Toward the gram-scale total synthesis of (+)-spongistatin 1
Abstract
This dissertation describes the evolution of a large-scale synthetic campaign directed at the total synthesis (+)-spongistatin 1, one of the most potent and architecturally complex antitumor marine macrolides discovered to date. Chapter one provides an introduction to the spongistatin family of natural products. Specifically, the isolation, structure elucidation, and biological activity of the spongistatins are discussed. Furthermore, relevant synthetic approaches toward the spongistatins are delineated.* Chapter two provides a critical analysis of our previous syntheses of the spongistatins in the form of a detailed retrosynthesis, and describes our latest synthetic strategy for overcoming the deficiencies associated with our earlier work. The (+)-spongistatin 1 macrolide framework was assembled via Wittig union of an EF phosphonium salt and an ABCD aldehyde. For construction of the advanced ABCD fragment, disconnection at the C(15)-C(16) aldol linkage revealed the AB aldehyde and CD ketone. The linear precursors of both spiroketal moieties were assembled in a highly efficient manner via methods developed in our laboratories, namely the three component union of 2-silyl-1,3-dithianes with terminal epoxides.* As anticipated from the precedent set forth by Evans, aldol union of the AB and CD fragments proceeded in both good yield (72%) and with high selectivity (9:1). The complex aldol reaction was ultimately performed on a 2 g scale; approximately 5 g of coupled product were prepared. The synthesis of the advanced ABCD aldehyde was achieved with a longest linear sequence of 22 steps (6.5% overall yield) and is 15 steps shorter than our previous synthesis.* Chapters three and four describe our long-standing efforts toward an efficient and scalable synthesis of the EF Wittig salt. The difficulty in this regard lies in the installation of the highly sensitive chlorodiene side chain moiety present in (+)-spongistatin 1. In response, we have developed a novel method for side chain introduction via cyanohydrin alkylation. Construction of the EF bis-tetrahydropyran subunit was achieved via dithiane alkylation to an F-ring aldehyde, using chelation control to establish the requisite C(38) stereochemistry.* Successful installation of the chlorodiene side chain was achieved via cyanohydrin alkylation of an appropriately functionalized EF bis-tetrahydropyran allyl iodide. Subsequent synthetic operations, involving cyanohydrin hydrolysis, elimination to afford the diene moiety, asymmetric ketone reduction, and phosphonium salt formation completed the synthesis of the EF Wittig salt.* (Abstract shortened by UMI.) *Please refer to dissertation for diagrams.
Recommended Citation
Chris Sfouggatakis,
"Toward the gram-scale total synthesis of (+)-spongistatin 1"
(January 1, 2004).
Dissertations available from ProQuest.
Paper AAI3152102.
http://repository.upenn.edu/dissertations/AAI3152102
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