Amino acids benzyloxycarbonyl

AcOH, HBr, 10°, 10 min, 70% yield. Phthaloyl or trifluoroacetyl groups on amino acids are stable to these conditions benzyloxycarbonyl (Cbz) or /-butoxycarbonyl (BOC) groups are cleaved. 

Lipase-catalyzed methanolysis of racemic N-benzyloxycarbonyl (Cbz) amino acid trifluoroethyl esters carrying aliphatic side chains afforded the L-methyl esters and the D-trifluoromethyl esters (Figure 6.16). The released alcohol (CF3CH2OH) is a weak nucleophile that cannot attack the ester product. The nucleophilidty of the leaving group is depleted by the presence of an electron-withdrawing group [63]. 

Examples are given in Table 4—1 for the synthesis of amides of AT-protected amino acids by means of imidazolides and triazolides (where Z and Boc represent the protecting groups benzyloxycarbonyl and terf-butoxycarbonyl) ... 

Two amino acid stereoisomers protected by benzyloxycarbonyl groups were deprotected in different ways. One isomer was hydrogenolyzed on 5% Pd/C (0.05 mol Pd/mol) in AcOEt-MeOH for 16 hours at ambient pressure and temperature. The other isomer was dissolved in MeOH, and cyclohexene (10 mol/mol) was added under nitrogen followed by 5% Pd/C (0.18 mol Pd/mol). The temperature was immediately raised to reflux, and stirring was continued for 7 minutes (Scheme 4.60).266... 

Recently, chloromethylated benzocoumarin 11c, hydroxylmethylated benzocou-marin 12, and chloromethylated coumarin 13 were used in the efficient preparation of several fluorescent ester conjugates of /V-benzyloxycarbonyl-neurotransmitter amino acids, such as p-alanine, tyrosine, 3,4-dihydroxyphenylalanine (DOPA), glutamic acid, and y-aminobutyric acid (GABA) [39, 40],... 

Scheme 18.47 Synthesis of the allenic amino acid derivative 149 by chelate-controlled Claisen rearrangement [135] (LDA= lithium diisopropylamide Cbz = benzyloxycarbonyl).

T Yamada, N Isono, A Inui, T Miyazawa, S Kuwata, H Watanabe. Esterification of iV-(benzyloxycarbonyl)amino acids and amino acids using BF3-etherate as catalyst. Bull Chem Soc Jpn 51, 1897, 1978. 

Synthesis of N-Protected a-Amino Acids from N-(Benzyloxycarbonyl)-L-Serine via Its g-Lactone N -(Benzyloxycarbonyl)-p-(Pyrazol-1-yl)-L-Alanine... 

Alternatively, oxazolones have been used as reagents to activate and to couple N-protected dicarboxylic amino acids wherein the carboxylate moiety acts as the nucleophile. For example, 2,4-dimethyl-5(4//)-oxazolone 255 reacts with N-benzyloxycarbonyl-L-aspartic acid to give a mixture of the anhydrides 256 and 257. Subsequent reaction of 256 and 257 with phenylalanine methyl ester hydrochloride and A-methylmorpholine produces a mixture of the a-isomer 258 and p-isomer 259 of Al-benzyloxycarbonyl-aspartylphenylalanine methyl ester (Scheme 7.83). °... 

X-ray analysis of the saturated 5(4f/)-oxazolone from A-benzyloxycarbonyl-(Aib)40H 798 (Fig. 7.67) has been determined. The oxazolone ring is nearly planar. The conformation of the amino acid residue preceding the residue of the ring system is semiextended although the Aibj and Aib2 residues are folded. 

Benzyloxycarbonyl chloride [501-53-1] M 170.6, b 103 /20mm, d 1.195, n 1.5190. Commercial material is better than 95% pure and may contain some toluene, benzyl alcohol, benzyl chloride and HCl. After long storage (e.g. two years at 4°. Greenstein and Winitz [The Chemistry of the Amino Acids Vol 2, p 890, J Wiley and Sons NY, 1961] recommended that the liquid should be flushed with a stream of dry air, filtered and stored over sodium sulphate to remove CO2 and HCl which are formed by decomposition. It may further be distilled from an oil bath at a temperature below 85° because Thiel and Dent [Annalen 301 257 1898] stated that benzyloxycarbonyl chloride decarboxylates to benzyl chloride slowly at 100° and vigorously at 155°. Redistillation at higher vac below 85° yields material which shows no other peaks than those of benzyloxycarbonyl chloride by NMR spectroscopy. LACHRYMATORY. 

To a mixture of the TV-benzyloxycarbonyl-TV-methyl amino add 17 (1 mmol) and EtOH (30 mL) in a 100-mL round-bottomed flask was added 10% Pd/C catalyst (20 mg). The mixture was stirred at rt in an atmosphere of H2 until the required amount of H2 had been absorbed. The mixture was then taken to dryness. The residue was taken up in hot distilled H20 (15 mL) and filtered through Celite. The filter cake was washed with hot H20 (2 x 10 ml) and the combined filtrates were taken to dryness in vacuo to afford a white solid. The solid was then dissolved in the minimum of hot distilled water and crystallized by addition of EtOH to afford the pure TV-methyl amino acid. 

The carbodiimide method has been employed in several syntheses of depsipeptides. However, direct application of DCC for the formation of the ester bond between the amino acid and hydroxy acid components under the usual conditions of amide coupling affords the desired depsipeptides in acceptable yields only in the case of unhindered co-hydroxy units [54] or an active hydroxy group, such as in TV-benzoyl-u-hydroxyglycine benzyl ester. For example, Ravdel et al.[55 have performed the esterification of various benzyloxycarbonyl- and phthalylamino acids with /V-benzoyl-a-hydroxyglycine benzyl ester with DCC in 50-65% yield. On the other hand, Shemyakin et all21 failed to obtain the expected depsipeptide products on condensation of bulky benzyloxycarbonyl- or phthalylvaline with a-hydroxy-isovaleric acid benzyl ester. The main product was acylurea in the first case and phthalylvaline anhydride in the second. Thus, the classical carbodiimide procedure could not be applied in practical depsipeptide preparation. 

In 1959 Shchukina et a I. 56 showed that the addition of pyridine to DCC increases the yield (65-85%) of depsipeptides constructed from Z-protected amino acids and serine, threonine, or salicylic acid derivatives. The ferf-butyl ester of Af-(benzyloxycarbonyl)-leucylleucic acid (Table 2) was prepared in 60% yield under the same conditions of addition using a 2 molar excess of pyridine to carbodiimide. 57 The DCC/pyridine technique was successfully utilized in the ring closure between ()-alanine and leucic acid residues during the synthesis of the cyclic hexadepsipeptide destruxin B.[58 Under this modified approach the... 

The active ester methodology, which is widely used in peptide chemistry, has found only limited application in depsipeptide synthesis. A more vigorous activation of the carboxy component is apparently required to form an ester bond compared to the peptide analogue. Nevertheless, active esters have been utilized for this purpose in combination with some catalyst additives. The first successful attempt in this direction was described by Mazur.1103 The modification of the 4-nitrophenyl ester procedure included addition of 1-10 equivalents of imidazole to the reaction mixture. This accelerated technique presumably involves formation of the highly reactive intermediate imidazolide. The reaction resulted in the preparation of model benzyloxycarbonyl didepsipeptide esters in good yields within several hours at room temperature from 4-nitrophenyl esters of Z-amino acids and the pentamethylbenzyl ester of glycolic acid, while in the absence of imidazole this reaction failed to give any product. 

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