Asymmetric Synthesis of γ-Amino-Functionalised Vinyl Sulfones: De Novo Preparation of Cysteine Protease Inhibitors

In memory of Prof. Ron Grigg FRS (Emeritus Professor, University of Leeds) and in recognition of his many achievements in the field of organic chemistry and his support in the careers of others

Abstract

The enantioselective azo-based α-amination of an aldehyde followed by a Horner–Wadsworth–Emmons-based vinyl sulfone formation is reported. The thus obtained optically active N,N′-diprotected trans-(phenylsulfonyl)vinyl hydrazine products were then converted into the corresponding N-functionalised trans-(phenylsulfonyl)vinyl amines. Specifically, reaction of 4-phenylbutanal with di-tert-butyl azodicarboxylate (DBAD) in the presence of l- or d-proline, followed by addition of diethyl [(phenylsulfonyl)methyl]phosphonate, gave either enantiomer of di-tert-butyl trans-1-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]hydrazine-1,2-dicarboxylate. The enantiomeric excesses of the (+)- and (–)-enantiomers prepared in this manner were in the range 86–89%. The conversion of these γ-hydrazino vinyl sulfones into the corresponding γ-amino-substituted compounds was achieved following a Boc deprotection, Zn reduction, N-functionalisation sequence. This three-step sequence was reasonably efficient (approx. 50%) and no erosion of enantiopurity was found to have taken place. The compounds accessed via this process include both enantiomers of tert-butyl trans-[5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl]carbamate and epimeric dipeptide mimetics including 4-methyl-N-{(S)-1-oxo-3-phenyl-1-[((S,E)-5-phenyl-1-(phenylsulfonyl)pent-1-en-3-yl)amino]propan-2-yl}piperazine-1-carboxamide (also known as K777).

Key words

organocatalysis - amination - azo compounds/diazenes - hydrazine reduction - stereoselectivity - cysteine protease inhibitors - K777

Publication History

Received: 12 October 2021

Accepted after revision: 17 November 2021

Article published online:
27 January 2022

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