A flexible approach toward trisubstituted piperidines and indolizidines:: Synthesis of 6-epi-indolizidine 223A

2,5,6-Trisubstituted piperidines are readily prepared by a combination of an aza-Achmatowicz oxidation of a furyl-substituted benzenesulfonamide followed, by a conjugate addition to the resulting 2H-pyridone and subsequent addition of various nucleophiles to a transient N-sulfonyliminium ion. The stereochemistry of the conjugate addition product is the result of axial attack from the face opposite the diaxial substituents at C-2 and C-6. This can be attributed to steric hindrance between the pseudoaxially oriented 2,6-substituents and the equatorially approaching nucleophile, thereby leading to the exclusive formation of the kinetically favored axial 1,4-adduct. Indolizidine alkaloid 223A was isolated from a skin extract of a Panamanian population of the dendrobatid Dendrobates pumilio Schmidt (Dendrobatidae). Synthesis of the originally proposed structure of this alkaloid was achieved in 13 steps in 13.1% overall yield by using an aza-Achmatowicz oxidative rearrangement and a diastereoselective 1,4-conjugate addition as the key steps. The structure of the natural 223A alkaloid (5b) differs from that of the epi-isomer 5a synthesized in this study. in the configuration at the 6-position of the indolizidine ring.