The First Catalytic Asymmetric Aza-Henry Reaction of Nitronates with Imines:  A Novel Approach to Optically Active β-Nitro-α-Amino Acid- and α,β-Diamino Acid Derivatives

Abstract

The Henry (nitro aldol) reaction, 1 and its aza analogue, 2 are fundamental C-C bond-forming reactions in organic chemistry. Compared with the development of catalytic enantioselective aldol reactions, there are astonishingly few examples on asymmetric catalytic nitro aldol reactions. Only the chiral heterobimetallic catalysts reported by Shibasaki et al. have proven to be effective for asymmetric Henry reactions. 3 In extension of this work, they have developed a catalytic asymmetric aza-Henry reaction (nitro-Mannich reaction). 3c When nitromethane was used as the substrate, high enantioselectivities were obtained for this reaction using N-phosphinoylimines. However, 60 mol % of the chiral ligand in the chiral ytterbium catalyst was required, and successful reactions were reported for only nitromethane.This communication presents the first catalytic highly diastereoand enantioselective aza-Henry reaction that proceeds in the absence of a base and with lower catalyst loading. In this reaction, the presence of a base is avoided by the application of silyl nitronates 1a-d instead of nitro compounds for the reaction with R-imino esters 2a-c in the presence of a chiral Lewis acid. It should be noted that a racemic fluoride-induced reaction of silyl nitronates with aldehydes has been described by Seebach et al., 4 and very recently another racemic version of this reaction using Sc(OTf) 3 was reported. 5

Synthesis of 4,5‐Dihydroisoxazoles by Condensation of Primary Nitro Compounds with Alkenes by Using a Copper/Base Catalytic System

“…In fact, poorer results are obtained from reactions of nitropentane with sluggish dipolarophiles that are unable to coordinate with Cu II (Table 5, entries 4, 7, and 11). The catalytic effect of Cu II on additions of nitronates [35,36] or of silyl nitronates [37] is well documented. In the present condensation, there is evidence that coordination with Cu II catalyses the cycloaddition step and the loss of water as well.…”

Use of polymer-supported amines in catalytic nitroaldol reaction of nitroalkanes with aldehydes

“…The high synthetic potential of the Henry reaction has been demonstrated previously for β-nitroalcohols 15 and for β-nitro-α-amino acid derivatives, 16 as well as for the easy conversion of the β-nitro-α−hydroxy acid derivatives into a variety of important functionalities-for example, β-amino-α-hydroxy esters. 17 During the last several years, enantioselective synthesis of β-amino-α-hydroxy acids has attracted much attention not only because of the synthetic interest to put the right functional moieties in the right positions in a stereospecific manner but also because of their presence in various medicinally important molecules.…”

Asymmetric aza‐Henry reaction of N‐tosyl imine

“…[1][2][3][4][5][6] A number of electron-deficient imines, carrying either anchor groups (such as P¼ ¼O bonds) or imine-activating groups, such as N-phosphinoyl imine, 4,5 a-iminoester 6 and N-Boc imines, 2,6 have been studied. However, the more available and stable N-tosyl imine got little attention in Aza-Henry reaction, as so far there was only one example of N-tosyl imine with very low enantioselective (99%, 4% ee).…”