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.

Unified Approach to ent-Eudesmane-Type Terpenoid Synthesis: Total Synthesis of Sinupol and Eutyscoparin A

“…mons reaction using lithium hexamethyldisilazide (LiHMDS) and ethyl (E)-4-(diethoxyphosphoryl)but-2enoate 24 (13) to give (E,E)-,,,-unsaturated ester 12 as a single geometric isomer in 90% yield (2 steps). Finally, we converted ester 12 into sinupol (1) in 96% yield.…”

“…Hz, 1 H), 2.59 (dt, J = 14.5, 7.8 Hz, 1 H), 2.42 (dt, J = 14.5, 6.8 Hz, 1 H), 2.03 (t, J = 7.6 Hz, 2 H), 1.94 (m, 1 H), 1.76 (s, 3 H), 1.71 (s, 3 H), 1.66 (m, 1 H). 13 Butylated hydroxytoluene (BHT; 65.4 mg, 0.297 mmol) was added to a solution of triene 4 (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 rt over a period of 1 h, concentrated in vacuo, and the residue was filtered through a thin pad of silica gel.…”

“…12 Our interest in its unique biological activity led us to recently report the first total synthesis of sinupol (1). 13 Eutyscoparin A (2; Figure 1) is a C-12 hydroxylated ent-eudesmane-type sesquiterpenoid that was isolated from the endophytic fungus Eutypella scoparia and reported in 2021 by Tan and colleagues. 14 The overall planar structure and the relative stereochemistry were assigned on the basis of 1 H and 13 C NMR, COSY, HSQC, HMBC, and NOESY spectroscopic experiments.…”

“…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). IR (neat): 2924, 2853, 1690, 1467, 1454, 1377 cm -1 .1 H NMR (400 MHz, CDCl 3 ):  = 5.32 (m, 1 H), 2.85 (t, J = 7.4 Hz, 2 H), 2.53 (m, 1 H), 2.09 (m, 1 H), 2.02-1.86 (m, 3 H), 1.86-1.72 (m, 2 H), 1.65 (m, 1 H), 1.60 (s, 3 H), 1.56 (m, 1 H), 1.55-1.42 (m, 2 H), 1.43-1.13 (m, 21 H), 0.88 (t, J = 6.9 Hz, 3 H), 0.82 (s, 3 H) 13. C NMR (100 MHz, CDCl3 ):  = 135.1 (C), 121.0 (CH), 73.0 (C), 50.0 (CH), 46.6 (CH), 40.1 (CH 2 ), 37.8 (CH 2 ), 32.2 (C), 27.6 (CH 3 ), 26.8 (CH 3 ), 24.3 (CH 2 ), 22.9 (CH 2 ), 22.4 (CH 2 ), 21.2 (CH 3 ), 15.5 (CH 3 ).…”

“…The residue was purified by flash column chromatography (silica gel, hexanes-EtOAc, 10:1) to give alcohol 15. H NMR (400 MHz, CDCl 3 ):  = 5.32 (m, 1 H), 5.04 (dt, J = 1.3, 1.4 Hz, 1 H), 4.94 (dq, J = 1.3, 1.0 Hz, 1 H), 4.17-4.15 (m, 2 H), 2.18-1.90 (m, 5 H), 1.81 (m, 1 H), 1.63 (m, 1 H), 1.62-1.59 (m, 3 H), 1.55 (dd, J = 3.8, 13.3 Hz, 1 H), 1.47 (m, 1 H), 1.45 (brs, 1 H), 1.34 (m, 1 H), 1.22 (t, J = 12.7 Hz, 1 H), 1.19 (dt, J = 12.3, 12.7 Hz, 1 H), 0.81 (s, 3 H) 13. C NMR (100 MHz, CDCl 3 ):  = 154.3 (C), 134.9 (C), 121.0 (CH), 107.9 (CH 2 ), 65.3 (CH 2 ), 46.9 (CH), 42.4 (CH), 40.3 (CH 2 ), 37.9 (CH 2 ), 32.3 (C), 29.4 (CH 2 ), 27.4 (CH 2 ), 22.9 (CH 2 ), 21.1 (CH 3 ), 15.6 (CH 3 ).To a solution of alcohol 15 (23.4 mg, 0.106 mmol) in pyridine (0.200 mL) was added Ac 2 O (0.200 mL) at rt, and the mixture was stirred at the same temperature for 15 min.…”