Chiral Aminoalcohols and Squaric Acid Amides as Ligands for Asymmetric Borane Reduction of Ketones: Insight to In Situ Formed Catalytic System by DOSY and Multinuclear NMR Experiments.

Yana Nikolova,Georgi M Dobrikov,Zhanina Petkova,Pavletta Shestakova

doi:10.3390/molecules26226865

Abstract

A series of squaric acid amides (synthesized in 66–99% isolated yields) and a set of chiral aminoalcohols were comparatively studied as ligands in a model reaction of reduction of α-chloroacetophenone with BH3•SMe2. In all cases, the aminoalcohols demonstrated better efficiency (up to 94% ee), while only poor asymmetric induction was achieved with the corresponding squaramides. A mechanistic insight on the in situ formation and stability at room temperature of intermediates generated from ligands and borane as possible precursors of the oxazaborolidine-based catalytic system has been obtained by 1H DOSY and multinuclear 1D and 2D (1H, 10/11B, 13C, 15N) NMR spectroscopy of equimolar mixtures of borane and selected ligands. These results contribute to better understanding the complexity of the processes occurring in the reaction mixture prior to the possible oxazaborolidine formation, which play a crucial role on the degree of enantioselectivity achieved in the borane reduction of α-chloroacetophenone.

Highlights

IntroductionAsymmetric reduction of ketones still attracts significant interest since it is one of the most efficient ways of generating enantiomerically pure secondary alcohols as important intermediates or chiral building blocks for the synthesis of biologically relevant structures [1,2,3,4,5,6,7,8]
Our results clearly demonstrate that the free aminoalcohols were more efficient ligands to induce enantioselectivity in comparison to the corresponding squaramides
The catalytic system was studied in situ in reaction mixtures modeling the catalyst formation between

Summary

Introduction

Asymmetric reduction of ketones still attracts significant interest since it is one of the most efficient ways of generating enantiomerically pure secondary alcohols as important intermediates or chiral building blocks for the synthesis of biologically relevant structures [1,2,3,4,5,6,7,8]. Among the various well-known approaches, borane reduction has been demonstrated to allow fine-tuning for attaining a higher degree of selectivity. Remarkable success in this reaction has been achieved using chiral oxazaborolidines prepared from (semi)synthetic aminoalcohols derived from natural amino acids, terpenoids [9,10,11], etc

Methods

Results

Conclusion