A-Benzyloxycarbonyl Derivatives

Treatment of benzyl 2-(A-benzyloxycarbonyl)amino-2-deoxy-a-D-gluco-pyranoside with oxygen in the presence of platinum oxide catalyst causes oxidation at C6 hydrogenolysis of the substituents yields 2-amino-2-deoxy-D-glucuronic acid.64 Under similar conditions of oxidation, the A-acetyl derivative is less stable than the A-benzyloxycarbonyl derivative, and complete degradation of the molecule occurs. Glycosides of 2-amino-2-de-oxy-D-glucuronic acid are remarkably resistant to acidic hydrolysis, and the free acid itself is much more stable toward mineral acids than are other uronic acids. 

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 A-benzyloxy carbonyl amino acid gives an unstable carbamic acid that quickly decarboxylates to give the deprotected amino acid. 

Derivatives of threonine have also been used as chiral building blocks in natural product synthesis. For example, a synthesis of the rare monosaccharide Callipel-tose [Scheme 3.125] began with the A -benzyloxycarbonyl derivative of D-threo-nine methyl ester (125.1). Simultaneous protection of the amino and hydroxyl... 

N-Terminal amino group. The A -benzyloxycarbonyl derivative of the jV-terminal amino group in bestatin and its corresponding amide displayed only weak inhibitory activity suggesting that a free A -terminal amino group was essential for interaction with the active site of the enzyme. 

V. P. Kumar, M. S. Reddy, M. Narender, K. Surendra, Y. V. D. Nageswar, K. R. Rao, Aqueous phase mono-protection of amines and amino acids as A-benzyloxycarbonyl derivatives in the presence of j8-cyclodextrin. Tetrahedron Lett., 2006, 47, 6393-6396. 

Methods have been described for the A-acylation of glycine esters with cinnamyl, O-ethoxycarbonyl-p-coumary or aa-diethoxy-carbonylcaffeyl chlorides deprotection of the latter derivative to A-calfeylglycine is best effected with hydrazine hydrate. Eckstein has recorded a simple method for the direct acylation of histidine to its A -benzyloxycarbonyl derivative. 

When cysteine reacts with an alkyl or aryl chloroformate, both the -SH and -NH groups are protected, as a thiocarbonate and as a carbamate, respectively. Selective or simultaneous removal of the protective groups is possible. (See cleavage conditions 3-6 for an S-benzyloxycarbonyl derivative, page 485.)... 

Figure 4. Three naturally occurring tyrosine derivatives (desaminotyrosine, tyrosine, and tyramine) were used to prepare four different monomeric diphenols that carry no pendent chains (Dat-Tym), only a benzyloxycarbonyl (Z) group, only a hexyl ester group, or both types of pendent chains (Z-Tyr-Tyr-Hex).

Scheme 2 illustrates a synthesis of the benzyloxycarbonyl derivative (H) of the ester (9a) using chemistry analogous to that for anisomycin (Scheme 1). In the formation of the D-allo-triol (.12),...

The precursor to (5) was made diastereoselectively by Fessner and coworkers [44]. When the intermediate ketose 1-phosphate was immediately submitted to hydrogenation conditions, l,5,6-trideoxy-l,5-imino-D-galactitol (1,6-dideoxygalactonojirimycin, 10) was obtained in fair yield [42]. The latter derivative was also obtained by a hetero Diels-Alder cycloaddition of a benzyloxycarbonyl nitroso dienophile to ( , )-sorbaldehyde dimethylacetal [45]. 

Oxazoline formation under Mitsunobu conditions is very facile. As shown in the last example in Table 8.10, as much as 30% of the oxazoline is formed in addition to the desired vinylaziridine that is obtained in 64% yield. Only amide groups participate in this cyclization since the oxazoline is not formed when the nitrogen is protected as a benzyloxycarbonyl (Cbz) or ferf-butyloxycarbonyl (Boc) derivative. 

A further approach for the synthesis of nonsymmetrically protected lanthionines is the conversion of thiosulfinates of symmetrically protected cystine derivatives into nonsymmetrically protected cystines via a reaction with a cysteine derivative and subsequently the conversion of the resulting unsymmetrically protected cystine into the nonsymmetrically protected lanthionines with a tris(dialkylamino)phosphineJ26l The oxidation of the symmetrically protected cystine, e.g. A,AT-bis(benzyloxycarbonyl)-L-cystine diethyl ester, of one stereochemical configuration to the thiosulfinate with m-chloroperoxybenzoic acid is essentially quantitative. The nonsymmetrical cystine is then formed in a subsequent step by the addition of the /V-/er/-butoxycarbonyl-L-cysteine tert-butyl ester derivative to give N-Z-N -Boc-L-cystine ethyl ferf-butyl diester. The desired 2f ,6f -lanthionine is then formed in the presence of P(NEt2)3 in yields of >50%. 

The final step, incorporation of ALmethyl-D-leutine, can be carried out as follows. D-Leucine was protected as its benzyloxycarbonyl derivative, and methylation was carried out by the phase-transfer method described above for tyrosine. BOP-promoted coupling between Z,Me-D-Leu-OH and the macrocycle, followed by deprotection, gives didemnin A (60). 

Intramolecular cascade cyclization of compounds 481 in the presence of catalytic amount of HgCl2 gave l,2,3,4-tetrahydro-6H-pyrido[l,2-a]pyr-azin-6-ones 483 (09TL4050). NMR investigations indicated that the reaction goes through intermediate 482, which then cyclized to 483. In the absence of catalyst, the cyclization was found to be sluggish. When instead of (2-N02-Ph)S02 derivative N-benzyloxycarbonyl derivative was used, no cyclized product was obtained. Similar reaction of compound 484 provided a mixture of tricyclic compounds 485 and 486. 

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