10.1016/S0040-4039(00)86037-2
The study focuses on the total synthesis of the methyl ester of L-660631, a novel natural product obtained from actinomyces fermentation, which is a potent inhibitor of cytosolic P-ketothiolase. The researchers aimed to develop a synthetic route that allows for the systematic replacement of the 1,3,5-hexatriyne subunit with more stable fragments to enhance the compound's stability while retaining its inhibitory activity. Key chemicals involved include cyclooctene, which serves as the starting material, and various reagents such as vinyl magnesium bromide, phenyl isocyanate, and lithium trifluoroborate organoalkyls. The study details the synthesis process, highlighting challenges such as the instability of concentrated L-660,631 and the difficulty in achieving selective addition reactions. The researchers employed techniques like asymmetric Sharpless kinetic resolution to set the stereochemistry at C.6 and C.9, and explored different methods for the oxidation and reduction steps to overcome the instability issues. The final product, L-660,631 methyl ester, was synthesized and found to be stable at room temperature, with future plans to evaluate its inhibitory activity against mammalian P-ketothiolase.
