Carbobenzoxy compounds

Stepwise degradation of polypeptides involving benzoylation, conversion to azides and treatment of the azides with benzyl alcohol this treatment yields, via rearrangement to isocyanates, carbobenzoxy compounds which undergo catalytic hydrogenation and hydrolysis to the amide of the degraded peptide ... 

An important example is the preparation of carbobenzoxy chloride (PhCH20C0Cl) from phosgene and benzyl alcohol. This compound is widely used for protection of amino groups during peptide synthesis (see 10-55). 

The syntheses of these three compounds share a common route as described by Brickner et al. [53] and Barbachyn et al. [54]. Namely, the coupling reaction of 3,4-difluoronitrobenzene (82) with piperazine, morpholine, or thiomorpholine to yield the corresponding 4-substituted 3-fluoro-nitrobenzene (83), which upon reduction gives rise to the aniline derivative (84). Carbobenzoxy protection of the active nitrogen of 84 using benzyloxy-carbonyl chloride (CbzCl) results in the formation of carbamates 85a and 85b. Treatment of 85a,b with n-BuLi and (i -glycidyl butyrate yields a 5-(R)-... 

A similar result was obtained when the piperazinedione carried an N-sulfonyl group. Thus deprotection of the Af-carbobenzoxy taurine derivative (71) of cyclo(Phe-D-Pro) led to the 10-membered cyclic compound (73) via the cyclol (72) (89MI1). 

Total synthetic studies at Roussel-UCLAF produced a large number of compounds having this type of extended unsaturation. A ,A"-Nortes-tosterone 17-acetate (N-103), A, A -nortestosterone 17/3-methoxymethyl ether (N-104), A ,A -nortestosterone 17/3-decanoate (N-105), A A -nortestosterone 17-carbobenzoxy-ate (N-106), A ,A"-17a-methyl-... 

Bartlett and Marlowe (153) designed a series of five phosphonamidate analogs of the peptide carbobenzoxy-Gly-Leu-X (X = NH2, Gly, Phe, Ala, Leu), where a -POz-NH- replaces the Gly-Leu peptide bond, and showed that these compounds were potent transition-state analog inhibitors of the zinc endopeptidase thermolysin. They also synthesized the corresponding phos-phonate analogs, where the -NH- (13A) is replaced by -O- (I3B). The... 

Aromatic compounds, carboxylation of, 28 L-Asparagine, carbobenzoxy- [L-Asparagine, -[(phenylmethoxy[carbonyl]-], 89 L-Asparagine, IP -(trifluoroacetyl)-, 125 L-ASPARAGINYL-L-LEUCINE, CARBOBENZOXY-, METHYL ESTER [L-LEUCINE, A -[AT -[(PHENYLMETH-OXY)CARBONYL] -L-ASPAR-GINYL] -, METHYL ESTER, 88 2-Asp.Gly-OEt [Glycine, N- [Al -[(phenyl-methoxy)carbonyl] -L-asparaginyl] -, ethyl ester], 93... 

Other efficient separations accomplished using a PRP-1 column were of compounds involved in the synthesis of carbobenzoxy- -serln-amlde mesylate starting from the amino acid, -serine (Figure 11). 

Mesylsugars. An ice-cooled soln. of benzyl N-carbobenzoxy-3-acetyl-4,6-di-mesyl-a-D-glucosamine in abs. dioxane treated with a soln. of Na in iso-propanol, and kept 12 hrs. at 0° -> benzyl N-carbobenzoxy-3,4-anhydro-6-mesyl-a-D-galactosamine. Y 92-95%. P. H. Gross, K. Brendel, and H. K. Zimmerman, Jr., A. 680, 155 (1964) oxido compounds from acoxytosylates, with methanolic Na-methoxide, cf. E. J. Reist, D. E. Gueffroy, and L. Goodman, Am. Soc. 87, 677 (1965) H. Kaufmann, Helv. 48, 769 (1965). 

N-carbobenzoxy-DL-alanine (Y 88%) and DL-trans-5-methyl-2-oxazolidone-4-carboxylic acid (Y 91%). F. e., also with optically active compounds without racemization, s. T. Kaneko and T. Inui, Bull. Ghem. Soc. Japan 36, 1541 (1963). 

F. Synthesis of N bemyl-3- m-amidinophenoxy) propylamine p-Toluenesulfonate SO). To a solution of 16 mmoles of m-cyanophenol S4) (Aldrich) in 10 ml of dry DMF are added 16 mmoles of anhydrous powdered potassium carbonate and 20 mmoles of iV-carbobenzoxy-3-bro-mopropyl ether (4S). The resulting mixture is stirred at 70 for 15 hr, poured into 100 ml of 1.0 N NaOH, and extracted with ethyl acetate. The crude oily product, 2 T-carbobenzoxy-3(3-cyanophenoxy) propylamine (44), is dissolved in 10 ml of 32% hydrobromic acid in acetic acid (Eastman) and stirred at room temperatime for 2 hr. The solution is diluted with 90 ml of ether. The product is collected an recrystallized from acetone to yield white crystals of m-(3-cyanophenoxy) propylamine hydrobromide (45). To 8 mmoles of 45 are added 20 ml of chloroform and 20 mmoles of triethylamine followed by 8 mmoles of benzoylchloride (40)-The resulting solution is stirred at ambient temperature for 24 hr, then washed successively with three 30-ml portions of 1.0 N NaOH and three 30-ml portions of water. The dried solutions (dried over magnesium sulfate) are evaporated under reduced pressure. Recrystallization from benzene gives N-benzyl-3-(3-cyanophenoxy) propylamine (47) with a melting point of 96°-98°. The nitrile (47) is treated in the Pinner reaction to give compound SO, m.p. 208°-210°. 

By means of the azide reaction N-carbobenzoxy 3,5 diiodothyronine was joined to horse serum globulin, albumin, and thyro-globulin (223). After iodination to form the thyroxyl compound anti sera to these, conjugated proteins were produced and the authors report that "passive immunization with anti sera to these derivatives protects against normal physiological effects of exogenously administered thyroglobulin and thyroxine. ... 

Selenophenyl N-carbobenzoxy-dl-alaninate and methyl glycinate in acetonitrile allowed to stand 12 hrs. at room temp. -> methyl N-carbobenzoxy-dl-alanyl-glycinate. Y 78.5%. F. e., also with the Na-salts of the free acids by refluxing 4 hrs. in tetrahydrofuran, s. H.-D. Jakubke, Z. Ghem. 3, 65 (1963) B. 97, 2816 (1964) peptide synthesis with other active acyl compounds, such as acyloximes or 3-methyl-1-phenylpyrazolyl esters, s. G. Losse, A. Barth, and K. Schatz, A. 677, 185 (1964). 

A large excess of liq. isobutylene added to a suspension of N-carbobenzoxy-L-threonine in methylene chloride, then a small amount of coned. H2SO4 added, and shaken 6-10 hrs. at room temp, in a pressure flask until a soln. is formed N-carbobenzoxy-O-ferf-butyl-L-threonine ferf-butyl ester. Y ca. 90%.— The protective group can be easily removed by dissolving the compounds at or below room temp, in anhydrous trifluoroacetic acid. The optical activity is maintained. F. e. and application in peptide synthesis s. H. G. Beyerman and J. S. Bontekoe, Proc. Ghem. Soc. 1961, 249. 

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