Unified Mechanistic Understandings of Pictet-Spengler Reactions

Abstract

Summary Pictet-Spengler reactions are extensively utilized in the synthesis of various indole alkaloids. However, their mechanisms have been a controversial research topic. The role of spiroindolenine, the generally proposed key intermediate in catalytic asymmetric Pictet-Spengler reactions, remains elusive. Herein, combined density functional theory calculations and direct molecular dynamics simulations reveal that the role of this intermediate is divergent. The spiroindolenine acts as either a productive or a non-productive intermediate depending on the shape of the potential energy surface. In the former case, dynamic effects play an important role in the rearrangement of spiroindolenine, which can occur without passing through the intervening transition states along the reaction coordinates. In the latter case, the formation of spiroindolenine is only an off-cycle equilibrium. These theoretical predictions were verified experimentally. Furthermore, these insights were applied to seven reported catalytic asymmetric Pictet-Spengler reactions, leading to unified mechanistic understandings of this synthetically enabling reaction.