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

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. Unfortunately, it is unavailable from natural sources and its size and complex stereostructure render chemical synthesis highly time- and resource-intensive. As a result, the design and synthesis of more acid-stable and linker functional group-equipped analogs that retain the low picomolar potency of the parent natural product requires more efficient and step-economical synthetic access.

Exploiting pseudo C2-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 C2-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.