Electron-rich diphosphine ligands, preparation and use thereof

Abstract

This invention relates to the field of asymmetric hydrogenation technology, specifically disclosing an electron-rich chiral bisphosphine ligand, specifically L1 to L5, and disclosing the synthetic pathways of ligands L1 to L5 and the intermediate compounds 1 to 5 in the synthetic route. This invention uses L1 to L7 to complex with different transition metal precursors, such as [Rh(COD)2]BAr. F 4. A series of stable, simple-to-prepare, and low-cost catalysts were obtained, including [Rh(NBD)2]BF4, [Rh(NBD)Cl]2, Rh(acac)(CO)2, Rh(ethylene)2(acac), and [Rh(ethylene)2Cl]2. These catalysts can be used for asymmetric hydrogenation, especially in the asymmetric hydrogenation step of the N-Boc amino alcohol synthesis pathway, effectively overcoming the steric hindrance effect under different amino protecting group conditions. With the participation of this catalyst, the asymmetric hydrogenation step in the N-Boc amino alcohol synthesis pathway overcomes the technical defects of using hazardous materials in existing technologies, improving the production safety factor. Furthermore, with the participation of this catalyst, the asymmetric yield and selectivity both meet the requirements of industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical catalysts, specifically to an electron-rich chiral bisphosphine ligand, its preparation, and its application. Background Technology

[0002] Endogenous atrial natriuretic peptide (ANP) in mammals, also known as atrial natriuretic peptide (ANF), has diuretic, sodium-excreting, and vasodilatory functions. Natural ANF peptides are inactivated through metabolism, particularly by an enzyme believed to be equivalent to NEP that also causes metabolic inactivation of enkephalins.

[0003] Sacubitril (AHU-377) is one of the main components of LCZ696 (CAS: 936623-90-4), a heart failure drug developed by Novartis. This heart failure drug is a supramolecular complex (complex) formed by the non-covalent bonding of valsartan and sacubitril (AHU-377). It has dual effects of angiotensin receptor blocking and neutral endopeptidase inhibition, reducing the risk of cardiovascular disease. It is primarily used to treat heart failure and can also be used for hypertension.

[0004] Sabuvir (AHU-377) is typically prepared via a key intermediate, N-Boc amino alcohol [formula (10-a)], chemically named N-[(1R)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamate tert-butyl ester (CAS: 1426129-50-1); its structural formula is:

[0005]

[0006] There are many existing patent documents concerning the synthesis method of N-Boc amino alcohol, an intermediate of sacubitril. For example, patents WO 2013 / 026773 and CN 103764624 disclose a method for preparing sacubitril intermediate amino alcohol using p-phenylbenzaldehyde as a raw material. The key synthetic steps are as follows:

[0007]

[0008] This route offers a higher yield for the synthesis of compound 6a compared to currently reported routes. However, the process involves a large amount of asymmetric catalyst in the synthesis of compound 4a from compound 3a, leading to high costs. Furthermore, the use of lithium aluminum hydride to reduce the ester group and the protecting group Bz increases operational risks. Therefore, the preparation of the key chiral intermediate N-Boc amino alcohol (10-a) for sacubitril is limited by factors such as raw materials, reagents, and post-processing. Additionally, the long synthetic route, low diastereomer ratio, and environmental unfriendliness result in high production costs, cumbersome operations, and are not conducive to industrialization. Therefore, developing a simpler, more economical, and industrially feasible production route for the key chiral intermediate N-Boc amino alcohol (10-a) is of great significance. Summary of the Invention

[0009] In the existing synthesis pathways of N-Boc amino alcohols, there are inherent risks such as steric hindrance in asymmetric hydrogenation, low diastereomer ratios, environmental unfriendliness, and the use of unstable hazardous chemicals, which increase operational hazards and pose safety risks to relevant production personnel. Consequently, the production costs are high, the operation is cumbersome, and it is not conducive to industrialization. To address these issues, this invention proposes an electron-rich chiral bisphosphine ligand that can complex with various metal transition metal precursors to form metal complex catalysts for use in the asymmetric hydrogenation step.

[0010] The first aspect proposes an electron-rich chiral bisphosphine ligand with the structure of formula (Ⅰ).

[0011]

[0012] The asterisk (*) represents a chiral center.

[0013] Each of the multiple carbon chiral centers is independently either in the R configuration or the S configuration;

[0014] The -X1- is -(CH2). n - where n is selected from 1 to 5, preferably 1 to 3, particularly preferably 1, or, optionally -(CH2). n Any methylene unit in - is optionally and independently replaced by -NR5-, -O-, -S- and -C(O)-, wherein R5 is selected from H, alkyl, alkenyl, alkynyl or haloalkyl;

[0015] The R2 and R3, together with the atoms they are attached to, form substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or substituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl.

[0016] R4 is selected from substituted or unsubstituted alkyl groups;

[0017] Each of the plurality of R1s is independently selected from, substituted or unsubstituted straight-chain alkanes, substituted or unsubstituted branched alkanes, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, substituted or unsubstituted adamantyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic alkenyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylheteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroarylthio.

[0018] or,

[0019] The plurality of R1s together with the atoms to which they are connected form substituted or unsubstituted heterocyclic alkyl groups, substituted or unsubstituted heterocyclic alkenyl groups, substituted or substituted heteroaryl groups;

[0020] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from straight-chain alkanes containing 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1, 2 or 4 carbon atoms.

[0021] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from branched alkanes containing 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, and more preferably 3, 4, or 5 carbon atoms.

[0022] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from cycloalkyl groups, which comprise 1 to 10 carbon atoms. Preferably, it comprises 5 to 7 carbon atoms, and more preferably 6 carbon atoms.

[0023] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from aryl groups, including monocyclic aryl or fused-ring aryl groups.

[0024] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from sec-butyl and tert-butyl.

[0025] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from alkylaryl groups, wherein the alkylaryl group contains a monocyclic aryl group, and any hydrogen atom on the monocyclic aryl group is replaced by an alkyl group containing 3 to 5 carbon atoms.

[0026] In some specific embodiments of electron-rich chiral bisphosphine ligands, R1 is selected from straight-chain alkanes, branched alkanes, cycloalkyl, aryl, and alkylaryl. In specific embodiments of R1, the hydrogen of R1 may be arbitrarily substituted by R6, which is independently selected from alkoxy, aryloxy, n-butyl, sec-butyl, tert-butyl, halogen, nitro, cyano, and alkylyl groups each time it appears.

[0027] In some specific embodiments of electron-rich chiral bisphosphine ligands, the hydrogen on the ligand may be optionally replaced by D, up to complete deuteration.

[0028] In some specific embodiments of electron-rich chiral bisphosphine ligands, the ligands of formula (Ⅰ) are specifically L1 to L5, and the ligands L1 to L5 are specifically as follows:

[0029]

[0030] The second aspect of this invention provides a method for preparing a ligand, the method being used to prepare the ligand shown in the first aspect formula (Ⅰ), or the ligands shown in L1 to L5, comprising steps S1 to S4:

[0031]

[0032] In M1, X2 is selected from M1 specifically refers to

[0033] In M2, X2 is selected from M2 specifically refers to

[0034] In M3, X2 is selected from M3 specifically refers to

[0035] In M4, X2 is selected from M4 specifically refers to

[0036] In M5, X2 is selected from M5 specifically refers to

[0037] S1: NaBH4 was added in batches to the alcoholic solution of compound 2 to obtain compound 3;

[0038] S2: Br2 and PPh3 were added to the container one after another, and then dissolved with an organic solvent. The mixture was stirred, and the organic solvent of compound 3 was added dropwise to the solution. The mixture was stirred to obtain compound 4.

[0039] S3: The corresponding LiP(Ad)2, LiP(Ph)2, LiP(tBu)2, LiP(Cy)2 or LiP(DTBM)2 are mixed with compound 4 respectively, and then DMF is added to the reaction. After stirring, the corresponding M1 to M5 are obtained.

[0040] S4: M1 to M3 are independently mixed with P(NMe2)3 and heated to obtain the corresponding L1 to L3. Specifically, M1 is mixed with P(NMe2)3 alone and heated to obtain L1, M2 is mixed with P(NMe2)3 alone and heated to obtain L2, and M3 is mixed with P(NMe2)3 alone and heated to obtain L3.

[0041] Alternatively, M4 to M5 can be mixed independently with Si2Cl6 and heated to obtain the corresponding L4 to L5. Specifically, M4 can be mixed with Si2Cl6 alone and heated to obtain L4, and M5 can be mixed with Si2Cl6 alone and heated to obtain L5.

[0042] The third aspect of this invention provides a method for preparing a catalyst, wherein a complexation reaction occurs in an organic solvent involving a ligand of the formula (I) structure described in the first aspect and a transition metal precursor, both of which serve as substrates for the complexation reaction, and the complexation reaction yields a catalyst.

[0043] Alternatively, any one of the L1 to L5 ligands described in the first aspect participates in a complexation reaction in an organic solvent with a transition metal precursor, wherein any one of the L1 to L5 ligands described in the first aspect and the transition metal precursor serve as substrates for the complexation reaction, and a catalyst is obtained from the complexation reaction.

[0044] Alternatively, any ligand of structure L6 to L7 and a transition metal precursor participate in a complexation reaction occurring in an organic solvent, with any ligand of structure L6 to L7 and the transition metal precursor serving as the substrate for the complexation reaction, and the complexation reaction yields a catalyst.

[0045] In some specific embodiments of the catalyst preparation method proposed in the third aspect, the organic solvent is selected from a mixed solvent of DCM and THF.

[0046] In some specific embodiments of the catalyst preparation method proposed in the third aspect, the transition metal precursor is selected from [Rh(COD)2]BAr F 4.

[0047] [Rh(NBD)2]BF4, [Rh(NBD)2]X; [Rh(NBD)Cl]2; Rh(acac)(CO)2; [Rh(COD)Cl]2; Rh(ethylene)2(acac);

[0048] [Rh(ethylene)2Cl]2; [Rh(COD)2]X;

[0049] X is a negative anion, selected from any one of Cl-, Br-, I-, BF4-, ClO4-, SbF6-, PF6-, TfO-, RCOO-, or B(Ar)4-.

[0050] The fourth aspect of this invention provides a metal complex catalyst obtained by the preparation method of the third aspect.

[0051] The fifth aspect of this invention proposes the application of the metal complex catalyst described in the fourth aspect in asymmetric hydrogenation.

[0052] The sixth aspect of this invention is a method for preparing a sacubitril intermediate, characterized in that it comprises:

[0053]

[0054] The asterisk (*) indicates a chiral center, and the chiral carbon atom is either in the R or S configuration.

[0055] R7 is selected from any amino protecting group.

[0056] In some specific embodiments of the preparation method of sacubitril intermediates, R7 is selected from Cbz, Boc, Fmoc, Alloc, Teoc, Pht, Tfa, Trt, Dmb, and Bn.

[0057] In some specific embodiments of the preparation method of sacubitril intermediates, R7 is selected from alkyl acyl groups.

[0058] In some specific embodiments of the preparation method of sacrobitril intermediates, R7 is selected from aryl acyl groups.

[0059] In some specific embodiments of the preparation method of sacubitril intermediates, R7 is selected from... Any one.

[0060] A seventh aspect of the present invention provides an intermediate or a deuterated compound thereof, said intermediate having the structure described in formula (III):

[0061]

[0062] The asterisk (*) represents a chiral center, and each of the plurality of carbon chiral centers is independently either an R configuration or an S configuration;

[0063] The -X1- is -(CH2). n - where n is selected from 1 to 5, preferably 1 to 3, especially preferably 1, or -(CH2) nAny methylene unit in - is optionally and independently replaced by -NR5-, -O-, -S- and -C(O)-, wherein R5 is selected from H, alkyl, alkenyl, alkynyl or haloalkyl;

[0064] R2 and R3, together with the atoms they are attached to, form substituted or unsubstituted C5-C7 carbocyclic groups and 3-7 membered heterocyclic groups;

[0065] X2 is selected from hydroxyl, halogen, ... In any one of the three, a and b are each independently selected from any one of 1, 2, and 3;

[0066] Each of the plurality of R1s is independently selected from hydrogen, C1 to C2. 10 Straight-chain alkanes, C3-C 10 Branched alkanes, monocyclic aryl, fused-ring aryl, cycloalkyl, adamantyl, wherein the hydrogen on R1 is arbitrarily replaced by R8, wherein each occurrence of R8 is independently selected from alkoxy, sec-butyl, tert-butyl, halogen, nitro, cyano, alkylyl;

[0067] Abbreviation / Chemical Name / Structure Reference Table:

[0068] TMEDA N,N,N',N'-Tetramethylethylenediamine; CAS: 110-18-9 DMF N,N-Dimethylformamide; CAS: 68-12-2 THF Tetrahydrofuran; CAS: 109-99-9 <![CDATA[LiPAd2]]> CAS: 1073511-77-9 <![CDATA[LiPPh2]]> CAS: 55087-99-5 <![CDATA[LiP t Bu2]]> CAS: 2634722-52-2 <![CDATA[LiPCy2]]> CAS: 198079-96-8 <![CDATA[HPAr2 / HP(DTBM)2]]> CAS: 1173023-24-9 <![CDATA[Si2Cl6]]> Hexachlorosilane; CAS: 13465-77-5 <![CDATA[P(NMe2)3]]> Tris(dimethylamino)phosphine; CAS: 1608-26-0 Cbz benzyloxycarbonyl protecting group Boc tert-Butyloxycarbonyl protecting group Alloc allyloxycarbonyl protecting group Trt Triphenylmethyl protecting group Bn benzyl protecting group <![CDATA[HPPh2]]> CAS: 829-85-6 <![CDATA[HPCy2]]> CAS: 829-84-5 <![CDATA[HP t Bu2]]> CAS: 819-19-2 <![CDATA[HPAd2]]> CAS: 131211-27-3

[0069] The L1 structure is written as Where Ad represents the adamantyl group;

[0070] The L2 structure is written as Where Ph represents phenyl;

[0071] The L3 structure is written as Where tBu represents tert-butyl;

[0072] The L4 structure is written as Where Cy represents the cyclohexyl group;

[0073] The L5 structure is written as Where DTBM is

[0074] The L6 structure is as follows Represented as ZhangPhos;

[0075] The L7 structure is as follows: Represented as MeO-POP;

[0076] Terminology Explanation:

[0077] Unless otherwise specified, the "degree" in this invention refers to Celsius.

[0078] Unless otherwise specified at temperature and pressure, all weighings in this invention are performed under standard atmospheric pressure.

[0079] "Room temperature" refers to a temperature ranging from approximately 10°C to approximately 40°C. In some embodiments, "room temperature" refers to a temperature ranging from approximately 20°C to approximately 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0080] "Cycloalkyl" refers to a saturated monocyclic hydrocarbon group, the carbon ring may contain 3 to 20 carbon atoms, preferably 3 to 12 (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms, the cycloalkyl does not include cases where the carbon atoms are connected in an arrangement such as adamantyl alkyl.

[0081] "Aryl" refers to any C5-C26 carbon-based aromatic group, heteroaromatic group, fused heteroaromatic group, or fused heteroaromatic group. For example, "aryl" can include 5-, 6-, 7-, 8-, 9-, 10-, 14-, 18-, and 24-membered monocyclic aromatic groups, including but not limited to benzene. "Aryl" also encompasses polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings (i.e., "fused aromatic ring"), wherein at least one ring is aromatic, for example, the other ring or additional rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic.

[0082] "Alkoxy" and "aryloxy" refer to the formula -OR x The compound shown, wherein R x This includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, heteroaryl, polyaryl, polyheteroaryl, arylalkyl, heteroalkyl, alkylaryl, alkylheteroaryl, aralkyl, and carbonyl. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, etc.

[0083] "alkylaryl" refers to any hydrogen atom on the ring that is replaced by R. c Substituted aryl, wherein R c Only here can it be interpreted as saturated or unsaturated alkyl groups, saturated or unsaturated alkenes, saturated or unsaturated alkynes, R c When it is an alkane, the number of carbon atoms can range from 1 to 10, R c When it is an olefin or alkyne, the number of carbon atoms can be 3 to 6, more preferably 4 carbon atoms, exemplarily including m R c When they appear, each hydrogen atom on the benzene ring is substituted independently, and m is the hydrogen atom on the benzene ring that is replaced by R. c The number of substitutions, m, is selected from 1 to 5, further up to 2, and even further examples are... R c It is tert-butyl, m is 2, and the number of tert-butyl groups is 2;

[0084] "Arylalkyl" refers to any alkyl group in which hydrogen is replaced by R d Substituted alkyl groups, wherein R d Selected from monocyclic aryl or fused-ring aryl, exemplified by...

[0085] "Aryl acyl" indicates COR e R f OR - COR f The compound shown, wherein R e -(CH2) p - where p is selected from positive integers from 1 to 10, R f The optional component is a monocyclic aryl group, including 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 14-membered, 18-membered, and 24-membered monocyclic aromatic groups, including but not limited to benzene, R f It can also be a fused aryl group, which comprises a polycyclic system of two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is aromatic; for example, the other ring or additional rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclic. The aryl acyl group is exemplarily...

[0086] The reagents used in this invention are purchased from Sigma reagents, Aladdin reagents, Sinopharm reagents, and Xilong reagents. The purity can be any of AR, GR, or HPLC, and they have not undergone further purification.

[0087] "ee" indicates enantiomer excess, which in this invention, specifically in chiral synthesis, generates (a). The percentage content minus (b) The percentage content.

[0088] The catalyst cycle number is the number of times the catalyst is used until the yield (%) is less than 95% of the yield of the first catalytic reaction, or the number of times the catalyst is used until the enantiomeric excess ee% is less than 95% of the enantiomeric excess of the first catalytic reaction.

[0089] “S / C” represents the molar ratio of the reaction substrate to the catalyst.

[0090] The advantages of this invention are:

[0091] The various electron-rich chiral bisphosphine ligands prepared by this invention can complex with various transition metal precursors. The resulting catalyst can be used for the asymmetric hydrogenation step in the N-Boc amino alcohol synthesis pathway. The ligands exhibit strong complexation stability with transition metals, resulting in high catalyst yield. Furthermore, with a variety of transition metal precursors and ligands available, inexpensive raw materials can be used, reducing production costs.

[0092] The catalyst used in this invention has also been applied to reaction substrates constructed with various amino protecting groups, and has achieved high yields and selectivity. It exhibits high yields and selectivity under different amino protecting groups, has good adaptability to the structure of the reaction substrate, avoids steric hindrance effects, and has low activity decay after multiple cycles of use, reducing the workload of production personnel and decreasing the frequency of reactivation in production.

[0093] With the participation of the catalyst prepared by this ligand, the selectivity and yield of asymmetric hydrogenation in the N-Boc amino alcohol pathway meet the requirements of industrial production. This overcomes the drawbacks of existing technologies, such as being environmentally unfriendly, using unstable hazardous chemicals, increasing operational risks, posing safety risks to relevant production personnel, and resulting in cumbersome production operations, high costs, and being unfavorable for industrialization. Detailed Implementation

[0094] Through the detailed description of the embodiments of the present invention below, those skilled in the art will gain a clearer and more thorough understanding of the further features, advantages and effects of the present invention.

[0095] The technical solutions of the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0096] Example 1: Synthesis of Compound 2

[0097]

[0098] A magnetic stir bar was placed in a 250 mL Schlenk reaction flask. The flask was heated with an electric torch and then cooled under vacuum. Dry nitrogen was then introduced, and the evacuation was repeated three times. Under nitrogen protection, a mixed solution of 3.9 mL TMEDA and 45 mL diethyl ether was added, and the system was stirred at -78 °C for 10–15 minutes. 22.4 mL of sec-butyllithium (1.16 M, 26 mmol) was then added dropwise to the reaction system, and the mixture was stirred at -78 °C for 30 minutes. 5 g of reactant 1 (21.7 mmol) was dissolved in 32.5 mL of dry toluene and added dropwise to the reaction system using a syringe. The mixture was then stirred at this temperature for 5 hours. 8.4 mL of DMF was added to the reaction system, and the mixture was stirred for 5 minutes. The mixture was then heated to room temperature and stirred overnight. The reaction system was purified by saturated NH4Cl aqueous solution, followed by extraction with ether or ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The white solid product, compound 2, was separated by silica gel column chromatography, yielding 4.936 g (88% yield).

[0099] 1 H NMR (400MHz, CDCl3) δ9.64(d,J=3.7Hz,1H),2.70(ddd,J=12.6,9.2,3.7Hz,1H),2.60(ddd,J=14.9,6.9,1.6Hz,1H),2.32(qdd, J=11.6,3.5,1.7Hz,1H),2.03-1.89(m,2H),1.89-1.74(m,3H),1.65(s,1H),1.40-1.24(m,12H),1.05(qd,J=12.5,3.4Hz,1H).

[0100] 13 C NMR (101MHz, CDCl3) δ200.21, 54.91 (d, J = 37.3Hz), 44.89 (d, J = 6.6Hz), 44.42, 38.75 (d, J = 46.2Hz) ,34.73(d,J=42.7Hz),33.26(d,J=14.5Hz),31.44(d,J=12.4Hz),25.69,25.51,24.49(d,J=2.5Hz).

[0101] 31 P NMR (162MHz, CDCl3) δ 77.56.

[0102] Example 2: Synthesis of Compound 3

[0103]

[0104] Compound 2 (18.57 mmol) and a magnetic stir bar were added to a 250 mL round-bottom flask, followed by 100 mL of ethanol. The reaction system was then cooled to 0 °C and stirred for 10–15 minutes. 1.5 g of NaBH4 was gradually added to the reaction system in three portions. The reaction temperature was then raised to room temperature, and the reaction was monitored by TLC until completion (usually 1–2 hours). After the reaction was complete, excess NaBH4 was gradually extracted dropwise with water at 0 °C. The system was then concentrated under vacuum to remove most of the ethanol. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The remaining solid was filtered through a short silica gel column to give a clean white solid product, compound 3 (18.03 mmol), in 97% yield.

[0105] 1H NMR (400MHz, CDCl3) δ3.98 (dt, J=20.8, 6.0Hz, 2H), 2.50 (ddd, J=14.9, 6.4, 3.2Hz, 1H), 2.06-1. 88(m,3H),1.78(s,2H),1.72-1.51(m,4H),1.25(m,11H),1.19-1.09(m,1H),1.09-0.96(m,1H).

[0106] 13 C NMR (101MHz, CDCl3) δ59.97 (d, J = 2.7Hz), 44.68 (d, J = 7.5Hz), 44.21 (d, J = 3.1Hz), 37.53, 37.07, 33.94, 33.46 (d, J = 14.0Hz), 31.17 (d, J = 13.4Hz), 25.93 (d, J = 2.0Hz), 25.61, 24.91 (d, J = 2.0Hz).

[0107] 31 P NMR(162MHz, CDCl3)δ77.68.HRMS(ESI-MS):calc.260.1364[M] + ,found261.1439[M+H] + Example 3: Synthesis of Compound 4

[0108]

[0109] Br2 and PPh3 compounds (5.54 mmol) were added sequentially to a 50 mL dry reaction flask and dissolved in 16 mL dry acetonitrile. The reaction system was stirred at -30 °C for 10 min. Compound 3 (3.96 mmol) dissolved in 8 mL dry acetonitrile and was then added dropwise to the reaction system. The reaction system was stirred for 5 min and then brought to room temperature and stirred overnight for 12 h. The reaction was quenched with a saturated sodium thiosulfate aqueous solution. After complete bromine extraction, ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then separated by silica gel column chromatography (TLC PE:EA = 10:1) to obtain 3.71 mmol of clean white solid product compound 4 in 93.7% yield.

[0110] 1H NMR (400MHz, CDCl3) δ3.95 (ddd, J=13.2, 11.0, 5.2Hz, 1H), 3.42 (ddd, J=14.0, 11.0,5.9Hz,1H),2.56(ddd,J=14.8,6.6,2.9Hz,1H),2.35(dd,J=12.2,3.2Hz, 1H),2.18(ddt,J=11.6,7.6,5.6Hz,1H),1.97-1.89(m,1H),1.87-1.72(m,2H) ,1.61(ddd,J=16.5,14.8,12.1Hz,1H),1.49-1.38(m,1H),1.28-1.06(m,14H).

[0111] 13 C NMR (101MHz, CDCl3) δ50.43 (d, J = 7.7Hz), 44.38 (d, J = 42.2Hz), 43.48 (d, J = 1.8Hz), 37.60 (d, J = 47.4Hz), 33.92 (d, J = 4 2.5Hz), 33.47 (d, J = 14.1Hz), 31.99 (d, J = 12.6Hz), 30.12 (d, J = 4.5Hz), 25.82 (d, J = 2.1Hz), 25.68, 25.11 (d, J = 2.0Hz).

[0112] 31 P NMR(162MHz, CDCl3)δ81.69.HRMS(ESI-MS):calc.322.0520[M] + ,found323.0595[M+H] + .

[0113] Example 4: Synthesis of Compound 5

[0114]

[0115] A magnetic stir bar was added to a 50 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. 5 mmol HPAd2 and 10 mL THF were added, followed by 8 mL of nBuLi in n-hexane (1.3 M). The tube was sealed, and the reaction system was taken out of the glove box and heated to reflux at 80 °C for 2 hours. After cooling, the solvent was removed under vacuum. The remaining solid was washed three times with ice-cold n-hexane and filtered to obtain LiPAd2 (white solid product, yield >79%).

[0116] A magnetic stir bar was added to a 10 ml reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. Pre-prepared LiPAd2 (2.33 mmol) and compound 4 (1.55 mmol) were weighed and added to the reaction tube. The tube was sealed with a rubber stopper and removed from the glove box. The mixture was cooled to -78°C for 10-15 minutes. Then, 4 ml of dry DMF was added to the reaction while the temperature was slowly increased. Stirring was started, and the reaction system was stirred overnight at room temperature for twelve hours. The reaction system was purified by water extraction, followed by extraction with n-hexane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain a clean white solid product, compound 5 (1.14 mmol). Compound 5 was defined as compound M1, in 73.5% yield.

[0117] 1 H NMR (600MHz, CDCl3) δ2.63-2.52(m,2H),2.12(td,J=17.0,7.9Hz,1H),2.02-1.96(m,3H),1.94-1.85(m,17H),1.85-1 .80(m,1H),1.71(d,J=9.8Hz,14H),1.47-1.38(m,1H),1.30(d,J=15.9Hz,9H),1.26-1.17(m,4H),1.14-0.98(m,2H).

[0118] 13 C NMR(151MHz, CDCl3) δ51.60(dd,J=8.0,4.0Hz),43.74(d,J=2.6Hz),41.37(dd,J =41.4,20.6Hz),40.86(dd,J=10.6,8.0Hz),38.19(d,J=47.1Hz),37.06,37.01( d,J=4.0Hz),36.87(d,J=2.8Hz),33.94,33.84(d,J=4.1Hz),33.55,33.28(dd,J =13.6,8.7Hz),28.63(dd,J=7.8,5.6Hz),26.29-25.74(m),16.39(d,J=25.7Hz).

[0119] 31 P NMR (243MHz, CDCl3) δ85.65 (d, J = 14.7Hz), 16.83 (d, J = 15.8Hz).

[0120] HRMS (ESI-MS): calc. 544.3421 [M] + Found 545.3497[M+H]+ .

[0121] Example 5: Synthesis of ligand L1

[0122]

[0123] In a 10 mL Schlenk sealed reaction tube, compound 5 (1.10 mmol) and 4 mL of P(NMe2)3 were added. Air was removed from the system using a freeze-pump-thaw method. The sealed tube was then heated to 130 °C, and the reaction proceeded via... 31 After the reaction was monitored by P NMR, the system was cooled to room temperature and excess P(NMe2)3 was removed under high vacuum. The remaining oily mixture was filtered through a short silica gel column plug, dried, and crystallized in ethanol to give a clean white solid product compound L1 (0.99 mol), with a yield of 90%.

[0124] 1 H NMR (400MHz, CDCl3) δ1.97-1.81(m,15H),1.81-1.75(m,1H),1.74-1.61(m,12H), 1.61-1.50(m,1H),1.50-1.20(m,6H),1.10(d,J=11.4Hz,9H),1.02-0.76(m,10H).

[0125] 13 C NMR (101MHz, CDCl3) δ55.16 (d, J = 6.7Hz), 47.34, 43.53 (dd, J = 20.1, 15.5Hz) ,40.90(dd,J=17.9,11.0Hz),37.12(d,J=4.2Hz),36.75(d,J=24.0Hz),36.10 (d,J=22.1Hz),34.82(d,J=2.7Hz),32.96(t,J=4.6Hz),30.09(t,J=6.8Hz),2 9.85-29.55(m),29.50(d,J=4.7Hz),28.62(dd),26.26(d,J=25.8Hz),11.94.

[0126] 31 P NMR(162MHz, CDCl3)δ23.34(d,J=17.4Hz),17.22(d,J=16.2Hz).m / z(ESI-MS):calc.512.3701[M] + Found 513.3773[M+H] + .

[0127] Example 6: Synthesis of Compound 6

[0128]

[0129] A magnetic stir bar was added to a 50 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. 5 mmol of HPPh2 and 10 mL of THF were added, followed by 8 mL of nBuLi in n-hexane (1.3 M). The tube was sealed, and the reaction system was taken out of the glove box and heated to reflux at 80 °C for 1 hour. After cooling, the solvent was removed under vacuum. The remaining solid was washed three times with ice-cold n-hexane and filtered to obtain LiPPh2 (white solid product, yield >82%).

[0130] A magnetic stir bar was added to a 10 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. LiPPh2 (0.8 mmol) and compound 4 (0.4 mmol) were weighed and added to the reaction tube. The tube was sealed with a rubber stopper and then removed from the glove box. The mixture was cooled to -78 °C for 10–15 minutes. Then, 3 mL of dry DMF was added to the reaction mixture, and the temperature was slowly increased while stirring was started. The reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was purified by water extraction, followed by extraction with n-hexane. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain a clean white solid product, compound 6 (0.273 mmol), which was defined as M2, in 68% yield.

[0131] 1 H NMR (400MHz, CDCl3) δ7.48 (ddd, J=8.7, 5.5, 1.9Hz, 2H), 7.41 (dq, J=7.2, 3.0Hz, 2H), 7.37-7.31 ( m,3H),7.28(td,J=3.5,1.8Hz,3H),2.75(ddd,J=16.9,14.3,5.0Hz,1H),2.51(ddd,J=14.9,6.6, 3.3Hz,1H),2.35-2.23(m,1H),2.14(dddd,J=14.7,12.3,6.8,2.6Hz,1H),1.91-1.83(m,1H),1.8 0-1.50(m,4H),1.47-1.33(m,1H),1.19-1.11(m,3H),1.01(d,J=15.9Hz,10H),0.92-0.76(m,1H).

[0132] 13C NMR (151MHz, CDCl3) δ139.14 (d, J = 15.1Hz), 138.18 (d, J = 13.8Hz), 133.32 (d, J = 18.6Hz), 132.9 6(d,J=18.5Hz),128.75(d,J=3.4Hz),128.54,128.48(d,J=3.6Hz),128.43,51.52(dd,J=7.7,3. 2Hz),43.57(d,J=2.3Hz),37.71(d,J=15.3Hz),37.68(d,J=47.3Hz),37.42(d,J=15.6Hz),33.75 (d,J=27.9Hz),33.56,32.44(dd,J=14.0,9.2Hz),28.08(d,J=15.5Hz),26.24-25.75(m),25.22.

[0133] 31 P NMR(162MHz, CDCl3)δ83.53(d,J=21.2Hz),-17.81(d,J=21.3Hz).m / z(ESI-MS):calc.428.1856[M] + ,found429.1935[M+H] + .

[0134] Example 7: Synthesis of compound L2

[0135]

[0136] In a 10 mL Schlenk sealed reaction tube, compound 6 (1.63 mmol) and 4 mL of P(NMe2)3 were added. Air was removed from the system using a freeze-pump-thaw method. The sealed tube was then heated to 130 °C, and the reaction proceeded as follows: 31 After the reaction was monitored by P NMR, the system was cooled to room temperature and excess P(NMe2)3 was removed under high vacuum. The remaining oily mixture was filtered through a short silica gel column plug, dried, and crystallized in ethanol to give a clean white solid product compound L2 (1.55 mmol), 95% yield.

[0137] 1H NMR (400MHz, CDCl3) δ7.47(ddd,J=8.2,5.1,1.8Hz,2H),7.44-7.39(m,2H),7.36-7.31(m,3H),7.31-7.26(m,3H),2.51(td,J=15.4,5.9Hz,1 H),2.39(dd,J=15.0,7.0Hz,1H),2.16(d,J=12.0Hz,1H),1.85(d,J=12.8Hz,1H),1.76-1.58(m,4H),1.36-1.22(m,2H),1.07-0.73(m,14H).

[0138] 13 C NMR (101MHz, CDCl3) δ140.20 (d, J = 15.1Hz), 138.99 (d, J = 14.0Hz), 133.28 (d, J = 19.1Hz), 132 .72(d,J=17.9Hz),128.40(d,J=5.7Hz),128.31,128.27(d,J=5.0Hz),53.75(d,J=6.7Hz),47 .04(d,J=3.6Hz),39.68(dd,J=14.9,12.4Hz),34.68(d,J=2.5Hz),33.86(dd,J=32.3,13.7Hz ), 32.53 (t, J = 4.9Hz), 28.75, 28.60, 28.58, 28.35 (dd, J = 13.5, 2.2Hz), 26.09 (d, J = 11.3Hz).

[0139] 31 P NMR(162MHz, CDCl3)δ20.15(d,J=41.3Hz),-19.82(d,J=41.1Hz).m / z(ESI-MS):calc.396.2136[M] + Found 397.2204[M+H] + .

[0140] Example 8: Synthesis of Compound 7

[0141]

[0142] A magnetic stir bar was added to a 50 ml Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. 5 mmol of HP was added. tBu2, 10 mL THF, followed by 8 mL of nBuLi in n-hexane (1.3 M), sealed, and the reaction system was heated under reflux at 80 °C for 1 hour in a glove box. After cooling, the solvent was removed under vacuum, and the remaining solid was washed three times with ice-cold n-hexane and filtered to obtain LiP. t Bu2 (white solid product, yield >85%)

[0143] A magnetic stir bar was added to a 25 ml Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon gas. LiP was weighed separately. t Bu2 (6.2 mmol) and compound 4 (3.1 mmol) were added to a reaction tube, sealed with a rubber stopper, and taken out of the glove box. The mixture was cooled to -78°C for 10-15 minutes. Then, 8 mL of dry DMF was added to the reaction mixture while the temperature was slowly increased and stirring was started. The reaction mixture was then brought to room temperature and stirred overnight. 500 mg of sulfur powder was then added to the reaction mixture under an inert gas atmosphere and stirred for 5 hours. The reaction mixture was purified by adding water and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain a clean white solid product, compound 7 (1.97 mmol), which was defined as M3, in 63.5% yield.

[0144] 1 H NMR (600MHz, CDCl3) δ3.35(dddd,J=25.1,16.7,8.9,5.0Hz,1H),2.70(dddd,J=21.8,10.7,5.1Hz,1H),2.64(ddd,1H),2.28(d,J=8.6Hz,1H),1. 97-1.91(m,1H),1.87-1.80(m,1H),1.79-1.67(m,2H),1.66-1.60(m,1H ),1.44-1.27(m,28H),1.25-1.13(m,4H),1.04(qd,J=12.6,3.6Hz,1H).

[0145] 13C NMR (151MHz, CDCl3) δ54.02(dd,J=8.5,5.0Hz),42.83(d,J=2.7Hz),39.01,38.72,38.45,38.37,38.05,37.52(dd,J=40.0,2.9Hz),35.20(d,J =41.5Hz), 34.04(d,J=14.2Hz), 32.68(d,J=13.0Hz), 28.04(d,J=20.6Hz), 26.27(d,J=2.0Hz), 25.74(d,J=2.2Hz), 21.50(dd,J=39.2,2.8Hz).

[0146] 31 P NMR(243MHz, CDCl3)δ87.85(d,J=18.1Hz),81.17(d,J=16.7Hz).m / z(ESI-MS):calc.420.2203[M] + ,found421.2278[M+H] + .

[0147] Example 9: Synthesis of compound L3

[0148]

[0149] In a 10 mL Schlenk sealed reaction tube, compound 7 (1.90 mmol) and 4 mL of P(NMe2)3 were added. Air was removed from the system using a freeze-pump-thaw method. The sealed tube was then heated to 130 °C, and the reaction proceeded via... 31 After the reaction was completed, the system was cooled to room temperature and excess P(NMe2)3 was removed under high vacuum. The remaining oily mixture was purified by a silica gel column to give the colorless oily product compound L3 (1.51 mmol, 80% yield).

[0150] 1 H NMR (400MHz, CDCl3) δ1.16-1.02(m,27H),1.01-0.72(m,15H).

[0151] 13C NMR (101MHz, CDCl3) δ55.03 (d, J = 7.6Hz), 47.32 (d, J = 3.6Hz), 43.40 (dd, J = 20.2, 15.7Hz), 37.10, 34.84 (d, J = 2.4Hz), 31.93, 30.08 (d, J = 9.3Hz), 29. 90(d,J=4.5Hz),29.79,29.72(d,J=3.4Hz),29.53(d,J=4.7Hz),29.39(d, J=4.8Hz), 28.89(d,J=13.6Hz), 28.55(d,J=18.3Hz), 26.24(d,J=22.5Hz).

[0152] 31 P NMR (162MHz, CDCl3) δ22.93 (d, J = 17.7Hz), 20.53 (d, J = 18.2Hz). m / z (ESI-MS): calc.356.2762[M] + Found 357.2829[M+H] + .

[0153] Example 10: Synthesis of Compound 8

[0154]

[0155] A magnetic stir bar was added to a 50 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. 5 mmol HPCy2 and 10 mL THF were added, followed by 8 mL of nBuLi in n-hexane (1.3 M). The tube was sealed, and the reaction system was taken out of the glove box and heated to reflux at 80 °C for 1 hour. After cooling, the solvent was removed under vacuum. The remaining solid was washed three times with ice-cold n-hexane and filtered to obtain LiPCy2 (all white solid products, yield >80%).

[0156] A magnetic stir bar was added to a 25 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The tube was then transferred to a glove box protected by dry argon. Pre-prepared LiPCy2 (6.2 mmol) and compound 4 (3.1 mmol) were weighed and added to the tube. The tube was sealed with a rubber stopper and removed from the glove box. The mixture was cooled to -78 °C for 10–15 minutes. Then, 6 mL of dry DMF was added to the reaction mixture while the temperature was slowly increased. Stirring was started, and the reaction mixture was allowed to reach room temperature and stirred overnight for 12 hours. 500 mg of sulfur powder was then added to the reaction mixture under inert gas protection. The mixture was stirred for 5 hours, purified by water, and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain a clean white solid product, compound 8, defined as M4 (2.16 mmol), in 69.5% yield.

[0157] 1 H NMR (600MHz, CDCl3) δ3.14-2.94(m,1H),2.89-2.71(m,1H),2.60(ddd,J=14.8,6.4,3.2Hz,1H),2.10(d,J=11.3Hz,2H), 2.03-1.67(m,14H),1.59-1.53(m,2H),1.47(dq,J=14.4,6.7Hz,2H),1.38-1.15(m,22H),1.03(qd,J=12.4,3.6Hz,1H).

[0158] 13 C NMR (101MHz, CDCl3) δ52.45 (dd, J = 8.0, 6.4Hz), 43.16 (d, J = 2.0Hz), 39.41 (d, J = 22.2Hz), 38.94 (d, J = 22.4 Hz),37.75(d,J=47.9Hz),35.78(dd,J=42.6,1.9Hz),34.83(d,J=42.8Hz),33.53(d,J=14.2Hz),31.36(d, J=13.4Hz),27.00-26.69(m),26.69(d,J=1.6Hz),26.56(d,J=2.4Hz),26.43(d,J=3.7Hz),26.13(d,J=3.2 Hz), 26.00, 25.89 (d, J = 1.7Hz), 25.80 (dd, J = 4.8, 1.9Hz), 25.71 (d, J = 2.0Hz), 22.30 (dd, J = 45.7, 2.5Hz).

[0159] 31P NMR(243MHz, CDCl3)δ84.83(d,J=14.6Hz),61.63(d,J=14.6Hz).m / z(ESI-MS):calc.472.2516[M] + ,found473.2596[M+H] + .

[0160] Example 11: Synthesis of ligand L4

[0161]

[0162] A magnetic stir bar was added to a 100 ml three-necked reaction flask, and a reflux condenser was connected. The reaction apparatus was heated with an electric torch and then dried under vacuum. Compound 8 (1.06 mmol) was then weighed and added to the reaction apparatus. The atmosphere was purged three times to create an inert gas atmosphere. 25 ml of freshly distilled dry toluene and 3 ml of Si₂Cl₆ (5 g, 10 equivalents) were added. The reaction was heated to 130 °C and refluxed for 20 hours, then cooled. 31 The reaction endpoint was monitored by P NMR. The reaction system was then cooled to 0°C, and 50 mL of 30% NaOH aqueous solution was added. The reaction system was heated to 50°C until the aqueous phase became clear. The aqueous phase was extracted three times with 30 mL of degassed benzene. Anhydrous sodium sulfate was added to the organic phase for drying, and the mixture was concentrated under vacuum. The remaining colorless oily mixture was purified by filtration through a short silica gel column to obtain a clean, colorless oily product compound L4 (0.72 mol) in 68.0% yield. After drying, it gradually solidified into a solid the next day.

[0163] 1 H NMR (400MHz, CDCl3) δ1.93-1.61(m,4H),1.39-1.10(m,26H),1.10-1.02(m,3H),0.99-0.71(m,13H).

[0164] 13C NMR (101MHz, CDCl3) δ53.84 (d, J = 7.0Hz), 47.11 (d, J = 3.3Hz), 42.57-41.31 (m), 39.45 (d, J =5.8Hz),34.72(d,J=6.5Hz),34.49(d,J=9.9Hz),33.83(d,J=14.8Hz),30.33,30.11,29.99 (d,J=5.0Hz),29.54-29.31(m),28.95(d,J=2.8Hz),28.81(d,J=2.8Hz),28.57(d,J=5.0Hz ), 28.01, 27.53 (d, J = 8.8Hz), 27.16 (d, J = 2.6Hz), 26.74 (d, J = 12.4Hz), 26.22 (d, J = 8.3Hz).

[0165] 31 P NMR(162MHz, CDCl3)δ19.90(d,J=34.3Hz),-9.57(d,J=34.5Hz).m / z(ESI-MS):calc.408.3075[M] + ,found409.3143[M+H] + .

[0166] Example 12: Synthesis of Compound 9

[0167]

[0168] A magnetic stirrer was added to a 50 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. 5 mmol of HPAr2 (CAS: 1173023-24-9) and 10 mL of THF were added, followed by 4 mL of nBuLi in n-hexane (1.3 M). The tube was sealed, and the reaction system was removed from the glove box and reacted overnight at room temperature. The solvent was removed under vacuum, and the remaining solid was washed three times with ice-cold n-hexane. The mixture was then filtered to obtain LiPAr2 (Ar = DTBM, pale yellow solid, yield >95%).

[0169] A magnetic stir bar was added to a 25 mL Schlenk reaction tube. After heating with an electric torch, the tube was dried and cooled under vacuum. The reaction tube was then transferred to a glove box protected by dry argon. LiPAr2 (10 mmol) and compound 4 (4 mmol) were weighed and added to the reaction tube. The tube was sealed with a rubber stopper and removed from the glove box. The mixture was cooled to -78 °C for 10–15 minutes. Then, 10 mL of dry DMF was added to the reaction while the temperature was slowly increased and stirring was started. The reaction system was then heated to room temperature and stirred overnight. 500 mg of sulfur powder was then added to the reaction system under inert gas protection and stirred for 5 hours. The reaction system was purified by adding water and then extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain a clean white solid product, compound 9 (3.12 mmol). Compound 9 was defined as M5, in 78% yield.

[0170] 1 H NMR (400MHz, CDCl3) δ7.78(d,J=13.5Hz,2H),7.69(d,J=13.6Hz,2H),3.68(d,J=1.8Hz,6H),3.62-3.44(m,1H),3.07-2.90(m,1H),2.58(ddd,J=1 4.3,6.2,3.4Hz,2H),2.40-2.25(m,1H),1.96-1.81(m,1H),1.72-1.48(m ,5H),1.40(d,J=8.1Hz,37H),1.16(d,J=16.1Hz,9H),1.11-0.96(m,3H).

[0171] 13 C NMR (101MHz, CDCl3) δ162.52, 144.28, 144.19 (d, J = 12.7Hz), 144.02, 130.55 (d, J = 11.7Hz), 130.31 (d, J = 12.0Hz), 129.60 (d, J = 12.4Hz), 64.64 (d ,J=12.1Hz),64.51,51.41-51.60(m),43.19,36.25(d,J=5.4Hz),36.21, 34.79, 34.37, 32.14-31.79 (m), 26.02 (d, J = 22.7Hz), 25.06 (d, J = 1.8Hz).

[0172] 31 P NMR(162MHz, CDCl3)δ84.02(d,J=32.7Hz),45.76(d,J=32.5Hz).m / z(ESI-MS):calc.744.4292[M] +Found 767.4180[M+Na] + .

[0173] Example 13: Synthesis of ligand L5

[0174]

[0175] A magnetic stir bar was added to a 25 ml Schlenk sealed tube. The reaction apparatus was heated with an electric torch and then dried under vacuum. Compound 9 (1.4 mmol) was then weighed and added to the reaction apparatus. The atmosphere was purged three times to create an inert gas atmosphere. 7 ml of freshly distilled dry benzene and 5.65 mmol of Si₂Cl₆ were added. The reaction was heated to 80 °C and refluxed for 15 hours. After cooling, the solution was... 31 The reaction endpoint was monitored by PNMR. The reaction system was then cooled to 0°C, and 50 mL of 30% NaOH aqueous solution was added. The reaction system was heated to 50°C until the aqueous phase became clear. The aqueous phase was extracted three times with 30 mL of degassed benzene. The organic phase was dried with anhydrous sodium sulfate and concentrated under vacuum. The remaining colorless oily mixture was purified by filtration through a short silica gel column to obtain a clean white solid product, ligand compound L5 (1.26 mmol), in 90% yield.

[0176] 1 H NMR (400MHz, C6D6) δ7.79(d,J=7.3Hz,2H),7.67(d,J=7.3Hz,2H),3.38(d,J=12.0Hz,6H),2.89-2.58(m,2H),2.37(d,J=7.3Hz,1H ),1.94-1.73(m,2H),1.72-1.54(m,4H),1.45(d,J=13.4Hz,36H),1.40-1.31(m,3H),0.99(m,J=11.2Hz,10H),0.94-0.78(m,2H).

[0177] 13C NMR (101MHz, C6D6) δ160.51 (d, J = 16.7Hz), 143.80 (d, J = 6.7Hz), 143.64 (d, J = 6.7Hz), 134.76 (d, J=14.2Hz),133.08(d,J=12.5Hz),132.24(d,J=9.8Hz),132.03(d,J=9.4Hz),128.07(d,J=24.5Hz ),64.15(d,J=5.8Hz),54.19(m),47.56,40.43(m),36.10(d,J=6.5Hz),35.05,33.34(m),32.33(d ,J=6.1Hz),29.07(d,J=10.2Hz),28.89(d,J=13.6Hz),28.70(d,J=14.0Hz),26.58(d,J=11.3Hz).

[0178] 31 P NMR (162MHz, C6D6) δ19.75 (d, J = 36.6Hz), -19.39 (d, J = 36.3Hz).

[0179] Example 14:

[0180] 1 eq of electron-rich chiral bisphosphine ligands L1–L7 were in situ complexed with 1.02 eq of transition metal precursors in a 1:1 DCM / THF mixed solvent. After 3 hours of reaction, the complexes were obtained by... 31 The reaction was detected by P NMR, and the solvent was then removed under vacuum. The remaining orange solid was washed three times with n-hexane. The orange solid could be recrystallized from a dichloromethane-n-hexane mixed solvent to obtain a series of catalysts with a yield of 1 eq.

[0181] Example 14-1:

[0182] Hydrogenation reaction steps for compound a: In an argon-protected glove box, weigh 0.05 mmol of compound (A) and add it to a 1 ml ampoule. Add a small magnetic stir bar, then add 0.5 ml of alcohol, and finally add the catalyst. Transfer the reaction mixture to a dry autoclave, then remove it from the glove box. Connect the autoclave to a hydrogen cylinder and purge the gas three times, maintaining the pressure inside the autoclave at 10 bar. Stir the reaction at room temperature for 3 hours. After depressurization, remove the ampoule. Dry the solvent under vacuum, and filter the remaining solid through a short silica gel column to remove the metal catalyst. Dry the organic phase under vacuum to obtain a white solid product. NMR analysis confirms it is a hydrogenation product. The chemical reaction formula is as follows:

[0183]

[0184] The yield (%) of the hydrogenation product and the enantiomeric excess ee (%) were determined, and the results are shown in Table 1:

[0185] Table 1. Asymmetric hydrogenation table (Formula A)

[0186]

[0187]

[0188] The above-described embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of this application, and should all be included within the protection scope of this application.

Claims

1. An electron-rich chiral bisphosphine ligand, characterized in that, It has the structure described in equation (Ⅰ): ； The asterisk (*) represents a chiral center. Each of the multiple chiral centers is independently either an R configuration or an S configuration; The -X1- is -CH2-; R2 and R3, together with the atoms connected to them, form a cyclohexyl group. ; R4 is selected from tert-butyl; Each of the plurality of R1s is independently selected from straight-chain alkanes with 2 to 6 carbon atoms, branched alkanes with 3 to 5 carbon atoms, cycloalkyl groups with 5 to 7 carbon atoms, 6 to 8-membered monocyclic aryl groups, and adamantyl groups; The hydrogen in R1 can be arbitrarily replaced by R6, wherein R6 is selected from methoxy, n-butyl, sec-butyl, and tert-butyl.

2. The ligand according to claim 1, wherein R1 is selected from a straight-chain alkane with 4 carbon atoms, or a cycloalkyl group with 6 carbon atoms, or a sec-butyl or tert-butyl group.

3. An electron-rich chiral bisphosphine ligand, wherein the ligands L1 to L5 are specifically as follows: 、 、 、 、 。 4. A method for preparing an electron-rich chiral bisphosphine ligand, characterized in that, include: ； In M1, X2 is selected from In M2, X2 is selected from... ; In M3, X2 is selected from In M4, X2 is selected from... ; In M5, X2 is selected from ; S1: NaBH4 was added in portions to an alcoholic solution of compound 2 to obtain compound 3; S2: After dissolving Br2 and PPh3 in an organic solvent to obtain a solution, stir the solution and add the organic solution of compound 3 dropwise to the solution to obtain compound 4; S3: The corresponding LiP(Ad)2, LiP(Ph)2, LiP(tBu)2, LiP(Cy)2 or LiP(DTBM)2 are mixed with compound 4 respectively, and then DMF is added to the reaction. After stirring, the corresponding M1~M5 are obtained. S4: M1~M3 are each mixed separately with P(NMe2)3 and heated to obtain the corresponding L1~L3; or, M4~M5 are each mixed separately with Si2Cl6 and heated to obtain the corresponding L4~L5.

5. A method for preparing a catalyst, characterized in that, The ligand of claim 1 participates in the complexation reaction of the transition metal precursor in an organic solvent, and the complexation reaction forms a catalyst; the transition metal precursor is selected from [Rh(NBD)2]X, [Rh(COD)2]OTf, [Rh(COD)2]X, [Rh(COD)2]ClO4; X is a negative anion selected from the group consisting of BF4 - , SbF6 - Any of the above.

6. A method for preparing a catalyst, characterized in that, At least one of the ligands L1 to L5 in claim 3 participates in a complexation reaction of the transition metal precursor in an organic solvent, which forms a catalyst. The transition metal precursor is selected from [Rh(NBD)2]X, [Rh(COD)2]OTf, [Rh(COD)2]X, and [Rh(COD)2]ClO4; X is a negative anion, selected from BF4. - SbF6 - Any one.

7. The method according to any one of claims 5 or 6, characterized in that, The organic solvent is selected from a mixture of DCM and THF.

8. A catalyst prepared by the method of any one of claims 5 to 7.

9. The use of the catalyst of claim 8 in asymmetric hydrogenation.

10. A method for preparing a sacurib intermediate, characterized in that, include: ； The * represents a chiral center, and the chiral carbon atom is either R-configuration or S-configuration; R7 is selected from , Any; In the presence of the catalyst cata, compound (A) undergoes asymmetric hydrogenation to generate compound (B); The catalyst cata is prepared by a complexation reaction, and any ligand of the structure of formula (I) of claim 1 and any metal precursor of claim 5 or 6 participate in the complexation reaction as a substrate.

11. The method for preparing the sakubiqu intermediate according to claim 10, characterized in that, ； The * represents a chiral center, and the chiral carbon atom is either in the R or S configuration. R7 is selected from , Any; In the presence of the catalyst cata, compound (A) undergoes asymmetric hydrogenation to generate compound (B); The catalyst cata is prepared by a complexation reaction, and any ligand L1 to L5 of claim 3 and any metal precursor of claim 5 or 6 participate in the complexation reaction as a substrate.

12. An intermediate having the structure of formula (III): ； The asterisk (*) represents a chiral center, and each of the plurality of chiral centers is independently either an R configuration or an S configuration; The -X1- is -CH2-; R2 and R3, together with the atoms connected to them, form a cyclohexyl group. ; X2 is selected from hydroxyl, halogen, ... , In either of these, a and b are selected from 2; R4 is selected from tert-butyl; Each of the plurality of R1s is independently selected from C4 straight-chain alkanes, C3-C5 branched alkanes, 6-8 membered monocyclic aryl groups, cyclohexyl groups, and adamantyl groups; the hydrogen on the monocyclic aryl group is arbitrarily replaced by R8, and each time R8 appears, it is independently selected from methoxy and tert-butyl groups.

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