Details

Autor(en) / Beteiligte

• Wayama, Toshiaki
• Arai, Yuta
• Oguri, Hiroki

Titel

Regiocontrolled Dimerization of Densely Functionalized 1,6-Dihydropyridines for the Biomimetic Synthesis of a Halicyclamine-type Scaffold by Preventing Disproportionation

Ist Teil von

• Journal of organic chemistry, 2022-05, Vol.87 (9), p.5938-5951

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• The biomimetic dimerization of 1,6-dihydropyridines (DHPs) remains a daunting challenge due to competitive disproportionation pathways. Herein we report the regioselective dimerization of densely functionalized 1,6-DHPs that allow direct access to the bis-nitrogen bicyclic scaffold of halicyclamines. Disproportionation triggered by the hydride shift of 1,6-DHP was suppressed by the use of geminal disubstituted substrates. Installation of an electron-withdrawing substituent at the C3 position was demonstrated to be crucial for facilitating biomimetic dimerization under metal-free conditions, with exquisite control of regioselectivity at ambient temperature. Our approach, featuring an appropriately functionalized and substantially stabilized substrate rather than merely adopting the highly reactive and labile hypothetical biosynthetic intermediate, allowed gram-scale and atom-economical synthesis of the bis-nitrogen bicyclic scaffold. Furthermore, conversion of a series of 1,6-DHPs provided mechanistic insights by circumventing the competitive disproportionation reaction. This revealed not only the innate reactivity of the conjugate diene system for [4 + 2] cycloaddition but also the reversibility of the dimerization reaction with multiple cationic intermediates in equilibrium.