Stereoselective Synthesis of (–)-Cinmethylin

Abstract

We synthesized optically active (–)-cinmethylin with a high stereoselectivity. Sharpless asymmetric dihydroxylation of g-terpinene afforded an optically active diol with 98% ee. This diol was converted into (–)-cinmethylin in seven reaction steps. Dehydroxylation by the Barton–McCombie method was applicable, depending on the type of substituent, with the reaction affording the desired product when the substrate bore an OTBS group, but not when the substrate contained a benzyl ether. Decarbonylation gave the desired product regardless of the type of substituent. Furthermore, the stereoselectivity of the epoxidation reaction of an olefin with m-CPBA depended on the substituent, and up to 31% of the desired epoxide was obtained. Cyclization of the epoxide with PPTS proceeded with a good yield.

Key words

cinmethylin - asymmetric synthesis - stereoselective synthesis - Sharpless asymmetric dihydroxylation - epoxidation - cyclization

Publication History

Received: 11 November 2024

Accepted after revision: 30 December 2024

Accepted Manuscript online:
30 December 2024

Article published online:
03 February 2025

• References and Notes

• 1a Payne GB, Soloway SB, Powell JE, Roman SA, Kollmeyer WD. EP 0081893, 1983
• 1b Payne GB. US 4487945, 1984
• 2 Campe R, Hollenbach E, Kämmerer L, Hendriks J, Höffken HW, Kraus H, Lerchl J, Mietzner T, Tresch S, Witschel M, Hutzler J. Pestic. Biochem. Physiol. 2018; 148: 116
• 3a Ditrich K, Rack M, Benson S, Goetz R, Kraus H. WO 2018210663, 2018
• 3b Rack M, Benson S, Wolf B, Goetz R. WO 2019115347, 2018
• 4 Ogawa N, Toyoshima S, Sekikawa S, Ishijima M, Katagiri K, Uematsu C, Hirano T, Ootaka A, Suzuki J. J. Pestic. Sci. 2023; 48: 11
• 5 Becker H, Soler MA, Sharpless B. Tetrahedron 1995; 51: 1345
• 6 Barton DH. R, McCombie SW. J. Chem. Soc., Perkin Trans. 1. 1975; 1574
• 7 (–)-Cinmethylin [(–)-2] A 60% dispersion of NaH in mineral oil (19.4 mg, 0.485 mmol) was added to an ice-cold solution of alcohol 9 (63.5 mg, 0.373 mmol) in DMF (1.2 mL). After 1 h at 0 °C, α-bromo-o-xylene (0.065 mL, 0.49 mmol) was added and the resulting mixture was stirred at r.t. for 20 h, then diluted with sat. aq NH₄Cl. The resulting mixture was extracted with 4:1 hexane–EtOAc (×3), and the combined extracts were dried (MgSO₄) and concentrated. The residue was purified by chromatography (silica gel, hexane–EtOAc) to give a colorless oil; yield: 65.3 mg (64%, >99% ee); [α]_D ²⁷ –78 (c 0.52, CHCl₃); R_f = 0.66 (hexane–EtOAc, 3:1). HPLC [Chiralcel OD-H, hexane–i-PrOH (99:1), 0.5 mL/min, 20 °C]: t _R = 1.2 min [(–)-2, major]; 12.2 min [(+)-2, minor]. IR (neat): 2963, 1464, 1092, 1068 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.96 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.39–1.62 (m, 5 H), 1.47 (s, 3 H), 1.94 (dd, J = 12.4, 6.8 Hz, 1 H), 2.11 (sept, J = 6.8 Hz, 1 H), 2.31 (s, 3 H), 3.53 (dd, J = 6.8, 2.4 Hz, 1 H), 4.35 (d, J = 12.4 Hz, 1 H), 4.54 (d, J = 12.4 Hz, 1 H), 7.12–7.22 (m, 3 H), 7.29–7.34 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.7, 18.2, 18.3, 18.9, 32.0, 32.8, 34.0, 42.1, 68.5, 82.8, 85.5, 88.7, 125.7, 127.6, 128.5, 130.2, 136.5, 136.7. HRMS (FD): m/z [M⁺] calcd for C₁₈H₂₆O₂: 274.19328; found: 274.19297.
• 8 Hutchins RO, Milewski CA, Maryanoff BE. J. Am. Chem. Soc. 1973; 95: 3662