Synthetic Studies Toward the Total Synthesis of Xestocyclamine A

Abstract

Progress toward the total synthesis of the manzamine alkaloid xestocyclamine A is described. Due to the architecturally interesting structures and biological activity of the manzamine alkaloids, xestocyclamine A remains an attractive target for total synthesis. Moreover, such an endeavor would enable the exploration and development of new synthetic methodology in addition to further biological testing which would determine the potential of xestocyclamine A as a therapeutic or tool compound. Inspired by Jack Baldwin’s proposed biosynthesis of the manzamine alkaloids, our synthetic strategy focused on constructing the central scaffold through employment of a [4+2] cycloaddition. Access to the resulting cycloadduct was nontrivial and required several routes which included the use of trialkyl-stannyl and silyl substituted pyridines, pyridones as dihydropyridine surrogates, and alkyl-substituted dihydropyridines. Ultimately, we were able to successfully furnish the isoquinuclidine core containing four contiguous stereocenters, including the pivotal quaternary carbon. Upon desymmetrization of the resulting cycloadduct, we discovered an unexpected ring-closure which led to the adoption of a new maleimide dienophile. Investigations into alkynyl ring-closing metathesis (RCM) substrates were unsuccessful and encouraged future directions toward alkenyl RCM substrates. From the advanced cycloadduct intermediate, a number of investigations were conducted to develop routes toward the remaining ring systems. Employment of a RCM macrocyclization successfully installed the Southern 13-membered ring utilizing Grubbs Z-Selective catalyst. Another route focused on expansion of the 5-membered ring and led to an eneamide precursor and aziridination/fragmentation strategy that awaits further functionalization. Lastly, use of a B-alkyl Suzuki cross-coupling provided limited success toward the Northern macrocycle and afforded product in low irreproducible yields. Current efforts are focused on construction of the Northern macrocycle by RCM to furnish the ΔC23 unsaturation which may facilitate the former ring expansion.