59th Annual Report on Research 2014

Heterocycloaddition reactions are arguably among the most powerful transformations available to synthetic chemists. The hetero-analog of the Diels-Alder reaction and cycloadditions of 1,3-dipolar have been widely developed as powerful transformations that deliver 5 and 6 membered heterocycles from simple starting materials. Despite these developments, heterocyclic analogs of higher order carbocyclizations have not been widely developed. In 2010, our group became interested in exploring aza-analogs of the thermally allowed (4+3) cycloaddition reaction of allylic cations with dienes. Aza-oxy allylic cations are nitrogenous analogs to the oxyallylic cation and were first proposed by Sheehan and Lengyl in 1964 as intermediates relevant to the nucleophilic ring opening of alpha-lactams. Sheehan's proposal stimulated numerous mechanistic studies, which ultimately ruled out the relevance of this proposed intermediate to the unique reactivity of alpha-lactams. Relying on the precedent that nitrenium ions are stabilized by pi-donating substituents (e.g. OR and NR₂), our group re-opened the case against this speculated intermediate and pursued the hypothesis that a pi-donating would provide stabilization to the proposed aza-oxyallylic cation. Once generated we hypothesized that this intermediate would react in a thermally allowed aza-(4+3) cycloaddition reaction with 4-pi reactants to directly deliver caprolactamsfrom simple starting materials.

Our initial theoretical studies highlighted the significant stabilization that an alkoxy- substituent provided the proposed intermediate, and these initial investigations were experimentally supported by establishing the first example of an aza-(4+3) cycloaddition reaction of an aza-oxyallylic cation only 3 months into my independent career. This work was later disclosed in 2011 in our first publication in JACS, which has been cited 21 times since publication. Since the initial disclosure, our work with this reactive intermediate has yielded a number of new discoveries in the context of the synthesis of heterocyclic scaffolds, polyhydroxylated piperidines, and macrocyclic compounds. We have taken advantage of this symmetry rules that dictate the regioselectivity of this reaction to develop one of the few methods to regioselectivity 1,4-diaminate 1,3-dienes and aromatic heterocycles.

Other studies ongoing in our group will extend our capabilities to providing enantioselective analogs and approach direct oxidative methods for generating this promising intermediate. Recently, our work was summarized in an invited review article that was published in 2014 as Tetrahedron-Digest article, entitled "Trapping the elusive aza-oxyallylic cation: new opportunities in heterocycloaddition chemistry."