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Synthesis of alpha, alpha-Disubstituted Glycines and Their Peptides under High Pressure

Research Project

Project/Area Number 03640468
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 有機化学一般
Research InstitutionKonan University

Principal Investigator

YAMADA Takashi  Konan University Faculty of Science, Department of Chemistry Professor, 理学部, 教授 (00068123)

Project Period (FY) 1991 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1992: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1991: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordsalpha, alpha-disubstituted glycine / diisopropylglycine / alpha, alpha-diphenylglycine / high pressure synthesis / Ugi reaction / bicyclic acylamidine / N-hydroxypeptide / conformational analysis / α,αージ置換グリシン / α,αージイソプロピルグリシン / α,αージフェニルグリシン / イソシアニド / α、αージ置換グリシン / α、αージイソプロピルグリシン / α、αージフェニルグリシン / エンケファリン・アナロ-グ / デルモルフィン(1ー4)・アナロ-グ
Research Abstract

Syntheses of peptides containing very bulky alpha, alpha-disubstituted glycines, alpha, alpha-diisopropyl-glycine (Dip) and alpha, alpha-diphenylglycine (Dph), were investigated by using four-component condensation (Ugi reaction) at high pressure (9 kbar) and at atmospheric pressure. The results are as follows :
1. Dip which is the most bulky amino acid as far as we know, could be first synthesized by the Ugi reaction at 9 kbar using formic acid, Schiff base derived from diisopropyl ketone and benzyl-amine, and cyclohexyl isocyanide, followed by acidic hydrolysis and catalytic hydrogeno-lysis.
2. Various protections of N- and C-termini of Dip were tried but only esterification by HCI/MeOH at 9 kbar could afford Dip-OMe・HCI in a 10% yield.
3. Several tripeptides containing N-benzyl-Dip residue were first synthesied in good yields by the Ugi reaction at 9 kbar using Schiff base from diisopropylketone and benzylamine, several Z-amino acids, and methyl isocyanoacetate.
4. Catalytic hydrogenoly … More sis for removing N-benzyl group from Dip-containing tripeptides obtained above could afford no desired tripeptide esters, but the unexpected bicyclic acylamidines in medium yields.
5. By the Ugi reaction using formic acid, Schiff base from diisopropylketone and benzylamine, and methyl isocyanoacetate, N-benzyl-N-formyl-Dip-Gly-OMe was obtained. Catalytic hydrogenolysis of this compound could afford the first protected dipeptide containing Dip, HCO-Dip-Gly-OMe.
6. The Ugi reaction using diphenylmethanimine as a Schiff base, various Z-amino acids, and some isocyanides could first afford various tripeptides containing Dph, Z-AA_1-Dph-AA_3-OMe. Significantly, tripeptides in which both AA_1 and AA_3 are alpha, alpha-disubstituted glycines could be prepared easily by this method.
7. X-Ray crystal structural analysis of 6 tripeptides containing Dph clarified that Dph prefers not only C_5-conformation but also beta-turn.
8. The Ugi reaction using cyclohexanone oxime as a Schiff base could afford several N-hydroxytripeptides containing l-aminocyclohexanecarboxylic acid (Ac_6c). These peptides could be saponified quantitively and further converted to N-hydroxytetrapeptides in good yields. Less

Report

(3 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] T,YAMADA: "Four-component Condensation(Ugi Reaction)at High Pressure:Novel Synthesis of Peptides confaining Very Bulky α,α-Disubstituted Glycines" J.Chem.Coc.,Chem.Commun.,. 1640-1641 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.YAMADA: "Synthesis of α,α-Diisopropylglycine by the Modified Ugi Reaction at High Pressure" Chem.Express. 6. 575-578 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.YAMADA: "Synthesis of peptides containing very bulky α,α-disubstituted glycines by the four component condensation at high pressure" Peptides 1990. 41-42 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.YAMADA: "Synthesis of Peptides Containing α,α-Diphenylglycine" Peptide Chemistry 1991. 367-372 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.YAMADA: "Synthesis of Peptides Containing Very Bulky α,α-Disubstiduted Glycines" Proc.4th Akabori Conference;German-Japanese Symposium on Peptide Chemistry. 26-31 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.YAMADA: "Synthesis of Tripeptides Containing N-Hydroxy-1-aminocyclohexane carboxylic Acid by a Modified Ugi Reaction" Chem.Express. 8. 161-164 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Four-component Condensation (Ugi reaction) at High Pressure : Novel Synthesis of Peptides containig Very Bulky alpha, alpha-Disubstituted Glycines" J.Chem.Soc., Chem.Commun.1640-1641 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of peptides containing very bulky alpha, alpha- disubstituted glycines by the four component condensation at high pressure" Peptides. 1990. 41-42 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of alpha, alpha-diisopropylglycine, alpha, alpha-diphenyl- glycine and Their Peptides" Peptide Chemistry. 1990. 33-36 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of alpha, alpha-diisopropylglycine, by the Modified Ugi Reaction at High Pressure" Chem.Express. 6. 575-578 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of Peptides Containing Very Bulky alpha, alpha-Disubstituted Glycines" Proc.4th Akabori Conference ; Japanese-German Symposium on Peptide Chemistry. 26-31 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of Peptides Containing alpha, alpha-Diphenyl- glycine" Peptide Chemistry. 1991. 367-372 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of Tripeptides Containing N-Hydroxy- l-aminocyclohexanecarboxylic Acid by a Modified Ugi Reaction" Chem.Express. 8. 161-164 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Comparison of Various Coupling Methods for the Synthesis of Peptides Containing alpha, alpha-Diphenylglycine" Peptide Chemistry. 1992. (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] T.Yamada: "Synthesis of Tripeptides Containing N-Hydroxy-l-aminocyclohexanecarboxylic Acid by a Modified Ugi Reaction" Chemistry Express. 8. 161-164 (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Yamada: "Comparison of Various Coupling Methods for the Synthesis of Peptides Containing α,αーDiphenylglycine" Peptide Chemistry 1992. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Yamada: "Synthesis of α,α-Diisopropylglycine by the Modified Ugi Reaction at High Pressure" Chemistry Express. 6. 575-578 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Yamada: "Synthesis of Peptides Containing α,α-Diphenylglycine" Peptide chemistry 1991. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Yamada: "Synthesis of Peptides Containig Very Bulky α,α-Disubstituted Glycines" Proceedings of the 4th akabori Conference;German-Japanese Symposium on Peptide Chemistry. (1992)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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