Stereoselective synthesis of highly substituted 1-isomorphans (1-azabicyclo[3.3.1]nonanes)

We describe the first enantioselective synthesis of highly functionalized 1-azabicyclo[3.3.1]nonanes (1-IM). The 1-IM scaffold is present in natural products and drugs and is an isomer of the morphan moiety. The proposed methodology is based on an organocatalytic Michael addition of N-protected piperidine ketoesters to nitroalkenes and an intramolecular nitro-Mannich reaction as key transformations. The 1-IMs feature 6 contiguous stereocenters, substituents at positions 2 and 4, and nitro, ester, and hydroxyl functional groups at positions 3, 5, and 6 respectively. The synthesis is straightforward, highly stereoselective (up to 98% ee, >99 : 1 d.r.), with overall yields of up to 83% and requires only two purification steps.