CATALYTIC, ENANTIOSELECTIVE ALDOL ADDITION REACTIONS

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We have prepared two members of a class of Ti(IV) complexes which catalyze (0.5-2mol%) the addition of silyl enol eithers, alkyl enol ethers, and dienolates to aldehydes. The parent complex is readily prepared from Ti(OiPr)4 and a Schiff-base tridentate ligand derived from 2-amino-2'- hydroxy-1,1'-binapthyl. A ligand scaffolding motif based on this binaphthyl possesses several salient features for ligand design: (1) facile synthesis; (2) easy derivatization of the amine by condensation with aldehydes and sulfonyl chlorides, and, consequently, (3) amenability to incremental variation in the overall electronics and sterics of the metal- ligand complex. These feature will allow us to fully examine the scope of these catalysts for aldehyde addition reactions. On the basis of these preliminary observations, the broad aims of this proposals are: (1) To study the enantioselective aldol addition process with the intent of developing powerful catalytic, C-C bond-forming methodology for the addition of silyl and alkyl enolates and dienolates to aldehydes. (2) To expand our study of reaction parameters to include solvent effects, reaction concentration, and method of catalyst preparation with the intent of developing a practical large-scale protocol. (3) To develop a reagent based catalyst that is able to override the inherent stereochemical biases of chiral aldehyde chiral methyl ketone- enolate addition reactions. (4) To gain insight into the solution structure of the catalyst and catalyst-aldehyde complex by 1H NMR spectroscopy and X-ray crystallography. (5) To apply the catalytic process to the synthesis of macrolactin A, an antibiotic not readily available from natural sources but shown to protect T-lymphoblasts from HIV infection. The successful development of a catalytic, enantioselective methodology for the preparation of optically active beta-hydroxy esters and delta-hydroxy- alpha, beta-unsaturated esters provide access to compounds that are not otherwise directly available by modern, catalytic enantioselective methodology. moreover, these optically adducts are useful starting materials for the synthesis of stereochemically complex structures with potential applications in human medicine. We anticipate that the study of novel Ti(IV) complexes with tri-dentate ligands will lay a foundation for the development of other catalysts for related carbonyl addition reactions.