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.

Pictet-Spengler反应广泛用于各种吲哚生物碱的合成中。然而，它们的机制一直是一个有争议的研究主题。螺环吲哚碱是催化不对称Pictet-Spengler反应中普遍提出的关键中间体，其作用仍难以捉摸。在此，结合的密度泛函理论计算和直接的分子动力学模拟表明该中间体的作用是不同的。螺环吲哚啉根据势能表面的形状而充当生产性或非生产性中间体。在前一种情况下，动态作用在螺螺吲哚的重排中起着重要作用，螺重氮可在不通过沿着反应坐标的中间过渡态的情况下发生。在后一种情况下，螺环吲哚的形成只是一个周期外的平衡。这些理论预测已通过实验验证。此外，这些见解被应用于七个已报道的催化不对称Pictet-Spengler反应，从而导致对该合成反应的统一机理理解。