Urea-catalyzed transthioesterification: towards a new kinetic resolution methodology

Sean Tallon,Stephen J Connon,Alana C Lawlor,Thomas Kurz

doi:10.3998/ark.5550190.0012.410

Abstract

The efficient catalysis of transthioesterification reactions by a urea-based (but not thiourea-based) hydrogen bond donor in the presence of an amine co-catalyst has been demonstrated for the first time. The process is of wide substrate scope and the efficient exchange between unhindered achiral thiols and bulkier chiral thioesters is possible in the presence of the catalyst, which is a key first milestone towards the development of kinetic resolution processes based on transthioesterification processes.

Highlights

Transthioesterification is a reversible process involving the reaction of a thioester with a thiol in the presence of base (Scheme 1).[1,2] This exchange process is an essential component of fatty acid biosynthesis[3] and constitutes the rate-determining step of the powerful Native Chemical Ligation (NCL)[4,5] peptide coupling methodology
Our preliminary experiments were focused on establishing the catalytic competence of a urea catalyst (8 - which we have shown to be useful in a variety of catalytic processes previously) in a simple thioester exchange reaction
Increasing the basicity of the amines further led to faster rates of exchange: DABCO, DMAP and DIPEA all promoted the reaction almost to equilibrium inside 44 h in conjunction with the urea catalyst, while promoting the formation of less than 3% exchange in the same time period in the absence of 8

Summary

Introduction

Transthioesterification is a reversible process involving the reaction of a thioester with a thiol in the presence of base (Scheme 1).[1,2] This exchange process is an essential component of fatty acid biosynthesis[3] and constitutes the rate-determining step of the powerful Native Chemical Ligation (NCL)[4,5] peptide coupling methodology. These processes are often slow in the absence of a strong base and/ or strongly activated thiolate leaving group, which makes the design of catalysts for this reaction potentially desirable.

Objectives

Results

Conclusion