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Issue 30, 2012
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The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments

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Abstract

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.

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

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Publication details

The article was received on 13 Jan 2012, accepted on 08 Mar 2012 and first published on 16 Apr 2012


Article type: Paper
DOI: 10.1039/C2OB25100K
Citation: Org. Biomol. Chem., 2012,10, 5861-5872
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    The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments

    I. Paterson, E. A. Anderson, S. M. Dalby, J. H. Lim, P. Maltas, O. Loiseleur, J. Genovino and C. Moessner, Org. Biomol. Chem., 2012, 10, 5861
    DOI: 10.1039/C2OB25100K

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