Total synthesis of callystatin A and development of trifloyl heterocycle cross-coupling strategies

Callystatin A is a polyketide-based natural product that displays the remarkable ability to interfere with the cell cycle, acting as a potent disruptor of nuclear export signal-dependent protein transport. Because this biological mode of action represents an underdeveloped target for therapy in cancer and immunodeficiency diseases, we commenced studies directed toward the total synthesis of this molecule. A major focus of this project involved the development of cross-coupling and hydrometalation techniques for the stereoselective formation of trisubstituted alkenes. Specifically, we employed a stereoselective cross-coupling of a 1,1-dibromoalkene to install the natural product's C14--C15 trisubstituted (E)-alkene, and discovered a complementary hydrozirconation-based method for the formation of callystatin A's C8--C9 trisubstituted (Z)-alkene moiety. In completing the synthesis of this natural product target, we demonstrated the utility of chiral ( E)-crotylsilane reagents toward the synthesis of polypropionate fragments, developed a biocatalytic enzymatic resolution using vinyl acrylate as a transesterifying reagent, and performed a hydrozirconation-Negishi cross-coupling cascade for the late-stage installation of callystatin A's C1--C5 lactone functional group.; Oxazoles and thiazoles represent pivotal substructures found in bioactive natural products and pharmaceutical agents. The use of O-trifloyl oxazoles and thiazoles in cross-coupling sequences represents a powerful, yet underdeveloped, strategy for installing these heterocycles into complex molecules. We have discovered a general Pd(0)/Cu(I)-catalyzed Sonogashira coupling protocol that combines alkynes with oxazole and thiazole triflates in a highly efficient manner. We applied this method toward the formation of a small library of synthetic products, using heterocycles possessing triflates in the 2-, 4-, or 5-position. This reaction proved effective in the synthesis of the oxazole-containing C1'--C11' side chain of leucascandrolide A, a natural product subunit possessing potent antifungal activity.; WS75624 A and WS75624 B are natural inhibitors of endothelin-converting-enzyme (ECE), a protein implicated in a wide variety of vascular disorders including heart disease. We have developed a successful synthetic strategy for these molecules based on regioselective cross-couplings of 2,4-ditrifloyl thiazole. In our approach to the synthesis of the target structures, we investigated directed ortho-lithiations, employed complementary N-directed lithiations, and evaluated transition metal catalysts for the cross-couplings of electron-rich heteroaryl chlorides.