Interaction of L-histidine methyl ester (2) with N,N'-carbonyldiimidazole gave nearquantitative ring closure between the N' and the N" function to form (7S)-5,6,7.8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[l,5-c~]pyrimidine (3). Alkylation of 3, c.g. with an alkyl halide. trialkyloxonium tetrafluoroborate or dialkyl sulfate, is then only possible at the "N' function" to form (7S)-2-alkyl-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[ I ,5-r,]pyrimidinium salt (4).Hydrolysis of 4, aided by hydrochloric acid, afforded L-W-alkylhistidines in high yield. The L-Wmethylhistidine (523) was found to be identical with the costly natural amino acid and,optically purc.
introductionA method for preparing L-W-methylhistidine was discovered in this Laboratory'. We now wish to report a convenient method for the regioselective synthesis of L-Walkylhistidines in general and of L-N'-methylhistidine (5), a costly natural amino acid, in particular.
The synthesis is described of (-)-pelletierine picrate identical with Tanref's pelletierine picrate from Punica granaturn L. and of its antipode by oxidation, respectively, of (-)-and of (+)-sedridine. The sedridines are alkaloids with known absolute configuration of the piperidine asymmetric carbon atom. From this follows the Ds-configuration of (-)-pelletierine.
1. From the bark of the pomegranate tree (Punica granatum L.) CharlesTanret isolated four alkaloids, which he named pelletierine, methylpelletierine, isopelletierine, and pseudopelletierine 2, 3 . The structure of pseudopelletierine was the first to be elucidated 4. Tanret's methylpelletierine proved to be N-methylisopelletierine 4. Isopelletierine was soon inferred to have structure I, 1-(2-piperidyl)-propan-2-0ne 4 ; this was confirmed by certain syntheses 5 , 6 . Pelletierine, the fourth alkaloid of the group, presented an intriguing structural problem 7, which is summarized below. Ch. Tanref had described pelletierine as an optically active liquid-base isomeric with an optically inactive base, which he therefore named isopelletierine and regarded as being probably the racemate of pelletierine. Tanret, in 1880, recorded the rotation of the sulphate, [a]D -30" 3. This report was discounted, however, when K. Hess in 1917 in a reinvestigation of the isolation confirmed the optical inactivity of isopelletierine, but A preliminary account has been given by H. C.
Zur Analyse wurde zunachst im Hochvakuum bei 50° getrocknet, unmittelbar vor der Verbrennung noch 10 Stunden bei 200 uber P,O, nachgetrocknet und im Schweinchen eingewogen.3,656 mg Subst. gaben 6,510 mg CO, und 2,676 mg H1O
The synthesis of the fully protected N‐terminal decapeptide of human growth hormone, Boc‐Phe‐Pro‐Thr(Bzl)‐Ile‐Pro‐Leu‐Ser(Bzl)‐Arg(NO2)‐Leu‐Phe‐OMe (HGH 1‐10) by the repetitive excess mixed anhydride (REMA) method is described.
Starting from Phe‐OMe this sequence was synthesized in a stepwise manner in an overall yield of 59%. In the coupling of Boc‐Ile to Pro‐Leu‐Ser(Bzl)‐Arg‐(NO2)‐Leu‐Phe‐OMe the isobutoxycarbonyl derivative of the amino‐component was isolated. This problem of reaction on the undesirable side of the mixed anhydride in the couplings to proline‐peptides was circumvented by the coupling of dipeptides, viz. Boc‐Ile‐Pro and Boc‐Phe‐Pro. Also a larger peptide fragment, ZPhe‐Pro‐Thr‐Ile‐Pro (HGH 1‐5), was conveniently coupled to the C‐terminal pentapeptide. Synthesis of Boc‐Leu‐Ser(Bzl)‐Arg(NO2)‐Leu‐Phe‐OMe (HGH 6‐10) was performed with and without intermediate purification. It was found that the yield was higher when no purifications were applied.
HGH 6‐10 was compared with the corresponding peptide synthesized by the solid phase method. Both products were found to be identical with regard to melting point, optical rotation and chromatographic behaviour. The decapeptide, on deprotection, showed identical chromatographic behaviour with a product obtained by the solid phase method. The optical rotations showed a small difference; no significant racemization could be detected on digestion with L‐amino‐acid oxidase.
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