Synthesis of Bridged Heterocycles via Sequential 1,4- and 1,2-Addition Reactions to α,β-Unsaturated N-Acyliminium Ions: Mechanistic and Computational Studies

Abstract

Novel tricyclic bridged heterocyclic systems can be readily prepared from sequential 1,4- and 1,2-addition reactions of allyl and 3-substituted allylsilanes to indolizidine and quinolizidine α,β-unsaturated N-acyliminium ions. These reactions involve a novel N-assisted, transannular 1,5-hydride shift. Such a mechanism was supported by examining the reaction of a dideuterated indolizidine, α,β-unsaturated N-acyliminium ion precursor, which provided specifically dideuterated tricyclic bridged heterocyclic products, and from computational studies. In contrast, the corresponding pyrrolo[1,2-a]azepine system did not provide the corresponding tricyclic bridged heterocyclic product and gave only a bis-allyl adduct, while more substituted versions gave novel furo[3,2-d]pyrrolo[1,2-a]azepine products. Such heterocyclic systems would be expected to be useful scaffolds for the preparation of libraries of novel compounds for new drug discovery programs.

My 37 years of working with nitrogen heterocycles and alkaloids

“…My research group also pioneered the discovery of cyclization reactions of α,β-unsaturated N-acyliminium ions with tethered bisnucleophiles to provide access to novel spirocyclic and bridged heterocycles and 5,5-disubstituted pyrrolidines (Scheme 35), [84][85][86] including those shown in Scheme 36, that have promising biological activities. The analogous reactions of α-cyclopropyl N-acyliminium ions with tethered bisnucleophiles were also developed leading to novel spirocycles (Scheme 37).…”

Asymmetric Synthesis of Methylphenidate and Quinolizidinones by Addition of Aldehydes to Piperidine-Based Conjugated N-Acyl­iminium Ions

“…5b,6 It should be noted that the use of α,β-unsaturated N-acyliminium ions such as 1 has been largely underdeveloped (Scheme 1). 7 Asymmetric addition to a conjugated N-acyl-iminium ion of this kind have only been reported by Matsumura and co-workers using enolates starting from electrochemically generated α-alkoxy derivative 2 (i.e., an N,O-acetal). 8 The vinylogouos γ-hydroxy(alkoxy)derivatives 3, easily obtained via Luche reduction of the corresponding 4-oxo-1,2,3,4-tetrahydropyridine, have been used as precursors of conjugated N-acyliminium ion 1 only in nonasymmetric Ferrier-type reactions.…”