Catalytic Strategies to Enantiopure Benzoins: Past and Future

Abstract

The catalytic strategies developed so far for the synthesis of enantiomerically pure benzoins are reviewed. Particular attention is given to their substrate scope and limitations. Finally, this short review highlights the advantages of more atom-economic methods that have been reported recently.1 Introduction2 Benzoin Condensation2.1 Nucleophilic Carbenes as Catalysts2.2 Homocondensation of Aromatic Aldehydes2.3 Cross-Benzoin Condensation2.4 Acyloin Condensation2.5 Biocatalytic Methods3 Organocatalytic Friedel–Crafts Reaction4 Oxidative Methods4.1 α-Hydroxylation of Ketones4.2 Ketohydroxylation of Alkenes4.3 Enantiospecific Oxidation of meso-Hydrobenzoins4.4 Kinetic Resolution of Racemic Hydrobenzoins4.5 Biocatalytic Dynamic Kinetic Resolution5 Asymmetric Hemireduction of Benzils5.1 Biocatalytic Reductions – A Brief Summary5.2 Piers Hydrosilylation of Benzils5.3 Photoreduction of Benzils to Benzoins5.4 Metal-Catalyzed Hemihydrogenation of Benzils6 Conclusion and Future Challenges

Chiral Benzoins via Asymmetric Transfer Hemihydrogenation of Benzils: The Detail that Matters

“…During our recent mechanistic study of the ATH of acetophenone, we treated the bromoisonitrile complex [FeBr(CNR)(1)]BF 4 (7) with NaO i Pr (1 equiv) at 25 °C in 2-propanol. 35 The primary product of the reaction is the 2-propoxo complex [Fe(O i Pr)-(CNR)(1)]BF 4 (8), which is the resting species of the catalytic cycle. The elimination of acetone from 8 produces the catalytically active hydride complex 3 (Scheme 1).…”

“…A variety of oxidative methods have been applied to the synthesis of enantioenriched benzoins, but no catalyst for the direct asymmetric ketohydroxylation of alkenes has been reported to date. 8 As an alternative, Sharpless' asymmetric dihydroxylation (AD) of alkyl and silyl enol ethers gave benzoin with excellent enantioselectivity (99% ee). 44 With alkenes as α-ketol surrogates, Plietker developed the regioselective catalytic mono-oxidation of enantiomerically pure vicinal diols to prepare (S)-benzoin in high yield (82%) and excellent enantioselectivity (96% ee).…”

“…Yet, the optical lability of their α-stereocenter under basic conditions 9−12 poses a remarkable challenge to the preparation of αhydroxyketones, particularly in the case of benzoins. 8 In the light of their synthetic relevance, 3 several strategies have been developed to prepare optically active benzoins, with the benzoin condensation of aromatic aldehydes, 13−17 opening the way. Oxidative methods such as the α-hydroxylation of ketones, 5,18,19 the enantiospecific oxidation of meso-hydrobenzoins, 20 and the kinetic resolution (KR) of racemic benzoins 21−25 followed shortly afterward.…”

“…Thanks to the combination of a highly directing hydroxy group with the easily functionalized prostereogenic carbonyl, the α-hydroxyketone substructure is a valuable tool in synthetic organic chemistry and is frequently exploited as a chiral template and building block . Also, as enantiomerically pure acyloins are frequent structural subunits in natural products and bioactive molecules, − their preparation via chemical and enzymatic methods has received much attention. Yet, the optical lability of their α-stereocenter under basic conditions − poses a remarkable challenge to the preparation of α-hydroxyketones, particularly in the case of benzoins …”

Cyanide Anions as Nucleophilic Catalysts in Organic Synthesis

“…Most importantly, optically active NHC catalysts enable asymmetric benzoin condensations. 58 But NHC catalysis is of course out of the scope of this review.…”