JACS: Construction of cyclobutene by enantioselective [2 + 2] cycloaddition of alkyne and alkene Derivatives Catalyzed by cobalt

The functionalized cyclobutane and cyclobutene are a kind of important molecular skeleton, which widely exist in many natural products with biological activity and drug molecular structure (Figure 1a) They are also useful precursors for the synthesis of other organic compounds, such as cycloalkane derivatives, heterocyclic compounds, stereospecific 1,3-dienes and ligands in asymmetric catalysis At present, there have been a lot of reports on the synthesis of cyclobutane precursors with appropriate functional groups from simple and easily available materials, but there is still a large optimization space in the diversity of functional groups on the ring and stereoselectivity Among them, 3-substituted cyclobutene has great advantages in later transformation, including double bond transformation, substituent transformation and C-H bond activation (Figure 1b) The most direct way to synthesize cyclobutene is the enantioselective [2 + 2] cycloaddition reaction of alkyne and alkene derivatives Professor hilt reported the cycloaddition of alkynes to bicyclic alkenes or activated alkenes, and Professor ogoshi reported the cycloaddition of arylethene alkenes to alkynes The products were racemates Enantioselective [2 + 2] cycloaddition is rarely reported, and is limited to specific substrates, which usually requires alkenes with tension or activated alkynes (Figure 1c) Recently, Professor T v Rajan Babu of Ohio State University reported that cyclobutene was constructed by the enantioselective [2 + 2] cycloaddition reaction catalyzed by cobalt This method is suitable for a wide range of alkynes and olefin derivatives, and has a good application prospect Relevant research results were recently published on J am Chem SOC (DOI: 10.1021 / JACS 9b07885) (photo source: J am Chem SOC.) firstly, based on the previous research of the research group, the author used 4-octyne (4a), methyl acrylate (5a) or trifluoroethylacrylate (5b) as the model substrate for the condition investigation (Table 1) At the same time, the more active alkyne (8a) and methyl acrylate (5a) were also investigated In this paper, cobalt source, ligands, reducers, activators and solvents were investigated in detail Finally, it was determined that non coordination solvents, such as DCM, DCE or toluene, and nabarf, were selected as activators It can be seen from table 1 that the best result is given by the phox ligand (L9, figure 2) In Table 2, in addition to the target product, a certain amount of dimer (11a) and regional isomer (10a) will be generated Finally, by optimizing the ligands, we found that 98% yield, good regioselectivity (RR > 95:5) and enantioselectivity (94% ee) could be obtained by using L8 (photo source: J am Chem SOC.) later, the author investigated the range of substrates Firstly, the substrate range of cycloaddition of alkynes and alkene derivatives [2 + 2] was investigated (Figure 3) Simple symmetrical alkynes and asymmetric alkynes can give excellent results, and the reaction is also applicable to functional asymmetric alkynes Then the author investigated the substrate range of cycloaddition of 1,3-alkyne and alkene derivatives (Figure 5) It is found that (E) - 1-ALLYL substituent is the best substituent of alkyne substrate All kinds of alkylacrylates, functionalized alkenes, allyl derivatives, arylethenes and disubstituted alkenes are suitable alkene substrates Alkyne substrates including various alkyl, cycloalkenyl, aryl, halogen, amino and other substituents can also be compatible with the reaction (photo source: J Am Chem Soc.) next, the author proposed a possible catalytic cycle mode (Figure 7) Co catalyst produces CO (I) cation under the action of nabarf, which is coordinated by alkynes and alkenes to form an intermediate 17, which is then reduced to product 6 or 9 At the same time, the byproducts 7 and 14 were obtained when the intermediate 17 was eliminated by β - hydrogen (photo source: J am Chem SOC.) Summary: T.V Rajan Babu research group has developed a cobalt catalyzed enantioselective [2 + 2] cycloaddition reaction to construct cyclobutene, which is applicable to a wide range of alkyne and olefin derivatives This provides an efficient and convenient method for the synthesis of cyclobutane and cyclobutene with high enantioselectivity.