Structural optimization of enantiopure 2-cyclialkylamino-2-aryl-1,1-diphenylethanols as catalytic ligands for enantioselective additions to aldehydes.

The structural optimization of a family of modular, enantiopure beta-amino alcohol ligands with a common 2-amino-2-aryl-1,1-diphenylethanol skeleton, whose stereogenicity was introduced through the Jacobsen epoxidation of 1,1-diphenyl-2-arylethylenes, has led to the identification of a small set of optimal catalysts with enhanced activity and enantioselectivity in the addition of alkylzinc and arylzinc reagents to aldehydes. Criteria for the discrimination between apparently analogous, highly enantioselective ligands are proposed.

Synthesis of heavily substituted 1,2-amino alcohols in enantiomerically pure form.

[reaction: see text] A simple and convenient methodology for the preparation of optically pure 2-amino-2-aryl-1,1-diphenylethanols is presented. Allylamine was found to produce the ring-opening of triaryloxiranes in a regioselective and a stereospecific fashion. Removal of the allyl protecting group provided the free 1,2-amino alcohols in enantiomerically pure form.

Addition of diethylzinc to dicobalt hexacarbonyl complexes of alpha,beta-acetylenic aldehydes with virtually complete enantioselectivity. A formal synthesis of (+)-incrustoporin.

[reaction: see text] The addition of diethylzinc to dicobalt hexacarbonyl complexes of acetylenes mediated by (R)-2-piperidino-1,1,2-triphenylethanol takes place with very high enantioselectivity (96-99% ee) to afford the S enantiomers of dicobalt hexacarbonyl complexes of 1-alkynyl-1-propanols. The utility of this process is exemplified by the development of a short, highly enantioselective (99% ee) synthesis of unnatural incrustoporin.

A Superior, Readily Available Enantiopure Ligand for the Catalytic Enantioselective Addition of Diethylzinc to alpha-Substituted Aldehydes.

The lithium perchlorate-induced ring opening of (S)-triphenylethylene oxide (3) with secondary amines (piperidine (a), N-methylpiperazine (b), N-phenylpiperazine (c) and morpholine (d)) takes place in a stereospecific and completely regioselective manner to afford (R)-2-(dialkylamino)-1,1,2-triphenylethanols (4a-d). These amino alcohols catalytically induce the addition of diethylzinc to benzaldehyde with high enantioselectivity at 0 degrees C and at room temperature. Ligand 4a, which provides the highest enantioselectivity at 0 degrees C, has been studied in the addition of Et(2)Zn to a family of 20 representative aliphatic and aromatic aldehydes 5a-t. For a 17-membered set of alpha-substituted substrates (5a-m,q-t), including ortho-, meta-, and para-substituted benzaldehydes, the naphthaldehydes, alpha,beta-unsaturated and aliphatic (cyclic and acyclic) aldehydes, the mean enantiomeric excess of the resulting alcohols 6a-m,q-t is 97%, whereas for three alpha-unsubstituted specimens (5n-p) the addition takes place with an enantioselectivity of 92-93%.