Angelw: asymmetric conjugation addition catalyzed by borane copper complex to construct chiral organoboron compounds

The asymmetric conjugation addition of α, β - unsaturated compounds catalyzed by organometallic reagents is one of the important methods for the construction of chiral C-C bonds In the past few decades, organometallic nucleophiles, such as Grignard reagent, organozinc reagent, organoaluminum reagent and Organozirconium reagent, which are sensitive to air and are unstable, have been commonly used However, their application in synthesis is limited by the shortcomings of using stoichiometry and being difficult to deal with Organoboron reagent, as an alternative reagent of organometallic reagent, has been widely concerned It has excellent functional compatibility, non-toxic, stability and easy to handle However, there are few examples of organoboron reagents used for asymmetric conjugation addition because of their relatively low reactivity Asymmetric conjugation addition of aryl compounds and alkenylboronic acid derivatives catalyzed by noble metals has been reported for a long time Recently, copper catalyzed asymmetric conjugation addition has been reported by researchers SP 2 - carbon is used as nucleophilic reagent in this reaction, which is compatible with aryl, alkenyl and dienylboron reagents (scheme1a, a) On the contrary, the asymmetric conjugation addition of alkylboron reagents is rarely reported Only one case of asymmetric conjugation addition of alkyl9-bbn catalyzed by copper by sawamura group (scheme 1a, a) 1,1-diborane can retain another C-B bond after being activated by catalyst, so it is often used for enantioselective C-C bond coupling reaction with various electrophilic reagents Since the first report of Shibata group, 1, A series of transition metal catalyzed reactions have been reported (scheme 1a, b): enantioselective Suzuki coupling of aryl and alkenyl halides, S N 2 'selective allylation, S N 2 substitution of propargylic electrophilic reagents, aldehydes, α- Enantioselective 1,2-addition of ketone ester and imine However, conjugated addition of 1,1-diborane has not been reported Recently, jaesook Yun, Professor of chengjunguan University, South Korea, reported the enantioselective conjugation addition of α, β - unsaturated carbonyl compounds by 1,1-diborane catalyzed by copper The chiral organic boron products can be converted into various forms The results were recently published in angelw Chem Int ed (DOI: 10.1002 / anie 201909712) (picture source: angelw Chem Int ed.) firstly, the author used diethyl phenylmethylene malonate 1A as the model substrate to investigate the conditions (Table 1) Through the optimization of ligand, catalyst ratio, temperature and other factors, the optimal reaction conditions were determined as follows: L4 was used as chiral ligand, the ratio of cuprous chloride to ligand was 1:2, and the reaction was carried out in tetrahydrofuran at 60 ℃ for 24 hours In the process of optimization, it is found that the heterocyclic carbene ligands have strong coordination with copper, and they are a kind of dominant ligands in this reaction (image source: angelw Chem Int ed.) later, the author investigated the range of substrates (Table 2) Many functional groups can be compatible, including fluorine, bromine, cyano, trifluoromethyl, ether and heterocycles At the same time, the site selectivity (1,4-addition vs 1,6-addition) was also investigated It can be seen from the products 3q and 3R that the reactions are all 1,4-addition products Finally, the amount of catalyst was reduced to 2.5 mol% and a gram scale experiment (3a) was carried out (image source: angelw Chem Int ed.) next, the author examined the non enantioselectivity of substrate 1s and 1s' in the reaction (scheme2) The product 3S was obtained with good yield and excellent enantioselectivity in 1s, while the product 3S' was obtained with substrate control in 1s' The reason is that the enantiomers of the chiral boranyl copper species are inhibited due to the steric hindrance between the copper catalyst and the OTBs group when they are close to the re surface of β - carbon Finally, the enantioselectivity of the product can be completely maintained (scheme 3) The chiral γ - lactone 4 can be obtained by intramolecular transesterification of product 3a, compounds 5 and 6 can be obtained by alkenylation and heteroarylation, and the key intermediate 8 of antianxiety drug (s) - phenibut can be obtained by amination after decarboxylation of product 3a Summary: jaesookyun group has developed copper catalyzed enantioselective conjugation addition of 1,1-diborane to α, β - unsaturated esters In this method, the background reaction is suppressed by using the chiral azacyclic carbene reaction, and a new kind of chiral alkylboron compound is provided Moreover, the obtained chiral organoboron compounds can be transformed in many ways.