Macrocyclization through ene-yne cross-coupling/alkyne reduction tandem reaction and its application in natural product synthesis

Chapter 1 --- Macrocyclization Through Copper-Catalyzed Castro--Stephens Coupling/Alkyne Reduction Tandem Reaction: Macrocycles, incorporating conjugated polyene subunits within the ring, are structural features found in a number of natural products that exhibit diverse and potent biological activities. Existing methods for the construction of such structures are limited and in many cases inefficient. We discovered an unprecedented copper-mediated reductive ene--yne macrocyclization reaction during our pursuit of the total synthesis of oximidine II. The reaction selectively generates an endocyclic Z-double bond through an intramolecular coupling of a vinyl iodide and a terminal alkyne fragment followed by in situ alkyne reduction. We developed this transformation as a general method for the preparation of polyunsaturated macrocycles. The reaction conditions were optimized and the scope of the reaction was extensively explored. It was found that the alkyne reduction step is driven by the release of the ring strain. Thus, the reaction is particularly efficient for suitably strained 11- to 13-membered E,Z-1,3-diene macrocycles. A complementary stepwise procedure was employed for the synthesis of larger rings. Finally, a plausible reaction mechanism was proposed based on experimental findings.;Chapter 2 --- Formal Total Synthesis of Lactimidomycin: Lactimidomycin is a macrocyclic natural product that possesses potent in vitro and in vivo anti-tumor activities. We accomplished a facile, 9-step synthesis of an advanced intermediate for the total synthesis of lactimidomycin. The crucial 12-membered polyene lactone core structure was constructed employing our newly developed Castro--Stephens coupling/alkyne reduction tandem reaction. The stereocenters were established via asymmetric a vinylogous aldol reaction and a Marshall's propargylation reaction.;Chapter 3 --- Synthesis and Biological Evaluation of Oximidine II Analogues: Oximidine II belongs to a family of benzolactone enamide natural products that exert their cytotoxic effects through inhibition of V-ATPases. Unlike other members of this family, the structure-activity relationship (SAR) of oximidines has not been extensively investigated. Guided by computational analysis and previous studies in our group, we designed and synthesized two oximidine II analogues with simplified scaffold. The simplified benzolactone core was accessed through a ring-closing metathesis (RCM) reaction and the enamide side chain was installed via a copper-mediated C--N coupling reaction. The analogues were evaluated for their biological activity. The results revealed that these molecules were weakly cytotoxic to a number of cancer cell lines.