Abstract:The key factors for carbonyl‐stabilised ammonium ylide‐mediated epoxidation reactions were systematically investigated by experimental and computational means and the hereby obtained energy profiles provide explanations for the observed experimental results. In addition, we were able to identify the first tertiary amine‐based chiral auxiliary that allows for high enantioselectivities and high yields for such epoxidation reactions.
“…This step is followed by torsional rotation to yield the transoid conformer B , and finally ring closure (elimination of the amine) to give the corresponding epoxide 3 (Scheme 2). The observed high trans -diastereoselectivity was found to be a consequence of the more favoured elimination from trans betaine ( B ) as compared to the analogous cis -pathway [11].
…”
Section: Resultsmentioning
confidence: 99%
“…The use of easily available ammonium ylides [1] has emerged as a powerful alternative to classically used sulfonium ylides [2] for the synthesis of three-membered ring compounds like epoxides [3–11], aziridines [12, 13], and cyclopropanes [14–16]. These reactions usually benefit from very high and predictable diastereoselectivities and broad application scopes [3–16], as illustrated for epoxidation reactions using amide-based ylides 1 with different aldehydes 2 (Scheme 1a) [7].…”
Section: Introductionmentioning
confidence: 99%
“…However, some limitations were observed: While the use of Cinchona alkaloids as chiral amine leaving groups was found to be a very versatile strategy for enantioselective cyclopropanation reactions [14, 15], these simple naturally occurring chiral amines were not suited for epoxidations and aziridinations [6, 11, 13]. Our group has for years been interested in the development of new catalytic [17, 18] and auxiliary-based methods [8, 11] for the synthesis of chiral heterocycles. Based on this general interest, we recently carried out an extensive screening and optimization of different chiral amines for ammonium ylide-mediated epoxidation reactions.…”
Section: Introductionmentioning
confidence: 99%
“…Based on this general interest, we recently carried out an extensive screening and optimization of different chiral amines for ammonium ylide-mediated epoxidation reactions. This allowed us to overcome the above mentioned obstacles when using Cinchona alkaloids and to develop the first highly enantioselective and high yielding ammonium ylide 4 mediated epoxidation protocol (Scheme 1b) [11]. Alternatively, very high stereoselectivities were also obtained by using chiral amide-based ylides 5 , which resulted in complete control of the absolute and relative configuration (Scheme 1c) [8].…”
Section: Introductionmentioning
confidence: 99%
“…Impressed by the extraordinarily high stereoselectivities obtained using the chiral phenylglycinol-derived auxiliary-containing ylides 5 [8] and based on our recently gathered mechanistic understanding of the analogous racemic reactions with ylides 1 [11], we have now performed detailed DFT calculations for the reaction of 5 with benzaldehyde ( 2 ) to elucidate the origin of this high stereoselectivity.…”
Detailed DFT studies provide an in-depth mechanistic understanding for the use of chiral amide-based ammonium ylides in epoxidation reactions. It is shown that the used chiral auxiliary efficiently shields one face of the ylide, which thus results in an extraordinarily high stereoselectivity giving only one trans-isomer with perfect control of the absolute configuration.Graphical abstract
Electronic supplementary materialThe online version of this article (doi:10.1007/s00706-016-1866-8) contains supplementary material, which is available to authorized users.
“…This step is followed by torsional rotation to yield the transoid conformer B , and finally ring closure (elimination of the amine) to give the corresponding epoxide 3 (Scheme 2). The observed high trans -diastereoselectivity was found to be a consequence of the more favoured elimination from trans betaine ( B ) as compared to the analogous cis -pathway [11].
…”
Section: Resultsmentioning
confidence: 99%
“…The use of easily available ammonium ylides [1] has emerged as a powerful alternative to classically used sulfonium ylides [2] for the synthesis of three-membered ring compounds like epoxides [3–11], aziridines [12, 13], and cyclopropanes [14–16]. These reactions usually benefit from very high and predictable diastereoselectivities and broad application scopes [3–16], as illustrated for epoxidation reactions using amide-based ylides 1 with different aldehydes 2 (Scheme 1a) [7].…”
Section: Introductionmentioning
confidence: 99%
“…However, some limitations were observed: While the use of Cinchona alkaloids as chiral amine leaving groups was found to be a very versatile strategy for enantioselective cyclopropanation reactions [14, 15], these simple naturally occurring chiral amines were not suited for epoxidations and aziridinations [6, 11, 13]. Our group has for years been interested in the development of new catalytic [17, 18] and auxiliary-based methods [8, 11] for the synthesis of chiral heterocycles. Based on this general interest, we recently carried out an extensive screening and optimization of different chiral amines for ammonium ylide-mediated epoxidation reactions.…”
Section: Introductionmentioning
confidence: 99%
“…Based on this general interest, we recently carried out an extensive screening and optimization of different chiral amines for ammonium ylide-mediated epoxidation reactions. This allowed us to overcome the above mentioned obstacles when using Cinchona alkaloids and to develop the first highly enantioselective and high yielding ammonium ylide 4 mediated epoxidation protocol (Scheme 1b) [11]. Alternatively, very high stereoselectivities were also obtained by using chiral amide-based ylides 5 , which resulted in complete control of the absolute and relative configuration (Scheme 1c) [8].…”
Section: Introductionmentioning
confidence: 99%
“…Impressed by the extraordinarily high stereoselectivities obtained using the chiral phenylglycinol-derived auxiliary-containing ylides 5 [8] and based on our recently gathered mechanistic understanding of the analogous racemic reactions with ylides 1 [11], we have now performed detailed DFT calculations for the reaction of 5 with benzaldehyde ( 2 ) to elucidate the origin of this high stereoselectivity.…”
Detailed DFT studies provide an in-depth mechanistic understanding for the use of chiral amide-based ammonium ylides in epoxidation reactions. It is shown that the used chiral auxiliary efficiently shields one face of the ylide, which thus results in an extraordinarily high stereoselectivity giving only one trans-isomer with perfect control of the absolute configuration.Graphical abstract
Electronic supplementary materialThe online version of this article (doi:10.1007/s00706-016-1866-8) contains supplementary material, which is available to authorized users.
An ammonium ylide mediated access towards trans‐β,γ‐disubstituted, all‐trans‐α,β,γ‐trisubstituted, and α,α,β,γ‐tetrasubstituted γ‐butyrolactones bearing a broad variety of functionalities was developed. Starting from widely accessible benzylidene Meldrum's acid derivatives and α‐bromo carbonyl compounds, γ‐butyrolactones were obtained in yields between 32–99% with up to excellent diastereoselectivities (>95:5) via a DABCO‐mediated [2+1] annulation. Utilization of enantiomerically pure cinchona alkaloid derivatives enables the first asymmetric ammonium ylide mediated method to provide (3R, 4R)‐β,γ‐disubstituted and (2R, 3R, 4R)‐α,β,γ‐trisubstituted γ‐butyrolactones in moderate to good yields with up to very good enantiomeric ratios (97:3). The scalability of the transformation was proven while determining the absolute configuration.
The use of readily accessible ammonium ylides for (asymmetric) transformations, especially cyclization reactions, has received considerable attention over the past two decades. A variety of highly enantioselective protocols to facilitate annulation reactions have recently been introduced as an alternative to other common methods including S-ylide-mediated strategies. It is the intention of this short review to provide an introduction to this field by highlighting the potential of ammonium ylides for (asymmetric) cyclization reactions as well as to present the limitations and challenges of these methods.
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