Get access

Total Synthesis of (−)-Spirangien A, an Antimitotic Polyketide Isolated from the Myxobacterium Sorangium Cellulosum



A stereocontrolled total synthesis of the cytotoxic spiroacetal-containing polyketide (−)-spirangien A is described. This utilizes an aldol-based strategy to construct a common stereotetrad intermediate that was elaborated into the spiroacetal core, followed by the introduction of the unstable pentaene-containing side chain, performed with exclusion of light, using sequential Stille cross-coupling reactions.

original image

An expedient first total synthesis of (−)-spirangien A, a potent cytotoxic and antifungal polyketide of myxobacterial origin, is described. By using a common 1,3-diol intermediate obtained by an efficient aldol-reduction sequence for installation of the C15–C18 and C25–C28 stereotetrads and a reagent-controlled boron aldol coupling followed by spiroacetalization, a highly convergent strategy was developed for construction of the elaborate spiroacetal core. Conversion of this advanced spiroacetal intermediate into (+)-spirangien diene, obtained previously by controlled degradation of spirangien A, was then achieved by installation of the truncated side-chain using an allylboration–Peterson sequence. The total synthesis of (−)-spirangien A was then achieved by the controlled attachment of the unsaturated C1–C12 side-chain, avoiding exposure to light. A Stork–Wittig olefination and double Stille cross-coupling sequence was exploited to install the delicate conjugated pentaene chromophore featuring alternating (Z)- and (E)-olefins, leading initially to the methyl ester of spirangien A, which proved significantly more stable than the corresponding free acid. Subsequent careful hydrolysis afforded (−)-spirangien A, validating the relative and absolute configuration.