Camphor-based phosphite as well as preparation method and application thereof

Abstract

The preparation method comprises the following steps: firstly, synthesizing to obtain planar chiral camphor-based phosphonite, then taking the camphor-based phosphonite as a chiral induction reagent, taking aldehyde, aldimine and nitroolefin as substrates, and carrying out asymmetric Pudovik reaction at the temperature of 80 DEG C below zero to 0 DEG C under the action of an alkaline additive, so as to obtain the chiral compound of the camphor-based phosphonite. A series of chiral alpha-hydroxyl, alpha-amino and beta-nitro phosphine ester compounds are synthesized with high yield and excellent stereoselectivity. Compared with the prior art, the synthesis method disclosed by the invention is a chiral induction method, and is green, efficient and mild in condition; the reaction system is simple and convenient to operate; the yield is high, and the substrate application range is wide. Alpha-hydroxyl, alpha-amino and beta-nitrophosphonate efficiently synthesized by the method are important skeletons of many medicines and bioactive molecules, and a widely applicable preparation method is provided for synthesizing the compounds.

Description

Technical Field

[0001] The present invention relates to a phosphite ester having a novel conformation and a preparation method thereof, and also relates to its application as an auxiliary group in the Pudovik reaction; specifically, the present invention relates to a face-chiral camphor phosphite ester and a preparation method thereof, and also relates to a method for synthesizing a compound containing an optically pure α-hydroxy, α-amino or β-nitro phosphonic acid structure by using the face-chiral camphor phosphite ester as an auxiliary group in the Pudovik reaction. Background Art

[0002] α-Functionalized organophosphorus compounds are important structural units commonly found in bioactive compounds such as natural products, active pharmaceutical ingredients, and pesticides. In particular, organophosphorus compounds and their derivatives containing optically pure α-hydroxy, α-amino, and β-amino phosphonic acid structures are the core motifs of multi-purpose drugs. For example, Fosfazinomycin A is a novel antibiotic; Fosfomycin is a broad-spectrum antibiotic that can be used for the treatment of bone, lung, and abscess infections; Alafosfalin can be used as an antibacterial and antifungal reagent; and Phosphotyrosine can reduce stress hormone levels and is an alternative reagent for tyrosine.

[0003] Currently, a variety of methods have been developed to synthesize these optically pure organophosphorus compounds to meet the increasing demand for such compounds. Among these synthetic methods, the Pudovik reaction is a reaction in which a dialkyl phosphite ester or a related P(O)H compound is added to an unsaturated chemical bond (C═C, C≡C, C═O, C═N, etc.) to generate a P-C functionalized phosphonate ester, which is one of the most effective and direct methods for inducing the synthesis of phosphorus-containing functional compounds. In this context, three main asymmetric hydrophosphorylation methods have been developed for the Pudovik reaction, namely, chiral Lewis acid complex catalysis, organocatalysis, and chiral auxiliary group induction. However, these widely developed asymmetric catalytic methods are still limited in practicality due to the need to use special reagents and a relatively narrow substrate range, etc.

[0004] Among them, the chiral auxiliary-induced method, which has made good progress in the stereoselective Pudovik reaction, is a method of using recyclable chiral auxiliaries (CAs) with different skeletons to derivatize P-chiral phosphonites (hereinafter simply referred to as CA-PHO). For example, Menthyl-PHO by Mislow (Org. Biomol. Chem. 2014, 12, 9457-9465.), CHDA-PHO by Spilling (Tetrahedron Lett 1991, 32, 6297-6300.), TADDOL-PHO by Enders (Angew. Chem. Int. Ed. 2000, 39, 4605-4607) and BINOL-PHO by Kee (Synth. Commun. 1993, 23, 1651-1657) have all been studied in this regard and achieved pioneering results. These CA-PHO compounds can easily react with a variety of substrates to form structurally diverse phosphorus-containing α-C-stereomolecules. In addition, a pair of diastereomers in the CA-PHO compounds can be clearly identified by NMR, so that the stereochemical reaction process of these diastereoselective reactions can be monitored in real time by 31 P / 1 H NMR or HPLC. More importantly, the chiral auxiliary-induced method can simultaneously generate P-C bonds and the required C-X (X = C, O, N, etc.) chemical bonds, thus avoiding the inconvenience of pre-synthesizing phosphorus-containing substrates. However, due to relatively harsh preparation conditions, low diastereoselectivity or limited substrate scope, the further application of these CA-PHOs is still greatly limited to some extent.

[0005] Therefore, in the continuous research of the stereoselective Pudovik reaction, a key goal is to design and implement new induction modes to promote the construction on chiral carbon atoms, especially to achieve this goal by developing more effective chiral auxiliaries.

[0006] At present, point-chiral and axially chiral phosphonite compounds have been synthesized by the chiral auxiliary-induced method. However, when used as an auxiliary for the Pudovik reaction to synthesize compounds containing optically pure α-hydroxy, α-amino or β-nitrophosphonic acid structures, the yield and diastereoselectivity still cannot reach the expected values. Summary of the Invention

[0007] Technical Problem

[0008] An object of the present invention is to provide a novel camphor phosphonite to improve the yield and diastereoselectivity when used as an auxiliary for the Pudovik reaction.

[0009] Another object of the present invention is to provide a method for preparing camphor-based phosphonite, so as to simply and effectively obtain planar chiral camphor-based phosphonite.

[0010] Another object of the present invention is to provide a method for synthesizing compounds containing optically pure α-hydroxy, α-amino or β-nitro phosphonic acid structures by using planar chiral phosphonite as a co-group in the Pudovik reaction, so as to improve the yield and enantioselectivity.

[0011] Technical solutions

[0012] To solve the above technical problems, the present invention provides a camphor-based phosphonite, which is a planar chiral camphor-based phosphonite (hereinafter referred to as CAMDOL-PHO).

[0013]

[0014] The present invention provides a method for synthesizing planar chiral camphor-based phosphonite. The synthesis method includes the following steps: adding camphor-derived 2,3-diol as a substrate to a reactor, adding triethylamine and a reaction solvent to the reaction tube under an inert gas atmosphere, controlling the reaction temperature at 0-40 °C and reacting for 1-6 hours, then adding phosphorus trichloride and continuing the reaction until the substrate completely disappears; then adding sodium methoxide (MeONa) reagent to the reactor, controlling the reaction temperature at 0-40 °C and reacting for 1-6 hours until the reaction is complete; subjecting the obtained product to silica gel column chromatography to obtain the planar chiral camphor-based phosphonite of the present invention.

[0015] In a specific embodiment, the molar ratio of camphor-derived 2,3-diol to triethylamine is 1:(1.1-3).

[0016] In a specific embodiment, the molar ratio of camphor-derived 2,3-diol to sodium methoxide is 1:(1.1-3).

[0017] In a specific embodiment, the reaction solvent is tetrahydrofuran (THF).

[0018] In addition, the present invention also provides a method for obtaining chiral camphor-based α-hydroxy phosphonate compounds by asymmetric synthesis using the above planar chiral camphor-based phosphonite as a co-group in the Pudovik reaction. The method includes the following steps: mixing the planar chiral camphor-based phosphonite with an aryl aldehyde or an alkyl aldehyde in a reactor, adding a reaction solvent and a basic additive to the reactor under an inert gas atmosphere, controlling the reaction temperature at -80-0 °C and reacting for 20-28 hours to obtain chiral camphor-based α-hydroxy phosphonate compounds.

[0019] In a specific embodiment, the aryl aldehyde or alkyl aldehyde is one of benzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 2-naphthaldehyde, cinnamaldehyde, 2-furaldehyde, n-butanal, and cyclohexanecarbaldehyde.

[0020] In a specific embodiment, the molar ratio of the planar chiral camphor phosphonite to the aryl aldehyde or alkyl aldehyde is 1:(1.1 - 3).

[0021] In a specific embodiment, the basic additive is lithium diisopropylamide (LDA), and the dosage is 1 equivalent.

[0022] In a specific embodiment, the reaction solvent is tetrahydrofuran.

[0023] In addition, the present invention also provides a method for obtaining a chiral camphoryl α-aminophosphonate compound by asymmetric synthesis using the above-mentioned planar chiral camphor phosphonite as a cofactor in the Pudovik reaction. The method includes the following steps: adding the planar chiral camphor phosphonite and the aryl aldehyde imine or alkyl aldehyde imine into a reactor for mixing, adding a reaction solvent and a basic additive into the reactor under an inert gas atmosphere, controlling the reaction temperature at -80 to 0 °C and reacting for 20 to 28 hours to obtain the chiral camphoryl α-aminophosphonate compound.

[0024] In a specific embodiment, the aryl aldehyde imine or alkyl aldehyde imine is one of N-benzylidene-4-methylbenzenesulfonamide, N-(2-chlorobenzylidene)-4-methylbenzenesulfonamide, 4-methyl-N-(pyridin-3-ylmethylene)benzenesulfonamide, 4-methylbenzenesulfonyl-N-n-butylimine, and 4-methylbenzenesulfonyl-N-cyclohexylimine.

[0025] In a specific embodiment, the molar ratio of the planar chiral camphor phosphonite to the aryl aldehyde imine or alkyl aldehyde imine is 1:(1.1 - 3).

[0026] In a specific embodiment, the basic additive is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), and the dosage is 1 equivalent.

[0027] In a specific embodiment, the reaction solvent is tetrahydrofuran.

[0028] In addition, the present invention also provides a method for asymmetric synthesis using the above-mentioned face-chiral camphor-based phosphonite as a co-group in the Pudovik reaction to obtain a chiral camphor-based β-nitro phosphonate compound. The method includes the following steps: mixing the face-chiral camphor-based phosphonite and an aryl β-nitroolefin or an alkyl β-nitroolefin in a reactor, adding a reaction solvent and a basic additive to the reactor under an inert gas atmosphere, controlling the reaction temperature at -80 to 0 °C and reacting for 20 to 28 hours to obtain the chiral camphor-based β-nitro phosphonate compound.

[0029] In a specific embodiment, the aryl β-nitroolefin or the alkyl β-nitroolefin is one of β-nitrostyrene, 4-chloro-β-nitrostyrene, 1-(2-nitrovinyl)naphthalene, 2-(2-nitrovinyl)pyridine, β-isopropylbenzene nitrostyrene, ((e)-2-nitrovinyl)cyclohexane.

[0030] In a specific embodiment, the molar ratio of the face-chiral camphor-based phosphonite to the aryl β-nitroolefin or the alkyl β-nitroolefin is 1:(1.1 to 3).

[0031] In a specific embodiment, the basic additive is sodium bis(trimethylsilyl)amide (NaHMDS), and the dosage is 1 equivalent.

[0032] In a specific embodiment, the reaction solvent is methyltetrahydrofuran (Me-THF).

[0033] In addition, the present invention also provides a chiral camphor-based α-hydroxy phosphonate compound, a camphor-based α-amino phosphonate compound or a camphor-based β-nitro phosphonate compound, all of which are synthesized by the above method of the present invention.

[0034] The chiral camphor-based α-hydroxy phosphonate compound, the camphor-based α-amino phosphonate compound or the camphor-based β-nitro phosphonate compound provided by the present invention includes any one of the following compounds 3a to compound 3h, compounds 5a to compound 5e, compounds 7a to compound 7f:

[0035]

[0036]

[0037]

[0038] Beneficial effects

[0039] The camphor-based phosphonite with a novel conformation provided by the present invention is face-chiral, which is different from the conformations of the point-chiral or axis-chiral phosphonites recorded in the prior art.

[0040] The method for preparing planar chiral phosphonates provided by the present invention has significant advantages. The core of this method lies in the adoption of a simple "one-pot" synthesis process. Since all reaction reagents directly react in a reaction vessel without going through cumbersome multi-step separation and purification processes, the time and labor costs are significantly reduced, especially when mass-producing on an industrial scale, it can have great advantages.

[0041] The present invention uses this planar chiral camphor phosphonate as a chiral inducing reagent and as a co-group for the Pudovik reaction, and uses aldehydes, aldehyde imines or nitroolefins as substrates to carry out asymmetric synthesis (Pudovik reaction). A series of chiral camphor-based α-hydroxyphosphonate compounds, chiral camphor-based α-aminophosphonate compounds, or chiral camphor-based β-nitrophosphonate compounds can be obtained with a yield of up to 97% and a diastereomeric ratio (dr) of 99:1. Compared with the prior art that uses point chiral or axial chiral camphor phosphonates, the method for synthesizing chiral α-hydroxyphosphonate compounds, α-aminophosphonate compounds or β-nitrophosphonate compounds using the planar chiral camphor phosphonate as a chiral inducing reagent in the present invention has the following advantages: green and efficient, mild conditions; simple reaction system, easy to operate; high yield, wide substrate scope. Detailed implementation manners

[0042] To make the objectives, contents and advantages of the present invention clearer, the following further describes in detail the specific implementation manners of the present invention in conjunction with examples.

[0043] Example 1. Synthesis of planar chiral camphor phosphonate CAMDOL-PHO

[0044] Using camphor-derived 2,3-diol (CAMDOL) as a substrate to synthesize planar chiral camphor phosphonate CAMDOL-PHO (1):

[0045]

[0046] Add CAMDOL (6.44 g, 20 mmol) into a 500 mL reaction tube, fill with nitrogen, add THF (200 mL) and triethylamine (8.4 mL, 3 equivalents) into the reaction tube, control the temperature to 0 °C and react for 0.5 h, then slowly add phosphorus trichloride (19.2 mL, 1 M in THF, 1.1 equivalents) and continue to react until the substrate CAMDOL completely disappears (monitored by TLC, 1 h). Then add sodium methoxide (7.5 mL, 5.4 M, 3 equivalents) until the reaction intermediate completely disappears ( 31 monitored by ³¹P NMR, 1 h). After the reaction is complete, quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 85%.

[0047] 1 H NMR (300 MHz, Chloroform-d) δ 7.69 - 6.61 (m, 10H), 6.22 (s, 1H), 2.96 (d, J = 5.4 Hz, 1H), 2.15 (dddd, J = 14.8, 11.5, 5.5, 3.8 Hz, 1H), 1.71 (s, 4H), 1.40 - 1.21 (m, 2H), 1.16 (s, 3H), 0.94 (s, 3H). 13 C NMR (75 MHz, Chloroform-d) δ 138.15 (d, J = 2.9 Hz), 136.41 (d, J = 3.6 Hz), 129.95 (d, J = 26.7 Hz), 128.20, 127.77 (d, J = 4.3 Hz), 127.46 (dd, J = 13.9, 6.4 Hz), 126.40, 100.63, 99.45, 98.90 (d, J = 4.1 Hz), 74.57, 67.57, 54.95 (d, J = 3.3 Hz), 51.97, 51.29 (d, J = 5.6 Hz), 51.05 (d, J = 4.1 Hz), 48.86, 30.59, 29.45, 25.66, 24.09, 24.01, 23.50, 23.07, 22.18, 20.27 (d, J = 5.2 Hz), 11.47, 9.81, 9.70. 31 P NMR (122 MHz, Chloroform-d) δ 16.27.

[0048] Example 2. Synthesis of chiral camphoryl α-hydroxyphosphonate compound 3a

[0049] Using the enantiopure camphorylphosphite CAMDOL-PHO (1) and benzaldehyde (2a) as starting materials to synthesize (3a):

[0050]

[0051] Add the enantiopure camphorylphosphite CAMDOL-PHO (1) (0.4 mmol), benzaldehyde (2a) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube, purge with nitrogen, control the temperature to -78 °C and react for 1 h, then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by 31P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 85%.

[0052] 11H NMR (300 MHz, Chloroform-d) δ 7.29 (dd, J = 15.3, 7.5 Hz, 11H), 7.11 (t, J = 7.7 Hz, 2H), 6.88 (d, J = 7.9 Hz, 2H), 4.78 (d, J = 7.4 Hz, 1H), 3.06 (d, J = 5.4 Hz, 1H), 2.15 - 2.01 (m, 1H), 1.77 (s, 3H), 1.62 - 1.50 (m, 1H), 1.27 (d, J = 7.0 Hz, 2H), 1.15 (s, 3H), 0.79 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 138.16 (d, J = 3.3 Hz), 136.59, 136.03 (d, J = 4.8 Hz), 130.31 (d, J = 5.3 Hz), 128.80 (d, J = 2.7 Hz), 128.71 (d, J = 2.3 Hz), 128.28 (d, J = 6.9 Hz), 128.01 (d, J = 5.2 Hz), 126.24, 101.81, 99.32 (d, J = 1.8 Hz), 73.87, 71.98, 55.68 (d, J = 2.6 Hz), 52.06 (d, J = 3.3 Hz), 49.12, 48.29, 29.89, 26.56, 24.52, 21.64, 9.85. 31 31P NMR (122 MHz, Chloroform-d) δ 36.76.

[0053] Example 3. Synthesis of chiral camphoryl α-hydroxyphosphonate compound 3b

[0054] Using facial chiral camphoryl phosphite CAMDOL-PHO (1) and 4-chloro-benzaldehyde (2b) as raw materials to synthesize (3b):

[0055]

[0056] Add facial chiral camphoryl phosphite CAMDOL-PHO (1) (0.4 mmol), 4-chloro-benzaldehyde (2b) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube. Fill with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitored by 31P NMR, 24 h). Quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 78%.

[0057] 11H NMR (300 MHz, Chloroform-d) δ 7.47 - 7.36 (m, 2H), 7.36 - 7.15 (m, 8H), 6.98 (d, J = 8.2 Hz, 2H), 6.80 (dd, J = 8.6, 2.3 Hz, 2H), 4.74 (d, J = 9.5 Hz, 1H), 3.04 (d, J = 5.2 Hz, 1H), 2.09 (dt, J = 12.6, 6.4 Hz, 1H), 1.82 (s, 3H), 1.54 (h, J = 8.2 Hz, 2H), 1.38 (dq, J = 12.9, 7.0, 4.6 Hz, 1H), 1.19 (s, 3H), 1.01 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 138.09, 136.27, 135.27, 133.72, 130.53, 130.24, 128.64, 128.41 (d, J = 6.1 Hz), 128.24, 127.83, 126.65, 100.66, 99.89, 72.52, 70.61, 60.47, 55.92, 52.24, 48.40, 29.57, 26.56, 24.46, 21.53, 14.27, 10.05. 31 31P NMR (121 MHz, Chloroform-d) δ 34.82.

[0058] Example 4. Synthesis of chiral camphoryl α-hydroxyphosphonate compound 3c

[0059] Using facial chiral camphoryl phosphonite CAMDOL-PHO (1) and 4-methoxy-benzaldehyde (2c) as raw materials to synthesize (3c):

[0060]

[0061] Add facial chiral camphoryl phosphonite CAMDOL-PHO (1) (0.4 Mmol), 4-methoxy-benzaldehyde (2c) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube, fill with nitrogen, control the temperature to -78 °C and react for 1 h, then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by 31P NMR, 24 h). Quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate three times, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 86%.

[0062] 11H NMR (300 MHz, Chloroform-d) δ 7.35 - 7.21 (m, 8H), 7.12 (t, J = 7.7 Hz, 2H), 6.88 (t, J = 7.6 Hz, 4H), 4.71 (d, J = 6.7 Hz, 1H), 3.83 (s, 3H), 3.06 (d, J = 5.5 Hz, 1H), 2.07 (ddd, J = 13.9, 8.0, 4.2 Hz, 1H), 1.75 (s, 3H), 1.63 - 1.46 (m, 1H), 1.32 - 1.24 (m, 2H), 1.14 (s, 3H), 0.78 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 160.05 (d, J = 2.4 Hz), 138.20 (d, J = 3.2 Hz), 136.01 (d, J = 4.6 Hz), 130.28, 129.77 (d, J = 7.2 Hz), 128.63 (d, J = 3.3 Hz), 127.97 (d, J = 5.6 Hz), 126.18, 114.08 (d, J = 1.5 Hz), 101.60, 99.16 (d, J = 1.9 Hz), 73.36, 71.44, 55.61 (d, J = 2.8 Hz), 55.46, 52.01 (d, J = 3.3 Hz), 48.25, 29.79, 26.51, 24.51, 21.59, 9.85. 31 31P NMR (121 MHz, Chloroform-d) δ 36.87.

[0063] Example 5. Synthesis of chiral camphor-based α-hydroxyphosphonate compound 3d

[0064] Synthesis of (3d) using planar chiral camphor phosphite CAMDOL-PHO (1) and 2-naphthylbenzaldehyde (2d) as starting materials:

[0065]

[0066] Add planar chiral camphor phosphite CAMDOL-PHO (1) (0.4 mmol), 2-naphthylbenzaldehyde (2d) (0.48 mmol), and THF (8 mL) to a 25 mL reaction tube. Fill with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitored by 31P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 88%.

[0067] 11H NMR (300 MHz, Chloroform-d) δ 7.80 (t, J = 7.1 Hz, 2H), 7.75 - 7.66 (m, 1H), 7.64 - 7.54 (m, 2H), 7.54 - 7.40 (m, 2H), 7.31 (d, J = 4.1 Hz, 5H), 7.21 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.7 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.96 (d, J = 7.9 Hz, 1H), 3.25 (s, 1H), 3.00 (d, J = 5.2 Hz, 1H), 2.03 (dq, J = 14.0, 7.4 Hz, 1H), 1.69 (s, 3H), 1.53 (dt, J = 14.4, 7.1 Hz, 1H), 1.22 (t, J = 7.5 Hz, 2H), 1.08 (s, 3H), 0.72 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 138.00 (d, J = 3.2 Hz), 135.85 (d, J = 4.7 Hz), 134.09, 133.41 (d, J = 1.9 Hz), 132.97 (d, J = 1.6 Hz), 130.35, 130.18, 128.50, 128.42 (d, J = 1.7 Hz), 128.20, 127.88, 127.81, 127.72, 127.66, 127.54, 126.33, 126.12, 125.57 (d, J = 4.8 Hz), 101.72, 99.18 (d, J = 2.0 Hz), 73.90, 71.99, 55.48 (d, J = 2.7 Hz), 51.86 (d, J = 3.2 Hz), 48.04, 29.70, 26.42, 24.41, 21.43, 9.73. 31 31P NMR (121 MHz, Chloroform-d) δ 36.92.

[0068] Example 6. Synthesis of chiral camphor-based α-hydroxyphosphonate compound 3e

[0069] Compound (3e) was synthesized using facial chiral camphor-based phosphonite CAMDOL-PHO (1) and cinnamaldehyde (2e) as starting materials:

[0070]

[0071] Add chiral camphor-based phosphite CAMDOL-PHO(1) (0.4 mmol), cinnamaldehyde (2e) (0.48 mmol), and THF (8 mL) to a 25 mL reaction tube. Charge with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitor by ³¹P NMR for 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 85%.

[0072] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.45 - 6.99 (m, 15H), 6.56 (dd, J = 15.8, 4.3 Hz, 1H), 6.31 (ddd, J = 15.9, 7.3, 5.4 Hz, 1H), 4.45 (t, J = 8.0 Hz, 1H), 3.24 (s, 1H), 3.02 (d, J = 5.2 Hz, 1H), 2.12 - 1.97 (m, 1H), 1.74 (s, 3H), 1.56 (dt, J = 14.8, 7.2 Hz, 1H), 1.27 (t, J = 7.1 Hz, 2H), 1.12 (s, 3H), 0.84 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 137.97 (d, J = 3.2 Hz), 136.14 (dd, J = 6.4, 3.4 Hz), 133.88 (d, J = 14.1 Hz), 130.25, 128.55, 128.43, 128.09, 127.76, 126.88 (d, J = 1.8 Hz), 126.19, 124.04 (d, J = 3.4 Hz), 101.42, 99.12 (d, J = 1.8 Hz), 72.77, 70.83, 55.50 (d, J = 2.8 Hz), 51.90 (d, J = 3.3 Hz), 48.13, 31.58, 29.65, 26.39, 24.47, 22.66, 21.56, 14.17, 9.88. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 36.79

[0073] Example 7. Synthesis of chiral camphor-based α-hydroxyphosphonate compound 3f

[0074] Synthesize (3f) using chiral camphor-based phosphite CAMDOL-PHO(1) and 2-furaldehyde (2f) as starting materials:

[0075]

[0076] Add chiral camphor-based phosphonite (1) (0.4 mmol), 2-furaldehyde (2f) (0.48 mmol), and THF (8 mL) to a 25 mL reaction tube. Fill it with nitrogen, control the temperature at -78 °C and react for 1 h. Then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitored by ³¹P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 82%.

[0077] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.49 - 7.01 (m, 11H), 6.89 (t, J = 2.1 Hz, 1H), 5.91 (d, J = 1.8 Hz, 1H), 4.65 (d, J = 8.3 Hz, 1H), 3.86 (s, 1H), 3.04 (d, J = 5.4 Hz, 1H), 2.16 - 2.04 (m, 1H), 1.79 (s, 3H), 1.62 - 1.50 (m, 1H), 1.48 - 1.29 (m, 2H), 1.18 (s, 3H), 0.94 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 142.89, 140.79 (d, J = 10.5 Hz), 138.16 (d, J = 3.3 Hz), 136.20 (d, J = 4.0 Hz), 130.21 (d, J = 13.0 Hz), 128.40 (d, J = 24.3 Hz), 127.81, 126.73, 121.22, 109.21 (d, J = 4.7 Hz), 100.55, 99.41, 66.48, 64.50, 55.86 (d, J = 3.2 Hz), 52.13 (d, J = 3.2 Hz), 48.47, 29.51, 26.46, 24.55, 21.70, 10.09. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 35.10.

[0078] Example 8. Synthesis of chiral camphor-based α-hydroxyphosphonate compound 3g. Using chiral camphor-based phosphonite CAMDOL-PHO (1) and n-butyl formaldehyde (2g) as raw materials to synthesize (3g):

[0079]

[0080] Add chiral camphor-based phosphonite CAMDOL-PHO(1) (0.4 mmol), n-butyl formaldehyde (2 g) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube. Fill it with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add dropwise LDA (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitored by \(^{31}\)P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 70%.

[0081] 1 \(^1\)H NMR (300 MHz, Chloroform-d) δ 7.23 (dh, J=16.1, 9.2, 8.0 Hz, 10H), 3.76 (dd, J=9.1, 4.6 Hz, 1H), 3.03 (d, J=5.3 Hz, 1H), 2.36 (s, 1H), 2.08 (ddt, J=14.7, 9.3, 5.6 Hz, 1H), 1.77 (s, 5H), 1.55 (ddd, J=14.4, 11.8, 6.7 Hz, 2H), 1.46 - 1.35 (m, 1H), 1.29 (dd, J=8.9, 5.3 Hz, 2H), 1.15 (s, 3H), 0.91 - 0.81 (m, 6H). 13 \(^{13}\)C NMR (75 MHz, Chloroform-d) δ 138.25 (d, J=3.3 Hz), 136.48 (d, J=4.5 Hz), 130.06 (d, J=18.3 Hz), 128.39, 128.05, 127.73, 126.31, 101.33, 98.70 (d, J=1.8 Hz), 70.41, 68.50, 55.46 (d, J=2.8 Hz), 51.93 (d, J=3.2 Hz), 48.14, 34.12, 29.68, 26.40, 24.54, 21.54, 18.61, 18.45, 13.69, 9.94. 31 \(^{31}\)P NMR (121 MHz, Chloroform-d) δ 40.67.

[0082] Example 9. Synthesis of chiral camphor-based α-hydroxyphosphonate compound 3h. Using chiral camphor-based phosphonite CAMDOL-PHO(1) and cyclohexyl formaldehyde (2h) as raw materials to synthesize (3h):

[0083]

[0084] The chiral camphor-based phosphonite CAMDOL-PHO(1) (0.4 mmol), cyclohexyl formaldehyde (2h) (0.48 mmol), and THF (8 mL) were added to a 25 mL reaction tube. Nitrogen was filled in, and the temperature was controlled at -78 °C for reaction for 1 h. Subsequently, LDA (0.4 mmol) was slowly added dropwise and the reaction was continued until the substrate completely disappeared ( 31 monitored by ³¹P NMR, 24 h). It was quenched by adding saturated aqueous ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, dried, and separated by column chromatography to obtain a white solid with a yield of 82%.

[0085] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.27 (t, J = 7.5 Hz, 10H), 3.42 (dd, J = 6.1, 4.1 Hz, 1H), 3.04 (d, J = 5.3 Hz, 1H), 2.17 - 2.07 (m, 1H), 1.79 (s, 3H), 1.74 (s, 1H), 1.57 (p, J = 8.2, 7.4 Hz, 2H), 1.39 (qd, J = 11.6, 6.9 Hz, 4H), 1.26 (t, J = 7.1 Hz, 2H), 1.17 (s, 3H), 0.88 (d, J = 8.3 Hz, 8H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 137.99 (d, J = 3.3 Hz), 136.34 (d, J = 4.1 Hz), 130.01, 128.38, 128.03, 126.56, 99.88, 99.10 (d, J = 1.5 Hz), 75.79, 73.96, 60.48, 55.62 (d, J = 3.1 Hz), 51.98 (d, J = 3.0 Hz), 48.38, 39.49 (d, J = 4.3 Hz), 29.54 (t, J = 6.0 Hz), 26.83 (d, J = 6.1 Hz), 26.39, 26.00 (d, J = 1.9 Hz), 25.74 (d, J = 6.5 Hz), 24.48, 21.63, 14.27, 9.99. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 39.98.

[0086] Example 10. Synthesis of chiral camphor-based α-aminophosphonate compound 5a

[0087] Using chiral camphor-based phosphonite CAMDOL-PHO(1) and N-benzylidene-4-methylbenzenesulfonamide (4a) as raw materials to synthesize (5a):

[0088]

[0089] Add chiral planar camphor phosphite CAMDOL-PHO(1) (0.4 mmol), N-benzylidene-4-methylbenzenesulfonylbenzene (4a) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube. Fill it with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by ³¹P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 95%.

[0090] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.38 (dd, J = 5.5, 1.9 Hz, 3H), 7.30 - 7.24 (m, 4H), 7.22 (d, J = 3.7 Hz, 1H), 7.20 - 7.11 (m, 4H), 7.08 - 6.97 (m, 4H), 6.83 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 5.75 (dd, J = 9.2, 6.7 Hz, 1H), 4.72 (dd, J = 18.9, 9.3 Hz, 1H), 3.00 (d, J = 5.3 Hz, 1H), 2.26 (s, 3H), 2.12 - 1.96 (m, 1H), 1.67 (s, 3H), 1.63 - 1.46 (m, 1H), 1.27 - 1.20 (m, 2H), 1.11 (s, 3H), 0.71 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 142.49, 137.94, 137.46 (d, J = 3.1 Hz), 135.32 (d, J = 4.6 Hz), 134.18, 130.35 (d, J = 7.9 Hz), 129.29 (d, J = 6.8 Hz), 129.09, 128.80, 128.63 (d, J = 1.4 Hz), 128.53 (d, J = 2.4 Hz), 128.13, 128.02, 126.64, 101.89, 99.67 (d, J = 1.8 Hz), 58.31, 56.40, 55.59 (d, J = 3.0 Hz), 51.91 (d, J = 3.6 Hz), 48.14, 29.82, 26.51, 24.34, 21.53 (d, J = 6.0 Hz), 9.68. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 33.88.

[0091] Example 11. Synthesis of chiral camphor-based α-aminophosphonate compound 5b

[0092] (5b) was synthesized using facial chiral camphor phosphonite CAMDOL-PHO(1) and N-(2-chlorobenzylidene)-4-methylbenzenesulfonylbenzene (4b) as starting materials:

[0093]

[0094] Facial chiral camphor phosphonite CAMDOL-PHO(1) (0.4 mmol), N-(2-chlorobenzylidene)-4-methylbenzenesulfonylbenzene (4b) (0.48 mmol), and THF (8 mL) were added to a 25 mL reaction tube. Nitrogen was filled, and the temperature was controlled at -78 °C for 1 h. Subsequently, BTMG (0.4 mmol) was slowly added dropwise and the reaction continued until the substrate completely disappeared ( 31 monitored by ³¹P NMR, 24 h). The reaction was quenched by adding saturated ammonium chloride aqueous solution, and extracted three times with ethyl acetate. The organic phases were combined, dried, and separated by column chromatography to obtain a white solid with a yield of 97%.

[0095] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.40–7.15 (m, 13H), 6.94–6.83 (m, 1H), 6.77–6.62 (m, 4H), 6.48 (dq, J = 8.3, 4.4 Hz, 1H), 5.18 (dd, J = 21.9, 10.8 Hz, 1H), 2.99 (d, J = 5.2 Hz, 1H), 2.03 (s, 4H), 1.85 (s, 3H), 1.49 (d, J = 10.3 Hz, 2H), 1.32 (dd, J = 11.7, 7.9 Hz, 1H), 1.15 (s, 3H), 1.07 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 142.38, 137.81 (d, J = 2.2 Hz), 136.78 (d, J = 3.3 Hz), 135.66 (d, J = 4.4 Hz), 132.72 (d, J = 8.5 Hz), 131.80, 131.48 (d, J = 4.0 Hz), 130.60, 128.88, 128.80, 128.44 (d, J = 2.7 Hz), 128.29, 128.06, 127.93, 126.79, 126.60, 126.50, 101.57, 101.40, 55.97 (d, J = 3.2 Hz), 52.23 (d, J = 3.5 Hz), 48.50, 29.96, 26.72, 24.49, 22.16, 21.29, 10.02. 31P NMR (121 MHz, Chloroform-d) δ 33.09.

[0096] Example 12. Synthesis of chiral camphoryl α-aminophosphonate compound 5c

[0097] Compound (5c) was synthesized using facial chiral camphoryl phosphite CAMDOL-PHO (1) and 4-methyl-N-(pyridin-3-ylmethylene)benzenesulfonamide (4c) as starting materials:

[0098]

[0099] Facial chiral camphoryl phosphite CAMDOL-PHO (1) (0.4 mmol), 4-methyl-N-(pyridin-3-ylmethylene)benzenesulfonamide (4c) (0.48 mmol), and THF (8 mL) were added to a 25 mL reaction tube. Nitrogen was filled, and the temperature was controlled at -78 °C for reaction for 1 h. Subsequently, BTMG (0.4 mmol) was slowly added dropwise and the reaction continued until the substrate completely disappeared ( 31 monitored by ³¹P NMR, 24 h). The reaction was quenched by adding saturated ammonium chloride aqueous solution, and extracted three times with ethyl acetate. The organic phases were combined, dried, and separated by column chromatography to obtain a white solid with a yield of 90%.

[0100] 1 ¹H NMR (300 MHz, Chloroform-d) δ 8.08 - 8.00 (m, 1H), 7.91 (dd, J = 10.6, 3.2 Hz, 1H), 7.42 (d, J = 6.4 Hz, 9H), 7.31 - 7.15 (m, 5H), 6.80 (d, J = 8.1 Hz, 2H), 6.51 (dd, J = 7.9, 4.8 Hz, 1H), 4.88 (dd, J = 21.9, 10.5 Hz, 1H), 3.06 (d, J = 5.2 Hz, 1H), 2.13 (s, 3H), 1.88 (s, 3H), 1.59 (ddq, J = 26.3, 13.6, 7.9, 6.9 Hz, 2H), 1.41 (td, J = 12.5, 4.5 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 3H). 1313C NMR (75 MHz, Chloroform-d) δ 148.89 (d, J = 7.0 Hz), 148.24, 142.38, 138.23 (d, J = 2.2 Hz), 137.50 (d, J = 3.2 Hz), 135.71 (d, J = 4.3 Hz), 135.15 (d, J = 4.1 Hz), 130.45, 129.11, 128.85 (d, J = 3.4 Hz), 128.31, 126.66, 122.77, 101.42, 100.52, 56.04 (d, J = 3.2 Hz), 55.42, 53.44, 52.25 (d, J = 3.4 Hz), 48.45, 29.68, 26.44, 24.16, 22.11, 21.19, 9.82. 31 31P NMR (121 MHz, Chloroform-d) δ 31.26.

[0101] Example 13. Synthesis of Chiral Camphoryl α-Aminophosphonate Compound 5d

[0102] Compound (5d) was synthesized using facial chiral camphoryl phosphite CAMDOL-PHO (1) and 4-methylbenzenesulfonyl-N-butylimine (4d) as starting materials:

[0103]

[0104] Facial chiral camphoryl phosphite CAMDOL-PHO (1) (0.4 mmol), 4-methylbenzenesulfonyl-N-butylimine (4d) (0.48 mmol), and THF (8 mL) were added to a 25 mL reaction tube. Nitrogen was filled, and the temperature was controlled at -78 °C for 1 h. Then, BTMG (0.4 mmol) was slowly added dropwise and the reaction continued until the substrate completely disappeared ( 31 monitored by 31P NMR, 24 h). The reaction was quenched by adding saturated aqueous ammonium chloride solution, and extracted three times with ethyl acetate. The organic phases were combined, dried, and separated by column chromatography to obtain a white solid with a yield of 80%.

[0105] 11H NMR (300 MHz, Chloroform-d) δ 7.88 (d, J = 7.9 Hz, 2H), 7.62 - 7.50 (m, 1H), 7.47 - 7.22 (m, 6H), 7.19 - 7.03 (m, 3H), 6.71 (d, J = 80.9 Hz, 3H), 5.87 (dd, J = 9.8, 4.8 Hz, 1H), 3.50 (p, J = 7.5 Hz, 1H), 2.98 (d, J = 5.3 Hz, 1H), 2.45 (s, 3H), 2.06 (dd, J = 15.0, 7.5 Hz, 1H), 1.53 (dt, J = 14.7, 7.2 Hz, 1H), 1.32 - 1.23 (m, 2H), 1.14 (s, 3H), 1.03 (dt, J = 22.8, 10.4 Hz, 4H), 0.75 (s, 3H), 0.44 (t, J = 7.0 Hz, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 143.22, 139.26, 137.55 (d, J = 3.4 Hz), 135.51 (d, J = 4.3 Hz), 129.55, 128.48, 128.04, 126.89, 101.06, 99.21, 55.54 (d, J = 2.9 Hz), 53.98, 52.11, 48.29, 32.73, 29.68, 26.48, 24.40, 21.66 (d, J = 6.1 Hz), 18.43 (d, J = 10.4 Hz), 13.43, 9.61. 31 31P NMR (121 MHz, Chloroform-d) δ 37.69.

[0106] Example 14. Synthesis of chiral camphor-based α-aminophosphonate compound 5e

[0107] Using face-chiral camphor phosphonite CAMDOL-PHO (1) and 4-methylbenzenesulfonyl-N-cyclohexylimine (4e) as raw materials to synthesize (5e):

[0108]

[0109] Add face-chiral camphor phosphonite CAMDOL-PHO (1) (0.4 mmol), 4-methylbenzenesulfonyl-N-cyclohexylimine (4e) (0.48 mmol), and THF (8 mL) into a 25 mL reaction tube, fill with nitrogen, control the temperature to -78 °C and react for 1 h, then slowly add dropwise BTMG (0.4 mmol) and continue the reaction until the substrate completely disappears ( 31PNMR monitoring (24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 85%.

[0110] 1 H NMR (300 MHz, Chloroform-d) δ 8.08 - 8.00 (m, 1H), 7.91 (dd, J = 10.6, 3.2 Hz, 1H), 7.42 (d, J = 6.4 Hz, 9H), 7.31 - 7.15 (m, 5H), 6.80 (d, J = 8.1 Hz, 2H), 6.51 (dd, J = 7.9, 4.8 Hz, 1H), 4.88 (dd, J = 21.9, 10.5 Hz, 1H), 3.06 (d, J = 5.2 Hz, 1H), 2.13 (s, 3H), 1.88 (s, 3H), 1.59 (ddq, J = 26.3, 13.6, 7.9, 6.9 Hz, 2H), 1.41 (td, J = 12.5, 4.5 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 3H). 13 C NMR (75 MHz, Chloroform-d) δ 148.89 (d, J = 7.0 Hz), 148.24, 142.38, 138.23 (d, J = 2.2 Hz), 137.50 (d, J = 3.2 Hz), 135.71 (d, J = 4.3 Hz), 135.15 (d, J = 4.1 Hz), 130.45, 129.11, 128.85 (d, J = 3.4 Hz), 128.31, 126.66, 122.77, 101.42, 100.52, 56.04 (d, J = 3.2 Hz), 55.42, 53.44, 52.25 (d, J = 3.4 Hz), 48.45, 29.68, 26.44, 24.16, 22.11, 21.19, 9.82. 31 P NMR (121 MHz, Chloroform-d) δ 31.26.

[0111] Example 15. Synthesis of chiral camphoryl β-nitrophosphonate compound 7a

[0112] Synthesize (7a) using facial chiral camphorylphosphite CAMDOL-PHO (1) and β-nitrostyrene (6a) as starting materials:

[0113]

[0114] Add chiral camphor-based phosphonite CAMDOL-PHO(1) (0.2 mmol), β-nitrostyrene (6a) (0.24 mmol), and methyl tetrahydrofuran (Me-THF) (4 mL) into a 25 mL reaction tube. Fill it with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add sodium bis(trimethylsilyl)amide (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitor by ³¹P NMR for 24 h). Quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 95%.

[0115] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.51 - 7.16 (m, 14H), 7.10 - 6.96 (m, 1H), 4.74 (ddd, J = 13.7, 12.1, 4.5 Hz, 1H), 4.21 (ddd, J = 13.7, 6.0, 3.4 Hz, 1H), 3.81 (ddd, J = 20.5, 12.1, 3.4 Hz, 1H), 3.09 (d, J = 5.4 Hz, 1H), 2.10 (ddd, J = 19.6, 10.0, 4.9 Hz, 1H), 1.65 - 1.49 (m, 1H), 1.39 - 1.30 (m, 2H), 1.16 (s, 3H), 0.76 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 138.01 (d, J = 3.3 Hz), 135.42 (d, J = 4.1 Hz), 131.24 (d, J = 7.5 Hz), 130.34, 130.05 (d, J = 6.4 Hz), 129.11 - 128.66 (m), 128.56, 101.87, 99.46, 75.57 (d, J = 6.1 Hz), 55.79 (d, J = 3.4 Hz), 52.19 (d, J = 3.3 Hz), 48.27, 46.48, 44.79, 29.62, 26.45, 24.44, 21.49, 9.85. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 34.78.

[0116] Example 16. Synthesis of chiral camphor-based β-nitro phosphonate compound 7b

[0117] Synthesize (7b) using chiral camphor-based phosphonite CAMDOL-PHO(1) and 4-chloro-β-nitrostyrene (6b) as raw materials:

[0118]

[0119] Add chiral camphor phosphite CAMDOL-PHO(1) (0.2 mmol), 4-chloro-β-nitrostyrene (6b) (0.24 mmol), and Me-Me-THF (4 mL) into a 25 mL reaction tube. Fill it with nitrogen, control the temperature at -78 °C and react for 1 h. Then slowly add NaHMDS (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 Monitor by \(^{31}\)P NMR for 24 h). Quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 90%.

[0120] 1 \(^1\)H NMR (300 MHz, Chloroform-d) δ 7.46 - 7.19 (m, 12H), 7.01 (d, J = 24.3 Hz, 2H), 4.68 (ddd, J = 13.9, 12.2, 4.2 Hz, 1H), 4.19 (ddd, J = 13.8, 5.9, 3.4 Hz, 1H), 3.78 (ddd, J = 20.5, 12.2, 3.4 Hz, 1H), 3.09 (d, J = 5.3 Hz, 1H), 2.11 (ddt, J = 15.3, 10.7, 5.7 Hz, 1H), 1.72 (s, 3H), 1.57 (dt, J = 14.5, 7.3 Hz, 1H), 1.38 - 1.29 (m, 2H), 1.16 (s, 3H), 0.77 (s, 3H). 13 \(^{13}\)C NMR (75 MHz, Chloroform-d) δ 137.93 (d, J = 3.4 Hz), 135.40 (d, J = 4.1 Hz), 134.95 (d, J = 3.2 Hz), 131.43 (d, J = 6.4 Hz), 130.25, 129.88 (d, J = 7.4 Hz), 129.20 (d, J = 2.2 Hz), 128.84 (d, J = 17.9 Hz), 128.35, 127.16 - 125.90 (m), 102.01, 99.66 (d, J = 1.3 Hz), 75.38 (d, J = 5.8 Hz), 55.84 (d, J = 3.4 Hz), 52.20 (d, J = 3.3 Hz), 48.28, 45.90, 44.21, 29.60, 26.43, 24.43, 21.47, 9.85. 31 \(^{31}\)P NMR (121 MHz, Chloroform-d) δ 34.01.

[0121] Example 17. Synthesis of chiral camphor-based β-nitrophosphonate compound 7c: Using fac-chiral camphor phosphite CAMDOL-PHO (1) and 1-(2-nitrovinyl)naphthalene (6c) as starting materials to synthesize (7c):

[0122]

[0123] Add fac-chiral camphor phosphite CAMDOL-PHO (1) (0.2 mmol), 1-(2-nitrovinyl)naphthalene (6c) (0.24 mmol), and Me-THF (4 mL) into a 25 mL reaction tube. Fill it with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add NaHMDS (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by ³¹P NMR, 24 h). Quench with saturated ammonium chloride aqueous solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 90%.

[0124] 1 ¹H NMR (300 MHz, Chloroform-d) δ 7.98 - 6.96 (m, 15H), 6.73 (t, J = 7.4 Hz, 2H), 5.33 - 5.14 (m, 1H), 4.87 - 4.53 (m, 2H), 2.95 (d, J = 5.4 Hz, 1H), 2.14 - 1.96 (m, 1H), 1.82 (s, 3H), 1.62 - 1.45 (m, 1H), 1.32 (t, J = 7.6 Hz, 2H), 1.16 (s, 3H), 0.95 (s, 3H). 13 ¹³C NMR (75 MHz, Chloroform-d) δ 136.78 (d, J = 3.4 Hz), 135.96 (d, J = 4.2 Hz), 133.98, 131.18, 131.04, 130.06, 129.39, 128.88, 128.41, 127.88 (dd, J = 10.7, 5.4 Hz), 127.65, 127.22, 127.08 - 126.63 (m), 125.76, 125.37 (d, J = 1.9 Hz), 121.31, 101.49, 99.83 (d, J = 1.6 Hz), 55.80 (d, J = 3.3 Hz), 51.95 (d, J = 3.5 Hz), 48.32, 42.66, 40.90, 29.82, 29.56, 26.49, 24.66, 21.61, 10.12. 31 ³¹P NMR (121 MHz, Chloroform-d) δ 36.62.

[0125] Example 18. Synthesis of chiral camphor-based β-nitrophosphonate compound 7d. Using facial chiral camphor phosphite CAMDOL-PHO(1) and 2-(2-nitrovinyl)pyridine (6d) as starting materials to synthesize (7d):

[0126]

[0127] Add facial chiral camphor phosphite CAMDOL-PHO(1) (0.2 mmol), 2-(2-nitrovinyl)pyridine (6d) (0.24 mmol), and Me-THF (4 mL) into a 25 mL reaction tube. Charge with nitrogen, control the temperature to -78 °C and react for 1 h. Then slowly add NaHMDS (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by \(^{31}\)P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 87%.

[0128] 1 \(^1\)H NMR (300 MHz, Chloroform-d) δ 8.63 (d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 7.94 - 7.85 (m, 1H), 7.37 (ddd, J = 24.0, 17.5, 11.4 Hz, 9H), 7.02 (s, 2H), 4.70 (td, J = 13.1, 4.0 Hz, 1H), 4.20 (ddd, J = 14.0, 5.9, 3.4 Hz, 1H), 3.82 (ddd, J = 20.5, 12.3, 3.3 Hz, 1H), 3.11 (d, J = 5.4 Hz, 1H), 2.14 (dq, J = 9.6, 5.0 Hz, 1H), 1.71 (s, 3H), 1.58 (dt, J = 14.5, 7.4 Hz, 1H), 1.46 - 1.23 (m, 2H), 1.17 (s, 3H), 0.78 (s, 3H). 1313C NMR (75 MHz, Chloroform-d) δ 151.24 (d, J = 7.9 Hz), 150.17 (d, J = 2.9 Hz), 137.84 (d, J = 3.3 Hz), 137.01 (d, J = 4.7 Hz), 135.23 (d, J = 4.1 Hz), 129.80, 128.97 (d, J = 8.0 Hz), 127.70 (d, J = 7.3 Hz), 123.92 (d, J = 2.3 Hz), 102.18, 99.83, 74.85 (d, J = 5.6 Hz), 55.85 (d, J = 3.4 Hz), 52.17 (d, J = 3.4 Hz), 48.27, 43.85, 42.16, 29.53, 26.38, 24.41, 21.45, 9.83. 31 31P NMR (121 MHz, Chloroform-d) δ 33.49.

[0129] Example 19. Synthesis of chiral camphor-based β-nitrophosphonate compound 7e

[0130] Using facial chiral camphor phosphite CAMDOL-PHO (1) and β-isopropylbenzene nitrostyrene (6e) as starting materials to synthesize (7e):

[0131]

[0132] Add facial chiral camphor phosphite CAMDOL-PHO (1) (0.2 mmol), β-isopropylbenzene nitrostyrene (6e) (0.24 mmol), and Me-THF (4 mL) into a 25 mL reaction tube, purge with nitrogen, control the temperature to -78 °C and react for 1 h, then slowly add dropwise NaHMDS (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by 31P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 75%.

[0133] 11H NMR (300 MHz, Chloroform-d) δ 7.31 (d, J = 28.9 Hz, 10H), 4.36 (ddd, J = 14.0, 11.1, 4.6 Hz, 1H), 3.90 (ddd, J = 13.8, 10.4, 3.0 Hz, 1H), 3.04 (d, J = 5.4 Hz, 1H), 2.54 (dddd, J = 20.0, 11.2, 5.2, 3.1 Hz, 1H), 2.37 - 2.01 (m, 2H), 1.76 (s, 3H), 1.65 - 1.49 (m, 1H), 1.31 (td, J = 7.5, 6.7, 4.0 Hz, 2H), 1.21 - 1.06 (m, 9H), 0.90 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 137.81 (d, J = 3.4 Hz), 136.05 (d, J = 4.3 Hz), 128.70, 128.48, 101.90, 99.06 (d, J = 1.6 Hz), 72.59 (d, J = 5.0 Hz), 55.76 (d, J = 3.1 Hz), 52.05 (d, J = 3.2 Hz), 48.20, 45.37, 43.70, 29.74, 28.38 (d, J = 3.9 Hz), 26.53, 24.55, 21.46, 20.96 (d, J = 7.0 Hz), 19.79 (d, J = 6.5 Hz), 9.99. 31 31P NMR (121 MHz, Chloroform-d) δ 39.08.

[0134] Example 20. Synthesis of chiral camphoryl β-nitrophosphonate compound 7f

[0135] Using facial chiral camphoryl phosphite CAMDOL-PHO (1) and ((e)-2-nitrovinyl) cyclohexane (6f) as raw materials to synthesize (7f):

[0136]

[0137] Add facial chiral camphoryl phosphite CAMDOL-PHO (1) (0.2 mmol), ((e)-2-nitrovinyl) cyclohexane (6f) (0.24 mmol), and Me-THF (4 mL) into a 25 mL reaction tube, fill with nitrogen, control the temperature to -78 °C and react for 1 h, then slowly add NaHMDS (0.2 mmol) and continue the reaction until the substrate completely disappears ( 31 monitored by 31P NMR, 24 h). Quench with saturated aqueous ammonium chloride solution, extract three times with ethyl acetate, combine the organic phases, dry, and separate by column chromatography to obtain a white solid with a yield of 87%.

[0138] 1 1H NMR (300 MHz, Chloroform-d) δ 7.54 - 6.99 (m, 10H), 4.38 (ddd, J = 14.2, 10.8, 5.4 Hz, 1H), 3.93 (ddd, J = 14.2, 10.9, 3.2 Hz, 1H), 3.04 (d, J = 5.3 Hz, 1H), 2.64 - 2.46 (m, 1H), 2.09 (ddt, J = 15.1, 10.3, 5.4 Hz, 1H), 1.97 - 1.43 (m, 11H), 1.43 - 1.20 (m, 6H), 1.17 (s, 3H), 0.91 (s, 3H). 13 13C NMR (75 MHz, Chloroform-d) δ 137.80 (d, J = 3.3 Hz), 136.11 (d, J = 4.2 Hz), 128.69, 128.47, 101.86, 99.02 (d, J = 1.6 Hz), 72.42 (d, J = 4.7 Hz), 55.77 (d, J = 3.2 Hz), 52.04 (d, J = 3.5 Hz), 48.23, 45.20, 43.54, 38.25 (d, J = 3.8 Hz), 31.59 (d, J = 7.3 Hz), 30.10 - 29.63 (m), 26.82, 26.55 (d, J = 3.6 Hz), 25.96, 24.54, 21.49, 10.02. 31 31P NMR (121 MHz, Chloroform-d) δ 39.72.

[0139] Comparative Examples 1 to 3

[0140] The α-hydroxyphosphonate compounds were synthesized in the same manner as in Example 2, except that the point-chiral phosphonite Menthyl-PHO(2), the axial-chiral phosphonite TADDOL-PHO(3), and the axial-chiral phosphonite BINOL-PHO(4) were used to replace the face-chiral camphor-based phosphonite CAMDOL-PHO(1), respectively, to synthesize the α-hydroxyphosphonate compounds 3i, 3j, and 3k, respectively.

[0141] The products of each reaction and their comparison results are listed in Table 1 below.

[0142] Table 1

[0143]

[0144]

[0145] As can be seen from Table 1, in Comparative Example 1, the point-chiral phosphonite 2 was used as a chiral induction reagent (auxiliary group), and the yield of the resulting compound 3i was 45%, and the diastereomeric ratio was 68:32. In Comparative Example 2, the axially chiral phosphonite 3 was used as a chiral induction reagent (auxiliary group), and the yield of the resulting compound 3j was 75%, and the diastereomeric ratio was 97:3. In Comparative Example 3, the axially chiral phosphonite 4 was used as a chiral induction reagent (auxiliary group), and thus the target compound 3k could not be synthesized.

[0146] In contrast, in Example 2 of the present invention, the face-chiral phosphonite 1 was used as a chiral induction reagent (auxiliary group), and the yield of the resulting compound 3a was as high as 85%, and the diastereomeric ratio was 99:1. Obviously, when the face-chiral phosphonite provided by the present invention is used as an auxiliary group in the Pudovik reaction to synthesize compounds containing an optically pure α-hydroxyphosphonic acid structure, the reaction yield and diastereoselectivity can be improved simultaneously.

[0147] Comparative Examples 4 to 6.

[0148] The α-aminophosphonate compounds were synthesized in the same manner as in Example 10, except that the point-chiral phosphonite Menthyl-PHO (2), the axially chiral phosphonite TADDOL-PHO (3), and the axially chiral phosphonite BINOL-PHO (4) were used to replace the face-chiral camphor-based phosphonite CAMDOL-PHO (1), and the α-hydroxyphosphonate compounds 5f, 5g, and 5h were synthesized respectively.

[0149] The products of each reaction and their comparison results are listed in Table 2 below.

[0150] Table 2

[0151]

[0152]

[0153] As can be seen from Table 2, in Comparative Example 4, the point-chiral phosphonite 2 was used as a chiral induction reagent (auxiliary group), and the yield of the resulting compound 5f was 35%, and the diastereomeric ratio was 60:40. In Comparative Example 5, the axially chiral phosphonite 3 was used as a chiral induction reagent (auxiliary group), and the yield of the resulting compound 5g was 50%, and the diastereomeric ratio was 66:34. In Comparative Example 6, the axially chiral phosphonite 4 was used as a chiral induction reagent (auxiliary group), and thus the target compound 5h could not be synthesized.

[0154] In contrast, in Example 10 of the present invention, a face-chiral phosphonite 1 was used as a chiral induction reagent (auxiliary group), and the yield of the obtained compound 5a was as high as 95%, and the diastereomeric ratio was 99:1. Obviously, when the face-chiral phosphonite provided by the present invention is used as an auxiliary group in the Pudovik reaction to synthesize a compound containing an optically pure α-aminophosphonic acid structure, the yield and diastereoselectivity of the reaction can be improved simultaneously.

[0155] Comparative Examples 7 to 9.

[0156] α-Hydroxyphosphonate compounds were synthesized in the same manner as in Example 15, except that the point-chiral phosphonite Menthyl-PHO (2), the axially chiral phosphonite TADDOL-PHO (3), and the axially chiral phosphonite BINOL-PHO (4) were used to replace the face-chiral camphor-based phosphonite CAMDOL-PHO (1), respectively, to synthesize α-hydroxyphosphonate compounds 7g, 7h, and 7i.

[0157] The products of each reaction and their comparison results are listed in Table 3 below.

[0158] Table 3

[0159]

[0160]

[0161] As can be seen from Table 3, in Comparative Example 7, the point-chiral phosphonite 2 was used as a chiral induction reagent (auxiliary group), and the yield of the obtained compound 7g was less than 5%. In Comparative Example 8, the axially chiral phosphonite 3 was used as a chiral induction reagent (auxiliary group), and the yield of the obtained compound 7h was 40%, and the diastereomeric ratio was 79:21. In Comparative Example 9, the axially chiral phosphonite 4 was used as a chiral induction reagent (auxiliary group), and thus the target compound 7i could not be synthesized.

[0162] In contrast, in Example 15 of the present invention, a face-chiral phosphonite 1 was used as a chiral induction reagent (auxiliary group), and the yield of the obtained compound 7a was as high as 95%, and the diastereomeric ratio was 95:5. Obviously, when the face-chiral phosphonite provided by the present invention is used as an auxiliary group in the Pudovik reaction to synthesize a compound containing an optically pure β-nitrophosphonic acid structure, the yield and diastereoselectivity of the reaction can be improved simultaneously.

[0163] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the technical principle of the present invention, several improvements and deformations can be made, and these improvements and deformations should also be regarded as the protection scope of the present invention.

Claims

1. A camphor-based phosphite ester, which is a face-chiral camphor-based phosphite ester, as shown in the following formula:

2. A method for synthesizing a face-chiral camphor-based phosphite ester, the method comprising the following steps: Under an inert gas atmosphere, a camphor-derived 2,3-diol as a substrate, triethylamine and a reaction solvent are reacted at a reaction temperature of 0 to 40 °C for 1 to 6 hours; Then phosphorus trichloride is added and the reaction is continued until the substrate completely disappears; Sodium methoxide is then added, and the reaction temperature is controlled at 0 to 40 °C and the reaction is carried out for 1 to 6 hours until the reaction is complete; The obtained product is subjected to silica gel column chromatography to obtain the desired face-chiral camphor-based phosphite ester.

3. The method for synthesizing a face-chiral camphor-based phosphite ester according to claim 1, wherein The molar ratio of the camphor-derived 2,3-diol to the triethylamine is 1:(1.1 to 3); The molar ratio of the camphor-derived 2,3-diol to the sodium methoxide is 1:(1.1 to 3); The reaction solvent is tetrahydrofuran.

4. The application of the face-chiral camphor-based phosphite ester according to claim 1 in the synthesis method of a chiral camphor-based α-hydroxyphosphonate compound, wherein The face-chiral camphor-based phosphite ester is used as a co-base in the Pudovik reaction and mixed with an aryl aldehyde or an alkyl aldehyde; Under an inert gas atmosphere, it is reacted with a reaction solvent and a basic additive at a reaction temperature of -80 to 0 °C for 20 to 28 hours to obtain the desired chiral camphor-based α-hydroxyphosphonate compound; Among them, the aryl aldehyde or alkyl aldehyde is one of benzaldehyde, 4-chlorobenzaldehyde, 4-methoxybenzaldehyde, 2-naphthaldehyde, cinnamaldehyde, 2-furaldehyde, n-butanal, cyclohexanecarbaldehyde; the basic additive is lithium diisopropylamide.

5. The application according to claim 4, wherein The molar ratio of the face-chiral camphor-based phosphite ester to the aryl aldehyde or alkyl aldehyde is 1:(1.1 to 3); The dosage of the basic additive is 1 equivalent; The reaction solvent is tetrahydrofuran.

6. The application of the face-chiral camphor-based phosphite ester according to claim 1 in the synthesis method of a chiral camphor-based α-aminophosphonate compound, wherein The face-chiral camphor-based phosphite ester is used as a co-base in the Pudovik reaction and mixed with an aryl aldehyde or an alkyl aldehyde; Under an inert gas atmosphere, it is reacted with a reaction solvent and a basic additive at a reaction temperature of -80 to 0 °C for 20 to 28 hours to obtain the desired chiral camphor-based α-aminophosphonate compound; Among them, the aryl aldehyde imine or alkyl aldehyde imine is one of N-benzylidene-4-methylbenzenesulfonylbenzene, N-(2-chlorobenzylidene)-4-methylbenzenesulfonylbenzene, 4-methyl-N-(pyridin-3-ylmethylene)benzenesulfonylbenzene, 4-methylbenzenesulfonyl-N-n-butylimine, 4-methylbenzenesulfonyl-N-cyclohexylimine; the basic additive is 2-tert-butyl-1,1,3,3-tetramethylguanidine.

7. The application according to claim 6, wherein The molar ratio of the face-chiral camphor-based phosphite to the aryl aldimine or alkyl aldimine is 1:(1.1 - 3); The dosage of the basic additive is 1 equivalent; The reaction solvent is tetrahydrofuran.

8. Use of the face-chiral camphor-based phosphite according to claim 1 in a method for synthesizing a chiral camphor-based β-nitro phosphonate compound, wherein, The face-chiral camphor-based phosphite is used as a co-group for the Pudovik reaction and mixed with an aryl β-nitroolefin or an alkyl β-nitroolefin; Under an inert gas atmosphere, it reacts with a reaction solvent and a basic additive at a reaction temperature of -80 to 0 °C for 20 to 28 hours to obtain the desired chiral camphor-based β-nitro phosphonate compound; wherein, the aryl β-nitroolefin or alkyl β-nitroolefin is one of β-nitrostyrene, 4-chloro-β-nitrostyrene, 1-(2-nitrovinyl)naphthalene, 2-(2-nitrovinyl)pyridine, β-isopropylbenzene nitrostyrene, ((e)-2-nitrovinyl)cyclohexane; the basic additive is sodium bis(trimethylsilyl)amide.

9. According to the use described in claim 8, wherein The molar ratio of the face-chiral camphor-based phosphite to the aryl β-nitroolefin or alkyl β-nitroolefin is 1:(1.1 - 3); The dosage of the basic additive is 1 equivalent. The reaction solvent is methyltetrahydrofuran.

10. A chiral phosphonate compound, including any one of the following compounds 3a to 3h, compounds 5a to 5e, compounds 7a to 7f:

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