Acc. chem. Res.: asymmetric catalytic reactions involving p-chiral phosphine ligands based on the structural units of 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran

Chiral phosphine ligands play an important role in asymmetric synthesis catalyzed by different transition metals However, since Knowles developed camp and dipamp ligands for rhodium catalyzed asymmetric hydrogenation in the early 1970s, the development of p-chiral phosphine ligands has been very slow Until the late 1990s, with the emergence of BISP *, tangphos and other ligands, the development of p-chiral phosphine ligands received more and more attention Until now, many chiral phosphine ligands have been developed by organic synthesis chemists, which have made a breakthrough contribution to asymmetric catalysis However, most p-chiral phosphine ligands are difficult to prepare, inconvenient to operate or poor in reactivity and selectivity, which results in their limited application Only a few ligands are available, such as dipamp, BISP *, tangphos, duanphos and quinoxp * (Figure 1) Therefore, the search for novel, efficient and practical chiral phosphine ligands has always been the focus of organic synthesis chemists (photo source: acc chem Res.) in view of the fact that most p-chiral phosphine ligands are sensitive to air and have poor reactivity and selectivity in asymmetric catalysis, it is necessary to design p-chiral ligand framework suitable for various reactions of diphosphones and monophosphones Recently, Tang Wenjun, research group of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, reported the synthesis of p-chiral diphosphones and monophosphones based on 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran structural units and their application in the synthesis of chiral natural products and drugs The results were published in acc chem Res (DOI: 10.1021 / accounts Accounts 9b00029) First of all, the synthetic route of 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran framework has been explored repeatedly Finally, the author chooses tert butyl phosphine dichloride (5) as the starting material (Figure 3) After lithium treated with 1,3-dimethoxybenzene, water and formaldehyde, it can be converted into compound 6 in 80% yield by "one pot method" 6 was converted to compound 4 in 88% yield after methoxyl deprotection, formation of methanesulfonate and ring closing reaction in alkaline condition Finally, the optical pure compound (R) - 4, i.e 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran, was obtained in 42% yield (photo source: acc chem Res.) next, the author synthesized many p-chiral diphosphone ligands by modifying the two sites of the skeleton, such as Bibop (L2), wingphos (L4), chiral diphosphonic indole ligand (L5) and IPR babibop (L7) Among them, Bibop (L2) is stable to air and is an excellent ligand for rhodium catalyzed asymmetric hydrogenation of (E) - β - aryleneamide In this reaction, L2 provides an excellent C2 symmetric chiral environment, which can generate chiral α - and β - amino acids, chiral amines and carboxylic acid derivatives (Figure 4) with excellent enantioselectivity and high tons Then, the ligand meo-bibop (L3) was obtained by introducing two electron donating substituents (methoxy) at the 4-position It can be used for asymmetric hydrogenation catalyzed by rhodium, asymmetric propynylation catalyzed by copper and asymmetric reduction catalyzed by ruthenium (photo source: acc chem Res.) the author obtained wingphos (L4) by introducing two 9-anthracene groups into r-bibop RH wingphos complex is a kind of high efficient catalyst, which can be used in RH catalyzed asymmetric hydrogenation (Figure 7) and Rh catalyzed addition reactions, as well as the efficient synthesis of various chiral β - arylamines and chiral diaryl alkylcarbinol It still has excellent enantioselectivity and high ton value under the condition of low catalyst loading Then, based on the reaction mechanism, we designed meo-pop (L8), a C 1-symmetric ligand, which is stable to air and easy to synthesize It is very effective for rhodium catalyzed asymmetric hydrogenation, and can obtain products with excellent enantioselectivity and high ton (photo source: acc chem Res.) compared with the chiral diphosphonic ligands, the development of chiral monophosphonic ligands is slow Therefore, based on the structure of 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran, we have synthesized a series of chiral biaryl monophosphones, which can be widely used in various asymmetric catalytic reactions due to their stable to air, alkali, high temperature and highly controllable properties (photo source: acc chem Res.) the author has synthesized many p-chiral monophosphonic ligands by substituting at the 4-position of the skeleton Because the rigid structure of the skeleton can effectively prevent the formation of other conformational isomers and the monophosphonic ligands are conducive to the metal transfer and reduction elimination process, antphos (rac-l15) (Figure 13), me-bi-dime（ L10), I pr-bi-dime (L11) and nitinphos (L17) are excellent ligands for Suzuki miyaara coupling reaction (photo source: acc chem Res.) the author used Bi dime (L9) for asymmetric borohydride and diborization The results showed that the corresponding martensite products (Figure 16) could be obtained by the reaction with excellent EE value, good regioselectivity and enantioselectivity (S) L12 can be obtained by modifying the 4-aryl structure of - bi-dime (L9) to pyrrole structure, and L12 can be used for palladium catalyzed asymmetric de aromatization and cyclization This reaction can obtain the multi ring skeleton containing chiral quaternary carbon center with excellent EE value and high yield, so it can be used for the synthesis of chiral natural products (photo source: acc chem Res.) the author used the anti Phos (L15), di-bidimen (L18), bi-dime (L9) ligands for the reduction coupling (Figure 17) catalyzed by nickel The reactions can all obtain chiral products with excellent yields and EE values Other research groups have also developed Chiral P, N-Ligands MEO boqphos (L20) and p-π ligands joshphos (L22) based on the framework of 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran, which can be used for IR catalyzed asymmetric hydrogenation and Rh catalyzed asymmetric nucleophilic addition, respectively (photo source: acc chem Res.) conclusion: the author has developed a series of chiral phosphine ligands based on the structural units of 2,3-dihydrobenzo [D] [1,3] phosphine heterodihydrofuran These ligands have the characteristics of stable chemical properties, simple and efficient preparation, which can be widely used in the synthesis of chiral natural products and drugs, greatly promoting the progress of asymmetric catalysis and synthesis of organic chemistry.