Enantioconvergent Access to the Enantiomerically Pure Building Blocks (+)- or (-)-4-Hydroxy-3-methyl-2-cyclohexenone Using a Chemoenzymatic Process

Abstract

A convenient chemoenzymatic enantioconvergent access to enantiomerically pure (+)- or (-)-4-hydroxy-3-methyl-2-cyclohexenone is described using a one-pot two-step kinetic resolution-stereoinversion protocol followed by hydrolysis. The key step of the sequence is the spontaneous elimination of an undesired stereocenter. The choice between enzymatic acyl transfer or ester alcoholysis of the corresponding racemic starting material, together with the selectivity of a lipase, determines the absolute configuration of the desired single enantiomer.

enantioconvergence - biocatalysis - kinetic resolution - stereoinversion - chiral building blocks

References and Notes

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12

Characterization of Compound 2: white solid; mp 62 °C. IR (KBr): ν = 3412, 1728, 1211, 1159 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.80 (dd, J = 7.2, 3.6 Hz, 1 H), 3.07 (s, 2 OH), 2.66 and 2.35 (ABX, J = 14.0, 1.5 Hz, 2 H), 2.49 (dddd, J = 14.2, 7.9, 6.2, 1.7 Hz, 1 H), 2.25 (dddd, J = 14.2, 7.2, 6.0, 1.1 Hz, 1 H), 2.05 (dtd, J = 13.6, 7.2, 6.2 Hz, 1 H), 1.93 (dddd, J = 13.6, 7.9, 6.0, 3.6 Hz, 1 H), 1.24 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 209.8 (C), 75.0 (C), 72.8 (CH), 51.3 (CH₂), 36.8 (CH₂), 28.1 (CH₂), 26.1 (CH₃). Anal. Calcd for C₇H₁₂O₃: C, 58.32; H, 8.39. Found: C, 58.21; H, 8.43.
Characterization of Compound 3: white solid; mp 106 °C. IR (KBr): ν = 3391, 1757, 1723, 1148 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 5.00 (dd, J = 8.8, 4.1 Hz, 1 H), 2.54 and 2.40 (ABX, J = 14.6, 1.7 Hz, 2 H), 2.36 (m, 2 H), 2.18-2.05 (partially overlapped m, 1 H), 2.08 (s, 3 H), 1.97 (m, 1 H), 1.20 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 207.7 (C), 170.4 (C), 75.0 (CH), 73.7 (C), 51.7 (CH₂), 37.4 (CH₂), 26.3 (CH₃), 25.3 (CH₂), 20.9 (CH₃). Anal. Calcd for C₉H₁₄O₄: C, 58.05; H, 7.58. Found: C, 57.89; H, 7.60.

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15

CAL-B and RML lipases also showed high enantio-selectivity, but with a slightly lower ee.

16 Using commercially available AD-mix-α or AD-mix-β, the Sharpless AD reaction applied to 3-methyl-3-cyclohexen-one, also afforded directly the target molecule 1 by an in situ elimination of the tertiary hydroxyl group in 2 (64% yield), but in the racemic form, see: Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2768