Stereoselective synthesis of amino alcohols

Abstract

New synthetic routes toward several classes of amino alcohols, such as 1, 2-amino alcohols, α-hydroxy-β-amino acids, and polyhydroxylated amino alcohols have been developed based on conceptually novel disconnections. The synthetic routes involve starting materials which are commercially available or easily obtainable via asymmetric catalysis. Various 1, 2-amino alcohols were obtained through direct condensation of alkoxymethyl lithium reagent and activated imines formed in situ from alpha-amidoalkyl phenylsulfones. The synthesis of chiral 1, 2-amino alcohols was achieved through the use of [(dimethylphenylsilyl)methyl] magnesium chloride reagent, an alternative reagent of alkoxymethyl lithium easily convertible to the corresponding alcohols. By highly diastereoselective addition of Grignard reagents to tert-butanesulfinimines, several 1, 2-amino alcohols were obtained with high stereoselectivity and good yield (up to 98 % ee). Starting from chiral allylic alcohols, α-hydroxy-β-amino acids were synthesized in only 4 steps with high stereoselectivity (> 45 % yield, > 95 % ee). Chiral allylic alcohols were prepared through asymmetric catalysis involving cheap chiral catalysts. The resulting α -hydroxy-β-amino acid 26a was converted to the unnatural enantiomer of Taxol side chain in good yield without loss of enantiopurity. This route provides both syn- and anti- α-hydroxy-β-amino acids in good yields with high enantioselectivity. To develop practical and versatile way for the synthesis of polyhydroxylated amino alcohols, Claisen rearrangement of allylic esters of amino acid derivatives such as 38 was studied. Starting from chiral propargyl alcohol 45 Claisen rearrangement, selective epoxidation-regioselective ring opening, and Flemming-Tamao oxidation was successively applied efficiently to provide arabino-phytosphingosine, which is one of the simplest polyhydroxylated amino alcohols.