Professor Yu Dagang and Professor Lan Yu of Sichuan University reported the method of copper catalyzed highly selective functionalization of 1,3-diene and carbon dioxide to construct chiral quaternary carbon centers

All carbon quaternary carbon chiral centers are widely found in natural products and drug molecules However, it is still a challenge to construct all carbon quaternary carbon chiral centers with different functional groups In addition, most of the methods for the preparation of quaternary carbon chiral centers depend on the use of fine chemicals Therefore, it is still necessary to develop a method for the preparation of quaternary carbon chiral centers from cheap and easily available materials 1,3-diene has attracted much attention in organic synthesis because it is easy to obtain and has many activities Using electrophilic reagents (such as aldehydes, ketones, imines) or nucleophiles to functionalize 1,3-dienes with high efficiency and selectivity, researchers have developed a variety of catalytic systems to construct tertiary carbon chiral centers (Figure 1, left a) However, it is still challenging to generate chiral all carbon quaternary centers by functionalization of substituted 1,3-dienes, especially to generate non cyclic products (Figure 1, a right) At present, only krische group has realized the highly selective coupling of 1,3-diene and methanol catalyzed by IR through the hydrogen automatic transfer strategy, thus forming the quaternary carbon center (Figure 1, b) Recently, Professor Yu Dagang of Sichuan University and Professor Lan Yu of Chongqing University have reported for the first time the method of copper catalyzed highly selective functionalization of 1,3-diene and inert carbon dioxide to construct chiral all carbon quaternary centers in acyclic substrates A variety of easily obtained 1,1-disubstituted 1,3-diene can successfully carry out copper catalyzed reduction hydroxymethylation reaction, and the reaction has high chemical, regional, E / Z - and enantioselectivity (Figure 1, c) Relevant research results were published on J am Chem SOC (DOI: 10.1021 / JACS 9b09721) (source: J am Chem SOC.) at the beginning of the study, the author used (E) - 4 - (pent-2,4-diene-2-yl) - 1,1 '- biphenyl 1A as the model substrate, 5 mol% Cu (OAC) 2 as the pre catalyst, and me (MEO) 2sih as the hydride donor to screen the reaction conditions In a CO 2 atmosphere, the author first screened the commonly used chiral phosphine ligands The results showed that (s, s) - ph-bpe ligands had the best effect The required product 2A (Table 1, entries 1-7) was obtained in 74% yield and 96% ee value Changing other conditions such as solvent, silicon hydrogen source and copper catalyst can not further improve the activity of the reaction The control experiments showed that catalysts, ligands and silanes were all important in the reaction (entries 12-14) (source: J am Chem SOC.) after determining the best reaction conditions, the author investigated the substrate range of 1-aryl-1-methyl substituted 1,3-diene (Table 2) Dienes with donor or acceptor groups in the o -, M - and p-position of benzene ring can react smoothly, and the target product (2A - 2q) can be obtained with medium to good yield (53% - 82%) and medium to excellent enantioselectivity (up to 98% ee) Naphthyl (1s - 1R) and other heterocyclic substituted (1af - 1aj) dienes showed good reactivity In addition, 1,3-diene with polysubstituted benzene can also obtain the corresponding product (2t-2w), and has excellent enantioselectivity The yield of the product will not decrease when methyl is replaced with other groups with high steric hindrance, such as ethyl (1x - 1AA), n-butyl (1ab) and isobutyl (1Ac) (source: J am Chem SOC.) then, the author examined the application scope of 1,3-diene, which is more challenging, substituted by 1,1-dialkyl (Table 3) Under the standard reaction conditions, 1,1-dialkyl 1,3-diene 3 can be efficiently converted into the required enantiomer alcohol 4, and the enantioselectivity is good A variety of functional groups have good tolerance, such as fluorine, bromine, methoxy, trifluoromethyl, indolyl, cyclohexyl and so on (source: J am Chem SOC.) based on previous literature reports and DFT calculation results, the author speculated on a possible reaction mechanism (Figure 2) Firstly, the complex of Cu precatalyst and chiral phosphine ligand reacts with silane to form chiral L * cuh species I with catalytic activity Then, I and 1,3-diene 1C were added to form the chiral allyl copper intermediate II by highly regioselective and stereoselective 1,2-cis addition The nucleophilic addition of II to CO 2 may involve the transition state of 6 yuan ring and produce the copper carboxylate species III Silane can further reduce III to alkoxy copper Ⅳ Finally, the active catalyst I was regenerated by the σ bond decomposition of IV and silane In this process, methylsilyl ether V will also be produced, which will provide the required alcohol 2C after reacting with ammonium fluoride (source: J am Chem SOC.) conclusion: the author realized the highly selective and catalytic preparation of chiral all carbon quaternary carbon solid center by functionalization of carbon dioxide and 1,3-diene A variety of easily obtained 1,1-disubstituted 1,3-dienes can successfully carry out reductive hydroxymethylation reactions with high chemistry, region, E / Z and enantioselectivity These results are also the first example of asymmetric copper catalyzed conversion of 1,1-dialkyl substituted 1,3-diene to chiral all carbon quaternary centers This method has good functional group tolerance, simple expansibility and introduces a variety of functional groups The products can be further transformed to prepare valuable chiral structural units.