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.