Benzyloxycarbonyl-amino acid esters

Kazmaier reported the synthesis of several racemic a-aminoaldols in which the a-amino group and the j5-hydroxyl group are anti [63]. Reactions of N-benzyloxycarbonyl amino acid ester enoiates with a variety of aldehydes afforded moderate to good yields and good to excellent diastereoselectivity as shown in Table 2.32. Titanium enoiates were generated by deprotonation of 179 with LDA in THF followed by the addition of 2 equiv. Ti(Oi-Pr)3Cl in THF at -78 °C. 

In 1951, Feodor Lynen (1911-1979) and his coworker E. Reichert demon-started that S-acetyl coenzyme A is a more generally implicated form of active acetate than acetyl phosphate that was recognized in this role by Fritz Lipmann in 1940. The thiol ester character of 5-acetyl Co A called the attention of Th. Wieland to energy-rich S-acyl compounds as promising intermediates for the formation of the peptide bond. In 1951, the same year when the isolation of 5-acetyl CoA was published [3], Wieland and his coworkers described [4] the preparation of thiophenyl esters of benzyloxycarbonyl-amino acids and benzyloxycarbonyl-peptides and their application in the synthesis of blocked peptides ... 

The amino group of the A -benzyloxycarbonyl derivative is protected as the amide half of a carbamate ester (a urethane, Section 21-16), which is more easily hydrolyzed than most other amides. In addition, the ester half of this urethane is a benzyl ester that undergoes hydrogenolysis. Catalytic hydrogenolysis of the /V-benzyloxycarbonyl amino acid gives an unstable carbamic acid that quickly decarboxylates to give the deprotected amino acid. 

In the third method benzyloxycarbonyl-L-glutamic anhydride is condensed with an amine, amino acid or amino acid ester with subsequent removal of the benzyloxycarbonyl group by hydrogenation. This method gives a mixture of the a- and y-isomers, which are easily separated by... 

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]. 

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],... 

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). °... 

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. 

Enantiomerically pure, unprotected tetramic acids are accessible by hydrogenolytic deprotection of 4-(benzyloxycarbonyl)amino-3-oxocarboxylic esters 31 (X= Z Y = H) followed by ring closure (Scheme 11)J55 In the absence of TV-carbamate protection, the next reduction step is not totally stereoselective/54 ... 

After years of work, we in Bristol-Myers created an elegant and very practical process for the manufacture of Amikacin which we commercialized. In brief, the process involves solubilization of Kanamycin A in organic solvents by trimethylsilylation (hexamethyldisilazane-HMDS) followed by acylation with. S-4-benzyloxycarbonyl amino-2-hydroxybutyric acid activated by formation of an active ester with N-hydroxynorbornene-2,3-dicarboximide (BHBA active ester) (Scheme 4). 

However, most nucleophiles attack 5-oxazolones at the carbonyl group and the products are derivatives of a-amino acids formed by acyl-oxygen fission. Thus the action of alcohols, thiols, ammonia and amines leads, respectively, to esters, thioesters and amides orthophosphate anion gives acyl phosphates (Scheme 18). The use of a-amino acids in this reaction results in the establishment of a peptide link. Cysteine is acylated at the nitrogen atom in preference to the sulfur atom. Enzymes, e.g. a-chymotrypsin and papain, also readily combine with both saturated and unsaturated azlactones. A useful reagent for the introduction of an a-methylalanine residue is compound (202). Both the trifluoroacetamido and ester groups in the product are hydrolyzed by alkali to give a dipeptide. The alkaline hydrolyzate may be converted into the benzyloxycarbonyl derivative, which forms a new oxazolone on dehydration. Reaction with an ester of an amino acid then yields a protected tripeptide (equation 45). 

To prevent side reactions, the amino group of alanine must be protected to make it nonnucleophilic. In Section 24-7B, we saw that an amino acid reacts with benzyl chlo-roformate (also called benzyloxycarbonyl chloride) to form a urethane, or carbamate ester, that is easily removed at the end of the synthesis. This protecting group has been used for many years, and it has acquired several names. It is called the benzyloxycarbonyl group, the carbobenzoxy group (Cbz), or simply the Z group (abbreviated Z). 

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