A Versatile, Diels–Alder Reaction-Based Approach to Prenyleudesmane Diterpenoids: A Concise Total Synthesis of Sinupol

Abstract

Herein, a concise strategy designed to provide general and diversifiable access to various prenyleudesmane terpenoids is described and utilized in the asymmetric synthesis of a biologically active prenyleudesmane diterpenoid, sinupol, which is accomplished in a seven-step procedure.

Key words

prenyleudesmane diterpenoid - sinupol - PTP1B inhibitor - Diels–Alder reaction - total synthesis

• References and Notes

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• 18 (R)-4-Benzyl-3-((2S,4aS,8aS)-4a,8-dimethyl-1,2,3,4,4a,5,6,8a-octahydronaphthalene-2-carbonyl)oxazolidin-2-one (2): BHT (65.4 mg, 0.297 mmol) was added to a solution of triene 3 (1.09 g, 2.97 mmol) in mesitylene (29.7 mL) in a sealed tube. The solution was degassed and heated at 220 °C for 168 h. The reaction mixture was cooled to ambient temperature over a period of 1 h, concentrated in vacuo, and the residue was filtered through a thin pad of silica gel. Concentration of the filtrate followed by flash column chromatography on silica gel (hexane/EtOAc = 5:1) gave trans-fused decalin 2 (959 mg, 88% yield) as an amorphous solid along with an unidentified diastereomeric mixture (87.2 mg, 8% yield). R_f 0.25 (hexane/EtOAc = 4:1); [α] _d ²⁵ –52.6 (c 0.81, CHCl₃); IR (KBr): 2913, 2847, 1780, 1698, 1386, 1212 cm^–1. ¹H NMR (CDCl₃, 400 MHz): δ = 7.36–7.24 (m, 3 H), 7.24–7.19 (m, 2 H), 5.34 (m, 1 H), 4.68 (ddt, J = 7.4, 9.4, 3.2 Hz, 1 H), 4.21 (dd, J = 7.4, 9.0 Hz, 1 H), 4.18 (dd, J = 3.2, 9.0 Hz, 1 H), 3.57 (tt, J = 3.9, 12.1 Hz, 1 H), 3.27 (dd, J = 3.2, 13.4 Hz, 1 H), 2.81 (dd, J = 9.4, 13.4 Hz, 1 H), 2.13 (m, 1 H), 2.05 (m, 1 H), 2.02 (m, 1 H), 1.98 (m, 1 H), 1.89 (dq, J = 4.0, 13.4 Hz, 1 H), 1.70 (m, 1 H), 1.64 (s, 3 H), 1.50 (ddd, J = 2.8, 4.0, 13.2 Hz, 1 H), 1.44 (d, J = 11.9 Hz, 1 H), 1.41–1.34 (m, 2 H), 1.28 (dt, J = 4.2, 13.4 Hz, 1 H), 0.87 (s, 3 H). ¹³C NMR (CDCl₃, 100 MHz): δ = 176.4 (C), 153.0 (C), 135.3 (C), 134.3 (C), 129.4 (CH)×2, 128.9 (CH)×2, 127.3 (CH), 121.3 (CH), 66.0 (CH₂), 55.3 (CH), 45.9 (CH), 43.2 (CH), 39.1 (CH₂), 38.0 (CH₂), 37.7 (CH₂), 32.2 (C), 26.4 (CH₂), 23.8 (CH₂), 22.8 (CH₂), 21.0 (CH₃), 15.5 (CH₃). MS (ESI-TOF): m/z (%) = 390 (100) [M + Na]⁺. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₉NO₃Na: 390.2045; found: 390.2038