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On the N,O-acyl migration reaction of β-hydroxy-α-amino acids with concentrated sulfuric acid, a configuration of the carbon atom carrying hydroxyl group was found to be inverted through the reaction. Thus, threonine residue in peptide was converted to allothreonine residue and vice versa in the selective chemical cleavage of threonine peptide employing the N,O-migration with concentrated sulfuric acid. The reaction mechanism involving SNi elimination of O-sulfate formed as an intermediate was suggested. The inversion did not occur in the N,O-acyl migration reaction with other mineral acids than sulfuric acid.

Streptolidine (roseonine, geamine) (1), a guanidino amino acid component of the streptothricin group antibiotics, was synthesized starting from D-ribose (8). The epimino compound (11b) was prepared from 8 in five synthetic steps. Azidolysis of 11b gave the arabino-type compound (12b), which in turn was converted to the key intermediate tribenzyloxycarbamido lactone (23b) by oxidation of C-1. The lactone 23b was rearranged to the free lactam (4) after deprotection, and then guanidinated with cyanogen bromide. The identity of the hydrolysis product of this guanidino lactam with natural streptolidine in all respects certified the proposed structure involving the steric configurations.

γ-Hydroxy-β-lysine is a new basic amino acid isolated from the hydrolyzates of antitubercular peptides, tuberactinomycin A and N. In order to confirm the structure and establish the stereochemistry of the amino acid, two diastereoisomers of γ-hydroxy-DL-β-lysine were synthesized by Arndt-Eistert synthesis via β-hiydroxyornithine. Synthetic erythro and threo isomers were found to be identical spectroscopically and chromatographically with the corresponding forms obtained from the antibiotics respectively.

Ethyl 2-(1-benzyloxycarbonylaminoethyl)-R-Δ2-thiazoline-4-carboxylate (III), ethyl 2-(1-benzyloxycarbonylamino-2-methyl-n-butyl)-R-Δ2-thiazoline-4-carboxylate (VI) and their acid amide derivatives (V, VII and VIII) were prepared by either the iminoether coupling method or the dehydration method. As a general character of thiazoline peptide, it was found that the amino acid residue connected to thiazoline ring at N-terminal side is completely racemized at the stage of thiazoline ring formation, and further epimerized, in the case of isoleucine, by treatment with the basic reagent.

A simple synthesis of various forms of radioactive L-thyroxine, carrying the label (I/sup 131/ or C/sup 14/) either in the phenolic ring or in the nonphenolic ring and in the side chain, is described, It is based on the coupling of 4hydroxy-3,5-diiodophenylpyruvic acid and 3,5-diiodotyrosine. Labeled 4- hydroxy-3,5-diiodophenylpyruvic acid was prepared by iodination of p- hydroxybenzaidehyde foilowed by condensation with acetylglycine and hydrolysis of the azlactone formed, or by enzymic oxidative deamination of diiodotyrosine. (auth)

Synthesis of thiazoline peptide from cysteine peptide by dehydration with hydrochloric acid in non-aqueous solvent was investigated. By this method, ethyl 2-benzyloxycarbonylaminomethyl-R-Δ2-thiazoline-4-carboxylate and 2 - benzyloxycarbonylaminomethyl-R-Δ2-thiazoline-4-carbonyl-L-leucine ethyl ester were prepared and isolated in pure states. This synthetic method could give a promising route to a total synthesis of bacitracin A. However, the cysteine residue in the latter thiazoline peptide ester was found to be easily racemized under the basic condition.

Tuberactidine (III) is a guanidino amino acid component of an ti tubercular pep tides, tuberactinomycin A and B, while the known guanidino amino acid capreomycidine (V) is involved in tuberactinomycin N and O. The structure of tuberactidine was assigned to be α-(4-hydroxy-2-iminohexahydro-6-pyrimidinyl)glycine and its stereochemistry was also established. During isolation of tuberactidine from an eluate in the column chromatography of tuberactinomycin hydrolyzate, it was converted to Nα-formyltuberactidine dimer (I). In this dimer, structural alternation between a carbinolamine form of cyclol type and an amide lactone form was noticed depending to a pH of the solution. I was hydrolyzed to tuberactidine and viomycidine (IV) with hydrobromic acid. In addition, a plausible pathway for the formation of viocidic acid (VII), one of the artifacts formed during hydrolysis of tuberactinomycin, was proposed.

For the purpose of synthesis of antibiotic bacitracin of six amino acids-membered ring formula, the following intermediate peptides, i.e., cyclo-(Nα-benzy]oxycarbonyl-L-lysyl-Nδ-cyclopentyloxycarbonyl-D-ornithyl-L-isojeucyl-D-phenylalanyl-L-histidyl-α-methyl-L-aspartyl) (III) and Nα-benzyloxycarbonyl-Ne-t-butyloxycarbonyl-L-lysyl-Nδ-cyclopentyloxycarbonyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-Nim-benzyl-L-histidyl-L-aspartyl-D-isoasparagine benzyl ester (IV) were prepared. In this synthesis, cyclopentyloxycarbonyl group was introduced to protect δ-amino group of ornithine residue and cleavability of this protecting group for hydrogen fluoride was investigated.

A protected heptapeptide, the formyl-L-isoleucyl-e-benzyloxycarbonyl-L-lysyl-δ-5-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-im-benzyl-L-histidyl-L-aspartic acid α-methyl-β-benzyl ester, was synthesized by the azide method and the carbodiimide method. It is an intermediate peptide for the total synthesis of the antibiotic bacitracin A, the structure of which is still ambiguous at a few points. β-Benzyl benzyloxycarbonyl-L-aspartate was prepared by a novel method similar to that used in the synthesis of γ-benzyl glutamate. The α-methyl-β-benzyl L-aspartate prepared could be useful in the synthesis of branched aspartic acid peptide. Phenomena of dimorphism were observed in crystals of δ-tosyl-D-ornithine and δ-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanine ethyl ester hydrobromide, and two crystal forms of each compound were isolated in pure states.

Threonine peptide was converted to an oxazolidone derivative via an O-chlorocarbonyl derivative by treatment with phosgene and dimethylaniline followed by refluxing in xylene, wherever the threonin...

In the synthetic study of bacitracins, peptide fragments corresponding to a branched part of bacitracin F, i.e., (S)-2-(2-methylbutyryl)thiazole-4-carboxylic acid 1-succinimidyl ester (III) and L-leucyl-γ-t-butyl-D-glutamyl-L-isoleucine (IV), were prepared. As a macrocyclic part of bacitracin A and F of cycloheptapeptide formula, cyclo- (Nα-benzyloxycarbonyl-L-lysyl-Nδ-cyclopentyloxycarbonyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-L-histidyl-β-benzyl-D-aspartyl-L-asparaginyl) (V) was synthesized through cyanomethyl ester method.

A new basic amino acid, hypusine, was isolated from the homogenate of bovine brain tissue by ion-exchange column chromatography. The structure of this amino acid was determined to be N 6 -4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid on the basis of its physical properties involving NMR and mass spectra, as well as chemical degradation including periodate oxidation and reduction with HI and P.

Asparagine peptide was selectively cleaved by the Hofmann rearrangement followed by an alkaline treatment at the peptide linkage in which an amino group of the asparagine residue participated. Upon reaction of N-benzyloxycarbonyl-L-alanyl-L-asparagine with one equivalent of bromine and three equivalents of aqueous sodium hydroxide solution at 60°C, 1-(N-benzyloxycarbonyl-L-alanyl)-2-oxoimidazolidine-5-carboxylic acid was obtained in quantitative yield. When this was treated with an aqueous methanolic sodium hydroxide solution at room temperature, a cleavage reaction occurred to give N-benzyloxycarbonyl-L-alanine and 2-oxo-imidazolidine-5-carboxylic acid. Under the same condition of the rearrangement, N-benzyl-oxycarbonyl-L-asparaginyl-L-phenylalanine was converted to 1-benzyloxycarbonyl-2-oxoimidazo-lidine-5-carbonylphenylalanine. Since glutamine peptide could not give the corresponding ring compound, this cleavage reaction was found to be specific to asparagine peptide.

The structure of putreanine, a new amino acid isolated from mammalian brain, was studied by its dissociation constants, mass spectrum, NMR spectrum and ORD. The structure N-(4-aminobutyl)-3-aminopropionic acid was assigned to it from the results obtained. This amino acid was synthesized by condensation of 4-phthalimino-1-bromobutane and ethyl β-alaninate followed by add hydrolysis. The identity of the synthetic compound with the natural amino acid confirmed the structural assignment.

For a total synthesis of bacitracian A, a synthetic method to secure unprotected thiazoline peptides must be established. 2-Aminomethyl-R-Δ2-thiazoline-4-carboxamide, 2-aminomethyl-R-Δ2-thiazoline-4-carboxylic acid, 2-aminomethyl-R-Δ2-thiazoline-4-carbonyl-L-leucine were synthesized by either the iminoether coupling method or by the dehydration method using N-benzyloxycarbonyl group and benzyl ester as protecting groups.

An optical active 2-(2-methylbutyryl)thiazole-4-carboxylic acid obtained from bacitracin F by an acid hydrolysis was synthesized starting from L-isoleucine. Applying the usual methods for the peptide synthesis, 2-(2-methylbutyryl)thiazole-4-carbonyl-L-leucyl-D-glutamic acid α-methyl-γ-t-butyl ester corresponding to the N-terminal tetrapeptide of bacitracin F, was then synthesized from the thiazole carboxylic acid. UV spectrum of the synthetic tetrapeptide was very similar to that of bacitracin F.

For the purpose of a total synthesis of bacitracin A, a synthetic method of the thiazoline peptide was investigated. A benzyloxycarbonylaminoalkylimino ethyl ether derived from glycine, L-alanine, L-valine, L-leucine or L-isoleucine was coupled with ethyl L-cysteinate hydrochloride to afford the corresponding thiazoline peptide, that is, a dehydrated form of cysteine peptide. While L-cystine was obtained from acid hydrolyzates of those thiazoline peptides, hydrolysis of them after treatment with alkali or ammonia gave DL-cystine. Furthermore, alkaline treatment caused a racemization of the amino acid residue adjacent to the thiazoline ring too.

Aus dem nach bekannten Methoden dargestellten Tetrapeptidester (Ia) bzw. -hydrazid (Ib) wird schrittweise nach der Azid-Methode das Hexapeptidderivat (IIa) erhalten.

A nonenzymic model for the biosynthesis of thyroxine from diiodotyrosine is described. In this reaction, l -thyroxine is formed from 3,5-diiodo- l -tyrosine at neutral pH and at room temperature in the presence of sodium glyoxylate, cupric acetate, and oxygen. The reaction proceeds rapidly through transamination via a metal chelate of the Schiff base of diiodotyrosine and glyoxylic acid, followed by oxidative coupling of the 4-hydroxy-3,5-diiodophenylpyruvic acid thus formed, with diiodotyrosine.

For the purpose of making a total synthesis of bacitracin A, a protected heptapeptide with a ring structure, Nα- (formyl-L-isoleucyl)-cyclo-(L-lysyl-δ-tosyl-D-ornithyl-L-isoleucyl-D-phenyl-alanyl-im-benzyl-L-histidyl-α-methyl-β-L-aspartyl) was first prepared by a high dilution method. After deformylation, it was coupled with a tetrapeptide corresponding to the N-terminal part of bacitracin A, the benzyloxycarbonyl-L-isoleucyl-S-benzyl-L-cysteinyl-L-leucyl-D-glutamic acid (α-azide)-γ-t-butyl ester, to afford an undecapeptide derivative. This was converted to a hydrazide, which was then coupled with β-benzyl-D-isoasparaginate to give the Nα-(benzyloxycarbonyl-L-isoleucyl-S-benzyl-L-cysteinyl-L-leucyl-γ-t-butyl-D-glutamyl-D-isoleucyl)-cyclo-(L-lysyl-δ-tosyl-D-ornithyl-L-isoleucyl-D-phenylalanyl-im-benzyl-L-histidyl-β-L-aspartyl)-D-isoasparagine β-benzyl ester. The removal of all protecting groups from it gave a free dodecapeptide, which has the same amino acid sequence, including optical properties, as that ...

Tuberactinomycin O, one of the four congeners of the antituberculous peptide tuberactinomycin, was totally synthesized. The β-ureidodehydroalanine moiety was constructed from β, β-diethoxyalanine with excess urea in acidic medium after a cyclization reaction of a pentapeptide was finished. Cyclization was carried out by means of the 1-succinimidyl ester method. To the cyclic pentapeptide, β-lysine was introduced as the branched moiety and then deprotected to afford tuberactinomycin O which was completely identified with the natural form of the antibiotic.