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The azirine/oxazolone approach to the synthesis of Aib-Pro endothiopeptides


Budzowski, A; Linden, A; Heimgartner, H (2008). The azirine/oxazolone approach to the synthesis of Aib-Pro endothiopeptides. Helvetica Chimica Acta, 91(8):1471-1488.

Abstract

The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a) with thiobenzoic acid at room temperature gave the endothiopeptide Bz AibY[CS]-Pro-OMe (7) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)-protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z-Pro-AibY[CS]-Pro-OMe (12). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H2S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro2 was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe-OMe and 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-1H-benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer BzY[CS]-Aib-Pro-AibY[CS]-N(Me)Ph (21) was achieved via isomerization of 7 to BzY[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1a). The structures of 12 and 21 were established by X-ray crystallography.

Abstract

The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a) with thiobenzoic acid at room temperature gave the endothiopeptide Bz AibY[CS]-Pro-OMe (7) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)-protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z-Pro-AibY[CS]-Pro-OMe (12). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H2S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro2 was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe-OMe and 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-1H-benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer BzY[CS]-Aib-Pro-AibY[CS]-N(Me)Ph (21) was achieved via isomerization of 7 to BzY[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1a). The structures of 12 and 21 were established by X-ray crystallography.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2008
Deposited On:06 Feb 2009 08:15
Last Modified:06 Dec 2017 17:45
Publisher:Verlag Helvetica Chimica Acta
ISSN:0018-019X
Funders:Dr. Helmut Legerlotz-Foundation, F. Hoffmann-La Roche AG, Basel
Publisher DOI:https://doi.org/10.1002/hlca.200890160

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