Design, Synthesis and Evaluation of Chiral Auxiliaries, Ligands and Catalysts for Asymmetric

A series of chiral acetals were prepared from 7-hydroxyindan- 1 -one and a variety of substituted chiral nonracemic C2-symmetric 1,2-ethanediols [R = Me, Ph, CH20Me, CH20Bn, CH20(l -Np), i-Pr] in an experimentally simple acid-catalyzed condensation reaction. These acetals were evaluated as chiral auxiliaries for use in asymmetric synthesis. Saturated and a,gunsaturated substrates were attached to the chiral acetals and alkylation, cyclopropanation, 1,3-dipolar cycloaddition as well as Diels-Alder reactions were performed. A high degree of stereochemical induction was observed in the diethylaluminum chloride-promoted Diels-Alder reaction of an acrylate derivative (R = i-Pr) with cyclopentadiene (9 1:9 diastereomeric ratio). This result demonstrated that these acetals could serve as effective chiral directors in asymmetric synthesis. A chiral bidentate 1,2-amino alcohol and several chiral tridentate Schiff bases were synthesized in one or two steps from the chiral auxiliary (R = Ph). These novel acetals were evaluated as chiral ligands in metal-catalyzed sulfoxidation, Diels-Alder and hetero Diels-Alder reactions as well as in alkylzinc addition reactions. The chromium(111)-complex of a tridentate Schiff base was found to catalyze the hetero Diels- Alder reaction of 1 -methoxy-3-trimethylsilyloxy- l,3-butadiene and benzaldehyde in good yield (88%) and enantioselectivity (74:26 enantiomeric ratio). Heterocyclic analogs of the chiral acetals were also prepared for evaluation as chiral catalysts in a variety of asymmetric transformations. Chiral pyridine and NJVpyrrolidinopyridine- derived acetals were synthesized in three and twelve steps, respectively. These chiral pyridine and substituted pyridine derivatives were evaluated as chiral catalysts in the kinetic resolution of a racemic secondary alcohol under a variety of reaction conditions. These structures were found to be ineffective catalysts in these asymmetric processes. The two chiral substituted pyridine derivatives (R = Me, Ph) were examined in several other catalytic asymmetric reactions. A modest level of asymmetric induction was observed in the dihydroxylation reaction of (E)-stilbene involving catalytic quantities of both osmium tetroxide and the chiral substituted pyridine (R = Ph , 54:46 enantiomeric ratio). In a related study, a series of chiral tetrahydroquinolines were synthesized by experimentally simple acid-catalyzed three-component imino Diels-Alder reactions of cyclopentadiene with substituted aldehydes and anilines. The racemic tetrahydroquinolines were resolved and the absolute stereochemical configurations were determined by X-ray crystallography. The chiral nonracemic tetrahydroquinolines were evaluated as secondary amine catalysts in the iminium ion-promoted Diels-Alder reaction of cinnamaldehyde and cyclopentadiene and good levels of stereochemical induction were observed (79:2 1 enantiomeric ratio).