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Six analogs of an antituberculous antibiotic capreomycin were synthesized in order to clarify the structure-activity relationship, especially with regard to the significance of the β-amino group in α,β-diaminopropionic acid residue as well as the position of linkage of the branch residue, β-lysine, to the cyclic peptide moiety. All the synthetic products were found to have the same conformations in solution as those of the natural antibiotics in terms of NMR spectra. It was found from their antibacterial activities that an amino group located at β-position of the α,β-diaminopropionic acid residue adjacent to ureidodehydroalanine residue remarkably strengthens the biological activity, and that the position of a branch does not significantly influence the antibacterial potency.

Cyclic guanidino amino acid, capreomycidine, is a component of antituberculous peptides, capreomycin and tuberactinomycin N and O. Its epimer was also found in protease inhibitors, chymostatin and elastatinal. A new synthetic approach to DL-capreomycidine via β-hydroxyornithine was studied for the purpose of total synthesis of capreomycidine and epicapreomycidine of natural forms or its hydroxy derivative, tuberactidine.

Total syntheses of [Ala3, Ala4]-, [Ala3]-, and [Ala4]-tuberactinomycin O corresponding to deoxy analogs of natural antibiotic tuberactinomycin O were achieved for the purpose of elucidation of relationship between chemical structure and biological activity. Cyclization of the pentapeptide intermediates at two different positions was investigated. Minimum inhibitory concentrations of the synthetic analogs against Mycobacterium or Corynebacterium indicated that both hydroxy groups of two serine residues of tuberactinomycins are not required for antibacterial activity, nor participated to drug-resistancy of bacilli. These analogs were found to have the same conformations in solution as those of natural antibiotic from the results of NMR, ORD, and CD measurements.

A new amino acid, galantinic acid, was found as one of the constituent amino acids in a peptide antibiotic galantin I. The structure of galantinic acid was determined to be (2S,4S,5S)-5-amino-2-carboxymethyl-4-hydroxytetrahydropyran on the basis of NMR and CD studies.

threo-3-Methyl-D-cysteine as a moiety of β-methyllanthionine in the peptide antibiotic nisin was synthesized stereospecifically. The reaction of (2R,3R)-3-methyl-2-aziridinecarboxylic acid derivative prepared from D-threonine with thiobenzoic acid gave the β-mercapto α-amino acid derivative of the same configuration as the starting material. A stereochemistry of the product was retained as a result of double inversion mechanism through the reactions. Thus, we could prepare threo-3-methyl-D-cysteine, i.e., (2S,3S)-2-amino-3-mercaptobutanoic acid which is required for the synthetic study of nisin.

4-Azidobutyryl esters formed from hydroxyl compounds and 4-azidobutyryl chloride were shown to be cleaved via reduction to 4-aminobutyrate followed by intramolecular O→N-acyl migrations to regenerate the free hydroxyl groups. High susceptibility of azide group to reduction enables the selective removal of this acyl group leaving many other functional groups unchanged.

Seven acyl derivatives of N-acetylmuramyl-L-alanyl-D-isoglutamine, which had previously been shown to be a minimum structure required for the immunoadjuvant activity, were synthesized in order to evaluate the significance of lipophilicity on the adjuvant activity and on the possible antitumor effect. Among them, are included 6-O-docosanoyl, stearoyl, lauroyl, octanoyl, butyryl, acetyl, and 4,6-di-O-acetyl derivatives. Some of these compounds were found to serve an improvement in the administration method to living body.

Synthesis of threo-3-methyl-D-cysteine, a moiety of β-methyllanthionine as a component of the peptide antibiotics nisin and subtilin, was achieved via (2R,3R)-1-t-butoxycarbonyl-3-methyl-2-aziridinecarboxamide derived from D-threonine. An addition of thioacetic acid or thiobenzoic acid to the aziridinecarboxamide gave S-acyl-β-mercapto-α-amino acid amide derivatives which were hydrolyzed directly or after the preformation of disulfide bond to afford the desired amino acid.

For the purpose of the verification of an expectation that the structural analogs of D-alanyl-D-alanine which participates in the biosynthesis of cell wall peptides might inhibit the growth of microorganisms, alanyl-1-aminoethanesulfonic acid was synthesized by the mixed anhydride method. Four diastereomers were separated and their absolute configurations were deduced on the basis of X-ray analysis. None of these dipeptide analogs and their benzyloxycarbonyl or t-butoxycarbonyl derivatives showed appreciable activity against E. coli.

As a basic study in the synthetic approach to immunoactive cell wall peptidoglycan whose backbone is a β(1–4)-linked saccharide of alternating glucosamine and muramic acid, methods for the direct condensation of these sugar components were studied and O-(N-acetyl-β-muramyl)-(1→4)-N-acetyl-D-glucosamine and O-(N-acetyl-β-D-glucosaminyl)-(1→4)-N-acetylmuramic acid were synthesized. In the synthesis of the latter disaccharide, previous formation of an ester bond between the carboxyl group of muramic acid and the 6-hydroxyl group of glucosamine proved to facilitate the glycoside bond fromation between these sugar moieties.

The enantioface-differentiating hydrogenation of methyl 3-oxotetradecanoate over (R,R)-tartaric acid-NaBr-modified nickel gave methyl (R)-3-hydroxytetradecanoate(III) in 85% e.e.. After HI was converted to dicyclohexylammonium salt of 3-hydroxytetradecanoic acid (I), the salt was recrystallized three times from acetonitrile and was then treated with acid to give optically pure (R)-I in a good yield.

Four stereoisomers of β-methyllanthionine were synthesized by coupling of N-enzyloxycarbonyl-3-methyl-D-cysteine with β-chloroalanine. 1H NMR analysis and retention time in amino acid analysis were studied on these compounds.

N-Acetylmuramyl peptides of successive length corresponding to the partial structures of cell wall in Staphylococcus aureus were synthesized in order to elucidate the minimum effective structure responsible for immunoadjuvant activity of bacterial cell walls. In view of the finding that N-acetylmuramyl-L-alanyl-D-isoglutamine was the least structure moiety for exhibition of the activity, nine analogs of either N-acetylmuramyl amino acid or N-acetylmuramyl dipeptide were also synthesized.

Ausgehend von dem aus der Vorstufe (I) dargestellten Alkohol (IIa) werden durch verschiedene Folgereaktionen bzw. deren Wiederholung die Analogen (IIb) und (IIc) dargestellt; die aus (IIa)-(IIc) erhaltlichen Bromderivate (IId)-(IIf) werden in die Ester (IV) und (V) und weiter in die Sauren (VIa)-(VIc) bzw. (VIIa)-(VIIc) ubergefuhrt.

α-Glycosyl phosphates and 4-phosphates of N-acylglucosamine derivatives were prepared in high yields via the reaction of corresponding O-lithium salts with dibenzyl or diphenyl phosphorochloridate at low temperature.

Hypusine, a new basic amino acid occurring in the homogenate of bovine brain tissue, was synthesized to determine the absolute structure. Nα-Benzyloxycarbonyl-L-lysine benzyl ester was coupled with (S)- or (R)-4-benzyloxycarbonylamino-1-bromo-2-butanol derived from L- or D-malic acid, respectively. The products were deprotected by catalytic hydrogenation. One of the synthetic compounds, i.e., (2S,9R)-2,11-diamino-9-hydroxy-7-azaundecanoic acid, was completely identical with natural hypusine in all respects.

A cyclic guanidino amino acid, L-epicapreomycidine, isolated from hydrolyzates of protease inhibitors such as chymostatin and elastatinal was synthesized. This amino acid is a diastereomer of L-capreomycidine which is a component amino acid of tuberactinomycin N,O and capreomycin. A new synthetic route from β-hydroxy-DL-orni thine via an aziridine compound to DL-capreomycidine was applied to the synthesis of L-epicapreomycidine starting from erythro-β-hydroxy-L-ornithine. A convenient and one-step technique to obtain L-erythro form from a mixture of four diastereomers of β-hydroxyornithine by means of enzymatic reaction was newly exploited. The synthetic L-epicapreomycidine obtained was identical with natural one in all respects, thus confirming the proposed structure.

For the investigation on the action mechanism of immunoadjuvant active N-acetylmuramyl-L-alanyl-D-isoglutamine, its labeled compound, i.e., N-acetylmuramyl-L-[U-14C]alanyl-D-isoglutamine was synthesized. For this purpose, an entirely novel synthetic route for the muramyl dipeptide was exploited using cold materials and applied to the preparation of the labeled compound. A convenient synthetic procedure of isoglutamine derivatives is also described.

threo-γ-Hydroxy-L-β-lysine which is a constituent amino acid of antibiotics tuberactinomycin A and N, was synthesized from threo-β-hydroxy-L-ornithine derivative by the Arndt-Eistert reaction. The synthetic amino acid was identical with the natural sample in all respects. Furthermore, a route was established to prepare a protected γ-hydroxy-β-lysine derivative useful for the peptide synthesis.

Two disaccharide dipeptides, i.e., O-(N-acetyl-β-D-glucosaminyl)-(1→4)-N-acetylmuramyl-L-alanyl-D-isoglutamine (2) and O-(N-acetyl-β-muramyl-L-alanyl-D-isoglutamine)-(1→4)-N-acetyl-D-glucosamine (3), which correspond to partial structures of cell wall peptidoglycan were synthesized via the same glucosamine disaccharide as a common intermediate. Thus, selective introduction of lactic acid moiety on either one of the sugar moieties of the intermediate gave two disaccharides respectively which contain muramic acid on either reducing or nonreducing side. Coupling of the peptide moiety followed by deprotection afforded 2 and 3. The results of biological tests showed that both 2 and 3 have the same magnitude of immunostimulating activities as those of N-acetylmuramyl-L-alanyl-D-isoglutamine which is the minimum structure required for expression of the activities.

For the purpose of study on racemization of exo methine carbon atom of thiazoline, oxazoline or imidazoline ring, the following four compounds were synthesized from amino acid imino ether: 2-(1-benzyloxycarbonylaminoethyl)-2-thiazoline (I), methyl 2-(1-benzyloxycarbonylaminoethyl)-2-thiazoline-4-carboxylate (II), methyl 2-(1-benzyloxycarbonylaminoethyl)-2-oxazoline-4-carboxylate (III), and 2-(1-benzyloxycarbonylaminoethyl)-2-imidazoline (IV). A racemization rate of the alanine residue was measured from an optical rotation of 2,4-dinitrophenyl derivative obtained from the acid hydrolyzate and from hydrogen-deuterium exchange reaction at α-carbon atom. All these compounds were found to be racemized very easily particularly in the presence of proton source. From the experimental results, a plausible mechanism for racemization peculiar to such heterocyclic compounds through protonation-deprotonation process was presented.

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