Asymmetric glycine imine

Another structurally modified guanidine was reported by Ishikawa et al. as a chiral superbase for asymmetric silylation of secondary alcohols [122]. Soon after, Ishikawa discovered that the same catalyst promoted asymmetric Michael additions of glycine imines to acrylates [123]. The additions were promoted in good yield and great asymmetric induction under neat reaction conditions with guanidine catalyst 250 (Scheme 68). The authors deduced that the high conversion and selectivity were due to the relative configuration of the three chiral centers of the catalyst in... 

Table 7.2 Asymmetric C-benzylation of glycine imine 20 using chiral PTCs 30-32.

Lygo, B. and Andrews, B.I. (2004) Asymmetric phase-transfer catalysis utilizing chiral quaternary ammonium salts asymmetric alkylation of glycine imines. Ace. Chem. Res., 37, 518. 

Glycine imine esters, Ph2C=N-CH2-C02R, undergo asymmetric Michael addition to enones using an ether-water phase-transfer system.218 A chiral ammonium salt, in conjunction with cesium carbonate, gives high ees. 

KOH/kaolin combined with a chiral catalyst was used for asymmetric alkylation of glycine imine esters, and recycled for subsequent reactions without loss of activity over three times [55, 56]. 

ASYMMETRIC PHASE-TRANSFER CATALYSED ALKYLATION OF GLYCINE IMINES USING CINCHONA ALKALOID DERIVED QUATERNARY AMMONIUM SALTS... 

FIG. 7 Asymmetric phase transfer catalysis alkylation of glycine imine esters. 

Numerous guanidine-catalysed asymmetric Michael reactions and its related variants such as aza-Michael, oxa-Michael, phospha-Michael, sulfa-Michael have been reported in the literature. A nonexhaustive selection of conjugate addition reactions that is relevant to green chemistry will be presented. Glycine imines are commonly employed in Michael additions. They are protected a-amino acids and must he deprotected if an amino acid derivative is desired (Scheme 23.5). The large molecular mass of the imine group then makes waste generation a problem. 

In addition, in 2(X)4 Mamoka and co-workers [72] synthesized a recyclable fluorous chiral phase-transfer catalyst which was successfully applied for the catalytic asymmetric alkylation of a glycine-imine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent. Later, in 2010 Itsuno and co-workers [73] published a new type of polymer-supported quarternary ammonium catalysts based on either cinchona alkaloids or Maruoka s-type catalyst bound via ionic bonds to the polymeric sulfonates. 

Phase-transfer catalysis is a vast area of organic chemistry, and there are many different examples of the applications of phase-transfer catalysts to asymmetric synthesis, particularly in the area of enantioselective a-ami-noacid synthesis. This area has been extensively reviewed by Maruoka, Lygo and O Donnell. However, there are limited examples where asymmetric phase-transfer catalysis has been applied to drug discovery. One notable example is the asymmetric allylation of glycine imine 337, catalysed by quaternary ammonium bromide 340, which has been used by Kumar et al, as the key step in the synthesis of local anaesthetic levobupivacaine " (339) (Scheme 14.102). 

Asymmetric Phase-Transfer Reactions of Glycine Imine Derivatives... 

Scheme 12.1 Asymmetric phase-transfer catalytic alkylation of glycine imine ester 65a.

Some phase-transfer catalytic asymmetric alkylation reactions of glycine imine derivatives have been explored to access natural products and biologically active compounds. For example, by employing an enantioselective phase-transfer catalytic alkylation, Kim et al. accomplished the first asymmetric total synthesis of the naturally occurring phenanthroindolizidine alkaloid (—)-antofine (Scheme 12.2) [102]. The key feature of this synthesis is the creation of the stereogenic center by reacting 65a with electrophile 66 in the presence of the dimeric catalyst 28 under the phase-transfer conditions. 

Scheme 12.5 Asymmetric double alkylation of glycine imine ester 72 under phase-transfer conditions.

Scheme 12.7 Asymmetric phase-transfer catalytic conjugate addition of glycine imine esters to o, l-unsaturated carbonyl compounds and its application to the synthesis of functionalized prolines.

By using the catalyst (S)-37b, Maruoka s group reported the asymmetric addition of glycine imine ester 65c to a,p-enone 81 to afford the corresponding adduct 82 [111]. Subsequently, the one-pot transformation including intramolecular reductive amination, acetal hydrolysis, and second reductive amination was effected with the Hantzsch ester and trifluoroacetic acid in aqueous ethanol to furnish the octahydropyrrolizine core structure with excellent enantioselectivity. This product was further converted into (-I-) -monomorine in three additional steps (Scheme 12.9). 

Some chiral phase-transfer catalysts can also promote enantioselective aldol and Mannich condensations of glycine imine donors with aldehyde and imine acceptors. These reactions provide important tools for the asymmetric constmction of P-hydroxy-a-amino acid and a,p-diamino acid derivatives, which are extremely interesting chiral units in the synthesis of pharmaceutical and natural products. For... 

Scheme 12.11 Asymmetric phase-transfer catalytic aldol condensation of glycine imine ester 6Sa with aldehyde and its application to the synthesis of p-hydroxy-a-amino ester 85.

By using tartrate-derived bisammonium salts as chiral phase-transfer catalysts, Shibasaki and coworkers developed the asymmetric Mannich condensation of glycine imine ester 65a with N-Boc-protected aldimines [82,115]. The condensation products were obtained with high diastereoselectivities and moderate to good enantioselectivities. This method could be applied to access the enantiomerically enriched 3-amino pyrrolidine intermediate 88 for the further synthesis of (-1-)-nemonapride (Scheme 12.13). 

Scheme 12.12 Asymmetric phase-transfer catalytic Mannich reaction of glycine imine ester 65a with a-amino ester and its further conversion into streptolidine lactam precursor 87.

The imines of ( )-(l/ ,2/ ,5/ )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were highly successful as Michael donors in the asymmetric synthesis of 2,3-di-substituted glutamates. The chiral azaallyl anions derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 "C undergo addition to various ,/ -unsaturated esters with modest to high diastereoselectivities210,394. 

Abelian T., Chinchilla R., Galindo N., Guillena G., Najera C., Sansano J. M. Glycine and Alanine Imines As Templates for Asymmetric Synthesis of a-Amino Acids Eur. J. Org. Chem. 2000 2689-2697... 

More recently, catalytic asymmetric allylations of imines and imine derivatives in aqueous media have been studied. An /V-spiro C2-symmetrical chiral quaternary ammonium salt (5,5)-I-Br (,S, .S )-()-Np-NAS-Br] has been evaluated in the allylation of glycine tert-Bu ester benzophenone Schiff base [Ph2C=NCH2COOCMe3] for synthesis of both natural and unnatural a-amino acids (Eq. 11,45).76... 

Asymmetric induction has been noted [64] when ethyl glycine, protected as its imine by (S)-menthone, is allowed to react with ethyl acrylate under phase-transfer catalytic conditions using tetra-n-butylammonium bromide. An overall yield of 43% was achieved with 46% ee. The stereoselectivity of the reaction was not enhanced when A-benzylquininium or cinchoninium chloride were used and, unlike reactions catalysed by chiral catalysts, the enantiomeric excess increased, when a more polar solvent was used. 

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