Excess Mixed Anhydride Method Research Articles

Synthesis of novel morphinan peptides based on ethenoisomorphinans and enkephalin residues containing L‐ and D‐phenylalanine; conformational analysis and preliminary pharmacology (Chemistry of opium alkaloids, Part XXXIII)

AbstractThe morphinan peptides N‐(4,5α‐epoxy‐3,6‐dihydroxy‐17‐methyl‐6α,14α‐ethenoisomorphinan‐7α‐carbonyl)‐L‐phenylalanine ethyl ester (4), N‐(4,5α‐epoxy‐3,6‐dihydroxy‐17‐methyl‐6α,14α‐ethenoisomorphinan‐7α‐carbonyl)‐D‐phenylalanine ethyl ester (5) and N‐[N‐(4.5α‐epoxy‐3.6‐dihydroxy‐17‐methyl‐6α,14α‐ethenoisomorphinan‐7α‐carbonyl)glycinyl]‐L‐phenylalanine ethyl ester (6) have been prepared from 4,5α‐epoxy‐3,6‐dimethoxy‐17‐methyl‐6α,14α‐ethenoisomorphinan‐7α‐carboxylic acid (7) and the protected amino acids. The morphinan moiety was coupled to the peptide residue via the acid chloride of 7, after which the morphinan peptides were O‐demethylated with the aid of hydrogen bromide in glacial acetic acid. The dipeptide N‐glycinyl‐L‐phenylalanine ethyl ester was synthesized via the Excess Mixed Anhydride method (EMA). The new morphinan peptides have been characterized by 1H and 13C NMR spectroscopy. For conformational analysis, the relative stabilities of two possible hydrogen bonds around the C7‐C20 bond have been calculated on a model compound 11, using molecular mechanics.

Studies on the synthesis of the protected C‐terminal segment of vasoactive intestinal peptide (VIP) via its 28‐aspartic acid analogue

AbstractA major problem in the synthesis in solution of the gastrointestinal peptide VIP is the solubility of C‐terminal intermediates. Already in the tripeptide stage, the solubility in the usual solvents is very low and gives rise to low coupling yields. The C‐terminal asparagine amide, in combination with leucine and isoleucine, seems to play an important role in this phenomenon. We synthesized the protected C‐terminal segments, VIP(27‐28), VIP(22‐28) and VIP( 14‐28), via the temporary substitution of 28‐asparagine by a β‐tert‐butyl protected aspartic acid. This substitution resulted in a dramatic improvement in solubility. The synthesis could easily be performed via the repetitive excess mixed anhydride method. In the last stage of the synthesis, the β‐tert‐butyl protection of 28‐aspartic acid could be removed selectively. The deprotected aspartic acid was converted into asparagine by amidation using the mixed anhydride or the carbodiimide method.

A convenient synthesis of human calcitonin mainly via the repetitive excess mixed anhydride method

AbstractThe synthesis is described of the sequence containing 32 amino acid residues proposed for human calcitonin (HCT), presumably a thyroid hormone (Fig. 1)4.Our strategy employed the coupling of four fragments: 1–7 (with closed disulfide bridge), 8‐10, 11‐19 and 20‐32 via the azide or dicyclohexylcarbodiimide (DCCI) method. With the exception of two DCCI couplings (Asn3 and Asn17), these fragments were prepared exclusively by stepwise synthesis via the repetitive excess mixed anhydride (REMA) méthod (Fig. 2).Removal in one operation of all protecting groups with cold concentrated hydrochloric acid and chromatographic purification afforded HCT with full hypocalcemic potency (Table 1).

ChemInform Abstract: SUCCESSFUL SYNTHESIS OF GLYCYL‐GLYCINE PEPTIDE BONDS VIA THE EXCESS MIXED ANHYDRIDE METHOD

Chemischer InformationsdienstVolume 7, Issue 18 Natural Products ChemInform Abstract: SUCCESSFUL SYNTHESIS OF GLYCYL-GLYCINE PEPTIDE BONDS VIA THE EXCESS MIXED ANHYDRIDE METHOD J. A. HOFFMANN, Search for more papers by this authorM. A. TILAK, Search for more papers by this author J. A. HOFFMANN, Search for more papers by this authorM. A. TILAK, Search for more papers by this author First published: May 4, 1976 https://doi.org/10.1002/chin.197618382Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume7, Issue18May 4, 1976 RelatedInformation

ChemInform Abstract: PSEUDOSYMMETRY IN THE STRUCTURE OF LUTEINIZING HORMONE‐RELEASING HORMONE STUDIES ON A SERIES OF NOVEL ANALOGS

Abstract11 verschiedene LH‐RH‐Analoga werden hergestellt und ihre pharmakologischen Eigenschaften diskutiert.

Pseudosymmetry in the structure of luteinizing hormone-releasing hormone. Studies on a series of novel analogs.

Pseudosymmetry in the LH-RH structure is described. Eleven analogs of LH-RH (SMALLER THAN Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) have been synthesized by the fragment condensation method and the repetitive excess mixed anhydride method. Multiple substitutions have been made in the LH-RH sequence, which retain the pseudosymmetry of the LH-RH molecule, while presenting fewer problems of synthesis than the corresponding residues in the natural decapeptide. Thus Trp3, Ser4, Tyr5, Gly6, Leu7, and Arg8 residues were replaced by amino acids having similar properties to the residues that they replace. In all but one of the peptides the Gly10-NH2 residue was replaced by ethylamide, while in the remaining peptide, 1-methyl-5-aminomethyltetrazole (AMT-Me) was substituted at position 10. The compounds were assayed in vitro and in vivo. The following analogs had in vivo and in vitro activities in the range 1-28 percent relative to LH-RH: I, smaller than Glu-His-Phe-Ala-Tyr-Gly-Leu-Arg-Pro-NHEt; II, smaller than Glu-His-Phe-Gly-Tyr-Gly-Leu-Arg-Pro-NHEt; VII, smaller than Glu-His-Phe-Ala-Tyr-Gly-Phe-Arg-Pro-NHEt; IX, smaller than Glu-His-Phe-Ala-Tyr-D-Ala-Leu-Arg-Pro-NHEt; XI, smaller than Glu-His-Phe-Gly-Tyr-Gly-Leu-Arg-Pro-AMT-Me.

Excess mixed anhydride peptide synthesis with histidine derivatives

AbstractThe coupling of histidine derivatives by the excess mixed anhydride method was investigated with respect to the yield, the racemization, and the formation of by‐products. The tert‐butyloxycarbonyl‐ (Boc‐), isobutyloxycarbonyl‐ (i‐Boc‐), benzyloxycarbonyl‐ (Z‐), and p‐toluenesulfonyl‐(Tos‐) groups were found to be suitable for protection of the imidazole nucleus.A new way of selective removal of the Nim‐Tos group, with pyridine hydrochloride, is described.

On the repetitive excess mixed anhydride method for the synthesis of peptides. Synthesis of the sequence 1‐10 of human growth hormone

AbstractThe 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, ZPhe‐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.