Diastereo- and Enantioselective Synthesis ofN-Protected 2-Amino 1,4-Diols by an Oxa Michael Addition/1,3-Dipolar Cycloaddition Protocol

Abstract

An enantioselective synthesis of N‐protected amino diols has been accomplished by employing a diastereoselective inter‐ and intramolecular 1,3‐dipolar cycloaddition reaction of optically active nitrile oxides as a key step. The nitro alkane starting materials were obtained by diastereoselective oxa Michael addition of (1R,2S)‐(–)‐N‐formylnorephedrine (1) to aliphatic (E)‐nitro alkenes 2, 6a, b (de = 96 – ≥ 98%). Subsequent diastereo‐ and regioselective cycloaddition reactions to highly substituted 4,5‐isoxazolines 5a–e, 8a, b (52‐81%) and reductive ring opening led – after cleavage of the auxiliary – to amino diols 13, 14 in good overall yields (27‐40%, over five steps) and with excellent diastereomeric and enantiomeric excesses (de,ee ≥ 96%).

Resolution of Racemic 2-Aminocyclohexanol Derivatives and Their Application as Ligands in Asymmetric Catalysis

“…Many existing synthetic routes rely on the derivatization of the available pool of amino acids, inherently limiting the number of accessible analogues nitroalkenes, imines, epoxides, 11a, aziridines, 11a, or cyclic sulfates . Moreover, novel syntheses of vicinal amino alcohols by enantioselective direct catalytic Mannich-type reactions were recently reported by Trost, List, Barbas, and Shibasaki .…”

A Regio- and Stereodivergent Route to All Isomers of vic-Amino Alcohols

“…When one of the two stereocenters is set, the other can be created with good diastereoselectivity, as in the case of addition of organometallic nucleophiles to α-aminocarbonyls . By concurrent creation of two stereocenters, amino alcohols can be obtained with high enantioselectivity, i.e., by addition of nucleophiles to nitroalkenes or imines. , Similar selectivities can be obtained by reaction of chiral aminoallylboranes and aldehydes . In this category, the addition of α-alkoxyenolates to aldimines is the most flexible reaction, as the choice of enolate decides which isomer (syn/anti) will be the major product.…”

Highly Stereoselective Intermolecular Oxy-Michael Addition Reaction to α,β-Unsaturated Malonate Esters

“…The stereoselective addition of oxygen-centered nucleophiles to Michael acceptors has received little attention over the years despite the potential utility of the protected hydroxyl products in synthesis . Our group and others have been involved in the development of such chiral water equivalents for addition to highly reactive nitro olefin acceptors and to this end the highly diastereoselective oxy-Michael addition of the “naked” anions of enantiopure δ lactols has been described. Although useful for the asymmetric synthesis of 1,2-amino alcohols, we believed an extension of this chemistry to incorporate other Michael acceptors, while maintaining reaction efficiency and diastereoselectivity, would expand significantly the utility and scope of the reaction.…”