Approaches to 3,4,5-substituted piperidines via 1,2,5,6-tetrahydropyridines prepared by ring-closing metathesis

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• 作者：Maxime G.P. Buffat ; Eric J. Thomas ; ^{e.j.thomas@manchester.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：1 ; 2 ; 5 ; 6-Tetrahydropyridines ; Ring-closing metathesis ; Nucleophilic aromatic substitution ; Muscarinic receptor agonists ; Aziridines
• 刊名：Tetrahedron
• 出版年：2016
• 出版时间：28 January 2016
• 年：2016
• 卷：72
• 期：4
• 页码：451-463
• 全文大小：738 K

文摘

Synthetic approaches to (1RS,2SR,6SR)-7-arylmethyl-2-alkoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, potentially selective muscarinic M₁ receptor agonists, by hydration of 1,2,5,6-tetrahydropyridines were investigated. 3-Substituted N-tosyl-1,2,5,6-tetrahydropyridines were prepared by ring-closing metathesis (RCM). The direct hydration of these by hydroboration-oxidation was not usefully selective, but cis-3-hydroxymethyl-4-tert-butyldimethylsilyloxy-N-tosylpiperidine was prepared from 3-hydroxymethyl-N-tosyl-1,2,5,6-tetrahydropyridine by epoxidation, mesylation, reductive elimination, silylation and hydroboration-oxidation. Problems were encountered during attempts to prepare 3-alkoxymethyl-1,2,5,6-tetrahydropyridines with protected amino and cyclobutyl substituents at C5 by ring-closing metathesis, perhaps because of steric hindrance. Nevertheless interesting chemistry was encountered during the synthesis of the RCM precursors including a novel coupling via a 2-ethenyl-N-nosylaziridine and the formation of an oxaazathiocin by an intramolecular substitution of the nitro group of an N-nosyl protected amine by a proximate hydroxyl substituent.