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Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation

Substituted seven-membered N-heterocycles are prevalent bioactive epitopes and useful synthons for preparing enzyme inhibitors or molecular recognition systems. To fully exploit the chemical properties of this flexible N-heterocycle scaffold, efficient methods for its diverse functionalization are r...

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Autores principales: Spedding, Harold, Karuso, Peter, Liu, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150284/
https://www.ncbi.nlm.nih.gov/pubmed/29088108
http://dx.doi.org/10.3390/molecules22111871
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author Spedding, Harold
Karuso, Peter
Liu, Fei
author_facet Spedding, Harold
Karuso, Peter
Liu, Fei
author_sort Spedding, Harold
collection PubMed
description Substituted seven-membered N-heterocycles are prevalent bioactive epitopes and useful synthons for preparing enzyme inhibitors or molecular recognition systems. To fully exploit the chemical properties of this flexible N-heterocycle scaffold, efficient methods for its diverse functionalization are required. Here we utilize the late-stage oxidation of tetrahydroazepines as an approach to access densely functionalized oxo-azepines in a total of 8 steps and ~30% overall yield from commercially available starting materials. Hydroboration of tetrahydroazepines proceeded with diastereoselectivity in a substrate-dependent manner to yield regioisomeric azepanols before their oxidation to the corresponding oxo-azepines. Regioselectivity of the hydroboration step may be improved moderately by a rhodium catalyst, albeit with loss of conversion to a competing hydrogenation pathway. Overall our method allows efficient access to azepanols and oxo-azepines as versatile epitopes and synthons with a high degree of diastereoselectivity and moderate regioselectivity.
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spelling pubmed-61502842018-11-13 Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation Spedding, Harold Karuso, Peter Liu, Fei Molecules Article Substituted seven-membered N-heterocycles are prevalent bioactive epitopes and useful synthons for preparing enzyme inhibitors or molecular recognition systems. To fully exploit the chemical properties of this flexible N-heterocycle scaffold, efficient methods for its diverse functionalization are required. Here we utilize the late-stage oxidation of tetrahydroazepines as an approach to access densely functionalized oxo-azepines in a total of 8 steps and ~30% overall yield from commercially available starting materials. Hydroboration of tetrahydroazepines proceeded with diastereoselectivity in a substrate-dependent manner to yield regioisomeric azepanols before their oxidation to the corresponding oxo-azepines. Regioselectivity of the hydroboration step may be improved moderately by a rhodium catalyst, albeit with loss of conversion to a competing hydrogenation pathway. Overall our method allows efficient access to azepanols and oxo-azepines as versatile epitopes and synthons with a high degree of diastereoselectivity and moderate regioselectivity. MDPI 2017-10-31 /pmc/articles/PMC6150284/ /pubmed/29088108 http://dx.doi.org/10.3390/molecules22111871 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Spedding, Harold
Karuso, Peter
Liu, Fei
Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title_full Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title_fullStr Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title_full_unstemmed Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title_short Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation
title_sort synthesis of substituted oxo-azepines by regio- and diastereoselective hydroxylation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150284/
https://www.ncbi.nlm.nih.gov/pubmed/29088108
http://dx.doi.org/10.3390/molecules22111871
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