cascade upon treatment with boron trifluoride etherate (Scheme 228). Olefin attack was at the SN2 position of the vinyl epoxide. Ensuing polyene cyclizations resulted in formation of the tetracyclic system 548 along with 549 resulting from an interrupted cyclization. In stark contrast, the lithium enolate of related cyclopentenone 550 underwent macrocyclization only with the Lewis acidactivated vinyl epoxide (Scheme 229). In an attempt toward a biomimetic synthesis of emindole SB by Clark et al., treatment of vinyl epoxide 552 with Lewis acid afforded polyene cyclization product 553 initiated by an SN2 alkylation (Scheme 230).242 Recently, Pronin and Shenvi reported the synthesis of terpenes from vinyl epoxides 554 and 555 (Schemes 231 and 232).243 The substrates were cyclized via attack of the vinyl epoxides at the SN2′ positions of these substrates. Nicolaou’s group synthesized hirsutellone B using a polyene cyclization cascade strategy initiated from an electron-deficient vinyl epoxide.47b As shown in Scheme 233, activation of the vinyl epoxide 556 required an excess of Et2AlCl. The polyene attacked the epoxide at the homoallylic position in order to form cyclohexane 557. An in-situ intramolecular Diels−Alder reaction ensued to afford tricyclic compound 558 as product.

added to a range of vinyl epoxides 525 having electron-rich and electron-deficient double bonds to afford both the SN2 product 527 and the SN2′ product 528. The ratio of 527 to 528 was Scheme 226

mainly governed by steric factors. In some cases, O-alkylation occurred concomitantly, particularly when THF was used as solvent (Scheme 222). The Friedel−Crafts products were used in the synthesis of cycloalkenobenzofurans (Scheme 223) Aromatic heterocycles have reacted as the nucleophilic component in the Friedel−Crafts alkylations with vinyl epoxides. Indoles are of particular interest because of their applications in medicinal and natural product chemistry. Hudlicky et al. reported a Friedel−Crafts-type reaction between indole on an activated silica surface with cyclic vinyl epoxides (Scheme 224).237 The unprotected indole was alkylated by 532 or 533 via attack at the allylic position to give 3-substituted indoles 534 or 535 as products in moderate yield and with exclusive anti-diastereoselectivity. Gruber et al. studied a similar transformation using a Ru(IV) complex as the catalyst.238 As depicted in Scheme 225, indole 8079


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Scheme 228

Scheme 229

Scheme 232

Scheme 230

Scheme 233

Scheme 231

Application of this strategy is an elegant and attractive approach for synthesis of complex natural products and is a direction that merits further exploration and efforts. 3.1.6.3. Enolate or Enolate Derivatives. Bisvinyl silyl epoxide 559 was nucleophilically attacked by chloroenolate

The varieties of polycyclic frameworks that can be constructed or initiated by the polyene cyclization strategy call for creative design and juxtapositioning of appropriately substituted and functionalized polyene oxirane substrates. 8080


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cleavage, yielded 570 (Scheme 235).245 A second Brook rearrangement resulted in intramolecular attack of the ketone

Scheme 234

Scheme 236

to yield divinylcyclopropane (E)-571. This intermediate was poised to undergo an anionic oxy-Cope rearrangement and finally produced cycloheptanone derivative 572. Alternatively, Scheme 237

560 in a Michael reaction to generate 561. Epoxide cleavage, followed by a carefully designed Brook rearrangement, produced enolates 563 (Scheme 234).244 Enolates 563 underwent cyclization to generate diastereomeric cyclopropanes 565 and 566. In the case of 563 (Y = NEt2, M = Li+), only diastereomer 565 was obtained as product. This was rationalized by the cyclization proceeding by a chelated structure 564 that resulted in cyclopropane 565 in which the carbonyl groups are cis. Silylated epoxide 567 also bearing an unsaturated acylsilane was nucleophilically attacked by enolate 568 to generate 569. Subsequently, a Brook rearrangement, followed by epoxide

the same intermediate 570 could be obtained from addition of vinyl epoxy enolate 573 to acylsilane 574, which could undergo Brook rearrangement and cyclization to give divinylcyclopro-

Scheme 235

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pane 576. Silyl migration and decomposition of the cyclopropane resulting in vinyl epoxide cleavage yielded 570. Use of the sodium enolate 573 provided a better yield of 572, because the increased ionic character of the enolate accelerated silyl migration to convert 576 to 577. Use of (−)-trans-567 of 90% ee in this reaction provided 572 with only 15% ee. The authors surmised that racemization occurred at 571, which could undergo cyclopropane ring opening and closure with scrambling of stereochemistry before the oxy-Cope rearrangement. The kinetic enolate of cycloheptenone 579 was subjected to the same reaction with 578, and as the rate of the oxy-Cope rearrangement increased using potassium as the counterion,

Scheme 240

Scheme 238

Scheme 241

580 having an eight-membered carbocyclic ring was formed with an improved retention of enantiomeric purity (Scheme 236).245 Lovchik et al. reported an intramolecular enolate alkylation with a vinyl epoxide that generated a cyclobutanone (Scheme 237).246 The SN2′ cyclization product 582 was obtained from optically enriched 581 in the presence of an excess of Lewis

attack and resulted in good regioselectivity for 586 (Scheme 238). 3.1.6.4. Sulfur Ylides. Nucleophilic ring opening of epoxyvinylsulfone 587 and 589 with dimethylsulfonium methylide 591 showed high regioselectivity for SN2′ addition

Scheme 239

Scheme 242

to afford one carbon homologated allylic alcohols 588 and 590, respectively (Scheme 239).248 Superstoichiometric amounts of the ylide were required as they were understood to play dual roles of nucleophile and base (Scheme 240). Alcaraz’s group used a similar strategy to prepare dienols (Scheme 241).249 The vinyl epoxides 595 required were prepared in situ by reaction of the same sulfonium ylide 591 with epoxy bromides 594. The vinyl epoxide then reacted with another equivalent of ylide to generate dienols 596. In this case, addition of the ylide to epoxide 595 occurred in an SN2 fashion. Although there have only been a limited number of examples of the reaction of vinyl epoxides with sulfur ylides, this reaction is synthetically unique because it is a homologation by addition of a methylene group. This reaction opens up a new disconnection for the retrosynthetic analysis of dienols and

acids. The authors found that BF3·Et2O, TMSOTf, and Et3Al facilitated cyclization to give low to acceptable yields of cyclobutanone 582 with varying degrees of loss of enantiomeric purity. On the basis of these results, cyclization was rationalized to have proceeded via achiral or associated allyl cation intermediates 583 and 584. Hübscher and Helmchen reported their studies on an intramolecular ring-opening reaction of vinyl epoxynitriles 585.247 Both the SN2 cyclization product, cyclopentene 586, and the SN2′ cyclization product, a cyclopropane, were observed, and the ratio of the two varied with reaction conditions. However, use of lithium amide as base in the polar aprotic solvent N,N-dimethylacetamide (DMA) promoted SN2 8082


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possibly other multifunctionalized motifs and deserves further investigations. 3.1.6.5. Cyanide. D’Antona et al. observed the ring opening of bisepoxide 597 in the presence of TMSCN to give unstable intermediate 598 via SN2 substitution by cyanide (Scheme 242).250 Upon acidic hydrolysis, triol 599 from the SN2 ring opening of epoxide 598 was obtained, along with 600. Kulinkovich and co-workers investigated the reaction of hydroxy tosylate 601 with cyanide. Cyclization yielded vinyl epoxide intermediate 602, which was isolable (Scheme 243). Subsequently, SN2 epoxide opening by cyanide afforded cyanohydrin 603.37 As depicted in Scheme 244, treatment of 604 with TMSCN yielded 605, the 1,2-addition product to the ketone,251 but in the presence of an equivalent amount of cyanide nucleophile, conjugate addition to the dienone was observed, representing an addition by pathway d with respect to the vinyl epoxide (Figure 2) resulting in 606 and 607.252

Scheme 243

Scheme 244

Scheme 247

Scheme 245 Similar to other nucleophilic additions to the β-vinyl epoxide 53a derived from D-glucal, TMSCN also added to give the syn1,4-addition product 609 via a coordinated delivery (Scheme 245).41a Takeda and co-workers designed a double-fold Brook rearrangement sequence by treating trans-δ-silyl-γ,δ-epoxy-α,βScheme 246

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unsaturated acylsilanes 610 with cyanide in the presence of electrophiles.253 Addition of cyanide addition to acylsilane 610

Scheme 250

Scheme 248

generated an oxyanion 611 that underwent the first Brook rearrangement, leading to ring opening of the vinyl epoxide moiety to generate oxyanion 612 (Scheme 246). A second Brook rearrangement occurred to generate the more stable nitrile carbanion, whose fate was quenching by alkylation with MeI, chloroformate, or Mander’s reagent.254 3.1.6.6. Stoichiometric Organometallic Reagents. Organometallic reagents continue to be routinely employed in Scheme 249

lithium acetylide as well as the SN2 regioselectivity so that lithium ethoxyacetylide reacted with vinyl epoxides with the highest regioselectivity. Treatment of either trans- or cis-epoxide Scheme 251

nucleophilic opening of vinyl epoxides. In general, SN2 addition to vinyl epoxides is achieved by hard organometallic species such as alkyllithium reagents,255 Grignard reagents, 256 alkylzincates, and alkylaluminates257 (Scheme 247), while SN2′ additions are favored by soft organometallic reagents such as organocopper(I) reagents,258 which is the topic of the following section. 3.1.6.6.1. Organolithium, Aluminum, Zinc, and Tin Reagents. Smith et al. found that the regioselectivity of the nucleophilic attack by lithiated dithianes to vinyloxiranes such as 614 was controlled by the steric properties of the dithiane anions.259 Sterically less demanding lithiated dithianes attacked 614 at the allylic position in an SN2 fashion, while more bulky dithianes preferred to add at the more accessible site in an SN2′ manner (Scheme 248). Somfai reported divergent strategies for regioselective alkynylation of vinyl epoxides.260 Studies showed that electron-donating substituents increased the reactivity of the

615 with lithium ethoxyacetylide and BF3·OEt2 afforded the expected SN2 products 616 with high dr (Scheme 249). In contrast, treatment of trans-618 with alkynylalane generated SN2′ addition products 620 as a mixture of geometric isomers (Scheme 250), whereas treatment of cis-618 generated both SN2 and SN2′ products 619 and 620, the latter being obtained selectively as the (E)-isomer. The authors proposed that alkynylalane reacted by precomplexation to the epoxide and then intramolecular alkynylation.260 The lack of E/Z selectivity in the reaction of trans-618 (R2 = H) was due to energetically unbiased transition states leading to both (E)- and (Z)-620. However, reaction of cis-epoxides (R1 = H) clearly had a less favorable, sterically encumbered transition state 622 that steered the reaction toward the alternative transition state 621, resulting in SN2′ product (E)-620 almost exclusively. 8084


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Scheme 252

Scheme 255

Transition state 621 was destabilized in the case of cis-618 due to the interaction between the R2 group and the alane, and therefore, transition state 623 became favorable as well, resulting also in SN2 products 619. Scheme 253

Mahapatra and Carter reported that Me3Al induced exclusively the SN2 methylation of vinyloxirane 624 that tolerated a vinyl iodide functionality (Scheme 251).261 The vinyl iodide as well as the hard alkyl nucleophile probably discouraged competitive SN2′ addition. The authors found that low reaction temperatures facilitated a high diastereoselectivity in this reaction, because the dr decreased to 3.5:1 at −50 °C, indicating the emergence of an SN1-like reaction pathway under more vigorous conditions. For TBS-substituted trans-vinyl epoxide 235, organolithium reagents added exclusively in an SN2′ manner to afford allylic alcohols 627 (Scheme 252),262 in contrast to azide which attacked at the homoallylic position of trans-235 (Scheme 84,

reaction temperatures favored formation of (Z)-627, likely to be derived from intramolecular attack via 628 (Scheme 253). However, employing nonpolar solvents and additives that increased the aggregation of RLi or using LiCl that competed with RLi for coordination to the epoxide steered the reaction toward intermolecular nucleophilic attack via 629 that favored formation of (E)-627. On the other hand, treatment of TBSsubstituted cis-vinyl epoxide 235 with organolithium reagents only resulted in deprotonation and alkylation. Sulikowski reported that generation of an organolithium by metal halide exchange of 630 proceeded to a copper-mediated intramolecular nucleophilic ring opening of the vinyl epoxide to yield bicyclobutane 631 (Scheme 254).263 Acid 632 underwent a similar reaction cascade, terminating in epoxide formation to give 633, albeit in a low yield.

Scheme 254

Scheme 256

vide infra).104,262b This regioselectivity could be due to the organolithium reagents being sterically more demanding than azide, and they were prevented from attacking the particularly encumbered SN2 addition site of trans-235. Marié et al. extensively explored the effects of solvent, additives, and temperature on the stereoselectivity for (E)- or (Z)-627.262a Both the reactivity of the alkyllithium reagent and the low 8085


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Dialkylzinc reagents underwent asymmetric SN2′ addition to cyclic vinyl epoxide 14 in the presence of copper(II) phosphoramidite (R,R,R)-634 complex as Lewis acids, resulting in kinetic resolution (Scheme 255).264 Both the alkylated product 635 and unreacted 14 were obtained in high ee when a stoichiometric amount of dimethylzinc was used. Interestingly, when the dialkylzinc reagents were used in excess and the

Scheme 259

Scheme 257

RLi to vinyl epoxides 164 and 649 generated the lithium alkoxides 645 and 650. The carbenoid species XMgCH2X, generated in situ from Grignard reagent and CH2X2, induced the cyclopropanation of 645 and 650 to afford cis-cyclopropyl carbinols 647, 648, and 651 (Scheme 257). reaction was allowed to go to full conversion, a regiodivergent kinetic resolution was achieved, which afforded both SN2′ and SN2 products in high optical purity. 1,3,5,7-Cyclooctatetraene monoepoxide 639 was desymmetrized under similar conditions to generate 640 in high yield, regioselectivity, and ee.

Scheme 260

Scheme 258

For D-glucal-derived vinyloxiranes 53b and 314, the regioselectivity of nucleophilic attack by carbon nucleophiles was dependent on the chelating ability of the reagents, as also been observed in the addition of other nucleophiles (sections 3.1.1 and 3.1.2). Alkyllithium reagents were highly chelating due to lithium and selectively generated syn-1,4-adducts 642 and 644 through coordinated transition states 641 and 643 (Scheme 256).41a,c,160 Grignard reagents were generally unreactive toward these vinyl oxirane compounds, except for one case involving PhMgCl.41a,c A one-pot SN2′ alkylation/cyclopropanation reaction of vinyl epoxides was reported by Schröder.265 The SN2′ addition of

For vinyl oxiranes which are also Michael acceptors such as 652, conjugate addition by pathway d (Figure 2) could compete with typical SN2 or SN2′ attack (section 3.1.1). Shanmugam and Miyashita reported the methylation of 652 by Me3Al in the presence of silyl triflates (Scheme 258).266 This protocol generated predominantly or exclusively anti-SN2 methylation products with silylation of the hydroxyl group. The SN2 opening of the epoxide is presumably steered and facilitated by Lewis acid activation. However, for trisubstituted 8086


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Alkyllithium reagents induced the alkylation of gemdifluorinated vinyl epoxides 434 with exclusive SN2′ selectivity, due to the effect of the highly electron-deficient vinylic site (Scheme 261).270 The related gem-dibromovinyl oxiranes 669 and 671 underwent a Lewis acid-mediated SN2 epoxide ring opening with allyltributylstannane.271 The tin reagent regioselectively attacked the allylic position with excellent stereoselectivity (Scheme 262). Fuchs studied reactions of cyclic epoxy vinylsulfones such as 673 and 674 (Scheme 263). syn-SN2′ alkylation was observed in the reactions with alkyllithium reagents with or without LiClO4, and addition was directed by the epoxide.220b,272 SN2 alkylation proceeded with high regioselectivity in the presence of Me3Al with a catalytic amount of H2O.220b,273 3.1.6.6.2. Organocopper Reagents. Organocopper reagents, whether stoichiometric or catalytically generated, figure prominently in the alkylation reactions of vinyl epoxides and therefore have been organized into a separate section. Typically, SN2′ addition occurs as shown in the regioselective reaction of

Scheme 261

epoxide 654, methylation occurred at the alternative epoxide cleavage site to afford allylic alcohol 656 as the major product. Scheme 262

Scheme 265

Use of Me3Al−H2O to methylate 657 produced the analogous SN2 regioisomer sluggishly but induced the alkylative Scheme 263

447 with both organocopper reagents and cuprates to generate allylic alcohol 675 (Scheme 264).274 Anti addition of the organocopper reagent with respect to the stereochemistry of the vinyl epoxide is often observed. This area has been previously reviewed by Marshall,258b Somfai,1 and Dieter.275 While the reaction details of many other organometallics have been understood for a long time, the mechanistic details of the various types of organocopper reagents and their mechanisms of reactions have been unclear and rather controversial. Our understanding of their structures and

ring opening of 658 very effectively (Scheme 259).267 This suggested that the epoxide opening of 659 under these conditions was aided by a chelation of the aluminum reagent to the benzyl ether moiety, possibly through transition states 661 and/or 662. Lithiated dithianes underwent conjugate addition and then subsequent cyclization with epoxide cleavage to give cyclopropane hydroxyester 664 in the open or lactonized form 665 (Scheme 260).268 Even the phenylated derivative 666 underwent addition via pathway d (Figure 2) when treated with various organolithium reagents, including lithated dithianes, to yield cyclopropanes 667 in good yields with moderate to excellent dr.269

Scheme 266

Scheme 264

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mechanisms has been greatly clarified through recent work on the structural characterization of organocopper reagents and cuprates in solution and copper(III) intermediates and their reaction pathways as well as through experimental, analytical, and computational studies. The conventional mechanistic understanding of allylic substitution with cuprates, of which the reaction with vinyl epoxides would be considered a subclass, has been previously understood as an equilibrium between various σ-allylcopper-

Scheme 269

Scheme 267

= OR2) that could exert a resonance-donating effect. It is likely that some previous experimental results will need to be reinterpreted in light of these mechanistic details. For example, addition of cuprate to 52 occurred selectively via anti-1,2-addition (Scheme 268).41a Whereas RLi was rationalized to have undergone syn addition to generate syn1,4-adducts through coordinated transition states (Scheme 266), generation of 686 was simply described as addition by a nonchelating mode. However, no explanation was offered as to why it was an anti-1,2-addition instead of an anti-1,4-addition. In light of the present mechanistic picture, formation of 686 could be explained by reductive elimination favored by a resonance contribution from the pyran oxygen.276 Another example is the additions to epoxycyclohexene 687, where cuprate added exclusively with anti selectivity but with low regioselectivity; however, reaction with MeMgBr/CuCN afforded much higher anti-1,4-selectivity (Scheme 269).145 Similarly, treatment of 311 with cyanocuprates resulted in dramatically higher SN2′ selectivity to give adduct 690. This phenomenon had been rationalized by reductive eliminations from equilibrating σ-allylcopper complexes, but the recent theoretical studies could explain this selectivity by formation and reductive elimination from the more favorable [σ + π]-type allylcopper(III) complex 684.276 These and other results on cuprate additions will need to be revisited and reinterpreted based on the revised mechanistic framework. Copper-catalyzed SN2′ addition to 692 yielded allylic alcohols 693.275 Use of cyanocuprates derived from organolithium or organozinc reagents showed excellent regioselectivity (88−98% re) for SN2′ attack via transition state 697 due to both the steric and the electronic effects of the cyano ligand. Dieter exploited this reaction in a general strategy toward construction of vicinal stereochemical arrays 694 from vinyl epoxides such as 692 (Scheme 270). It was important that the selectivity for generating the (E)-isomer of 693 was also high, because this was crucial in the following reaction to induce SN2′ substitution diastereoselectively after activation of the hydroxyl leaving group. Even with electron-deficient vinyl oxiranes 26 that could competitively react by a conjugate addition pathway, the addition reaction remained SN2′ selective when lithium or magnesium salt-free cuprates are employed (Scheme 271).275 Addition of LiBr or use of Grignard reagent-derived cuprates resulted in formation of the SN2 addition product. The authors suggested that SN2′ addition occurred via transition state 707 in which the cyanide ligand facilitated epoxide cleavage due to

species 677−679 that interconvert through the intermediacy of the π-allylcopper species 676 and that it is through the σallylcopper species that reductive elimination proceeded to offer the final alkylation products (Scheme 265).276 Many former studies and experiments have therefore reported and rationalized their reaction outcomes with reference to the stabilities and the rate of reductive elimination from the putative σ-allylcopper species. However, the picture that has emerged more recently regarding the mechanism of cuprate allylic substitutions, as reviewed by Yoshikai and Nakamura in 2012, shows the πScheme 268

allylcopper(III) complex 676 as the most stable intermediate (Scheme 266).276 Complex 676 is generated via an anti elimination due to a more effective orbital overlap, in preference to a syn elimination, which is a favorable alternative mode if there is coordination between the copper and the leaving group. The π-allylcopper(III) complex 676 equilibrates with the less stable σ-allylcopper(III) complex 681 assisted by a fourth ligand such as a solvent molecule. [However, depending on the ligands on copper, such as cyanide groups in the case of heterocuprates, another configurationally stable [σ + π]-type of allylcopper(III) complex 682 emerges as the most stable intermediate (Scheme 267).276] Although both 676 and 681 could undergo reductive elimination, reaction of the πallylcopper(III) complex is kinetically favored, proceeding via an enyl [σ + π]-like transition state 680. For unsymmetrically substituted 676 (R1 ≠ H), reductive elimination at the unsubstituted position is preferred, and it is even more favored when the allyl system has an electron-rich substituent (e.g., R1 8088


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Scheme 270

Scheme 271

Divergently regio- and stereoselective alkylations have been observed in the reactions of 434 using different organocopper species (Scheme 272).274 The lower order cuprates RCuLi generate (E)-allylic alcohols 709 via SN2′ alkylation of 434, while higher order cuprates provided SN2 alkylation product anti-710 in moderate yield but good regioselectivity. The diastereomeric homoallylic alcohols syn-710 can be obtained by treatment with R3Al. Diastereomeric epoxy vinyl sulfoxides undergo SN2′ addition exclusively, due to the polarization of the vinyl group.76,279 Lower order lithium cyanocuprates added to epoxy vinyl sulfoxides stereospecifically to give either syn adduct 711 or anti adduct 713 as major product resulting from addition anti with respect to the sulfoxide. However, magnesium cyanocuprates could chelate with the sulfoxide to yield instead anti adducts 712 and 713 predominantly (Scheme 273).78,277 The Fuchs group developed regio- and stereoselective protocols for alkylation of cyclic epoxy vinylsulfones such as 673 and 674 (Scheme 274). syn-SN2′ alkylation has been accomplished by treatment with alkyllithium reagents,220b,272 while SN2 methylation was observed with high regioselectivity in the presence of Me3Al with catalytic H2O (Scheme 263).220b,273 Addition of various kinds of organocopper reagents such as Me3Al/CuMe,272,273,278 Me3Al/cuprate,220b,279 Gilman cuprates, and Grignard derived cuprates220b,278 all yielded anti-SN2′ alkylation products.

Scheme 272

favorable FMO interactions. On the other hand, SN2 addition resulted from reaction via complex 708 via an alternative conformer in which chelating metals coordinated with the cyanocuprate and the ester and directed delivery of the R group toward the allylic site. To further generate ester 706 having α,βstereocenters, the hydroxyl group was esterified and subjected to a second SN2′ displacement. 8089


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Scheme 273

Scheme 274

Scheme 276


A similar set of protocols was employed to generate an ensemble of reagent-controlled and stereoselective additions to obtain 16 permutations of stereochemically defined cycloheptenes from substituted epoxy vinylsulfones.20d,280 In all cases, the anti-SN2′ methylations of the cyclic vinyl epoxides were achieved using copper reagents, such as Me3Al/MeCu, MeMgBr/CuCN, or MeMgBr/cat. Li2CuCl4. Some directly inaccessible stereochemistries were obtained by double substitutions or epimerizations (Scheme 275). Alexakis reported the asymmetric kinetic resolution of cyclic vinyl epoxides using organocopper(I) reagents modified by chiral ligands (Scheme 276). Good to excellent SN2′ to SN2 selectivities produced 720 and 722 as the major regioisomers and with enantiomeric excesses of up to 92%.281

3.1.6.7. Transition-Metal-Catalyzed Reactions. Many transition metal-catalyzed carbon−carbon bond-forming reactions use vinyl epoxides as π-allylmetal complex precursors. Overall, platinoid metal catalysis (in particular, palladium) still dominate the field. 8090


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Scheme 278

Scheme 280

Scheme 281

According to the report by Gómez et al., in the presence of palladium(0), π-allylpalladium(II) complexes are generated with epoxide ring opening (Scheme 277).282 Nucleophilic attack by various organometallic reagents, including organoScheme 279

showed that the regioselectivity can be manipulated by modifying the ligands.284 In addition, use of chiral ligands makes dynamic kinetic resolutions possible. The mechanism of these asymmetric reactions has been described in section 3.1.1 in the context of other nucleophiles, but the same principles apply to carbon nucleophiles. Scheme 282 stannanes, occurred on the less hindered terminus of the πallylpalladium(II) intermediate and afforded the linear product as major regioisomer. Usefully, this addition reaction showed a regioselectivity complementary to that obtained under Lewis acid conditions as reported by Miyashita (Scheme 262).271 A cooperative copper- and palladium-catalyzed, threecomponent coupling reaction of vinyl epoxides, terminal alkynes, and benzynes to generate 728 was reported by Cheng recently (Scheme 278).283 Benzyne generated in situ underwent alkynylcupration to yield arylcopper 730, which also added to the less hindered terminus of the π-allylpalladium complex 731 that was obtained from reaction of the palladium catalyst with the vinyl epoxide. Stabilized enolate species are common nucleophiles for catalytically generated π-allylpalladium intermediates. While palladium-catalyzed nucleophilic reactions tend to add at the less hindered terminus to give SN2′ products, studies also

Recently, Xie applied this methodology to the synthesis of some spirolactone natural products (Scheme 279).285 Using Trost’s DPPBA ligand (R,R)-233, the dynamic kinetic resolution of isoprene monoxide enabled synthesis of 734 bearing tertiary and quaternary stereocenters in good yields and excellent ee. Deprotection and lactonization afforded hyperolactone C. Subsequently, a [2 + 2] cycloaddition accomplished the asymmetric synthesis of biyouyanagin A. 8091


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Takikawa and co-workers reported the addition of pyrone 736 to the π-allylpalladium derived from vinyl epoxide 735 at the less hindered terminus to give intermediate 737.239c This intermediate spontaneously underwent a further SN2′ displacement to yield oxaspirocyclic compound 738 in moderate yield (Scheme 280). Welker et al. investigated the palladium-catalyzed ring opening of vinyl epoxides with metal enolates.286 Attack at the less hindered terminus of the π-allylpalladium intermediates resulted in products from an overall SN2′ addition of the zinc or

Scheme 285

Scheme 283

aluminum enolate (Scheme 281). Allyl alcohols 741 were obtained in moderate yield and stereoselectivity. Similarly,

cyclic boronates instead of Suzuki−Miyaura type of coupling products (Scheme 123, section 3.1.2).149 Apparently, the boronic acids preferred to act as oxygen nucleophiles rather than carbon nucleophiles under catalysis by this Pd(0) complex. However, Szabó found that under catalysis by Pd2(dba)3 carbon−carbon bond formation occurred between vinyl

Scheme 284

Scheme 286

epoxides and boronic acids to afford SN2′ addition product 748 and SN2 addition product 749 in high yields but rather low regioselectivity (Scheme 283).107 In the total synthesis of montabuphine, Zhang applied the Pd2(dba)3-catalyzed coupling reaction of 750 and boronic acid 753 to give the desired SN2′ addition product 755 (Scheme 284).30 The authors suggested that the stereochemical outcome resulted from palladium(0) displacement of the π-allylpalladium(II) intermediate (i.e., 751 to 752). Transmetalation of 753 with the π-allylpalladium(II) complex intermediate 752 followed by reductive elimination afforded 755. Interestingly, use of pincer ligands such as 756 significantly increased the selectivity for SN2′ addition in the reaction of vinyl epoxides with boronic acids. Mechanistic studies revealed that while Pd2(dba)3 was able to form a stable π-allylpalladium complex by oxidative addition to the vinyl epoxide (Scheme 285), the Pd(II) pincer complexes could not react directly with vinyl epoxides. Instead, the Pd(II) pincer complexes underwent transmetalation with boronic acid to form intermediate 759, which then transferred the Ar group to the vinyl epoxide substrates.107 Reaction with the vinyl epoxide appeared to be the rate-determining step of the whole reaction. Increasing the electron density on the palladium(II) complex or using electron-poor vinyl epoxides as substrates increased the

under palladium catalysis, cyclic vinyl epoxide 742 also reacted with zinc enolate 743 to afford 744 in moderate yield. Kazmaier’s group reported another palladium-mediated ring opening of vinyl epoxides by zinc enolates.287 As shown in Scheme 282, addition of zinc enolate 746 to the πallylpalladium intermediate generated from vinyl epoxides 745 also afforded the SN2′ products 747 in good yields, with the (E)-isomers as the major products. Alkylation has been achieved for acyclic vinyl epoxides but failed upon further extension of the scope to cyclic substrates. This reaction has been applied to modification of peptides. According to Miyashita’s studies, the Pd(PPh3)4-catalyzed reaction between vinyl epoxides and boronic acids generated 8092


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reaction and found that under catalysis by NCN- and SCSpincer Pd compounds 762 and 763 the rate-determining step became the transmetalation step, Figure 3.288 Therefore, decreasing the electron density at the palladium accelerated the process of transmetalation and therefore the overall reaction rate. A nickel-catalyzed coupling reaction of vinyl epoxides, alkynes, and dimethylzinc to produce skipped dienols was recently reported by Nakamura (Scheme 287).289 The E/Z ratio of the allylic alcohol was moderate. The authors proposed that the reaction proceeded via the intermediacy of πScheme 289

Figure 3. Some pincer ligands.

Scheme 287

allyloxanickelacycle intermediate 765 in equilibrium with the 6-membered oxanickelacycle 766 from the reaction of vinyl epoxide with nickel. After transmetalation with dimethylzinc and reductive elimination, (E)- and (Z)-767 were obtained, respectively. Base metal catalysis is an area of intense current interest.290 In this connection, anti-1,2-alkylation products of vinyl epoxy esters 768 and vinyl epoxy amides 769 were produced under catalysis by iron(II).291 Urabe reported that in the presence of Grignard reagents and FeCl2 the π-allyliron intermediate 770 was formed with inversion of the configuration with respect to the epoxide stereochemistry. Intramolecular delivery of the nucleophile resulted in SN2 addition product 771 (Scheme 288). 3.1.7. Other Nucleophiles. Other than the traditional nucleophiles routinely employed in synthesis, recent work on additions of heteroatomic nucleophiles, in particular boron and silicon, have been fruitful. This area is likely to see further development. Borylation of vinyl epoxides has been reported by Pineschi to occur under catalysis by Ni(cod)2. Addition of B2pin2 to cyclic vinyl epoxides 772 and 14 occurred stereoselectively in an antiSN2′ fashion.292 The boronate product 773 appeared to be unstable to column chromatography but could be induced to react in situ with benzaldehyde to afford 1,3-diols 774 bearing three contiguous stereocenters in high yields and excellent selectivity (Scheme 289). Acyclic vinyl epoxides, such as butadiene monoxide and isoprene oxide, were also examined under the same conditions. However, although the reaction proceeded, the selectivity was poor in those cases. Copper(I) has been reported to catalyze the borylation of vinyl epoxides. Tortosa reported a CuCl/Xantphos catalyzed anti-1,4-addition of B2pin2 to vinyl epoxides 775 to afford the corresponding boronates 776 (Scheme 290).293 The bisphosphine−copper−boron complex coordinated to the double bond of the vinyl epoxide anti with respect to the stereochemistry of the epoxide (Scheme 291). Borylcupration generated 782, which proceeded to elimination to produce copper alkoxide 781. Transmetalation with B2pin2 completed the catalytic cycle. However, the boronates 776 were unstable, and the products were isolated after in-situ oxidation with

reaction rate. However, reaction of cyclic vinyl epoxides failed to show SN2′ regioselectivity (Scheme 286).107 Gebbink’s group studied another series of palladium(II) complexes to mediate the vinyl epoxide−boronic acid coupling Scheme 288

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Scheme 290

Scheme 291

Scheme 293


diastereoselectively. Acyclic vinyl epoxide 164 also underwent SN2′ addition under more vigorous conditions to give (E)-784 in moderate yield. The proposed mechanism, supported by computational studies, is initiated by formation of the Lewis acid−base adduct of the diboron reagent and methoxide, i.e., 785. The increased nucleophilicity of this ate complex enabled boron addition to the vinyl epoxide in an SN2′ manner and produced allyl oxide 786. Protonation by MeOH regenerated methoxide to continue the catalytic cycle (Scheme 293).294 Interestingly, when copper(I) salt was added to this reaction, the borylation became syn-1,2-selective (Scheme 294).294 The boration product 787 could not be isolated but was captured by benzaldehyde to generate 788, whose stereochemistry inferred that the borylation was syn, a result that is complementary to the stereochemistry and regiochemistry observed by Tortosa under copper catalysis (Scheme 290, vide infra).293 The mechanism of formation of 787 is unclear.

alkaline H2O2. Moderate to very good yields of anti-1,4-diols 777 were secured with good diastereoselectivity. Alternatively, it is possible to in-situ protect the alkyl borate of 776 prior to oxidation of the alkylboronate. In this manner, 1,4-siloxyboronates 778 could be isolated in 60−80% yields. Similarly, cycloalkenol derivatives 779 can be obtained in 60−75% yields with excellent diastereoselectivity from cyclic vinyl epoxides 14 and 636. More recently, Bo and Fernández reported a metal-free borylative ring opening of cyclic and acyclic vinyl epoxides (Scheme 292).294 For cyclic vinyl epoxide 14, the borylation proceeded in an SN2′ manner and provided anti-783 as product 8094


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Scheme 295

enes 793 as side products (Scheme 295). The reaction was initiated by addition of the epoxide to the silylene and then subsequent rearrangement of the oxonium ylides. The [1,2]rearrangement to give 792 could proceed via either s-cis conformation 791 or s-trans conformation 791′, whereas the [2,3]-rearrangement to give 793 only occurred via s-cis conformation 791. For epoxides where R1 = H, both

Scheme 296

Scheme 298

conformations were relatively stable due to the weak steric interactions between H and the vinyl moiety, and as a result, there was a significant production of 793. Interestingly, spiroepoxide 794 also underwent silylene insertion to give 1,2-silaoxetane 795, which was characterized spectroscopically. However, it was too unstable to be isolated, A novel silver-catalyzed insertion reaction of silylene into vinyl epoxides was observed by Woerpel’s group.295 Treatment of vinyl epoxide 789 with silacyclopropane 790 in the presence of AgOTs gave 1,2-silaoxetanes 792 along with oxasilacyclohex-

Scheme 299

Scheme 297

and allowing 795 to undergo allylation with aldehydes yielded bridged bicyclic disiloxanes 796 containing anti-Bredt olefins (Scheme 296).295a Furthermore, it was observed that the chirality of epoxide (+)-797 was perfectly transferred to (E)cycloalkene (−)-799, presumably via transition state 798. 8095


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In 1974, Riley et al. first reported a lithium amide-induced isoprene oxide elimination to generate isoprenol, which was subsequently converted to isoprenyl bromide (Scheme 298).296 Nishikawa and co-workers used a similar strategy to synthesize, on a 100 g scale, tert-butyldiphenylsilyl-protected isoprenol 800 (Scheme 299),297 which was required for a regio- and stereoselective Diels−Alder reaction with bromolevoglucose-

Scheme 300

Table 10. 1,4-Eliminative Ring Opening of Vinyl Epoxide 814

Scheme 301

entry

R

T (°C)

yield

(E,Z):(E,E)

1 2 3 4 5 6 7 8

F PhCH2O CH3 CH3CH2 (CH3)2CH PhCH2S Ph (CH3)3C

−78 −78 25 25 25 −78 25 25

82% 83% 88% (conv.) 89% 79% 70% 83% 67%

>99:1 >99:1 70:30 73:27 56:44 29:71 4:96 5:95

none (801) to procure 802, a precursor in the synthesis of tetrodotoxin.

3.2. Eliminative Ring-Opening Reactions

Base-induced elimination and ring opening to generate dienols is a common transformation of vinyl epoxides. In general, deprotonation of the more acidic allylic protons of the vinyl epoxide occurs most readily (Scheme 297, pathway a). In

Scheme 303

Scheme 302

Oxidation of vinyl epoxide 804 yielded β,γ-epoxy ketone 805 that readily underwent deprotonation, enolate formation, and epoxide cleavage to give 806 (Scheme 300).298 Oxidation of 807 to give ketone 808 proceeded to ring opening alternatively under acidic conditions via the enol to afford 809 (Scheme 301).299 Fused bicyclic vinyl epoxide 811 was a key intermediate in Trost’s total synthesis of pseudolaric acid B. Epoxidation of diene 810 generated an inseparable mixture of epoxides, of which 811β was the major diastereomer. Treatment of the mixture directly with base induced deprotonation and vinyl epoxide cleavage to yield dienol 813 (Scheme 302).300 This

substrates which do not have allylic protons, other eliminative pathways are then possible (Scheme 297, pathways b and c). However, appropriately positioned activating groups could favor deprotonation and elimination by all pathways. For cyclic molecules and molecules with restricted rotations, the elimination pathways and stereochemical outcomes would also depend on the ability to achieve proper orbital alignments. 8096


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reaction was directed by the epoxide; thus, only the 811β diastereomer in which the γ-proton is also syn with respect to the epoxide underwent cleavage, producing 811α and 813, which were able to be readily separated at this stage. Acyclic vinyl epoxide systems with greater degrees of freedom of rotation could undergo elimination to give

Scheme 305

Scheme 304

Scheme 306

Scheme 307 diastereomeric product dienols. Ukaji and Inomata studied the stereochemical outcome of eliminative ring openings of (E)-vinyl spirooxiranes 814 to the corresponding 2,4-dienyl alcohols 815 and found that the geometry of the diene products depended on the δ-substituent of 814.301 High (E,Z) selectivity versus (E,E) selectivity was found for the series R = F− ≈ PhCH2O− > CH3− > CH3CH2− > (CH3)2CH− > PhCH2S− > (CH3)3C− ≈ Ph−, as shown by the examples in Table 10. The authors suggested that these effects could be rationalized by the eliminative ring opening requiring a σ → π* interaction between the C−H bond and the π*CC orbital (Scheme 303). Two conformations 816 and 817 have an orbital alignment in which the developing anion is aligned with the π*CC orbital. When R = F, O, conformation 816 is more favored than 817 because it allows more effective electron donation by hyperconjugation of the C−H bonds, resulting in formation of (E,Z)-815. However, when R is a large group such as tBu or Ph, conformation 817 is more favorable due to steric reasons and (E,E)-815 becomes the major product. Another explanation is that upon deprotonation conformation 818 leading to (E,Z)-815 could be stabilized by 6π electron homoaromaticity involving the developing charge at the δ position and a lone pair of electrons in a p orbital of the neighboring heteroatom when R = F or O. Fernández de la Pradilla et al. developed a highly stereocontrolled preparation of acyclic 2-sulfinyl dienes through

the eliminative ring opening of epoxy vinyl sulfoxides (Scheme 304).302 With sequential additions of KOtBu, epoxy vinyl sulfone 822 was first generated from sulfinyl chlorohydrin 820, then deprotonation and eliminative ring opening followed to give (Z,E)-dienes 823 predominantly. Similarly, from the diastereomeric vinyl epoxide 825 was obtained (E,E)-dienes 827 as the major products. The sulfinyl group directed deprotonation and elimination at the γ position such that competitive benzylic deprotonation did not occur in substrates 820b−c or 821b−c. Takeda’s group realized an eliminative ring opening of a silylated vinyl epoxide that could continue to a Brook rearrangement (829 → 830) to give a siloxy dienyl carbanion. The cascade reaction was terminated by an electrophile reacting 8097


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Scheme 308

Scheme 313

Scheme 314

Scheme 309

Scheme 315

Scheme 310

inter- or intramolecularlywith 828 to generate 831 (Scheme 305). Scheme 311

3.3. Rearrangements

Treatment of enantiomerically pure 832a with base resulted in deprotonation at the allylic position of the vinyl epoxide to set off the 1,4-elimination, Brook rearrangement cascade, which was terminated by a [2,3]-Wittig rearrangement, to yield 833 as products having a tertiary alcohol and silyl enol ether as functional groups (Scheme 306).303 Similarly, the diastereomeric 832b underwent the same cascade to yield (R,E)-833 with good E/Z selectivity. The chirality of the epoxide was transferred with varying degrees of fidelity to the chiral tertiary alcohol (Scheme 307).

Vinyl epoxides have inherent strain that potentiates them to undergo various rearrangement reactions toward the relief of strain. 3.3.1. Pericyclic Reactions. Braun et al. reported the first Cope rearrangement of divinyl epoxides in 1963.304 Since then, the scope of this thermal rearrangement reaction has been vastly expanded by the work of many groups.81,305 Some typical examples of this rearrangement are shown in Scheme 308.306 Substitution at every position of the divinyl epoxide has been examined. Even triflate, acetate (Scheme 309),305a and Si, B, and Sn heteroatom substituents (Scheme 310)305b,306a were found to be compatible under reaction conditions which typically involve heating with or without Lewis acid promoters.305b,306a Boyd and co-workers reported the retro-Diels−Alder reaction of the syn-benzene dioxide 64 into its valence tautomer dioxocin 834 (Scheme 311).44a,b The equilibrium of the retroDiels−Alder reaction varied greatly from substrate to substrate, depending on the substituents on the syn-benzene dioxide. One effect of this tautomerization was the racemization of synbenzene dioxide. Similarly, the retro-Diels−Alder reaction also

Scheme 312

8098


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Scheme 316

Table 12. Meinwald Rearrangements of 851

occurred on substrates 835 and 67, the isomers of toluene dioxide 64 (R = Me), and the equilibria vastly favored the dioxocins 836 and 837 (Scheme 312). However, the antibenzene dioxide 838 did not undergo the retro-Diels−Alder reaction readily (Scheme 313). a

Scheme 317

entry

R1

R2

R3

1 2 3 4 5

H H H Me H

c-Hex n-C9H19 Ph p-F-C6H4 p-MeOC6H4

TMS TMS TMS TMS H

yield (852:853:854) 87% 93% 95% 76% 65%

(3:97:0) (1:99:0) (>99:1:0) (>99:1:0) (0:0:100)a

Cis/trans = 9:91.

state.308 For vinyl epoxides, cleavage usually occurs at the allylic position. Thus, rearrangement of vinyl epoxides typically yields β,γ-unsaturated carbonyl compounds as products. However, if the homoallylic site is more substituted or if it has a stronger

Liu’s group developed a ruthenium-catalyzed rearrangement of vinyl propargyl epoxides that furnished modest yields of substituted phenols as products (Scheme 314).307 The mechanism proposed by the authors is shown in Scheme 315. The reaction is initiated by reaction of ruthenium with the alkyne to form ruthenium vinylidene 839. Intermediate 839 then undergoes electrocyclic rearrangement to give a ruthenium carbene 840. Epoxide opening to generate intermediate 841 is followed by a pinacol-type rearrangement to give ruthenium



entry

Lewis acid (mol %)

reaction conditions

1 2 3 4 5

Y(OTf)3 (10) Ga(OTf)3 (10) Ga(OTf)3 (5) Ga(OTf)3 (5) Ga(OTf)3 (5)

DCM, 25 °C to reflux DCM, 25 °C DCM, 0 °C toluene, 0 °C toluene, −10 °C

yield (849:850) 48% 68% 80% 92% 87%

(13:87) (33:67) (8:92) (6:94) (3:97)

alkyl 842, which is protodemetalated to give dienone 843. The dienone−phenol rearrangement then takes place and yields product 844. 3.3.2. Meinwald Rearrangements. The general acid- or Lewis acid-promoted rearrangement of epoxides to aldehydes or ketones has been realized, in many cases with excellent selectivity, in the context of vinyl epoxides. The direction of ring opening is governed by the ability of the substituents of the epoxide to stabilize the partial positive charge in the transition 8099


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carbocation-stabilizing substituent, epoxide cleavage at this position has also been observed. For example, in Trost’s synthesis of pseudolaric acid B, treatment of vinyl epoxide 845 with Lewis acid induced cleavage of the allylic C−O bond, resulting in spiroketone 846 in high yield (Scheme 316).300 In the total synthesis of (−)-microbiotol and (+)-βmicrobiotene by Srikrishna et al.,309 however, treatment of 847 with Lewis acid resulted in C−O bond cleavage at the homoallylic position to yield an α,β-unsaturated ketone instead (Scheme 317). This can be attributed to the effect of the electron-deficient alkene. Tang’s group showed that the rearrangement of vinyl epoxide 848 was induced by Y(OTf)3 and Ga(OTf)3 but not by

Scheme 321

Table 12 shows that for vinyl epoxide 851 allylic C−O cleavage predominated to yield 853 from R1 migration. However, the substituents on the epoxide had a dramatic effect on the identity of the major product and the product ratios. Scheme 322

Scheme 318

magnesium or lithium triflates. While C−O bond cleavage occurred at the allylic position, variations in the reaction conditions altered the ratio of products resulting from migration of different substituents (Table 11),310 but it was Scheme 319

Changes in the migration and product outcome in Meinwald rearrangements due to electronic effects of the substituents are further demonstrated in studies of the rearrangements of vinyl epoxides 855 by Yamano’s group.311 In the model study for their total synthesis, they showed that when R1 was an unsaturated ester, allylic C−O cleavage still predominated and cyclization with the allyl cation gave rise to dihydrofuran 856 (Table 13, entries 1 and 2). However, when R1 was an unsaturated aldehyde, homoallylic C−O bond cleavage became favored due to the increased electron deficiency of the alkene, resulting in ring contraction and generation of 857 (Table 13, entries 3 and 5). However, increasing the extent of conjugation reduced the electronic impact of the electron-withdrawing groups, facilitating once again formation of dihydrofuran 856 (rearrangement of vinyl epoxides to dihydrofurans is discussed in section 3.3.3). In the presence of a hydroxyl substituent, intramolecular nucleophilic substitution to yield oxabicyclic 858 has also been observed (Table 13, entries 6 and 7).312 Silylated vinyl epoxides such as 859 have been induced to undergo rearrangement to give silylated aldehydes 861 in good yields. Under palladium catalysis, 859 reacted to yield the πallylpalladium species 860, and rapid silyl migration ensued to generate 861 in high yield (Scheme 318).313 This reaction occurred for disubstituted alkenes, even if the alkene were cis to

unclear whether the observed variations were a result of the differential tendencies toward decomposition. The major product 850 resulted from hydride migration. Scheme 320

8100


Chemical Reviews

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Scheme 323

Scheme 325

Scheme 326

Scheme 324

unsaturated aldehyde 870, which isomerized to 871 (Scheme 323).

the bulky silyl group. Spirolactone 862 underwent the same rearrangement to afford aldehyde 863 in excellent yield (Scheme 319). For some exceptionally reactive substrates that were able to form highly stabilized allylic cations, palladium catalysis was not needed for the rearrangement. Silica gel was acidic enough to promote the rearrangements of vinyl epoxides 864 and 865 (Schemes 320 and 321). Takanami’s group developed chromium porphyrin 866 and chromium metallophthalocyanine 867 as catalysts to promote Meinwald rearrangement at very low catalyst loadings (Scheme 322).314 Reaction yields were high, and migration was stereoselective, such that the products retained the enantiomeric purities of the epoxide substrates. Grubbs’ catalysts have also been found to be able to induce rearrangement of vinyl epoxides. In their attempt to synthesize derivatives of (−)-mycothiazole, Batt and Fache attempted the cross metathesis between vinyl epoxide 868 and thiazole 869 using the first-generation Grubbs catalyst.315 However, instead of obtaining the desired 872, only enal 871 was obtained along with unreacted 869. It became apparent that the Grubbs catalyst induced the Meinwald rearrangement of 868 to β,γ-

Scheme 327

Plummer et al. demonstrated that vinyl epoxide 873 underwent a cross-metathesis−epoxide rearrangement cascade reaction with alkene 874 catalyzed by the second-generation Hoveyda−Grubbs catalyst to yield 875 as product (Scheme 324).316 As rearranged ketone 876 (prepared separately by the Sc(OTf)3-induced epoxide rearrangement of 873) did not 8101


Chemical Reviews

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Scheme 328

Scheme 331

undergo metathesis with 874, the reaction sequence was deduced to have been initiated by metathesis and followed by Scheme 329

rearrangement. On the other hand, 877 obtained from the cross-metathesis of 873 and 874 was found to be inert when treated with the same catalyst. This control reaction indicated

sequences in which vinyl epoxides are induced to rearrange, and their rearranged products (often aldehydes) are used in situ for subsequent reactions. The key to the success of these reactions is the compatibility of the reagents in the same pot. Lautens reported a preparation of homopropargylic alcohols from vinyl epoxides 881.318 Catalyzed by scandium(III) triflate,

Scheme 330

Scheme 332

that the actual catalyst for rearrangement was not the Hoveyda−Grubbs complex but probably a less hindered, reactive ruthenium methylidene generated during the crossmetathesis reaction. Treatment of vinyl epoxide 878 with protic acid or SnCl4 induced its rearrangement to 879 via cleavage of the allylic C− O bond. Unconjugated 879 further isomerized to enone 880.317 (Scheme 325). Products generated from the acid-induced rearrangement of vinyl epoxides are obviously useful as substrates in many reactions. There have been efforts to design one-pot reaction

881 rearranged by allylic C−O cleavage and hydride migration to give a β,γ-unsaturated aldehyde 882 (Scheme 326). In the same pot, allenylborane 883, which is compatible with Sc(OTf)3 and 881, intercepted the aldehyde to yield homopropargyl alcohol product 884. If the chiral allenylborane 885 developed by Soderquist319 was used, an asymmetric homopropargylation of the aldehyde from rearrangement of 886 produced 887 in high yield and ee (Scheme 327). Using a similar strategy, preparation of optically enriched homoallylic alcohols was realized by intercepting the aldehydes from vinyl epoxide rearrangement to react with stoichiometric chiral allylsilanes 888−890 (Scheme 328).320 ́ reported a similar reaction using optically Hegedus and Rios active allenylstannane 891 as the nucleophile (Scheme 329).321 The reaction afforded the desired propargyl alcohol 892 in excellent diastereoselectivity. Albert and Koide reported a one-pot synthesis of propargyl alcohol 895 from cyclic vinyl epoxide substrate 893 (Scheme 8102


Chemical Reviews

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Scheme 333

Scheme 334

Scheme 336

Scheme 337

330).322 The substrate was treated with zirconium acetylide, which served both as a Lewis acid to promote rearrangement of Scheme 335

893 to aldehyde 894 as well as a nucleophile in the subsequent addition to afford propargyl alcohol 895 in moderate yield. Lautens’ group developed a one-pot synthesis of 1,2dihydropyridines from vinyl epoxides 896 and imines 897 in the presence of Sc(OTf)3 (Scheme 331).323 In this cascade reaction Sc(OTf)3 first catalyzed the rearrangement of 896 to 899, in which the R2 substituents of 896 ensured that the vinyl epoxide would be cleaved at the allylic position. Tautomerization of 899 to enol 900 facilitated the vinylogous imino−aldol reaction with 897 to yield aldol product 901. Isomerization of the double bond under Lewis acidic conditions afforded 902, which further underwent cyclization and imine formation to produce dihydropyridine 898 in high yield.

A related tandem vinyl epoxide rearrangement−Fischer indole synthesis was reported by Taylor and Donald, but the product yield was low (Scheme 332).324 Nokami and co-workers reported a synthesis of a bishomoallylic alcohol from vinyl epoxide 903 under acid catalysis (Scheme 333).325 Vinyl epoxide 903 first underwent a Meinwald rearrangement under indium triflate catalysis to aldehyde 905. Activation and hemiacetalization with alcohol 904 afforded complex 906. Elimination yielded oxonium species 907, which underwent a [3,3]-sigmatropic rearrange8103


Chemical Reviews

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Scheme 338

Scheme 341

Scheme 339

Scheme 342

ment to give 908. Hydrolysis yielded bishomoallylic alcohol 909 in moderate to high yields. A one-pot vinyl epoxide rearrangement−carbonyl ene cyclization was reported by Morimoto and co-workers.326 As shown in Scheme 334, TIPSOTf induced rearrangement of vinyl epoxide 910 with cleavage of the homoallylic C−O bond and vinyl group migration to yield activated aldehyde 911. A carbonyl ene reaction ensued to afford diastereomeric silylated secondary alcohols 912 and 913 in good overall yield. The same reaction, however, did not occur with diastereomeric vinyl epoxide 914, which underwent direct intramolecular electro-

A tandem vinyl epoxide rearrangement−Prins reaction was reported by Indukuri et al. using boron trifluoride diethyl etherate as catalyst (Scheme 337).327 Vinyl epoxide 163 underwent the Meinwald-type rearrangement to form 917, with which acetalization with the homoallylic alcohol produced hemiacetal 918. Decomposition to oxonium 919 was followed by a Prins cyclization to generate carbocation 920. This

Scheme 340

Scheme 343

carbocation underwent a Friedel−Crafts reaction with the solvent benzene to afford the final product 916. Indukuri et al. also demonstrated a one-pot synthesis of a dihydropyranone by a related strategy (Scheme 338).328 The BF3−Et2O-promoted Meinwald rearrangement of butadiene monoxide was an effective way to generate 3-butenal in situ. Reaction with cyclobutanone 921, a masked bis-enol, induced an aldol reaction which was followed by a substitutive oxa-

philic addition with the activated epoxide to give silylated tertiary alcohols 915 and 916 (Scheme 335). The authors explained the disparate outcomes as a result of the conformation of 910a that disfavored the direct addition reaction and allowed rearrangement to compete successfully (Scheme 336). 8104


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Scheme 344

Scheme 348

Scheme 349 Michael cyclization to give dihydropyranone 922 (Scheme 339). Scheme 345 Scheme 350

3.3.3. Ring Expansion Rearrangements. Thermal rearrangement of vinyl epoxides to dihydrofurans is well documented.329 However, prolonged heating at high temperScheme 346

atures is usually needed to facilitate this transformation. While this rearrangement can also be induced photochemically,330 Scheme 347

In the synthesis of a carotenoid by Otero et al.,333 vinyl epoxide 926 rearranged to dihydrofuran 927 and 928 under acidic conditions (Scheme 341). Kuzuya et al. reported a vinyl epoxide rearrangement to the dihydrofuran in the course of a DMP oxidation of 929 in the synthesis of racemic chamobtusin A (Scheme 342).52a The authors surmised that the rearrangement was promoted by the acetic acid generated in situ in the DMP oxidation. Subsequent olefination of the aldehyde 930 yielded tricyclic compound 931 in moderate overall yield. In 2006, Njardarson’s group described the rearrangement of vinyl epoxides to dihydrofurans using Cu(hfacac) 2 as catalyst.334 Vinyl epoxides 932 rearranged to dihydrofurans 933 smoothly and with good yields upon heating (Scheme 343).334a This rearrangement was found to be stereospecific: epoxide trans-934 rearranged to cis-935, while epoxide cis-934 rearanged to trans-935, but the latter proceeded with decreased chemoselectivity, as a greater proportion of 936 (a Meinwald product from homoallylic bond cleavage) was obtained

acid catalysis is more frequently employed, especially in the context of total synthesis. A recent example is found in the asymmetric synthesis of (−)-salviasperanol by Majetich’s group,331 in which the key rearrangement was first described by Simmons and Sarpong in the racemic context.332 The enantiomerically enriched vinyl epoxide 923 was induced to undergo acid-promoted rearrangement to dihydrofuran 924. Deoxygenation yielded key intermediate 925 in high yield (Scheme 340). 8105


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Scheme 351

Scheme 354

Scheme 355

Scheme 352

Scheme 356

of the ruthenium complex TpRuPy2Cl facilitated isomerization of the epoxides to give a diastereomeric mixture predominated by the vinyl epoxides trans-942. Similarly, vinyl epoxide 943 was also isomerized to a mixture of epoxides. The product mixture was dominated by the more stable epoxide, and the equilibrium of the reaction was substrate dependent. Notably, recovery of material is quantitative. It was unclear whether this isomerization proceeded by a radical or an ionic mechanism. Semipinacol rearrangements of 2,3-epoxyalcohols are well documented,336 and some have occurred in the context of vinyl

(Scheme 344).334c Mechanistic studies and calculations have been performed to explain the diastereoselectivity, which confirmed the role of the copper catalyst in the ring opening of the epoxide.334c,e Starting from an optically pure vinyl Scheme 353

Scheme 357

epoxide, the rearranged dihydrofuran product retains the enantiomeric purity (Scheme 345).334c This reaction has been applied successfully in natural product synthesis. In the synthesis of the core of platensimycin, this rearrangement was utilized to construct the oxabicyclic system 937 (Scheme 346).334b Preparation of 939 from enantiomerically pure 938 is a step in the synthesis of (+)-goniothalesdiol (Scheme 347).334c Similarly, this rearrangement has been applied to the formal synthesis of (+)-varitriol (Scheme 348).334d The optically enriched silylated vinyl epoxide 940 prepared by Evans and Aye (section 2.4.2) was induced to rearrange upon treatment with stoichiometric iodine. The silylated dihydrofuran 941 was obtained in excellent yield and with no loss of enantiomeric purity (Scheme 349).79 3.3.4. Other Rearrangement Reactions. Lo et al. reported a ruthenium-catalyzed isomerization of epoxides, which has also been applied to vinyl epoxides.335 As shown in Scheme 350, heating vinyl epoxides cis-942 in the presence 8106


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epoxides. In 2007, Coşkun et al. reported that reaction of cycloheptatriene 945 with mCPBA resulted in formation of benzoate 946.337 It was deduced that dienyl epoxide 947 was

Scheme 359

Scheme 358

959 to a highly functionalized vinyl epoxide, 960. As shown in Scheme 357, 959 underwent a Wharton fragmentation to afford vinyl epoxide 957 as a racemic mixture. A dynamic kinetic resolution based on equilibration via the vinylogous Payne Scheme 360

generated upon oxidation, and hydrolysis of the acetal yielded hemiacetal 948 that underwent semipinacol rearrangement and aromatization to afford benzoate 946 (Scheme 351). Yanagimoto et al. synthesized the precursor of (−)-sporochnol A employing the semipinacol rearrangement of optically enriched 949 (Scheme 352) to provide aldehyde 950 as the reaction product, albeit with some loss of ee.338 Performing the reaction under ketalization conditions at lower temperature resulted in formation of the corresponding acetal 951 in higher yield and enantiomeric excess (Scheme 353). 2,3-Epoxyalcohols are also well known to undergo basepromoted Payne rearrangement,339 and the vinylogous Payne rearrangement is known in the context of vinyl epoxides. In 2001, Myers’ group reported a novel vinylogous Payne rearrangement that occurred in the presence of palladium (Scheme 354) or under silylative conditions (Scheme 355).340 In both scenarios, the more substituted epoxides were favored in the equilibria. Hence, 953 and 955 were formed in good yields from vinyl epoxides 952 and 954, respectively. The mechanism of this rearrangement had not been elucidated, but the rearrangement of 952 did not proceed with phosphine alone or without palladium. In 2010, Hoye and co-workers demonstrated an interesting synthetic application of the vinylogous Payne rearrangement.341 Two vinyl epoxides 956 and 957 were synthesized, and at 80 °C, each vinyl epoxide equilibrated to form a 1:1 mixture, with a half-life of about 24 h (Scheme 356). The tertiary hydroxyl group was proposed to be involved in the transition state (958) of the rearrangement as shown in Scheme 356. This rearrangement was exploited by the authors to accomplish the asymmetric desymmetrization of cyclohexanone dioxide

rearrangement and a lipase-mediated acylation produced the enantiomerically enriched vinyl epoxide 960 in moderate yield. She’s group reported a novel rearrangement of vinyl epoxides using an N-hetereocyclic carbene (NHC) as catalyst.342 As shown in Scheme 358, upon heating vinyl epoxide 961 with NHC catalyst 962, dihydropyrone 963 and 964 were obtained. The rearrangement initiated with the nucleophilic addition of 962 to 961 to form the Breslow intermediate 965. Ring opening of the epoxide generated alkoxide 966, which was cyclized by acylation to afford 964 as the product with regeneration of the NHC catalyst. Dihydropyrone 964 was isomerized into 963 in situ to form a conjugated enone, which is more stable (Scheme 358). Scheme 361

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radical intermediates 968−970 propagate the chain reaction or become quenched. Oxirane radical 967 (Scheme 359) has not been captured experimentally or observed spectroscopically prior to fragmentation. Kinetic studies have been done using radical clocks to evaluate the reactivity of 967. Krosley and Gleicher designed the thioimidazole radical precursor 971 to study radical intermediate 972.344 Treatment of 971 with triphenylstannane overwhelmingly provided allylic alcohol 973 as the major product over vinyl epoxide 974 (Scheme 360). Since the rate constant for the ring opening of 1-cyclopropylethyl radical at 70 °C is estimated to be 4.7 × l08 s−1, the rate constant for epoxide ring opening must be greater than 1 × l010 s−1.344 The rate of carbon−carbon bond cleavage in radical 967 was investigated by Murphy’s group.345 The observation that radical intermediate 976, which was derived from another thioimidazole radical precursor 975, only generated carbon−carbon bond cleavage product 977 suggested that benzylic radical formation

Scheme 362

Scheme 364

3.4. Radical Reactions

was also faster than the 5-hexenyl radical cyclization process (Scheme 361). 3.4.1. Reactions of Alkoxy Radicals Derived from Vinyl Epoxides. Radical addition to yield intermediate 968 in Scheme 359 is the most common pathway in vinyl epoxide radical reactions. Direct quenching by abstraction of hydrogen would yield overall a 1,4-addition product. In comparison with alkylation by organometallic reagents, the radical-induced alkylation of vinyl epoxides usually showed a higher regioselectivity for 1,4-addition as well as a higher stereoselectivity for generating the (E)-alkene (Scheme 362).343 For example, radical additions to butadiene monoxide 163

The first reports on radical reactions of vinyl epoxides can be traced back to 1965.343 However, there have been few reviews covering this reaction type in the nearly five decades past. The most common pathways of radical-mediated vinyl epoxide ring-opening reactions are shown in Scheme 359. Most radicals attack the double bond of the vinyl epoxide to generate oxirane radical 967 initially (pathway a). However, radical intermediate 967 is not stable and rapidly undergoes ring opening to produce more stable radicals. The most common is C−O bond cleavage to give alkoxy radical 968. If the epoxide is substituted by a radical stabilizing group at R′, C−C bond cleavage could also occur to generate carbon radical 969. Direct radical attack at the epoxide with ring opening to form 970 occurs only when the radical source is highly oxophilic (pathway b). As in other radical reactions, these

Scheme 365

Scheme 363

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from the trialkylborane added to the vinyl epoxide with

Scheme 366

concomitant ring opening and the radical chain was propagated through reaction of alkoxy radical 983 with trialkylborane to Scheme 368

provided allylic alcohols 979 and 980 with high (E)-olefin selectivity, although the yields were low to fair. Huyser and Munson proposed that the stereoselectivity was the result of stereoselective β-elimination of the radical intermediate 981 or 982. Conformer 981′ was more favored for elimination because the CH2R group only eclipsed with protons in conformers 981′ and 981″, whereas 982′ and 982″ were destabilized due to the proximity of the large CH2R group to the methylene group and the epoxide oxygen, respectively. A more efficient radical alkylation protocol employed organoboranes and a range of radical initiators. Brown’s group first reported the radical addition of trialkylborane to butadiene monoxide, where 4-alkyl-2-buten-1-ols were obtained in moderate to good yields with high (E)-selectivity.346 As the mechanism in Scheme 363 shows, the alkyl radical generated

give borinate 984. Both primary and secondary trialkylboranes induced this reaction successfully.

Scheme 367

Scheme 369

Although Brown’s method was general for a range of trialkylboranes, alkylation with stoichiometric amounts of trialkylboranes were not versatile, due to the limited availability of alkylboranes commercially. A strategy that used catalytic amounts of organoboranes to mediate radical transfer of other radical precursors would broaden the reaction scope, since the range of alkyl groups that could be added depended on the range of radical precursors rather than that of the borane. Roberts and Zard separately developed organoborane-catalyzed radical alkylations utilizing this concept. 8109


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Roberts’ protocol used a quinuclidine−borane complex to catalyze the radical addition of esters like methyl acetate,

Scheme 372

Scheme 370

dimethyl malonate, and dimethyl methylmalonate to vinyl epoxides (Scheme 364).347 The α-hydrogen atom abstraction from the ester by the alkoxy radical was acelerated by replacing the slow direct transfer pathway (reaction a) to a faster process mediated by the amine−borane complex (Scheme 364, reactions b and c).347a Quinuclidine−borane (QNB) was found to be the most effective and convenient source of borane for this reaction. Cyclic vinyl epoxides 985 underwent this reaction successfully (Scheme 365), but acyclic vinyl epoxides, like butadiene

Boranes have also mediated similar reactions of vinyl epoxides, starting from other radical sources. Oshima’s group reported that triethylborane could mediate the radical reaction of vinyl epoxides with C6F13I, PhSH, or Ph3GeH as radical precursors and provided 4-substituted-2-buten-1-ols 991 in moderate to good yields (Scheme 368).350 Radical cyclization has been induced by a Ph3SnH−Et3B system by radical formation from a halide or an alkyne. In Oshima’s follow-up study on addition of triphenylgermane to vinyl epoxides, although the use of Et3B promoted good yields of 999 (Scheme 369), the data appeared to be more consistent with a direct triphenylgermane radical addition process.351 The high preference for generating (E)-999 was

Scheme 371

Scheme 373

monoxide, failed to generate the desired products, probably because of the competition from 1,5-hydrogen transfer.347b Zard and co-workers developed a triethylborane-mediated xanthate radical addition to vinyl epoxides (Scheme 366).348 In this reaction, triethylborane mediated radical transfer by trapping alkoxy radical 989 to give borinate 990 and an ethyl radical, which then propagated the reaction by reacting with xanthate 986. Zard’s protocol introduced tremendous flexibility into the alkyl radical addition, because xanthates bearing many kinds of alkyl groups could be readily synthesized, and a range of cyclic and acyclic vinyl epoxides could be used as substrates.348 Some examples are shown in Scheme 367. More recently, Banwell and co-workers applied this reaction as the first step in the total synthesis of (±)-limaspermidine.349

explained by a fast equilibrium between (Z)-1000 and (E)1000, where (E)-1000 having a more exposed alkoxide could undergo hydrogen-atom transfer more readily with germane than (Z)-1000. The germylated allylic alcohols have applications in the synthesis of 4-vinyltetrahydro-2-furanones. Kim et al. studied the development of a 1,4-radical alkylation catalyzed by hexabutylditin. Reaction with acyclic vinyl epoxide 8110


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1001 generated only a 28% yield of product 1002 with exclusive selectivity for the (E)-isomer (Scheme 370).352 The authors reasoned that the alternative radical ring-opened intermediate (Z)-1003 was geometrically favored to undergo a 1,5-hydrogen transfer to produce the unreactive radical intermediate (Z)-1004, which was unable to abstract a hydrogen atom from iPrOH.

Scheme 377

Scheme 374

Scheme 375

synthesis of dihydroxyenoate 1009. The diastereoselectivity was generally low for esters but could be improved to 7.8:1 by introducing an oxazolidinone as a chiral auxiliary to the substrate. As is typical for reactions involving SmI2, the carbonyl group was first reduced by SmI2 to generate allyl radical 1010. Reductive ring opening of the epoxide of 1010 by another equivalent of SmI2 produced samarium enolate 1011, which then underwent an aldol addition upon introduction of the aldehyde.

In order to verify whether the 1,5-hydrogen transfer was responsible for the low yield, the authors employed the vinyl endocyclic epoxide 1005 as substrate. Under the same reaction Scheme 376

Table 14. Tin Hydride-Mediated Cyclization of Epoxy Enolsilane 1030

conditions, radical alkylation of 1005 with various alkyl iodides generated the 1,4-alkylation products in good yields (Scheme 371).352 The alkylation reaction also proceeded well when cyclic acetals and ethers were used as alkylating reagents. Notably, alkylation with acetals is synthetically equal to formylation of α,β-unsaturated cyclic ketones at the γ position. A range of vinyl endocyclic epoxides, including epoxy vinyl acetates and phosphates, was effective substrates in this reaction. A samarium(II) iodide-mediated reductive aldol reaction of α,β-unsaturated γ,δ-epoxy esters via single electron transfer (SET) was reported by Mukaiyama and co-workers (Scheme 372).353 Treating ester 1008 with SmI2 and aldehyde at low temperatures constituted a high-yielding and (E)-selective

a

entry

1030

conditions

1 2 3 4 5 6 7

a b c d e b e

A A A A A B B

yield (%) of 1031 (dr)a 68 80 61 67 14 60 55

(100:0) (88:12) (95:5) (−)a (93:7) (65:35) (69:31)

yield of 1032 11 7 8 13 25 0 0

Determined by 1H NMR.

Radical translocation is a common transformation of alkoxy radicals like 968 (Scheme 359). The prerequisite for functional group transfer is a homolytically cleavable bond located at a favorable distance. Intramolecular 1,5-functional group transfer, which could proceed via a chair-like transition state, is observed for many alkoxy radicals 962 and usually results in cyclization products. Kim et al. reported on the 1,5-tributyltin group transfer reaction 8111


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of vinyl spirocyclic epoxides (Scheme 373).354 Treatment of vinyl epoxides 1012a−c with an excess of tributyltin first

Scheme 380

Scheme 378

generated radical intermediate 1013. Then 1,5-tributyltin group transfer led to formation of allyl radical 1014, which underwent 5-exo cyclization or 6-endo cyclization with a remote olefin. Although the 5-exo cyclization of radicals is kinetically favored, cyclization of stable radicals such as allyl is usually reversible and the 6-endo products are thermodynamically favored. Therefore, 6-endo products 1016a and 1016c were the major products in the reactions, and the 5-exo product became significant only when R2 was radical stabilizing (1017). epoxy enol acetate 1024, mediated by AIBN and diphenyl disulfide, generated bicyclic product 1025 in good yields with

Scheme 379

Scheme 381

The authors also demonstrated the versatility of this concept by extending the scope of the substrates.354 Radical alkylation of 1018 generated bicyclic [3.3.0] homoallylic alcohol 1019 (Scheme 374). Radical allylation using allylstannanes was also successful (Scheme 375). For vinyl endocyclic epoxides, 1,5-tributyltin group transfer was impossible due to the unfavorable geometry. However, 1,5hydrogen transfer could proceed (Scheme 376). Therefore, upon treatment with a catalytic amount of tributyltin hydride, endocyclic epoxides 1020a−d reacted to generate cis-fused bicyclic products 1023a−b in good yields via 1,5-hydrogen transfer of the oxygen radical 1021.354 Substrates with a radical stabilizing R group such as 1020b and 1020c reacted with superior yields. Rawal developed a two-step strategy to convert cyclic epoxy enol acetates to bicyclic compounds.355 Radical cyclization of

moderate to good diastereoselectivity (Scheme 377). The epoxy enol acetates with radical stabilizing groups (R = Ph) reacted with a diastereoselectivity of up to 14:1. Construction of a novel benzo-fused hydrindane skeleton was also achieved by this method. According to the proposed mechanism (Scheme 377), radical 1028 generated from addition of thiyl radical to 1024 underwent epoxide ring opening and 1,5hydrogen transfer. Cyclization of the radical to the enol acetate produced radical 1029. In the absence of a good hydrogen 8112


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1033a with tin hydride resulted in 1,5-trimethylsilyl transfer and generated product 1034a in good yields (Scheme 378). Transfer of the TMS group was faster than quenching by Bu3SnH, since under Bu3SnD−AIBN conditions deuterated 1034a′ was the only product. Transfer of the TBS group in the reaction of vinyl epoxide 1033b was comparatively slower, since quenched product 1035b could be isolated. Enolsilane 1039 with an exocyclic epoxide underwent a similar reaction with tin hydride to generate 1040 and proceeded to a cascade reaction of 1,5-TMS transfer and radical cyclization to provide bicyclic products 1042 and 1043 (Scheme 379).357 Kim and Lee further studied a one-carbon ring expansion reaction of vinyl spirocyclic epoxides (Scheme 380).358

Scheme 382

Scheme 384

donor, the thiyl radical was eliminated from 1029 to propagate the reaction. Tin hydride catalyzed the cyclization of epoxy enolsilanes 1030 to generate cis-fused Indane products 1031 (Table 14, entries 1−5).356 Although deoxygenation to give rise to 1032 is a side reaction which was not observed in the disulfide initiated cyclization, use of tin hydride as the radical initiator achieved comparatively higher diastereoselectivities (Table 14, entries 6 and 7).356 Kim et al. also showed that 1,5-transfer of a silyl group can also be induced for epoxy enolsilanes in which the geometry and distance are favorable.357 Treatment of epoxy enolsilane Scheme 383 Treatment of vinyl epoxides 1044 and 1049 with thiyl or tin radicals generated allyloxy radical 1045 and 1050, respectively, which underwent β-cleavage preferentially on the more highly substituted carbon to form the carbon-centered radical 1046 and 1051. Exo-cyclization, instead of endo-cyclization, with the enone produced 1047 and 1052 as the major products. Kim and Lee also explored a radical-mediated three-carbon ring expansion reaction of bicyclic epoxy enolsilanes 1053.358 Addition of thiyl radical to 1053 resulted in epoxide cleavage and produced alkoxy radical 1054, which underwent ring expansion by β-cleavage and then elimination and regeneration of PhS radical to produce cyclic enolsilanes 1056 and 1057 as a mixture of (E)- and (Z)-isomers (Scheme 381). The E:Z selectivity was dependent on the ring size. Desilylation yielded the ring-expanded enediones 1058 and 1059. Oshima et al. observed that reaction of siloxy-substituted vinyl epoxides 1060 produced γ-substituted α,β-unsaturated aldehydes 1061 under Et3B-mediated radical conditions (Scheme 382).359 This reaction occurred with a range of radical sources. Apparently, after radical addition to the vinyl epoxide and epoxide cleavage to give 1062, β-cleavage occurred to eliminate siloxymethylene radical and yielded the truncated unsaturated aldehyde as product. 3.4.2. Reactions of Carbon Radicals Derived from Vinyl Epoxides. Radical reactions of vinyl epoxides that result in epoxy radical C−C bond cleavage to give 969 are rare (Scheme 359), unless the carbon radical is particularly stabilized. Feldman and Fisher reported a radical-mediated 8113


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383). The stereochemistry of the products suggested that cyclization of 1067 took place through chair-like transition states 1070 and 1070′, rather than the boat-like transition state 1069. The higher preference to afford the 1064α diastereomer suggested that conformer 1070′, whose pseudoaxial substituent E eclipsed with a hydrogen, was less strained than conformer 1070, whose pseudoequatorial substituent E eclipsed with the double bond. 3.4.3. Reactions of Allylic Radicals Derived from Vinyl Epoxides. Allylic radicals 970 (Scheme 354) are generated

Scheme 385

Scheme 387

Scheme 386

from radical ring opening of the oxirane induced by oxophilic metals via a SET mechanism. Such reactions using Cp2TiCl or indium as the reducing agents have been documented. Yadav et al. used Cp2TiCl to reduce epoxy allyl alcohols to dienols in good yields (Scheme 384).361 One equivalent of Ti(III) reacted with the alcohol, and another equivalent induced the ring opening of epoxide to form the allylic radical 1074, which could interact intramolecularly with the unfilled p orbital of Ti(III) to form a four-membered titanacycle intermediate 1075. Reductive elimination produced the dienol with retention of stereochemistry. More recently, Barrero’s group reported a Ti(III)-catalyzed homocoupling reaction of vinyl epoxides 163 and 164.362 In this reduction, γ,γ′-coupling was preferred over γ,α′-coupling, especially for vinyl epoxides that are more substituted at the allylic position (Scheme 385). Reduction of cis- or trans-1080

formal cycloaddition of alkenes to aryl vinyl oxiranes which was an exploitation of this C−C bond homolytic cleavage process.360 Treatment of aryl vinyl epoxide 1063 with thiyl radical generated epoxy radical 1065. Homolytic C−C bond cleavage resulted in benzyl radical 1066. This species proceeded to add to electron-deficient alkenes and then cyclize with regeneration of PhS radical to produce 2,5-cis-tetrahydrofuran products 1064 as a mixture of epimers at C4 (Scheme

Figure 4. Cycloadditions and formal cycloadditions of vinyl epoxides. 8114


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provided only the γ,γ′-coupled product as the (E)-olefins, albeit as a mixture of diol diastereomers 1081−1083. The authors suggested that the reaction was initiated by reductive formation of the β-titanoxy allylic radical 1085 (Scheme 386).362 Although the possibility of direct dimerization via allylic radical 1085 could not be precluded, the author favored the mechanism in which dimerization occurred with equilibrating σ-allyltitanium intermediates 1086a−c. These allyltitanium species then acted as soft nucleophiles and underwent an SN2′ reaction with vinyl epoxide 1084 to give

Scheme 389

Scheme 388

dimer 1087. Ti(IV) was reduced back to Ti(III) by Mn. The predominance of 1086a was probably due to its stability over the more sterically hindered 1086b or 1086c. In the dimerization, 1086a and another molecule of vinyl epoxide 1084 adopted a chair-like transition state 1089 that resulted in γ,γ′-coupling and formation of another (E) double bond. Both Barrero362 and Fernández-Mateos363 attempted to capture the radical intermediate in the reaction of Ti (III) and vinyl epoxides by external radical traps, such as acrylonitrile and acetonitrile; however, in both cases, only the homocoupling product was obtained in high yield. A indium/indium(I) chloride-mediated epoxide deoxygenation reaction that converted oxiranes to alkenes was recently reported by Murphy’s group.364 The exact mechanism of the deoxygenation was unclear, but the authors proposed that the reaction occurred through the intermediacy of a stabilized radical 1092, formed via a SET process from the indium metal to the low-lying σ* orbital of the epoxide C−O bond.364 Treatment of vinyl epoxide 1090 with an excess of In/InCl in tBuOH−H2O however yielded alkenone 1091 instead of the expected β-ionone (1093). Since treatment of 1093 under the same reaction conditions also gave 1091 with a similar yield and E/Z ratio, the authors proposed that the ionone was further reduced by indium metal in situ to produce 1091 (Scheme 387).

Scheme 390

3.5. Cycloadditions and Formal Cycloadditions

Vinyloxiranes can react with unsaturated systems to form two bonds and result in ring structures. Some of these are true cycloaddition processes, e.g., Diels−Alder reactions. Others are metal-catalyzed or cascade reactions which are “formal cycloadditions” and not true pericyclic reactions. However, all of these transformations are brought together for discussion under this section and loosely described using the terminology of cycloadditions regardless of the actual reaction mechanisms. For example, the reactions are further organized into (3 + 2) and (4 + 2) cycloadditions and so on,365 with reference to the

backbones of the reacting partners; the atoms of the vinyl epoxide structure (Figure 4) that contributed to the newly synthesized ring would be emphasized. Comprehensive reviews on cycloadditions with vinyl epoxides as substrates are amiss in the literature, and many of the results are relatively recent. Vinyloxiranes as a cycloaddition building block are likely a development that would grow and should see increasing applications in the future. 8115


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3.5.1. (3 + 2) Cycloadditions of Vinyl Epoxides. 3.5.1.1. (3 + 2) Cycloadditions: Contribution of C1 and C2.

Scheme 394

Scheme 391

Yıldırım and Dürüst reported a 1,3-dipolar cycloaddition of nitrilimines with isoprene oxide reacting as a dipolarophile (Scheme 388).366 The C,N-diaryl nitrilimines 1095 were generated in situ by treatment of compound 1094 with base Scheme 392

Scheme 395

ultimately to H-pyrazolo[5,1-a]isoquinoline-1-carbaldehydes 1098 in moderate to good yields. Unfortunately, other more substituted vinyl epoxides failed to give significant yields of products.

and subject to reaction with an excess of vinyl epoxide. Yields of pyrazoline 1096 ranged from fair to good, but the diastereoselectivity was low.

Scheme 396

Scheme 393

3.5.1.2. (3 + 2) Cycloadditions: Contribution of C2 and C3. Wu reported a silver(I)−rhodium(I) cocatalyzed cycloaddition reaction of butadiene monoxide and N′-(2-alkynylbenzylidene)-hydrazide 1097 (Scheme 389).367 According to reaction mechanism proposed by the authors, Rh(I) inserted into the allylic C−O bond of the vinyl epoxide to form Rh(III) complex 1099a, which then equilibrated to the sigma complex 1099c via the π-allylrhodium(III) complex 1099b. In tandem, hydrazine 1097 cyclized to isoquinolinium-2-yl amide 1100 in the presence of Ag(I). The (3 + 2) dipolar cycloaddition between 1100 and 1099c generated another Rh(III) species 1101, which underwent β-hydride elimination and then reductive elimination to yield 1103. Detosylation and aromatization led

3.5.1.3. (3 + 2) Cycloadditions: Contribution of C3, C4, and O5. Cycloaddition of heterocumulenes (X = CY) with vinyl epoxides mediated by metal complexes and with halides as nucleophilic cocatalysts is an efficient method to prepare fivemembered ring heterocycles. Under these conditions, butadiene monoxide reacted with carbon dioxide to generate vinyl dioxolanones. Many metal complexes to induce this kind of transformation have been reported, for example, VO(acac)2,368 [FeTPhOA]2,369 Zn(salphen),370 Zn(bstc),371 zinc clusters,372 and Mg(TPP).373 Mechanistically, the metal complexes act as Lewis acids to activate the epoxide for an SN2 ring opening by the halide cocatalyst (Scheme 390). The metal alkoxide then 8116


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Brière and Metzner utilized this reaction to synthesize vinyl dioxolanones 1108 from vinyl epoxide 1107 with retention of stereochemistry (Scheme 392).144 Hydrolysis and acid-induced lactonization yielded cis-β-hydroxy-α-methylene lactones 1109. Moreover, a highly enantioselective version of the reaction has been realized using Trost’s chiral palladium complexes (Scheme 393).375

Scheme 397

Scheme 399

Isocyanates (OCNR) undergo similar cycloadditions with vinyl epoxides to afford 1,3-oxazolidin-2-one as products. The first palladium-catalyzed cycloaddition with isocyanates reported by Trost (Scheme 394) showed that both cis- and trans-epoxides 1110 reacted to offer cis-1111 as the major diastereomeric products.376 The authors rationalized that while both trans- and cis-1110 reacted with palladium to initially generate the corresponding π-allylpalladium complexes 1112 and 1113, the less favorable 1112 was converted to the more stable 1113, which reacted to yield cis-1110. This reaction has

adds to CO2 to form an alkyl carbonate, and intramolecular displacement of halide affords the dioxolanone.370,372,373 This Scheme 398

Scheme 400

transformation is not limited to vinyl epoxides but has been observed for epoxides in general. On the other hand, palladium-catalyzed reaction of vinyl epoxides with carbon dioxide and carbonates also yield dioxolanones. This reaction proceeded via a π-allylpalladium intermediate and has been reviewed.1,115 Other metal catalysts such as those of rhodium and nickel that form π-allylmetal complexes also promote this kind of reaction. On treatment with palladium, the vinyl epoxide formed a πallylmetal complex that reacted with carbon dioxide to form intermediate 1105.374 Cyclization and catalyst regeneration yielded the vinyl dioxolanone 1106 (Scheme 391). Table 15. Transition Metal-Catalyzed Cycloaddition of Vinyl Epoxides and Imines

entry

conditions

yield (%) (cis:trans)

ee (major)

1 2 3

5 mol % Pd2dba3·CHCl3/C3-Tunephos, THF, rt 5 mol % Pd2dba3·CHCl3,/Josiphos-6, THF, rt 10 mol % Ni(cod)2, 0.3 equiv of Ti(OiPr)4, TBAT, 10 mol % (R,R)-DIPAMP, −20 °C

92 (1:3) 96 (2:1) 88 (≥20:1)

82% 91% 65%

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been made enantioselective using Pd(0)−C4-TunePhos as catalyst (Scheme 395).125 Alper reported that under catalysis by Pd2(dba)3·CHCl3 and TolBINAP carbodiimides (ArNCNAr) added in a similar

Scheme 403

Scheme 401

manner to vinyl epoxides to generate 1,3-oxazolidin-2-imine 1114 as products with high enantioselectivity (Scheme 396).377 However, when the carbodiimides are unsymmetrical (i.e., RNCNAr), two isomeric 1,3-oxazolidin-2-imines products 1115 and 1116 are obtained through two modes of ring closure via π-allylpalladium conformers 1117 and 1118 (Scheme 397).378 The authors observed that the alkyl imine attacked the π-allyl intermediate preferentially over the aryl imine, was less repulsion between R1 and the tosyl group than in 1120b. Jarvo’s group attempted to increase the diastereoselectivity of this cycloaddition as well as induce enantioselectivity by employing chiral metal catalysts.380 Palladium catalysis in the presence of chiral ligands resulted in oxazolidines with good ee, but the diastereoselectivity remained moderate (Table 15, entries 1 and 2). Use of nickel as catalyst with (R,R)-DIPAMP

Scheme 402

Scheme 404

probably due to the higher electron density on nitrogen. Competitive attack by the aryl imine was further discouraged by increasing its steric encumbrance, such as through introducing ortho substituents on the aryl group. In this way, the regioselectivity for 1115 and 1116 could improve to 4.5:1. Yamamoto was the first to report the palladium-catalyzed (3 + 2) cycloaddition of imines and vinyl epoxides to afford oxazolidines (Scheme 398).379 Yields were good to excellent for a range of imines, and the cis/trans selectivity of 1119 was low, except when R1 = H where the selectivity for cis-1119 was high. To rationalize this, the author suggested that cyclization via 1120a became favored for butadiene monoxide, because there

as ligand resulted in high diasteroselectivity but lower ee (Table 15, entry 3). On the other hand, Jarvo and co-workers realized a rhodiumcatalyzed cycloaddition of vinyl epoxides and imines to produce 1,3-oxazolidines with complete retention of chirality.380 Using (R)-163 of 99% ee, cycloaddition with 1121 in the presence of 5 mol % Rh(cod)2OTf offered >80% yield of 1122 with a cis/ trans ratio of 6:1 and in 99% ee (Scheme 399). The authors 8118


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Scheme 405

Scheme 408

suggested that the perfect chirality transfer was due to a relatively slower racemization via σ−π−σ isomerization of σallylrhodium(III) intermediates compared with heterocycle formation. Du and co-workers studied the related imine cycloaddition reactions under catalysis by the rhodium complexes of a series of chiral unsaturated N-sulfinyl imine ligands, among which that of 1123 furnished spiro-oxindole oxazolidines 1125 or 1,3oxazolidines 1127 with high enantioselectivity via a dynamic kinetic resolution (Scheme 400).381 Cycloadditions with imines 1126 derived from aldehydes showed selectivity for the less stable trans-cycloadducts 1127. The authors found a σ−π−σ isomerization of π-allylrhodium intermediate slowly under the reaction conditions (Scheme 401). However, the sulfinyl imine ligand greatly accelerated the isomerization, and the stereo-

[Ni(cod)2] and iminophosphine ligand 1132 produced polysubstituted tetrahydrofurans 1133 in moderate to good yields (Scheme 403).383 The authors proposed a mechanism that initiated with oxidative addition of nickel catalyst to the activated alkene to form an oxa-nickelacycle 1134. Intermediate 1134 then inserted into vinyl epoxide 163 to generate another oxa-nickelacycle (1135), which underwent reductive elimination to afford the product. Hou attempted an asymmetric (3 + 2) cycloaddition of isoprene oxide and β-nitrostyrene derivatives (1136) catalyzed by a chiral palladium-1,1′-P,N-ferrocene complex 1137.384 Reactions of isoprene oxide with 164 provided tetrahydrofurans 1138 in moderate to good diasteroselectivities and moderate enantioselectivities (Scheme 404). 3.5.2. (4 + 2) Cycloadditions of Vinyl Epoxides. 3.5.2.1. (4 + 2) Cycloadditions of Vinyl Epoxides: Contribution of C1 and C2. Vinyl epoxides have reacted in (4 + 2) cycloadditions as dienophiles. Pale et al. reported a Lewis acidmediated hetero-Diels−Alder reaction between a vinyl epoxide (epoxy enol ether 1139) and acrolein to give spirocyclic acetal 1140 in very good yield (Scheme 405).385 The (4 + 2) cycloaddition exploited the strain of the exocyclic double bond which served as an efficient dienophile. The stereochemical outcome of 1140 could be rationalized by an endo cycloaddition that took place anti with respect to the epoxide to avoid repulsions with this moiety. 3.5.3. (4 + 3) Cycloadditions of Vinyl Epoxides. 3.5.3.1. (4 + 3) Cycloadditions of Vinyl Epoxides: Contribution of C1, C2, and C3. The classical (4 + 3) cycloaddition between allyl cations and dienes is a reaction isoelectronic with the Diels−Alder cycloaddition. Ohno et al. first reported the (4 + 3) cycloaddition of epoxy enolsilanes 82 with furan and cyclopentadiene that proceeded in 12−47% yields, mediated by several Lewis acids.386 Chiu successfully optimized this reaction using a catalytic amount of TESOTf and low reaction temperatures to procure bicyclic adducts 1141 and 1142 in synthetically useful yields (Scheme 406).61 An investigation of the scope of the epoxy enolsilanes and dienes revealed that in most cases diasteromeric cycloadducts were obtained from nonselective endo and exo cycloaddition modes. When both reacting partners were hindered, however, such as in the reaction of diene 1145 with 1143 and 1144, cycloadditions were diastereoselective for the endo cycloadducts 1146 and 1147, respectively (Scheme 407).387

Scheme 406

chemistry of the products was completely controlled by the chiral rhodium catalyst rather the epoxide. Michael acceptors can also undergo metal-catalyzed cycloadditions with vinyl epoxides to provide substituted tetrahydrofurans as products. Yamamoto first reported this palladiumcatalyzed reaction and that such a transformation required bisactivated olefins in order to proceed (Scheme 402).382 The πallylpalladium(II) intermediate 1129 was believed to be an intermediate in the reaction, and a subsequent, nonselective cyclization yielded 1128 as a 1:1 mixture of diastereomers. Nickel complexes have been shown to catalyze cycloaddition of activated olefins and vinyl epoxides. Matsubara’s group reported that treatment of vinyl epoxides and olefins 1131 with Scheme 407

8119


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Scheme 409

Scheme 410

Scheme 413

Scheme 411

As an application of this asymmetric synthetic method, a dopamine transporter (DAT) inhibitor 1151 having an oxatropane structure was synthesized from (R)-82 in 53% overall yield and with >99% ee (Scheme 408).388a This cycloaddition is also the basis of an enantiodivergent synthesis of both antipodes of bicyclic ketone 1153 from a single enantiomeric epoxide 1152 (Scheme 409).388b Epoxy enolsilanes can also effectively undergo the intramolecular (4 + 3) cycloaddition with a tethered furan.61 Catalyzed by TESOTf, cycloaddition of 1154 generated an 83% yield of tricyclic hydroxyenone 1156 as a single diastereomer via endo transition state 1155 (Scheme 410). The cycloaddition tolerates many functional groups and substituents and has been successfully applied to asymmetric synthesis of the pentacyclic core (1157) of anti-angiogenic natural product, cortistatin J (Scheme 411).389 3.5.4. (5 + 2) Cycloadditions of Vinyl Epoxides. 3.5.4.1. (5 + 2) Cycloadditions of Vinyl Epoxides: Contribution of C1, C2, C3, C4, and O5. Feng and Zhang reported a hetero-(5 + 2)-cycloaddition/Claisen rearrangement cascade of alkyne tethered vinyl epoxides 1158 catalyzed by a rhodium− NHC complex that provided bicyclo[3.1.0]hexane derivatives 1159 as the sole products (Scheme 412).390 The authors proposed a mechanism to account for formation of 1159 as shown in Scheme 413.390 The cationic rhodium(I) species first coordinated with the substrate and formed rhodacyclopentane 1161 by oxidative cyclometalation of the enyne. Ring expansion of 1161 yielded new rhodacycle 1162, and reductive elimination regenerated the rhodium(I) catalyst and produced the fused dihydroxepine 1163, constituting a formal (5 + 2) cycloaddition incorporating all five atoms of the

Scheme 412

When using enantiomerically pure epoxy enolsilanes (R)-82 as substrate, the corresponding cycloadducts 1141 and 1142 were each obtained with highly conserved ee (Scheme 408).388 Use of nonpolar solvents and an excess of diene was conducive to preservation of optical purity in the cycloaddition. The high retention of enantiomeric purity implied that this cycloaddition is to be distinguished from the classical, concerted [π4s + π2s] mechanism involving planar oxyallyl cations such as 1150 as dienophiles. Two possible electrophilic species 1148 and 1149 could conceivably be intermediates in this formal (4 + 3) cycloaddition (Scheme 408). 8120


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vinyl epoxide moiety. Further Claisen rearrangement of 1163 proceeded under thermal conditions to give rise to 1159.

4. CONCLUSION This paper has attempted to summarize the syntheses and reactions of vinyl epoxides since 2005, including radical and cycloaddition reactions of vinyl epoxides which have not been covered by previous reviews. As illustrated by the variety of transformations, vinyl epoxides are versatile building blocks for organic synthesis. They are readily obtained with optical purity, and their racemic forms have been parlayed to enantiomerically

Jesse Ling was born in Hong Kong. He received his B.Sc. degree (Chemistry) from the University of Hong Kong in 2012. After graduation, he was awarded a University Postgraduate Fellowship to conduct postgraduate research and he joined the group of Professor Pauline Chiu at the same university as a Ph.D. student. He is currently working on reactions of epoxy enolsilanes with carbon nucleophiles.

enriched products by dynamic kinetic resolutions. Much work has already been done to study and control the regio- and stereoselectivity of their reactions. Increasingly they have also become the centerpieces of novel cycloadditions and efficient cascade reactions. As a result of this chemistry along with their ready availability, many efforts have already skilfully utilized vinyl epoxides at various stages in the total synthesis of complex natural products. Due to the inherent potential and reactivity presented by vinyl epoxides, studies and investigations for novel reactions and applications will remain active.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes Pauline Chiu was born in Hong Kong and studied organic chemistry at the University of Toronto where she obtained her B.Sc. (Hons) degree in 1988, M.Sc. degree in 1990 working with the late Professor Adrian G. Brook on silene chemistry, and Ph.D. degree in 1994 under the guidance of Professor Mark Lautens on organometallic reactions of oxabicyclic compounds. Under an NSERC fellowship she continued to Columbia University, New York, in 1994 for postdoctoral studies with Professor Samuel J. Danishefsky on the synthesis of gelsemine. Subsequently, she started her independent career at the Department of Chemistry at the University of Hong Kong, where she has been Full Professor since 2010. Her research interests are in the development of novel synthetic methodology and total synthesis of natural products.

The authors declare no competing financial interest. Biographies

ACKNOWLEDGMENTS The University of Hong Kong and the State Key Laboratory of Synthetic Chemistry are thanked for their support. University Postgraduate Fellowship support from the University of Hong Kong to J.H. and J.L. is gratefully acknowledged.s Jiayun He was born in 1988 in Guangdong, China. She studied

REFERENCES

chemistry at Sun Yat-sen University, where she obtained her B.Sc.

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degree in 2011. She was awarded a University Postgraduate Fellowship from the University of Hong Kong to pursue Ph.D. studies in the group of Professor Pauline Chiu. Her research is focused on the intramolecular (4 + 3) cycloaddition of epoxy enolsilanes and its application to natural product synthesis. 8121


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Chemical Reviews

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Stereochemical studies of the opening of chloro vinyl epoxides: cyclic chloronium ions as intermediates.

Oxenoids in organic synthesis.

Efficient cycloaddition of epoxides and carbon dioxide over novel organic-inorganic hybrid zeolite catalysts.

Copper catalysis in organic synthesis.

Iron catalysis in organic synthesis.

Thiyl radicals in organic synthesis.

Indenylmetal Catalysis in Organic Synthesis.

Enzymatic catalysis in organic synthesis.

Machine-Assisted Organic Synthesis.

Induction of DNA-repair synthesis in primary rat hepatocytes by epoxides.

Amide synthesis by nucleophilic attack of vinyl azides.

Synthesis of two β-cyclodextrin derivatives containing a vinyl group.

Tf2NH-Catalyzed Amide Synthesis from Vinyl Azides and Alcohols.

Mutagenicity and cytotoxicity of benz[alpha]anthracene diol epoxides and tetrahydro-epoxides: exceptional activity of the bay region 1,2-epoxides.

Organic synthesis: The robo-chemist.

Organic synthesis by quench reactions.

Organic chemistry. Streamlining amine synthesis.

Organic chemistry: Streamlining drug synthesis.

Enantioselective biotransformations of nitriles in organic synthesis.

Magnetically recoverable ruthenium catalysts in organic synthesis.

Synthesis and properties of vinyl carbamate epoxide, a possible ultimate electrophilic and carcinogenic metabolite of vinyl carbamate and ethyl carbamate.

Regioselective synthesis of vinyl halides, vinyl sulfones, and alkynes: a tandem intermolecular nucleophilic and electrophilic vinylation of tosylhydrazones.

Cholesterol epoxides: formation and measurement.

Regio- and enantioselective catalytic monoepoxidation of conjugated dienes: synthesis of chiral allylic cis-epoxides.