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Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics

The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at...

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Autores principales: Wünsch, Matthias, Schröder, David, Fröhr, Tanja, Teichmann, Lisa, Hedwig, Sebastian, Janson, Nils, Belu, Clara, Simon, Jasmin, Heidemeyer, Shari, Holtkamp, Philipp, Rudlof, Jens, Klemme, Lennard, Hinzmann, Alessa, Neumann, Beate, Stammler, Hans-Georg, Sewald, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704752/
https://www.ncbi.nlm.nih.gov/pubmed/29234470
http://dx.doi.org/10.3762/bjoc.13.240
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author Wünsch, Matthias
Schröder, David
Fröhr, Tanja
Teichmann, Lisa
Hedwig, Sebastian
Janson, Nils
Belu, Clara
Simon, Jasmin
Heidemeyer, Shari
Holtkamp, Philipp
Rudlof, Jens
Klemme, Lennard
Hinzmann, Alessa
Neumann, Beate
Stammler, Hans-Georg
Sewald, Norbert
author_facet Wünsch, Matthias
Schröder, David
Fröhr, Tanja
Teichmann, Lisa
Hedwig, Sebastian
Janson, Nils
Belu, Clara
Simon, Jasmin
Heidemeyer, Shari
Holtkamp, Philipp
Rudlof, Jens
Klemme, Lennard
Hinzmann, Alessa
Neumann, Beate
Stammler, Hans-Georg
Sewald, Norbert
author_sort Wünsch, Matthias
collection PubMed
description The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at C(α), such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the C(α) of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the C(α)-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics.
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spelling pubmed-57047522017-12-11 Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics Wünsch, Matthias Schröder, David Fröhr, Tanja Teichmann, Lisa Hedwig, Sebastian Janson, Nils Belu, Clara Simon, Jasmin Heidemeyer, Shari Holtkamp, Philipp Rudlof, Jens Klemme, Lennard Hinzmann, Alessa Neumann, Beate Stammler, Hans-Georg Sewald, Norbert Beilstein J Org Chem Full Research Paper The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at C(α), such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman’s chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the C(α) of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the C(α)-position facilitate a base induced rearrangement to α,β-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics. Beilstein-Institut 2017-11-15 /pmc/articles/PMC5704752/ /pubmed/29234470 http://dx.doi.org/10.3762/bjoc.13.240 Text en Copyright © 2017, Wünsch et al. https://creativecommons.org/licenses/by/4.0https://www.beilstein-journals.org/bjoc/termsThis is an Open Access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc/terms)
spellingShingle Full Research Paper
Wünsch, Matthias
Schröder, David
Fröhr, Tanja
Teichmann, Lisa
Hedwig, Sebastian
Janson, Nils
Belu, Clara
Simon, Jasmin
Heidemeyer, Shari
Holtkamp, Philipp
Rudlof, Jens
Klemme, Lennard
Hinzmann, Alessa
Neumann, Beate
Stammler, Hans-Georg
Sewald, Norbert
Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title_full Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title_fullStr Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title_full_unstemmed Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title_short Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
title_sort asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics
topic Full Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704752/
https://www.ncbi.nlm.nih.gov/pubmed/29234470
http://dx.doi.org/10.3762/bjoc.13.240
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