Catalytic Asymmetric β‐Peroxidation of Nitroalkenes

Abstract

The first example of an asymmetric b-peroxidation of nitroalkenes is disclosed. The reaction is promoted by catalytic loadings of a commercially available diaryl-2-pyrrolidinemethanol derivative and tert-butyl hydroperoxide as the oxidant. A synthetically useful class of peroxides is obtained in good yield and enantioselectivity (up to 84% ee).Keywords: asymmetric catalysis; Michael addition; nitroalkenes; organocatalysis; peroxides Catalytic asymmetric conjugate additions are fundamental reactions in organic synthesis, widely used to form carbon-carbon and carbon-heteroatom bonds. [1] An impressive number of Michael addition reactions, either using metal-based chiral complex catalysis [2] or small chiral molecules as organocatalysts [3] have been developed. Among the different acceptors, easily accessible nitroalkenes have been intensively investigated as being compounds of a highly reactive nature. [4] Moreover, the nitro group can undergo a number of further transformations, after the addition, giving rise to a variety of enantioenriched compounds. [5] In this context, organocatalysts such as Cinchona alkaloids and thioureas, besides enamine activation of ketones and aldehydes as donors, [6] can promote efficient asymmetric conjugate additions of different acidic pronucleophiles to nitroalkenes. [7] In these examples, a bifunctional type of catalysis has been proposed, that involves activation of the acceptor via hydrogen bonding between the nitro moiety and a Brønsted acid functionality of the catalyst, whereas the pronucleophile is deprotonated by a basic group of the catalyst. Hence, a synergic network of hydrogen bonding and ion pairing interactions engaged between the reactants and the active sites of the chiral promoter assure a well-organized transition state leading to high stereocontrol.Despite the synthetic importance of epoxides or bhydroxy compounds, achievable through asymmetric conjugate addition to nitroalkenes, the strong basicity and poor nucleophilicity of oxygen nucleophiles render this approach problematic. Indeed, only a few examples of stereoselective oxa-Michael reactions were reported by the groups of Enders, [8] Dixon [9] and Jørgensen. [10] We have recently developed a simple methodology for the highly enantioselective epoxidation of a,benones catalyzed by diaryl-2-pyrrolidinemethanol compounds and tert-butyl hydroperoxide (TBHP) as the oxidant.[11] The same organocatalysts were found to be effective in the Michael addition of malonate esters to nitroalkenes although with only a moderate degree of asymmetric induction.[12] Encouraged by these results and the small number of asymmetric approaches based on oxa-Michael addition to nitroalkenes, we envisaged to exploit our organocatalytic system for their epoxidation.[13] Interestingly, peroxides 3 were formed as the result of the addition [Eq.(1)]. To the best of our knowledge, compounds 3 have been previously suggested as intermediates in the oxidation of trans-b-nitrostyrenes to a-nitroacetophenones using TBHP and n-BuLi a...

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

“…6 In fact, this type of reactions still represent one of the most challenging cases of conjugate addition of heteroatom-centered nucleophiles under organocatalytic activation because, in addition to reversibility issues, the typical oxygen-centered pronucleophiles, such as alcohols or carboxylic acids, typically show very poor reactivity towards Michael acceptors and normally undergo competitive 1,2-addition. Consequently, the reported examples of organocatalytic and enantioselective conjugate addition of oxygen pronucleophiles are limited to the use of oximes, 7 phenols, 8 enols, 9 alkoxyboronates, 10 hydroxylamines, 11 or peroxides 12 under iminium or H-bonding activation. 13 Organocatalytic cascade processes initiated by conjugate addition of O -nucleophiles have been mainly focused on the epoxidation of α,β-unsaturated carbonyls with peroxides 14 and some limited examples of conjugate addition followed by aldol, 15 Mannich, 16 Henry, 17 α-amination 18 and α-fluorination 19 have also been published.…”

Asymmetric Oxidations of Electron-Poor Alkenes Promoted by the β-Amino Alcohol/TBHP System

“…Peroxides 6 are known compounds, their analytical data were identical to those reported in the literature. 9 Enantiomeric excess was determined by chiral HPLC using Daicel Chiralcel OD-H and Daicel Chiralpak AS-H columns. 9…”

“…In this context, we recently found that commercially or readily accessible diarylprolinols 1 and primary b-amino alcohols 2 catalyze the epoxidation of a,b-enones in the presence of tert-butyl hydroperoxide (TBHP) as the oxygen source. 8 Moreover, this simple catalytic system could be applied to realize an unprecedentedly reported asymmetric b-peroxidation of nitroalkenes 9 (Scheme 1). Epoxides 4 and peroxides 6 could be obtained in good to high yield and enantioselectivity (70-92% ee).…”

Desymmetrization of meso‐N‐Acylaziridines with Benzenethiols Promoted by α,α‐Diaryl‐L‐prolinols

“…Recently, we disclosed that α,α‐diaryl‐ L ‐prolinols promote asymmetric Michael additions, such as the epoxidation of α,β‐enones,13 the β‐peroxidation of nitroalkenes14 and the malonate ester addition to nitroalkenes15 with high to moderate levels of enantioselectivity. We proposed a dual mode of activation of the nucleophile and the electrophile provided by the amine and the hydroxy groups of these organocatalysts, respectively.…”