Multi-Catalytic Route for the Synthesis of (S)-Tembamide

Laura Leemans,Frank Hollmann,Marc D Walter,Anett Schallmey,Luuk M Van Langen

doi:10.3390/catal9100822

Abstract

Enantiopure β-amino alcohols constitute one of the most significant building blocks for the synthesis of active pharmaceutical ingredients. Despite the availability of a range of chiral β-amino alcohols from a chiral pool, there is a growing demand for new enantioselective synthetic routes to vicinal amino alcohols and their derivatives. In the present study, an asymmetric 2-step catalytic route that converts 4-anisaldehyde into a β-amino alcohol derivative, (S)-tembamide, with excellent enantiopurity (98% enantiomeric excess) has been developed. The recently published initial step consists in a concurrent biocatalytic cascade for the synthesis of (S)-4-methoxymandelonitrile benzoate. The O-benzoyl cyanohydrin is then converted to (S)-tembamide in a hydrogenation reaction catalyzed by Raney Ni. To achieve hydrogenation of the nitrile moiety with highest chemoselectivity and enantioretention, various parameters such as nature of the catalyst, reaction temperature and hydrogen pressure were studied. The reported strategy might be transferrable to the synthesis of other N-acyl-β-amino alcohols.

Highlights

A crucial factor influencing selectivity in the catalytic hydrogenation of nitriles is the nature of the catalyst [48,49,50,51,52,53,54,55,56]
The results indicate that Raney Co generally requires higher temperature and H2 pressure to afford tembamide with similar selectivity as Raney Ni, but with lower reaction rate
The one-pot, two-step catalytic synthesis of (S)-tembamide was successfully accomplished on a preparative scale

Summary

Introduction

An asymmetric 2-step catalytic route that converts 4-anisaldehyde into a β-amino alcohol derivative, (S)-tembamide, with excellent enantiopurity (98% enantiomeric excess) has been developed. 1,2-amino alcohols are a common moiety present in numerous biologically active compounds and, play an increasingly important role as precursors in the synthesis of active pharmaceutical ingredients (APIs). In view of their high potential for the synthesis of APIs, considerable efforts have been directed towards the development of new asymmetric synthetic routes to vicinal amino alcohols and their derivatives [2,3,4,5,6,7,8,9]. A 2-step fully catalytic enantioselective route that converts 4-anisaldehyde into a β-amino alcohol derivative, (S)-tembamide, with excellent enantiopurity has been developed.

Methods

Results

Conclusion