Angelw: copper catalyzed intermolecular stereo inversion coupling of α - aminobenzyl borate

In asymmetric synthesis, the construction of SP 3 carbon chiral center by coupling reaction is a kind of promising chemical transformation In most cases, chiral or racemic second-order alkyl electrophilic reagents can be coupled with non chiral metal reagents, and the construction of chiral centers can be realized through stereospecific or stereoscopic aggregation coupling reactions In addition to this method, stereospecific coupling with chiral metal reagents is another attractive method, especially in Suzuki miyaara coupling reaction, which has attracted a wide interest of Chemists (Figure 1a) This kind of reaction has the following advantages: 1) chiral organoboron compounds have a wide range of sources, which can be obtained by asymmetric hydroboration; 2) in this stereospecific reaction, it can be carried out by stereoinversion or stereoretention, so that the transformation from a single raw material to two enantiomers can be realized However, up to now, the development of this kind of reaction is limited to the palladium catalyzed process, and it can be used to construct three substituted chiral centers The construction of four substituted chiral centers by this way has not been reported (Figure 1) In 2016, Dumas group reported the intramolecular coupling reaction of α - [O - (bromobenzoyl) amino] benzylborate catalyzed by 2,2 、bipyridine copper (II) to construct 3-arylisoindolinone Although it is a kind of simple cyclization reaction, the substrate is easy to obtain and has strong practicability However, we found that racemization occurs when chiral substrates are used Recently, the michinori suginome group of Kyoto University, Japan, inspired by this process, further explored this practical reaction Through bipyridine copper system, the intermolecular stereo inversion coupling reaction of α - aminobenzyl borate was realized The reaction has good stereoscopic control ability, and most importantly, it can also be used to construct four substituted chiral centers Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201914864) (source: angelw Chem Int ed.) firstly, the author used (s) - α - [(o-bromobenzoyl) amino] benzyl borate 1A as template substrate for scheme 1 Through the optimization of the reaction conditions such as ligand, leaving group, solvent, temperature, reaction time and catalyst dosage, the author finally determined that the optimal conditions for the reaction were: copper chloride as metal salt, L9 as ligand, cesium carbonate as base, toluene / chloroform as mixed solvent, water as additive, reaction at 10 ℃ for 24 hours, and finally 96% yield and 89% ee It's worth the target product (source: angelw Chem Int ed.) after determining the optimal reaction conditions, the author then expanded the range of substrates (scheme2) Through the modification of the aryl group of the chiral center, the author found that: 1) when the aryl group has a power supply group, the reaction has a good chiral control ability; 2) when the aryl group has an electric absorption group, the ES value of the reaction is low; 3) when the aryl group has a substituent, the enantioselectivity of the reaction is high In addition, the reaction has poor chiral control ability when the benzoyl group has an electric absorption group on the aryl group (source: angelw Chem Int ed.) later, the author realized the construction of four substituted chiral centers (scheme 3) by further optimizing the reaction ligands It is noteworthy that this process is difficult to achieve in palladium catalyzed coupling reactions It is found that all the substrates can get the product with high yield and high es value It is worth mentioning that the alkyl group in the chiral center can be butyl or 2-phenylethyl besides methyl group (source: angelw Chem Int ed.) in order to illustrate the practicability of the reaction, the author then magnified the reaction (5.0 mmol), and finally obtained the product with 94% yield and 99% es value Finally, the author explored the mechanism of the reaction (scheme 6), and thought that the products were obtained through the process of transition metallization and oxidation addition, among which the coordination of amide to borate ester promoted the transition metallization process (source: angelw Chem Int ed.) because br ø nsted Acid can promote the chiral control in the similar palladium catalyzed process, the author then explored the role of BR ø nsted Acid additive (scheme 7), and finally found that phenol compounds do have a positive role in promoting the chiral control of the reaction (source: angelw Chem Int ed.) Summary: michinori suginome group realized the copper catalyzed Suzuki miyaara reaction, and synthesized a series of chiral isoindolones, including compounds with four substituted chiral centers Among them, the selection of ligands is very important for the success of the reaction.