Lipase-Catalyzed Asymmetric Dealkoxylcarbonylation of σ-Symmetrical β-Ketodiesters and Its Application to the Synthesis of (-)-Podocarpic Acid

Abstract

Optically active 2,6-dimethylcyclohexanone-2-carb­oxylate was prepared by PLE-catalyzed dealkoxycarbonylation of σ-symmetrical β-ketodiesters, which possess quarternary carbons at α- and α′-positions. Moreover, (-)-podocarpic acid was prepared in a short sequence from 2,6-dimethylcyclohexanone-2-carboxylate.

Key words

dealkoxycarbonylation - PLE catalysis - β-ketodiesters - hydrolysis

References

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4

As shown below, the singlet signal assigned to the α-methyl group of 2a-cis appeared at lower magnetic field than that of 2a-trans, while methyl signals as doublets were observed at almost the same chemical shift.
2a- cis: [α]_D +69.6 (c 1.19, CHCl₃, 84% ee); IR (CHCl₃): 2951, 1736, 1705, 1458, 1273 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 3.74 (s, 3 H), 2.71-2.59 (m, 1 H), 2.46-2.45 (m, 1 H), 2.10-2.00 (m, 1 H), 1.90-1.78 (m, 3 H), 1.55-1.47 (m, 1 H), 1.47 (s, 3 H), 1.03 (d, J = 6.6 Hz, 3 H); MS (20 eV): m/z (%) = 184 (M⁺, 20), 152 (20), 124 (37), 101 (100), 58 (34); HRMS: m/z calcd for C₁₀H₁₆O₃ (M⁺): 184.1099, found: 184.1103.
2a- trans: [α]_D -153 (c 0.80, CHCl₃, 89% ee); IR (CHCl₃): 2939, 1709, 1454, 1258 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 3.72 (s, 3 H), 2.59 (m, 2 H), 2.08-2.00 (m, 1 H), 1.76-1.67 (m, 2 H), 1.46-1.30 (m, 2 H), 1.28 (s, 3 H), 1.05 (d, J = 6.4 Hz, 3 H); MS (20 eV): m/z (%) = 184 (M⁺, 59), 152 (35), 124 (56), 101 (100), 58 (62); HRMS: m/z calcd for C₁₀H₁₆O₃ (M⁺): 184.1099, found: 184.1094.

6

(1R)-(1-Methyl-2-oxocyclohexyl)carboxylic acid (60% ee) prepared by PLE-catalyzed optical resolution of ethyl (1-methyl-2-oxocyclohexyl)carboxylate [5] was derivatized to (1R,3R)- and (1R,3S)-methyl (1-methyl-2-oxocyclo-hexyl)carboxylate; the direction of optical rotation [(+) for cis isomer, and (-) for trans isomer] implied that the 2a-cis and 2a-trans should have an R configuration at C-1.

12

Recrystallization of 12 (258 mg, 84% ee) from n-hexane afforded the optically pure compound (61.0 mg, >99.5%).