Total synthesis of dolabelide D

Abstract

The first total synthesis of dolabelide D (or of any of the closely related dolabelides) has been achieved with a longest linear sequence of 17 steps. Key features of the synthesis include an application of the catalytic asymmetric silane alcoholysis, the tandem silylformylation-crotylsilylation, and a Brook-like 1,4-carbon to oxygen silyl migration.

Scheme 1

Scheme 2

(a) 4 mol% CuCl, 4 mol% NaO-t-Bu, 4 mol% (R, R)-BDPP, PhH. (b) i. 2 mol% [Rh(acetone)₂-(P(OPh)₃)₂]BF₄, CO, PhH, 60 °C; ii. MeLi, Et₂O −78 to 23 °C. (c) TESCl, Et₃N, CH₂Cl₂, −20 °C. (d) n-BuLi, THF, −78 °C; CuBr•Me₂S, DMPU, 23 °C; MeI, −78 to 23 °C. (e) 25 mol% PdCl₂, CuCl, DMF, THF, H₂O, O₂. (f) Ac₂O, pyridine, DMAP, CH₂Cl₂. (g) (+)-(ipc)₂BCl, Et₃N, 5-hexenal, Et₂O −78 to 23 °C. (h) Me₄NBH(OAc)₃, AcOH, CH₃CN, THF, −40 to −20 °C. (i) 1,1-dimethoxycyclopentane, PPTS, CH₂Cl₂. (j) n-Bu₄NF, THF.

Scheme 3

(a) 15, CH₂Cl₂, −20 °C. (b) NaH, PMBBr, THF, reflux, (c) 25 mol% PdCl₂, CuCl, DMF, H₂O, O₂. (d) ent-19, CH₂Cl₂. (e) 2 mol% Rh(acac)(CO)₂, 10 mol% PPh₃, H₂/CO, 2,2-dimethoxypropane, PPTS, 60 °C. (f) 9-BBN, THF, −78 to 23 °C; H₂O₂, NaOH. (g) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 °C. (h) NaClO₂, NaH₂PO₄,2-methyl-2-butene, t-BuOH, H₂O. (i) K₂CO₃, CH₂=CHCH₂Br, acetone, reflux, (j) PPTS, acetone, H₂O, reflux, (k) n-Bu₂BOTf, i-Pr₂NEt, Et₂O, −110 °C. (1) TESCl, imidazole, CH₂Cl₂. (m) L-Selectride, CH₂Cl₂, −78 °C. (n) Ac₂O, pyridine, DMAP, CH₂Cl₂. (o) 10 mol% Pd(PPh₃)₄, morpholine, THF.

Scheme 4

(a) Et₃N, DMAP, toluene, −78 to 0 °C. (b) PPTS, MeOH. (c) DDQ, CH₂Cl₂, pH 7 buffer, (d) 25 mol% 31, CH₂Cl₂, reflux.