This application consists of four major sections each with its own specific aims but unified in the common objective to understand and utilize the chemistry of chiral, phosphorus-stabilized carbanions. The goal of the first section is to establish the foundation of the project involving the fundamental issues of structure, bonding, configuration and conformation of phosphorus-stabilized carbanions in three important families: 1) phosphonic acids, 2) phosphinic acids and 3) phosphine oxides. These studies will employ a wide range of physical methods including variable temperature, multinuclear NMR, relaxation measurements, cryoscopy and X-ray crystallography. In addition, computational methods will be used to elucidate the theoretical structures of carbanions and details of bonding. The major issues to be addressed are the hybridization state, preferred conformation, rotational barrier and mechanism of stabilization of the carbanions. The principal objective of the second section is the rational design of chiral auxiliaries used to modify the reactivity and local environment of the anion. Based ont he structural information available from the studies in the first section, the specific requirements for size, shape and electronic properties will be incorporated into various amino alcohol and diamine adjuvants. The major criteria for an optimal auxiliary are: 1) ready availability in optically active form, 2) highly selective reactions of carbanion derivatives and 3) mild removal and easy recovery. The third section is the most diverse in its goals, all of which involve the chemical reactivity/selectivity of the phosphorus-stabilized carbanions. A myriad of electrophilic substitution reactions of the simple and allyl anions is planned including alkylation, Michael addition, epoxide opening, carbonyl addition, amination, oxidation and anionic rearrangements. In addition, a selection of non-carbanionic reactions of the chirally-modified phosphorus compounds will be examined. The number of biologically important phosphonic and phosphinic acid derivatives has increased rapidly in recent years. In nearly every case, the absolute configuration of the molecules has been critical for biological activity. The reactions developed in this project will provide efficient access to many classes of these compounds, in particular, the alpha-aminophosphonic acids. As analogs of alpha-aminocarboxylic acids these compounds have found application as enzyme inhibitors, antibiotics, insecticides and analgesics. The utility of the chiral carbanions for general synthetic applications requires the ability to remove the phosphorus appendage cleanly with high stereoselectivity. The principal objective of the fourth section of this proposal is the development of new reactions capable of cleaving carbon- phosphorus bonds and replacing them with carbon-nitrogen,-oxygen and - carbon bonds with preservation of configuration.
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