Exploiting Configurational Lability in Aza‐Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides

Michael J. Tilby,Damien F. Dewez,Carolina Martínez Lamenca,Michael C. Willis,Adrian Hall

doi:10.1002/ange.202109160

Michael J. Tilby, Damien F. Dewez + Show 3 more

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https://doi.org/10.1002/ange.202109160

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Abstract

AbstractMethods for establishing the absolute configuration of sulfur‐stereogenic aza‐sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. We have addressed this by exploiting, for the first time, a feature of sulfonimidamides in which it is possible for tautomeric structures to also be enantiomeric. Such sulfonimidamides can readily generate prochiral ions, which we have exploited in an enantioselective alkylation process. Selectivity is achieved using a readily prepared bis‐quaternized phase‐transfer catalyst. The overall process establishes the capability of configurationally labile aza‐sulfur species to be used in asymmetric catalysis.

Highlights

Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials
The majority of existing methods for the synthesis of enantioenriched sulfonimidamides rely on the addition of an enantiopure amine into a racemic sulfonimidoyl halide (F), which commonly results in a poor diastereomeric ratio of products.[8b,10c,24a] Alternative routes often proceed through the formation of a handful of enantioenriched sulfonimidoyl halides, followed by a stereoselective displacement, typically with inversion of stereochemistry.[13,18a,24b] In these sequences the use of sulfonimidoyl chlorides is often undesirable on account of their chemical instability.[25]
Whilst Boc-protected sulfonimidoyl fluorides have recently been shown to be a more stable substitute,[13] both species are prone to significant racemisation if not handled with care, and loss of stereochemical information can result.[18a,26] Limited reports have used more specific, stable enantioenriched precursors.[27,10g] the N-based reactivity of sulfonimidamides is well documented,[28] there are only a handful of methods that exploit this in asymmetric synthesis

Summary

Introduction

Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. As the X-ray structure of 2 a displays the presence of chirality, we attempted to prepare compound 2 b via a series of known stereoselective transformations, from a derivative of one of the few commercially available enantiopure sulfinamides ((S)-1, Scheme 2 b, see Supporting information).[9b,18a,b] From these experiments, the resulting 2 b showed no significant optical rotation.

Results

Conclusion