Synthesis of Beta-Amino Alcohols

Enantiomerically pure .-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 .-amino alcohols have also 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 .,.-unsaturated carbonyl compounds.

There are few methods for synthesizing racemic mixtures of .-amino alcohols (both enantiomers present). Enantiomerically pure .-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 .-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.

Researchers at UC Santa Cruz have developed a synthesis of a very wide range of .-amino alcohols from achiral precursors with isolated mass yields ranging from 60% to 85% and enantiomeric excesses ranging from 60% to 80% at 0°C; for reactions done at -25°C, enantiomeric excesses greater than 99% have been achieved.
REFERENCE: 1991-291

US 5,367,073   [MORE INFO]

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