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.

Synthesis of the Aglycon of the Antibiotic Disciformycin

“…With respect to yields, this sequence turned out to be superior to the one with reversed timing of protection and amide formation. Weinreb amide 18 was further elaborated towards macrolactone formation by first nucleophilic allylation followed by diastereocontrolled reduction of the intermediate ketone using the CBS‐reagent and BH 3 · SMe 2 (Scheme ) . The resulting ( S )‐configured alcohol 19 was obtained with excellent stereocontrol.…”

Stereoselective synthesis of the C79–C97 fragment of symbiodinolide

“…Treatment of epoxide 13 , which was prepared from L-aspartic acid ( 12 ) by the known procedure [8], with 3-butenylmagnesium bromide/CuI [16] provided the corresponding secondary alcohol. Protection of the alcohol with TBSCl afforded TBS ether 14 in 91% yield in two steps.…”

Stereoselective Halogenation in Natural Product Synthesis

“…Theuse of allylmetal reagents terminally substituted with halogens is ap owerful method for the stereocontrolled introduction of halogen-bearing stereogenic centers,y et it has seen relatively little use in the synthesis of halogenated natural products.T he most compelling showcase of this strategy is in the synthesis of the spirastrellolide family (see spirastrellolide Am ethyl ester, 380,S cheme 82). In completed syntheses by the groups of Paterson [156] and of Fürstner, [157] the Oehlschlager chloroallylboration [158] -a variant of the Brown asymmetric allylboration-is used to efficiently introduce the C28 and C29 stereogenic centers, including the key chloride.S imple aldehyde 381 was treated with the chiral chloroallylborane 382 to afford building block 383 with near perfect diastereoselectivity and high enantioselectivity;t he acetal was removed under workup conditions. [156a] That this reaction was able to support the synthesis of such ac omplex target indicates its robustness.Arelated bromoallylalumination reaction, wherein the bromide was eventually converted to ac hloride via an intermediate epoxide,w as utilized in chlorosulfolipid syntheses by Va nderwal and co-workers.…”