The aplyronines comprise a family of structurally unique marine macrolides isolated from the Japanese sea hare Aplysia kurodai with picomolar cancer cell growth inhibition. Recent observation of an unprecedented heterotrimeric complex of aplyronine A with the cytoskeletal proteins actin and tubulin renders these scarce natural products promising dual-targeting cytotoxic agents in the area of cancer therapeutics. Our interest lies in devising a robust and flexible total synthesis of the aplyronines to enable their further biological evaluation and initiate efforts towards developing antibody-drug conjugates with novel mechanisms of action. Our recently completed syntheses of the aplyronines utilised the tin and boron aldol methodology and barium hydroxide-mediated Horner-Wadsworth-Emmons reactions developed in the group to provide aplyronine A in 28 steps (LLS). Linkage of an advanced macrolactone fragment to the C28-C34 side chain via aldol coupling assembled the full carbon backbone. The second-generation route improves efficiency, scalability and control in key steps. The previously demanding aldol reactions mediated by tin(II) triflate to set up two stereotetrads were successfully substituted for titanium Lewis acid-mediated processes. The isolated C17 stereogenic centre was accessed via a straightforward enzymatic enantioselective hydrolysis of a meso diester. Adjusting the protecting groups based on findings of the first-generation synthesis, particularly on the C23 and C27 alcohols, enabled macrolactonisation exclusively onto the C23 hydroxyl. Finally, palladium-mediated removal of the orthogonal C27 allylic carbonate intercepted a known C1-C27 intermediate to complete the formal total synthesis. Current scale-up efforts aim to demonstrate the ability to gain easy access to multigram quantities of advanced intermediates for late-stage diversification. Ongoing studies aim to develop a suitable payload linker that will enable conjugation to antibodies and biological testing of the resulting antibody-drug conjugates.

Studies toward a scalable second-generation total synthesis of the aplyronines as novel payloads for antibody-drug conjugates

253rd National Meeting (2017)

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