Glycine alkylation

Elongation of the glycine alkyl chain (one methylene) in 184 to an undecanoic acid in 187 (ten methylenes) resulted in greatly increased activity and a different mechanism of action. This result also suggested that position-28 might accommodate various substituents. Therefore, more compounds were designed to optimize the side chain at this position. 

In all cases it was reported that the trifluoromethyl group enhances the interaction in the prochiral ion pair, resulting in higher ee. The exception appears to be the asymmetric synthesis of a-amino acids via alkylation of the benzophenone Schiff base of glycine alkyl esters with allyl bromide, which produced a 56% ee with the trifluoromethyl-substituted catalyst compared to 66% with the unsubstituted catalysts TY-benzylcinchoninium chloride (3) or TY-benzylcinchonidinium chloride (4) (eq 5). ... 

Hydrogen "Side Group" Glycine Alkyl Side Groups Gly -H... 

In 1978, O Donnell and coworkers developed the benzophenone imines of glycine alkyl esters 4 as glycine anion equivalents, which have been found to be perfed to use in the phase-transfer catalysis [10]. An essential feature of this reaction system lies in the selective mono substitution of the starting Schiff base, the O Donnell substrate 4. This can be possible because of the significant difference in acidity of a-hydrogen between starting substrate 4 p/C,(DMSO) 18.7 (R=Et)] and a-monosubstituted produd S p/C,(DMSO) 22.8 (R=Et, E = Me), 23.2 (R=Et, E = CH2Ph)] [11]. This dramatic acidity difference makes it possible for selective formation of only monoalkylated product without concomitant production of undesired dialkylated produd or racemization. 

A conceptually different approach to interligand asymmetric induction uses chiral phase transfer catalysts. Scheme 3.26 illustrates two examples of such a process using an A -benzylcinchonium halide catalyst. The first is an indanone methylation [150] and the second is a glycine alkylation [151]. Hughes et al. reported a detailed kinetic study of the indanone methylation which revealed a mechanism significantly more complicated than a simple phase-transfer process the reaction is 0.55 order in catalyst and 0.7 order in methyl chloride, deprotonation of the indanone occurs at the interface, and methylation of the enolate (not deprotonation) is rate-determining [150]. Nevertheless, the rationale for the... 

Table 3.11. O Donnell s asymmetric glycine alkylations by chiral phase transfer catalysis (Scheme 3.26b [151]).

For many years applications of the Bradsher reaction were restricted due to its limited substrate scope and requirement for harsh reaction conditions. However, after the advancement of the arene oxide concept concerning the metabolism of polycyclic aromatic hydrocarbons, synthesis of all the nuclear monohydroxylated derivatives of 7,12-dimethylbenz[a]-anthracene (DMBA), diol epoxide metabolites of DMBA, and fluoro derivatives of DMBA was undertaken for carcinogenicity and mutagenicity determination studies. " Interest in the Bradsher reaction has increased greatly as a consequence of the need to construct these polycyclic aromatic hydrocarbons. Development of fluoroanthracenylmethyl cinchonidine as an efficient phase-transfer catalyst for asymmetric glycine alkylation also expanded the scope of the Bradsher reaction. ... 

Andrus and co-workers developed fluoroanthracenylmethyl cinchonidine 57 as an efficient phase-transfer catalyst, and it was explored for asymmetric glycine alkylation." The fluoroanthracenylmethyl precursor was synthesized from an aryloxazolidinone and aldehyde using the Bradsher reaction in the key step. This cinehonidine eatalyst promotes... 

Scheme 4.7 Glycine alkylation through camphor-derived auxiliary 35.

Scheme 14.102 Asymmetric glycine alkylation in the synthesis of levobupivacaine. ...

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

V-Phenyl glycine [103-01 -5] the key intermediate for indigo, may be manufactured by alkylation of aniline with chloroacetic acid, but it is much more economical, even though three in situ stages are required, to use formaldehyde as the alkylating agent. 

O DONNELL Ammo Acid Synthesis Amino acid synthesis by alkylation ot glycine denvaiives... 

An imidazoquinazoline constitutes still another compound that does not fall in the classification of a nonsteroid antiinflammatory agent yet shows good platelet anti aggregating activity. Condensation of benzyl chloride 128 with the ethyl ester of glycine gives alkylated product... 

S,N-Ditrityl-L-cysteine diethylamine selt L-Tyrosine lower alkyl ester L-lsoleucine lower alkyl ester Benzyl-L-proline hydrochloride L-Leucine lower alkyl ester Ammonia Hydrogen chloride Glycine lower alkyl ester... 

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... 

V,/V-Bis(trimethylsilyl) alkyl glycinates can be deprotonated and then alkylated on carbon (4) to give homologous a-amino-acid derivatives ... 

To a solution of the silylated glycinate (50 mmol) in ether (50 ml), cooled to —10 to 0°C, was added a solution of sodium hexamethyldisilazide (55 mmol) in ether (100ml) with stirring. Stirring was continued at ambient temperature for a short time, and then the alkyl halide (50 mmol) was added dropwise. The mixture was heated under reflux for 10-15 h, cooled, filtered, and the product was distilled directly (52-70%). 

Aldehydes, 43 a-Chiral, 112 a/MJnsaturated, 85,110 /3-Aldchydosi lanes, 22 Aldol reaction, directed, 139 Alkoxytrimethylsilanes, 122 Alkyl lithium. 67 Alkyl silyl ethers, 91-97,127 Alkylation, 33 of ethyl glycinate, 88-89 t-Alkylation, 111-135... 

Dynamic kinetic resolution of a-alkyl-P-keto ester was conducted successfully using biocatalysts. For example, baker s yeast gave selectively syn(2R, 3S)-product [29a] and the selectivity was enhanced by using selective inhibitor [29b] or heat treatment of the yeast [29c]. Organic solvent was used for stereochemical control of G. candidum [29d]. Plant cell cultures were used for reduction of 2-methyl-3-oxobu-tanoate and afforded antialcohol with Marchantia [29e,f] and syn-isomer with Glycine max [29f]. 

Other cyclizations at phosphorus have been observed when certain phosphinates were used in the acid-catalyzed Mannich reaction. As observed previously with various phosphonous acid derivatives, reaction of aliphatic phosphinic acids with primary amines favored the formation of 2 1 adducts (73). Thus, glycine and other a-amino acids reacted under the typical conditions with excess formaldehyde and alkyl phosphonous acids to give the bis-phosphinylmethyl adducts 125. 

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