Monoorgano- and monosilylcuprate reagents and their application towards the total synthesis of Virginiamycin M(1)

Highly diastereoselective conjugate addition reactions are afforded when iodotrimethylsilane (TMSI) promoted monoorganocopper reagents, Li[RCuI], are applied to various chiral imides. These conditions demonstrate the highest yield and stereoselectivity to chiral oxazolidinones and pyrrolidinones when compared to a myriad of well studied reagent systems. When monoorganocopper reagents are applied to imides in ether, a reversal of stereochemistry takes place that helps elucidate a mechanistic aspect of the reaction. The lithium is found to play a key role in yield and stereoselectivity to the extent that the presence of TMSI has no effect on the outcome of the reaction. Adding 12-crown-4 to the reaction complexes lithium cation and renders the monoorganocopper reagent unreactive.; The discovery of a novel monosilylcuprate reagent, Li[Ph2MeSiCuI], demonstrates an economical method of generating high yielding beta-silyl carbonyl compounds from a variety of alpha,beta-unsaturated ketones, aldehydes, esters, amides, and imides. The monosilylcuprate, when reacted with chiral imides, affords beta-silyl products in extremely high yield and stereoselectivity. These products are subsequently oxidized, yielding the corresponding alpha-unsubstituted aldol product with retention of configuration at the beta-carbon. Application of the monosilylcuprate to less reactive beta,beta-disubstituted substrates in different solvents increases the reactivity and extends the range of the novel reagent system.; All successful monoorganocopper and monosilylcuprate reagents are formed using a CuI·DMS salt created by precomplexing CuI with dimethyl sulfide (DMS). Reagents developed without this precomplexed copper source are much less effective in yield and stereoselectivity during conjugate addition reactions.; The O2-C7 fragment of Virginiamycin M1 is synthesized using a novel route that employs monosilylcuprate methodology to generate high stereoselectivity. Completion of the fragment demonstrates that the monosilylcuprate can be applied to synthesis effectively.