N-protected glycine ester

The development of dimeric cinchona alkaloids as very efficient and practical catalysts for asymmetric alkylation of the N-protected glycine ester 18 was reported... 

Scheme 21.33 Alkylation of N-protected glycine ester under ball-milling conditions.

In an approach toward heterocycle synthesis two different three-step methods for solid-phase preparation of aminopropenones and aminopropenoates have been developed [29]. The first involved formation of the respective ester from N-protected glycine derivatives and Merrifield resin (Scheme 16.5) whereas the second used a different approach, use of simple aqueous methylamine solution for functionalization of the solid support [29]. The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the corresponding acetophenones, using N,N-dimethylformamide diethylacetal (DMEDEA) as reagent. The final step in the synthesis of the pyridopyrimidinones involved release of the products from the solid support by intramolecular cyclization. 

Ester enolates, much more sensitive and capricious than ketone and amide enolates, seemed to be unsuitable for palladium-catalyzed allylic alkylations. Thus, Hegedus and coworkers [24] reported on low yields and predominant side reactions in the allylation of the lithium enolate of methyl cyclohexanecarboxylate. It seems that so far the only reliable and efficient version of a Tsuji-Trost reaction with ester enolates is based on the chelated zinc enolates 41 derived from N-protected glycinates 40 - a procedure that was developed by Kazmaier s group. 

Among numerous studies employing this auxiliary [26], Davis enantiose-lective synthesis of (-)-agelastatin A (88), a cytotoxic tetracyclic marine alkaloid, is noteworthy (Scheme 11.13) [77]. In this synthetic endeavor, the major u,p-syn diamino ester 87 was obtained in 73% isolated yield through the dia-stereoselective addition of N-protected glycine enolate 85 to a,/S-unsaturated p-toluenesulfmyl imine 86. 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

For the elongation of the chain starting from 11 toward the N-terminal group, direct condensation of the activated p-nitrophenyl esters of such amino acids as N-protected L-cysteine, L-glutamic acid, glycine, L-leu-cine, L-proline, L-serine, L-tyrosine, andL-valine with 2-acetamido-3,4,6-... 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

The rapid aminolysis of cobalt(llI)-chelated glycine esters in aprotic solvents (Scheme 10 N4 = (en)2 or trien, R = Me, Et, R = H, CHR"C02Et) could be of value in peptide synthesis. The cobalt atom acts as both an N-protecting and an activating group. The synthesis of the chelated amino acid esters has presented some difficulties.207 A recent paper208 describes the use of methyl trifluoromethanesulfonate for the alkylation of chelated amino acids using dry trimethyl phosphate... 

In a more elaborate example, Thamm et al. (1980) selectively removed, by Edman degradation, the N-terminal glycine of the A-chain of an insulin derivative in which the B-chain amino terminus and the B-chain lysine were protected. The new N-terminus was reacted with theN-hydroxysuc-cinimide ester of A-(4-azido-2-nitrophenyl)glycine to yield, after deprotection, a derivative of insulin modified only at the NaA-terminus. The amino protecting group chosen for this procedure was the base labile, methylsulfonylethyloxycarbonyl. 

Sheehan and another Nobel laureate Khorana showed independently that the mild carbodiimide mediated synthesis is very useful in the condensation reaction of N-blocked amino acids with a different amino acid to form a peptide bond. The O-blocking of carboxylic acid groups in peptide synthesis with amino nucleophiles, such as glycine esters or amides, " or novel silicon containing protective groups is also mediated by carbodiimides. Likewise, alcohols are protected with 4-benzyloxybutyric acid, using EDC/DMPA. ... 

N-ProtecUve group. Although the trityl group has received some consideration for the N-protection of amino acids, a serious limitation is that, with the exception of the glycine derivative, the p-nitrophenyl esters of N-tritylamino acids do not couple with amino acid esters. ... 

Another attractive, though limited, route to fully protected (o-amino-(n-(hydroxycarbonyl)alkylphos-phonic acids involves the addition of sodium acetamidomalonate or potassium A-(diphenylmeth-ylene)glycine esters to dialkyl vinylphosphonates (Scheme 8.80). ° - ... 

N-Protection of amino acids.1 The reagent reacts with an amino acid ester hydrochloride, for example that of glycine (4) in chloroform containing triethyl-... 

Ohba and co-workers developed a general synthesis of chiral iV-protected 5-(aminomethyl)oxazoles from a-lithiated isocyanides and Af-protected amino acid esters (Scheme 1.101). Metalation of an alkyl or benzyl isocyanide with n-BuLi or LDA and acylation with an A-Boc-ot-amino acid methyl ester afforded an iV-Boc-a-amino acid acyl isocyanide 369, which cyclized to a chiral A-Boc-5-(aminomethyl) oxazole 370. The products were obtained in > 98% ee based on chiral HPLC analysis. The yields of 370 were somewhat variable, ranging from 45 to 91%. A-Boc-protected glycine, alanine, phenylalanine, proline, serine, and (9-benzyl serine were all compatible with these reaction conditions. 

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