title: The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments.
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.
authors.affiliation: University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ip100@cam.ac.uk
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.forename: Edward A
authors.initials: EA
authors.lastname: Anderson
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Dalby
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Lim
authors.forename: Philip
authors.initials: P
authors.lastname: Maltas
authors.forename: Olivier
authors.initials: O
authors.lastname: Loiseleur
authors.forename: Julien
authors.initials: J
authors.lastname: Genovino
authors.forename: Christian
authors.initials: C
authors.lastname: Moessner
mesh_terms: D000480:Alkynes / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D007700:Kinetics; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry*; D013141:Spiro Compounds / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity; D017971:Tin Compounds / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry
chemical_list: D000480:Alkynes; D018942:Macrolides; D013141:Spiro Compounds; D017971:Tin Compounds; D014753:Vinyl Compounds; C475125:spirastrellolide A; C569210:vinyl iodide; C031525:stannane