Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

Abstract

An enantioselective cyclopropanation of alpha-substituted alpha,beta-unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/alpha-alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the alpha-position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and alpha,beta-unsaturated aldehydes previously reported by other groups. Very good yields (up to 81%) and enantioselectivities (up to 97% ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.

Asymmetric Nitrocyclopropanation of α‐Substituted α,β‐Enals Catalyzed by Diphenylprolinol Silyl Ether for the Construction of All‐Carbon Quaternary ­Stereogenic Centers

“…We chose to study 2‐methylenenonanal as a model substrate of α‐substituted α,β‐unsaturated aldehydes and its reaction with bromonitromethane in EtOH in the presence of diphenylprolinol trimethylsilyl ether ( 1 ). First, the amine was investigated in the presence of diphenylprolinol trimethylsilyl ether (Figure 1) as a catalyst; racemic cyclopropane was obtained if triethylamine was employed,8a whereas N ‐methylimidazole5d gave the cis isomer with excellent enantioselectivity (93 % ee ) and the trans isomer with low enantioselectivity (24 % ee ; Table 1, entry 1). The effect of the silyl moiety was examined; if bulkier silyl ethers14 were employed, higher enantioselectivity was observed.…”

“…Our group reported the asymmetric epoxidation of α‐substituted α,β‐unsaturated aldehydes with H 2 O 2 catalyzed by diphenylprolinol silyl ether to afford epoxides with a tetrasubstituted carbon atom with excellent enantioselectivity 13. There is one example of the generation of all‐carbon quaternary stereogenic centers as part of a cyclopropane ring: Campagne and co‐workers reported the cyclopropanation of α‐substituted α,β‐unsaturated aldehydes with bromomalonate catalyzed by diphenylprolinol silyl ether 5d. We envisaged nitrocyclopropanes with all‐carbon quaternary stereogenic centers to be readily synthesized by the organocatalyzed reaction of α‐substituted α,β‐unsaturated aldehydes with bromonitromethane by using our catalyst.…”

Recent Developments in Asymmetric Organocatalytic Domino Reactions

“…[85] This method allowed the efficient formation of chiral cyclopropanes bearing a quaternary stereogenic center at the a-position of the aldehydes by using the iminium-enamine activation mode and gave a nice extension to this reaction with very good yields of up to 81% and excellent enantioselectivities of up to 97% ee. It is interesting to note the ambivalent character of the bromomalonate in this process which successively played the role of both nucleophile and electrophile.…”

Recent Advances in Organocatalytic Methods for Asymmetric CC Bond Formation

“…Campagne et al. were also able to accomplish very good results for reactions of α‐substituted acroleines and bromo malonates 187 212…”