Polypeptides. Part XIII. Preparation of α-aza-amino-acid (carbazic acid) derivatives and intermediates for the preparation of α-aza-peptides

Abstract

Esters and amides of several a-aza-amino-acids (carbazic acids), and intermediates of use in the introduction into peptides of a- aza-gtycyl, -alanyl, -valyl, -1eucyl. -isoleucyl, -phenylalanyl, -tyrosyl, -tryptophyl, -prolyl, -aspartyl. -asparaginyl, -glutamyl, -glutaminyl, and -pyroglutaminyl residues are described. t-Butyl 3-alkyl-or -aralkyl carbazates, obtained by catalytic hydrogenation of the corresponding hydrazones, were the most versatile intermediates ; they were converted in high yield into a-aza-amino-acid esters and amides, gave a-aza-dipeptide esters when treated with at-isocyanato-esters, and afforded ' active esters ' of N-t-butoxycarbonyl-a-aza-aminoacids when treated with 2,4,5-trichlorophenyI chloroformate.REPLACEMENT in peptides, of the a-CH groups of aminoacid residues by N has little effect on the overall polarity of the molecule and the relative spacing of side-chain residues, but would be expected to induce new chemical and biological properties by virtue of the changed conformational situation at the residue or residues concerned. Our interest over the past six years in analoguesof this type (a-aza-peptides) has led us to establish general methods for the synthesis of a-aza-amino-acid derivatives and the incorporation of a-aza-amino-acid residues into peptides. This aspect of our work is described in the present paper. Subsequent papers in the series will deal with the use of this methodology in the synthesis of a-aza-analogues of biologically active peptides and model enzyme substrates.a-Aza-amino-acid derivatives and a-aza-peptides have hitherto been little explored. Ethyl esters of a-azaphenylalanine, -alanine, -leucine, and -methionhe were prepared by Ronco et aL2 by alkylation/aralkylation of ethyl carbazate, using biacetyl for amino-protection (Scheme 1). Kurtz and Nieman found the methodReagents: see caption, Scheme 2 unattractive for the preparation of N-acetyl-a-azaphenylalanine ethyl ester preferring the ethoxycarbonylation of methyl 3-benzylcarbazate. Gante, in extensive studies: developed methods for the incorporation of aza-glycyl residues into peptides, and demonstrated that a-aza-alanine and -phenylalanine may be incorporated by selective acylation of methyl-and benzyl-hydrazine. Hess, Moreland, and Laubach prepared an analogue of bovine angiotensin I1 in which the 5-valyl residue is replaced by a-aza-valyl ; the incorporation of aza-valine involved the reaction of t-butyl-3-isopropylcarbazate with the adjacent amino-acid residue (tyrosine) as its N-carbonyl ethyl ester. Niedrich and his co-workers prepared a-aza-asparagine and aza-glycine analogues of oxytocin 6 and of eledoisin 7 octapeptide, and a-azaalanine analogues of eledoisin hexa-and penta-peptides ; the incorporation of a-aza-asparagine and -alanine involved selective acylation of hydrazinoacetamide or methylhydrazine.Our own work has shown that the most useful and versatile intermediates are t-butyl 3-alkyl-or -aralkylcarbazates (4). Carbazates of this type, suitable for the synthesis of aza-valine, -leucine, -...

Antiviral Activity of DG-35-VIII, a Potent Inhibitor of the Protease of Human Immunodeficiency Virus

“…A mixture of 2.03 g (6.83 mmol) of 2R,3S-1,2-epoxy-3-benzyloxycarbonylamino-4-phenylbutane 1 (D Grobelny, 1992: Amine derivatives of oxo-and hydroxy-substituted hydrocarbons; Australian Patent Application 92/1304; PTC International Application WO 938006) and 1.2 g (7.6 mmol) of t-butyl 3-isopropylcarbazate 2 (Dutta & Morley, 1975) in 8 mL of isopropanol was stirred for 12 h at 70±5°C under nitrogen. After evaporation of the solvent in vacuo the solid residue was recrystallized from hexane to give 2.6 g (80% yield) of compound 3 melting at 114-115°C; R f (A), 0.2; n, (B),0.61: NMR (CDC1 3 ) 0.95 (rn, 6H, isopropyl CH 3 ) ; 1.42 (s, 9H, t-butyl CH 3)j 2.44 (rn, 2H, butyl CH 2-1); 2.94 (m, 3H, butyl CH 2-4, CH-3)j 3.33-3.93 (rn, 2H, isopropyl CH, butyl CH-2)j 4.4 (broad m, IH, OH); 5.05 (s, 2H, methoxy CH 2)j 5.33 (broad m, 2H, NH)j 7.…”

Analogs of the Luteinizing Hormone Releasing Hormone having the Azagly10 Moiety with Antiovulatory Activity

“…T he final products w ere purified w ith significantly less difficulty than was o u r ex p eri ence on the A zagly10-analogs previously re p o rte d [1], T he new p rocedure on hydrazinolysis of N -a-f-Bocp ro tec ted peptide-resins is superior to the one w here N -acetyl-peptides w ere cleaved from the resin. A lso, conversion of the C -term inal hydrazide m oiety to A zagly1" by the m ethod of D u tta and M orley [6] us ing sodium cyanate was b etter than the laborious azide coupling w ith sem icarbazide.…”

“…T h e new p ro ce d u re consisted of (1) hydrazinolysis o f N -a-r-B o c-n o n ap ep tid e resin (side-chain p ro te c te d ); (2) reactio n of the resulting N -a-f-Bocn o n ap e p tid e w ith sodium cyanate u n d er acidic condi tions [1,6] to co n v ert th e hydrazide to the azaglycine am id e; (3) ro u tin e rem oval of f-Boc by T F A , fol low ed by acety latio n w ith 25% acetic anhydride in pyridine; (4) d eprotection of the pep tid e side-chains w ith liquid H F to yield the N -a-acety lated A zagly111-L H R H analogs. T he final products w ere purified w ith significantly less difficulty than was o u r ex p eri ence on the A zagly10-analogs previously re p o rte d [1], T he new p rocedure on hydrazinolysis of N -a-f-Bocp ro tec ted peptide-resins is superior to the one w here N -acetyl-peptides w ere cleaved from the resin.…”

A Review on Azapeptides: The Promising Peptidomimetics

“…A Review on Azapeptides: The Promising Peptidomimetics tryptophan, asparagine, ornithine, proline, pyroglutamic acid, aspartic acid and glutamine have been reported [2][3][4][5][6][7].…”