Asymmetric intramolecular α-cyclopropanation of aldehydes using a donor/acceptor carbene mimetic

Chaosheng Luo,Yong Huang,Zhen Wang

doi:10.1038/ncomms10041

Abstract

Enantioselective α-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. Common alkylation agents, that is, alkyl halides, are notorious substrates for both Lewis acids and organocatalysts. Recently, olefins emerged as a benign alkylating species via photo/radical mechanisms. However, examples of enantioselective alkylation of aldehydes/ketones are scarce and direct asymmetric dialkylation remains elusive. Here we report an intramolecular α-cyclopropanation reaction of olefinic aldehydes to form chiral cyclopropane aldehydes. We demonstrate that an α-iodo aldehyde can function as a donor/acceptor carbene equivalent, which engages in a formal [2+1] annulation with a tethered double bond. Privileged bicyclo[3.1.0]hexane-type scaffolds are prepared in good optical purity using a chiral amine. The synthetic utility of the products is demonstrated by versatile transformations of the bridgehead formyl functionality. We expect the concept of using α-iodo iminium as a donor/acceptor carbene surrogate will find wide applications in chemical reaction development.

Highlights

Enantioselective a-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis
We decided to explore the possibility of forming a cyclopropane through oxidative annulation between the aldehyde a-CH2 and a tethering double bond
We found that p-nitrobenzoic acid stabilizes 3a under the reaction condition

Summary

Introduction

Enantioselective a-alkylation of carbonyl is considered as one of the most important processes for asymmetric synthesis. In sharp contrast to their biological stability, fused cyclopropanes carry unique chemical reactivity for fragmentation and rearrangement that is often exploited in natural product synthesis[23,24,25] To access these structurally unique scaffolds, a number of synthetic methods have been developed. In 2013, MacMillan and co-workers accomplished intramolecular a-alkylation of aldehydes having a tethering double bond via enamine-singly occupied molecular orbital catalysis[41] Both MacMillan and Cordova reported methods to generate a-cyclopropane aldehydes from a,b-unsaturated aldehydes using an iminium-enamine cascade strategy[42,43,44,45]. We report an orthogonal approach for direct a-cyclopropanation of aldehydes via intramolecular C 1⁄4 C/CH2 annulation, enabling rapid access to bicyclo[3.1.0]hexanes and their aza analogues (Fig. 1) This strategy uses an a-iodo iminium species as a key donor/acceptor carbene mimetic

Methods

Results

Conclusion