Unified Mechanistic Understandings of Pictet-Spengler Reactions

Abstract

Pictet-Spengler reactions have widely been employed in the synthesis of polycyclic-indole-derived natural products. However, the mechanism of this reaction has remained as a controversial research topic. In this article, You and coworkers performed combined density functional theory calculations and direct molecular dynamics simulations to provide unified mechanistic understandings of Pictet-Spengler reactions with an emphasis on the divergent role played by spiroindolenine intermediates. The key theoretical predictions are well supported by further experiments.

Mechanism and origins of selectivity in the enantioselective oxa-Pictet–Spengler reaction: a cooperative catalytic complex from a hydrogen bond donor and chiral phosphoric acid

“…Such a sequence operates in gratifying agreement with prior computational studies on the Pictet-Spengler reaction mechanism. 46,47 With the aforementioned experimental observations and preliminary computational investigation established, we sought to computationally investigate the key C-C bond forming transition state. Due to the high energy/short lifetime of the oxocarbenium ion preceding the transition state, we hypothesized that the spirocyclization transition state conformation may be closely related to that of the phosphate-acetal.…”

Reductive Functionalization of Carboxamides: A Recent Update

“…For example, Dixon demonstrated the reductive intramolecular aza-Henry reaction of N-nitroalkyl tethered lactam 15, where initially formed enamine 16 via the Ircatalyzed hydrosilylation were protonated to generate iminium ion 17 and subsequent basification promoted cyclization to form aza-bicyclic product 18 (Figure 15). 38 Formation of tetrahydro β-carbolines via intramolecular Friedel Crafts type C-C bond formation of iminium ions 19 derived from tryptamine and carbonyl compounds is known as the Pictet-Spengler reaction ( Figure 16A). Mechanistic studies implicated that the process involves both C3-and C2-attack of the indole moiety to form spiro-indolenium ions 20 and pentahydro β-carbolinium ions 21, respectively as the intermediates which are linked under equilibrium via C-C bond migration.…”

A Cooperative Hydrogen Bond Donor–Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans

“…Subsequently, the CPA protonates the substrate enol ether, producing an oxocarbenium ion I that is rapidly trapped by the indole C3 position for form spirocyclic intermediate II . [28] Spirocyclic intermediate II undergoes a cationic 1,2-shift to produce the final connectivity through the indole C2 position. Deprotonation of the resulting tricycle restores aromaticity and furnishes the THPI product.…”