Zur Synthese von Human-Big-Gastrin I

The synthesis of the tetratriacontapeptide amide corresponding to the revised primary structure of human big gastrin I is described. For this purpose the fragments were designed in view of the maximum use of those utilized in our previous synthesis of human big gastrin I according to the first sequence proposal. Consequently the key tripeptide-Pro-Pro-His- (sequence 7–9) was prepared in suitably protected form to be used as amino or carboxyl component for assembly of the segments 1–9 and 1–14, respectively. Final condensation of the latter nona- and tetradecapeptide derivatives with the C-terminal segments 10–34 and 15–34 via the azide and the dicyclohexylcarbodiimide/N-hydroxysuccinimide procedure, respectively, leads to crude fully protected human big gastrin I. Upon deprotection by exposure to trifluoroacetic acid in presence of ethanedithiol-(1,2) as scavanger, ion exchange chromatography and partition chromatography, the desired tetratriacontapeptide amide was isolated in satisfactory yield with a high degree of purity. The identical immunological behaviour of the synthetic material, if compared with that of natural human big gastrin I, represents ulterior strong evidence for the correctness of the newly proposed structure for this putative prohormonal form of the gastrins.

Kurzmitteilung:Wünsch E., Wendlberger G., Mladenova-Orlinova L., Göhring W., Jaeger E., Scharf R., Gregory R. A., Dockray G. J., Hoppe-Seyler's Z. Physiol. Chem.362, 179 (1981).     

Zur Synthese von Human-Big-Gastrin I und seinem 32-Leucin-Analogon

The preparation of the pure tetratriacontapeptide amide 2 (human big gastrin I) and the analogue Leu³²-human big gastrin I from the crude synthetic materials obtained after deblocking of the overall protected tetratriacontapeptide amide derivatives by means of trifluoroacetic acid is described. The criteria for homogeneity obtained by chromatographic, electrophoretic, enzymatic and spectroscopic methods are reported.

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Abkürzungen HBG-I Human-Big-Gastrin I - LHBG-I 32-Leucin-Human-Big-Gastrin I - HBG-[1-20] N-terminale Teilsequenz [1–20] des Human-Big-Gastrins I - HG-17-I Human-Gastrin I - LHG-17-I 15-Leucin-Human-Gastrin I - HG-13-I Human-Minigastrin I - LHG-13-I 11-Leucin-Human-Minigastrin I Es werden hier die von der IUPAC-IUB Commission on Biochemical Nomenclature empfohlenen Abkürzungen für Aminosäuren und Schutzgruppen verwendet.Andere Abkürzungen.Anm.: Auf Grund der kürzlich erfolgten Strukturkorrektur (R. A. Gregory, H. J. Tracy, J. I. Harris, M. J. Runswick, S. Moore, G. W. Kenner undR. Ramage, Hoppe-Seylers Z. physiol. Chem.360, 73, 1979) sind HG-13-I und LHG-13-I neuderdings richtiger als Des-1-Tryptophan-Human-Minigastrin I bzw. [Des-1-Tryptophan]-11-Leucin-Human-Minigastrin I zu bezeichnen].Vorläufige Mitt.:E. Wünsch, G. Wendlberger, A. Hallett, E. Jaeger, S. Knof, L. Moroder, R. Scharf, I. Schmidt, P. Thamm undL. Wilschowitz, Z. Naturforsch.32c, 495 (1977).3. Mitt.:G. Wendlberger, L. Moroder, A. Hallett undE. Wünsch, Mh. Chem.110, 1407 (1979).     

Totalsynthese von Nojirimycin

Total synthesis of Nojirimycin Addition of the nitrone 3 (from 8 and 9 ) to furane, followed by oxidation with OsO₄ and then isopropylidenation gave the fully functionalized glycoside 12 (40% from 8 ) via the glycal 10 and the hemiacetal 11 . Since the glycoside cleavage of 12 , leading to 13 after benzyloxycarbonylation proceeded in a mediocre yield, and since the acetolysis of 12 giving 14 (69%) was not practical, compound 12 was transformed into the hydroxy ester 17 by sequential hydrogenolysis, hydrolysis and benzyloxycarbonylation (69% overall). The hydroxy ester 17 was lactonized to give 18 (87%). Reduction of 18 first with LiBH₄ (97%) and then with H₂/Pd gave the key compound 20 which was transformed into nojirimycin ( 1 ) and into 1-deoxy-nojirimycin ( 2 ) using prior art. The overall yield of 1 was 19.5%.     

Totalsynthese von Betalainen

Total Synthesis of Betalaines cis-4-Oxo-2,6-piperidinedicarboxylic acid dimethyl ester ( 10 ) was transformed (44%) into the semicarbazone of 2,3-dihydrobetalamic acid dimethyl ester ( 13/14 ) by a modified Horner-Wittig reagent 12 . Oxidation of 13/14 afforded 41% of a mixture of stereoisomers of betalamic-acid-dimethyl-ester semicarbazone ( 4 ), key intermediate for the synthesis of betalaine pigments. The utility of 4 in this respect was demonstrated on a small scale by its conversion to the dimethyl ester of indicaxanthine ( 9 , 11%) and to the trimethyl ester of betanidine ( 7 , 87%). Hydrolysis of 7 gave betanidine ( 6 ). We further describe the synthesis of the trimethyl ester of an oxidized form of betalamic acid ( 20/21 ) as well as model condensation reactions on the carbonyl group of cyclohexanone, cis-4-oxo-2,6-diphenylpiperidine ( 23 ) and its N-formyl derivative 27 . Reaction of 4-oxo-1,2,3,4-tetrahydro-2,6-pyridinedicarboxylic-acid dimethyl ester ( 40 ) with acetic anhydride or with triethyloxonium tetrafluoroborate resulted in O-acylation or in O-alkylation along with dehydrogenative aromatization to yield the derivatives 39 or 42 , respectively, of chelidamic acid.     

Totalsynthese von Betalainen

A total synthesis of betalaine pigments ( 6 ) is described. The key intermediate is betalamic acid in the form of its dimethyl ester semicarbazone ( 9 ), which was transformed with L-proline ( 16 ) into indicaxanthine dimenthl ester ( 5 ), with L-cyclodopa methul ester ( 17 ) into betanidine trimethyl ester ( 3 ) and by hydrolysis of the latter into betanidine ( 2 ).