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Title: Total synthesis of spongistatin 1/altohyrtin A and siphonariid derived marine natural products
Author: Chen, D. Y.-K.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2002
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Polypropionate metabolites of the genus Siphonaria constitute a class of marine natural products which exhibit a variety of structural features, and some interesting biological activity. In 1984, Faulkner and Clardy reported the isolation of siphonarin A (9) and B (10) and subsequently in 1989 the isolation of baconipyrones A-D (13-16) as representative examples. The first part of this thesis describes studies towards the total synthesis of the siphonarid derived marine natural products baconipyrone C (15), siphonarin B (10) and dihydrosiphonarin B (12). The primary aim of this project is to uncover the biogenetic origin of these secondary metabolites by means of chemical synthesis. The total synthesis of a possible isolation artifact, baconipyrone C (15), is first detailed. A Sn(II)-mediated aldol coupling between γ-pyrone aldehyde 65 and (R)-propionate-derived ketone 66, followed by stereoselective anti reduction efficiently installed the C10-C14 stereotetrad in acid 74. The synthesis of diketone 73 utilised a syn aldol reaction between lactate-derived ketone 77 and (E)-2-methyl-2-pentenal, followed by subsequent elaboration. Coupling of acid 74 and diketone 73 under modified Yamaguchi conditions followed by PMB ether removal then furnished baconipyrone C (15) in 18 steps with 13.3% overall yield from aldehyde 56. The total syntheses of siphonarin B (10) and dihydrosiphonarin B (12) were based on a biomimetic cyclisation of a linear triketone 201, which was constructed via a Sn(II)-mediated aldol coupling between ketone 186 and aldehyde 196. Ketone 186 was prepared using a boron-mediated aldol reaction between chiral ketone 23 and propionaldehyde, whereas aldehyde 196 was accessed from a common precursor to acid 74 in the baconipyrone synthesis. Desilylation of triketone 201 gave hemiacetal 202, which was further elaborated to allylic alcohols 208 and 209 employing the Nozaki-Kishi reaction. Catalytic hydrogenation then gave dihydrosiphonarin B (12) in 24 steps with 1.6% overall yield from aldehyde 56. Similarly, catalytic hydrogenation of enone 210 furnished siphonarin B (10) in 25 steps with 0.9% overall yield from aldehyde 56. The second part of this thesis details the completion of the total synthesis of the marine macrolide spongistatin 1 / altohyrtin A (1), which shows extraordinary cyclotoxicity against a subset of highly chemoresistant tumour types, comprising the National Cancer Institute panel of 60 human cell lines. However, its scarcity from sponge sources has effectively halted further preclinical development in cancer chemotherapy. The exceptional biological activity, combined with the supply problem, has provided an impetus to develop a practical route to these synthetically challenging bis-spiroacetal macrolides. In a highly convergent fashion, the AB and CD spiroacetals, 255 and 256, and EF phosphonium salt 257 were prepared in gram quantities, and sequentially coupled and elaborated into spongistatin 1 (1). Throughout the synthesis, boron-mediated aldol reactions were exploited as a powerful and versatile tool in key carbon-carbon forming steps with a high level of stereocontrol. In particular, the aldol reaction between AB and CD spiroacetals, 255 and 256, and the attachment of the C47-C51 chlorodiene side chain 260 are noteworthy. Wittig coupling between aldehyde 265 and phosphonium salt 257 under carefully optimised conditions furnished the fully protected seco-acid of spongistan 1 (1). Subsequent elaboration of 372 then enabled the total synthesis of spongistatin 1 / altohyrtin A (1) in 33 steps with ca. 0.6% overall yield from methyl ketone 275. In addition, the synthesis of a novel truncated spongipyran 403 is described, as part of an analogue program to investigate the role of the C47-C51 side chain in its biological activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available