Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach.

Alexandre V. Brethomé,Robert S. Paton,Stephen P. Fletcher

doi:10.1021/acscatal.9b01814

Abstract

The development of catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. Here, we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically demanding. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the synthesis of modified phosphoramidite ligands, designed using quantitative structure–selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert-butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across 20 examples.

Highlights

The development of catalytic asymmetric methods usually begins with the examination of a simple, readily available and prototypical substrate
During our work on Cu-catalyzed asymmetric conjugate additions[23−26] of alkylzirconium species we found that asymmetric additions to linear enones bearing linear alkyl chains work well (>90% ee),[27] but additions to electronic or sterically deactivated enones gave only very poor results (
Previous conditions for related asymmetric additions were reoptimized, and we subsequently found that the use of copper(I) triflate and a phosphoramidite ligand in the presence of TMSCl were critical to achieve high reactivity

Summary

Introduction

The development of catalytic asymmetric methods usually begins with the examination of a simple, readily available and prototypical substrate. While this approach is undeniably useful, it often leads to a reaction protocol that is not widely applicable beyond the simple starting scaffold. The copper-catalyzed asymmetric conjugate addition (ACA) of organometallic species is a powerful tool to synthesize new C−C bonds from α,β-unsaturated carbonyl compounds.[1−8] After tremendous attention for more than 20 years, the ACA is arguably one of the most useful asymmetric transformations available to synthetic chemists, and has been used in the synthesis of a variety of natural products.[8−15] there are still a number of challenges that need to be met to reach its full potential. A lack of robustness in Cu-catalyzed ACAs is well-known, and widely implicated in preventing the approach from enriching mainstream synthetic strategies and methods,[16,17] though it should be mentioned that examples of ACAs to give >50 g of product have recently been reported.[18,19] Another reason for the underutilization of this method stems from method development being carried out with commonly available substrates,[20] so that seemingly obvious extensions to slightly unusual or more highly decorated reaction partners do not display the desired reactivity patterns.[21,22]

Objectives

Results

Conclusion