Intramolecular Pyridinium Oxide Cycloadditions: Systematic Study of Substitution, Diastereoselectivity, and Regioselectivity

Abstract

Intramolecular pyridinium oxide cycloadditions form complex polycyclic nitrogenous architectures. The diastereoselectivity and regioselectivity of pyridinium oxide cycloadditions was systematicallyi nvestigated for the first time using complex substrates. Predictably high levels of diastereoselectivity and regioselectivity are observed, which can be attributed to minimization of steric (syn-pentane) and torsional strain in the products. The reaction is reversible under the reaction conditions, and it is stereospecific with respectt ot he dipolarophile geometry. Polycyclic nitrogenous architectures are widespreadi nb iologically active natural products. For example, the tropane alkaloids, exemplified by cocaine, are characterized by a8-aza-bicyclo[3.2.1]octane structure, 1. [1] Amaryllidaceae alkaloidss uch as siculine display at opologically distinct 1-azabicyclo[3.2.1]octane core (2). [2] Homopumiliotoxin 223G is aq uinolizidine alkaloid (3)i solated from poison dart frogs. [3] Finally,t he intriguing structure of the galbulimima alkaloid, himgaline, displays all of these component aza-bicyclic fragments in a2-azatricyclo[4.4.1.0 2,7 ]undecane architecture (4)(Figure 1). [4, 5] Such bridged polycyclic alkaloids represent enduring challenges for synthetic chemists. An otable difficulty associated with the synthesis of the natural products shown are the ste-reogenic carbonsb earing nitrogen. [6] In particular,a ll three carbons bearingt he nitrogen atom in the himgaline structure are stereogenic,m aking this target notably complex. Many synthetic strategies have appeared to access nitrogenous bicycles, and particularly successful approaches create multiple rings in as ingle transformation with control of stereochemical outcomes. [7] Cycloadditionr eactions are particularly well suited for the challenge of preparing multiple rings with controlo fs tereochemistry,a nd we wonderedi fs uch polycyclic nitrogenous frameworks could be prepared using as uitablec ycloaddition. We decided to focus on the tricyclic motif found in himgaline, complete with the equatorial methyl substituent (5,S cheme 1). Any method capable of preparing this tricyclica rchitecture could,a tl east in principle, be used to construct any of the component bicyclic structures (1-3).