The research team of you Shuli, Shanghai organic Research Institute, Chinese Academy of Sciences has made important progress in the study of Pictet Spengler reaction mechanism

Pictet Spengler reaction is an important method for the synthesis of indole alkaloids containing tetrahydro - β - carboline structure fragments, which has been discovered for more than 100 years But the mechanism of Pictet Spengler reaction has been debated for a long time One of the key issues in understanding the mechanism of Pictet Spengler reaction is whether the reaction undergoes the formation and ring expanding migration of spiroindoline intermediates (Fig 1, path B) As early as the 1950s, Woodward used the synthesis of spirocyclic pseudoindole in the synthesis of brucine Since then, it has been reported that spirocyclic pseudoindole species can be captured under Pictet Spengler like reaction However, none of these works is enough to show whether the formation and transformation of spirocyclic pseudoindole intermediates are directly related to the formation of Pictet Spengler reaction products The previous DFT theoretical calculation does not support the reaction mechanism of spirocyclic pseudoindole intermediate Fig 1 Pictet Spengler reaction (source: Chem) since 2010, the team of you Shuli, researcher of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has reported a series of methods for the synthesis of chiral spirocyclic pseudoindole compounds by asymmetric allylic de aromatization catalyzed by iridium complexes, and realized in the presence of acid with catalytic amount Stereoselective ring extension and migration of chiral spirocyclic pseudoindoles DFT calculation shows that the activity of migration reaction of spirocyclic pseudoindoles is closely related to the stereochemistry and electronic properties of migration groups Recently, based on the above results, the researchers realized that the electronic properties of ammonium ion in Pictet Spengler precursor I may have an important influence on the reaction process and stereochemistry In-depth DFT calculation shows that when the nitrogen atom in I has a strong electron absorption group (PG = TF), the spiro pseudoindole intermediate III can have an effective ring expanding migration reaction The strong interaction between ammonium sulfite positive ions and indole ring makes the migration reaction experience a typical caldera shape PES, which is likely to have significant dynamic effects Trajectory analysis confirmed that the intermediate III of spirocyclic pseudoindole can generate protonated tetrahydro - β - carboline II through rapid migration reaction (average time scale is hundreds of femtoseconds) The stereochemistry of the positive ion part of ammonium in the transfer reaction is completely maintained When the nitrogen atom in I has a strong electron donor group (PG = BN), the formation of spiro pseudoindole intermediate III is a reversible process, which has no direct relationship with the formation of the final product of Pictet Spengler reaction (Fig 2) On this basis, the researchers proposed two possible limiting mechanisms of Pictet Spengler reaction (Fig 3) Spirocyclic pseudoindole intermediate can be used as "productive intermediate" or "non productive intermediate" to participate in Pictet Spengler reaction The stereochemical information of spirocyclic pseudoindole intermediates may be transferred to the final product through stereospecific ring expansion and migration The theoretical prediction has also been confirmed by further experimental results In addition, the mechanism model is extended to a series of known asymmetric Pictet Spengler reactions By using two easily calculated energy parameters, it is convenient to make a quick judgment on the course of a given Pictet Spengler reaction The unified mechanism of Pictet Spengler reaction is helpful to further explore the reaction performance of spiro pseudoindole intermediates and develop new synthesis methods for indole polycyclic compounds Figure 2 Two typical potential energy surfaces of Pictet Spengler reaction (source: Chem) Figure 3 Two limit mechanisms of Pictet Spengler reaction (source: Chem) This achievement was recently published on chem (CHEM 2018, 4, 1952-1966) The research was supported by the Ministry of science and technology, the National Natural Science Foundation of China, the strategic leading science and technology program of the Chinese Academy of Sciences (category B) and the Shanghai Science and Technology Commission.