Synthesis of two diastereomeric C1-C22 fragments of spirastrellolide A.

The optimisation of a synthetic strategy towards the ABC segment of the cytotoxic macrolide spirastrellolide A is reported, together with its application to the synthesis of two diastereomeric C(1)-C(22) fragments for stereochemical correlation purposes with a putative spirastrellolide degradation product

Total synthesis of spirastrellolide A methyl ester--part 1: Synthesis of an advanced C17-C40 bis-spiroacetal subunit.

Out of the blue: The marine macrolide spirastrellolide A is a potent and selective inhibitor of protein phosphatase 2A and a lead for anticancer therapies. A flexible and modular synthetic strategy has been developed with two routes for the construction of the DEF bis-spiroacetal subunit. The optimized Suzuki coupling approach results in the efficient preparation of a C17-C40 aldehyde that forms the cornerstone of the first total synthesis. (Chemical Equation Presented). © 2008 Wiley-VCH Verlag GmbH and Co. KGaA

Total synthesis of spirastrellolide A methyl ester--part 2: Subunit union and completion of the synthesis.

(Figure Presented) Succumbing to synthesis: The stereocontrolled total synthesis of spirastrellolide A methyl ester is reported. The union of two key C1-C16 and C17-C40 subunits is followed by macrolactonization and late-stage side chain attachment by a cross-metathesis reaction anda π-allyl Stille coupling reaction with a C43-C47 stannane, thus confirming the 46R configuration. The full configuration and conformation of the 38-membered macrolide is revealed by single-crystal X-ray analysis of an advanced pentaol intermediate. © 2008 Wiley-VCH Verlag GmbH and Co. KGaA

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments.

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid