Synthesis of spongiolactone-based alkynyl proteomic probes, (+)-hypercalin C, and pharmacophore-directed retrosynthesis of ophiobolins.


The spongiolactones are β-lactone containing marine natural products with fused tricyclic β-lactone-containing ring system. We synthesized bis-epi-spongiolactone and its corresponding alkynyl probe. Our collaborators (Prof. Stephan Sieber, Technical University of Munich) discovered that the spongiolactone compounds likely exert their anticancer effects through a polypharmacology mechanism. We completed the first total synthesis of hypercalin C in 10 steps with an overall yield of 8%. The synthetic sequence featured a key Csp3 -Csp2 Suzuki coupling with an uncommon α-bromo enol ether coupling partner and a boronic monoester derived from carvone. In addition, we discovered an unexpected and conceptually novel C-H insertion Suzuki coupling process employing the α-bromo enol ether substrate. Several hypercalin C analogs were accessed and tested against two cancer cell lines for cytotoxicity. Some support for the proton shuttle hypothesis for hypercalin C was gathered through our studies. We completed the first two stages of the Pharmacophore-directed retrosynthesis (PDR) approach towards ophiobolins, and in particular the most potent member, ophiobolin A. In making the bicyclic analogs, we encountered synthetic challenges such as inherent 5-exo-trig cyclization and olefin isomerization, for which we adopted a defensive strategy by the careful refinement of designed intermediates. We developed an efficient cuprate addition desilylation diastereoselective protonation sequence to form the key C1-C2 bond while establishing the crucial C6 stereocenter that might have broader utility. We formed the 8-membered B ring by an RCM reaction. We developed a novel asymmetric allylation reaction for a particularly difficult substrate. We will synthesize the C ring building block and use it for the preparation of tricyclic analogs and some natural ophiobolins with our strategy developed to date for the bicyclic system (AB ring system). Our goal is to achieve the synthesis of certain ophiobolin A derivatives with simplified structures that retain the bioactivity of the natural product.

Spongiolactone. Hypercalin. Ophiobolin.