Advantage of Anaerobic Conditions in the Highly Enantioselective Synthesis of α,α-Dialkyl-α-Amino Acids by Chiral Phase-Transfer Catalysis

Abstract

Intervention of the enolate oxidation in the catalytic asymmetric phase-transfer alkylation of protected a-amino acid derivatives under aerobic conditions has been addressed, and anaerobic conditions have been introduced to obtain synthetically satisfactory chemical yields as well as a high level of enantioselectivity.Recently, we disclosed a broadly useful and practical procedure for the enantioselective synthesis of nonproteinogenic a,a-dialkyl-a-amino acids under solid-liquid phasetransfer conditions using rationally designed C 2 -symmetric chiral quaternary ammonium salts of type 1 as catalysts [(S,S)-3,4,5-trifluorophenyl-NAS-bromide [54, and (S,S)-b-naphthyl-NAS-bromide [54,839-1] from Aldrich Chemical Co. Ltd.]. 1,2 A wide variety of a,a-dialkyl-a-amino acids can be efficiently prepared with enantioselectivities as high as 99% ee either by the onepot, double alkylation of aldimine Schiff base of glycine tert-butyl ester or by the simple alkylation of aldimine Schiff base 2 derived from the corresponding a-amino acids. 3 Although excellent enantioselectivity was constantly observed, the chemical yields of the products were varied and generally modest, which prompted us to investigate the fundamental reason for this in relation to the mechanistic aspect of this asymmetric phase-transfer catalytic alkylation. Since we performed the reaction under aerobic conditions, it seemed conceivable that rapid oxidation of the in situ generated enolate with molecular oxygen could occur concurrently with the desired alkylation step, thereby resulting in a certain decrease of the chemical yield. In this letter, we address this problem and report the anaerobic conditions for the highly enantioselective alkylation of protected a-amino acid derivatives by chiral phase-transfer catalysis.Alkylation of aldimine Schiff base derived from leucine tert-butyl ester (2, R 1 = i-Bu) with benzyl bromide (1.2 equiv) in the presence of the catalyst 1 (1 mol%) and CsOH•H 2 O (5 equiv) in toluene proceeded smoothly at 0°C under aerobic conditions to give the corresponding benzylation product 3 (R 1 = i-Bu, R 2 = CH 2 Ph) in 64% isolated yield with 92% ee. 1 The observed asymmetric induction can be interpreted for by the generally proposed interfacial mechanism: the cesium enolate of 2 (R 1 = i-Bu) produced through interfacial deprotonation with CsOH•H 2 O experiences the extremely fast ion-exchange with 1 to give the corresponding chiral enolate that reacts with benzyl bromide in an asymmetric fashion as illustrated in Scheme 1. 4 This is consistent with the fact that attempted benzylation of 2 (R 1 = i-Bu) in the absence of catalyst under otherwise similar conditions afforded the racemic product 3 (R 1 = i-Bu, R 2 = CH 2 Ph) in 51% yield. Based on the plausible mechanistic profile, we assumed that the initially formed cesium enolate could be rapidly oxidized by molecular oxygen under aerobic conditions as also shown in Scheme 1, and this pathway would compete with the desired alkylation, lowering the chemical yield. Actually, upon mixing ...

Asymmetric Allylation of α‐Ketoester‐Derived N‐Benzoylhydrazones Promoted by Chiral Sulfoxides/N‐Oxides Lewis Bases: Highly Enantioselective Synthesis of Quaternary α‐Substituted α‐Allyl‐α‐Amino Acids

“…On the other hand, enantiomerically pure α‐allyl α‐amino acids have previously been prepared by enzymatic resolution or by diastereoselective alkylation of chiral α‐iminoesters . In this work, ( S )‐ N ‐benzoyl hydrazines 4a , 4b were converted to the corresponding amino esters 5a , 5b by treatment with excess SmI 2 .…”

Design and synthesis of quasi-diastereomeric molecules with unchanging central, regenerating axial and switchable helical chirality via cleavage and formation of Ni(II)–O and Ni(II)–N coordination bonds

“…Formation of the corresponding enolates 16 , in the presence of relatively strong bases (KO t -Bu), is an established step in general methods for homologation of the glycine moiety by alkyl halide alkylation [27,50–53], aldol [29,33,36–37] and Michael [28,31,34–35 38–39 43–47] addition reactions. The following oxidation step of the enolates 16 in the presence of atmospheric oxygen, is less studied [48]; however, plausible key transformations can be deduced based on the closely related results on the well-established general oxidation of enolates [55–64] and glycine-derived enolates [65–70], in particular, under similar conditions. Thus, the ionized form of α-hydroxy intermediate 17 can undergo the cleavage of the glycine C–N bond [65,68–70] resulting in the formation of neutral complex 18 .…”

“…The following oxidation step of the enolates 16 in the presence of atmospheric oxygen, is less studied [48]; however, plausible key transformations can be deduced based on the closely related results on the well-established general oxidation of enolates [55–64] and glycine-derived enolates [65–70], in particular, under similar conditions. Thus, the ionized form of α-hydroxy intermediate 17 can undergo the cleavage of the glycine C–N bond [65,68–70] resulting in the formation of neutral complex 18 . Previously, we demonstrated that in situ formed derivatives of type 18 , without the pendant side chain, undergo further stabilization through dimerization, giving rise to the corresponding binuclear complexes [48].…”

A Simple Chiral Cu(II) Complex as an Effective Phase‐Transfer Catalyst for the Enantioselective Alkylation of Dissymmetric Glycinate Ketimines

“…Therefore, the mechanism aspects of asymmetric alkylation need to be further explored in order to develop effective catalysts derived from simple structures. Although extensive studies of Schiff base asymmetric alkylation have been performed, leading to the discovery of a plethora of chiral catalysts, only very little empirical work has been carried out to characterize the effect of the imine structure within the substrate on stereoselctivity . Moreover, in the case of dissymmetric imines, hydrogenation serves as a route to enantiomerically enriched amines with multistereogenic centers.…”