Base-free enantioselective SN2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis.

Mili Litvajova,Stephen J Connon,Brendan Twamley,Emiliano Sorrentino

doi:10.3762/bjoc.17.146

Abstract

N-Protected oxindole derivatives of unprecedented malleability bearing ester moieties at C-3 have been shown to participate in enantioselective phase-transfer-catalysed alkylations promoted by ad-hoc designed quaternary ammonium salts derived from quinine bearing hydrogen-bond donating substituents. For the first time in such phase-transfer-catalysed enolate alkylations, the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst’s quinoline moiety aided in avoiding selectivity-reducing complications related to the production of HBr in these processes. The influence of steric and electronic factors from both the perspective of the nucleophile and electrophile were investigated and levels of enantiocontrol up to 90% ee obtained. The synthetic utility of the methodology was demonstrated via the concise enantioselective synthesis of a potent CRTH2 receptor antagonist.

Highlights

The 2-oxindole scaffold is an important motif present in a myriad of natural products
Among 2-oxidole derivatives, 3,3'disubstituted-2-oxindoles are widespread and can be found in a diverse array of pharmaceutical agents (Figure 1A) [1-4]. Their facile transformation into pyrroloindoline and spirooxindole derivatives as well as more structurally complex molecules renders them potentially highly valuable synthetic building blocks [5-12]. Both pyrroloindolines 1 and spirooxindoles 2 are conceivably available from key 3,3-disubstituted intermediates 3, which could be prepared via an enantioselective SN2 alkylation involving enolate 3a (Figure 1B)
We realised that phase-transfer catalysis, due to its operational simplicity and utility in mediating reactions involving charged intermediates, could be an excellent methodology for the enantioselective SN2 alkylation of enolates derived from the 2-oxindole core [13-23]

Summary

Introduction

The 2-oxindole scaffold is an important motif present in a myriad of natural products. We realised that phase-transfer catalysis, due to its operational simplicity and utility in mediating reactions involving charged intermediates, could be an excellent methodology for the enantioselective SN2 alkylation of enolates derived from the 2-oxindole core [13-23].

Results

Conclusion