Glycine imines, alkylation

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]. 

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. 

The introduction of alkyl groups at the a-carbon of amino acids has been accomplished most efficiently by formation of imine esters. For example, the benzaldehyde imine of ethyl glycinate can be deproton-ated and alkylated (equation 39)." Other imines also have been used." Optical activity has been introduced by using chiral palla um ligands during the alkylation step, ° chiral alcohols to form the ester, and chiral ketones to form the imine." Alkylation of 2-pyrrole acetate esters has been accomplished in a similar fashion." ... 

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... 

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. 

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... 

Recently, Sirit and co-workers [45] developed calixarene-based chiral phase-transfer catalysts derived from cinchona alkaloids successfully used for alkylation of glycine-imine esters. In 2010, Itsuno et al. [46] published quartemary ammonium sulfonate polymers used for a-alkylation reaction of a glycine imine ester with high yields and enantioselectivity. 

Based on the catalyst design limitation arising from their synthesis, other chiral quaternary ammonium salts were developed, such as Ca-symmetrical PTC catalysts XXVIII [53], spermidine- and spermine-based catalysts XXIX [54], bis-biphenyl quaternary ammonium salts XXX [55], and other chiral quaternary ammonium salts of types XXXI and XXXII [56]. V-spiro chiral ammonium salt XXXI and XXXII (the later, readily available from gallic acid) possessing flexible alkyl chains showed high catalytic efficiency in alkylations of glycine-imine esters even in the presence of 0.01-0.05 mol% of XXXI or XXXII (Scheme 8.6) [57]. 

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. 

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.

Diastereoselective preparation of a-alkyl-a-amino acids is also possible using chiral Schiff base nickel(II) complexes of a-amino acids as Michael donors. The synthetic route to glutamic acid derivatives consists of the addition of the nickel(II) complex of the imine derived from (.S )-,V-[2-(phenylcarbonyl)phenyl]-l-benzyl-2-pyrrolidinecarboxamide and glycine to various activated olefins, i.e., 2-propenal, 3-phenyl-2-propenal and a,(f-unsaturated esters93- A... 

Michael addition of methylene imines with alkenes under solid Iiquid two-phase conditions provides a route to substituted a-amino acids [26, 27] (Scheme 6.22). When ethyl glycine is (V-protected with (S)-menthone, C-alkylation under soliddiquid... 

The electron-deficient alkene (5.2 mmol) in MeCN (5 ml) is added to an intimate mixture of powdered K2C03 (1 g) and NaOH (0.2 g), the (S)-menthone-protected ethyl glycine (1.27 g, 5 mmol), and TBA-Br (0.16 g, 0.5 mmol) in MeCN (20 ml). The mixture is stirred for 1 h at 0°C and then filtered. The solid is washed with MeCN (10 ml) and the combined organic solutions are evaporated and the residue is taken up in Et20. The ethereal solution is washed well with H20, dried (MgS04), and evaporated to produce the alkylated imine, which can be converted into the amino acid upon hydrolysis with aqueous acid. 

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