Integrated Experimental and Computational Studies on the Organocatalytic Kinetic Resolution of β-Unfunctionalized Primary Alcohols Using a Chiral 1,2-Diamine: The Importance of Noncovalent Interactions

Abstract

The enantioselective kinetic resolution of β-unfunctionalized primary alcohols with benzoyl chloride was carried out in the presence of a catalytic amount of a novel chiral 1,2-diamine derived from (S)-proline. Several valuable chiral 2-substituted propan-1-ols were obtained with good enantioselectivities. Density functional theory calculations revealed that the noncovalent interaction, such as CH−π interaction, is crucial for the enantioselectivity of the resolution. This study was conducted through an interplay between experiment and computation.C hiral 2-phenyl-1-propanol is a promising synthon because this skeleton has applications in anti-inflammatory drugs such as naproxol, ibuprofen, and others. Its derivatives are also used as precursors for the total synthesis of natural products. 1 Chiral 2-phenyl-1-propanol can be obtained by various methods 2−6 (Scheme 1). In 2017, Rychnovsky et al. reported the kinetic resolution of 2-phenyl-1-propanol using homobenzotetramisole (HBTM) and resolution proceeded with a selectivity (s) of ≤6.2 (Scheme 1e). 6 The kinetic resolution of racemic alcohols has been widely utilized to construct valuable chiral building blocks for the synthesis of pharmaceuticals and natural compounds. 7 In particular, the enzymatic kinetic resolution of racemic alcohols has been used as one of the most effective methods 8 for the synthesis of optically active alcohols. In recent decades, the asymmetric acylation of alcohols using organocatalysts has emerged as a powerful approach, and the kinetic resolution of racemic secondary alcohols has been reported many times. 9 However, the kinetic resolution of racemic primary alcohols is limited to a few examples. 10 In 2005, our group reported the first non-enzymatic kinetic resolution of primary alcohols using chiral 1,2-diamine organocatalysts. 11 Chiral 1,2-diamines derived from (S)-proline are excellent organocatalysts for the catalytic asymmetric synthesis of many valuable organic compounds. Pioneering studies by T. Mukaiyama established various asymmetric syntheses using chiral 1,2-diamines readily derived from (S)-proline, including reduction of acetophenone, 12 Grignard reaction to alde-