ABSTRACT
Abstract Two methods for the synthesis of chiral 2-amino-1-phenylethanol have been developed. The first utilizes a chiral oxaborolidine catalyzed borane reduction of phenacyl chloride to give the chiral chloro-alcohol in very good yield with an ee in the 93%-97% range. Reaction with dilute ammonium hydroxide produced the amino-alcohol in very good yield with a high ee. The second approach involved first conversion of the phenacyl chloride to the succinimide which was then hydrogenated using a chiral ruthenium complex in conjuction with a base and an optically active amine (Noyori procedure) to give the optically active succinimido alcohol in very good yield with an ee of 98%. Hydrolysis with dilute base produced the optically active amino alcohol in very good yield and excellent enantioselectivity. Introduction Chiral β-amino alcohols such as (R) or (S) 2-amino-1-phenylethanol (1) are important intermediates in the synthesis of a variety of pharmaceutically important compounds. While there were some early procedures reported for the synthesis of 1,(1,2) several years ago an evaluation of the more promising of these approaches led to the conclusion that the most practical method for preparing 1 in larger quantities was by the resolution of the racemic material using di-O-toluoyltartaric acid (3) or dehydroabietic acid (4). In these resolutions, though, the chiral 1 was produced with 99% ee but was obtained in only about a 25% yield. In recent years, however, some efficient methods for the enantioselective reduction of ketones have been developed and it was considered that application of some of these newer reactions could lead to the efficient and enantioselective production of β-amino alcohols such as 1. The two procedures selected for investigation were the chiral oxazaborolidine catalyzed reduction of phenacyl chloride (2)(5-7) followed by amination of the chloro alcohol product (8) (Eqn. 1) and the Noyori hydrogenation (9) of an appropriately blocked βaminoacetophenone followed by unblocking of the amine group (Eqn. 2). Results and Discussion The chiral reduction of phenacyl chloride (2) was run using either the methyl-or methoxy-oxazaborolidine (3) as the catalyst. After optimization of the reaction
parameters the reduction was run at 65°C using a BH3 : ketone : catalyst ratio of 0.6 : 1 : 0.003. Reduction of a 0.9 M solution of 2 in THF under these conditions gave the chiral chloroalcohol (4) with 95-96% ee at 100% conversion. The aminoalcohol (1) was produced by treating a methanol solution of 4 with a large excess of 30% NH4OH at room temperature for 2-3 days. After evaporation of the methanol, 1 was isolated as a crude product having an ee of 95% in 85% yield.
