Total Synthesis of Lycopodium Alkaloids: (+/-)-Lycopodine, (+/-)-Lycodine, and (+/-)-Lycodoline

Article abstract of DOI:10.1021/ja00368a024

Intramolecular Mannich condensation is shown to be a powerful method for the synthesis of lycopodium alkaloids (eq 2).Two syntheses of (+/-)-lycopodine (1) have been developed.In the first (Scheme II), compound 1 is produced in 13 steps from 5-methyl-1,3-cyclohexanedione (16.6percent overall yield).In this synthesis, rings A and B are formed in the Mannich cyclization, and ring D is closed by aldol condensation.The alternative lycopodine synthesis (Scheme IV) is more convergent and produces (+/-)-1 in only eight operations from the same starting point (13percent overall yield).In this synthesis, primary amine 41 is employed in the Mannich reaction, and ring D is closed by intramolecular alkylation or a bromo amine.The synthesis of (+/-)-lycodine (3) also requires eight steps and provides the alkaloid in 13.2percent overall yield (Scheme V).This synthesis features an efficient, one-pot conversion of δ,ε-unsaturated ketone 46 into pyridine 3. (+/-)-Lycodoline (3) is produced by an 11-step route in 3.2percent overall yield as shown in eq 16, 18, and 22.In this synthesis, the angular hydroxyl is introduced by the stereoselective autoxidation of an octahydroquinone (eq.16).The Mannich cyclization is completed by a novel method which utilizes the base-catalyzed polymerization of 3-bromo-1-propanol as a method for slow delivery of HBr, thus allowing the reaction to be carried out under essentially neutral conditions (eq.18).The lycodoline synthesis is completed by use of a novel variant of the Oppenauer oxidation (61 -> 62).