A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-l-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters

The three-component reaction between a protected alpha-amino aldehyde, an alcohol and an alpha-silyloxymalononitrile provides an expedient access to protected alpha-hydroxy-beta-amino acid derivatives. The prototypical process, performed on N-Cbz-phenylalaninal, is known to proceed with syn diastereoselectivity. The present study demonstrates that the diastereoselectivity of the reaction can be inverted, using the rationale of a Felkin-Anh interaction model. Reactions performed on N,N-dibenzyl-l-phenylalaninal proceed with a high anti diastereoselectivity, providing a panel of synthetically useful ester derivatives of (2S,3S)-allophenylnorstatin. The procedure is exploited to accomplish one of the most efficient syntheses of the title compound to date, in 3 steps (66% yield) from N,N-dibenzyl-l-phenylalaninal.

Automated summary

This study demonstrates the inversion of the diastereoselectivity in a three-component reaction, leading to the synthesis of (2S,3S)-allophenylnorstatin ester derivatives with high anti diastereoselectivity. The procedure presented in this study is one of the most efficient methods to synthesize the title compound to date.