Highly Stereoselective Construction of Carbon-Carbon Bonds Using Phosphonyl and Phosphoramidite Auxiliaries (Chemistry)

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This research is being supported by the Organic and Macromolecular Chemistry Program. The synthesis of the complex structures that occur in nature requires the development of highly specific reactions. This work will produce new reagents based on the unique reactivity produced by a phosphorous atom. Investigations centering on (i) highly stereoselective Aldol reactions (both acid and base-mediated) with alpha-acylphosphonate diesters, (ii) stereochemical control of the Mukaiyama-Michael reaction, and (iii) the stereoselective alkylations of chiral phosphoramidite homoenolate anion synthons are described. The central feature of this three-part research program is the establishment of a highly stereoselective methodology for construction of carbon-carbon bonds within acyclic molecules. Both high diastereofacial and enantiofacial selectivity is predicted based on the stereochemistry and steric bulk of the auxiliary as well as intramolecular metal ion complexation ability. Specifically, the metal anions of alpha-acyl-1,3,2-dioxaphosphonates are used to control enolate geometry and diasteromer preference when alkylated. Introduction of chirality into the 1,3,2-dioxaphosphonyl skeleton creates potential for asymmetry transfer from the chiral auxiliary. Examination of transition state models provide insight into factors likely to control diastereoselectivy. Finally, condensation of chiral phosphoramidities derived from (1S,2R)-(+)-ephedrine and (E)-3-phenylpropenal or crotonaldehyde provide substrates suitable for chelation-controlled enantioselective alkylation of the prochiral organometallic intermediate.