Asymmetric Aza-[3 + 3] Annulation in the Synthesis of Indolizidines: An Unexpected Reversal of Regiochemistry

Abstract

An enantioselective and diastereoselective aza-[3 + 3] annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts is described. This asymmetric annulation manifold is possible because of an unexpected regiochemical reversal whereby head-to-tail annulations dominated over the predicted head-to-head. It should find prevalent synthetic applications in the enantioselective synthesis of indolizidines.

Construction of Dihydropyrido[2,3-d]pyrimidine Scaffolds via Aza-Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

“…5b , 17 Moreover, it is worth noting that [3 + 3] cycloaddition is rather typical for analogous aminocatalytic reactions. 18 …”

Diastereoselective synthesis of chiral 1,3-cyclohexadienals

“…For example, the citral dimer shows antibiotic activity [ 26 ] and the retinal dimer could contribute to macular degeneration. [ 27 ] As chiral aldehyde 2 has been intensively used as a synthetic building block in the synthesis of bioactive natural products, [ 28 – 33 ] this study sought to obtain chiral cyclohexadienals using 2 in combination with different β-methyl disubstituted-α,β-unsaturated aldehydes in the presence of different catalysts ( 5–10 ), which avoid the dimerization of these compounds ( Fig 1 ).…”

Organocatalytic Michael addition of 2-nitro methylene imidazolidines to α,β-unsaturated aldehydes: concise synthesis of chiral insecticide Paichongding

“…8 Almost at the same time, Dai and Hsung reported an asymmetric aza-[3þ3]-annulation of pyrrolidine-based exo-cyclic vinylogous amides and urethanes with chiral vinyl iminium salts. 9 Inspired by these works and as part of our continued interest in the application of asymmetric organocatalysis to the construction of useful structures, we have developed an organocatalytic [3þ3]-annulation way for the synthesis of chiral neonicotinoids from substituted nitroenamine 1 and a,bunsaturated aldehydes.…”