Exploiting Pseudo <i>C</i>₂‑Symmetry for an Efficient Synthesis of the F‑Ring of the Spongistatins

A concise and efficient synthesis of the F-ring fragment of the potent antimitotic marine macrolide spongistatin 1 has been developed. The key sequence involves double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to establish four stereocenters in a pseudo <i>C</i>₂-symmetric array, followed by a selective protection reaction that breaks the pseudosymmetry, establishes a fifth stereocenter, and effectively differentiates the ester termini. Overall, the six contiguous stereocenters in the C(37)–C(45) F-ring fragment are established in just seven steps

Exploiting Pseudo <i>C</i>₂‑Symmetry for an Efficient Synthesis of the F‑Ring of the Spongistatins

A concise and efficient synthesis of the F-ring fragment of the potent antimitotic marine macrolide spongistatin 1 has been developed. The key sequence involves double cross-metathesis/Sharpless asymmetric dihydroxylation reactions to establish four stereocenters in a pseudo <i>C</i>₂-symmetric array, followed by a selective protection reaction that breaks the pseudosymmetry, establishes a fifth stereocenter, and effectively differentiates the ester termini. Overall, the six contiguous stereocenters in the C(37)–C(45) F-ring fragment are established in just seven steps

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

With an average GI50 value against the NCI panel of 60 human cancer cell lines of 0.12 nM, spongistatin 1 is among the most potent anti-proliferative agents ever discovered rendering it an attractive candidate for development as a payload for antibody-drug conjugates and other targeted delivery approaches. It is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive, however, and its development requires more efficient and step-economical synthetic access. Using novel and uniquely enabling direct complex fragment coupling alkallyl- and crotylsilylation reactions, we have developed a 22-step synthesis of a rationally designed D-ring modified analog of spongistatin 1 that is equipotent with the natural product, and have used that synthesis to establish that the C(15) acetate may be replaced with a linker functional group-bearing ester with only minimal reductions in potency.<br><div><br></div