Total syntheses of (+)-alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A.

(+)-Alopecuridine, (+)-sieboldine A, and (-)-lycojapodine A, three structurally unique and related lycopodium alkaloids, have been synthesized in enantiomeric forms through an efficient strategy. The main synthetic approach for (+)-alopecuridine features a semipinacol rearrangement of hydroxyl epoxide to construct the spiro 6,9-azacarbocycles with an all-carbon quaternary center and a late-stage SmI(2)-mediated intramolecular coupling to form the 5-membered ring. Subsequently, the biomimetic synthesis of (+)-sieboldine A and (-)-lycojapodine A was accomplished successfully through two different bioinspired oxidations after a wide search for the oxidation methods. As a result, (+)-sieboldine A was derived from (+)-alopecuridine through an N-oxidation/nitrone formation process and (-)-lycojapodine A through an interesting cyclic hemiketal formation/oxidative diol cleavage pathway. These results confirmed the biogenetic relationship among the three alkaloids.