| Two independent routes for the total synthesis of the bioactive neolignan (-)-conocarpan are described. The first (98% ee) is based on formal radical cyclization onto a benzene ring, and involves a 5-exo-trigonal closure onto a double bond restrained within a 6-membered ring. The second route (88% ee), which is shorter, is based on 5-exo-trigonal cyclization of an aryl radical onto a pendant terminal double bond. The absolute configuration originally assigned to (+)-conocarpan had previously been called into question on the basis of empirical chiroptical rules; the present chemical work confirms the need for revision, and the assigned absolute configurations of several compounds correlated with (+)-conocarpan must also be changed.;Readily accessible 2-alkoxycarbonyl-6-hydroxy-5-halocoumarins can be converted into 4-halo-5-hydroxyindoles by conjugate reduction or conjugate addition, decarboxylation, lactone opening with ammonia, Hofmann rearrangement to an N-Boc ethylamine, oxidation to a quinone and deprotection of the nitrogen. The resulting beta-aminoethyl quinone cyclizes in-situ to a mixture of quinone imine and indole, and the imine tautomerizes to the indole spontaneously or on treatment with a catalytic amount (<1 mol%) of rhodium on alumina. 4-Chloro-, 4-bromo- and 4-iodoserotonin derivatives were synthesized from these 4-halo-5-hydroxyindoles. Synthesis of the 4-iodoserotonins involved conjugate addition of an ally) group to a 5-iodocoumarin, followed by conversion of the allyl group into an aminoethyl unit. The iodoserotonin derivative was then converted into the toad alkaloid dehydrobufotenine. |
