I. Mechanistic studies on a decarboxylative thioester aldol reaction. II. Enantioselective synthesis of cephalostatin 1

A mechanistic study on a Cu(II)-catalyzed, decarboxylative aldol reaction between methyl S-phenylmalonic acid half thioester (MeMAHT) and aldehydes is described. NMR studies confirmed that the catalyst resting state consists of nonenolized MeMAHT coordinated to a Cu(II) complex. Kinetics studies were used to rule out rate-limiting decarboxylation as the first mechanistic step. The 13C kinetic isotope effect at the MeMAHT carboxylate was measured, and a crossover experiment that simultaneously measured the extent of isotopic scrambling in deuterium-labeled MeMAHT and newly formed product was performed. These experiments show that the aldol reaction proceeds by enolization, reversible addition to an aldehyde, irreversible decarboxylation, and protonation of the resulting enolate to form a beta-hydroxy thioester. The Cu(II)-catalyzed reaction was inspired by nature's use of an enzyme-catalyzed, decarboxylative Claisen condensation for fatty acid and polyketide biosynthesis in which decarboxylation precedes condensation. The mechanistic difference between the Cu(II)- and enzyme-catalyzed reactions is explained by stereoelectronic effects.;A synthesis of the eastern half of marine natural product cephalostatin 1 is described. The eastern half is a hexacyclic steroid containing a 5,5-spiroketal in the thermodynamically less stable configuration. It was prepared in 25 chemical steps (21 in the longest linear sequence) and in an overall yield of 2.8%. Key steps in the synthesis include a remote C-H hydroxylation at the C12 position in trans-androsterone, Sonogashira coupling between a steroid-derived vinyl triflate and an enantiopure alkyne containing most of the atoms of the E and F rings, a Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization by cyclopropane ring opening. Pyrazine coupling of the eastern half with the western half, which was synthesized by Darryl Kato, followed by global deprotection completed the synthesis of cephalostatin 1. This synthesis will facilitate the identification of cephalostatin 1's cellular target and the investigation of its unique and potent anticancer activity. It will also contribute to the design of simplified analogues of the natural product.