JACS: the Morken research group of Boston University realizes the cross coupling of non enantioselective and enantioselective conjugation through the design of boron ligands

The stereocenter of diphenylmethyl with certain structure is an important structural fragment, which widely exists in natural products and drug molecules At present, researchers have developed a variety of catalytic methods to construct it, such as benzyl cross coupling, but when the benzyl stereocenter is located near other stereocenters, there will be additional challenges James P Morken group of Boston University has developed a catalytic cross coupling reaction in the early stage, which transforms the vinyl boron complex and electrophilic reagent into a pure secondary or tertiary alkyl borate (scheme 1, 1) with a stereocenter Recently, the team has designed and implemented scheme 1, 2 through boron ligands, and published the related results on j.am Chem SOC (DOI: 10.1021 / JACS 8b09909) (photo source: J am Chem SOC.) first, the author used β - substituted alkenyl borates for conjugated cross coupling When the vinylb (NEO) derived complex 1A was conjugated and cross coupled, the yield of the product 2a was 84% (scheme 1, 3); when 1A was replaced by 1b, the yield was only 13% The above different results can be explained by competitive catalytic reaction: metal induced metallization rearrangement is carried out by metal olefin combination (scheme 1, a), and then r m migration and C-Pd bond formation are carried out simultaneously in C β In contrast, the direct Suzuki miyaara reaction may be carried out by PD olefin coordination (scheme 1, b) or the combination of PD and oxygen atom of borate ester (scheme 1, c) In order to study the effect of boron ligands on the chemical selectivity of the coupling reaction, a series of styrylboric ester complexes were coupled (Table 1) When the steric resistance of the boron center of the ligand is small, sukuzi miyaara product is mainly generated; however, when the steric resistance of the boron center of the ligand is large, the proportion of conjugated cross coupling product (C3) increases; when the steric resistance of the boron center of the ligand is further increased, the chemical selectivity of the product is initially affected In consideration of the above results, the ligands were screened and it was found that the ligand L8 (MAC) could give good yield and enantioselectivity In addition, when CSF was added into the reaction and the substrate reacted at 40 ℃, 76% of the separation yield, > 20:1dr and 99:1er were obtained (photo source: J am Chem SOC.) the author used acenaphthene quinone to carbonyl in the condition of Al (me) 3 / toluene to obtain scheme 2A Then boric acid was converted into B (MAC) ester by esterification under the catalysis of FeCl3 Compared with the common borate ligands, when B (MAC) derivatives are converted into tetra coordinated derivatives, stereoisomerism will occur, and the selectivity and catalytic coupling reactions will be complicated In order to study its properties, the author added Phli to thf-d 8 solution of n-butylb (MAC) at room temperature, and through 1H NMR analysis, it was found that the kinetic addition product was generated by the CIS addition of nucleophiles to o-methyl (scheme2b) The experimental results show that the non enantiomeric boron complexes can be transformed into each other in the reaction, and their configuration may not affect the conjugation (photo source: J am Chem SOC.) after obtaining B (MAC) derivatives, the author studied their properties by conjugation coupling reaction (Table 2) B (MAC) ester can react with electron rich and electron deficient electrophilic reagents, and the secondary alcohols obtained after oxidation have excellent enantioselectivity (> 20:1 DR) and enantioselectivity (98:2 ER) Due to the competitive Suzuki miyaara coupling, the yield of B (MAC) ester is reduced when it reacts with electron deficient electrophilic reagent, while the substrate containing heteroatom functional group is not affected In addition, the substrate containing the migration blocked alkenyl group has low enantioselectivity Kotf needs to be added to the reaction of bromides electrophilic reagent to reduce the inhibition of bromate, but the yield is still low In addition, we also found that the substrate with rich electron transport group can get higher yield than that without electron transport group Under the current conditions, the boron complexes containing alkyl migration groups do not participate in the conjugate coupling pathway, but get Suzuki miyaara coupling product The results of the study on the substituents on β - carbon of alkenylborate showed that both the electron rich and electron deficient aromatics and the alkyl containing aromatics could participate in the reaction The electron rich β - substituents can increase the conversion of the reaction, but also lead to the increase of Suzuki miyuara products (23, conjugation: Suzuki = 1:1); the substrate containing electron deficient β - substituents has less Suzuki miyaara reaction, but needs higher temperature for conjugation (24, conjugation: Suzuki = 4:1); the substrate containing β- Although the yield of alkyl substituted substrate is general, it has good selectivity (photo source: J am Chem SOC.) due to the poor solubility of B (MAC) derivatives, it is easy to separate corresponding alcohols (Table 2) after oxidation of coupling products In order to solve the other transformations of B (MAC) derivatives, the author carried out gram scale coupling reaction, obtained the secondary borate ester 26 and carried out the derivatization (scheme 3) After oxidation, alcohol 2B can be obtained with excellent yield and selectivity In addition, 26 can be directly aminated / BOC protected, and a single non enantiomeric carbamate 27 can be obtained in excellent yield Finally, 26 the first-order B (MAC) derivative 28 can be obtained by the modified Matteson homologation reaction (photo source: J am Chem SOC.) non enantioselective conjugate coupling can also be used for the synthesis of natural product obtusafuran (scheme 4) Previously, obtusafuran needed to be synthesized by five steps of enantioselective ketone reduction and cyclization, while trans-2-propylb (MAC) coupled with Phli and aryl bromine 29 could obtain 30 with excellent yield and stereoselectivity, and the target molecule could be obtained by oxidation, cyclization and deprotection (photo source: J am Chem SOC.) conclusion: James P Morken's research group has established a catalytic non enantioselective and enantioselective conjugate coupling method of β - substituted alkenylborates In this method, a borate ester ligand derived from acenaphthoquinone is used to control the reaction of alkenyl boron complexes, so that the reaction tends to the metal transfer pathway rather than the direct metal transfer pathway.