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Novel heterospirocyclic 3-amino-2H-azirines as synthons for heterocyclic alpha-amino acids


Strässler, Christof; Linden, Anthony; Heimgartner, Heinz (1997). Novel heterospirocyclic 3-amino-2H-azirines as synthons for heterocyclic alpha-amino acids. Helvetica Chimica Acta, 80:1528-1554.

Abstract

The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N-methyl-N-phenylamino)-2H-azirines) 1a-d with a tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring, respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCl), and sodium azide (Scheme 4 ). The reaction of these aminoazirines with thiobenzoic acid in CH2Cl2 at room temperature gave the thiocarbamoyl-substituted benzamides 13a - d in high yield. The azirines l a - d were used as synthons for heterocyclic 1-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me (18) by following the protocol of the „azirine/oxazolone method“: treatment of Z-Aib with 1 to give the dipeptide amide 15, followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3-amine 17 gave 18, again in high yield (Scheme 5 ). With some selected examples of 18, the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a - d, as well as that of the corresponding carbocyclic analogue 18e, were determined by X-ray crystallography (Figs. 1 - 3 and Tables 1 - 3). All five tripeptides adopt a beta-turn conformation of type III or III’. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid beta-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.

Abstract

The heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines (3-(N-methyl-N-phenylamino)-2H-azirines) 1a-d with a tetrahydro-2H-pyran, tetrahydro-2H-thiopyran, and a N-protected piperidine ring, respectively, were synthesized from the corresponding heterocyclic 4-carboxamides 2 by consecutive treatment with lithium diisopropylamide (LDA), diphenyl phosphorochloridate (DPPCl), and sodium azide (Scheme 4 ). The reaction of these aminoazirines with thiobenzoic acid in CH2Cl2 at room temperature gave the thiocarbamoyl-substituted benzamides 13a - d in high yield. The azirines l a - d were used as synthons for heterocyclic 1-amino acids in the preparation of tripeptides of the type Z-Aib-Xaa-Aib-N(Ph)Me (18) by following the protocol of the „azirine/oxazolone method“: treatment of Z-Aib with 1 to give the dipeptide amide 15, followed by selective hydrolysis to the corresponding acid 16 and coupling with the 2,2-dimethyl-2H-azirin-3-amine 17 gave 18, again in high yield (Scheme 5 ). With some selected examples of 18, the selective deprotection of the amino and the carboxy group, respectively, was demonstrated (Scheme 6). The solid-state conformations of the protected tripeptides 18a - d, as well as that of the corresponding carbocyclic analogue 18e, were determined by X-ray crystallography (Figs. 1 - 3 and Tables 1 - 3). All five tripeptides adopt a beta-turn conformation of type III or III’. The solvent dependence of the chemical shifts of the NH resonances (Fig. 6) suggests that there is an intramolecular H-bond between H-N(4) and O(11) in all cases, which is an indication that a relatively rigid beta-turn structure also persists in solution. Surprisingly, the tripeptide acid 20a shows no intramolecular H-bond in the crystalline state (Fig. 7); O(11) is involved in an intermolecular H-bond with the OH group of the carboxy function.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:1997
Deposited On:18 Nov 2013 10:00
Last Modified:05 Apr 2016 17:09
Publisher:Wiley-Blackwell
ISSN:0018-019X
Funders:Swiss National Science Foundation, Stiftung für wissenschaftliche Forschung an der Universität Zürich, F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1002/hlca.19970800515

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