Glycinate imines

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... 

Treatment of the ethyl glycinate imine 6 with 2 equivalents of LDA and subsequent addition of bromoacetonitrile furnished 7 in good chemical yield but only with mediocre diastereoselectiv-ity. However, addition of zinc, or better magnesium salts, increased the diastereoselectivity to 100% 131. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

Another synthesis of pyrrolidines, in this case with high enantioselectivity, has seen several enones with a chiral alkoxy or amino substituent in the y-position react with azome-thine yields (derived from glycine imine derivatives) upon treatment with DBU/AgOAc (equation 171)612-614. This reaction may also be done using other alkene-containing substrates615,616. 

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... 

The B. subtilis thiazole synthase (ThiG) catalyzes the condensation of DXP (2), glycine imine (23), and ThiS-COSH (3) to give the thiazole tautomer 14. The current mechanistic hypothesis for this complex reaction is shown in Figure 5. DXP forms an imine with lysine 96, which then tautomerizes to ketone 17. Addition of ThiS-COSH... 

Glycine oxidase (ThiO) catalyzes the oxidation of glycine (1) to the glycine imine 23. The ThiO structure, with A -acetylglycine bound at the active site, has been determined. This structure, as well as the efficient utilization of cyclopropyl glycine as a substrate, supports a hydride transfer mechanism (Figure 7). ... 

In E. coli, ThiH catalyzes the formation of the glycine imine 23 from tyrosine (26). ThiH is an oxygen-sensitive radical 5-adenosyl-L-methionine (SAM) enzyme. Its activity has been reconstituted and the mechanism outlined in Figure 8 has been proposed. It is unclear why E. coli adopts such a complex route to the glycine imine when oxidation of glycine using nicotinamide adenine dinucleotide (NAD) would accomplish the same transformation. 

Cycloaddition of 565 with azomethine ylide, generated from aryl glycine imine, furnishes tetrasubstituted pyrrolidines 569 and 570 in a ratio of 78 22 [178]. The diastereomeric ratio can be increased to 96 4 by using debenzylated 565, which is available from the corresponding TBS-protected lactaldehyde. 

Ishikawa, T., Araki, Y, Kumamoto, T. era/. (2001) Modified guanidines as chiral supedrbases apphcation to as3munetric Michael reaction of glycine imine with acrylate or its related compounds. Chemical Communications, 245-246. 

GuiUena, G. and Najera, C. (1998) PTC and organic bases-LiCl assisted alkylation of imidazoUdinone-glycine iminic derivatives for the as3mimetric synthesis of a-amino acids. Tetrahedron Asymmetry, 9, 3935-3938. 

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

Scheme 4.42 89a-catalyzed enantioselective Michael addition of a glycine imine to... 

In this context, crown ether 101, which performed rather well in the reaction of glycine imines with vinyl ketones (see Scheme 5.4), has been employed in the addition of the same kinds of nucleophiles to different alkyl acrylates, furnishing good yields and enantioselectivities (Scheme 5.21). The same catalyst performed poorly in the same reaction with acrylonitrile, furnishing a rather low degree of enantioselection. Similarly, derivative 100b was employed to... 

Scheme 5.24 Enantioselective 114-catalyzed Michael reaction of a glycine imine with tert-butyl acrylate.

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

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