An Easy and Convenient Synthesis of Optically Active β-Amino Alcohols and 1,2-Diamines. Applications in Enantioselective Deprotonation of Cyclohexene Oxide

Abstract

Optically active β-dialkylamino alcohols and 1,2-diamines are not only a common structural component in a vast group of naturally occurring and synthetic molecules, but also can be widely used as versatile chiral building blocks and chiral catalysts or ligands in a variety of asymmetric synthesis, such as enantioselective dialkylzinc addition to aldehydes, enantioselective conjugated addition and enantioselective deprotonation of meso ketones and epoxides. Accordingly, many synthetic methods including aminolysis of chiral epoxides, optical resolution of their racemic mixtures and reduction of non-racemic O-acetyl mandelamides, reduction of chiral α-amino carboxamides, asymmetric reduction of α-amino ketones and aminolysis of aziridinium salts for those compounds have been reported. However, aminolysis of chiral epoxides is commonly accompanied by the formation of undesired regioisomers. The resolution method of racemic mixture suffers from providing intrinsic limitation where the maximum yield of one enantiomer from the starting material is only 50%. In the case of reduction of α-amino carboxamides, unnatural α-amino acids are not economical viable to use them as starting materials since they are expensive, but also racemization can occur in the reaction of some N-protected amino acids with dialkylamines to give α-amino carboxamides. For example, O’Brien et al. reported significant levels of racemization when N-protected phenylglycine was reacted with pyrrolidine in the presence of coupling reagent to form the corresponding α-amino carboxamide. Recently, we reported the synthesis of nearly enantiopure β-adrenergic agonists and β-hydroxy nitriles from optically active 1,2diol monotosylates 1 obtained from CBS-oxazaborolidinecatalyzed borane reduction of α-sulfonyloxyketones. We wish to report here an easy and simple method for the synthesis of nearly enantiopure β-dialkylamino alcohols 2 and 1,2-diamines 4-10 starting from 1 and their applications in enantioselective deprotonation of cyclohexene oxide using chiral lithium amides. The monotosylates 1 were directly reacted with 3 equiv. of N,N'-dialkylamines under solvent-free conditions at 40-50 C for 2-96 h to give 2 in 80-93% yield (Scheme 1). The optical purities and absolute configurations of 2 were determined by HPLC analysis using chiral columns and/or by comparing optical rotation values of the known compounds. As shown in Table 1, all the products 2 obtained have very high optical purities approaching 100% ee. To obtain chiral diamines 4-10, the reaction was carried out by treatment of 2.0 equiv. of methanesulfonyl chloride with each of the selected amino alcohols, such as 2e, 2h, 2j, and