Synlett 2019; 30(01): 49-53
DOI: 10.1055/s-0037-1611084
letter
© Georg Thieme Verlag Stuttgart · New York

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

Grigory A. Shevchenko +
,
Gabriele Pupo +
,
Benjamin List*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany   Email: list@mpi-muelheim.mpg.de
› Author Affiliations
The Max Planck Society, the DFG (Leibnitz award to B.L.) and the Fonds der Chemischen Industrie (fellowship to G.P.) are acknowledged for financial support.
Further Information

Publication History

Received: 07 September 2018

Accepted after revision: 10 October 2018

Publication Date:
14 November 2018 (online)

+ 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.

Supporting Information

 
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  • 18 Azoxybenzene 9 was both observed by 1H NMR spectroscopy and isolated from the crude reaction mixture (purification by FCC).
  • 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).