65048-57-9Relevant articles and documents
Unified Mechanistic Understandings of Pictet-Spengler Reactions
Zheng, Chao,Xia, Zi-Lei,You, Shu-Li
, p. 1952 - 1966 (2018)
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. The unique charm of synthetic chemistry stems from its room for creativity in breaking and constructing chemical bonds. Developing novel synthetic methodologies is the central task of fundamental organic chemistry, which can facilitate or enable access to valuable classes of compounds or materials. The Pictet-Spengler reaction is a key method for the synthesis of indole-derived natural products, an important class of compounds in drug discovery. Rational design of new chemical reactivity largely relies on deep mechanistic understandings. However, because of the inherent complexity of systems on the molecular level, usually a reaction mechanism can be perturbed by subtle changes of single reaction parameters. Hence, pursuing unified mechanistic understandings of synthetically enabling reactions is of great significance academically and can pave the way for crucial industrial synthetic applications in various fields. 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 co-workers 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.
Ruthenium Catalyzed Tandem Pictet-Spengler Reaction
Cherepakhin, Valeriy,Nalikezhathu, Anju,Williams, Travis J.
, (2020/07/15)
We report a pyridyl-phosphine ruthenium(II) catalyzed tandem alcohol amination/Pictet-Spengler reaction sequence to synthesize tetrahydro-β-carbolines from an alcohol and tryptamine. Our conditions use a Lewis acid cocatalyst, In(OTf)3, that is compatible with typically base catalyzed amination and an acid catalyzed Pictet-Spengler cyclization. This method proceeds well with benzylic alcohols, heterocyclic carbinols, and aliphatic alcohols. We also show how combining this reaction with a subsequent cycloamination enables a direct synthesis of tetracyclic alkaloids like harmicine.
Synthesis and Investigation of Tetrahydro-β-carboline Derivatives as Inhibitors of the Breast Cancer Resistance Protein (ABCG2)
Spindler, Anna,Stefan, Katja,Wiese, Michael
, p. 6121 - 6135 (2016/07/26)
The breast cancer resistance protein (ABCG2) transports chemotherapeutic drugs out of cells, which makes it a major player in mediating multidrug resistance (MDR) of cancer cells. To overcome this mechanism, inhibitors of ABCG2 can be used. Only a few potent and selective ABCG2 inhibitors have been discovered, i.e., fumitremorgin C (FTC), Ko143, and the alkaloid harmine, which contain a tetrahydro-β-carboline or β-carboline backbone, respectively. However, toxicity and or instability prevent their use in vivo. Therefore, there is a need for further potent inhibitors. We synthesized and pharmacologically investigated 37 tetrahydro-β-carboline derivatives. The inhibitory activity of two compounds (51, 52) is comparable to that of Ko143, and they are selective for ABCG2 over ABCB1. Furthermore, they are able to reverse the ABCG2-mediated resistance toward SN-38 and inhibit the ATPase activity. The cytotoxicity data show that their inhibitory effect is substantially higher than their toxicity.
