Study of the Reaction Between Organocopper Reagents and Vinylic Epoxides: Synthetic Exploration of Neolignan and Macrolide Compounds.

Alkyl and aryl cyanocuprates have been shown to react with the silyl enol ethers and enol phosphates of several 2,3-epoxycyclohexanones. The 1,4-trans addition products are obtained in high yield and with complete regio and stereospecificity. The synthetic utility of this reaction is demonstrated by the conversion of the initial 1,4-trans adducts into a variety of types of compounds. Thus, mild hydrolysis of the 1,4-trans adducts allows the stereospecific preparation of 6-substituted-2-cyclohexenones. The 1,4-trans adducts can also be stereospecifically transformed into 3-hydroxycyclohexanones and cis-2,3-dihydroxycyclohexanones. Vinylic cyanocuprates do not always react in a regiospecific manner with the epoxyenol ethers. In this case, the reaction product depends considerably on the substitution pattern of the epoxyenol ether. An attempt is made to explain these results by a mechanistic analysis of the cyanocuprate reaction. A new procedure has been developed which allows the 1,4-syn-addition of carboxylate salts to cyclic allylic epoxides. The use of a cuprous salt allows the regio and stereospecific preparation of monoprotected cis-cycloalkene-1,4-diols, which are compounds of considerable synthetic value. The reaction works best on five- and six-membered cyclic systems. Acyclic epoxides and cyclic ones which are locked in an s-trans conformation do not react with the new reagent under the mild conditions used for cyclic epoxides. The addition of optically active carboxylic salts provides a simple way to prepare optically active cis-1-acyloxy-2-cycloalken-4-ols. Several alternative routes to the 8.1' neolignan skeleton have been explored, all of which rely greatly on organocopper chemistry. A bicyclic epoxyenol ether was prepared and treated with several cyanocuprates. The resulting 1,4-trans adducts are potentially valuable intermediates for the synthesis of several neolignan structures. The behavior of 2(2-alkoxyalkylidene)cyclohexanones when treated with organocopper reagents has been studied. Reductive elimination of the alkoxy group is usually the predominant reaction. Finally, one of the 1,4-adducts from the cyanocuprate reaction was elaborated into a compound which is a potential synthon for the macrolide antibiotics.PhDOrganic chemistryUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/159956/1/8412167.pd