On November 23, 2022, Beijing time, the research team of Xia Chengfeng of Yunnan University published a research result entitled “Deprotection of benzyl-derived groups via photochemically mesolytic cleavage of C−N and C−O bonds” in the journal Chem.
This achievement reports for the first time the strategy of removing benzyl protecting groups by chemical reduction of visible light excited state, which will help solve the long-term problem of deprotection in the process of chemical synthesis and drug synthesis, and has a wide application potential.
The corresponding author of the paper is Xia Chengfeng; The first authors are Liang Kangjiang and Li Xipan.
Protecting groups play an important role in synthetic chemistry to ensure that various reactions are carried out in a chemically selective, regional, and stereoselective manner. Due to their ease of introduction and good tolerance, benzyl groups and their derivatives are often used as protective groups of functional groups such as hydroxyl, amine and carboxyl groups in chemical synthesis and drug synthesis. Benzyl protectors generally need to be reduced with hydrogen under transition metal catalysis during removal, but some catalytically hydrogenated sensitive groups, such as alkenyls, limit the scope of application of this protective group, and heavy metal residues caused by transition metal catalysts further limit their application in pharmaceutical processes (Figure 1). Because hydrogen is flammable and explosive, and many hydrogenation reactions require high temperature and high pressure conditions, there are serious safety problems in experimental research and industrial production. More importantly, catalytic hydrogenation cannot effectively remove benzyl protective groups attached to amide groups, and although Birch reduction can be used as an alternative, it requires the use of dangerous metal reagents such as lithium and sodium in low temperature and liquid ammonia solutions, and also has functional compatibility problems. Therefore, it is of great theoretical and practical value to realize the efficient removal of protection groups through the visible light excited state reduction strategy.
Figure 1: Benzyl detachment reaction
(a) Transition metal catalytic hydrogenation and Birch metal reduction and removal methods. (b) Visible light excitation, electron transfer and free radical fragmentation to remove benzyl groups. (c) The benzyl substituent effect regulates the reduction potential difference of the benzene ring.
In response to this scientific problem, Xia Chengfeng’s team at Yunnan University found that although the reduction potential difference of the benzene ring is very low, when it contains a nitrogen or oxygen functional group in the benzyl position, its reduction potential will be slightly increased. The team is based on a new visible light catalyst with super reducing ability developed in the early stageDBPP(Chemical Science 2020, 11, 6996 – 7002), the strategy of electron transfer is proposed to inject an electron into the benzyl ring by injecting an electron into the benzyl ring through the strong reduction formed by the electron transition under the excitation of a visible light catalyst, and then achieving the purpose of benzyl removal by carbon-nitrogen bonds or carbon-oxygen bond fragmentation through the generated free radical anion (Figure 1). The researchers systematically optimized the reaction conditions, and the results showed that under blue light irradiation, the results were used toDBPPAs a photocatalyst, combined with mercaptans as hydrogen transfer catalysts, efficient removal of benzyl groups on amide was achieved at room temperature with near-equivalent yields through a double catalytic cycle with formate as the terminal reducing agent, and the only by-product of the reaction was the release of an equivalent amount of carbon dioxide (Figure 2).
Figure 2: Model reaction and mechanism
This method is not only suitable for benzyl groups attached to amides, but also achieves high-yield removal of benzyl ethers on hydroxyl groups, benzyl esters on carboxyl groups, and benzylamine on amino groups (Figure 3). The reaction also has good functional group compatibility, such as esters, cyanogroups and acetals, and even unprotected hydroxyl, amino and carboxyl groups will not interfere with the normal progress of the reaction. At the same time, various cyclic benzylamides and benzyl quaternary ammonium salts can be used as receptors for reactions to efficiently obtain deprotection products. In addition, the advantages of this method are reflected in the compatibility with other benzyl-derived protection groups. For example, in the reaction of interest, protective groups such as benzyloxycarbonyl (Cbz), methoxybenzyl (PMB), para-phenylbenzyl, benzoxymethyl (BOM), 1-naphthylmethyl, benzylidene, and diphenylmethylene can be removed in an efficient manner.
Figure 3: Partial substrate range
(a) Substrate range of benzylamide, ether, amine. (b) Other benzyl-derived protection groups.
Further studies have found that the photochemical benzyl removal reaction has good chemical selectivity, very good compatibility with alkenyl groups and other benzene rings in the molecule, and the same substrate cannot achieve selective removal of benzyl groups under traditional transition metal catalytic hydrogenation and Birch reduction conditions (Figure 4). At the same time, the method uses the benzyl group protection groups at different sites in the same molecule to have different reduction potentials, which can realize the hierarchical removal of such protection groups with good regional selectivity. In addition, the paper also carried out efficient orthogonal detachment of benzyl groups in a variety of sugars, peptides, drug molecules and natural products, showing the wide application range of the photochemical benzyl removal reaction, large-scale scale-up experimental research and mild reaction conditions, showing the application prospect of this method in chemical and pharmaceutical research and production.
Figure 4: Synthetic applications of photochemical benzyl removal reactions
(a) Chemical selectivity studies. (b) Regional selectivity studies. (c) Selective removal of benzyl groups in sugar molecules. (d) Selective removal of benzyl groups in peptide molecules. (e) Selective removal of benzyl groups in drug and natural product molecules. (f) Large-scale reaction experiments.
In this study, the orthogonal removal of benzyl protective groups is realized under mild conditions through the visible light excited state reduction strategy, without the use of flammable and explosive dangerous reagents such as hydrogen and alkali metals, which provides a new method to solve the problem of selective deprotection in the process of chemical synthesis and drug synthesis. This work was supported by the National Natural Science Foundation of China ( 21871228 and 22101251 ) and the Innovation Team of the Ministry of Education (IRT?17R94). (Source: Science Network)
Related paper information:https://doi.org/10.1016/j.chempr.2022.11.001