Asymmetric Guerbet Reaction to Access Chiral Alcohols

Abstract

The first example of an asymmetric Guerbet reaction has been developed. Using commercially available, classic Noyori RuII‐diamine‐diphosphine catalysts, well‐known in asymmetric hydrogenation, racemic secondary alcohols are shown to couple with primary alcohols in the presence of a base, affording new chiral alcohols with enantiomeric ratios of up to 99:1. Requiring no reducing agents, the protocol provides an easy, alternative route for the synthesis of chiral alcohols. Mechanistic studies reveal that the reaction proceeds via a Ru‐catalyzed asymmetric hydrogen autotransfer process in concert with a base‐promoted allylic alcohol isomerization.

Ru-Catalyzed Asymmetric Addition of Arylboronic Acids to Aliphatic Aldehydes via P-Chiral Monophosphorous Ligands

“…1-(4-fluorophenyl)-3-phenylpropan-1-ol (3ag) [33] [a] 20 D = +22.1 (c 0.99, CH 2 Cl 2 ). Yield: 86% (98.8 mg) as a yellowish oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60-7.09 (m, 7H), 7.01 (t, J = 8.6, 2H), 4.63 (dd, J = 7.8, 5.4, 1H), 2.77-2.57 (m, 2H) and 2.16-1.90 (m, 3H).…”

“…Yield: 86% (98.8 mg) as a yellowish oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.60-7.09 (m, 7H), 7.01 (t, J = 8.6, 2H), 4.63 (dd, J = 7.8, 5.4, 1H), 2.77-2.57 (m, 2H) and 2.16-1.90 (m, 3H). 13 3-phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-ol (3ah) [33] [a] 20 D = +17.1 (c 1.32, CH 2 Cl 2 ). Yield: 94% (131.9 mg) as a yellow oil; 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (d, J = 8.0, 2H), 7.39 (d, J = 8.0, 2H), 7.34-6.99 (m, 5H), 4.68 (dd, J = 7.9, 5.2, 1H), 2.77-2.57 (m, 2H), 2.36 (s, 1H) and 2.13-1.91 (m, 2H).…”

“…As an alternative, strategies via the asymmetric homologation reaction [25][26][27][28], tandem Michael-MPV reaction and subsequent reductive desulfurization [29], as well as the asymmetric addition of aldehydes with arylboronic acids were also established [30,31]. It is worth noting that the tandem α-alkylation/asymmetric reactions of ketones with alcohols [32] and the asymmetric Guerbet reaction of alcohols [33,34] are green and high-efficient strategies.…”

Room‐Temperature Guerbet Reaction with Unprecedented Catalytic Efficiency and Enantioselectivity

“…Importantly, an unprecedent enantioselective variant of this transformation has been achieved, where kinetic resolution of the starting secondary alcohol and enantioselective synthesis of the product alcohol proceed simultaneously. [13] The development of more efficient and selective catalytic system and extension to other related transformations are underway in our laboratory.…”

Redox-enabled direct stereoconvergent heteroarylation of simple alcohols

“…Enantioselective variants of these transformations, on the other hand, have remained underdeveloped 22,23 . Highly enantioselective alkylation of amines and ketones has only been achieved in recent years by our group [24][25][26][27][28] , the Beller group 29 , the Donohoe group 30,31 , and others [32][33][34][35][36][37] to access chiral amines, ketones, alcohols, etc. The application of borrowing hydrogen strategy to an enantioconvergent heteroarylation, to our knowledge, has never been reported in the literature 38 .…”