Enantioselective, Organocatalytic Reduction of Ketones using Bifunctional Thiourea-Amine Catalysts

Abstract

Prochiral ketones are reduced to enantioenriched, secondary alcohols using catecholborane and a family of air-stable, bifunctional thiourea-amine organocatalysts. Asymmetric induction is proposed to arise from the in situ complexation between the borane and chiral thiourea-amine organocatalyst resulting in a stereochemically biased boronate-amine complex. The hydride in the complex is endowed with enhanced nucleophilicity while the thiourea concomitantly embraces and activates the carbonyl.The enantioselective reduction of prochiral ketones is a mainstay in the production of enantioenriched, secondary alcohols. 1 As in other areas of chiral synthetic methodology, the trend has been away from stoichiometric reductants 2 towards more economic and environmentally friendly catalytic processes 3 and, in recent years, has embraced organocatalysis. 4,5 One of the most prominent and frequently applied members of this latter category is the Corey-Bakshi-Shibata (CBS) catalyst, a chiral oxazaborolidine pioneered by Itsuno 6 and further developed by Corey 7 and other investigators. 8 However, the sensitivity of oxazaborolidines to oxygen and moisture as well as the need in conjunction with a current project for a highly enantioselective reducing agent compatible with a challenging combination of highly sensitive functionality, prompted us to explore the utility of urea-/ thiourea-based organocatalysts as an alternative to CBS oxazaborolidines. 9,10 Whilst chiral ureas and thioureas have emerged as efficacious catalysts for a variety of nucleophilic conjugate additions 11 and 1,2-carbonyl additions, e.g., hydrocyanation, 12 Henry reaction, 13 15,16 However, the insights gained developing asymmetric oxy-Michael additions of boronic acids with α,β-unsaturated ketones 17 revealed several unique attributes that we felt could be harnessed for enantioselective carbonyl reductions. Specifically, we envisioned that the union between a borane and a chiral thiourea-amine organocatalyst would result in a stereochemically biased boronate-amine complex. 18 The hydride in the complex is endowed with enhanced nucleophilicity (the push) while the thiourea concomitantly embraces and activates the carbonyl (the pull) ( Figure 1). As proof-of-concept, we developed of a family of robust, bifunctional thiourea-amine catalysts and describe herein their exploitation for the stereodefined reduction of prochiral ketones to enantioenriched, secondary alcohols.Despite its outstanding performance catalyzing the aforementioned oxy-Michael additions, 17 thiourea catalyst A 19 furnished (S)-(−)-1-phenylethanol (2) in poor yield and low enantioselectivity at room temperature in THF (Table 1, entry 1) using acetophenone (1) and BH 3 ·THF as the model substrate and hydride source, respectively. Reasoning that the cinchona alkaloid moiety might be responsible, it was replaced with the simpler (R,R)-trans-N,N′-dimethylcyclohexane-1,2-diamine. The resultant monobasic catalyst B provided a modest improvement in yield and enantioselectivity, albeit d...

Stereoselective Bioreduction of 1-(4-Methoxyphenyl)ethanone by Whole Cells of Marine-Derived Fungi

“…In addition, other studies have shown that different synthetic catalysts are being used in the reduction of 1-(4-methoxyphenyl)ethanone 1. This alcohol was obtained with good optical purity (96% ee) and excellent conversion (c 98%) by Wang et al (2009), and 97% ee and 80% yield isolated by Li et al (2010). In the present study, we showed that excellent results were achieved in the bioconversion of ketone 1 by several marine-derived fungi.…”

Asymmetric Reduction of Ketones by Phosphoric Acid Derived Catalysts

“…Both catalytic systems have been further developed by altering the ligand or by employing different metals in efforts to enhance the selectivity or improve practicality. [3][4][5] Despite extensive research, the utilization of simple chiral Brønsted acids as precatalysts for this asymmetric process is still unknown.…”

A Single Column Chiroptical HPLC Batch Analysis of Ten Aromatic Alcohols

“…Furthermore, the addition of the laser polarimetric detector in series to the UV detector showed the optical activity of the eluted peaks, revealing the elution order in each chromatographic run (Table 2), as showed for compound 2 ( Figure 2). Each of these optical rotation signs can easily be related to a particular AC through literature data 6,[11][12][13][14][15][16] , which allows the full characterization of the sample through the HPLC analysis. This avoids the need for conventional polarimetric measurements and considerably decreases the time to screen the stereoselectivity of new catalyst during the development phase.…”