Ethyl pyroglutamate

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

In an approach toward dipeptide mimetics, Laufersweiler condensed ethyl pyroglutamate 255 with a range of substituted aminopyrroles 254 to generate the tricyclic system 256 in good yield (Equation 69) <2005BML4322>. 

When glutamic acid (A) is heated with thionyl chloride and then with ethanol, a molecule called ethyl pyroglutamate is formed. Draw this molecule and give a mechanistic rationale for its formation. 

A number of functionalized chiral, nonracemic amino acids can be prepared using ethyl pyroglutamale as a chiral template. Silverman reduced ethyl pyroglutamate (5.4J) to the alcohol (5.42) with lithium borohydride.23 This was followed by treatment with bromine and triphenylphosphine to give 5-bromomethyl-2-pyrrolidinone, 5.48. Similarly prepared were 5-chloromethyl-2-pyrrolidinone (5.50) 5-fluoro-methyl-2-pyrrolidinone (5.52) and, 5-cyanomethyl-2-pyrrolidinone.23 In all cases, reaction with HCl and isolation via ion exchange chromatography gave the 5-halo-4-aminopentanoic acid [5-bromo-4-aminopentanoic acid 5.49) 5-chloro-... 

Pyrrolidinone derivatives can be useful synthons. Ethyl pyroglutamate (75), derived from L-glutamic acid (see chapter five, section S.l.C.ii), was converted to cyanomethyl-2-pyrrolidinone 6.14 Reduction to the amine l and Cope elimina-tionl2 gave 6.1S, which was hydrolyzed to 4-aminohex-5-enoic acid (6.16), also an... 

The electrophilic fluorination of chiral bicyclic lactams (prepared from the epimers of pyroglutamic acid) by means of A-fluoro sulfonimide (NFSI) yields l- and d-4, 4-difluoroglutamic acids and 4,4-difluoroglutamines (Figure 5.21). They have also been prepared with a good ee starting from ethyl (/ )-bromodifluoroalaninate. ... 

The (R)-enantiomer of (242) has also been prepared and used as a chiral auxiliary in an enantioselective aldol synthesis of (+)-(S )-gingerol (79CB3703). (R )-Glutamic acid (246) was thus converted into (i )-pyroglutamic acid by simply heating in water. Conversion of (247) to its methyl ester and LAH reduction delivered alcohol (248). Ethyl nitrite treatment of (248) gave nitrosoamine (249), which was methylated to furnish (250). Exposure of (250) to LAH completed the synthesis of the required chiral auxiliary RAMP [(R)- l-amino-2-(methoxymethyl)pyrrolidine]. The hydrazone (252), derived from RAMP and acetone, was... 

The pyrrolidine is prepared from ethyl (S)-N-(ethoxycarbonyl)pyroglutamate. 

It has been shown that ethyl A-Boc-l- or o-pyroglutamate reacts regioselectively at the amide function with diethyl 1-lithiomethylphosphonate in THF at low temperature to give diethyl N-(tert-butoxycarbony])-.5-amino-5-(ethoxycarbonyl)-2-oxopentylphosphonate in 60% yield without racemization at the chiral center (Scheme 7.29). ... 

Ezquerra, J., de Mendoza, J., Pedregal, C., and Ramirez, C., Regioselective nucleophilic attack on N-Boc-pyroglutamate ethyl ester, Tetrahedron Lett., 33, 5589, 1992. 

The vimcidal activity of monopercitric acid (MPCA) was determined by suspension tests against both nonenveloped and enveloped viruses including VACV [120], The study showed that vimses were 99.9% inactivated by a 0.5% concentration within 30 s demonstrating MPCA as a suitable candidate for a disinfectant. Sugimoto and Toyoshima [107] reported on the inactivation of VACV by N -Cocoyl-L-Arginine Ethyl Ester, DL-Pyroglutamic Acid Salt after a 30 min exposure at room temperature. At all tested concentrations (0.025%, 0.05%, 0.1%, and 0.25%), there was greater than 90% inactivation of VACV. 

Sugimoto, Y., and Toyoshima, S., 1997. Na-cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt, as an inactivator of hepatitis B surface antigen. Antimicrob. Agents Chemother., 16 329—332. 

The ethyl ester of (.S l-pyroglutamic acid (,S)-32 was applied for the preparation of dien-amines used as chiral dienes in enantioselective Diels-Alder reactions (Section D.l.6.1.1.1.1.5.1.). Thus, acrolein or methacrolein reacted with the auxiliary under acidic catalysis to form the corresponding dienamines 31. 

Treatment of 3,4-didehydro-L-pyroglutamate, protected as a cyclic orthoester, with ESTA gave a mixture of two diastereomeric products that differed in configuration at the a-ethyl ester position (eq 11). These diastereomers could be separated and converted to enantiomeiically pure, cyclopropane L-glutamate analogs, ... 

The Rigo methodology [169] was also found to be unsuccessful for the alkylation of (5)-methyl 5-oxo-l-(trimethylsilyl)pyrrolidine-2-carboxylate (III-68) with 3-(2-bromoethyl)-l//-indole or 3-(2-((trimethylsilyl)oxy)ethyl)-17/-indole (Scheme 4.39) [166]. Under these conditions, only (L)-methyl pyroglutamate was formed. 

A soln. of acryloyl diloride in toluene added portionwise at room temp, during 1.5-2 hrs. to a mixture of ethyl L-pyroglutamate, ethyldiisopropylamine, CuCl, and toluene, then heated 4 hrs. at 70° -> ethyl N-acryloyl-L-pyroglutamate. Y 74%. H. Suda et al., Kogyo Kagaku Zasshi 73, 1250 (1970) (Japan) C. A. 73, 77571. 

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