Allene ether Nazarov cyclization.

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Allene ether Nazarov cyclization Cite this: Chem. Soc. Rev., 2014, 43, 2979

Marcus A. Tiusab The ease of synthesis and the exceptional reactivity of alkoxyallenes has led to their use in a large number of highly diverse applications. This Report describes their use in various versions of the allene ether Nazarov cyclization. Following a brief introduction to the Nazarov cyclization (Section 1), the oxidative cyclization of vinyl alkoxyallenes is discussed first (Section 2). Nazarov cyclizations of a-alkoxyallenyl vinyl ketones and of a-alkoxyallenyl vinyl tertiary carbinols are covered (Section 3). The discovery and the subsequent rational design of acetals that serve as chiral auxiliaries on the allene in

Received 19th September 2013

highly enantioselective Nazarov cyclizations is explained (Section 4). Interrupted Nazarov cyclizations of alkoxyallenes that are generated in situ from the isomerization of propargyl ethers on solid supports are

DOI: 10.1039/c3cs60333d

discussed, including the evolution of a highly diastereoselective, chiral auxiliary controlled version of the reaction. Some applications of the methodology to natural products total synthesis have been included

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so as to provide the reader with benchmarks with which to judge the utility of the methodology.

1 Introduction The subjects of this Review are the types of Nazarov cyclization that proceed from acyclic allene ethers.1 The typical Nazarov cyclization is the process that converts a divinyl ketone such as 1 (Scheme 1) to cyclopentenones 4 and/or 5.2 The reaction is catalyzed by Brønsted (shown) or Lewis acids. The first intermediate that is formed is pentadienyl cation 2. The s-trans/ s-trans conformer 2b of the cation undergoes thermally allowed conrotatory 4p electrocyclization to give cyclic allylic cation 3 as a

University of Hawaii, 2545 The Mall, Honolulu, Hawaii 96822, USA. E-mail: [email protected]; Fax: +1 808 956 5908; Tel: +1 808 956 2779 b University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, USA

Marc Tius was born in 1953 in Izmir, Turkey. He moved to Greece with his parents when he was 5 years old. He attended elementary school in Kavala, Eastern Macedonia, and gymnasium in Thessaloniki, northern Greece. In 1971 he enrolled as an undergraduate at Dartmouth College in New Hampshire, where he majored in Mathematics and Chemistry. His first research experience was in Professor Gordon Gribble’s labs. In 1975 he started graduate studies at Harvard, where he joined Professor E. J. Corey’s group. For his thesis he completed the synthesis of aphidicolin, working with Larry Blaszczak, and then with Jagabandhu Das. After a brief postdoc in the Corey group, he moved to Hawaii in 1980, where he has been ever since. He currently has a joint appointment in the Chemistry Department of the University of Hawaii, and at the University of Hawaii Cancer Center.

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Scheme 1

Mechanism of the Nazarov cyclization.

a second intermediate. Proton loss terminates the reaction. In the absence of any biasing features in 3, the proton can be lost in two ways, leading to 4 and 5. In the typical Nazarov reaction of Scheme 1 the trans relationship between R1 and R4 in 3 is determined by the conrotation; however, this stereochemical information is lost when the termination step involves proton loss. The reactive s-trans/s-trans conformer 2b is in equilibrium with the s-trans/ s-cis conformer 2a that cannot undergo cyclization, and with several other unreactive conformers. Any factors that bias the conformational equilibrium away from 2b will inhibit the Nazarov cyclization. For this reason, sterically demanding substituent(s) that are cis to the carbonyl group on the b-carbon atoms typically lead to inferior yields of cyclic product. There are several aspects of the Nazarov cyclization that will be discussed briefly in what follows. Allylic cation 3 can be

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Fig. 1

A cyclopentadienone with complementary polarization.

intercepted by a nucleophile in an alternative termination process known as an interrupted Nazarov cyclization.3 This variant of the conventional Nazarov cyclization is significant because it maximizes the number of stereogenic carbon atoms that can be formed. West, Burnell, Flynn and others have published pioneering work on this reaction.4 A very effective technique to facilitate the Nazarov cyclization is to introduce functionality in the acyclic dienone that induces complementary polarization at the two reacting carbon atoms (Fig. 1).5 Introducing either an electron-withdrawing or an electron-donating group a to the carbonyl group results in a reactive substrate. Especially reactive substrates for the Nazarov cyclization that undergo rapid cyclization under mild conditions are those that incorporate a ‘‘push–pull’’ alkene into the structure of the acyclic dienone.6 An instructive example of such a Nazarov cyclization is due to Frontier’s work that will be discussed in the following section.

2 Allene oxide cyclization The key steps in Frontier’s successful synthesis of (D,L)-rocaglamide are summarized in Scheme 2.7 Propargyl ether 7 (PMB = 4-methoxybenzyl) was deprotonated at 40 1C with tert-butyllithium and the propargyl carbanion was trapped8 to produce allenyl stannane 8. This material was exposed to an excess of 3-chloroperbenzoic acid (m-CPBA) in N,N-dimethylformamide (DMF) at room temperature to give cyclopentenone 9 in 40–50% yield for the two steps from 7. The cyclization reaction assembles the entire rocaglamide carbon skeleton, less the dimethylamido group that was introduced through a subsequent series of steps. The likely mechanism of the oxidative cyclization is shown in Scheme 2. Selective epoxidation of the allenyl enol ether in the presence of the benzofuran leads to unstable epoxide 10 that rearranges to cation 11 under the influence of acid, presumably residual 3-chlorobenzoic acid. Protiodestannylation of 11 gives 12 that is activated to undergo the 4p electrocyclic ring closure that leads to 9 after proton loss. Several points and clarifications must be made. First, it is reasonable to expect epoxidation of the strained allenyl enol ether to be faster than the epoxidation of the benzofuran double bond. Competitive epoxidation of the benzofuran would erode the yield of 9. The regiochemistry of epoxidation within the allene is irrelevant, since both allene oxides lead to 11. A second point is that the geometry of the enol double bond in 12 has been shown as Z. This is consistent with the cis stereochemistry of the phenyl and 4-methoxyphenyl groups in 9, which is expected for a conrotation. It is unlikely that tributylstannane 11 is able to undergo efficient ring

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closure because of the effect that the large trialkyltin group has on the conformational equilibrium of 11. According to the analysis that has been discussed in the context of Scheme 1, the equilibrium surely favours the unreactive s-cis conformer of 11, therefore protiodestannylation must precede ring closure. Finally, the example of the cyclization that leads to 9 should be contrasted with Frontier’s earlier unsuccessful attempts to assemble the core structure of rocaglamide through the Nazarov cyclization of ketoester 13. All attempts to induce the cyclization of 13 with Lewis acids failed, presumably because 14 is not polarized in a complementary manner. Because of the electron withdrawing effect of the carboxymethyl group, both terminal carbon atoms of cation 14 bear a partial positive charge. Replacing the carbomethoxy with the electron donating hydroxyl group induces complementary polarization of the terminal carbon atoms in 12, resulting in a successful electrocyclization. This example provides an excellent illustration of the beneficial effect of polarizing the pentadienyl cation. The oxidative cyclization of eneallenes has been known since at least 1969 when Grimaldi and Bertrand9 described the process for 3-methylpenta-1,2,4-triene. The general reaction is of interest not only because of its applications in synthesis, but also because it is a key step in the biosynthesis of jasmonates and of some marine prostanoids. The importance of this reaction inspired two computational studies of the mechanism, the first due to Hess, Cha and associates10 in 1999, the second a more detailed exploration due to de Lera and associates11 that was published in 2004.12 There are two mechanisms that describe the conversion of eneallene oxides to cyclopentenones, one of which is concerted, the other stepwise and proceeding through a charged intermediate. The calculated activation barriers for each of the two pathways are very close in energy, therefore it is quite likely that in some cases both mechanisms are followed. In the case of epoxide 10 that is formed as a racemate it is not possible to use stereochemical information to distinguish between the two mechanistic alternatives that can lead to 9. Because the reaction was performed in DMF, a polar solvent, and because the allene ether oxygen atom strongly stabilizes the polar intermediate, it is highly probable that the polar, stepwise transformation of 10 to 12 that has been depicted in Scheme 2 is correct. The Frontier group has demonstrated that the oxidative vinyl alkoxyallene Nazarov cyclization is a general process.13 Propargyl ether 15 (Scheme 3) was exposed to tert-butyllithium and N,N,N 0 ,N 0 -tetramethylethylene diamine (TMEDA) in ether at 78 1C, then quenched with methanol to provide cyclohexenyl methoxyallene 16 that was unstable to the conditions for workup and chromatographic purification. Oxidation of 16 with dimethyl dioxirane (DMDO) in acetone at 0 1C led to cyclopentenone 17 in 63% overall yield for the two steps from 15. The use of other oxidants in the second step led to lower isolated yields of 17. For example, m-CPBA and the Davis oxaziridine led to 17 in 43% and 50% yield, respectively. The cyclization reaction is highly stereoselective, although the product partially isomerizes on silica gel during chromatographic purification, leading to the b-phenyl diastereomer of 17. The stereochemistry of 17 reflects the expected kinetic preference of a conrotatory process.


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Scheme 2

Key steps in the Frontier synthesis of (D,L)-rocaglamide.

The examples that are summarized in Scheme 4 reveal mechanistic information. Oxidative cyclization of allene 18 with DMDO led to cyclopentenone 19 as a single diastereomer in 64% yield for the two steps (isomerization, cyclization). The oxidative cyclization of 20 led to cyclopentenone 21 in 44% yield. This is an especially significant result because it demonstrates the highly stereoselective synthesis of two adjacent all-carbon atom quaternary centres. The oxidative cyclization of 16 must be contrasted with that of 22 which is not very stereoselective and which leads to 23 as a 4/1 mixture of isomers in 60% yield. Substituting DMDO for the more sterically demanding


oxaziridine 24 improves the diastereomeric ratio to 8/1, but at some expense to the yield (48% of 23). The results of Scheme 4 can be understood in terms of the mechanism that is summarized in Scheme 5 for the oxidative cyclization of 18. Epoxidation of the enol ether double bond in 18 can take place along two trajectories, as shown. Remembering that the two p bonds of allene 18 lie in orthogonal planes, the oxidant is expected to approach the enol ether from the b face that is cis to the small methyl group and not from the a face that would require the oxidant to approach the much larger phenyl group. This results in the formation of epoxide 25.

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Scheme 3

An example of oxidative cyclization of an eneallene.

Scheme 4 The effect of substitution on the oxidative cyclization of eneallenes.

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the complementary polarization ensures a rapid conrotatory cyclization to 19. The direction of the conrotation that is shown in 26, counterclockwise, was chosen arbitrarily. One could just as well have shown clockwise conrotation for 26 that would have led to the enantiomer of 19. Product 19 must be formed as a racemate because 26 is achiral. So long as the enolate geometry in 26 is maintained, the electrocyclization is highly stereoselective. A potential problem with these oxidative cyclizations is the regiochemistry of the epoxidation. The difference in reactivity between the allenic enol ether and the alkene toward the electrophilic oxidant provides a bias for a regioselective oxidation. It is tempting to attribute the lower yield for the formation of 21 versus 19 to competitive epoxidation of the more electrophilic tetrasubstituted alkene in 20. In the case of 22, the difference in size between the n-butyl substituent on the allene and the proton is small, so epoxidation of the enol ether with DMDO is not selective. The enolate (cf. 26) is formed as a mixture of geometrical isomers leading to a 4/1 diastereomeric mixture for 23. The sterically more demanding oxidant 24 is better able to discriminate between the two faces of the enol double bond and therefore leads to an improved 8/1 mixture of diastereomers of 23. The oxidative cyclization represents an important and useful contribution to the Nazarov reaction. It is not obvious how this process can be rendered enantioselective because it proceeds through a planar, achiral intermediate. This precludes transferring axial chirality from the allene to tetrahedral chirality in the product. Such a strategy has been demonstrated for a different type of Nazarov cyclization that also makes use of alkoxy allenes that will be discussed later in this Review.

3 Allene ethers

Scheme 5

Stereochemistry of the eneallene oxidative cyclization.

The stereochemical course of the cyclization is determined at this point. Epoxide ring opening leads to zwitterion 26 in which

Scheme 6

Brandsma and co-workers have performed the pioneering work that shows that propargyl ethers 28 that are derived from propargyl alcohol 27 are easily isomerized to allene ethers 29 by warming in the presence of potassium tert-butoxide (Scheme 6).14 The isomerization of propargyl ethers that are derived from 2-alkyn-1-ols other than propynol leads to acetylene–allene mixtures that are difficult to separate. The deprotonation of allene ethers 29 with n-butyllithium generally takes place with high selectivity at C1 unless R has a large steric demand (e.g. tert-butyl) in which case C3 deprotonation competes.15 The a-lithio alkoxy allenes are excellent nucleophiles that add to ketones to give tertiary alcohol products.16 For example (Scheme 7) lithioallene 30 added to the ketone carbonyl group of 31 leading to tertiary alcohol 32 in 78% yield.17 The tertiary, bis-allylic hydroxyl group in 32 was ionized by exposure to

Synthesis of allene ethers.

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Scheme 7

Key steps in the synthesis of (D,L)-xanthocidin.

trifluoroacetic anhydride (TFAA) and 2,6-lutidine at 20 1C, followed by warming to room temperature. The presumed intermediate pentadienyl cation 33 underwent the Nazarov cyclization that was terminated by loss of methoxymethyl cation, leading to cyclopentenone 34 in 62% yield. Conducting the reaction in the presence of silica gel led to a cleaner process. In the absence of silica gel the yield of 34 was attenuated and multiple products were formed. Cyclopentenone 34 was converted to (D,L)-xanthocidin in four steps. There is another reaction pathway that is available for the tertiary alcohols that can be formed from 30, as summarized in Scheme 8.18 Addition of 30 to enone 35 led to tertiary alcohol 36. When treated at room temperature in wet dichloromethane with 2 mol% dichloro(pyridine-2-carboxylato)gold(III) 37 a rearrangement took place that produced a single diastereomer of spirocyclopentanone 38 in 79% overall yield for the two steps from 35. This rearrangement is of course not a Nazarov

Scheme 8

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A gold(III) catalyzed rearrangement-cyclization.


cyclization, but it is discussed briefly so as to alert the reader to a very large body of literature that describes the ways in which the exceptional reactivity of alkoxy allenes can be used in ring-forming reactions.19 A somewhat different example of an alkoxy allene Nazarov cyclization is summarized in Scheme 9.20 1-Trimethylsilyl alkoxy allene 39 was prepared from 30.21 With C1 blocked, C3 deprotonation of 39 took place and the resulting 3-allenyllithium was trapped in high yield with 1,4-dibromobutane to give 40. Displacement of the primary bromide by lithium ethoxyacetylide 41 was carried out in liquid ammonia at 78 1C. This reaction led to desilylated allene 42 in 62% yield, in all likelihood because of cleavage of the trimethylsilyl group by adventitious dissolved lithium hydroxide that was present in the reaction medium. There is a substantial difference in acidity between the protons at C1 and C3 of 42, therefore selective deprotonation of C1 was easily accomplished by exposure to n-butyllithium. Addition of the lithioallene to Weinreb amide 43, followed by workup with aqueous sodium dihydrogen phosphate led to cyclopentenone 45 in 80% yield. Collapse of the tetrahedral intermediate during workup presumably led to allenyl ketone 44 that cyclized spontaneously. Whereas it is possible to isolate allenyl vinyl ketones,22 if there is an ether substituent on the allenyl carbon atom a to the carbonyl group, as is the case in 44, the Nazarov cyclization takes place spontaneously during workup.5b The exceptional reactivity of these allenyl ketones reflects complementary polarization due to the electron donating ether group, as well as the small steric requirement of the sp-hybridized allenic carbon atom. The Z-D7 geometrical isomer of cyclopentenone 45 was formed (Z/E = 6/1). The Z selectivity that was observed in the case of 45 was shown to be the result of a kinetic preference, because exposure

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Scheme 9

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Key steps in the synthesis of (D,L)-D7-10-chloro-15-deoxy PGA1.

of 45 to trichloroacetic acid led to the complete isomerization to the more stable E isomer. The conrotation takes place in a way that moves the allene away from the bulk of the octenyl side chain. This effect can be exploited to control the absolute stereochemistry of the product, as will be discussed in what follows. Cyclopentenone 45 was converted in three steps to D7-10-chloro-15deoxy PGA1 46, an analogue of a marine prostanoid. The strong preference for the Z geometry of the exocyclic double bond in 45 suggested that a non-racemic allene would be able to transfer asymmetry to the cyclopentenone ring carbon atom. The study that is summarized in Scheme 10 shows that this is the case.23 Racemic allenes 47a and 47b were independently converted to carboxylic acids 48a and 48b. Morpholino amides 49a and 49b were prepared from the corresponding acids in 68% and 76% yield, respectively, for the two steps from 47. There is as yet no effective asymmetric synthesis of allene ethers, therefore racemates 49a and 49b were resolved by semi-preparative hplc on a Chiralcel OD column. This produced the enantiomeric allenyl amides. Allene (S)-50a (93% ee) was combined with vinylic lithium species 51 at 78 1C and the reaction was quenched after 30 minutes leading to a mixture of diastereomeric cyclopentenones 52a (50%, 78% ee, 84% chirality transfer) and 53a (9%, 64% ee). The major reaction product was formed according to the clockwise conrotation that has been shown for 54 (Scheme 10), which moves the n-butyl group away from the sp3-hybridized ring carbon atom. The minor reaction product results from the counter clockwise conrotation. The lower enantiomeric excess

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of the minor isomer is due to some Z to E isomerization of 52a that took place during the chromatographic separation of the two diastereomers, therefore this erosion of stereochemical integrity is not evidence of some competing mechanism. Morpholino enamide (R)-50b (98% ee) was exposed to nucleophile 51 under the same conditions as (S)-50a. This time Z cyclopentenone 52b was formed as the sole reaction product (64%, 95% ee, >95% chirality transfer). None of the E isomer was detected from this reaction. This is consistent with what one would expect of the much more sterically demanding tertbutyl group. The exclusive direction of the conrotation is away from the bulk of the ring in this case. Although the examples of Scheme 10 all nicely follow the predictions that were made on the basis of the conrotatory mechanism, there is some unanticipated mechanistic complexity. The Hoppe group developed a convenient method for the synthesis of axially chiral allenyl carbamate 55 (Scheme 11).24 Allene 55 (80% ee) was deprotonated at 78 1C to produce lithio allene 56 that was combined with morpholino enamide 57.25 This presumably led to the tetrahedral intermediate 58 that was stable at 78 1C. The solution of 58 was transferred via cannula to a solution of 5% HCl in ethanol, leading to loss of morpholine with collapse of the tetrahedral intermediate. The protonated allenyl vinyl ketone 59 was not isolated, as it underwent conrotation leading to cyclopentenone 60 as the sole product in 74% yield and 78% ee (98% chirality transfer). The tert-butyl group in 59 conrotates away from the ring carbon atom, exactly as expected on the basis of the result obtained


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Scheme 10

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Asymmetry transfer from the allene during cyclization.

Scheme 11 The asymmetric Nazarov cyclization of an allenyl carbamate.

from (R)-50b (Scheme 10). The surprising result was obtained when the reaction of Scheme 11 was repeated and the tetrahedral intermediate 58 was allowed to warm to room temperature


before quenching the reaction into acidic ethanol (Scheme 12). Under these conditions two diastereomeric 2-morpholino cyclopentenones were isolated, 62 (50%, 79% ee) and 63 (24%, 80% ee),

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Scheme 12 Carbamoyl group transfer during the Nazarov cyclization.

both with >98% chirality transfer. The two diastereomers have the opposite absolute stereochemistry at the benzylic carbon atom and also different geometries of the exocyclic double bond. The very efficient chirality transfer strongly suggests a concerted mechanism that converts each diastereomer of the tetrahedral intermediate 58 either to 62 or to 63. Because the absolute stereochemistry of the benzylic carbon atom differs in 62 and 63, the stereochemical course of this cyclization is determined not by the axial stereochemistry of the allene, but by the stereochemistry of the tetrahedral intermediate. The mechanism shown in Scheme 12 can be envisioned in which carbamoyl transfer takes place in 58 to give allenolate 61. The cyclization of 61 takes place through a conrotation, but with the added constraint that it must also be a SE0 substitution that maintains orbital overlap as the carbamoyloxy group is lost from 61. This process is general and provides an apt illustration of unanticipated complexity in some of the cyclization reactions of allenes.26

4 Asymmetric allene ether Nazarov cyclization – chiral auxiliaries Hoppe’s elegant asymmetric synthesis of axially chiral allenyl carbamates (see 55 in Scheme 11) enables one approach to the asymmetric version of the allene ether Nazarov cyclization: exploit asymmetry transfer from the allene to the ring carbon atom. There are two limitations of this strategy. The first is that the optical purity of the final product can be no greater than the optical purity of the allene, which in the case of 55 was 80% ee. The second limitation concerns the substituent on C3 of the allene. When it is tert-butyl, as was the case in 52b, 60, 62 and 63, very high (essentially complete) levels of chirality transfer can be anticipated. For groups that have a smaller steric requirement, such as the n-butyl group in 52a and 53a, more modest levels of asymmetry transfer are expected, thereby

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imposing a second constraint on the optical purity of the cyclopentenone product. One might consider addressing the limitations of the asymmetry transfer by developing a catalytic asymmetric process through the use of a chiral Lewis or Brønsted acid catalyst. The problem of such an approach is the very rapid background reaction, since allenyl vinyl ketones bearing an oxygen atom on the a allenic carbon atom undergo spontaneous cyclization. Although it might be possible to overcome this problem, to do so would surely be very challenging. An alternative approach to develop an asymmetric allene ether Nazarov cyclization is by means of a chiral auxiliary. Deploying a chiral auxiliary on the allene has an obvious advantage. Since the auxiliary is cleaved from the allene during the cyclization, it is traceless.27 One of the successful chiral auxiliaries that was developed for the allene ether Nazarov cyclization was based on camphor (Scheme 13).28 Lithioallene 64 was added to morpholino enamide 65 at 78 1C and the reaction was warmed to 30 1C over the course of an hour to ensure a complete reaction. The nucleophilicity of 64 is somewhat lower than that of 30 (Scheme 7), hence the higher reaction temperature. After one hour the reaction mixture was transferred to an acidic solution of 1,1,1,3,3,3-hexafluoro-2propanol (HFIP) and 2,2,2-trifluoroethanol (TFE) at 78 1C. Cyclopentenone 66 was isolated from the reaction mixture in 78% yield and 86% ee. The chiral auxiliary is lost from the product during the cyclization and is therefore traceless, requiring no additional step for its cleavage. Cleavage of the chiral auxiliary is facile because it involves the generation of 67 as a stable cation. In addition to stabilizing 67, the tetrahydropyranyl oxygen atom in 64 plays a second critical role in the cyclization, as will be discussed later (Scheme 17). The enantiomeric excess of 66 (86% ee, 93/7 er) is modest, but serviceable. Cyclopentenone 66 was converted to ansa diketone 68 in four steps. The racemate of 68 was highly crystalline, therefore after a single recrystallization of 68 (86% ee) followed by recovery of the mother liquor, product 68 that was essentially


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Scheme 13 Key steps in the asymmetric synthesis of roseophilin.

optically pure (99% ee) was obtained in 77% overall yield for the two steps leading to 68. It is worth remembering that a reaction need not proceed to >98/2 er in order to be synthetically useful. Optically pure roseophilin was formed from 68 in five steps. Lithioallene 64 (Scheme 14) can be applied to diverse asymmetric Nazarov cyclizations.29 With enamide 57 the yield of cyclopentenone 69 was 71% and 77% ee. Substitution at C3 of the allene renders it stereogenic and leads to a matched–mismatched issue. The stereochemistry shown for lithioallene 70 in which a methyl group has been introduced at C3 represents the matched case. The combination of 70 with enamide 57 as before leads to product 71 in 67% yield and slightly improved enantiomeric excess (79% ee). Z to E isomerization of the kinetic product took place during the

Scheme 14

isolation/purification process. The effect of the small methyl group on the torquoselectivity of the cyclization is, as expected, modest. The result of eqn (2) in Scheme 14 should be contrasted with the result of eqn (3) of Scheme 14 in which the allene bears a tert-butyl substituent. In this case cyclopentenone 73 was formed in 80% yield and 96% ee, reflecting the very large effect of the sterically demanding allene substituent on the torquoselectivity. In fact, the effect of the tert-butyl group completely overwhelms the influence of the camphor-derived chiral auxiliary on the absolute stereochemistry of the product. The highest levels of asymmetric induction in the case of the camphor-derived chiral auxiliaries were observed in the case of tert-butyl substitution on the allene. Although this result illuminates

The effect of allene substitution on the stereochemical outcome of the chiral auxiliary-controlled allene ether Nazarov cyclization.


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Scheme 15 Some pyranose-derived chiral auxiliaries for the allene ether Nazarov cyclization.

aspects of the mechanism of the allene ether version of the Nazarov cyclization, tert-butyl substitution is uncommon in cyclopentanoid natural products, therefore it would be useful to have access to improved chiral auxiliaries that do not require tert-butyl substitution on the allene for the highest levels of asymmetry transfer. Carbohydrates have served as starting materials for many chiral auxiliaries, including auxiliaries on alkoxy allenes.27 The first chiral auxiliaries that were developed for the allene ether version of the Nazarov cyclization were, in fact, derived from pyranoses (Scheme 15).30 The chiral auxiliary that appears in lithioallene 74 was combined with 65 in THF in the presence of several equivalents of lithium chloride. The reaction mixture was quenched into HCl in ethanol to provide cyclopentenone 66 in 67% yield and 67% ee. Sugars, however, have a liability as chiral auxiliaries. Although many D-sugars are commercially available and cheap, the L-sugar enantiomers are available only at great cost, if at all. Consequently, a problem when using sugar-derived chiral auxiliaries may be that one enantiomer of product is available whereas the other is not. This might have been expected in the case of 74, because the chiral auxiliary is derived from cheap D-glucose, whereas L-glucose is, for practical purposes, unavailable. In fact both enantiomers of 66 are available from D-glucose-derived chiral auxiliaries as eqn (5) and (6) show (Scheme 15). Lithioallene 75 differs from 74 only in the stereochemistry of the anomeric carbon atom: 74 is derived from permethylated a-D-glucose, whereas 75 was

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derived from b-D-glucose. Allenes 74 and 75 lead to enantiomeric products. The optical purity of ent-66 (from 75) is significantly higher than for 66 that was derived from a-anomer 74. The examples of eqn (5) and (6) represent an unusual case in which two chiral auxiliaries derived from the same optical isomer of a natural product give rise to enantiomeric products. The results of eqn (5) and (6) point to the importance of the anomeric stereochemistry for controlling the torquoselectivity of the Nazarov cyclization but do not illuminate the reason(s) for the effect. It is reasonable to expect the two substituents that are closest to the allene, those at C2 and C5, to exert the dominant effects on the stereochemical outcome. A number of pyranose-derived chiral auxiliaries were prepared in order to test this hypothesis, starting with 76. One can imagine ‘‘deleting’’ the C2 methoxy substituent from 74 to form lithioallene 76 (eqn (7)). The reaction of 76 with 65 led to 66 in 61% yield and 61% ee. Although the optical purity of 66 that was prepared from 76 was somewhat lower compared to 66 that was prepared from 74 (61% vs. 67% ee) this result makes it clear that the C2 methoxy group does not play a critical role in controlling the torquoselectivity. The chiral auxiliary in 77 (eqn (8)) is permethylated 6-deoxyL-glucose that was prepared from commercially available di-Oacetyl L-rhamnal, therefore lithioallenes 75 and 77 are pseudo enantiomers. The combination of 77 with 65 led to 66 in 48% yield and 81% ee, demonstrating that the C5 substituent in 75


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also plays essentially no role in controlling the torquoselectivity. The somewhat puzzling conclusion from these two experiments is that neither the C2 nor the C6 methoxy groups has much of an effect on the optical purity of the product. The absolute stereochemistry of the product appears to be solely under the control of the anomeric carbon atom of the chiral auxiliary. This suggests that the pyran ring oxygen atom may be involved in the stereochemistry-determining transition state. A hint regarding the mechanism for the transmission of stereochemical information from the chiral auxiliary can be gleaned from a comparison of the results that were obtained from lithioallenes 64, 74 and from 78, which differs from 76 only in having tert-butyldimethylsilyl (TBS) ethers in place of methyl ethers (Table 1).31 As can be seen from the results that are summarized in Table 1, lithioallene 78 leads to products with greatly improved optical purity compared to the other two allenes. For example, cyclopentenone 69 was formed in 67% ee from camphor-derived lithioallene 64, in 77% ee from D-glucosederived 74 and in 86% ee from 78. In every case 78 proved to be the superior reactant by far. Lithioallene 78 was evaluated in a challenging application, the enantioselective generation of an all-carbon atom quaternary centre. The results of Scheme 16 show that useful levels of asymmetric induction can be observed for the reactions of 78 with each of the two geometrical isomers, 82 and 84, of a fully substituted morpholino enamide. The reaction of 78 with E-enamide 82 (eqn (9)) led to cyclopentenone 83 in 64% yield

Table 1

and 69% ee. The product from Z-enamide 84 was ent-83 that was isolated in 42% yield and 77% ee (eqn (10)). These results indicate that Z to E isomerization of 84 or of its adduct with 78 is insignificant and also that enantiomeric products can be prepared from the same chiral auxiliary by simply changing the geometry of the alkene starting material. The lower yield of ent-83 probably is due to the higher barrier of forming the reactive U-shaped conformer of the pentadienyl cation in which a large phenyl group occupies the inside position. The structural features of 78 that render it exceptionally effective in its role are not obvious from these results, however, in order for the pyranose chiral auxiliaries to exert their effect on the torquoselectivity of the Nazarov cyclization, three conditions must be met. First, the chiral auxiliary must be close to the ring bond as it is being formed. Second, there must be some mechanism that allows close approach of the pyran substituents that are all equatorial in 78 and pointing away from the ring that is being formed. Third, the ring-forming bond must be substantially formed before cleavage of the anomeric C–O bond (bold in 85, Scheme 17) has taken place.32 These hypotheses are illustrated in Scheme 17. Quenching the reaction of 78 with enamide 57 with acid is presumed to lead initially to tetrahedral ammonium ion 85 that collapses to 86 with loss of morpholine. As 86 approaches transition state 87, ring inversion of the pyran ring takes place so as to position all three substituents at C3, C4 and C5 axially.33 At the same time the pyran ring oxygen atom interacts with the developing pentadienyl carbocation through one of its

A comparison of three chiral auxiliaries for the allene ether Nazarov cyclization

58% yield 67% ee

69% yield 63% ee


71% yield 77% ee

84% yield 86% ee

53% yield 78% ee

78% yield 93% ee

69% yield 74% ee

66% yield 90% ee

62% yield 69% ee

75% yield 91% ee

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Scheme 16

All-carbon atom quaternary centre from the asymmetric allene ether Nazarov cyclization.

non-bonding electron pairs. This interaction is essential, for without it the chiral auxiliary would be too far to exert any influence on the reaction. Because of this interaction, the axial OTBS group at C4 is ideally positioned to block inward conrotation, and leads to the (R) enantiomer of 69 with loss of 88 as shown in Scheme 17. The larger size of the OTBS relative to OMe is the reason 78 is a far more effective reactant than 76. This raises the question of why 76, or any of the other permethylated pyranoses should exert a large influence on the conrotation. Relief of steric compression between C3 and C4 substituents is not a significant driving force for chair-tochair ring inversion in the ground state of these compounds. A convincing resolution of the conundrum was provided by Woerpel’s studies of pyrylium ion alkylations that show that C4 ether substituents, but not alkyls, have an axial preference in the ion.34 This is the result of electron pair donation from the ether oxygen atom to the positively charged ring carbon atom of the pyrylium ion that can take place when the OTBS group is (pseudo) axial (see 83 in Scheme 17), but that is prevented from occurring when the OTBS is equatorial. To determine whether this unusual conformational behaviour contributes to the greater effectiveness of 78 in the Nazarov cyclization, a series of pyranose-derived chiral auxiliaries was prepared and evaluated through their respective reactions with enamide 57.35

Scheme 17

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Table 2 summarizes some of the results that have been obtained with various pyranose-derived chiral auxiliaries. The yields and enantiomeric ratios that are recorded in Table 2 refer to the reaction with enamide 57 leading to (R)-69 and (S)-69. If the C4 silyloxy group is largely responsible for the reaction outcome and the C3 group is far from the developing stereogenic ring carbon atom, as shown in 87 (Scheme 17), then it follows that removing the C3 substituent will have little effect on the reaction outcome. This is what was observed in the case of lithioallene 90 that retains only the C4 and C5 substituents, yet leads to cyclic product in 89% yield and 94/6 er, which is within experimental error the same result that was observed with 78. To demonstrate the critical role of the pyranyl ring oxygen atom, cyclohexyl compound 91 was evaluated. Lithioallenes 90 and 91 differ only with regard to the presence or absence of the ring oxygen atom, yet 91 does not function at all well in the reaction, both with respect to the yield as well as the transmission of asymmetry. The yield of nearly racemic 69 from 91 was below 30% in a complex reaction mixture. The reason for the low yield is related to the termination event, the loss of the chiral auxiliary as a cation from the cyclic intermediate. Loss of a stabilized cation (e.g. 67 in Scheme 13 and 88 in Scheme 17) takes place rapidly, thereby preventing any competing reactions of the cyclic cation

The mechanistic hypothesis for transfer of asymmetry from the chiral auxiliary.

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Table 2

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Examples of pyranose-derived chiral auxiliaries for the allene ether Nazarov cyclization leading to (R)- or to (S)-69

that could have eroded the yield from taking place. Loss of the cyclohexyl cation in the case of 91 is not a rapid process. The reason for the very low asymmetric induction is because the transition state has many degrees of freedom, and in the absence of the pyran ring oxygen atom transmission of stereochemical information from the chiral auxiliary does not take place effectively.36 The C4 substituent is not only necessary but it must also be equatorial in order for it to play the desired role after chair-tochair inversion during the stereochemistry-determining step. Therefore it is no surprise that lithioallene 92, in which there is no C4 substituent, and lithioallene 93, in which the C4 OTBS group is axial, are both inferior to 90. Both lead to cyclic product (R)-69 in 86.5/13.5 er. Since good asymmetric induction depends on the presence of a large (larger than methoxy) group to block one face of the acyclic pentadienyl cation so as to bias the direction of conrotation, it should be possible to do this without the need for chair-to-chair conformational change. Lithioallene 94 demonstrates this concept by locking the conformation of the pyran chair and by placing an axial OTBS group at C3. Because the pyran ring cannot invert, the group at C3 is expected to block the face of the pentadienyl cation so as to bias the sense of conrotation. In fact 94 was an excellent reactant, leading to 69 in 97/3 er. Up to this point, the discussion has focused exclusively on the a-anomeric series. The situation is a bit different with the b-anomers. For example, in the case of lithioallene 95 one would have predicted that pyran ring inversion in the stereochemistrydetermining transition state (viz. 87, Scheme 17) would have placed the C3 and C6 substituents in the axial orientation,


ideally for control of torquoselectivity. This does not seem to be the case since the enantiomeric ratio of product from 95 was only 11/89. On the other hand, lithioallene 96, which has an axial C4 OTBS group, was an outstanding reactant, leading to cyclic product in 92% yield and 3.5/96.5 er. Consideration of these two results suggests that the b-anomers are unlike the a-anomers and that conformational inversion does not take place in the stereochemistry-determining transition state in the b-series. This begs the question of why this should be the case. It may be that in the absence of the destabilizing effects of a large axial anomeric substituent, pyran ring inversion is suppressed. Table 3 summarizes some of the published results that have been obtained with the two best lithioallenes 94 and 96. The synthesis of 83 from 96 in 78% yield and 5/95 er is noteworthy, and is a much better result than the reaction of 78 (Scheme 16). Cyclopentenone 98 was the key intermediate for the synthesis of terpestacin, an anti-angiogenic fungal secondary metabolite.37 Unlike the other cyclopentenones of Table 3, 98 was prepared from the addition of 94 or 96 to an unsaturated butyrolactone, a reaction that will be described in what follows. Applications of the allene ether Nazarov cyclization The key steps of the synthesis of (D,L)-terpestacin are shown in Scheme 18.38 Combining lactone 99 with lithioallene 30 in THF at 78 1C, followed by quenching with strong acid led to cyclopentenone 98 in 65% yield. The asymmetric synthesis of 98 from lithioallene 94 that has been discussed in the context of Table 3 constitutes a formal asymmetric total synthesis of terpestacin. The two free hydroxyl groups in 98 can be protected as acetonide 100 and the exocyclic double bond selectively reduced to provide enone 101 in 91% overall yield for the two

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Table 3

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The results from the best two chiral auxiliaries

1

59% yield 95/5 er

57% yield 4/96 er

2

90% yield 97/3 er

93% yield 7/93 er

3

57% yield 93/7 er

83% yield 9/91 er

4

54% yield 89/11 er

78% yield 5/95 er

steps from 98. Exposure of 101 to strong base led to the a-enolate that was trapped selectively with a primary allylic bromide to give intermediate 102 in 75% yield. This compound was converted to (D,L)-terpestacin through a series of transformations that included Horner–Emmons macrocyclization and 100% stereoselective reduction of a C11 keto group. The C23 methyl group was introduced via the extended enolate. A noteworthy feature of the synthesis is that the stereochemistry at C1, C11 and C23 was controlled by the C15 stereochemistry. The synthesis was accomplished in 15 steps and 6.4% overall yield. One reason for the high efficiency is the optimal array of oxygenated functionality that is produced during the allene ether Nazarov cyclization that matches the natural product. The application of the allene ether Nazarov cyclization to the enantiodivergent synthesis of madindolines A and B is summarized in Scheme 19.39 Madindolines A and B were isolated from a Streptomyces species and are selective inhibitors of interleukin-6.40 The synthesis commences with the addition of lithioallene 30 to vinylogous silyl ester 103 to give tertiary alcohol 104. The Nazarov cyclization of 104 took place under very mild conditions at 20 1C, leading to cyclopentenone 105 in 88% yield for the two steps from 103. The ease of this cyclization is due to the complementary polarization of the pentadienyl cation that is formed. The asymmetric version of this type of Nazarov cyclization has not been studied. Selective saturation of the exocyclic double bond took place quantitatively, leading to enone 106. The kinetic enolate of 106 was

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trapped with triethylsilyl chloride, leading to cyclopentadiene 107. This material was thermally stable at room temperature and no products from [1,5] hydrogen shifts were observed. Racemic cyclopentadiene 107 was allowed to react with nonracemic hydroxyfuroindoline fragment 108 that had been prepared from tryptophol.41 The Lewis acid catalyzed Mannich reaction of the silyl enol ether led to a 1/1 mixture of optically active diastereomers 109 and 110 in which addition of the electrophile had taken place cis to the silyloxy group. Although the relative stereochemistry in 109 and 110 is of no consequence for madindoline synthesis, its counterintuitive course deserves some comment. It was postulated that electrostatic attractions between the positively charged iminium ion derived from 108 and the non-bonding electron pairs of the oxygen atom of the silyloxy group could have directed the cis addition. Fluorodesilylation of the TES and TIPS groups followed by oxidation with pyridinium dichromate (PDC) led from 109 to madindoline A and from 110 to madindoline B. The yield of the two natural products was 30% overall for the four steps from 106. More highly substituted allene ethers Up to this point most of the discussion has focused on unsubstituted (e.g. 30, 64) or at most monosubstituted lithioallenes (e.g. 56, 70, 72). The question arose of whether more highly substituted allene ethers could be prepared in good yield and whether they would participate in the allene ether Nazarov cyclization. As indicated earlier in this Review in the context of


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Scheme 18

Key steps in the synthesis of (D,L)-terpestacin.

Scheme 19

Enantiodivergent synthesis of madindolines A and B.


Review Article

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Scheme 6, the base-induced isomerization of ethers derived from 2-alkynyl-1-ols leads to mixtures of allene and alkyne that are always very difficult to separate. Furthermore, the isomerization approach precludes the synthesis of C3 disubstituted alkoxy allenes. One way to successfully overcome the difficulty of preparing the fully substituted alkoxy allenes is shown in Scheme 20.42 Propargyl alcohols 111a (R = n-C6H13) and 111b (R = c-C6H11) were converted to the respective OTBS ethers and subsequently deprotonated with n-butyllithium. This follows a method developed by Ohfune43 and leads to 112a (98%) or 112b (83%) through a reverse Brook rearrangement. Protection of the secondary alcohol group in 112 led to methoxymethyl ethers 113a (92%) and 113b (74%). Deprotonation of the propargylic proton in 113 took place with secbutyllithium in THF at 78 1C. Subsequent alkylation with methyl iodide led to allene 114a (96%) or 114b (86%). Cleavage of the TBS group from 114 was accomplished using one equivalent of TBAF and one equivalent of lithium hydroxide at room temperature, furnishing allenes 115a (82%) or 115b (87%). In the absence of lithium hydroxide the desilylation was extremely slow even in the presence of a large excess of TBAF, whereas under the optimized conditions the reaction was complete within 2 hours. The anions derived from the deprotonation of 113a or 113b could be trapped in good yield with a variety of electrophiles including ketones, Weinreb amides and silyl chlorides. Allenes 115 were used successfully in the Nazarov cyclization as shown in Scheme 21. Deprotonation of 115 with n-butyllithium at 78 1C led to lithioallenes 116a or 116b that were combined with enamide 57 (eqn (11)). Transferring the reaction mixture to anhydrous ferric chloride in dichloromethane at room temperature produced cyclopentenones 117a (72%) or 117b (58%) both as mixtures of E and Z isomers. The conventional conditions for inducing the cyclization, HCl in ethanol, led to hydrolysis of the allene ether that was used in modest excess. Because the hydrolysis products interfered with the purification of 117, the milder conditions were developed. This result highlights the fact that there is considerable latitude for the choice of reaction conditions for the acid catalyzed cyclization.

Scheme 20

Chem Soc Rev

Eqn (12) in Scheme 21 shows that the same protocols that were successful for enamides can also be applied successfully in the case of enone 118 that was converted to cyclopentenones 120a (69%) or 120b (64%). Unless there is a large difference in size between the two substituents at C3 of the allene, these cyclizations can be expected to lead to mixtures of geometrical isomers at the exocyclic double bond, thereby limiting their utility in synthesis. Allenes with a single C3 substituent do not suffer from this liability; however, their synthesis according to the method outlined in Scheme 20, by quenching the anions derived from 113 with ethanol, requires a large number of steps. A more attractive approach to the synthesis of C3 substituted allene ethers would have been through 1,3-dianion 121 (Scheme 22). By exploiting the acidity of the C3 allene ether protons, deprotonation of 30 might have led to dianion 121 that was expected to react with electrophiles with C3 selectivity. Although 1,3-dilithioallenes have been described, in all cases the negatively charged carbon atom was stabilized by a heteroatomic substituent or by a phenyl,44 and 121 could not be formed. Instead, an indirect approach to the problem was developed.45 The tetrahedral intermediate 122 (Scheme 22) that was formed from the addition of 30 to enamide 57 is an alkoxide rather than a lithioallene, suggesting that deprotonation at the indicated site might be possible. Exposure of 122 to a small excess of sec-butyllithium for 20 minutes at 78 1C presumably led to O,C-dianion 123 that was trapped with iodomethane before the reaction mixture was quenched into aqueous HCl. The cyclic product rac-71 was isolated in 75% overall yield from 57. Only the E product was isolated, indicating that the kinetic Z product had undergone isomerization under the influence of strong acid. This result demonstrates a much easier alternative to the preparation of 1,3-disubstituted alkoxyallenes. O,C-Dianion 123 was trapped with trimethylsilyl chloride (56%), 3-pentanone (50%), butyl iodide (54%) and allyl bromide (57%), and in each case cyclization was successful. When trimethylsilyl chloride was the electrophile, cyclization was catalyzed by potassium dihydrogen phosphate so as to avoid the protiodesilylation that would have taken place had HCl been used. In all these reactions the

Synthesis of trisubstituted allene ethers.

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Scheme 21 The use of trisubstituted allene ethers in the Nazarov cyclization.

Scheme 22

The triply convergent addition-alkylation–cyclization reaction.

quality of the sec-butyllithium was critical. Older bottles of the reagent inevitably led to lower product yields. Since this was not due to any uncertainty regarding the titer, it may be due to a solvent effect. Aged solutions of alkyllithiums are also likely to be contaminated with hydroperoxides from oxygen in air that could consume 123 once formed. The allene ether Nazarov cyclization that is illustrated in Scheme 22 is triply convergent, as it combines allene, enamide and electrophile. As shown in Scheme 23, the method is also successful in the case of enones. Addition of 30 to enone 118, followed by allene deprotonation and electrophilic trapping with Mander’s reagent led to tertiary alcohol 125. Cyclization


was induced with anhydrous ferric chloride to give cyclopentenone 126 in 55% overall yield from 118. This result demonstrates that compounds like 126 that cannot be prepared directly because of the incompatibility of the carboethoxy group with the lithioallene are easily accessible through the triply convergent method.46 Isomerization–cyclization The triply convergent approach that has been discussed above represents a significant saving of effort. Even greater savings of effort can be had by dispensing with the allene altogether. For example, propargyl ether 127 is easily converted to 1,3-dianion

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128 by exposure to a modest excess of sec-butyllithium (Scheme 24).47 The dianion was trapped selectively at the more reactive C1 position with enamide 57 to give tetrahedral intermediate 129 that was subsequently intercepted at the sp-hybridized carbon atom with allyl bromide to give ketone 130 following aqueous workup. This material was loaded onto a silica gel chromatography column that was eluted 12 hours later. Allowing ample contact time for the propargyl ketone 130 with the silica gel enables isomerization to the allenyl ketone to take place. The allenyl vinyl ketones that are substituted with an ether group on the a-allenic carbon atom undergo spontaneous Nazarov cyclization, so cyclopentenone 131 was isolated in 46% overall yield from 57. When dianion 129 was quenched with water during workup and the product exposed to silica gel column chromatography, rac-69 (see Scheme 14) was formed in 65% yield. Alternatively, a substituted propargyl ether can be used in place of 127, leading to cyclopentenones bearing substitution on the exocyclic methylene. The alkoxy allenes are formed as transient intermediates in these processes. Interrupted Nazarov The isomerization of propargyl ketone 130 (Scheme 24) to the reactive allenyl ketone must have been catalyzed by silica gel. Surprisingly, in the absence of solvent (ethyl acetate/hexanes) no reaction took place on silica gel. However, if 1.2 equiv. of

Chem Soc Rev

triethylamine was added to silica gel and the propargyl ketone 132 and the dry mixture was stirred vigorously for 3 hours at room temperature, a complete reaction leading to cyclopentenone 133 took place in 63% yield (Scheme 25, eqn (13)).48 This process can be understood as follows: the added tertiary amine base assisted the initial isomerization of the propargyl ketone, leading to the reactive allenyl ketone that underwent Nazarov cyclization. Silica gel was the acid catalyst for cyclization. The termination event was proton abstraction by the amine from the methyl group of cyclic cation 134 leading to the exocyclic methylene group in 133 (box in Scheme 25). In this regard, the reaction differs from all other examples discussed up to this point, in which the termination process involved loss of a stable alkoxyalkyl carbocation. Because loss of methyl cation from the methoxy group in 134 would have required very high activation energy, the reaction was terminated by rapid proton loss instead. Cations like 134 could be trapped by primary or even secondary amines in a process known as an interrupted Nazarov cyclization. West and others have published numerous insightful papers on a large variety of interrupted Nazarov cyclizations involving a variety of intercepting nucleophiles.4 In the present example there could be some concern that proton loss would always outcompete any C–N bond forming process; however, this proved not to be the case. Exposure of 135 (Scheme 25, eqn (14)) to dry silica gel and 1.2 equiv.

Scheme 23

The triply convergent approach leads to products that cannot be prepared by other means.

Scheme 24

The isomerization-cyclization method.

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Scheme 25

The interrupted Nazarov cyclization with amines.

benzylamine for 3 hours at room temperature led to a-aminocyclopentenone 136 in 75% yield along with 4% of cross conjugated dienone 137, the product resulting from proton loss. The reaction was even successful in the case of secondary amines as the example of 138 demonstrates (Scheme 25, eqn (15)). The intermediate cation in this case was intercepted by morpholine leading to aminocyclopentenone 139 in 66% yield. These reactions are noteworthy because they result in the formation of a quaternary centre in good yield. It is very surprising that the highly reactive cyclic cation (see 134) can be intercepted so efficiently in the absence of any solvent when only 1.2 equiv. amine was used and when there are other reaction pathways available. It may be the case that because the amine catalyses the isomerization that leads to the allenyl ketone, it is in close proximity to it when it is formed. It is possible to interrupt this Nazarov cyclization with highly basic amines only because the allenyl ketones are able to undergo cyclization using the weakest of Brønsted acids, silica gel.

Scheme 26

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The question of whether carbon nucleophiles can be used to interrupt this Nazarov cyclization is answered in Scheme 26. The conditions that had been developed for preparing the aminocyclopentenones were not optimal for the interrupted Nazarov cyclization with indoles.49 The appearance of byproducts suggested that a more rapid process for isomerization to the allenyl ketones would be beneficial. The addition of propargyl anion 141 to enamide 140 led to 138 that was converted to trimethylsilyl enol ether 142 as a single geometrical isomer. Exposure of a solution of 142 and 1.25 equiv. of 5-methoxyindole 143 in dichloromethane at room temperature to 0.2 equiv. scandium triflate led to 144 in 72% overall yield for the three steps from 140. The reaction is reasonably general, subject to the constraint that the indole must bear no substituent larger than methyl at C2. Asymmetric amine-interrupted Nazarov cyclization Because of the difficulty in controlling the very fast background reaction referred to earlier in this Review that converts allenyl

The interrupted Nazarov cyclization with 5-methoxyindole.


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vinyl ketones to cyclopentenones, the best approach for an asymmetric interrupted Nazarov cyclization would be to make use of a chiral auxiliary. The camphor-derived chiral auxiliary that was introduced in Scheme 13 was utilized for the asymmetric interrupted Nazarov. Propargyllithium species 145 (Scheme 27) was allowed to react with enamide 57 to produce propargyl ketone 146 in 86% yield.50 Agitating a mixture of 146 and 10 equiv. 2-phenethylamine adsorbed on Florisil for 45 minutes at room temperature in the absence of solvent led to the isolation of aminocyclopentenone 147 in 67% yield as a single optically active diastereomer. The individual steps that convert 146 to 147 presumably closely follow what was discussed in the context of Scheme 25. The means by which the chiral auxiliary controls the absolute sense of conrotation was not explained. In contrast with the results of Schemes 13–16 and Tables 1 and 3, the chiral auxiliary in 146 controls the formation of two asymmetric carbon atoms rather than one. The mildness of the reaction conditions is evidenced by the good yield for the formation of 148 in which no hydrolysis of the dimethyl acetal was detected. The reaction can also be performed intramolecularly (Scheme 28). Addition of a small excess of 145 to enamide 149 led to propargyl ketone 150. Agitating 150 on Florisil with 10 equiv. triethylamine in the absence of solvent led to tricyclic

Chem Soc Rev

enone 151 in 50% overall yield from 149. The relative stereochemistry of cyclopentenone 151 differs from that of 147 and 148 because of the constraints on the direction of attack of the aniline nitrogen atom on the cyclic cation. Imino and aza-Nazarov cyclizations Although the Nazarov cyclization of an iminium ion instead of an oxonium ion offers attractive possibilities for asymmetric catalysis, such a process is rendered difficult because of unfavourable energetics for the cyclization step. Computational work by Smith has indicated that the acyclic iminium ion is considerably more stable than the cyclic 2-aminoallyl cation to which it would be converted.51 The problem can be overcome by raising the energy of the acyclic starting material. One way to do this is to incorporate an allene, or allene ether into the acyclic precursor.52 Release of the strain of the allene (ca. 10–11 kcal mol1) then favours the cyclic product. The addition of lithioallene 153 to nitrile 152 led to lithioimine 154 (Scheme 29). Exposure of this material to ammonium dihydrogen phosphate during workup led to the anticipated Nazarov product via the protonated imine. For ease of isolation the reaction product was converted to acetamide 155 that was isolated in 92% overall yield from 152 as a 4/1 mixture of E and Z isomers of the exocyclic double

Scheme 27

The asymmetric interrupted Nazarov with amines.

Scheme 28

The intramolecular asymmetric interrupted Nazarov with an aniline.

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Scheme 29

The imino Nazarov cyclization.

bond. This reaction apparently represents the first imino Nazarov cyclization.53 An alternative strategy to overcome the unfavourable energetics of the imino Nazarov cyclization is shown in Scheme 30. Although the starting materials are allenes, it is likely that the allene function is lost before the five membered ring is formed. Exposure of allenamide 156 to 5 mol% of a cationic Au(I) salt at room temperature in dichloromethane led to the formation of aminoindene 157 in 94% yield.54 The reaction presumably proceeds through intermediate cation 158 that undergoes 4p electrocyclization. Protiodeauration regenerates the catalyst. This imino Nazarov cyclization is successful because iminium ion 158 is destabilized by the tosyl substituent.55 Substituting one of the carbon atoms of the pentadienyl cation for a nitrogen atom leads to the substrate of an azaNazarov cyclization, a process that has not been extensively

Scheme 30

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explored. A reaction that has been reported by Brandsma that may represent the aza-Nazarov cyclization of an alkoxyallene is summarized in Scheme 31.56 Addition of methoxyallenyllithium 159 to methyl isothiocyanate was followed by trapping of the intermediate thiolate with iodomethane to give 161. Dropwise addition of 161 to paraffin oil heated to 260 1C led to a mixture of pyrrole 162 (54%) and dihydropyridine 163 (23%). The dihydropyridine presumably arises from a [1,5]-hydrogen shift of 161 followed by 6p electrocyclization. Alternatively, loss of a proton from the N-methyl group of 164 followed by electrocyclization would also lead to 163. The formation of pyrrole 162 is intriguing. Brandsma and co-workers stated that they were unable to elucidate the reaction mechanism for the formation of 162, but speculated that protonation of the enol ether in 161 had led to pentadienyl cation 164 which then underwent cyclization. If this postulated mechanism is correct, the ring closure can be

Gold(I) catalyzed allenamide Nazarov cyclization.

Scheme 31 A cyclization that may be an aza-Nazarov.


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Scheme 32

Chem Soc Rev

Butatrienyl ether Nazarov cyclization.

interpreted as an aza-Nazarov process. The cyclization was also catalyzed by cuprous bromide but not by nickel of palladium salts. Reissig has disclosed a closely related silver catalyzed cyclization.57 Cyclization of cumulenyl ketones The factors that render the allene ether Nazarov cyclization a favourable process are also present in the higher cumulenyl ethers. Consequently it is unsurprising that Nazarov cyclizations of 1,2,3-butatrienyl ethers have also been described. Whereas allene ethers are generally quite stable and can be isolated and stored, the same cannot be said about butatrienyl ethers that are more susceptible to air oxidation. Fortunately, the ethers need not be isolated, for they can be prepared according to Brandsma’s protocol and trapped in situ.58 Propargyl ether 165 (Scheme 32) was treated with a little more than 2 equiv. n-butyllithium at 40 1C in degassed THF.59 The first equivalent of base deprotonates 165 a to the methoxymethyl group, generating a propargyllithium that rearranges to eliminate trimethylsilyloxide. This generates the butatrienyl ether that undergoes deprotonation directed by the methoxymethyl group, leading to 166. The butatrienyl anion 166 is combined with enamide 57 at 78 1C, warmed to 40 1C so as to allow the addition reaction to proceed to completion and then quenched with aqueous potassium dihydrogen phosphate to give a-allenyl cyclopentenone 167 in 74% yield from 57. Because the allene is stereogenic, 167 was isolated as a 4/1 mixture of diastereomers. This version of the Nazarov cyclization is general and can be applied to the synthesis of fully substituted allenic products such as 168 (Scheme 32).

5 Summary and conclusions This Review has attempted to summarize what is known about Nazarov cyclizations of acyclic alkoxyallenes. There is considerable mechanistic diversity within this broad class, so an attempt to present the material according to mechanistic type has been made. These reactions are facile because of the combination of the strain energy of the allene and the favourable polarization of the acyclic precursor. The synthetic versatility of this family of reactions has

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been highlighted with some examples of applications to natural products total synthesis.

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11, 1229; (d) V. M. Marx, R. L. Stoddard, G. S. HeverlyCoulson and J. D. Burnell, Chem.–Eur. J., 2011, 17, 8098. H. Hu, D. Smith, R. E. Cramer and M. A. Tius, J. Am. Chem. Soc., 1999, 121, 9895. ¨hlich and C. Schultz-Fademrecht, B. Wibbeling, R. Fro D. Hoppe, Org. Lett., 2001, 3, 1221. C. Schultz-Fademrecht, M. A. Tius, S. Grimme, B. Wibbeling and D. Hoppe, Angew. Chem., Int. Ed., 2002, 41, 1532. Hoppe and co-workers have demonstrated a similar reaction from the addition of carbamoyloxy allenes with ketones. M. Zimmermann, B. Wibbeling and D. Hoppe, Synthesis, 2004, 765. A number of applications of such species to diverse reactions have been reported: (a) S. Kaden, M. Brockmann and H.-U. Reissig, Helv. Chim. Acta, 2005, 88, 1826; (b) S. Cai, B. K. Gorityala, J. Ma, M. L. Leow and X.-W. Liu, Org. Lett., 2011, 13, 1072; (c) A. Hausherr, B. Orschel, S. Scherer and H.-U. Reissig, Synthesis, 2001, 1377. P. E. Harrington and M. A. Tius, J. Am. Chem. Soc., 2001, 123, 8509. P. E. Harrington, T. Murai, C. Chu and M. A. Tius, J. Am. Chem. Soc., 2002, 124, 10091. P. E. Harrington and M. A. Tius, Org. Lett., 2000, 2, 2447. D. B. delos Santos, A. R. Banaag and M. A. Tius, Org. Lett., 2006, 8, 2579. A. R. Banaag and M. A. Tius, J. Org. Chem., 2008, 73, 8133. The release of steric compression caused by two adjacent OTBS groups at C3 and C4 is a well known effect: (a) M. A. Tius and J. Busch-Petersen, Tetrahedron Lett., 1994, 35, 5181; (b) T. Hosoya, Y. Ohashi, T. Matsumoto and K. Suzuki, Tetrahedron Lett., 1996, 37, 663; (c) C. H. Marzabadi, J. E. Anderson, J. Gonzalez-Outeirino, P. R. J. Gaffney, C. G. H. White, D. A. Tocher and L. J. Todaro, J. Am. Chem. Soc., 2003, 125, 15163. See also: W. R. Roush, D. P. Sebesta and C. E. Bennett, Tetrahedron, 1997, 53, 8825. (a) L. Ayala, C. G. Lucero, J. A. C. Romero, S. A. Tabacco and K. A. Woerpel, J. Am. Chem. Soc., 2003, 125, 15521; (b) S. R. Shenoy and K. A. Woerpel, Org. Lett., 2005, 7, 1157; (c) C. G. Lucero and K. A. Woerpel, J. Org. Chem., 2006, 71, 2641. See also: R. J. Woods, C. W. Andrews and J. P. Bowen, J. Am. Chem. Soc., 1992, 114, 859. A. R. Banaag and M. A. Tius, J. Am. Chem. Soc., 2007, 129, 5328. Lithioallene 91 was used as a 88/12 mixture of enantiomers, hence asymmetry transfer was approximately 11%. (a) S. Iimura, M. Oka, Y. Narita, M. Konishi, H. Kakisawa, Q. Gao and T. Oki, Tetrahedron Lett., 1993, 34, 493; (b) M. Oka, S. Iimura, O. Tenmyo, Y. Sawada, M. Sugawara, N. Ohkusa, H. Yamamoto, K. Kawano, S.-L. Hu, Y. Fukagawa and T. Oki, J. Antibiot., 1993, 46, 367; (c) M. Oka, S. Iimura, Y. Narita, T. Furumai, M. Konishi, T. Oki, Q. Gao and H. Kakisawa, J. Org. Chem., 1993, 58, 1875. (a) G. O. Berger and M. A. Tius, J. Org. Chem., 2007, 72, 6473; (b) G. O. Berger and M. A. Tius, Org. Lett., 2005, 7, 5011.

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Nazarov-like cyclization reactions.

Enantioselective palladium(0)-catalyzed Nazarov-type cyclization.

Template-induced diverse metal-organic materials as catalysts for the tandem acylation-Nazarov cyclization.

Origins of large rate enhancements in the Nazarov cyclization catalyzed by supramolecular encapsulation.

An efficient synthesis of pyrido[1,2-a]indoles through aza-Nazarov type cyclization.

Catalytic enantioselective Nazarov cyclization: construction of vicinal all-carbon-atom quaternary stereocenters.

Catalysis and chemodivergence in the interrupted, formal homo-Nazarov cyclization using allylsilanes.

Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates.

Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s.

Convergent access to polycyclic cyclopentanoids from α,β-unsaturated acid chlorides and alkynes through a reductive coupling, nazarov cyclization sequence.

The first calcium-catalysed Nazarov cyclisation.

The photo-Nazarov reaction: scope and application.

The role of methoxy group in the Nazarov cyclization of 1,5-bis-(2-methoxyphenyl)-1,4-pentadien-3-one in the gas phase and condensed phase.

Formation of ketols from linolenic acid 13-hydroperoxide via allene oxide. Evidence for two distinct mechanisms of allene oxide hydrolysis.

Pd-catalyzed cross-coupling.

Pd-catalyzed cascade cyclization by intramolecular Heck insertion of an allene-allylic amination sequence: application to the synthesis of 3,4-fused tricyclic indoles.

Torquoselectivity in the Nazarov reactions of allenyl vinyl ketones.

Fluorinated Amine Stereotriads via Allene Amination.

yne-allene substrates: reactivity and theoretical mechanistic studies.

Stereoselective Electrophilic Cyclization.

Pyrrolysine-inspired protein cyclization.

Preparation of alkyl ether and vinyl ether substrates for phospholipases.

Gold-catalyzed intermolecular synthesis of alkylidenecyclopropanes through catalytic allene activation.

allene-induced disproportionation of cationic gold(I) catalyst.