Direct Asymmetric α-Hydroxylation of Cyclic α-Branched Ketones through Enol Catalysis

⁺ These authors contributed equally to this work.

Abstract

Enantiopure α-hydroxy carbonyl compounds are common scaffolds in natural products and pharmaceuticals. Although indirect approaches towards their synthesis are known, direct asymmetric methodologies are scarce. Herein, we report the first direct asymmetric α-hydroxylation of α-branched ketones through enol catalysis, enabling a facile access to valuable α-keto tertiary alcohols. The transformation, characterized by the use of nitrosobenzene as the oxidant and a new chiral phosphoric acid as the catalyst, delivers a good scope and excellent enantioselectivities.

Key words

enol catalysis - α-hydroxy ketones - Brønsted acid catalysis - hydroxylation - chiral phosphoric acid

• References and Notes

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For a non-enantioselective version of the reaction reported here, see:
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• 19 General Procedure: Catalyst B₅ (16.4 mg, 0.02 mmol, 10 mol%) and 2-phenyl cyclohexanone (1a, 0.2 mmol, 1.0 equiv) were placed in a plastic GC vial. After the addition of benzene (0.8 mL) and acetic acid (40 μL, 0.7 mmol, 3.5 equiv), nitrosobenzene (21.4 mg, 0.2 mmol, 1.0 equiv) was added in one portion and the reaction mixture was stirred for 2 h. Then, additional nitrosobenzene (32.1 mg, 0.3 mmol, 1.5 equiv) was added and stirring was continued for additional 22 h. The crude reaction mixture was directly purified by flash column chromatography (hexanes/EtOAc gradient 100:0 to 10:1) to give hydroxy ketone 2a (21.5 mg, 56%, 98:2 er) as an orange oil. ¹H NMR (500 MHz, C₆D₆): δ = 7.18–7.12 (m, 2 H), 7.11–7.01 (m, 3 H), 4.61 (s, 1 H), 2.73 (dq, J = 14.3, 3.2 Hz, 1 H), 2.19 (dddd, J = 13.5, 4.1, 2.7, 1.6 Hz, 1 H), 1.95 (td, J = 13.5, 6.3 Hz, 1 H), 1.69–1.61 (m, 1 H), 1.34 (ddt, J = 12.5, 6.3, 3.1 Hz, 1 H), 1.29–1.07 (m, 3 H) ppm. ¹³C NMR (125 MHz, C₆D₆): δ = 211.9, 141.2, 129.1, 126.8, 80.1, 39.2, 38.8, 28.2, 23.1 ppm (one aromatic signal missing because of overlap with solvent). HRMS (ESI⁺): m/z [M + Na]⁺ calcd for C₁₂H₁₄O₂Na: 213.0886; found 213.0885. HPLC (Chiralpak AD-3, n-Hept/EtOH = 80:20, flowrate: 1.0 ml/min, λ = 206 nm): t _r(major) = 6.88 min, t _r(minor) = 9.73 min. [α]_D ²⁵: +166.0 (c 0.20, CHCl₃, 98:2 er).