General Approach for the Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids Including (−)-12-Methoxy-<i>N</i><sub>b</sub>-methylvoachalotine, (+)-12-Methoxy-<i>N</i><sub>a</sub>-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-<i>N</i><sub>a</sub>-methylvellosimine, (+)-12-methoxyaffinisine, (−)-fuchsiaefoline, and 12-methoxy-<i>N</i><sub>b</sub>-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-<i>N</i><sub>b</sub>-methylvoachalotine was established via the Tollens reaction between (+)-12-methoxy-<i>N</i><sub>a</sub>-methylvellosimine and formaldehyde to form diol <b>17</b>. The two prochiral primary alcohols in diol <b>17</b> were differentiated by the oxidative cyclization(DDQ) of the hydroxyl group at the axial position of <b>17</b> 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/Et<sub>3</sub>SiH in high yield. The DDQ-mediated oxidative cyclization and TFA/Et<sub>3</sub>SiH reductive cleavage served as protection/deprotection steps in order to provide a versatile entry into the voachalotine alkaloids.