Xinyuan Liu’s Research Group Successively Publishes Five Top-Level Papers in the Field of Radical Chemistry

Research

| 05/31/2017

Fig. 1 Cover Picture of ACIE highlighting SUSTech and Shenzhen City

The radical-mediated 1,2-difunctionalization of alkenes has evolved into an efficient tool for the preparation of complex organic molecules. Although great endeavors have been devoted to various radical difunctionalization of alkenes in the past decades, the development of catalytic asymmetric methods has proven a formidable challenge, largely because of the intrinsic reactivity of the involved odd electron species. Recently, Xin-Yuan Liu and co-workers from department of chemistry of SUSTech have made significant progress in the field of radical asymmetric chemistry. They have published five top-level papers in Nat. Commun., J. Am. Chem. Soc. (JACS) and Angew. Chem. Int. Ed. (ACIE). More importantly, one of their papers in ACIE is selected as a cover, wherein the element of SUSTech and Shenzhen City are highlighted.

Recently, Liu’s group developed a novel asymmetric radical aminotrifluoromethylation of alkenes for the first time, providing straightforward access to densely functionalized CF₃-containing azaheterocycles bearing an α-tertiary stereocenter with excellent enantioselectivity. The key to success is not only the introduction of a Cu(I)/chiral phosphoric acid dual-catalytic system but also the use of urea with two acidic N−H as both the nucleophile and directing group. The utility of this method is illustrated by facile transformations of the products into other important compounds useful in organic synthesis and medicinal chemistry. This work was published in J. Am. Chem. Soc. 2016, 138, 9357 and highlighted by “Synfacts 2016, 12, 86” and “Chin. J. Org. Chem. 2016, 36, 2247”.

Fig. 2 Asymmetric Radical Aminotrifluoromethylation

Afterward, Liu’s group reported a catalytic asymmetric radical aminofluoroalkylation of alkenes to versatile enantioenriched-fluoroalkyl amines with commercially available fluoroalkylsulfonyl chlorides as the radical sources. The key to success is not only the introduction of the CuBr/chiral phosphoric acid dual-catalytic system but also the use of silver carbonate to suppress strong background and side hydroamination reactions caused by a stoichiometric amount of the in situ generated HCl. Broad substrate scope, excellent functional group tolerance and versatile functionalization of the products make this approach very practical and attractive. This paper was published in Nat. Commun. 2017, 8, 14841.

Fig. 3 Asymmetric Radical Aminofluoroalkylation

Meanwhile, Liu’s group reported a conceptually novel strategy with achiral pyridine as the ancillary ligand to stabilize high-valent copper species for the first challenging asymmetric radical oxytrifluoromethylation of alkenols under Cu(I)/phosphoric acid dual-catalysis. The transformation features mild reaction conditions, a remarkably broad substrate scope and excellent functional group tolerance, offering an efficient approach to wide range of trifluoromethyl-substituted tetrahydrofurans bearing an α-tertiary stereocenter with excellent enantioselectivity. Mechanistic studies support the presumed role of the achiral pyridine as a coordinative ligand on copper metal to stabilize the key transient reaction species involved in the asymmetric induction process. The result was published in Angew. Chem. Int. Ed. (2017, DOI: 10.1002/anie.201702925). Due to the high novelty and its application in asymmetric radical synthesis, this work is selected for the cover of ACIE as shown in Fig. 1.

Fig. 4 Asymmetric Radical Oxytrifluoromethylation

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavorable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. Liu’ group recently reported a radical aryl migration-enabled skeletal reorganization strategy for diversity-oriented synthesis of such challenging and useful medium-sized structural motifs. They rationally design alkenyl alcohols 1 bearing cyclic benzyl alcohol groups. The in situ generated radicals attack the alkene selectively to generate alkyl radial A, which would undergo remote radical aryl migration/ring expansion sequence to provide the relatively stable ketyl radical C. The SET oxidation of intermediate C would afford the expected medium-sized ring. Demonstration of this method as a highly flexible tool for the construction of synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Due to its potential application in synthesis of medium-sized rings, this work was published on Nat. Commun. 2016, 7, 13852.

Fig. 5 Radical Aryl Migration for Assembly of Medium/Macro– or Bridged-Rings

Based on the previous work, Liu and co-workers also design alkenyl cyclic ketones and utilize diverse radicals to trigger the remote carbonyl migration process to afford the synthetically challenging benzannulated medium-sized ring scaffolds. Different types of ring systems including complex 6-5(6,7)-6(5) fused rings and bridged rings can be obtaind from the obtained medium-sized scaffolds via further transformation. Meanwhile, they also realize the first radical olefinic 1,2-difunctionalization-type formylation via a 1,2-, 1,4- or 1,5-formyl radical migration triggered by addition of diverse radicals to unactivated alkenes, to afford synthetically valuable β-functionalized aldehydes. These important findings were published in Angew. Chem. Int. Ed. 2016, 55, 15100.

Fig. 6 Radical Strategy for 1,2-Formyl/carbonyl-Functionalization of Alkenes

Since joining SUSTech, Xin-Yuan Liu and his coworkers have published more than 40 papers in high-level international journals, including Nat. Commun. (3), JACS (4) and ACIE (8), etc. All of studies are financially supported by the National Natural Science Foundation of China, National Key Basic Research Program of China (973 Program), Shenzhen Scientific Innovation Commission and especially from the SUSTech President Foundation. They also greatly appreciate the colleagues of the Department of Propaganda of SUSTech for designing the cover picture.