Diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles by a tandem reduction-reductive amination reaction

A two-step diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed from cyclic beta-ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2-oxocycloalkanecarboxylates with 2-nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxylamine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans-fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis-fused heterocycle.