The Dalian Institute of Chemistry of the Chinese Academy of Sciences proposes a new strategy for constructing unnatural chiral cyclic monoterpenoids

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Recently, the team of researcher Chen Qing’an of the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences has made new progress in the construction of unnatural chiral ring monoterpenes. Based on the concept of bionic catalysis, the team efficiently synthesized a series of unnatural chiral monoterpenes and their derivatives by using a large-steric chiral azirocyclic carbine ligand using a low-cost Ni metal catalyst.

On August 18, 2022, the study was published in the journal Nature Catalysis under the title “Nickel-catalysed asymmetric heteroarylative cyclotelomerization of isoprene.” The first author of this work is Zhang Gong, a doctoral candidate at the Dalian Institute of Chemicals, Chinese Academy of Sciences; The corresponding author is Researcher Chen Qing’an.

Terpenoids are a class of natural products that are widely present in living organisms and have isoprene units, and because of their important physiological activities, the synthesis and transformation of terpenoids is one of the most important metabolic pathways in organisms. In biosynthesis, most of these thousands of terpenoids are derived from two C5 synthetic blocks: isoprenyl pyrophosphate (IPP) and dimethyl allenyl pyrophosphate (DMAPP). The two C5 units can be coupled to each other to form geranolate pyrophosphate (GPP) and then, enzymatically catalyzed, by cyclization, rearrangement or coupling reactions to generate a variety of open-chain or cyclic terpenoids. As one of the most representative terpenoids, monoterpenes and their derivatives have been widely used in pharmaceutical, cosmetic, agricultural and food industries. The more common monoterpenoids are geraniol, linalool, citronellol, camphor, menthol, etc., which have a decisive role in human daily life. However, due to the limited skeleton of the common natural ring monoterpenoids, the application of monoterpenoids in drug development and other aspects is limited.

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Figure 1: Schematic diagram of a machine learning workflow

As an inexpensive and readily available bulk chemical, the high value-added transformation of isoprene has always been the focus of academic and industrial attention, and it is theoretically an ideal precursor for the economic construction of monoterpenes on the plateau. However, due to the similar electronic effects and steric hindrance effects of isoprene conjugated double bonds, the regional selectivity and stereoselectivity of the reaction are difficult to control effectively. In addition, previous work has shown that the direct hydrogen functionalization of isoprene is easier to achieve than the nucleophilic dimer reaction, making the chemically selective regulation of the reaction more difficult. Current research on the synthesis of monoterpenes in isoprene is limited to reports of chiral non-cyclic monoterpenes. Heterocyclic compounds, such as purines and imidazoles, play an important role in drugs and natural products. Therefore, there is widespread commitment to the functionalization of these compounds. Among them, the transition metal-catalyzed C-H functionalization process has efficient atomic and step economy, and is at the forefront of research in the field of chemical catalysis today. Then, combining transition metal-catalyzed C-H bond activation with the diverse transformation of isoprene will be a very interesting and practical research area.

In this work, the team was inspired by the biosynthesis of monoterpenes to develop a novel nickel-catalyzed asymmetric heteroarylization cyclization catalytic system of isoprene. The catalytic system consisting of inexpensive metal nickel and chiral macrostatic carbene ligands enables a series of unnatural monoterpene derivatives with high yield, high regional selectivity and high stereoselectivity synthesis. Mechanism studies have shown that the reaction is first dipolymerized by isoprene itself under nickel catalysis to form a chiral ring monoterpene intermediate. Subsequently, nickel-catalyzed sp2 C-H bond alkylation was used to efficiently construct a series of unnatural cyclic monoterpene derivatives containing quaternary carbon chiral centers. In addition, when isoprene is replaced with longer chains of monoterpenes, sesquiterpenes, and diterpenoid analogues, the reaction is also well compatible, further demonstrating the universality of this reaction strategy. This strategy not only provides a new idea for the high value-added transformation of isoprene, but also has reference significance for the synthesis of unnatural chiral cyclic monoterpenoids.

Chen Qingan’s team has been committed to the development of different catalytic systems to achieve the catalytic conversion of bulk chemicals. In the preliminary work, the team developed the strategy of “metal regulation” to achieve isoprene hydrogen arylation, the strategy of “ligand regulation” to achieve hydrogen siliconylation, and the strategy of “additive regulation” to achieve hydrogen ammonization and hydrogen alkylation (Angew. Chem. Int. Ed.,2019;Chem. Sci.,2019;Chin. J. Catal.,2020;Angew. Chem. Int. Ed.,2020;Angew. Chem. Int. Ed.,2021;Angew. Chem. Int. Ed., 2022; ACS Catal., 2022; Trends in Chem., 2022) and other diversity transformations, in addition, isoprenol and its analogues have been studied, and the oxidative coupling of ketones to isoprenol and the rapid programmed synthesis of thiophene, dihydrothiophene and their derivatives have been realized through the strategy of “redox regulation” (Angew. Chem. Int. Ed.,2021;ACS Catal.,2021;Chin. J. Catal.,2021)。

The above research work has been funded by the National Natural Science Foundation of China and other projects. (Source: Science Network)

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