SYNTHESIS0039-78 1 437-210X © Georg Thieme Verlag Stuttgart · New York 2015, 47, 22–33 short review
Syn thesis
22
Short Review
H. Li, J. Wu
(3+2)-Cycloaddition Reactions of Oxyallyl Cations (3+2)-Cycloaddition Reactions of Oxyallyl Cations
Hui Li
(3+2) cycloaddition
O
Jimmy Wu*
O O
Y
Z or
Y
Z
Y
Z
O Y, Z = C, O, N [2p + 2p]
Received: 30.07.2014 Accepted after revision: 09.10.2014 Published online: 10.11.2014 DOI: 10.1055/s-0034-1378918; Art ID: ss-2014-m0477-sr
Abstract The (3+2)-cycloaddition reaction involving oxyallyl cations has proven to be a versatile and efficient approach for the construction of five-membered carbo- and heterocycles, which are prevalent frameworks in natural products and pharmaceuticals. The following article will provide a brief summary of recent disclosures on this process featuring chemo-, regio- and diastereoselective oxyallyl cycloadditions with both electron-rich and electron-deficient 2π partners. 1 Introduction 2 Heteroatom-Substituted Oxyallyl Cations 3 Oxyallyl Cations Derived from Substituted Ketones 4 Oxyallyl Cations Intercepted from Nazarov Cyclization 5 1-Alkylidene-2-oxyallyl Cations 6 Summary and Outlook
Key words cycloaddtion, oxyallyl cation, heterocycles, regioselectivity, diastereoselectivity
1
Introduction
The chemistry of oxyallyl cations 1 has been a fertile ground for the design and development of powerful reaction processes. Cycloaddition reactions, in particular, are highly valued for their synthetic utility. This one-step process represents a facile approach to construct a variety of ring types and increase molecular complexity.1 Both (4+3)and (3+2)-cycloaddition modes of oxyallyl cations are known under thermal conditions and have been investigated for decades.2 As shown in Scheme 1, the (4+3) cycloadditions with dienes provide access to seven-membered carbocycles 2 and have been incorporated in a number of elegant syntheses of natural products.3 The (3+2) cycloaddition of oxyallyl cations 1 with a 2π partner, although less intensively investigated compared to the (4+3) counterpart, remains an attractive research topic. In this [2π+2π] process (Scheme 1), orbital symmetry considerations indicate that a concerted mechanism is not al-
Hui Li received his B.Sc. degree in pharmaceutical science from Tianjin University (China) under the supervision of Prof. Kang Zhao in 2010. He then moved to the USA in 2011 and joined Prof. Jimmy Wu’s research group at Dartmouth College to continue his interest in organic synthesis. Jimmy Wu received his A.B. degree in chemistry from Princeton University (USA) in 1998. He then spent two years as an associate chemist at Merck Process Research (USA) before moving to Harvard University (USA) in 2001. There, he obtained his Ph.D. in organic chemistry from Prof. David A. Evans in 2005. He continued his studies as a postdoctoral fellow with Prof. Barry M. Trost at Stanford University (USA). He then joined the Department of Chemistry at Dartmouth College (USA) in the summer of 2007 and is now an associate professor. His current interest includes novel annulation of indoles, redox-chain reactions, the chemistry of phosphorothioate esters, and natural product synthesis.
lowed under thermal conditions. Instead, the reaction can proceed via a step-wise pathway, which makes it reasonable to regard this process as a formal cycloaddition. Generally, the reaction would start with electrophilic bond formation of the oxyallyl cation with one atom of the 2π partner to give a zwitterionic intermediate. The cation on the other atom of the 2π partner may then be captured by either the O or C atom on the oxyallyl moiety to furnish fivemembered rings 4–5 (e.g., cyclopentanones), which are ubiquitous in nature as well as useful building blocks.4,5 The (3+2) cycloaddition possesses several different features relative to the (4+3) process. First, the (4+3) cycloaddition typically provides carbocycles with the formation of two C–C bonds. In the case of (3+2) annulations, the oxygen
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Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA+16(03)496 [email protected]
or
23
Short Review
H. Li, J. Wu
X
2 Heteroatom-Substituted Oxyallyl Cations
O
X X = O, N, C
2
(4+3) [4π+2π]
O
1
or O Y
O
Z or
Y, Z = C, O, N (3+2) [2π+2π]
Y
Z
O
HOMO
O LUMO O
Y
Z 3
or
Y
O
Z
4
5
Scheme 1 Generic (4+3)- and (3+2)-cycloaddition reactions of oxyallyl cations
atom of oxyallyl intermediates may also participate in the reaction to afford oxacyclic species 4. Second, electron-rich 4π partners (i.e., dienes) are generally required in the (4+3) cycloaddition reactions since oxyallyl cations are electrophilic. However, electron-deficient 2π partners such as carbonyls or diethyl azodicarboxylate have been demonstrated by Noyori,6 Hoffmann,7 Fry,8 and Cookson9 in 1970s to be compatible with the (3+2) mode. This distinct difference enables facile access to a broader range of five-membered heterocycles including furanones, 1,3-dioxolanes, pyrazolidones, etc. Third, an alkyne may also capture the oxyallyl cations in the (3+2) cycloaddition to produce cyclopentenones 5 while a diene is generally used in the (4+3) approach. Recent advances in the oxyallyl (3+2) cycloadditions featured the emergence of highly chemo-, regio- and diastereoselective processes, which indicated renewed interest in this field. To the best of our knowledge, reviews concerning oxyallyl (3+2) cycloadditions have remained relatively scarce since the 1990s. Thus, in this article we focus on some of these reactions, developed during the past two decades, that involve the cycloaddition of various oxyallyl cations with both electron-rich and -deficient 2π partners. The discussion will be divided into sections based on the types of oxyallyl cations and/or precursors.
Heteroatom-substituted oxyallyl cations have been extensively studied to participate in dipolar cycloaddtions since the last century.10 Although they are commonly utilized in (4+3) cycloadditions, Kuwajima demonstrated a highly regio- and stereoselective (3+2) cyclopentannulation by employing sulfur-substituted oxyallyl cations.11,12 As shown in Scheme 2, the 3-(alkylthio)-2-siloxyallyl cation 7, which was generated from allyl acetate 6 by the treatment of EtAlCl2 or AlCl3, was able to react with various kinds of olefins including enol ethers, vinyl sulfides, stryrenes, and trialkylolefins to afford the corresponding cyclopentanones in good yields (e.g., 9–12). Notably, these reactions proceeded in almost complete regioselectivity by forming the sterically more hindered isomers as the predominant product in every case. Moreover, surprisingly high stereoselectivity was observed in the reaction of 6 with vinyl sulfides. As shown in Scheme 3 (a), both the Eand the Z-isomers of 2-(benzylthio)but-2-ene (13) afforded the same diastereomer 14 as the major product. This may be due to the rapid geometric isomerization between (E)13 and (Z)-13 under the influence of EtAlCl2 (Scheme 3, b). To further rationalize the origin of diastereoselectivity, chair-like six-membered transition-state models TS-1 and TS-2 were also proposed, which featured the orbital interaction between the sulfur atom of the vinyl sulfide and the α-carbon of the oxyallyl cation (Scheme 3, b). Since TS-2 contains a 1,3-diaxial steric repulsion between the β-methyl group of (Z)-13 and the siloxy group of the oxyallyl cation, this cycloaddition would be slower than that of (E)-13. The authors propose that the cycloaddition reactions of both (E)-13 and (Z)-13 proceed through TS-1 in a step-wise manner to first form the C–C bond distal to both sulfur atoms. This generates an intermediate that proceeds to forge the second C–C bond without further bond rotation to give 14 as the major product.
OTIPS MeS
OAc
EtAlCl2 or AlCl3
O
O
MeS
MeS
7
8
O
Y
O
MeS
MeS H
H Ph 9 95% dr > 99:1
MeS Y
MeS
CH2Cl2 –45 °C
6
MeO
O OTIPS
10 95% dr > 99:1
S 11 76% dr > 99:1
(CH2)4Ph 12 78% dr = 72:28
Scheme 2 (3+2) Cycloadducts derived by using various olefins
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Syn thesis
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Syn thesis
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H. Li, J. Wu
(a)
BnO
OBn (E)-13
BnS
SMe O +
SMe EtAlCl2
O
EtAlCl2 84%, dr = 95:5
OTIPS
BnO
SMe
6
MeS
H
16
17
O H
(ca. 1:1)
18
OAc BnO 6
BnS
(Z)-13
BnS
H
1) Bu3SnH, AIBN
EtSH, TMSCl
14
O
EtAlCl2 66%, dr = 96:4
2) H2, Pd/C 73% from 16
96% H
(b)
19
OTIPS Me
H
H
O
H Me
BnS
MeS
Bn
S
H
H
14
H
H
H
O
H H
BnS Me
S Me
Due to its wide range of applicability, as well as the high selectivity, the above (3+2)-cycloaddition strategy was successfully incorporated in the total synthesis of (–)-coriolin in a following report by the same group.13,14 As shown in Scheme 4, the ABC triquinane ring system of coriolin was constructed via two successive (3+2)-cycloaddition reactions. Treatment of benzyl ether 16 with vinyl sulfide 6 in the presence of EtAlCl2 provided a 1:1 mixture of annulated products 17 and 18 in diastereomerically pure forms. The crude mixture was then subjected to a desulfurization– hydrogenation sequence to give bicyclic ketone 19 in a yield of 73% for three steps. The use of enthanethiol and chlorotrimethylsilane transformed 19 to vinyl sulfide 20. Subsequently, 20 underwent a second (3+2) cycloaddition with 21 to install the A-ring unit of (–)-coriolin, which was followed by the TBAF-mediated β-elimination of ethanethiol to give enone 23, which was eventually taken on to (–)-coriolin. The heteroaromatic oxidopyrylium species, which are widely used in (5+2) dipolar cycloadditions,15 may also act as stabilized oxyallyl cations. For example, Porco and co-
H
SMe
SEt
O H
O
O C 23
H
SMe
15
Scheme 3 (a) Stereoselective cycloaddition using vinyl sulfides (E)-13 and (Z)-13. Reagents and conditions: CH2Cl2, –45 °C. (b) Proposed transition-state model resulting in high stereoselectivity.
22
OH
BnS
OTIPS TS-2
OBn H
TBAF 87% from 20
H H
MeS Bn
(Z)-13
MeS
EtAlCl2
20
EtAlCl2 Me
O
21
SEt BnS
OTIPS
TS-1
(E)-13
OBn H
OAc
H
H Me
MeS
H
BnO
MeS
A B
O OH (–)-coriolin H
Scheme 4 Construction of the A and B rings of coriolin by (3+2)-cycloaddition reactions
workers demonstrated that the oxidopyrylium betaine 25 or 26 derived from excited-state intramolecular proton transfer (ESIPT) of 3-hydroxyflavone 24 could undergo (3+2) cycloaddition with electron-deficient methyl cinnamate (27) (Scheme 5, a).16 The resulting (3+2)-cycloadduct 28 could be further transformed into methyl rocaglate with an α-ketol rearrangement/reduction sequence. The (3+2) photocycloaddition of 24 and 27 may also proceed enantioselectively by using functionalized TADDOL derivative 29 as chiral Brønsted acids (Scheme 5, b).17 As a result, (–)-methyl rocaglate was obtained in 94% ee with a similar strategy as mentioned above. It was proposed that the hydrogen bonding interaction between the phenoxide oxygen of oxidopyrylium 25 or 26 and the free hydroxyl group of TADDOL derivative 29 may play an important role in stabilizing the oxyallyl intermediate, as well as controlling the stereofacial approach of the 2π partner 27. Notably, the above (3+2) photocycloaddition involving oxidopyrylium ions allowed facile access to several other rocaglate natural products including rocaglaol, rocaglamide, silvestrol, episilvestrol, as well as several derivatives (e.g., 30–32) (Figure 1).18
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MeS
25
Syn thesis
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H. Li, J. Wu
(a) O
MeO
O
MeO
hν (>300 nm)
OH PMP
MeOH 0 °C
OH
MeO
OH
O MeO
O
24
O
PMP
MeO
O
25
PMP
26 Ph
(3+2)
CO2Me 27
O
HO MeO
CO2Me
HO
CO2Me Ph
Ph PMP
O
MeO
MeO HO
1) NaOMe, MeOH 2) Me4NBH(OAc)3
MeO
O
methyl rocaglate 48%
28 33%
PMP
(b) R
R
O
O
Ar Ar +
24
29 R = cyclooctyl Ar = pyren-1-yl Ar
OH HO
1) NaOMe, MeOH 2) Me4NBH(OAc)3
Ar
27
(–)-28
(–)-methyl rocaglate
58%
52%, 94% ee
hν (>300 nm) toluene–CH2Cl2 –70 °C
Scheme 5 (a) Synthesis of methyl rocaglate by employing (3+2) photocycloaddition as a key step; PMP = p-methoxybenzyl. (b) TADDOL-mediated enantioselective (3+2) photocycloaddition and its application towards (–)-methyl rocaglate.
HO MeO
HO
O
HO R1 R2
MeO
O rocaglaol
Ph PMP
MeO
HO
OMe silvestrol, R1 = H, R2 = OH episilvestrol, R1 = OH, R2 = H HO MeO
NMe2
O
Ph PMP
rocaglamide
Ph PMP
O
O
HO MeO
O
O
HO MeO
CO2Me
HO
MeO
R1
HO
O
R2 PMP
30, R1 = CN, R2 = Ph 31, R1 = CO2Me, R2 = C6F5 32, R1 = CO2Me, R2 = 2-thiophene
Afterwards, an analogous photocycloaddition involving an oxidoquinolinium variant was also disclosed by the same group.19 As shown in Scheme 6 (a), irradiation of 1,2-dimethyl-3-hydroxylquinolinone (33) could promote the generation of 3-oxidoquinolinium species 34, which may then participate in (3+2) cycloadditions with appropriate 2π partners. While the reaction of 33 with electron-deficient 2π partners afforded only single cycloadducts 36 and 37, respectively, electron-rich olefins such as cyclohexadiene tend to afford two regioisomers (e.g., 38 and 39). Notably, attempts to use the electron-deficient methyl butynoate 40 as a 2π partner did not give the presumed (3+2) product 42, but a rearranged cycloadduct 41. The doubly conjugated enone of 42 is assumed to provide a strong, thermodynamic driving force for the α-ketol rearrangement.
Figure 1 Rocaglate natural products and derivatives synthesized by employing (3+2) photocycloaddition as a key step
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MeO
26
Short Review
H. Li, J. Wu
(a)
O
R2 OH
O
HO
hν 1,4-dioxane
OH
O
R2
pyrex filter
(3+2])
N
N Me 33
N
Me
Me
34
35
O HO
R1
R1
O
O
HO
R1
HO
CO2Me N
N
+
N
Me
Me
Me 38 55%
36, R1 = Me, 50% 37, R1 = Ph, 47%
39 9%
(b) O
O OH
hν, 1,4-dioxane pyrex filter CO2Me
N 33
HO
N
40
Me
Me
CO2Me 41
O HO
α-ketol rearrangement
via CO2Me N Me
42
Scheme 6 (a) (3+2) Photocycloaddition of oxidoquinolinium ions with electron-rich and -deficient olefins. (b) (3+2) Photocycloaddition of oxidoquinolinium ions with electron-deficient alkyne.
In addition to the above heteroatom-substituted oxyallyl cations, Hsung, Houk, Krenske, and co-workers recently reported an unexpected (3+2) cycloaddition of nitrogenstabilized oxyallyl cations with the electron-deficient carbonyl groups of a tethered dienone.20 Despite the fact that other oxyallyls like 44 do undergo intramolecular (4+3) cycloadditions (Scheme 7, a),21 the treatment of allene amide 47 with dimethyldioxirane (DMDO) proceeds only through the (3+2) pathway to generate oxabicyclic species 49 (Scheme 7, b). The density functional theory calculations (DFT) on current system indicated a transition state that features simultaneous interactions of the oxyallyl LUMO with the carbonyl π and lone-pair orbitals. They termed this process as ‘hemipseudopericyclic’, which is halfway between purely pericyclic and purely pseudopericyclic reactions. Further investigation on (3+2) cycloadditions was conducted theoretically and experimentally by employing various carbonyl sources including aldehydes, ketones, esters, and amides. Only tethered ketones with electron-rich substituents are amenable in this process (e.g., 51–54).
3 Oxyallyl Cations Derived from Substituted Ketones Αs mentioned earlier, the use of α,α-dihalo ketones as oxyallyl sources has been well established since the 1970s upon the treatment with reducing agents such as Fe2(CO)9, Fe(CO)5, and Zn/Cu couple.22 Other disubstituted ketones, in principle, may also produce oxyallyl cations under appropriate reductive conditions. For example, Hardinger showed that bis(sulfonyl) ketone 55 could generate oxyallyl intermediate 56 upon treatment with Fe(CO)5 and TiCl4.23 Subsequent (3+2) trapping of 56 with alkenes would furnish the corresponding cyclopentanones (e.g., 59 and 60). Moreover, electron-rich alkynes also turned out to be compatible 2π partners (e.g., 61 and 62) (Scheme 8).
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Syn thesis
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Short Review
H. Li, J. Wu
(a) conventional
O
XcN
Ph
Ph O
O
O
N
O
N
DMDO
O
O
O CH2Cl2 –78 °C
O
O
43
75% dr 95:5
45 NXc
O
44 46
In addition to disubstituted ketones, monosubstituted ones may also act as oxyallyl precursors. Recently, Wu and Hughes reported a regio- and diastereoselective (3+2) annulation of electron-rich 3-substituted indoles 63 with αhalo ketones 64 (Scheme 9).24 This method provides easy access to highly functionalized cyclopenta- or cyclohexafused indoline compounds 65, which are common structures of many natural products. Impressive regiochemical control was observed in the cycloaddition employing acyclic α-halo ketones (e.g., 68, 69).
(b) unexpected
O
Ph Ph
O
O
O
Ph O
N
O
R3
N
N
DMDO
O
R2 +
O
O
49, 85%
Ph
O O
O
O
N
O
51, R = 4-MeOC6H4, 82% 52, R = Ph, 84% 53, R = 4-FC6H4, 70% 54, R = vinyl, 64%
O
O
H
R2 R1
O
R1
or
SO2Ph TiCl4
O
R4
R2 57
56 R3 R3
O
Ph
O
O
Ph
Ph 59 70%
60 65%
Ph
R4 58
O
Ph 61 92%
MeO
R2
H
Bn
O
55
65
O
Scheme 7 (a) Intramolecular (4+3) cycloadditions of allene amidederived oxazolidinone substituted oxyallyls with tethered furan; (b) Intramolecular (3+2) cycloadditions of allene amide-derived oxazolidinone substituted oxyallyls with tethered carbonyls.
PhO2S
R4
O
O
50, 0%
Fe(CO)5
H
R1
64
N
R
O
N
O R3
Ph
R3
Na2CO3
X = Cl, Br
63
O 48
47
R2
TFE, 40 °C
R1
CH2Cl2 –78 °C
R4
X
N
O
O
O
Ph 62 90%
Scheme 8 (3+2) Cycloaddition between bis(sulfonyl) ketone-derived oxyallyls with alkenes and alkynes
66, R2 = allyl, R3 = H 83%, dr 11:1 67, R2 = i-Pr, R3 = I 92%, dr 27:1
N
H
N
Bn
Bn
68 72%
69 77%
Scheme 9 (3+2) Cycloaddition between 3-substituted indoles and αhalo ketones
It is also interesting that the regioisomeric, acyclic αhalo ketones 71 and 72 both afforded 73 as the major product with high diastereoselectivity (>20:1) (Scheme 10, a). Notably, a common O-alkylated intermediate 77 was isolated (Scheme 10, b), suggesting that the reactions of α-halo ketones 71 and 72 may proceed via the same hydroxyallyl intermediate 76. As illustrated in their proposed mechanism (Scheme 10, b), the first C–C bond formation between hydroxyallyl 75 and N-benzylskatole (70) generates intermediate 76, which possesses a weak C···OH interaction. Removal of the proton with carbonate base at this point would furnish the observed intermediate 77. Alternatively, the pronated form 77 could re-dissociate and alkylate at carbon to generate the kinetically favored cycloadduct 74, which can then isomerize to the thermodynamically favored product 73. The above rearrangements, as well as the kinetic and thermodynamic properties of 73 and 74 are in accordance with experimental observations and computational studies.
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H. Li, J. Wu
Furthermore, DFT calculations in the above (3+2) cycloaddition did raise the question of whether hydroxyallyl cation 75 or its zwitterionic form is the real reactive species. While other cycloaddition reactions are thought to proceed through zwitterionic oxyallyl cations,25 DFT studies on the current system predicted that a pathway for the formation of product 74 via hydroxyallyl 75 is a lower-energy route than that emanating from the corresponding zwitterionic form. Harmata and Schreiner have also observed similar divergent reactivity between oxyallyl and hydroxyallyl cations before.26 The synthetic potential of this (3+2)-cycloaddition process was demonstrated by a concise synthesis of the core structures of vincorine, isocorymine, and aspidophylline A. As shown in Scheme 11, Baeyer–Villiger oxidation of the (3+2)-cycloadduct 78 afforded tertracyclic lactone 80 in 70% yield. Compound 80 was then subject to a debenzylation–oxidation sequence to give hemiaminal 82. Cleavage of the phthalimide group with MeNH2 liberated the amine, which spontaneously closed to furnish the pyrrolidine ring of pentacycle 84. Compound 84 maps well to the cores of vincorine and isocorymine. By employing a similar strategy, pentacycle 85 was obtained from (3+2)-cycloadduct 79, which provided a good starting point for the synthesis of aspidophylline A.
O (a)
Ph
O Cl
71
N Bn
46%, dr > 20:1, 9 d
Ph 73 (major)
H
+ O N 70
O
Ph
Bn
Cl
72
N
74%, dr > 20:1, 49 h
Bn
Ph 74 (minor) H
(b) OH
70
Bn N
Ph
O
H HO
H 75
76
N
Ph 74 kinetically favored over 73 H
Bn
H
Ph
H O Ph O N
N
H
Bn
73
77
H
Ph
Bn
thermodynamically favored over 74
Scheme 10 (a) (3+2) Cycloaddition of N-benzylskatole with α-halo ketones. Reagents and conditions: Na2CO3, TFE, 40 °C. (b) Proposed mechanism.
HO MeO2C
MeO
O O
H
N N
R
H
Bn 78, R = NPhth 79, R = OTBS
aspidophylline A
R
MeNH2 or p-TsOH
O N
Bn 80, R = NPhth, 70% 81, R = OTBS, 61%
O
O
2) DMP H
O
O
1) H2, Pd(OH)2 or Pd/C
AcOOH NaHCO3 N
N
O
CHO
N H
Me Me isocorymine
Me vincorine O
O N
O
N
R
CO2Me
N H
N H
OH
82, R = NPhth, 82% 83, R = OTBS, 90%
84, X = NH, 81% 85, X = O, 99%
Scheme 11 Synthesis of core structures for vincorine, isocorymine, and aspidophylline A (n.b., drawn as their enantiomers)
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X
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H. Li, J. Wu
4 Oxyallyl Cations from Interrupted Nazarov Cyclizations
O
The Nazarov cyclization entails the 4π-electrocyclic ring closure of a conjugated pentadienyl cation 87, which is derived from dienone 86 upon treatment with acids or irradiation, to form a cyclopentenyl cation 88 (Scheme 12).27 Conventionally, a β-elimination of the adjacent proton would furnish cyclopentenone 89. In the interrupted Nazarov reaction;28 however, the reactive intermediate 88 may be intercepted by a 2π partner (an alkene or alkyne) to undergo a (3+2) cycloaddition at a rate competitive to the normal elimination route. O
O
R1
R3
R2
R4
A
R1
acid or hν
R2
86
O R3
A
R1
R4
R3 R2
87
R4 88
R6
R8
conventional
or R5
R7
O
interrupted R1
O R2
R2
O R1
R2
R8
R3
R1
HO
BF3·OEt2, CH2Cl2
t-Bu
O
t-Bu
–78 °C to r.t.; H2O 89%
H
93 BF3
94
H3O+
BF3
O
H
O
H
(3+2) t-Bu
t-Bu H H
95
96
Scheme 13 (3+2) Cycloaddition of Nazarov-derived oxyallyl cation with pendant olefin
Afterwards, the same group found allylsilanes and vinyl sulfides to be amenable in the intermolecular mode of (3+2) cycloaddition involving Nazarov-derived oxyallyls (Figure 2).30,31 Complete regioselectivity was observed in the reactions employing allylsilanes as 2π partners (e.g., 97), since allylsilane selectively attacks the least substituted end of unsymmetrically substituted oxyallyl cations. This is in accordance with Noyori’s earlier observation that regioselectivity is predicated on pathways intercepting the more stabilized enolate.
R4 O
89 O
R6 Ph
3 R4 R
R7
90
or
3 R4 R
R5
91
R6
H
O R1
Si(i-Pr)3
R5 R3 R2
Si(i-Pr)3 97 72%a
98 90%b
O
O
92
R4
Scheme 12 Conventional versus interrupted Nazarov reaction
Ph
SEt 2
In 1998, West and co-workers reported the first intramolecular (3+2) cycloaddition of olefins and Nazarovderived oxyallyl cations.29 As shown in Scheme 13, diquinane 94 was obtained from achiral trienone 93. It was presumed that activation of trienone 93 generated the reactive cyclopentenyl intermediate 95, which underwent intramolecular (3+2) trapping by the proximal olefin to afford tricyclic compound 96. It is noteworthy that the oxygen atom of the oxyallyl moiety preferentially participated in the annulation with the formation of a C–O bond.24 Upon aqueous workup, the structurally strained enol moiety was hydrolyzed to give hemiketal 94 with selective protonation from the convex face.
SPh Ph 99 71%a dr 7:1
100 37%a
Figure 2 (3+2) Cycloadducts by using allylsilanes and vinyl sulfides as 2π partners. Reagents and conditions: (a) BF3·OEt2; (b) SnCl4.
As mentioned earlier, irradiation may also promote the formation of oxyallyl speices. Stephenson and Porco recently demonstrated a tandem dienone photorearrangementcycloaddition reaction of alkyne-tethered cyclohexadienones (Scheme 14, a) to produce highly complex architectures.32 It was surmised that photochemical rearrangement of substituted dienone 101 would lead to the formation of
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oxyallyl cation 103 via the Nazarov-type cyclopentenone 102.33 The reactive 1,3-dipole 103 then underwent intramolecular (3+2) cycloaddition with tethered alkyne to form cycloadduct 104. The resulting strained cyclic alkene 104, which turned out to be unstable during purification, could be further elaborated by either inter- (Scheme 14, a) or intramolecular cycloaddition (Scheme 14, b) with furans or a nitrile oxide (via oxime) to generate polycyclic, bridged frameworks. Impressively, in the reaction to yield compound 112 (Scheme 14, b), four rings and six stereogenic centers were generated in this single process. (a) O
O hν (>300 nm) O
benzene O
102
101
O O (3+2) O O
103 104 O
O
O
O
70% 105/106 3:2
+ O O
Ph
106
O
N
O O
Cl
N
Ph 52% 107/108 5.5:1
N
+
O
Et3N
Ph O
O 107
108
(b)
O
R
O
O
R O
O
5 1-Alkylidene-2-oxyallyl Cations
O 105
HO
While the reactive cyclic oxyallyl cations 88 have usually been derived from dienones 86 in traditional Nazarov reactions, they may also be generated from different sources (Scheme 15). For example, Burnell and co-workers reported in 2010 that treatment of allenyl vinyl ketone 113 with BF3·OEt2 could lead to the cyclic oxyallyl cation 114 through Nazarov cyclization.34 In the presence of appropriate olefins, the reactive intermediate 114 may be captured in the (3+2) cycloadditions. As shown in Scheme 15, electron-rich styrenes reacted smoothly to afford bridged (3+2) cycloadducts 116, 117, and 118 as single diastereomers. When aliphatic dienes were employed, the reaction provided a mixture of (3+2) and (4+3) products regioselectively and diastereoselectively (e.g., 119–122). It was indicated that the proportion of (3+2) to (4+3) products is highly dependent on the diene substituents. In addition, Yadav and co-workers recently described (3+2) trapping of oxyallyl cations generated from homoNazarov cyclization of 2-(tert-butyldiphenylsilylmethyl)cyclopropyl vinyl ketones 123 with allylsilanes (Scheme 16).35 This reaction was proposed to begin with the cleavage of σC–C bond of the cyclopropyl ring on 123 to generate enolate 124. The positive charge was proposed to be stabilized by the proximal silyl group. Intermediate 124 then underwent ring-closure to give oxyallyl cations 125, which was then captured by allylsilanes in a (3+2) manner. Although the reaction proceeded with only moderate regioselectivity (e.g., 128/129 = 2:1), exclusive exo-cycloaddition was observed.
In 2006, Fujita reported that the ring opening of alkylidenecyclopropanone acetal 130 under acidic conditions would produce the 1-alkylidene-2-oxyallyl cation 131 as an intermediate, which then undergoes (3+2) or (4+3) cycloadditions in the presence of olefins or dienes (Scheme 17).36 While the reaction of 131 with excess furan delivered a mixture of (4+3) cycloadducts and rearranged products from the (3+2) cycloadducts, the reaction with 2,3-benzofuran 132 furnished (3+2) cycloadduct 133 as a single regioisomer in 76% yield.
hν (>300 nm) benzene
109, R = H 110, R = CO2Et
O O
6 Summary and Outlook
O
111, R = H, 71% 112, R = CO2Et, 55%
Scheme 14 Tandem dienone photorearrangement-cyclization to afford polycyclic structures
The cycloaddition chemistry of oxyallyl cations represents a versatile process in the rapid generation of molecular diversity and complexity. The (3+2) cycloaddition, in particular, enables efficient construction of five-membered carbo- and heterocycles. As discussed above, a variety of oxyallyl cations are able to participate in this [2π+2π] process including those stabilized by heteroatoms and those
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O O
Lewis acid "LA" R
1
R3
LA
O R1
R2
–78 °C
R3
(3+2) R2
R1 113
115
114 O
O
O
i-Pr
Ph OMe
OMe
OMe
OMe
OMe
116 81%
117 79%
O
118 59%
O
Ph
O
O
Ph
Ph
Ph
+ H
119 85%
120 54%
121 122 121/122 2.7:1, 51%
Scheme 15 (3+2) Cycloaddition of allenyl vinyl ketone-derived oxyallyl cation with olefins
O
O
R2
R3
Lewis acid "LA"
R2
–78 °C
R1
R1 TBDPS
123
LA
O
LA OR
R2
R3
R3
OTMS
MeO
R1 TBDPS
124
SnCl4 CH2Cl2 –78 °C
125
TBDPS
130
131 R = Me, TMS
R2 O
TMS (3+2)
R1
R3
TBDPS
R2 R1
+
O R3
TBDPS TMS
126
TMS
127
O
132 O 133 76%
O +
TBDPS
O O
TBDPS
SiMe3
SiMe3 128
Scheme 17 (3+2) Cycloaddition of 1-alkylidene-2-oxyallyl cation with 2,3-benzofuran
129 128/129 2:1, 81%
Scheme 16 (3+2) Cycloaddition of cyclopropyl vinyl ketone-derived oxyallyl cation with allylsilanes
‘unstablized’ species. Both classes of oxyallyl cations can either be cyclic or acyclic and may be derived from different sources. Due to the electrophilic nature of oxyallyl cations, electron-rich alkenes or alkynes are generally favorable 2π partners. However, electron-deficient 2π partners including
α,β-unsaturated ketones (e.g., methyl cinnamate, methyl butynoate), carbonyl groups, and diethyl azodicarboxylate are also amenable in some cases. The past twenty years have witnessed the development of many chemo-, regio- and diastereoselective oxyallyl (3+2) cycloadditions. Some of them have also been successfully employed in the elegant syntheses of natural products. Despite the impressive progress that has been made in the oxyallyl (3+2) cycloadditions, there is still plenty of room for improvement and further exploration. For example, the development of catalytic and enantioselective processes
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still remains relatively rare. It is our hope that this article will stimulate continued interest in the (3+2) cycloaddition of oxyallyl cations and make it a prolonged and prominent research area for developing novel methods used for natural product syntheses.
Acknowledgment The NIH-NIGMS (1R01GM111638-01) and Dartmouth College are gratefully acknowledged for generous support of research in the current area.
References (1) For reviews on cycloaddition involving oxyallyl cations, see: (a) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1. (b) Chiu, P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1. (c) Davies, H. M. L. In Advances in Cycloaddition; Harmata, M., Ed.; JAI Press: Stamford, 1999. (d) Harmata, M. Acc. Chem. Res. 2001, 34, 595. (e) Harmata, M.; Rashatasakhon, P. Tetrahedron 2003, 59, 2371. (f) Rigby, J. H.; Pigge, F. C. Org. React. 1997, 51, 351. (g) Niess, B.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 2005, 44, 26. (h) Harmata, M. Adv. Synth. Catal. 2006, 348, 2297. (i) Harmata, M. Chem. Commun. 2010, 46, 8886. (j) Harmata, M. Chem. Commun. 2010, 46, 8904. (k) Lohse, A. G.; Hsung, R. P. Chem. Eur. J. 2011, 17, 3812. (2) (a) For cycloadditions using photochemically derived oxyallyl cations, see review: West, F. G. CRC Handbook of Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W.; Lenci, F., Eds.; CRC Press: Boca Raton, 2004, Chap. 83. (b) The designation (m+n) herein describes the number of atoms participating in the cycloadditions, while [m+n] indicates the number of electrons. (3) (a) Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 2004, 43, 1934. (b) Battiste, M. A.; Pelphrey, P. M.; Wright, D. L. Chem. Eur. J. 2006, 12, 3438. (c) Jones, D. E.; Harmata, M. Methods and Applications of Cycloaddition Reactions in Organic Syntheses; Nishiwaki, N., Ed.; Wiley: Hoboken, 2014, 599–630. (4) For reviews on reactivity of oxyallyl cations containing (3+2) mode, see: (a) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163. (b) Noyori, R. Acc. Chem. Res. 1979, 12, 61. (c) Frühauf, H-W. Chem. Rev. 1997, 97, 523. (d) Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet. Chem. 2004, 689, 3873. (e) Ramaiah, M. Synthesis 1984, 529. (f) Martin, S. F. Tetrahedron 1980, 36, 419. (g) Mann, J. Tetrahedron 1986, 42, 4611. (5) For precedents of oxyallyl (3+2) cycloaddition to access cyclopentanones before 1995, see: (a) Noyori, R.; Yokoyama, K.; Makino, S.; Hayakawa, Y. J. Am. Chem. Soc. 1972, 94, 1772. (b) Hayakawa, Y.; Yokoyama, K.; Noyori, R. Tetrahedron Lett. 1976, 48, 4347. (c) Hayakawa, Y.; Yokoyama, K.; Noyori, R. J. Am. Chem. Soc. 1978, 100, 1799. (d) Noyori, R.; Hayakawa, Y.; Takaya, H.; Murai, S.; Kobayashi, R.; Sonoda, N. J. Am. Chem. Soc. 1978, 100, 1959. (e) Jacobson, R. M.; Abbaspour, A.; Lahm, G. P. J. Org. Chem. 1978, 43, 4650. (f) Hegedus, L. S.; Holden, M. S. J. Org. Chem. 1985, 50, 3920. (g) Fukuzawa, S.; Fukushima, M.; Fujinami, T.; Sakai, S. Bull. Chem. Soc. Jpn. 1989, 62, 2348. (h) Corriu, R. J. P.; Moreau, J. J. E.; Pataud-Sat, M. J. Org. Chem. 1990, 55, 2878.
(6) (a) Hayakawa, Y.; Takaya, H.; Makino, S.; Hayakawa, N.; Noyori, R. Bull. Chem. Soc. Jpn. 1977, 50, 1990. (b) Noyori, R.; Hayakawa, Y.; Makino, S.; Hayakawa, N.; Takaya, H. J. Am. Chem. Soc. 1973, 95, 4103. (7) Barrow, M.-A.; Richards, A. C.; Smithers, R. H.; Hoffmann, H. M. R. Tetrahedron Lett. 1972, 13, 3101. (8) Fry, A. J.; Ginsburg, G. S.; Parente, R. A. J. Chem. Soc., Chem. Commun. 1978, 1040. (9) (a) Cookson, R. C.; Nye, M. J. Proc. Chem. Soc. 1963, 129. (b) Cookson, R. C.; Nye, M. J. J. Chem. Soc. 1965, 2009. (10) For representative reviews, see: (a) References 1i, 1j. (b) Lu, T.; Lu, Z.; Ma, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862. For recent examples, see: (c) Lo, B.; Lam, S.; Wong, W.-T.; Chiu, P. Angew. Chem. Int. Ed. 2012, 51, 12120. (d) Han, X.; Li, H.; Hughes, R. P.; Wu, J. Angew. Chem. Int. Ed. 2012, 51, 10390. (e) Du, Y.; Krenske, E. H.; Antoline, J. E.; Lohse, A. G.; Houk, K. N.; Hsung, R. P. J. Org. Chem. 2013, 78, 1753. (f) He, S.; Hsung, R. P.; Presser, W. R.; Ma, Z.; Haugen, B. J. Org. Lett. 2014, 16, 2180. (11) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. Synlett 1996, 157. (12) Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 1724. (13) Mizuno, H.; Domon, K.; Masuya, K.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1999, 64, 2648. (14) For a formal synthesis of racemic coriolin, see:Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. Tetrahedron Lett. 1997, 38, 465. (15) For a review containing (5+2) cycloaddition of oxidopyrylium ions, see: (a) Katritzky, A. R. Chem. Rev. 1989, 89, 827. For recent examples, see: (b) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976. (c) Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee, J.; Ohmura, H. Org. Lett. 2006, 8, 5373. (d) Burns, N. Z.; Witten, M. R.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 14578. (16) Gerard, B.; Jones, G.; Porco, J. A. Jr. J. Am. Chem. Soc. 2004, 126, 13620. (17) Gerard, B.; Sangji, S.; O’Leary, D. J.; Porco, J. A. Jr. J. Am. Chem. Soc. 2006, 128, 7754. (18) (a) Gerard, B.; Cencic, R.; Pelletier, J.; Porco, J. A. Jr. Angew. Chem. Int. Ed. 2007, 46, 7831. (b) Roche, S. P.; Cencic, R.; Pelletier, J.; Porco, J. A. Jr. Angew. Chem. Int. Ed. 2010, 49, 6533. (c) Adams, T. E.; Sous, M. E.; Hawkins, B. C.; Hirner, S.; Holloway, G.; Khoo, M. L.; Owen, D. J.; Sawage, G. P.; Scammells, P. J.; Rizzacasa, M. A. J. Am. Chem. Soc. 2009, 131, 1607. (19) Xia, B.; Gerard, B.; Solano, D. M.; Wan, J.; Jones, G.; Porco, J. A. Jr. Org. Lett. 2011, 13, 1346. (20) Krenske, E. H.; He, S.; Huang, J.; Du, Y.; Houk, K. N.; Hsung, R. P. J. Am. Chem. Soc. 2013, 135, 5242. (21) Rameshkumar, C.; Hsung, R. P. Angew. Chem. Int. Ed. 2004, 43, 615. (22) (a) For leading reviews on using α,α-dibromo ketones as an oxyallyl source, see references 1a and 1b. For a more recent use of diiodo ketones as oxallyl sources, see: (b) Montaña, A. M.; Grima, P. M. Tetrahedron Lett. 2001, 42, 7809. (c) Montaña, A. M.; Grima, P. M. Synth. Commun. 2003, 33, 265. (23) Hardinger, S. A.; Bayne, C.; Kantorowski, E.; McClellan, R.; Larres, L.; Nuesse, M. J. Org. Chem. 1995, 60, 1104. (24) Li, H.; Hughes, R. P.; Wu, J. J. Am. Chem. Soc. 2014, 136, 6288. (25) See references 1g, 1h, 1i, 1j. (26) Harmata, M.; Huang, C.; Rooshenas, P.; Schreiner, P. R. Angew. Chem. Int. Ed. 2008, 47, 8696.
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(32) Bos, P. H.; Antelek, M. T.; Porco, J. A. Jr.; Stephenson, C. R. J. J. Am. Chem. Soc. 2013, 135, 17978. (33) Schultz, A. G.; Puig, S.; Wang, Y. J. Chem. Soc., Chem. Commun. 1985, 785. (34) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010, 132, 1685. (35) Yadav, V. K.; Naganaboina, V. K.; Hulikal, V. Tetrahedron Lett. 2014, 55, 2015. (36) Fujita, M.; Oshima, M.; Okuno, S.; Sugimura, T.; Okuyama, T. Org. Lett. 2006, 8, 4113.
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(27) For an overview of the conventional Nazarov reaction, see: Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: London, 2005, 304. (28) For a review on the interrupted Nazarov reaction, see: Grant, T. G.; Rieder, C. J.; West, F. G. Chem. Commun. 2009, 5676. (29) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G. J. Org. Chem. 1998, 63, 2430. (30) Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem. Int. Ed. 2000, 39, 1970. (31) Mahmound, B.; West, F. G. Tetrahedron Lett. 2007, 48, 5091.
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(3+2)-Cycloaddition Reactions of Oxyallyl Cations (3+2)-Cycloaddition Reactions of Oxyallyl Cations
Hui Li
(3+2) cycloaddition
O
Jimmy Wu*
O O
Y
Z or
Y
Z
Y
Z
O Y, Z = C, O, N [2p + 2p]
Received: 30.07.2014 Accepted after revision: 09.10.2014 Published online: 10.11.2014 DOI: 10.1055/s-0034-1378918; Art ID: ss-2014-m0477-sr
Abstract The (3+2)-cycloaddition reaction involving oxyallyl cations has proven to be a versatile and efficient approach for the construction of five-membered carbo- and heterocycles, which are prevalent frameworks in natural products and pharmaceuticals. The following article will provide a brief summary of recent disclosures on this process featuring chemo-, regio- and diastereoselective oxyallyl cycloadditions with both electron-rich and electron-deficient 2π partners. 1 Introduction 2 Heteroatom-Substituted Oxyallyl Cations 3 Oxyallyl Cations Derived from Substituted Ketones 4 Oxyallyl Cations Intercepted from Nazarov Cyclization 5 1-Alkylidene-2-oxyallyl Cations 6 Summary and Outlook
Key words cycloaddtion, oxyallyl cation, heterocycles, regioselectivity, diastereoselectivity
1
Introduction
The chemistry of oxyallyl cations 1 has been a fertile ground for the design and development of powerful reaction processes. Cycloaddition reactions, in particular, are highly valued for their synthetic utility. This one-step process represents a facile approach to construct a variety of ring types and increase molecular complexity.1 Both (4+3)and (3+2)-cycloaddition modes of oxyallyl cations are known under thermal conditions and have been investigated for decades.2 As shown in Scheme 1, the (4+3) cycloadditions with dienes provide access to seven-membered carbocycles 2 and have been incorporated in a number of elegant syntheses of natural products.3 The (3+2) cycloaddition of oxyallyl cations 1 with a 2π partner, although less intensively investigated compared to the (4+3) counterpart, remains an attractive research topic. In this [2π+2π] process (Scheme 1), orbital symmetry considerations indicate that a concerted mechanism is not al-
Hui Li received his B.Sc. degree in pharmaceutical science from Tianjin University (China) under the supervision of Prof. Kang Zhao in 2010. He then moved to the USA in 2011 and joined Prof. Jimmy Wu’s research group at Dartmouth College to continue his interest in organic synthesis. Jimmy Wu received his A.B. degree in chemistry from Princeton University (USA) in 1998. He then spent two years as an associate chemist at Merck Process Research (USA) before moving to Harvard University (USA) in 2001. There, he obtained his Ph.D. in organic chemistry from Prof. David A. Evans in 2005. He continued his studies as a postdoctoral fellow with Prof. Barry M. Trost at Stanford University (USA). He then joined the Department of Chemistry at Dartmouth College (USA) in the summer of 2007 and is now an associate professor. His current interest includes novel annulation of indoles, redox-chain reactions, the chemistry of phosphorothioate esters, and natural product synthesis.
lowed under thermal conditions. Instead, the reaction can proceed via a step-wise pathway, which makes it reasonable to regard this process as a formal cycloaddition. Generally, the reaction would start with electrophilic bond formation of the oxyallyl cation with one atom of the 2π partner to give a zwitterionic intermediate. The cation on the other atom of the 2π partner may then be captured by either the O or C atom on the oxyallyl moiety to furnish fivemembered rings 4–5 (e.g., cyclopentanones), which are ubiquitous in nature as well as useful building blocks.4,5 The (3+2) cycloaddition possesses several different features relative to the (4+3) process. First, the (4+3) cycloaddition typically provides carbocycles with the formation of two C–C bonds. In the case of (3+2) annulations, the oxygen
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Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA+16(03)496 [email protected]
or
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H. Li, J. Wu
X
2 Heteroatom-Substituted Oxyallyl Cations
O
X X = O, N, C
2
(4+3) [4π+2π]
O
1
or O Y
O
Z or
Y, Z = C, O, N (3+2) [2π+2π]
Y
Z
O
HOMO
O LUMO O
Y
Z 3
or
Y
O
Z
4
5
Scheme 1 Generic (4+3)- and (3+2)-cycloaddition reactions of oxyallyl cations
atom of oxyallyl intermediates may also participate in the reaction to afford oxacyclic species 4. Second, electron-rich 4π partners (i.e., dienes) are generally required in the (4+3) cycloaddition reactions since oxyallyl cations are electrophilic. However, electron-deficient 2π partners such as carbonyls or diethyl azodicarboxylate have been demonstrated by Noyori,6 Hoffmann,7 Fry,8 and Cookson9 in 1970s to be compatible with the (3+2) mode. This distinct difference enables facile access to a broader range of five-membered heterocycles including furanones, 1,3-dioxolanes, pyrazolidones, etc. Third, an alkyne may also capture the oxyallyl cations in the (3+2) cycloaddition to produce cyclopentenones 5 while a diene is generally used in the (4+3) approach. Recent advances in the oxyallyl (3+2) cycloadditions featured the emergence of highly chemo-, regio- and diastereoselective processes, which indicated renewed interest in this field. To the best of our knowledge, reviews concerning oxyallyl (3+2) cycloadditions have remained relatively scarce since the 1990s. Thus, in this article we focus on some of these reactions, developed during the past two decades, that involve the cycloaddition of various oxyallyl cations with both electron-rich and -deficient 2π partners. The discussion will be divided into sections based on the types of oxyallyl cations and/or precursors.
Heteroatom-substituted oxyallyl cations have been extensively studied to participate in dipolar cycloaddtions since the last century.10 Although they are commonly utilized in (4+3) cycloadditions, Kuwajima demonstrated a highly regio- and stereoselective (3+2) cyclopentannulation by employing sulfur-substituted oxyallyl cations.11,12 As shown in Scheme 2, the 3-(alkylthio)-2-siloxyallyl cation 7, which was generated from allyl acetate 6 by the treatment of EtAlCl2 or AlCl3, was able to react with various kinds of olefins including enol ethers, vinyl sulfides, stryrenes, and trialkylolefins to afford the corresponding cyclopentanones in good yields (e.g., 9–12). Notably, these reactions proceeded in almost complete regioselectivity by forming the sterically more hindered isomers as the predominant product in every case. Moreover, surprisingly high stereoselectivity was observed in the reaction of 6 with vinyl sulfides. As shown in Scheme 3 (a), both the Eand the Z-isomers of 2-(benzylthio)but-2-ene (13) afforded the same diastereomer 14 as the major product. This may be due to the rapid geometric isomerization between (E)13 and (Z)-13 under the influence of EtAlCl2 (Scheme 3, b). To further rationalize the origin of diastereoselectivity, chair-like six-membered transition-state models TS-1 and TS-2 were also proposed, which featured the orbital interaction between the sulfur atom of the vinyl sulfide and the α-carbon of the oxyallyl cation (Scheme 3, b). Since TS-2 contains a 1,3-diaxial steric repulsion between the β-methyl group of (Z)-13 and the siloxy group of the oxyallyl cation, this cycloaddition would be slower than that of (E)-13. The authors propose that the cycloaddition reactions of both (E)-13 and (Z)-13 proceed through TS-1 in a step-wise manner to first form the C–C bond distal to both sulfur atoms. This generates an intermediate that proceeds to forge the second C–C bond without further bond rotation to give 14 as the major product.
OTIPS MeS
OAc
EtAlCl2 or AlCl3
O
O
MeS
MeS
7
8
O
Y
O
MeS
MeS H
H Ph 9 95% dr > 99:1
MeS Y
MeS
CH2Cl2 –45 °C
6
MeO
O OTIPS
10 95% dr > 99:1
S 11 76% dr > 99:1
(CH2)4Ph 12 78% dr = 72:28
Scheme 2 (3+2) Cycloadducts derived by using various olefins
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(a)
BnO
OBn (E)-13
BnS
SMe O +
SMe EtAlCl2
O
EtAlCl2 84%, dr = 95:5
OTIPS
BnO
SMe
6
MeS
H
16
17
O H
(ca. 1:1)
18
OAc BnO 6
BnS
(Z)-13
BnS
H
1) Bu3SnH, AIBN
EtSH, TMSCl
14
O
EtAlCl2 66%, dr = 96:4
2) H2, Pd/C 73% from 16
96% H
(b)
19
OTIPS Me
H
H
O
H Me
BnS
MeS
Bn
S
H
H
14
H
H
H
O
H H
BnS Me
S Me
Due to its wide range of applicability, as well as the high selectivity, the above (3+2)-cycloaddition strategy was successfully incorporated in the total synthesis of (–)-coriolin in a following report by the same group.13,14 As shown in Scheme 4, the ABC triquinane ring system of coriolin was constructed via two successive (3+2)-cycloaddition reactions. Treatment of benzyl ether 16 with vinyl sulfide 6 in the presence of EtAlCl2 provided a 1:1 mixture of annulated products 17 and 18 in diastereomerically pure forms. The crude mixture was then subjected to a desulfurization– hydrogenation sequence to give bicyclic ketone 19 in a yield of 73% for three steps. The use of enthanethiol and chlorotrimethylsilane transformed 19 to vinyl sulfide 20. Subsequently, 20 underwent a second (3+2) cycloaddition with 21 to install the A-ring unit of (–)-coriolin, which was followed by the TBAF-mediated β-elimination of ethanethiol to give enone 23, which was eventually taken on to (–)-coriolin. The heteroaromatic oxidopyrylium species, which are widely used in (5+2) dipolar cycloadditions,15 may also act as stabilized oxyallyl cations. For example, Porco and co-
H
SMe
SEt
O H
O
O C 23
H
SMe
15
Scheme 3 (a) Stereoselective cycloaddition using vinyl sulfides (E)-13 and (Z)-13. Reagents and conditions: CH2Cl2, –45 °C. (b) Proposed transition-state model resulting in high stereoselectivity.
22
OH
BnS
OTIPS TS-2
OBn H
TBAF 87% from 20
H H
MeS Bn
(Z)-13
MeS
EtAlCl2
20
EtAlCl2 Me
O
21
SEt BnS
OTIPS
TS-1
(E)-13
OBn H
OAc
H
H Me
MeS
H
BnO
MeS
A B
O OH (–)-coriolin H
Scheme 4 Construction of the A and B rings of coriolin by (3+2)-cycloaddition reactions
workers demonstrated that the oxidopyrylium betaine 25 or 26 derived from excited-state intramolecular proton transfer (ESIPT) of 3-hydroxyflavone 24 could undergo (3+2) cycloaddition with electron-deficient methyl cinnamate (27) (Scheme 5, a).16 The resulting (3+2)-cycloadduct 28 could be further transformed into methyl rocaglate with an α-ketol rearrangement/reduction sequence. The (3+2) photocycloaddition of 24 and 27 may also proceed enantioselectively by using functionalized TADDOL derivative 29 as chiral Brønsted acids (Scheme 5, b).17 As a result, (–)-methyl rocaglate was obtained in 94% ee with a similar strategy as mentioned above. It was proposed that the hydrogen bonding interaction between the phenoxide oxygen of oxidopyrylium 25 or 26 and the free hydroxyl group of TADDOL derivative 29 may play an important role in stabilizing the oxyallyl intermediate, as well as controlling the stereofacial approach of the 2π partner 27. Notably, the above (3+2) photocycloaddition involving oxidopyrylium ions allowed facile access to several other rocaglate natural products including rocaglaol, rocaglamide, silvestrol, episilvestrol, as well as several derivatives (e.g., 30–32) (Figure 1).18
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MeS
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Syn thesis
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H. Li, J. Wu
(a) O
MeO
O
MeO
hν (>300 nm)
OH PMP
MeOH 0 °C
OH
MeO
OH
O MeO
O
24
O
PMP
MeO
O
25
PMP
26 Ph
(3+2)
CO2Me 27
O
HO MeO
CO2Me
HO
CO2Me Ph
Ph PMP
O
MeO
MeO HO
1) NaOMe, MeOH 2) Me4NBH(OAc)3
MeO
O
methyl rocaglate 48%
28 33%
PMP
(b) R
R
O
O
Ar Ar +
24
29 R = cyclooctyl Ar = pyren-1-yl Ar
OH HO
1) NaOMe, MeOH 2) Me4NBH(OAc)3
Ar
27
(–)-28
(–)-methyl rocaglate
58%
52%, 94% ee
hν (>300 nm) toluene–CH2Cl2 –70 °C
Scheme 5 (a) Synthesis of methyl rocaglate by employing (3+2) photocycloaddition as a key step; PMP = p-methoxybenzyl. (b) TADDOL-mediated enantioselective (3+2) photocycloaddition and its application towards (–)-methyl rocaglate.
HO MeO
HO
O
HO R1 R2
MeO
O rocaglaol
Ph PMP
MeO
HO
OMe silvestrol, R1 = H, R2 = OH episilvestrol, R1 = OH, R2 = H HO MeO
NMe2
O
Ph PMP
rocaglamide
Ph PMP
O
O
HO MeO
O
O
HO MeO
CO2Me
HO
MeO
R1
HO
O
R2 PMP
30, R1 = CN, R2 = Ph 31, R1 = CO2Me, R2 = C6F5 32, R1 = CO2Me, R2 = 2-thiophene
Afterwards, an analogous photocycloaddition involving an oxidoquinolinium variant was also disclosed by the same group.19 As shown in Scheme 6 (a), irradiation of 1,2-dimethyl-3-hydroxylquinolinone (33) could promote the generation of 3-oxidoquinolinium species 34, which may then participate in (3+2) cycloadditions with appropriate 2π partners. While the reaction of 33 with electron-deficient 2π partners afforded only single cycloadducts 36 and 37, respectively, electron-rich olefins such as cyclohexadiene tend to afford two regioisomers (e.g., 38 and 39). Notably, attempts to use the electron-deficient methyl butynoate 40 as a 2π partner did not give the presumed (3+2) product 42, but a rearranged cycloadduct 41. The doubly conjugated enone of 42 is assumed to provide a strong, thermodynamic driving force for the α-ketol rearrangement.
Figure 1 Rocaglate natural products and derivatives synthesized by employing (3+2) photocycloaddition as a key step
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MeO
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Short Review
H. Li, J. Wu
(a)
O
R2 OH
O
HO
hν 1,4-dioxane
OH
O
R2
pyrex filter
(3+2])
N
N Me 33
N
Me
Me
34
35
O HO
R1
R1
O
O
HO
R1
HO
CO2Me N
N
+
N
Me
Me
Me 38 55%
36, R1 = Me, 50% 37, R1 = Ph, 47%
39 9%
(b) O
O OH
hν, 1,4-dioxane pyrex filter CO2Me
N 33
HO
N
40
Me
Me
CO2Me 41
O HO
α-ketol rearrangement
via CO2Me N Me
42
Scheme 6 (a) (3+2) Photocycloaddition of oxidoquinolinium ions with electron-rich and -deficient olefins. (b) (3+2) Photocycloaddition of oxidoquinolinium ions with electron-deficient alkyne.
In addition to the above heteroatom-substituted oxyallyl cations, Hsung, Houk, Krenske, and co-workers recently reported an unexpected (3+2) cycloaddition of nitrogenstabilized oxyallyl cations with the electron-deficient carbonyl groups of a tethered dienone.20 Despite the fact that other oxyallyls like 44 do undergo intramolecular (4+3) cycloadditions (Scheme 7, a),21 the treatment of allene amide 47 with dimethyldioxirane (DMDO) proceeds only through the (3+2) pathway to generate oxabicyclic species 49 (Scheme 7, b). The density functional theory calculations (DFT) on current system indicated a transition state that features simultaneous interactions of the oxyallyl LUMO with the carbonyl π and lone-pair orbitals. They termed this process as ‘hemipseudopericyclic’, which is halfway between purely pericyclic and purely pseudopericyclic reactions. Further investigation on (3+2) cycloadditions was conducted theoretically and experimentally by employing various carbonyl sources including aldehydes, ketones, esters, and amides. Only tethered ketones with electron-rich substituents are amenable in this process (e.g., 51–54).
3 Oxyallyl Cations Derived from Substituted Ketones Αs mentioned earlier, the use of α,α-dihalo ketones as oxyallyl sources has been well established since the 1970s upon the treatment with reducing agents such as Fe2(CO)9, Fe(CO)5, and Zn/Cu couple.22 Other disubstituted ketones, in principle, may also produce oxyallyl cations under appropriate reductive conditions. For example, Hardinger showed that bis(sulfonyl) ketone 55 could generate oxyallyl intermediate 56 upon treatment with Fe(CO)5 and TiCl4.23 Subsequent (3+2) trapping of 56 with alkenes would furnish the corresponding cyclopentanones (e.g., 59 and 60). Moreover, electron-rich alkynes also turned out to be compatible 2π partners (e.g., 61 and 62) (Scheme 8).
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Syn thesis
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Short Review
H. Li, J. Wu
(a) conventional
O
XcN
Ph
Ph O
O
O
N
O
N
DMDO
O
O
O CH2Cl2 –78 °C
O
O
43
75% dr 95:5
45 NXc
O
44 46
In addition to disubstituted ketones, monosubstituted ones may also act as oxyallyl precursors. Recently, Wu and Hughes reported a regio- and diastereoselective (3+2) annulation of electron-rich 3-substituted indoles 63 with αhalo ketones 64 (Scheme 9).24 This method provides easy access to highly functionalized cyclopenta- or cyclohexafused indoline compounds 65, which are common structures of many natural products. Impressive regiochemical control was observed in the cycloaddition employing acyclic α-halo ketones (e.g., 68, 69).
(b) unexpected
O
Ph Ph
O
O
O
Ph O
N
O
R3
N
N
DMDO
O
R2 +
O
O
49, 85%
Ph
O O
O
O
N
O
51, R = 4-MeOC6H4, 82% 52, R = Ph, 84% 53, R = 4-FC6H4, 70% 54, R = vinyl, 64%
O
O
H
R2 R1
O
R1
or
SO2Ph TiCl4
O
R4
R2 57
56 R3 R3
O
Ph
O
O
Ph
Ph 59 70%
60 65%
Ph
R4 58
O
Ph 61 92%
MeO
R2
H
Bn
O
55
65
O
Scheme 7 (a) Intramolecular (4+3) cycloadditions of allene amidederived oxazolidinone substituted oxyallyls with tethered furan; (b) Intramolecular (3+2) cycloadditions of allene amide-derived oxazolidinone substituted oxyallyls with tethered carbonyls.
PhO2S
R4
O
O
50, 0%
Fe(CO)5
H
R1
64
N
R
O
N
O R3
Ph
R3
Na2CO3
X = Cl, Br
63
O 48
47
R2
TFE, 40 °C
R1
CH2Cl2 –78 °C
R4
X
N
O
O
O
Ph 62 90%
Scheme 8 (3+2) Cycloaddition between bis(sulfonyl) ketone-derived oxyallyls with alkenes and alkynes
66, R2 = allyl, R3 = H 83%, dr 11:1 67, R2 = i-Pr, R3 = I 92%, dr 27:1
N
H
N
Bn
Bn
68 72%
69 77%
Scheme 9 (3+2) Cycloaddition between 3-substituted indoles and αhalo ketones
It is also interesting that the regioisomeric, acyclic αhalo ketones 71 and 72 both afforded 73 as the major product with high diastereoselectivity (>20:1) (Scheme 10, a). Notably, a common O-alkylated intermediate 77 was isolated (Scheme 10, b), suggesting that the reactions of α-halo ketones 71 and 72 may proceed via the same hydroxyallyl intermediate 76. As illustrated in their proposed mechanism (Scheme 10, b), the first C–C bond formation between hydroxyallyl 75 and N-benzylskatole (70) generates intermediate 76, which possesses a weak C···OH interaction. Removal of the proton with carbonate base at this point would furnish the observed intermediate 77. Alternatively, the pronated form 77 could re-dissociate and alkylate at carbon to generate the kinetically favored cycloadduct 74, which can then isomerize to the thermodynamically favored product 73. The above rearrangements, as well as the kinetic and thermodynamic properties of 73 and 74 are in accordance with experimental observations and computational studies.
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Syn thesis
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Short Review
H. Li, J. Wu
Furthermore, DFT calculations in the above (3+2) cycloaddition did raise the question of whether hydroxyallyl cation 75 or its zwitterionic form is the real reactive species. While other cycloaddition reactions are thought to proceed through zwitterionic oxyallyl cations,25 DFT studies on the current system predicted that a pathway for the formation of product 74 via hydroxyallyl 75 is a lower-energy route than that emanating from the corresponding zwitterionic form. Harmata and Schreiner have also observed similar divergent reactivity between oxyallyl and hydroxyallyl cations before.26 The synthetic potential of this (3+2)-cycloaddition process was demonstrated by a concise synthesis of the core structures of vincorine, isocorymine, and aspidophylline A. As shown in Scheme 11, Baeyer–Villiger oxidation of the (3+2)-cycloadduct 78 afforded tertracyclic lactone 80 in 70% yield. Compound 80 was then subject to a debenzylation–oxidation sequence to give hemiaminal 82. Cleavage of the phthalimide group with MeNH2 liberated the amine, which spontaneously closed to furnish the pyrrolidine ring of pentacycle 84. Compound 84 maps well to the cores of vincorine and isocorymine. By employing a similar strategy, pentacycle 85 was obtained from (3+2)-cycloadduct 79, which provided a good starting point for the synthesis of aspidophylline A.
O (a)
Ph
O Cl
71
N Bn
46%, dr > 20:1, 9 d
Ph 73 (major)
H
+ O N 70
O
Ph
Bn
Cl
72
N
74%, dr > 20:1, 49 h
Bn
Ph 74 (minor) H
(b) OH
70
Bn N
Ph
O
H HO
H 75
76
N
Ph 74 kinetically favored over 73 H
Bn
H
Ph
H O Ph O N
N
H
Bn
73
77
H
Ph
Bn
thermodynamically favored over 74
Scheme 10 (a) (3+2) Cycloaddition of N-benzylskatole with α-halo ketones. Reagents and conditions: Na2CO3, TFE, 40 °C. (b) Proposed mechanism.
HO MeO2C
MeO
O O
H
N N
R
H
Bn 78, R = NPhth 79, R = OTBS
aspidophylline A
R
MeNH2 or p-TsOH
O N
Bn 80, R = NPhth, 70% 81, R = OTBS, 61%
O
O
2) DMP H
O
O
1) H2, Pd(OH)2 or Pd/C
AcOOH NaHCO3 N
N
O
CHO
N H
Me Me isocorymine
Me vincorine O
O N
O
N
R
CO2Me
N H
N H
OH
82, R = NPhth, 82% 83, R = OTBS, 90%
84, X = NH, 81% 85, X = O, 99%
Scheme 11 Synthesis of core structures for vincorine, isocorymine, and aspidophylline A (n.b., drawn as their enantiomers)
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X
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Syn thesis
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H. Li, J. Wu
4 Oxyallyl Cations from Interrupted Nazarov Cyclizations
O
The Nazarov cyclization entails the 4π-electrocyclic ring closure of a conjugated pentadienyl cation 87, which is derived from dienone 86 upon treatment with acids or irradiation, to form a cyclopentenyl cation 88 (Scheme 12).27 Conventionally, a β-elimination of the adjacent proton would furnish cyclopentenone 89. In the interrupted Nazarov reaction;28 however, the reactive intermediate 88 may be intercepted by a 2π partner (an alkene or alkyne) to undergo a (3+2) cycloaddition at a rate competitive to the normal elimination route. O
O
R1
R3
R2
R4
A
R1
acid or hν
R2
86
O R3
A
R1
R4
R3 R2
87
R4 88
R6
R8
conventional
or R5
R7
O
interrupted R1
O R2
R2
O R1
R2
R8
R3
R1
HO
BF3·OEt2, CH2Cl2
t-Bu
O
t-Bu
–78 °C to r.t.; H2O 89%
H
93 BF3
94
H3O+
BF3
O
H
O
H
(3+2) t-Bu
t-Bu H H
95
96
Scheme 13 (3+2) Cycloaddition of Nazarov-derived oxyallyl cation with pendant olefin
Afterwards, the same group found allylsilanes and vinyl sulfides to be amenable in the intermolecular mode of (3+2) cycloaddition involving Nazarov-derived oxyallyls (Figure 2).30,31 Complete regioselectivity was observed in the reactions employing allylsilanes as 2π partners (e.g., 97), since allylsilane selectively attacks the least substituted end of unsymmetrically substituted oxyallyl cations. This is in accordance with Noyori’s earlier observation that regioselectivity is predicated on pathways intercepting the more stabilized enolate.
R4 O
89 O
R6 Ph
3 R4 R
R7
90
or
3 R4 R
R5
91
R6
H
O R1
Si(i-Pr)3
R5 R3 R2
Si(i-Pr)3 97 72%a
98 90%b
O
O
92
R4
Scheme 12 Conventional versus interrupted Nazarov reaction
Ph
SEt 2
In 1998, West and co-workers reported the first intramolecular (3+2) cycloaddition of olefins and Nazarovderived oxyallyl cations.29 As shown in Scheme 13, diquinane 94 was obtained from achiral trienone 93. It was presumed that activation of trienone 93 generated the reactive cyclopentenyl intermediate 95, which underwent intramolecular (3+2) trapping by the proximal olefin to afford tricyclic compound 96. It is noteworthy that the oxygen atom of the oxyallyl moiety preferentially participated in the annulation with the formation of a C–O bond.24 Upon aqueous workup, the structurally strained enol moiety was hydrolyzed to give hemiketal 94 with selective protonation from the convex face.
SPh Ph 99 71%a dr 7:1
100 37%a
Figure 2 (3+2) Cycloadducts by using allylsilanes and vinyl sulfides as 2π partners. Reagents and conditions: (a) BF3·OEt2; (b) SnCl4.
As mentioned earlier, irradiation may also promote the formation of oxyallyl speices. Stephenson and Porco recently demonstrated a tandem dienone photorearrangementcycloaddition reaction of alkyne-tethered cyclohexadienones (Scheme 14, a) to produce highly complex architectures.32 It was surmised that photochemical rearrangement of substituted dienone 101 would lead to the formation of
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Syn thesis
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H. Li, J. Wu
oxyallyl cation 103 via the Nazarov-type cyclopentenone 102.33 The reactive 1,3-dipole 103 then underwent intramolecular (3+2) cycloaddition with tethered alkyne to form cycloadduct 104. The resulting strained cyclic alkene 104, which turned out to be unstable during purification, could be further elaborated by either inter- (Scheme 14, a) or intramolecular cycloaddition (Scheme 14, b) with furans or a nitrile oxide (via oxime) to generate polycyclic, bridged frameworks. Impressively, in the reaction to yield compound 112 (Scheme 14, b), four rings and six stereogenic centers were generated in this single process. (a) O
O hν (>300 nm) O
benzene O
102
101
O O (3+2) O O
103 104 O
O
O
O
70% 105/106 3:2
+ O O
Ph
106
O
N
O O
Cl
N
Ph 52% 107/108 5.5:1
N
+
O
Et3N
Ph O
O 107
108
(b)
O
R
O
O
R O
O
5 1-Alkylidene-2-oxyallyl Cations
O 105
HO
While the reactive cyclic oxyallyl cations 88 have usually been derived from dienones 86 in traditional Nazarov reactions, they may also be generated from different sources (Scheme 15). For example, Burnell and co-workers reported in 2010 that treatment of allenyl vinyl ketone 113 with BF3·OEt2 could lead to the cyclic oxyallyl cation 114 through Nazarov cyclization.34 In the presence of appropriate olefins, the reactive intermediate 114 may be captured in the (3+2) cycloadditions. As shown in Scheme 15, electron-rich styrenes reacted smoothly to afford bridged (3+2) cycloadducts 116, 117, and 118 as single diastereomers. When aliphatic dienes were employed, the reaction provided a mixture of (3+2) and (4+3) products regioselectively and diastereoselectively (e.g., 119–122). It was indicated that the proportion of (3+2) to (4+3) products is highly dependent on the diene substituents. In addition, Yadav and co-workers recently described (3+2) trapping of oxyallyl cations generated from homoNazarov cyclization of 2-(tert-butyldiphenylsilylmethyl)cyclopropyl vinyl ketones 123 with allylsilanes (Scheme 16).35 This reaction was proposed to begin with the cleavage of σC–C bond of the cyclopropyl ring on 123 to generate enolate 124. The positive charge was proposed to be stabilized by the proximal silyl group. Intermediate 124 then underwent ring-closure to give oxyallyl cations 125, which was then captured by allylsilanes in a (3+2) manner. Although the reaction proceeded with only moderate regioselectivity (e.g., 128/129 = 2:1), exclusive exo-cycloaddition was observed.
In 2006, Fujita reported that the ring opening of alkylidenecyclopropanone acetal 130 under acidic conditions would produce the 1-alkylidene-2-oxyallyl cation 131 as an intermediate, which then undergoes (3+2) or (4+3) cycloadditions in the presence of olefins or dienes (Scheme 17).36 While the reaction of 131 with excess furan delivered a mixture of (4+3) cycloadducts and rearranged products from the (3+2) cycloadducts, the reaction with 2,3-benzofuran 132 furnished (3+2) cycloadduct 133 as a single regioisomer in 76% yield.
hν (>300 nm) benzene
109, R = H 110, R = CO2Et
O O
6 Summary and Outlook
O
111, R = H, 71% 112, R = CO2Et, 55%
Scheme 14 Tandem dienone photorearrangement-cyclization to afford polycyclic structures
The cycloaddition chemistry of oxyallyl cations represents a versatile process in the rapid generation of molecular diversity and complexity. The (3+2) cycloaddition, in particular, enables efficient construction of five-membered carbo- and heterocycles. As discussed above, a variety of oxyallyl cations are able to participate in this [2π+2π] process including those stabilized by heteroatoms and those
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Syn thesis
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H. Li, J. Wu
O O
Lewis acid "LA" R
1
R3
LA
O R1
R2
–78 °C
R3
(3+2) R2
R1 113
115
114 O
O
O
i-Pr
Ph OMe
OMe
OMe
OMe
OMe
116 81%
117 79%
O
118 59%
O
Ph
O
O
Ph
Ph
Ph
+ H
119 85%
120 54%
121 122 121/122 2.7:1, 51%
Scheme 15 (3+2) Cycloaddition of allenyl vinyl ketone-derived oxyallyl cation with olefins
O
O
R2
R3
Lewis acid "LA"
R2
–78 °C
R1
R1 TBDPS
123
LA
O
LA OR
R2
R3
R3
OTMS
MeO
R1 TBDPS
124
SnCl4 CH2Cl2 –78 °C
125
TBDPS
130
131 R = Me, TMS
R2 O
TMS (3+2)
R1
R3
TBDPS
R2 R1
+
O R3
TBDPS TMS
126
TMS
127
O
132 O 133 76%
O +
TBDPS
O O
TBDPS
SiMe3
SiMe3 128
Scheme 17 (3+2) Cycloaddition of 1-alkylidene-2-oxyallyl cation with 2,3-benzofuran
129 128/129 2:1, 81%
Scheme 16 (3+2) Cycloaddition of cyclopropyl vinyl ketone-derived oxyallyl cation with allylsilanes
‘unstablized’ species. Both classes of oxyallyl cations can either be cyclic or acyclic and may be derived from different sources. Due to the electrophilic nature of oxyallyl cations, electron-rich alkenes or alkynes are generally favorable 2π partners. However, electron-deficient 2π partners including
α,β-unsaturated ketones (e.g., methyl cinnamate, methyl butynoate), carbonyl groups, and diethyl azodicarboxylate are also amenable in some cases. The past twenty years have witnessed the development of many chemo-, regio- and diastereoselective oxyallyl (3+2) cycloadditions. Some of them have also been successfully employed in the elegant syntheses of natural products. Despite the impressive progress that has been made in the oxyallyl (3+2) cycloadditions, there is still plenty of room for improvement and further exploration. For example, the development of catalytic and enantioselective processes
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still remains relatively rare. It is our hope that this article will stimulate continued interest in the (3+2) cycloaddition of oxyallyl cations and make it a prolonged and prominent research area for developing novel methods used for natural product syntheses.
Acknowledgment The NIH-NIGMS (1R01GM111638-01) and Dartmouth College are gratefully acknowledged for generous support of research in the current area.
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