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.     

Über die Totalsynthese vo Betalainen

On the Total Synthesis of Betalains Improved total syntheses of the red-violet aglucone of the beet coloring matter and of the yellow cactus coloring matter indicaxanthine are presented. Formyl-olefination of the piperidone-diester 6 with the acetaldehyde synthon 5 led to the piperidylidene-acetaldehyde derivative 8 , which was converted into the 2,4,4-trimethylsemicarbazone of rac-betalamic acid dimethyl ester (10) by treatment with t-BuOCl and then Et₃N. Exchanging the semicarbazone moiety with the (S)-cyclodopa derivative 18 , with (S)-proline (19) and with indoline (20) transformed 10 to betanidin (21/22) , to indicaxantihin (23/24) and to rac-indo-betalaine (25) , respectively. The latter, a new, relatively stable betalaine, was hydrolyzed and esterified to rac-betalamic acid dimethyl ester (29) . Under the influence of NH₃/MeOH, 26 (the dimethyl ester of 25 ) was dehydrogenated spontaneously to indo-neobetalaine dimethyl ester (27) . Synthetic betanidin consisted of a 4:6 mixture of the (natural) (2S, 15S)- (21) and the (2S, 15R)-isomer (22) and both of a 75:25 mixture of the (E)- and the (Z)-isomer. Synthetic indicaxanthin (23/24) and the indo-betalaine (25) represented a 65:35 and a 70:30 mixture, respectively, of (E)- and the (Z)-isomers. All (E)- and (Z)-isomers are rapidly interconvertible. Temperature-dependent ¹ H-NMR -measurements of 25 established ΔG≠ = 84.7 kJ/mole for the (E)-to-(Z)-conversion. The t-BuOCl/NEt₃ method for the introduction of an enaminic double bond was applied to the model transformations of the amines 6, 12 and 15 to the conjugated enamiens 11, 13 and 17 , respectively.     

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%.     

Zur Totalsynthese von Human-Sekretin

Summary The synthesis of the heptacosapeptide amide with the primary structure of Human-secretin is described. For this purpose 7 fragments were designed, i.e. H-Gly-Leu-Val-NH₂ 25–27b,Z-Arg(Z ₂)-Leu-Leu-Gln-OH 21–24,Z-Arg(Z ₂)-Leu-Gln-OH 18–20,Z-Arg(Z ₂)-Glu(OtBu)-Gly-Ala-OH 14–17,Z-Arg(Z ₂)-Leu-OH 12–13,Z-Thr(tBu)-Ser(tBu)-Glu(OtBu)-Leu-Ser(tBu)-OH 7–11,Adoc-His(Adoc)-Ser(tBu)-Asp(OtBu)-Gly-Thr(tBu)-Phe-OH 1–6 these fragments were consequently assembled to the overall protected total sequence using the Wünsch/Weygand-method with dicyclohexylcarbodiimide. After deprotection by exposure to trifluoroacetic acid in presence of 1,2-ethanedithiol and water as scavenger, the isolated crude product was purified by column chromatography on CM-Sepharose, fast flow. This synthetized Human-secretin showed the full biological activity in comparison to Porcine-secretin.

Herrn Prof. Dr. E. Bayer zum 65. Geburtstag gewidmet.