Glycine equivalent

El fazepam (80) not only is a tranquilizer, but also stimulates feeding in satiated animals. One of several syntheses involves reaction of benzophenone derivative with a glycine equivalent masked as an oxazolidine-2,5-dione (79). ... 

Next the product is acylated with bromoacetyl chloride and the glycine equivalent is constructed in place by a Gabriel amine synthesis (phthalamide anion followed by hydrazine) subsequent to which cyclization to benzodiazepine occurs. The synthesis of the tranquilizer quazepam (88) is finished by thioamide conversion with phosphorus pentasulfide. ... 

An alternative sequence utilized 2-oxazolidone, which was readily synthesized from urea and ethanolamine, as the glycine equivalent. Subsequent treatment with phosphorous acid and formaldehyde produced iV-phosphonomethyl-2-oxazolidone 12 (16). Upon hydrolysis, and loss of CO2,12 provided the related derivative, iV-phosphonomethylethanolamine 13, which was oxidized at high temperature with a variety of metal catalysts including cadmium oxide (16) or Raney copper (17) to give GLYH3, after acidification. A similar oxidation route has also been reported starting from iV-phosphonomethy 1-morpholine (18). 

A regio-, diastereo- and enantioselective synthesis of amino acids was reported by Takemoto and coworkers. The glycine equivalent ethyl diphenylimino glycinate was used as pronucleophile (Scheme 9.14), while the Hgand was a bidentate chiral phosphite, and 3-arylaUyl diethyl phosphates were employed as allylic substrates [39, 46]. 

Scheme 9.14 Allylic alkylations with a glycine equivalent.

The Michael additions of various carbon nucleophiles such as cyanide [15b, 22b], anions generated from nitromethane [27], ferf-butyl acetate [9], malon-ates [27] and O Donnell s glycine equivalent [541, cuprates [9,15b] or Grignard reagents [53] under copper catalysis [55] have also been reported (Scheme 24). 

Enantiocontrolled anti-selective Michael additions of the metalated ylides derived from a-(alkylideneamino)alkanoates are attractive as a new synthetic route to enantiomers of a-amino esters. Although there are a variety of chiral glycine equivalents available, only the enolates derived from 1,4-dihydropyrazine have been successfully applied to asymmetric Michael additions (Scheme 11.22) (103-105). In these reactions, the diastereoselectivities are high. 

From Other A-Acylamino Acid Derivatives and Glycine Equivalents.. . 213... 

The displacement of the chlorine atom in 395 by triphenylphosphine or other phosphorus derivatives leads to the corresponding phosphorylated oxazolones 397 or 398 that have been used to prepare new and interesting substituted vinylphos-phonium salts (Scheme 7.127). Of particular interest is the synthesis of N-acyl-a-(triphenylphosphonio)glycinates as new cationic glycine equivalents. ... 

Enantioselective a-alkylation of the enolates of synthetic equivalents for glycine (R3 = H) and several other a-amino acids (R3 4= H) equivalents can be accomplished via 4-imidazolidinone derivatives of type 11,4,<5,7,8,1°-12. Both of the pure enantiomers of the glycine equivalent are readily available. Alkylation of these ultimately furnishes enantiomerically pure a-amino adds with a a-hydrogen11,12, whereas if R3 =t= H in the starting 4-imidazolidinones 1 then a-alkyl-a-amino acids 2 are obtained4,7 8,10-12. 

Mukaiyama-Michael addition of a chiral ketene acetal to nonprochiral vinyl ketones gives products of 72-75% ee.145 A chirally modified glycine derivative (Schiff-base) adds to vinylic phosphorus compounds to yield, after hydrolysis, products with 54-85% ee.146 Another chiral glycine equivalent was used for the preparation of homochiral proline derivatives via diastereoselective addition to a,3-unsatu-rated aldehydes and ketones.147-148... 

Mazurkiewicz, R. Grymel, M. N-Acyl-a-triphe-nylphosphonioglycinates a novel cationic glycine equivalent and its reactions with heteroatom nucleophiles. Monatsh. Chem. 1999, 130, 597-604. 

Related Reagent. For the complementary synthesis of a-substituted a-amino acids via a chiral electrophilic glycine equivalent, see 3-Bmmo-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one. 

As illustrated in the aeeompanying proeedure, (N-t-Boe)allylglyeine, this morpholinone has proven to be one of the most versatile and useful ehiral glycine equivalents from which a large variety of amino acids can be prepared. Several other, recent asymmetric electrophilic glycine enolate and cation equivalents have been devised." ... 

As shown in the scheme above, no other chiral glycine equivalent (from the laboratories of Seebach, Oppolzer, Evans, Myers, Schdllkopf, etc.) can provide the range of reactivity of this substance. 

Reaction of these N -protected amino acid derivatives with electrophiles have been shown to produce the desired compounds with superior stereoselectivity and in higher yields compared to the alkylations of A -benzylidene-protected derivatives.Best results were obtained with the Oppolzer s sultam-derived glycine equivalents 133 (Scheme 70). Dia-stereomeric ratios were usually better than 98 2, and yields were between 85-96%. Liberation of the unnatural amino acids is quantitative and the products are virtually en-antiomerically pure (>99.8% Good results have been further achieved with chiral... 

Scheme 70 Chiral Auxiliaries Used in the Derivatization of Glycine Equivalents and Diastereoselective Alkylation of Chiral A -Alkylidene Amino Acid Derivatives ...

Bromomethyl-5-methylisoxazole 231 was exploited in reactions with enantiopure benzyloxycarbonyl-protected glycine equivalents 232 for the synthesis of a-substituted and a,a-disubstituted amino acids 234 through hydrolysis of 233 (Scheme 54) <2004T7679>. 

Anodic decarboxylative methoxylation has also been used to generate an efficient electrophilic chiral glycine equivalent. This is produced from the cyclic dipeptide of L-proline and aminomalonic acid diester. Anodic decarboxylation of the remaining carboxylic function leads to the chiral iV,<9-acetal, which can undergo nucleophilic substitution followed by hydrolysis to give back L-proline and the nonproteinogenic new enantiopure i)-amino acid [Eq. (49)] [201]. 

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