Asymmetric [1,3]-dipolar cycloaddition reactions: synthesis of highly substituted proline derivatives

Williams, Robert M.; Zhai, Weixu; Aldous, David; Aldous, Suzanne C.

doi:10.1021/jo00050a029

Cited by 89 publications

(32 citation statements)

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“…Proline has been widely used as a scaffold and substitutions on the pyrrolidine ring have yielded a large variety of proline analogues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Such constrained templates have been introduced in peptides to elucidate their bioactive conformation: for instance, 3-methylthiomethylproline (3-prolinomethionine) in substance P (SP) [20], 3-(p-hydroxyphenyl)proline (3-prolinotyrosine) in opioid peptides [21] as well as 3-n-propylproline [22], 3-and 4-alkylthioprolines [23] in cholecystokinin analogues.…”

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confidence: 99%

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues

Quancard

Karoyan

Sagan

et al. 2003

European Journal of Biochemistry

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Residue Leu10 of substance P (SP) is critical for NK-1 receptor recognition and agonist activity. In order to probe the bioactive conformation of this residue, cis-and trans-3-substituted prolinoleucines were introduced in position 10 of SP. The substituted SP analogues were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in CHO cells transfected with the human NK-1 receptor. [trans-3-prolinoleucine10]SP retained affinity and potency similar to SP whereas [cis-3-prolinoleucine10]SP shows dramatic loss of affinity and potency. To analyze the structural implications of these biological results, the conformational preferences of the SP analogues were analyzed by NMR spectroscopy and minimum-energy conformers of Ac-cis-3-prolinoleucineNHMe, Ac-trans-3-prolinoleucine-NHMe and model dipeptides were generated by molecular mechanics calculations. From NMR and modeling studies it can be proposed that residue Leu10 of SP adopts a gauche(+) conformation around the v 1 angle and a trans conformation around the v 2 angle in the bioactive conformation. Together with previously published results, our data indicate that the C-terminal SP tripeptide should preferentially adopt an extended conformation or a PPII helical structure when bound to the receptor.

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confidence: 99%

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues

Quancard

Karoyan

Sagan

et al. 2003

European Journal of Biochemistry

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“…31 und 32 bilden ein chirales Azomethinylid mit E-Konfiguration, das eine bereitwillig ablaufende [3+2]-Cycloaddition mit dem Dipolarophil 33 eingeht und das Cycloaddukt 34 liefert. [24] Als Produkt entsteht in 82 % Ausbeute ein einziges Diastereoisomer mit der gewünschten Konfiguration des Naturstoffs, wie durch Einkristall-Rönt-genstrukturanalyse bestätigt wurde. Die für diese Cycloaddition benötigte Geometrie des Übergangszustandes ("Ebeta-exo") ist in Schema 5 gezeigt (E bezeichnet die Konfiguration des Ylids, beta den "von oben" erfolgenden Angriff des Dipolarophils und exo die Geometrie des Übergangszu-standes [29] Die Reaktionssequenz für die acht Kernstrukturen, die das Aryliodid enthalten, ist in Schema 7 gezeigt.…”

Section: Asymmetrische 13-dipolare Cycloadditionunclassified

Natürliche Pyrrolidinylspirooxindole als Vorlagen für die Entwicklung medizinischer Wirkstoffe

Galliford¹,

Scheidt²

2007

Angewandte Chemie

517

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Das 3,3′‐Pyrrolidinylspirooxindol‐System ist ein privilegiertes heterocyclisches Strukturmotiv, das die zentrale Einheit bei einer großen Familie von natürlichen Alkaloiden mit starken Bioaktivitätsprofilen und interessanten Struktureigenschaften bildet. Neue bedeutende Fortschritte bei der Synthese dieses kondensierten heterocyclischen Systems haben ein starkes Interesse an der Entwicklung verwandter Verbindungen als mögliche Wirkstoffe oder biologische Sonden hervorgerufen.

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“…i Br C0,-K ' -T I x ; 1 des auxiliaires chiraux sur le dipolarophile ( l , 2 ) , sur le dip6le (3,4,9), ou comme catalyseur (6). RCcemment, Harwood et coll.…”

Section: Schcma L Phunclassified

Étude de la stéréochimie de la réaction de cycloaddition dipolaire-1,3 de quelques 5-phényl-3,6-dihydro-2H-1,4-oxazin-2-ones avec les N-méthyl et N-phénylmaléimides

Monnier¹,

Schmitt²,

Laude³

et al. 1995

Can. J. Chem.

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RCsumC : La synthbse de six 5-phCnyl-3,4-dihydro-2H-1,4-oxazin-2-ones 1 i partir d'acides aminks est dCcrite.Ces composCs sont des prCcurseurs d'ylures d'azomkthine cycliques hexagonaux comportant un stCrCocentre. Ces produits 5 caractbre dipolaire rCagissent avec les N-phCnyl et N-mCthylmalCimides pour donner diastCrCospCcifiquement des cycloadduits pour lesquels l'approche du dipolarophile s'effectue sur la face la moins encombrCe du dipale et avec le reste malCimido en position exo. Malheureusement, on observe une rackmisation lors de la rCaction de cycloaddition, probablement par suite d'une tautomCrie imine-bnamine du dipale. Mots clis : a-aminoacides, ylures d'azomkthine cycliques, diastCrCospCcificitC.Abstract: Six derivatives of 5-phenyl-3,4-dihydro-2H-l,4-oxazin-2-ones 1 were synthetized from a-amino acids. These compounds are precursors of six-membered cyclic azomethine ylids involving one stereocenter. The 1,3-dipolar species react with N-methyl and N-phenylmaleimides, leading diastereospecifically to cycloadducts where the approach of the dipolarophile occurs from the less hindered side of the 1,3-dipole and with the maleimido moiety in an exo position. Unfortunately, racemization was observed during the cycloaddition reaction, presumably owing to reversible imine-enamine transformation.

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Asymmetric [1,3]-dipolar cycloaddition reactions: synthesis of highly substituted proline derivatives

Cited by 89 publications

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Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues

Natürliche Pyrrolidinylspirooxindole als Vorlagen für die Entwicklung medizinischer Wirkstoffe

Étude de la stéréochimie de la réaction de cycloaddition dipolaire-1,3 de quelques 5-phényl-3,6-dihydro-2H-1,4-oxazin-2-ones avec les N-méthyl et N-phénylmaléimides

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Asymmetric [1,3]-dipolar cycloaddition reactions: synthesis of highly substituted proline derivatives

Cited by 89 publications

References 0 publications

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH2 of substance P using [3‐prolinoleucine10]SP analogues

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH2 of substance P using [3‐prolinoleucine10]SP analogues

Natürliche Pyrrolidinylspirooxindole als Vorlagen für die Entwicklung medizinischer Wirkstoffe

Étude de la stéréochimie de la réaction de cycloaddition dipolaire-1,3 de quelques 5-phényl-3,6-dihydro-2H-1,4-oxazin-2-ones avec les N-méthyl et N-phénylmaléimides

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Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues

Characterization of the bioactive conformation of the C‐terminal tripeptide Gly‐Leu‐Met‐NH₂ of substance P using [3‐prolinoleucine10]SP analogues