Abstract

Enantiomerically pure beta-amino alcohols play an increasingly important role in both the treatment of a wide variety of human disorders and as chiral auxiliaries in organic synthesis. The importance of enantiomeric purity in pharmaceuticals has been amply demonstrated by the debilitating and sometimes tragic side-effects caused by the presence of the non-therapeutic enantiomer of an otherwise beneficial drug. Enantiomerically pure beta-amino alcohols have been shown to be exceedingly effective chiral auxiliaries in asymmetric carbon-carbon bond forming reactions such as additions of diethylzinc to aldehydes or conjugate additions of organocuprate reagents to alpha,beta-unsaturated carbonyl compounds.

There are few methods for synthesizing racemic mixtures of b-amino alcohols (both enantiomers present). Enantiomerically pure beta-amino alcohols are available only through reductions of amino acids, kinetic resolution of racemic mixes of amino alcohols, or chromatographic methods. The reduction of amino acids to the corresponding amino alcohols is economically feasible only for the naturally occurring L-amino acids. Kinetic resolution results in the immediate loss of at least 50% of possible product. Chromatography often involves laborious separations. The only synthetic methodologies available for the direct synthesis of amino alcohols in high yields are the amination of chiral epoxides and the asymmetric hydrogenation or reduction of prochiral b-amino ketones. The former method suffers from the limitations that chiral epoxides are not readily available, are extremely expensive, and that only mono-substituted and trans-symmetrically distributed epoxides can be used or a mixture of products results. The latter method requires extremely expensive rhodium or ruthenium and BINAP catalysts and specialized, high pressure equipment.

Current UCSC research in this area involves the synthesis of a very wide range of beta-amino alcohols from achiral precursors with isolated mass yields ranging from 60% to 85% and enantiomeric excesses ranging from 60% to 80% at 0 deg; for reactions done at -25 deg, enantiomeric excesses greater than 99% have been achieved.

Publications:

Watts, Cian Christopher; Thoniyot, Praveen; Hirayama, Lacie C.; Romano, Talia; Singaram, Bakthan. Enantioselective alkynylations of aromatic and aliphatic aldehydes catalyzed by terpene derived chiral amino alcohols. Tetrahedron: Asymmetry (2005), 16(10), 1829-1835.

Steiner, Derek; Ivison, Lacie; Goralski, Christian T.; Appell, Robert B.; Gojkovic, Jasna R.; Singaram, Bakthan. A facile and efficient method for the kinetic separation of commercially available cis- and trans-limonene epoxide. Tetrahedron: Asymmetry (2002), 13(21), 2359-2363. CODEN: TASYE3 ISSN:0957-4166. CAN 138:170368 AN 2002:862488 CAPLUS

Steiner, Derek D.; Ivison, Lacie; Goralski, Christian T.; Appell, Robert B.; Singaram, Bakthan. Facile and efficient approach to the isolation of enantio- and diastereopure limonene oxide. Abstracts of Papers, 223rd ACS National Meeting, Orlando, FL, United States, April 7-11, 2002 (2002), ORGN-381. CODEN: 69CKQP AN 2002:190916 CAPLUS

Steiner, Derek D.; Sethofer, Steven G.; Goralski, Christian T.; Singaram, Bakthan. Enantioselective addition of diethylzinc to prosteregenic aldehydes catalyzed by a limonene oxide derived b-amino alcohols.
Abstracts of Papers, 223rd ACS National Meeting, Orlando, FL, United
States, April 7-11, 2002.