Studies directed toward the total synthesis of leucascandrolide A, and, Catalytic asymmetric carbenoid insertions into the silicon-hydrogen bond catalyzed by chiral copper-(I) Schiff base complexes

Leucascandrolide A, an 18-membered macrolide with an oxazole containing side chain, is a marine natural product originally isolated from the sponge Leucascandra caveolata. Leucascandrolide A is biologically active displaying both antitumor and antifungal activities. At this writing leucascsandrolide A is not available from its initial natural source. The limited supply of the natural product limits further elucidation of its biological mechanisms of action. Studies toward the asymmetric synthesis of this natural product were therefore undertaken. A formal [4 + 2] annulation of chiral silanes was used to construct the left tetrahydropyran of the target molecule. A novel method of dethioketalization was developed using Dess-Martin periodinane and applied to the deprotection of the C17 thioketal. The key C8-C9 carbon-carbon bond was installed via a Mukaiyama like aldol reaction between the C9-C22 aldehyde and the C1-C8 silyl enol ether, which completed the carbon framework of the macrolide. A novel Sonogashira coupling of 2- O-trifluroroacetoxyoxazoles and terminal alkynes was developed and applied to the synthesis of leucascandrolide's C1'-C11 ' side-chain.; The application of chiral (E)-crotylsilanes to the total synthesis of complex polypropionate-based natural products has proven the utility of this class of reagent as an aldol surrogate. As part of an ongoing effort to expand this class of reagents, a transition metal mediated carbenoid insertion into a silicon-hydrogen bond was investigated. It was determined that chiral copper(I) Schiff base complexes provided a viable and economical system for the insertion process. For a model system, the insertions typically proceeded in good chemical yield (>85%) and in good levels of enantioselection (>80% ee). Application of the optimized Cu(I) catalyst system to the synthesis of chiral allylsilanes was less effective (<50% ee) and these reagents were found to readily decompose. Mechanistic and speciation studies were undertaken to learn about the nature of the active catalyst species. An X-ray crystal structure and an electrospray mass spectrum of the chiral Cu(I) Schiff base complex were obtained which showed that a trigonal planar Cu(I) Schiff base complex was likely the active catalyst.