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

作者：Buffat Maxime G P; Thomas Eric J^*

来源：Tetrahedron, 2016, 72(4): 451-463.

DOI：10.1016/j.tet.2015.11.040

• 1,2,5,6-Tetrahydropyridines
• Ring-closing metathesis
• Nucleophilic aromatic substitution
• Muscarinic receptor agonists
• Aziridines

Synthetic approaches to (1RS,2SR,6SR)-7-arylmethyl-2-alkoxymethyl-4,7-diaza-9-oxabicyclo[4.3.0] nonan-8-ones, potentially selective muscarinic M-1 receptor agonists, by hydration of 1,2,5,6-tetrahydropyridines were investigated. 3-Substituted N-tosy1-1,2,5,6-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-tosy1-1,2,5,6-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.

• 出版日期2016-1-28