合成路线1

Sagopilone is synthesized by the assembly of three modular building blocks, designated as segments A (V), B (II) and C (I). Wittig reaction of phosphonium salt (I) (segment C) with ketone (II) (segment B) in the presence of NaHMDS provides, after acidic hydrolysis of the tetrahydropyranyl protecting group, adduct (III) as a nearly equimolecular mixture of E/Z olefins. After chromatographic isolation of the target Z-isomer, Swern oxidation of the primary alcohol affords aldehyde (IV). This compound is then condensed with ketone (V) (segment A) in the presence of LDA and ZnCl2 to produce diastereoselectively the aldol adduct (VI). Subsequent acidic hydrolysis of the acetonide (VI) followed by protection of the free hydroxyls with TBDMSOTf and 2,6-lutidine generates the tetrasilyl ether (VII). The primary silyl ether of (VII) is then selectively removed by means of camphorsulfonic acid in MeOH/CH2Cl2, and the resulting alcohol is stepwise oxidized to carboxylic acid (VIII) by treatment with DMSO and oxalyl chloride followed by sodium chlorite in the presence of NaH2PO4 and 2-methyl-2-butene. Selective deprotection of the benzylic alcohol of (VIII) is accomplished by desilylation with TBAF, and the linear hydroxy acid is then cyclized to the key 16-membered macrolactone by means of 2,4,6-trichlorobenzoyl chloride (TCBCl) and DMAP under Yamaguchi conditions. After removal of the remaining silyl ether groups using hydrogen fluoride-pyridine complex in the presence of hexafluorosilicic acid, epoxidation of the endocyclic double bond with either dimethyldioxirane (DMDO) or methyl(trifluoromethyl)dioxirane (TFDO) furnishes the target epothilone (1, 2). Scheme 1.