Total synthesis of (-)-spirangien A, an antimitotic polyketide isolated from the myxobacterium Sorangium cellulosum.
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.
Paterson
Ian
I
University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK. ip100@cam.ac.uk
Findlay
Alison D
AD
Noti
Christian
C
D000080:Acetals / Q000138:chemical synthesis* / Q000737:chemistry; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis* / Q000737:chemistry; D009231:Myxococcales / Q000737:chemistry*; D013237:Stereoisomerism
D000080:Acetals; D050256:Antimitotic Agents; D005231:Fatty Acids, Unsaturated; C523683:spirangien A