Cis-selectivity in the Pictet-Spengler reaction and studies towards the synthesis of indole alkaloids

Previous work in our group as been directed towards the synthesis of (+)-ajmaline, a biologically important indole alkaloid. Its total synthesis was completed in the 1990s. An important early step in its total synthesis from D-tryptophan is the trans-selective Pictet-Spengler reaction. However, in our hands, we are able to force cis-selectivity in the reaction which allows us to begin our work towards its synthesis from the cheaper L-tryptophan. The group's previous progress had reached a key ring cyclisation step; however it was discovered that this step was sensitive to the type of protecting group on the Nb-nitrogen. The benzyl protecting group, which was originally in place, was found to position the electrophilic aldehyde group too far away from the nucleophile for the reaction to take place. Therefore, the previous work was re-investigated and the purposely-chosen pivaloyl Nb-protecting group was employed early in the new synthesis. The synthesis was progressed to the afore-mentioned cyclisation step whilst improving some of the individual steps. The conditions that allow for the observed cis-selectivity in the Pictet-Spengler reaction have only recently been developed. Further investigations now reveal that the temperature and the nature of the C(3) and C(5) substituents have a direct effect on the observed selectivity. Cis-specificity is generally achieved when the reaction is conducted at low temperature and both substituents contain a potential π-stacking group. However, it is still unclear whether it is the interaction of the potential π-stacking groups that is responsible for cis-specificity in this reaction.