Yang Xiaoyu group of Shanghai University of science and technology: kinetic resolution of 2-aminobenzyl alcohol catalyzed by chiral phosphoric acid asymmetric synthesis of 4h-3,1-benzoxazine

Introduction 4h-3,1-benzoxazine is a kind of benzo-6-membered heterocyclic compound containing nitrogen and oxygen, which widely exists in small molecule drugs and pesticides with physiological activities For example, etifoxine, a 2-amino-4h-3,1-benzoxazine compound, is a famous GABA receptor inhibitor, which is widely used in the treatment of anxiety and anticonvulsion However, there are few asymmetric catalytic methods for the 4-position chirality of these heterocyclic compounds, and all of them have some substrate limitations, which can not achieve the general asymmetric synthesis of these heterocyclic compounds Recently, Yang Xiaoyu's research group of Shanghai University of science and technology reported that the asymmetric synthesis of 4h-3,1-benzoxazine was realized by using chiral phosphoric acid as catalyst for the high-efficiency kinetic resolution of 2-aminobenzyl alcohol This method has a wide range of substrate applicability and can be compatible with various tertiary alcohol and secondary alcohol substrates The relevant results were published online in angew Chem Int ed (DOI: 10.1002 / anie 201913896) 。
Prof Yang Xiaoyu, assistant professor of material science and technology, Shanghai University of science and technology, doctoral supervisor In 2007, he received his bachelor's degree from the school of chemistry and chemical engineering of Nanjing University; in 2012, he received his doctor's degree in organic chemistry from Shanghai Institute of Organic Chemistry (Tutor: researcher Yu Biao); in 2013-2016, he engaged in postdoctoral research in the University of California, Berkeley and Lawrence Berkeley National Laboratory, with the research direction of asymmetric catalysis methodology and chemical biology as the cooperative tutor It's Professor Dean toste Since June 2016, Yang Xiaoyu has joined the school of material science and technology of Shanghai University of science and technology as an assistant professor, researcher and project leader Professor Yang Xiaoyu has won the honor of the 13th batch of National Youth Talents Program and Shanghai Pujiang Talents Program At present, the research direction of the research group includes asymmetric catalysis, sugar chemistry, etc The homepage of the research group: http://spst.shanghaitech.edu.cn/2018/0301/c2349a17316/page.htm https:// Xiaoyu project portfolio front research results: chiral phosphoric acid catalyzed 2-aminobenzyl alcohol kinetic resolution asymmetric synthesis 4h-3, The research group of Professor Yang Xiaoyu, Shanghai University of science and technology, 1-benzoxazine, recently devoted to the novel asymmetric catalytic reaction of aminoallyl alcohol substrate using chiral br ø nsted Acid Catalyst In 2018, the research group realized the regioselective and asymmetric addition reaction of indole to cyclic 2-aminoallyl alcohol (Fig 1a, angelw Chem Int ed 2018, 57, 13489) The reaction belongs to dynamic kinetic asymmetric conversion (DYKAT), in which the 2-aminoallyl cation matched by chiral anion is the key intermediate At the beginning of this year, the research group realized the high-efficiency kinetic resolution of acyclic 2-aminoallyl TERT alcohol through the molecular lactone exchange reaction catalyzed by chiral phosphoric acid, and realized the asymmetric synthesis of chiral oxazolidone products (Fig 1b, angel Chem Int ed 2019, 58, 10315) Figure 1 Previous achievements of the research group (source: angelw Chem Int ed.) recently, Yang Xiaoyu reported that the efficient kinetic resolution of 2-aminobenzyl alcohol (a special class of "3-aminoallyl alcohol") was realized by using chiral phosphoric acid catalyst, and the efficient synthesis of 4h-3,1-benzoxazine heterocycle was realized (Figure 2) It was found that 4h-3,1-benzoxazine could be produced by intramolecular dehydration of 2-aminobenzyl alcohol under the catalysis of chiral phosphoric acid when the amino group was protected by acyl group In this reaction, 3,3 '- Triphenylsilyl substituted chiral phosphoric acid catalyst (cat a) can achieve high-efficiency kinetic resolution of the substrate, and obtain the raw materials of chiral benzyl alcohol and benzoxazine products with high enantioselectivity The reaction has a wide range of substrate applications, all kinds of aryl / methyl, and phenyl / alkyldisubstituted tertiary alcohols can get good kinetic resolution; the acyl group on 2-amino group can also be compatible with various benzoyl, heteroarylformyl and alkanoyl groups; finally, the substitution on the benzene ring of benzyl alcohol substrate has good applicability Fig 2.4 efficient synthesis of h-3,1-benzoxazine heterocycle (source: angelw Chem Int ed.) the author also further extended the reaction to the secondary benzyl alcohol substrate through catalyst optimization for the construction of 4-position benzoxazine product containing chiral tertiary carbon center The 4-position substituent can be compatible with both aryl and alkyl groups (Fig 3) Fig 3 Construction of benzoxazine product containing chiral tertiary carbon center at 4-position (source: angelw Chem Int ed.) There are many possible mechanisms of this reaction, for example, the chiral phosphoric acid catalyst can selectively activate benzyl alcohol of one configuration to form carbocation or o-methylene quinoline imine to realize kinetic resolution, and then realize cyclization under the action of chiral phosphoric acid; or the hydroxy alcohol of one configuration can selectively attack amide as a nucleophilic reagent to achieve dynamic resolution, and then dehydrate Reaction products In order to reveal the mechanism of the reaction, the author has carried out an experimental study on the mechanism The author uses the chiral benzyl alcohol as the raw material, under the action of the non chiral phosphoric acid catalyst, to obtain the benzoxazine product with the configuration maintained by enantioselectivity The experiment shows that the chirality of the reaction is controlled by the substrate rather than the catalyst (FIG 4A) The author also labeled the oxygen atom in the amide of racemic raw material with O 18 Under the standard experimental conditions, the author observed that the o 18 mark in the recovered raw material remained, while the o 18 mark in the product disappeared completely, which means that the oxygen of H 2O eliminated in the reaction comes from the amide (Fig 4b) In combination with the above two experiments, the author proposed a new mechanism different from the previous synthesis of oxazole products: in the previous literature, amides were used as nucleophiles to attack a "chiral electrophilic reagent" In this reaction, the chiral phosphoric acid catalyst can activate the alcohol hydroxyl and amide simultaneously through the double hydrogen bond, and selectively induce a configuration of alcohol to amide to realize the addition to form the intermediate int a of orthoester, and then the intermediate continues to dehydrate to generate 4h-3,1-benzoxazine product (Fig 4C) Figure 4 Mechanism experimental study and reasonable reaction mechanism (source: angel Chem Int ed.) the author finally proved that the chiral raw materials and products obtained in this reaction can be used as useful chiral synthesis blocks for the rapid and efficient construction of a series of chiral heterocyclic compounds through a series of product conversion reactions (figure 5) Fig 5 Construction of chiral heterocyclic compounds (source: angelw Chem Int ed.) Summary: Yang Xiaoyu's research team reported a novel kinetic resolution method for 2-aminobenzyl alcohol through the intramolecular dehydration reaction catalyzed by chiral phosphoric acid, which realized the efficient asymmetric synthesis of 4h-3,1-benzoxazine This method has a wide range of substrate applicability, suitable for all kinds of tertiary alcohol, secondary alcohol substrates and various substituents compatible with benzoxazine 2-position, and the highest kinetic resolution selectivity factor can reach 94 A novel reaction mechanism for the formation of 1,3-oxazole structure has been revealed through mechanism experiments In this reaction, amide group is used as "electrophilic reagent" instead of "nucleophilic reagent" widely reported in previous literature Gram scale reactions and the convenient conversion of chiral products into various chiral heterocyclic derivatives have proved the potential of this reaction in the synthesis of chiral heterocyclic drugs Dr Rajkumar, a postdoctoral student of Yang Xiaoyu's research group, and Tang Mengyao, a postgraduate student, are the co authors of this paper This work was supported by the "Youth Program" of the thousand talents program, the National Natural Science Foundation of China and Shanghai University of science and technology Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.