Toward a more step-economical and scalable synthesis of spongistatin 1 to facilitate cancer drug development efforts

Abstract

An efficient, step-economical, and scalable synthesis of a diene-bearing AB spiroketal fragment of spongistatin 1, and a demonstration of its efficient coupling to an aldehyde derived from silylformylation of a homopropargyl alcohol to produce the entire complex C(13)–C(17) linker region are described. The scalability of the synthesis of the AB spiroketal fragment was demonstrated by the preparation of 34.5 grams by one chemist in ~60 workdays, and more than 40 grams overall. With this material in hand and having established a method for its efficient coupling to the CD fragment, we have set the stage for the rapid synthesis and evaluation of a series of analogs of the CD spiroketal.

Design and 22-step synthesis of highly potent D-ring modified and linker-equipped analogs of spongistatin 1

“…We were optimistic that our diamine- and diaminophenol-activated crotyl- and allylsilanes 37 , 38 would, uniquely, be well-suited for the proposed reactions due both to their reliably excellent reactivity and broad generality and to the fact that the requisite crotyl- and allylsilanes 8 and 10 (M = Si) appeared accessible from the simple precursors diene 12 (ref. 39 ) and allylchloride 13 by way of mild, functional group-tolerant, and chemoselective transition metal-catalyzed hydrosilylation and allylic substitution reactions, respectively.

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Marine Metabolites

“…The IC 50 value for this compound was evaluated at 10 26 M in colon cancer cells and 10 212 M for breast cancer cell lines [82]. Synthetic approaches to the compound have been presented by research groups including Petit and coworkers [83,84].…”

Beyond the Roche Ester: A New Approach to Polypropionate Stereotriad Synthesis

“…An alternative carbonylation-based approach is the tandem intramolecular alkyne silylformylation–crotylation/Tamao oxidation/diastereoselective tautomerization reaction (Figure 1 C). 8 This sequence rapidly assembles stereotriads from simple starting materials, and it seemed plausible that we might adapt it for use in an intermolecular alkyne silylformylation 9 reaction using either propyne or 2-butyne as the starting material (Figure 1 D). Crotylation of the resulting α-methyl-β-silyl-α,β-unsaturated aldehyde (an α-methyl-β-ketoaldehyde or β-dialdehyde in masked form) would be followed by Tamao oxidation 10 with concomitant diastereoselective enol tautomerization to deliver the target stereotriad building blocks.…”