General Approach for the Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids Including (−)-12-Methoxy-N_b-methylvoachalotine, (+)-12-Methoxy-N_a-methylvellosimine, (+)-12-Methoxyaffinisine, and (−)-Fuchsiaefoline

The enantiospecific synthesis of 7-methoxy-d-tryptophan ethyl ester was completed by combination of the Larock heteroannulation process with a Schöllkopf-based chiral auxiliary in good yield. This ester was then employed in the first regiospecific, stereospecific total synthesis of (+)-12-methoxy-N_a-methylvellosimine, (+)-12-methoxyaffinisine, (−)-fuchsiaefoline, and 12-methoxy-N_b-methylvoachalotine in excellent overall yield. The asymmetric Pictet−Spengler reaction and enolate-driven palladium-catalyzed cross-coupling processes served as key steps. The quaternary center at C(16) of 12-methoxy-N_b-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-N_a-methylvellosimine and formaldehyde to form diol 17. The two prochiral primary alcohols in diol 17 were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of 17 with the benzylic postion at [C(6)] to form a cyclic ether [C(6)−O(17)]. After oxidative formation of the α-ester at C(16), the ether bond was reductively cleaved with TFA/Et₃SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et₃SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids.