General Approach for the Synthesis of Ajmaline/Sarpagine Indole Alkaloids:  Enantiospecific Total Synthesis of (+)-Ajmaline, Alkaloid G, and Norsuaveoline via the Asymmetric Pictet−Spengler Reaction

A general approach (oxyanion-Cope strategy) for the synthesis of sarpagine/ajmaline indole alkaloids has been developed. (+)-Ajmaline 1 and alkaloid G 2 as well as norsuaveoline 3 have been synthesized from d -(+)-tryptophan in enantiospecific fashion via the asymmetric Pictet−Spengler reaction and a stereocontrolled oxyanion-Cope rearrangement as key steps. The synthesis of these indole alkaloids employed a stereospecific Pictet−Spengler/Dieckmann protocol to prepare the key intermediate, (−)- N b -benzyl tetracyclic ketone ( 7a or 7b ). This ketone was converted into α,β-unsaturated aldehyde ( 8a or 8b ) and further transformed into (+)-ajmaline 1 and alkaloid G 2 as well as norsuaveoline 3 . It was also found that reduction of 29 can be done stereospecifically to form the 2-epidiacetylajmaline derivative 30 which has the same configuration at C(2) as that of quebrachidine and of the bisindole alstonisidine. The ring closure reaction (from 27 to 28 ) to form the sarpagine skeleton was completed in 91% yield. It should now be possible to prepare the antipode of (+)-ajmaline via this approach for biological screening.