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Strategy Evolution in the Total Synthesis of Spirastrellolide A Methyl Ester
Author(s) -
Paterson Ian,
Dalby Stephen M.,
Maltas Philip
Publication year - 2011
Publication title -
israel journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.908
H-Index - 54
eISSN - 1869-5868
pISSN - 0021-2148
DOI - 10.1002/ijch.201100007
Subject(s) - chemistry , sharpless asymmetric dihydroxylation , hydroboration , stille reaction , stereochemistry , stereocenter , total synthesis , diene , aldol reaction , combinatorial chemistry , dihydroxylation , double bond , olefin metathesis , metathesis , stereoselectivity , enantioselective synthesis , organic chemistry , natural rubber , catalysis , polymerization , polymer
This review highlights the many challenges overcome during our recent synthetic campaign towards spirastrellolide A, a structurally unprecedented antimitotic marine macrolide that potently and selectively inhibits protein phosphatases, and represents a promising lead for anticancer drug discovery. Faced with the initial stereochemical ambiguities, a flexible and modular synthetic strategy was adopted for the construction of increasingly elaborate fragments of the architecturally complex macrolactone to enable further structural elucidation by detailed NMR analysis. A reliable and convergent synthetic route evolved to encompass the use of boron‐mediated aldol reactions to install much of the required oxygenation pattern and associated stereocenters, together with a tandem double Sharpless asymmetric dihydroxylation and cyclization to efficiently access the signature DEF ‐ [5,6,6]‐ bis ‐spiroacetal region from a linear diene precursor. A pivotal sp 2 ‐sp 3 Suzuki fragment coupling, followed by a double hydroboration of the resulting diene, then provided an advanced C17‐C40 aldehyde which was coupled with a suitable C1‐C16 alkyne. Following BC‐spiroacetalization, a high yielding Yamaguchi macrolactonization afforded the C1‐C40 macrocyclic core, where the full side chain was then introduced by sequential olefin cross‐metathesis and π‐allyl Stille cross‐coupling, culminating in the first total synthesis of spirastrellolide A methyl ester.