Chiral hydroxyphosphonates, processes for their preparation and uses thereof

Abstract

The application belongs to the technical field of chemical synthesis, and specifically provides a chiral hydroxyphosphonate, a preparation method and application thereof. The chiral hydroxyphosphonate has a structure as shown in formula II: each R is independently H, an alkyl group, an alkenyl group, an alkynyl group or a halogenated alkyl group; Ar is an aromatic ring or a heteroaromatic ring; X is a bond, -O-, -N(R 1 )- 2 q , -S(=O) m -; the chiral hydroxyphosphonate is obtained by reducing an alpha phosphonate substituted benzocycloalkanone compound through an asymmetric hydrogenation method, has two chiral centers, and has a yield of up to 99% and an enantiomeric selectivity of up to 99%. The chiral hydroxyphosphonate has wide application potential and value in skin tissue soothing, repairing, anti-aging and the like.​

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and provides a chiral hydroxyphosphonate, its preparation method and uses, specifically a method for preparing chiral hydroxyphosphonates from phosphonate-substituted benzo[a]cyclic ketone compounds, particularly involving an asymmetric catalytic hydrogen transfer method for α-phosphonate-substituted benzo[a]cyclic ketone compounds. Background Technology

[0002] Hydroxyphosphonates are an important class of organic reaction intermediates, possessing not only certain biological activities themselves but also serving as crucial intermediates for the synthesis of various phosphonite derivatives. Many phosphonite derivatives synthesized from hydroxyphosphonates have also exhibited remarkable pesticide and pharmaceutical activities. β-Hydroxyphosphonates are important raw materials for the synthesis of β-carbonylphosphonates, which are important β-lactam inhibitors; β-hydroxyphosphonate derivatives are also important raw materials for the synthesis of β-aminophosphonate derivatives. Chiral β-hydroxyphosphonates have received widespread attention in recent years due to their molecular characteristics that mimic the structure of hydroxyphosphonic acids, demonstrating significant application value in areas such as antibacterial agent development, enzyme activity regulation, and peptide analog construction. These compounds have been proven to be key intermediates for the synthesis of phosphate-based antibiotics, novel enzyme inhibitors, and bioactive peptide analogs.

[0003] CN104817590A uses 1,3,2-oxazolarane, generated in situ from 1-amino-2-indanol and borate ester, as a catalyst, combined with a borane reducing agent, to conduct an asymmetric chemical synthesis of β-carbonylphosphonates under mild conditions, thereby synthesizing chiral β-hydroxyphosphonate target compounds. CN103467522B employs a solvent-free solid-phase catalytic synthesis method, using solid catalysts such as anhydrous potassium carbonate and phosphite to react at room temperature, and obtaining hydroxyphosphonates through stirring, heating, cooling, filtration, and recrystallization. CN104370960B dissolves arylethylene derivatives, phosphoric acid reagents, and manganese acetate in a solvent, and carries out the reaction at 20–60 °C to prepare β-hydroxyphosphonate derivatives. Existing methods suffer from drawbacks such as poor substrate applicability, low yield, high cost, and harsh reaction conditions.

[0004] With the rapid development of catalysts for asymmetric hydrogenation methodologies, the number of substrates applicable to asymmetric hydrogenation reactions is also increasing. However, asymmetric hydrogen transfer reactions of α-phosphonate-substituted benzo[a]cyclic ketones, especially the reduction of α-phosphonate-substituted benzo[a]cyclic ketones by asymmetric catalytic hydrogen transfer to prepare chiral alcohols (chiral β-hydroxyphosphonates), have not yet been reported. Summary of the Invention

[0005] The present invention aims to provide a chiral hydroxyphosphonate, its preparation method and uses, wherein the chiral hydroxyphosphonate has bipolar centers; the method has simple reaction conditions, good substrate applicability, low cost, and not only high product yield, but also high enantioselectivity.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] In a first aspect, a chiral hydroxyphosphonate is provided having a structure as shown in Formula II:

[0008] ;

[0009] Each R is independently H, alkyl, alkenyl, alkynyl, or haloalkyl;

[0010] X represents the bond, -O-, -N(R) 1 )-、-C(=O)-、-(C(R 2 )2) q -、-S(=O) m -;

[0011] m is 0, 1, or 2;

[0012] q can be 0, 1, 2, or 3;

[0013] R 1 It is H or alkyl;

[0014] Each R 2 It can be independently H, -F, -Cl, -Br, -I, -NH2, -CN, or an alkyl group;

[0015] Ar is an aromatic ring or a heteroaromatic ring;

[0016] The alkyl, alkenyl, alkynyl, haloalkyl, aromatic, and heteroaromatic rings are further optionally each independently substituent R of the same or different substituents. 3 Mono- or poly-substituted; the substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl, heteroaryl or alkyl.

[0017] In some embodiments, each R is independently H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The haloalkyl group may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0018] In some embodiments, each R is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, ethynyl, chloromethane, chloroethane, or trifluoromethyl, and may be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0019] In some embodiments, R 1 Is it H or C? 1-6 Alkyl groups may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0020] In some embodiments, R 1 The substituents are H, methyl, ethyl, n-propyl, isopropyl, and n-butyl, which can be further substituents R as described in this invention, either the same or different. 3 Single or multiple substitutions.

[0021] In some embodiments, each R 2 Independently, it is H, -F, -Cl, -Br, -I, -NH2, -CN, or C. 1-6 Alkyl groups may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0022] In some embodiments, each R 2 Independently, it is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, -F, -Cl, -Br, -I, -NH2, -CN, which may be further substituents R as described in this invention. 3 Single or multiple substitutions.

[0023] In some embodiments, Ar is C 6-12 Aryl or C 1-12 Heteroaryl groups can be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0024] In some embodiments, Ar is phenyl, naphthyl, Or pyridyl, which may be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0025] In some embodiments, the substituent R 3 -Hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl group, -COOH, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-OC(=O)-, aryl-C(=O)-, amino, nitro, C1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-12 heteroaryl or C 1-6 alkyl.

[0026] In some embodiments, the substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, tert-butyl-C(=O)-, n-pentyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, n-butyl-OC(=O)-, tert-butyl-OC(=O)-, n-pentyl-OC(=O)-, amino, nitro, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.

[0027] In some embodiments, Ar is selected from one of the following groups:

[0028] .

[0029] In some embodiments, the chiral hydroxyphosphonate of the present invention is selected from one of the following structures:

[0030] .

[0031] Secondly, a method for preparing a chiral hydroxyphosphonate is provided, comprising:

[0032] In the presence of a catalyst, the α-phosphonate-substituted benzocycloketone compound of Formula I is reacted with a hydrogen source to prepare the chiral hydroxyphosphonate of Formula II.

[0033] ;

[0034] in,

[0035] Each R is independently H, alkyl, alkenyl, alkynyl, or haloalkyl;

[0036] X represents the bond, -O-, -N(R) 1 )-、-C(=O)-、-((C(R 2 )2) q -、-S(=O) m-;

[0037] m is 0, 1, or 2;

[0038] q can be 0, 1, 2, or 3;

[0039] R 1 It is H or alkyl;

[0040] Each R 2 It can be independently H, -F, -Cl, -Br, -I, -NH2, -CN, or an alkyl group;

[0041] Ar is an aromatic ring or a heteroaromatic ring;

[0042] The alkyl, alkenyl, alkynyl, haloalkyl, aromatic, and heteroaromatic rings are further optionally each independently substituent R of the same or different substituents. 3 Mono- or poly-substituted; the substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-C(=O)-, alkyl-OC(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclic, aryl, heteroaryl or alkyl.

[0043] In some embodiments, the catalyst is a rhodium catalyst.

[0044] In some embodiments, the catalyst is At least one of them.

[0045] In some embodiments, the hydrogen source is selected from at least one of the following: a mixture of HCOOH / Et3N, a mixture of HCOOH / DABCO (triethylenediamine, or 1,4-diazabicyclo[2.2.2]octane), a mixture of HCOOH / DBU (1,8-diazabicycloundec-7-ene), HCO2NH4, and HCO2Na.

[0046] In some embodiments, the molar ratio of HCOOH to Et3N in the HCOOH / Et3N mixture is 5:2, 3:2, or 1:1; the molar ratio of HCOOH to DABCO in the HCOOH / DABCO mixture is 2:1; and the molar ratio of HCOOH to DBU in the HCOOH / DBU mixture is 2:1.

[0047] In some embodiments, the reaction is carried out in an air atmosphere.

[0048] In some embodiments, the reaction temperature is 10-80°C, preferably any one of the ranges of 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or any two of the above values.

[0049] In this invention, "room temperature" or "normal temperature" both refer to a temperature of 15-35°C, preferably 25°C.

[0050] In some embodiments, the solvent used in the reaction includes, but is not limited to, at least one of alcohol solvents, ethyl acetate, and tetrahydrofuran. In some embodiments, the alcohol solvent includes, but is not limited to, at least one of methanol, ethanol, and isopropanol.

[0051] In some embodiments, the molar ratio of the hydrogen source to the compound shown in Formula I is (1-3):1. Preferably, the molar ratio of the hydrogen source to the compound shown in Formula I is 1:1, 2:1, 3:1, or any two of the above values ​​forming any one of the ranges.

[0052] In some embodiments, the molar ratio of the catalyst to the compound of Formula I is (0.00005~0.05):1. Preferably, the molar ratio of the catalyst to the compound of Formula I is (0.0001~0.05):1. Preferably, the molar ratio of the catalyst to the compound of Formula I is (0.001~0.01):1. Preferably, the molar ratio of the catalyst to the compound of Formula I is 0.0001:1, 0.005:1, 0.001:1, or any two of the above values ​​forming any one of the ranges.

[0053] In some embodiments, each R is independently H, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 The haloalkyl group may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0054] In some embodiments, each R is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, ethynyl, chloromethane, chloroethane, or trifluoromethyl, and may be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0055] In some embodiments, R 1 Is it H or C? 1-6 Alkyl groups may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0056] In some embodiments, R1 The substituents are H, methyl, ethyl, n-propyl, isopropyl, and n-butyl, which can be further substituents R as described in this invention, either the same or different. 3 Single or multiple substitutions.

[0057] In some embodiments, each R 2 Independently, it is H, -F, -Cl, -Br, -I, -NH2, -CN, or C. 1-6 Alkyl groups may be further substituented with the same or different substituents R as described in this invention. 3 Single or multiple substitutions.

[0058] In some embodiments, each R 2 Independently, it is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, -F, -Cl, -Br, -I, -NH2, -CN, which may be further substituents R as described in this invention. 3 Single or multiple substitutions.

[0059] In some embodiments, Ar is C 6-12 Aryl or C 1-12 Heteroaryl groups can be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0060] In some embodiments, Ar is phenyl, naphthyl, Or pyridyl, which may be further substituented by the same or different substituents R described in this invention. 3 Single or multiple substitutions.

[0061] In some embodiments, the substituent R 3 -Hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl group, -COOH, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-OC(=O)-, aryl-C(=O)-, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-12 heteroaryl or C 1-6 alkyl.

[0062] In some embodiments, the substituent R 3It can be hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, methyl-C(=O)-, ethyl-C(=O)-, n-propyl-C(=O)-, isopropyl-C(=O)-, n-butyl-C(=O)-, tert-butyl-C(=O)-, n-pentyl-C(=O)-, methyl-OC(=O)-, ethyl-OC(=O)-, n-propyl-OC(=O)-, isopropyl-OC(=O)-, n-butyl-OC(=O)-, tert-butyl-OC(=O)-, n-pentyl-OC(=O)-, amino, nitro, methoxy, ethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl.

[0063] In some embodiments, Ar is selected from one of the following groups:

[0064] .

[0065] In some embodiments, the α-phosphine ester-substituted benzocycloketone compound is prepared by reacting compound III with compound IV after treatment with a lithium reagent;

[0066]

[0067] in,

[0068] Y is -Cl, -Br, or -I;

[0069] Ar, X, and R all have the meanings described in this invention.

[0070] In some embodiments, the lithium reagent is at least one of lithium diisopropylaminolithium (LDA), methyllithium reagent, n-butyllithium, or 2,2,4,4-tetramethylpiperidine.

[0071] In some embodiments, the molar ratio of compound III to lithium reagent is 1:(1-4), preferably 1:1, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, and any two of the above values ​​forming any one of the ranges.

[0072] In some embodiments, the molar ratio of compound III to compound IV is 1:(1-4), preferably 1:1, 1:1.4, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, and any two of the above values ​​forming any one of the ranges.

[0073] In some embodiments, if compound III and compound IV do not react completely, the system is cooled to -78°C, and lithium reagent is added dropwise to carry out the reaction. In some embodiments, the molar ratio of compound III to the added lithium reagent is 1:(1-4), preferably 1:1, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, or any two of the above values ​​forming a range.

[0074] In some embodiments, the α-phosphonate-substituted benzocycloketone compound is selected from one of the following structures:

[0075] .

[0076] Thirdly, the present invention provides pharmaceutical compositions comprising the chiral hydroxyphosphonates described herein. For example, such pharmaceutical compositions may comprise any of the chiral hydroxyphosphonates of the present invention and pharmaceutically acceptable carriers and / or excipients.

[0077] Fourthly, the present invention provides the use of the chiral hydroxyphosphonate or pharmaceutical composition thereof described herein in the preparation of a medicament for the repair and anti-aging of skin wounds.

[0078] Compared with the prior art, one of the above technical solutions has the following advantages or beneficial effects:

[0079] This invention provides an important method for preparing chiral hydroxyphosphonates: reducing α-phosphonate-substituted benzocycloketone compounds by asymmetric hydrogenation to obtain corresponding highly optically active chiral β-hydroxyphosphonates, the resulting chiral β-hydroxyphosphonates having bipolar centers.

[0080] This invention utilizes an asymmetric catalytic hydrogen transfer method to reduce α-phosphonate-substituted benzocyclic ketone compounds. The preparation process is simple and efficient, can be carried out at room temperature, and yields chiral β-hydroxyphosphonates with a yield of up to 99% and an enantioselectivity of up to 99%.

[0081] The method of this invention provides a simple and efficient way to prepare chiral β-hydroxyphosphonates without the need for hydrogen gas, avoiding the drawbacks of existing technologies that require hydrogen gas, and simplifying and making the operation safer.

[0082] The chiral β-hydroxyphosphonate provided by this invention has a significant promoting effect on keratinocyte migration and repair, and shows broad application potential and value in wound healing, skin tissue soothing, repair and anti-aging.

[0083] The chiral β-hydroxyphosphonate prepared by the method of this invention has high optical purity and can serve as an important backbone for many drug molecules.

[0084] The preparation method disclosed in this invention has mild reaction conditions, simple reaction operation and post-processing, stable and controllable reaction process, high catalytic efficiency, greatly reduces the amount of reagents used and the generation and emission of reaction waste, and has a high product yield, making it suitable for large-scale production. Attached Figure Description

[0085] Figure 1 This is a comparative diagram showing how compounds (II-v, II-ab) in the efficacy examples promote the migration and repair of human keratinocytes. Detailed Implementation

[0086] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0087] Raw materials: HCOOH (formic acid), Et3N, lithium diisopropylamino (LDA), tetrahydrofuran, dimethyl chlorophosphate (CAS: 813-77-4), diisopropyl chlorophosphate (CAS: 2574-25-6), 1-tetrahydronaphthone, 7-methyl-3,4-dihydro-2H-1-naphthone (CAS: 22009-37-6), 7-methoxy-1-naphthone (CAS: 6836-19-7), 6-methoxy-1-naphthone (CAS: 1 078-19-9), 5-methoxy-1-naphthoquinone (CAS: 33892-75-0), 6,7-dimethoxy-1-tetrahydronaphthoquinone (CAS: 13575-75-2), 7-bromo-3,4-dihydronaphtho-1(2H)-one (CAS: 32281-97-3), 8-bromo-3,4-dihydro-2H-naphtho-1-one (CAS: 651735-60-3), 4-dihydrochromone (CAS: 491-37-2), 6-methyl-4- Dihydrochromenolide (CAS: 39513-75-2), 6-bromo-4-dihydrochromenolide (CAS: 49660-57-3), 6-chlorobenzodihydropyran-4-one (CAS: 37674-72-9), 6-fluoro-4-dihydrochromenolide (CAS: 66892-34-0), N-Boc-3,4-dihydroquinoline-4(2H)-one (CAS: 179898-00-1), thiochrome-4-one (CAS: 3528-17-4) 6-Methylthiobenzodihydropyran-4-one (CAS: 6948-34-1), 6,7-dihydro-4(5H)-benzofuranone (CAS: 16806-93-2), and 6,7-dihydro-4-benzo[b]thiophenone (CAS: 13414-95-4) were purchased from Aladdin Company; 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylic acid tert-butyl ester (CAS: 877170-76-8) was purchased from Nanjing Qiafenghe Pharmaceutical Technology Co., Ltd.

[0088] Synthesis Scheme 1: The preparation process of one compound of the present invention is as follows:

[0089]

[0090] Wherein Y is a leaving group known to those skilled in the art, such as -Cl, -Br, -I; wherein Ar, X, and R all have the definitions described in this invention;

[0091] Compound III was treated with LDA and then reacted with compound IV to obtain compound I.

[0092] Synthesis Scheme 2: The preparation process of one compound of the present invention is as follows:

[0093]

[0094] Wherein, Ar, X, and R all have the meanings described in this invention;

[0095] In the presence of a catalyst, compound I reacts with a hydrogen source to yield compound II.

[0096] Example 1

[0097]

[0098] Compound III (10 mmol, 1.0 equivalent) was dissolved in anhydrous tetrahydrofuran (30 mL) and treated with LDA (1.1 equivalent) at -60 °C. Compound IV (e.g., dimethyl chlorophosphate or diisopropyl chlorophosphate) (1.4 equivalent) was then added, and the mixture was gradually heated to 0 °C over 1 h. The reaction mixture was then cooled to -78 °C, and LDA (2.2 equivalent) solution was added dropwise. The resulting reaction mixture was stirred at room temperature and gradually heated to room temperature for 2 h.

[0099] After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction mixture. The reaction mixture was extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: V(petroleum ether) / V(ethyl acetate) = 2 / 1 ~ 1 / 1) to obtain the target product compound I. The specific reaction conditions are shown in Table 1 below:

[0100]

[0101] The verification data for the obtained raw materials are as follows:

[0102] Dimethyl (1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Ia)

[0103] 1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 7.9, 1.5 Hz, 1H), 7.45 (td, J = 7.5, 1.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 3.79(d, J= 10.9 Hz, 3H), 3.74 (d, J = 11.1 Hz, 3H), 3.26 – 3.16 (m, 2H), 2.90(dt, J = 16.8, 6.0 Hz, 1H), 2.49 – 2.39 (m, 2H).

[0104] 31 P NMR (162 MHz, CDCl3) δ 26.1.

[0105] 13 C NMR (101 MHz, CDCl3) δ 192.4 (d, J = 5.8 Hz), 143.8, 134.0, 132.1(d, J = 3.2 Hz), 128.8, 127.8, 126.9, 53.1 (dd, J = 28.9, 6.8 Hz), 47.5,46.2, 27.6 (d, J = 8.2 Hz), 24.4.

[0106] HRMS (ESI) m / z: [M + H] + Calcd for C 12 H 16 O4P 255.0781; Found 255.0781

[0107] Diisopropyl(1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Ib)

[0108] 1 H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.9, 1.5 Hz, 1H), 7.37 (td, J = 7.5, 1.5 Hz, 1H), 7.22 – 7.17 (m, 1H), 7.14 (d, J = 7.7 Hz, 1H), 4.76 –4.60 (m, 2H), 3.27 – 3.18 (m, 1H), 3.07 (dt, J = 26.0, 5.6 Hz, 1H), 2.81 (dt, J= 16.9, 5.4 Hz, 1H), 2.44 – 2.27 (m, 2H), 1.24 (dd, J = 13.5, 6.1 Hz, 6H), 1.12 (dd, J = 6.2, 4.3 Hz, 6H).

[0109] 31 P NMR (162 MHz, CDCl3) δ 20.7.

[0110] 13 C NMR (101 MHz, CDCl3) δ 192.5 (d, J = 5.5 Hz), 143.8, 133.5, 132.3(d, J = 2.4 Hz), 128.6, 127.4, 126.5, 71.2 (d, J = 7.2 Hz), 70.9 (d, J = 6.8Hz), 48.6, 47.2, 27.2 (d, J = 6.6 Hz), 24.5 (d, J = 5.0 Hz), 24.0 (d, J = 3.6Hz), 23.9 (d, J = 3.5 Hz), 23.6 (dd, J = 5.4, 2.2 Hz).

[0111] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 24 O4P 341.1407; Found 341.1399

[0112] Dimethyl (7-methyl-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (Ic); Melting point: 57.08-57.15 ℃

[0113] 1 H NMR (500 MHz, CDCl3) δ 7.87 – 7.80 (m, 1H), 7.30 (dd, J = 7.9, 2.0Hz, 1H), 7.14 (d, J= 7.8 Hz, 1H), 3.82 (d, J = 11.0 Hz, 3H), 3.77 (d, J =11.0 Hz, 3H), 3.27 – 3.15 (m, 2H), 2.93 – 2.84 (m, 1H), 2.50 – 2.41 (m, 2H), 2.34 (s, 3H).

[0114] 31 P NMR (203 MHz, CDCl3) δ 26.2.

[0115] 13 C NMR (126 MHz, CDCl3) δ 192.5 (d, J = 5.6 Hz), 140.9, 136.4, 134.8,131.7 (d, J = 3.2 Hz), 128.6, 127.6, 52.9 (dd, J = 38.3, 6.7 Hz), 47.3, 46.2,27.1 (d, J = 8.2 Hz), 24.4 (d, J = 4.6 Hz), 20.8.

[0116] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 26 O4P 325.1564; Found 325.1563

[0117] Diisopropyl (7-methyl-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Id)

[0118] 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 7.8, 2.1 Hz, 1H), 7.05 (d, J= 7.8 Hz, 1H), 4.78 – 4.62 (m, 2H), 3.26 – 3.14 (m,1H), 3.13 – 2.99 (m, 1H), 2.83 – 2.72 (m, 1H), 2.48 – 2.32 (m, 2H), 2.27 (s,3H), 1.29 – 1.24 (m, 6H), 1.14 (dd, J = 5.2, 2.4 Hz, 6H).

[0119] 31 P NMR (162 MHz, CDCl3) δ 13.7.

[0120] 13 C NMR (101 MHz, CDCl3) δ 192.9 (d, J = 5.4 Hz), 141.0, 136.2, 134.6,132.1 (d, J = 2.6 Hz), 128.6, 127.7, 71.1 (dd, J = 26.8, 7.0 Hz), 48.7, 47.4,27.0 (d, J = 6.8 Hz), 24.7 (d, J = 4.9 Hz), 24.1 (d, J = 3.6 Hz), 24.0 (d, J = 3.4 Hz), 23.8 (dd, J = 5.3, 3.5 Hz), 22.4 (d, J = 1.7 Hz), 20.9.

[0121] HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 26 O4P 325.1564; Found 325.1563

[0122] Dimethyl (7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Ie)

[0123] 1 H NMR (400 MHz, CDCl3) δ 7.31 (q, J= 3.0 Hz, 1H), 6.98 (dd, J = 8.4, 3.0 Hz, 1H), 6.88 (dt, J = 8.5, 2.9 Hz, 1H), 3.67 – 3.59 (m, 9H), 3.11 – 2.93(m, 2H), 2.74 – 2.64 (m, 1H), 2.33 – 2.20 (m, 2H).

[0124] 31 P NMR (162 MHz, CDCl3) δ 26.0.

[0125] 13 C NMR (101 MHz, CDCl3) δ 192.4 (d, J = 5.5 Hz), 158.1, 136.4, 132.9(d, J = 2.7 Hz), 129.7, 121.9, 109.3, 71.1 (d, J = 7.2 Hz), 70.8 (d, J = 6.8Hz), 55.3, 48.4, 47.0, 26.4 (d, J = 6.8 Hz), 24.7 (d, J = 4.9 Hz), 24.0 (d, J= 3.6 Hz), 23.9 (d, J = 3.5 Hz), 23.6 (dd, J = 5.4, 2.7 Hz).

[0126] HRMS (ESI) m / z: [M + H] + Calcd for C 13 H 18 O5P 285.0887; Found 285.0885

[0127] Diisopropyl (7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (If). Melting point: 55.29-55.35 ℃

[0128] 1 H NMR (400 MHz, CDCl3) δ 7.37 (t, J= 3.0 Hz, 1H), 7.00 (dd, J = 8.4,2.9 Hz, 1H), 6.91 (dt, J = 8.4, 3.0 Hz, 1H), 4.69 – 4.56 (m, 2H), 3.67 (d, J = 3.1 Hz, 3H), 3.14 – 3.05 (m, 1H), 3.04 – 2.94 (m, 1H), 2.69 (dt, J = 16.6,5.0 Hz, 1H), 2.37 – 2.20 (m, 2H), 1.23 – 1.18 (m, 6H), 1.09 (d, J = 5.9 Hz,6H).

[0129] 31 P NMR (162 MHz, CDCl3) δ 20.8.

[0130] 13 C NMR (101 MHz, CDCl3) δ 192.4 (d, J = 5.5 Hz), 158.1, 136.4, 132.9(d, J = 2.7 Hz), 129.7, 121.9, 109.3, 71.1 (d, J = 7.2 Hz), 70.8 (d, J = 6.8Hz), 55.3, 48.4, 47.0, 24.7 (d, J = 4.9 Hz), 24.0 (d, J = 3.6 Hz), 23.9 (d, J = 3.5 Hz), 23.6 (dd, J = 5.4, 2.7 Hz).

[0131] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 25 NaO5P 363.1332; Found363.1332

[0132] Dimethyl (6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (Ig). Melting point: 63.84-63.89 ℃

[0133] 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8,2.6 Hz, 1H), 6.70 – 6.65 (m, 1H), 3.84 (d, J = 0.9 Hz, 3H), 3.81 (dd, J =11.0, 0.8 Hz, 3H), 3.76 (dd, J = 11.1, 0.8 Hz, 3H), 3.26 – 3.13 (m, 2H), 2.87(dt, J = 16.8, 5.9 Hz, 1H), 2.50 – 2.39 (m, 2H).

[0134] 31 P NMR (162 MHz, CDCl3) δ 26.5.

[0135] 13 C NMR (101 MHz, CDCl3) δ 192.4 (d, J = 5.5 Hz), 158.1, 136.4, 132.9(d, J = 2.7 Hz), 129.7, 121.9, 109.3, 71.1 (d, J = 7.2 Hz), 70.8 (d, J = 6.8Hz), 55.3, 48.4, 47.0, 26.4 (d, J = 6.8 Hz), 24.7 (d, J = 4.9 Hz), 24.0 (d, J = 3.6 Hz), 23.9 (d, J = 3.5 Hz), 23.6 (dd, J = 5.4, 2.7 Hz).

[0136] HRMS (ESI) m / z: [M + Na] +Calcd for C 13 H 17 NaO5P 307.0706; Found 307.0709

[0137] Diisopropyl (6-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-2-yl) phosphonate (Ih).

[0138] 1 H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 8.8, 3.4 Hz, 1H), 6.60 – 6.54(m, 1H), 6.46 (t, J = 2.8 Hz, 1H), 4.58 – 4.47 (m, 2H), 3.61 (d, J = 3.3 Hz,3H), 3.10 – 2.99 (m, 1H), 2.94 – 2.83 (m, 1H), 2.62 (dt, J = 16.8, 5.1 Hz,1H), 2.28 – 2.10 (m, 2H), 1.13 – 1.07 (m, 6H), 1.04 – 0.99 (m, 6H).

[0139] 31 P NMR (162 MHz, CDCl3) δ 21.2.

[0140] 13 C NMR (101 MHz, CDCl3) δ 190.5 (d, J = 5.2 Hz), 163.2, 145.9, 129.4,125.4 (d, J = 2.7 Hz), 112.7, 111.8, 70.6 (d, J = 7.0 Hz), 70.3 (d, J = 6.8Hz), 54.8, 47.7, 46.4, 27.1 (d, J = 7.0 Hz), 24.1 (d, J = 4.7 Hz), 23.5 (d, J = 3.6 Hz), 23.4 (d, J = 3.3 Hz), 23.3 – 23.0 (m).

[0141] HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 26 O5P 341.1513; Found 341.1509

[0142] Dimethyl (5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (Ii); Melting point: 116.87-116.94 ℃

[0143] 1 H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.9, 1.1 Hz, 1H), 7.27 – 7.22(m, 1H), 7.00 (dd, J = 8.1, 1.1 Hz, 1H), 3.83 (s, 3H), 3.81 – 3.76 (m, 3H), 3.74 (dd, J = 11.0, 0.7 Hz, 3H), 3.18 (dt, J = 25.6, 6.4 Hz, 1H), 3.12 – 3.03(m, 1H), 2.85 (dt, J = 17.9, 6.2 Hz, 1H), 2.42 (ddt, J = 13.7, 7.6, 4.6 Hz, 2H).

[0144] 31 P NMR (162 MHz, CDCl3) δ 26.2.

[0145] 13 C NMR (101 MHz, CDCl3) δ 192.7 (d, J = 5.7 Hz), 156.6, 133.0 (d, J =3.4 Hz), 133.0, 126.9, 119.2, 114.7, 55.7, 53.1 (dd, J = 24.6, 6.7 Hz), 47.3,45.9, 23.7 (d, J = 4.7 Hz), 21.1 (d, J = 8.5 Hz).

[0146] HRMS (ESI) m / z: [M + H] + Calcd for C 13 H 18 O5P 285.0887; Found 285.0886

[0147] Diisopropyl (5-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Ij).

[0148] 1 H NMR (400 MHz, CDCl3) δ 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.18 (d, J =8.0 Hz, 1H), 6.94 (dd, J = 8.1, 1.1 Hz, 1H), 4.74 – 4.61 (m, 2H), 3.78 (s,3H), 3.11 – 3.00 (m, 2H), 2.86 – 2.77 (m, 1H), 2.44 – 2.27 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.2 Hz, 6H).

[0149] 31 P NMR (162 MHz, CDCl3) δ 20.8.

[0150] 13 C NMR (101 MHz, CDCl3) δ 192.9 (d, J = 5.8 Hz), 156.7, 133.4, 133.1,126.7, 119.2, 114.5, 71.2 (d, J = 7.2 Hz), 71.0 (d, J = 6.8 Hz), 55.7, 48.4,47.1, 24.2 (d, J = 3.6 Hz), 24.0 (d, J = 3.5 Hz), 23.9 (d, J = 5.3 Hz), 23.8(t, J= 4.9 Hz), 20.9 (d, J = 6.9 Hz).

[0151] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 25 NaO5P 363.1322; Found 363.1328

[0152] Dimethyl(6, Calcd for C) 17 H 25 NaO5P 363.1322; Found 363.1328

[0153] 7-Dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (Ik); Melting point: 76.06-76.14 ℃

[0154] 1 H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.62 (s, 1H), 3.90 (d, J = 1.1Hz, 3H), 3.86 (d, J = 1.1 Hz, 3H), 3.78 (dd, J = 10.9, 1.0 Hz, 3H), 3.74 (d, J = 11.2 Hz, 3H), 3.22 – 3.10 (m, 2H), 2.82 (dt, J = 16.8, 5.8 Hz, 1H), 2.49– 2.35 (m, 2H).

[0155] 31 P NMR (162 MHz, CDCl3) δ 19.2.

[0156] 13 C NMR (101 MHz, CDCl3) δ 191.2 (d, J = 5.4 Hz), 154.1, 148.1, 139.0,125.3 (d, J = 3.0 Hz), 110.2, 109.0, 56.2, 56.0, 53.1 (dd, J= 40.9, 6.8 Hz),47.0, 45.6, 27.4 (d, J = 7.7 Hz), 24.8 (d, J = 4.5 Hz).

[0157] HRMS (ESI) m / z: [M + H] + Calcd for C 14 H 20 O6P 315.0993; Found 315.0993

[0158] Diisopropyl (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II); Melting point: 78.45-78.52℃

[0159] 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 1.2 Hz, 1H), 6.63 (s, 1H), 4.81– 4.68 (m, 2H), 3.92 (d, J = 1.2 Hz, 3H), 3.88 (d, J = 1.2 Hz, 3H), 3.30 –3.18 (m, 1H), 3.09 (dt, J = 26.1, 5.6 Hz, 1H), 2.80 (dt, J = 16.7, 5.3 Hz,1H), 2.54 – 2.34 (m, 2H), 1.37 – 1.28 (m, 6H), 1.25 – 1.18 (m, 6H).

[0160] 31 P NMR (162 MHz, CDCl3) δ 21.2.

[0161] 13 C NMR (101 MHz, CDCl3) δ 191.5 (d, J = 5.1 Hz), 153.9, 148.1, 139.1,125.7 (d, J = 2.4 Hz), 110.1, 109.0, 71.4 (d, J = 7.2 Hz), 71.1 (d, J= 6.8Hz), 56.2, 56.1, 48.2, 46.9, 27.2 (d, J = 6.4 Hz), 25.1 (d, J = 4.7 Hz), 24.3(d, J = 3.6 Hz), 24.2 (d, J = 3.2 Hz), 24.0 – 23.8 (m).

[0162] HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 28 O6P 371.1619; Found 371.1621

[0163] Dimethyl (7-bromo-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Im)

[0164] 1 H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.2, 2.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 3.77 (d, J = 11.0 Hz, 3H), 3.72 (d, J = 10.9 Hz, 3H), 3.25 – 3.15 (m, 2H), 2.83 (dt, J = 16.9, 5.5 Hz, 1H), 2.47 –2.38 (m, 2H).

[0165] 31 P NMR (203 MHz, CDCl3) δ 25.3.

[0166] 13 C NMR (126 MHz, CDCl3) δ 191.2 (d, J = 5.5 Hz), 142.5, 136.7, 133.4(d, J = 3.2 Hz), 130.7, 130.4, 120.8, 53.2 (dd, J= 33.5, 6.8 Hz), 47.0,45.9, 27.0 (d, J = 7.7 Hz), 24.1 (d, J = 4.6 Hz).

[0167] HRMS (ESI) m / z: [M + H] + Calcd for C 12 H 15 BrO4P 332.9886; Found 332.9886

[0168] Diisopropyl (7-bromo-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (In)

[0169] 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 2.2 Hz, 1H), 7.46 (dd, J = 8.2, 2.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.73 – 4.60 (m, 2H), 3.23 – 3.11 (m,1H), 3.06 (dt, J = 26.1, 5.4 Hz, 1H), 2.76 (dt, J = 17.0, 5.2 Hz, 1H), 2.47 –2.28 (m, 2H), 1.26 – 1.22 (m, 6H), 1.12 (dd, J = 6.2, 4.4 Hz, 6H).

[0170] 31 P NMR (162 MHz, CDCl3) δ 20.0.

[0171] 13 C NMR (101 MHz, CDCl3) δ 191.4 (d, J = 5.6 Hz), 142.6, 136.3, 133.7(d, J = 2.4 Hz), 130.5, 130.2 (d, J = 2.2 Hz), 120.5, 71.5 (d, J = 7.2 Hz), 71.2 (d,J = 6.8 Hz), 48.3, 47.0, 26.7 (d, J = 6.1 Hz), 24.3 (d, J = 5.0 Hz), 24.1 (d, J = 3.7 Hz), 24.0 (d, J = 3.5 Hz), 23.7 (t, J = 5.2 Hz).

[0172] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 23 BrO4P 389.0511; Found 389.0512

[0173] Diisopropyl (8-bromo-1-oxo-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (Io)

[0174] 1 H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 4.76 – 4.52 (m, 2H), 3.23 – 3.13 (m, 1H), 3.08 (dt, J = 25.4, 5.3 Hz, 1H), 2.94 (dt, J = 17.9, 5.2 Hz, 1H), 2.53 – 2.44(m, 1H), 2.37 – 2.24 (m, 1H), 1.26 (dd, J = 16.8, 6.3 Hz, 6H), 1.12 (t, J =6.9 Hz, 6H).

[0175] 31 P NMR (203 MHz, CDCl3) δ 19.9

[0176] 13 C NMR (126 MHz, CDCl3) δ 161.9 (d, J= 7.9 Hz), 142.9, 137.4, 134.3(d, J = 2.2 Hz), 127.6, 126.8, 124.5, 71.3 (d, J = 7.2 Hz), 71.2 (d, J = 6.6Hz), 47.6, 46.6, 27.8 (d, J = 5.9 Hz), 24.1 (d, J = 3.6 Hz), 23.9 (d, J = 3.6Hz), 23.7 (d, J = 11.9 Hz), 23.5 (d, J = 5.3 Hz).

[0177] HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 22 BrNaO4P 411.0331; Found411.0334

[0178] Dimethyl (4-oxobenzodihydropyran-3-yl)phosphonate (Ip)

[0179] 1 H NMR (400 MHz, CDCl3) δ 7.83 (dd, J = 7.9, 1.8 Hz, 1H), 7.46 – 7.40(m, 1H), 7.00 – 6.94 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.82 – 4.75 (m, 1H), 4.66 – 4.55 (m, 1H), 3.73 (d, J = 11.2 Hz, 3H), 3.66 (d, J = 11.2 Hz, 3H),3.31 – 3.20 (m, 1H).

[0180] 31 P NMR (162 MHz, CDCl3) δ 22.3.

[0181] 13 C NMR (101 MHz, CDCl3) δ 186.4 (d, J= 5.3 Hz), 161.2, 136.4, 127.5,121.8, 120.8 (d, J = 2.4 Hz), 117.8, 67.1 (d, J = 4.5 Hz), 53.2 (dd, J =45.9, 6.4 Hz), 47.2, 45.9.

[0182] HRMS (ESI) m / z: [M + H] + Calcd for C 11 H 14 O5P 257.0574; Found 257.0573

[0183] Diisopropyl(4-oxobenzodihydropyran-3-yl)phosphonate (Iq)

[0184] 1 H NMR (500 MHz, CDCl3) δ 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.51 – 7.44(m, 1H), 7.04 – 7.00 (m, 1H), 6.97 (dd, J = 8.4, 1.1 Hz, 1H), 4.93 – 4.85 (m,1H), 4.79 – 4.71 (m, 2H), 4.71 – 4.58 (m, 1H), 3.18 (dt, J = 25.0, 4.5 Hz, 1H), 1.33 (dd, J = 11.9, 6.2 Hz, 6H), 1.21 (d, J = 6.2 Hz, 3H), 1.10 (d, J =6.2 Hz, 3H).

[0185] 31 P NMR (162 MHz, CDCl3) δ 17.0.

[0186] 13 C NMR (101 MHz, CDCl3) δ 187.0 (d, J = 4.9 Hz), 161.6, 136.3, 127.7,121.7, 121.3 (d, J= 1.5 Hz), 118.0, 72.0 (dd, J = 29.1, 7.0 Hz), 67.6 (d, J = 5.1 Hz), 48.5, 47.2, 29.8, 24.2 (d, J = 3.6 Hz), 23.9 (d, J = 5.1 Hz), 23.6(d, J = 6.1 Hz).

[0187] HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 21 NaO5P 335.1019; Found 335.1019

[0188] Dimethyl (6-methyl-4-oxobenzodihydropyran-3-yl)phosphonate (Ir)

[0189] 1 H NMR (500 MHz, CDCl3) δ 7.67 (d, J = 2.3 Hz, 1H), 7.31 – 7.25 (m,1H), 6.86 (dd, J = 8.4, 1.2 Hz, 1H), 4.85 – 4.76 (m, 1H), 4.67 – 4.54 (m,1H), 3.77 (dd, J = 11.2, 1.3 Hz, 3H), 3.70 (dd, J = 11.1, 1.3 Hz, 3H), 3.32 –3.21 (m, 1H), 2.28 (s, 3H).

[0190] 31 P NMR (203 MHz, CDCl3) δ 22.6

[0191] 13 C NMR (126 MHz, CDCl3) δ 186.8 (d, J = 5.1 Hz), 159.5, 137.7, 131.5,127.2, 120.5 (d, J = 2.0 Hz), 117.7, 67.2 (d, J= 4.6 Hz), 53.4 (dd, J =60.7, 6.5 Hz), 47.3, 46.2, 20.5.

[0192] HRMS (ESI) m / z: [M + Na] + Calcd for C 12 H 15 NaO5P 293.0549; Found 293.0550

[0193] Diisopropyl (6-methyl-4-oxobenzodihydropyran-3-yl)phosphonate (Is)

[0194] 1 H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.29 – 7.24 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.88 – 4.80 (m, 1H), 4.78 – 4.70 (m, 2H), 4.66 – 4.53 (m,1H), 3.15 (dt, J = 25.1, 4.6 Hz, 1H), 2.28 (s, 3H), 1.32 (d, J = 6.3 Hz, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.21 (d, J = 6.2 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H).

[0195] 31 P NMR (203 MHz, CDCl3) δ 17.3

[0196] 13 C NMR (126 MHz, CDCl3) δ 186.2 (d, J = 5.1 Hz), 158.7, 136.4, 130.2,126.1, 119.8 (d, J = 1.9 Hz), 116.7, 71.1 (d, J = 6.9 Hz), 70.8, 66.5 (d, J =5.1 Hz), 47.4, 46.3, 23.2 (dd,J = 6.7, 3.4 Hz), 22.9 (d, J = 5.1 Hz), 22.6(d, J = 6.3 Hz), 19.5.

[0197] HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 23 NaO5P 349.1175; Found 349.1173

[0198] Dimethyl (6-bromo-4-oxobenzodihydropyran-3-yl)phosphonate (It)

[0199] 1 H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 2.6, 1.1 Hz, 1H), 7.55 (ddd, J = 8.8, 2.5, 1.1 Hz, 1H), 6.89 (dd, J = 8.8, 1.1 Hz, 1H), 4.88 – 4.82 (m, 1H), 4.67 (ddd, J = 11.8, 4.3, 1.1 Hz, 1H), 3.79 (dd, J = 11.2, 1.1 Hz, 3H), 3.72(d, J = 10.1 Hz, 3H), 3.28 (dt, J = 25.3, 4.9 Hz, 1H).

[0200] 31 P NMR (162 MHz, CDCl3) δ 21.6.

[0201] 13 C NMR (101 MHz, CDCl3) δ 185.5 (d, J = 5.1 Hz), 160.3, 139.2, 133.3,130.1, 120.1, 114.7, 67.4 (d, J = 4.6 Hz), 53.5 (dd, J = 41.9, 6.5 Hz), 47.1,45.7.

[0202] HRMS (ESI) m / z: [M + H] + Calcd for C 11 H 13 BrO5P 334.9679; Found 334.9678

[0203] Dimethyl (6-fluoro-4-oxobenzodihydropyran-3-yl)phosphonate (Iu)

[0204] 1 H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 3.2 Hz, 1H), 7.34 – 7.12(m, 1H), 7.12 (dd, J = 9.1, 4.2 Hz, 1H), 4.89 – 4.80 (m, 1H), 4.71 – 4.60 (m,1H), 3.78 (d, J = 11.2 Hz, 3H), 3.76 (d, J = 11.2 Hz, 3H), 3.38 – 3.36 (m,1H).

[0205] 31 P NMR (203 MHz, CDCl3) δ -20.0.

[0206] 13 C NMR (101 MHz, CDCl3) δ 186.0 (d, J = 7.2 Hz), 158.7, 157.7 (d, J =1.6 Hz), 156.3, 124.2 (d, J = 24.6 Hz), 119.7 (d, J = 7.4 Hz), 112.7 (d, J =23.6 Hz), 67.5 (d, J = 4.6 Hz), 53.5 (dd, J = 45.6, 6.6 Hz), 47.2, 45.9.

[0207] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 12ClNaO5P 313.0004; Found313.0001

[0208] Dimethyl (6-fluoro-4-oxobenzodihydropyran-3-yl)phosphonate (IV); Melting point: 68.34-68.42 ℃

[0209] 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 3.2 Hz, 1H), 7.24 – 7.17(m, 1H), 6.97 (dd, J = 9.1, 4.2 Hz, 1H), 4.87 – 4.80 (m, 1H), 4.69 – 4.57 (m,1H), 3.79 (d, J = 11.2 Hz, 3H), 3.72 (d, J = 11.2 Hz, 3H), 3.34 – 3.24 (m,1H).

[0210] 31 P NMR (162 MHz, CDCl3) δ 14.6.

[0211] 19 F NMR (376 MHz, CDCl3) δ -127.8.

[0212] 13 C NMR (101 MHz, CDCl3) δ 186.0 (d, J = 7.2 Hz), 158.7, 157.7 (d, J =1.6 Hz), 156.3, 124.2 (d, J = 24.6 Hz), 119.7 (d, J = 7.4 Hz), 112.7 (d, J =23.6 Hz), 67.5 (d, J = 4.6 Hz), 53.5 (dd, J = 45.6, 6.6 Hz), 47.2, 45.9.

[0213] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H12 NaO5P 297.0299; Found 297.0295

[0214] tert-Butyl 3-(dimethoxyphosphoryl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylic acid ester (Iw).

[0215] 1 H NMR (500 MHz, CDCl3) δ 7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.76 (d, J =8.4 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 4.69 – 4.61 (m,1H), 4.27 – 4.18 (m, 1H), 3.79 (d, J = 11.3 Hz, 3H), 3.73 (d, J = 11.2 Hz, 3H), 3.26 (dt, J = 26.3, 5.2 Hz, 1H), 1.56 (s, 9H).

[0216] 31 P NMR (203 MHz, CDCl3) δ 22.5.

[0217] 13 C NMR (126 MHz, CDCl3) δ 188.8 (d, J = 5.4 Hz), 152.6, 144.0, 134.6,127.9, 124.2 (d, J = 2.3 Hz), 124.0, 123.6, 82.6, 53.5 (dd, J = 27.5, 6.6Hz), 48.0, 46.9, 44.9 (d, J = 4.0 Hz), 28.3.

[0218] HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 22 NaO6P 378.1077; Found 378.1079

[0219] Dimethyl (4-oxobenzodihydrothiaran-3-yl)phosphonate (Ix)

[0220] 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 3.81 (d, J =11.2 Hz, 6H), 3.55 – 3.45 (m, 3H).

[0221] 31 P NMR (203 MHz, CDCl3) δ 23.6.

[0222] 13 C NMR (126 MHz, CDCl3) δ 189.4 (d, J = 5.5 Hz), 141.6, 133.7, 130.5(d, J = 3.3 Hz), 129.9, 127.7, 125.4, 53.3 (dd, J = 86.9, 6.6 Hz), 48.4,47.4, 27.5 (d, J = 4.1 Hz).

[0223] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 13 NaO4PS 295.0164; Found295.0166

[0224] Dimethyl (6-methyl-4-oxobenzodihydrothiaran-3-yl)phosphonate (Iy)

[0225] 1 H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 3.76 (d,J = 11.2 Hz, 6H), 3.48 – 3.41 (m,3H), 2.27 (s, 3H).

[0226] 31 P NMR (203 MHz, CDCl3) δ 23.8.

[0227] 13 C NMR (126 MHz, CDCl3) δ 189.5 (d, J = 5.5 Hz), 138.2, 135.2, 134.8,130.2 (d, J = 3.2 Hz), 129.9, 127.5, 53.2 (dd, J = 93.8, 6.6 Hz), 48.5, 47.4,27.5 (d, J = 4.0 Hz), 20.8.

[0228] HRMS (ESI) m / z: [M + Na] + Calcd for C 12 H 15 NaO4PS 309.0321; Found309.0323

[0229] tert-Butyl 5-(dimethoxyphosphoryl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylic acid ester (Iz)

[0230] 1 H NMR (500 MHz, CDCl3) δ 7.18 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.5Hz, 1H), 3.81 (d, J = 11.0 Hz, 3H), 3.77 (d, J = 11.0 Hz, 3H), 3.41 – 3.31(m, 1H), 3.21 (dt, J = 18.6, 5.4 Hz, 1H), 3.16 – 3.07 (m, 1H), 2.56 – 2.42(m, 2H), 1.62 (s, 9H).

[0231] 31P NMR (203 MHz, CDCl3) δ 26.4.

[0232] 13 C NMR (126 MHz, CDCl3) δ 188.3 (d, J = 4.6 Hz), 148.4, 145.0, 123.7(d, J = 3.2 Hz), 121.9, 107.6, 85.3, 53.1 (dd, J = 63.9, 6.8 Hz), 46.1, 45.0,27.9, 24.7 (d, J = 4.6 Hz), 22.7 (d, J = 5.9 Hz).

[0233] HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 22 NNaO6P 366.1077; Found366.1075

[0234] Dimethyl (4-oxo-4,5,6,7-tetrahydrobenzofuran-5-yl)phosphonate (I-aa)

[0235] 1 H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 2.1Hz, 1H), 3.77 (d, J = 11.0 Hz, 3H), 3.71 (d, J = 11.0 Hz, 3H), 3.20 – 3.03(m, 2H), 2.88 – 2.77 (m, 1H), 2.58 – 2.39 (m, 2H).

[0236] 31 P NMR (203 MHz, CDCl3) δ 25.8.

[0237] 13 C NMR (126 MHz, CDCl3) δ 188.0 (d, J = 4.6 Hz), 167.2, 143.0, 120.9(d, J= 2.9 Hz), 106.8, 53.2 (dd, J = 46.4, 6.8 Hz), 46.4, 45.4, 24.0 (d, J =4.4 Hz), 21.7 (d, J = 5.3 Hz).

[0238] HRMS (ESI) m / z: [M + Na] + Calcd for C 10 H 13 NaO5P 267.0393; Found 267.0395

[0239] Dimethyl (4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene-5-yl)phosphonate (I-ab)

[0240] 1 H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 5.3, 1.1 Hz, 1H), 7.02 (d, J =5.3 Hz, 1H), 3.75 (dd, J = 11.1, 1.2 Hz, 3H), 3.71 (dd, J = 11.0, 1.2 Hz,4H), 3.31 – 3.24 (m, 1H), 3.15 – 3.07 (m, 1H), 2.98 (dt, J = 17.2, 5.4 Hz, 1H), 2.51 (dt, J = 10.4, 5.3 Hz, 2H).

[0241] 31 P NMR (203 MHz, CDCl3) δ 25.9.

[0242] 13 C NMR (126 MHz, CDCl3) δ 185.8 (d, J = 5.1 Hz), 155.0, 124.0, 122.3,121.3, 52.1 (dd, J = 47.8, 6.9 Hz), 45.3, 44.2, 24.8 (d, J = 4.3 Hz), 22.7(d, J= 6.5 Hz).

[0243] HRMS (ESI) m / z: [M + Na] + Calcd for C 10 H 13 NaO4PS 283.0164; Found283.0166

[0244] Example 2

[0245]

[0246] Cyclic ketone compound I (1 eq) was added to a reaction flask, followed by catalyst Cat.E (0.001 eq), hydrogen source (2 eq), and methanol. The reaction was carried out at 25 °C for 16 h. After the reaction was completed, the solvent was evaporated to obtain the crude product, which was then purified by column chromatography to obtain the clean product compound II.

[0247] The synthesis method of catalyst Cat.E is referenced in (SynOpen 2022; 06(01): 75-79, DOI:10.1055 / s-0040-1719914, Tethered Rh(III)-N-(p-Tolylsulfonyl)-1,2-Diphenylethylene-1,2-Diamine Complexes: Efficient Catalysts for Asymmetric Transfer Hydrogenation) R,R The preparation process of )-B.

[0248]

[0249] The specific preparation processes for each substance are as follows:

[0250] Preparation Example 2-1: Synthesis of dimethyl((1S,2R)-1-hydroxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-a):

[0251] An α-phosphonate-substituted benzocycloketone derivative, Ia (77 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.0003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-a, which was then purified by column chromatography to obtain clean product II-a. The product yield was 99%, >20:1 dr, >99% ee, and it was a white solid.

[0252] 1 H NMR (400 MHz, CDCl3) δ 7.37 – 7.32 (m, 1H), 7.18 (dq, J = 6.2, 3.0,2.5 Hz, 2H), 7.08 (dd, J = 6.7, 2.2 Hz, 1H), 5.05 – 4.98 (m, 1H), 3.83 (d, J = 4.0 Hz, 1H), 3.77 (d, J = 6.0 Hz, 3H), 3.75 (d, J = 6.0 Hz, 3H), 2.96 –2.87 (m, 1H), 2.80 – 2.69 (m, 1H), 2.29 – 2.16 (m, 2H), 2.06 – 1.94 (m, 1H).

[0253] 31 P NMR (162 MHz, CDCl3) δ 33.4.

[0254] 13 C NMR (101 MHz, CDCl3) δ 137.0 (d, J = 14.3 Hz), 135.6, 129.9 (d, J = 1.9 Hz), 129.0, 128.1, 126.3, 65.9 (d, J = 5.6 Hz), 52.7 (dd, J = 75.7, 6.6Hz), 39.8, 38.4, 28.7 (d, J = 15.6 Hz), 17.6 (d, J = 3.3 Hz).

[0255] HRMS (ESI) m / z: [M + H] + Calcd for C 12 H 18 O4P 257.0938; Found 257.0936

[0256] Preparation Example 2-2 Synthesis of diisopropyl((1S,2R)-1-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (II-b):

[0257] An α-phosphonate-substituted benzocycloketone derivative, Ib (93 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-b, which was then purified by column chromatography to obtain clean product II-b. The product yield was 94%, >20:1 dr, >99% ee, and it was a yellow oily substance.

[0258] 1 H NMR (400 MHz, CDCl3)δ 7.34 (dd, J = 6.8, 2.2 Hz, 1H), 7.23 – 7.15(m, 2H), 7.12 – 7.07 (m, 1H), 5.06 – 5.00 (m, 1H), 4.84 – 4.70 (m, 2H), 3.92– 3.87 (m, 1H), 2.99 – 2.90 (m, 1H), 2.83 – 2.71 (m, 1H), 2.29 – 2.18 (m,1H), 2.17 – 1.99 (m, 2H), 1.37 – 1.30 (m, 12H).

[0259] 31 P NMR (162 MHz, CDCl3) δ 29.21.

[0260] 13 C NMR (101 MHz, CDCl3) δ 137.0 (d, J = 15.5 Hz), 135.9, 130.0 (d, J = 1.7 Hz), 129.1, 128.2, 126.3, 70.9 (d, J= 6.9 Hz), 70.6 (d, J = 6.9 Hz), 66.4 (d, J = 5.5 Hz), 40.2, 38.8, 28.9 (d, J = 15.6 Hz), 24.4 (d, J = 3.1Hz), 24.2 (dd, J = 5.8, 4.2 Hz), 24.0 (d, J = 5.4 Hz), 17.5.

[0261] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 26 O4P 313.1564; Found 313.1564

[0262] Preparation Example 2-3 Synthesis of dimethyl((1S,2R)-1-hydroxy-7-methyl-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-c):

[0263] An α-phosphonate-substituted benzocycloketone derivative, Ic (80 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-c, which was then purified by column chromatography to obtain clean product II-c. The product yield was 92%, >20:1 dr, >99% ee, and it was a white solid.

[0264] 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 7.06 – 6.98 (m, 2H), 4.99 (q, J = 3.7, 2.7 Hz, 1H), 3.82 – 3.80 (m, 3H), 3.78 (dd, J = 5.4, 0.9 Hz, 3H), 3.39 (d, J= 3.7 Hz, 1H), 2.96 – 2.86 (m, 1H), 2.77 – 2.67 (m, 1H), 2.30 (s, 3H), 2.28 – 2.18 (m, 2H), 2.07 – 1.98 (m, 1H).

[0265] 31 P NMR (162 MHz, CDCl3) δ 33.5.

[0266] 13 C NMR (101 MHz, CDCl3) δ 136.6 (d, J = 14.5 Hz), 135.9, 132.6, 130.3(d, J = 1.8 Hz), 129.2, 129.0, 66.2 (d, J = 5.6 Hz), 52.8 (dd, J = 62.3, 6.7Hz), 39.8, 38.4, 28.4 (d, J = 15.6 Hz), 21.0, 17.7 (d, J = 3.2 Hz).

[0267] HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 19 NaO4P 293.0913; Found 293.0915

[0268] Preparation Example 2-4 Synthesis of diisopropyl((1S,2R)-1-hydroxy-7-methyl-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (II-d):

[0269] An α-phosphonate-substituted benzocycloketone derivative, Id (97 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-d, which was then purified by column chromatography to obtain clean product II-d. The product yield was 91%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0270] 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 1.8 Hz, 1H), 7.05 – 6.98 (m,2H), 4.99 (d, J = 4.6 Hz, 1H), 4.84 – 4.73 (m, 2H), 3.83 (s, 1H), 2.96 – 2.87(m, 1H), 2.79 – 2.67 (m, 1H), 2.30 (s, 3H), 2.27 – 2.18 (m, 1H), 2.16 – 1.99(m, 2H), 1.39 – 1.32 (m, 12H).

[0271] 31 P NMR (162 MHz, CDCl3) δ 29.3.

[0272] 13 C NMR (101 MHz, CDCl3) δ 136.7 (d, J = 14.7 Hz), 135.8, 132.7, 130.5(d, J = 1.8 Hz), 129.1, 129.0, 70.9 (d, J = 6.9 Hz), 70.5 (d, J = 6.9 Hz),66.4 (d, J = 5.4 Hz), 40.3, 38.8, 28.5 (d, J = 15.8 Hz), 24.4 (d, J = 3.1Hz), 24.2 (dd, J = 6.6, 4.3 Hz), 24.0 (d, J = 5.4 Hz), 21.0, 17.6 (d, J = 2.8Hz).

[0273] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 27 NaO4P 349.1539; Found349.1538

[0274] Preparation Example 2-5 Synthesis of dimethyl((1S,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-e):

[0275] An α-phosphonate-substituted benzocycloketone derivative, Ie (85 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-e, which was then purified by column chromatography to obtain clean product II-e. The product yield was 95%, >20:1 dr, >99% ee, and it was a pale yellow oil.

[0276] 1 H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.7Hz, 1H), 6.78 (dd, J = 8.5, 2.8 Hz, 1H), 4.98 (dd, J = 6.3, 2.6 Hz, 1H), 4.12– 3.61 (m, 10H), 2.91 – 2.82 (m, 1H), 2.73 – 2.62 (m, 1H), 2.30 – 2.12 (m,2H), 2.04 – 1.96 (m, 1H).

[0277] 31 P NMR (162 MHz, CDCl3) δ 33.5.

[0278] 13 C NMR (101 MHz, CDCl3) δ 158.0, 137.9 (d, J = 14.5 Hz), 130.0,127.7, 115.2, 113.9 (d, J = 2.1 Hz), 66.2 (d, J = 5.6 Hz), 55.3, 52.7 (dd, J = 74.3, 6.7 Hz), 39.9, 38.4, 28.0 (d, J = 15.6 Hz), 18.0 (d, J= 3.3 Hz).

[0279] HRMS (ESI) m / z: [M + H] + Calcd for C 13 H 20 O5P 287.1043; Found 287.1044

[0280] Preparation Example 2-6 Synthesis of diisopropyl((1S,2R)-1-hydroxy-7-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-f):

[0281] An α-phosphonate-substituted benzocycloketone derivative, If (102 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-f, which was subsequently purified by column chromatography to obtain clean product II-f. The product yield was 94%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0282] 1 H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.8Hz, 1H), 6.78 (dd, J = 8.4, 2.7 Hz, 1H), 4.99 (dd, J = 6.2, 3.1 Hz, 1H), 4.82– 4.70 (m, 2H), 4.02 (d, J = 3.2 Hz, 1H), 3.76 (s, 3H), 2.91 – 2.82 (m, 1H), 2.73 – 2.62 (m, 1H), 2.25 – 2.15 (m, 1H), 2.14 – 1.98 (m, 2H), 1.37 – 1.29(m, 12H).

[0283] 31 P NMR (162 MHz, CDCl3) δ 29.3.

[0284] 13C NMR (101 MHz, CDCl3) δ 158.0, 137.9 (d, J = 14.7 Hz), 130.1,127.8, 115.3, 113.9 (d, J = 1.9 Hz), 70.9 (d, J = 7.0 Hz), 70.5 (d, J = 7.0Hz), 66.6 (d, J = 5.3 Hz), 55.4, 40.2, 38.8, 28.2 (d, J = 15.6 Hz), 24.4 (d, J = 3.2 Hz), 24.2 (t, J = 4.0 Hz), 24.0 (d, J = 5.5 Hz), 17.8 (d, J = 2.9Hz).

[0285] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 27 NaO5P 365.1489; Found 365.1486

[0286] Preparation Example 2-7 Synthesis of dimethyl((1S,2R)-1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-g):

[0287] An α-phosphonate-substituted benzocycloketone derivative, Ig (85 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-g, which was subsequently purified by column chromatography to obtain clean product II-g. The product yield was 92%, >20:1 dr, >99% ee, and it was a white solid.

[0288] 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 1H), 6.71 (dd, J= 8.5, 2.7 Hz, 1H), 6.58 (d, J = 2.7 Hz, 1H), 4.96 (dd, J = 5.5, 2.4 Hz, 1H), 3.77(d, J = 2.3 Hz, 3H), 3.74 (d, J = 2.3 Hz, 3H), 3.73 (s, 3H), 3.64 – 3.46 (m,1H), 2.87 (dt, J = 17.2, 4.7 Hz, 1H), 2.75 – 2.66 (m, 1H), 2.24 – 2.13 (m,2H), 2.01 – 1.93 (m, 1H).

[0289] 31 P NMR (162 MHz, CDCl3) δ 33.5.

[0290] 13 C NMR (101 MHz, CDCl3) δ 159.4, 137.2, 131.2 (d, J = 2.0 Hz), 129.5(d, J = 14.6 Hz), 113.4, 112.8, 65.7 (dd, J = 5.7, 2.2 Hz), 55.3, 53.1 (d, J = 6.4 Hz), 52.5 (d, J = 6.8 Hz), 39.3 (d, J = 143.9 Hz), 29.1 (d, J = 15.8Hz), 17.5 (d, J = 3.2 Hz).

[0291] HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 19 NaO5P 309.0863; Found 309.0861

[0292] Preparation Example 2-8 Synthesis of diisopropyl((1S,2R)-1-hydroxy-6-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-h):

[0293] An α-phosphonate-substituted benzocycloketone derivative, Ih (102 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-h, which was then purified by column chromatography to obtain clean product II-h. The product yield was 91%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0294] 1 H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.5, 2.6 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 4.98 (dd, J = 5.8, 2.5 Hz, 1H), 4.80 –4.72 (m, 2H), 3.74 (s, 3H), 3.70 – 3.63 (m, 1H), 2.95 – 2.86 (m, 1H), 2.79 –2.68 (m, 1H), 2.26 – 2.14 (m, 1H), 2.11 – 2.04 (m, 1H), 2.04 – 1.96 (m, 1H), 1.37 – 1.30 (m, 12H).

[0295] 31 P NMR (203 MHz, CDCl3) δ 29.3.

[0296] 13 C NMR (126 MHz, CDCl3) δ 159.3, 137.3, 131.2 (d, J = 1.8 Hz), 129.6(d, J = 14.8 Hz), 113.4, 112.6, 70.8 (d, J = 6.9 Hz), 70.5 (d, J = 7.0 Hz), 65.8 (d, J = 5.3 Hz), 55.3, 40.3, 39.1, 29.2 (d, J= 15.9 Hz), 24.3 (d, J =3.0 Hz), 24.2 (dd, J = 6.9, 4.2 Hz), 24.0 (d, J = 5.5 Hz), 17.3 (d, J = 2.8Hz).

[0297] HRMS (ESI) m / z: [M + Na] + Calcd for C 17 H 27 NaO5P 365.1488; Found 365.1491

[0298] Preparation Examples 2-9: Synthesis of dimethyl((1S,2R)-1-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-i):

[0299] An α-phosphonate-substituted benzocycloketone derivative, IIi (85 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-i, which was then purified by column chromatography to obtain clean product II-i. The product yield was 86%, >20:1 dr, >99% ee, and it was a white solid.

[0300] 1 H NMR (500 MHz, CDCl3) δ 7.16 (t, J = 7.9 Hz, 1H), 6.95 (dd, J = 7.8, 1.0 Hz, 1H), 6.74 (dd, J = 8.2, 1.1 Hz, 1H), 5.00 (dd, J = 5.9, 2.3 Hz, 1H), 3.81 – 3.77 (m, 6H), 3.76 (d, J = 3.9 Hz, 3H), 3.67 – 3.53 (m, 1H), 3.01 –2.92 (m, 1H), 2.48 – 2.37 (m, 1H), 2.23 – 2.08 (m, 2H), 2.07 – 1.99 (m, 1H).

[0301] 31 P NMR (203 MHz, CDCl3) δ 33.7.

[0302] 13 C NMR (126 MHz, CDCl3) δ 157.1, 138.0 (d, J = 14.3 Hz), 126.8,124.7, 121.9 (d, J = 1.7 Hz), 109.2, 65.9 (d, J = 5.6 Hz), 55.4, 52.7 (dd, J = 89.6, 6.7 Hz), 39.2, 38.0, 22.8 (d, J = 15.6 Hz), 17.0 (d, J = 3.2 Hz).

[0303] HRMS (ESI) m / z: [M + Na] + Calcd for C 13 H 19 NaO5P 309.0862; Found 309.0864

[0304] Preparation Example 2-10 Synthesis of diisopropyl((1S,2R)-1-hydroxy-5-methoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-j):

[0305] An α-phosphonate-substituted benzocycloketone derivative, Ij (102 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-j, which was then purified by column chromatography to obtain clean product II-j. The product yield was 91%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0306] 1 H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.7Hz, 1H), 6.78 (d, J= 8.1 Hz, 1H), 5.04 – 5.00 (m, 1H), 4.84 – 4.74 (m, 2H), 3.82 (s, 3H), 3.62 (d, J = 2.5 Hz, 1H), 3.06 – 2.96 (m, 1H), 2.54 – 2.43 (m,1H), 2.24 – 2.05 (m, 3H), 1.39 – 1.33 (m, 12H).

[0307] 31 P NMR (162 MHz, CDCl3) δ 29.5.

[0308] 13 C NMR (101 MHz, CDCl3) δ 157.3, 138.0 (d, J = 14.6 Hz), 126.8,125.1, 122.1, 109.4, 71.0 (d, J = 6.9 Hz), 70.7 (d, J = 7.2 Hz), 66.4 (d, J =5.4 Hz), 55.5, 39.8, 38.3, 24.4 (d, J = 3.2 Hz), 24.3 (dd, J = 6.9, 4.3 Hz), 24.1 (d, J = 5.4 Hz), 23.1 (d, J = 15.7 Hz), 16.8 (d, J = 2.9 Hz).

[0309] HRMS (ESI) m / z: [M + H] + Calcd for C 17 H 28 O5P 343.1669; Found 343.1668

[0310] Preparation Example 2-11 Synthesis of dimethyl((1S,2R)-1-hydroxy-6,7-dimethoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-k):

[0311] An α-phosphonate-substituted benzocycloketone derivative, Ik (94 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-k, which was then purified by column chromatography to obtain clean product II-k. The product yield was 93%, >20:1 dr, >99% ee, and it was a pale yellow oil.

[0312] 1 H NMR (500 MHz, CDCl3) δ 6.85 (s, 1H), 6.52 (s, 1H), 4.93 (d, J = 4.0Hz, 1H), 3.89 (d, J = 4.3 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74 (d, J =5.3 Hz, 3H), 3.72 (d, J = 5.4 Hz, 3H), 2.83 – 2.74 (m, 1H), 2.70 – 2.60 (m,1H), 2.24 – 2.08 (m, 2H), 2.00 – 1.91 (m, 1H).

[0313] 31 P NMR (203 MHz, CDCl3) δ 33.6.

[0314] 13 C NMR (126 MHz, CDCl3) δ 148.9, 147.5, 129.0 (d, J = 15.0 Hz), 127.9, 112.3 (d, J = 2.2 Hz), 111.1, 65.6 (d, J = 5.5 Hz), 55.8 (d, J = 1.8Hz), 53.0 (d, J = 6.4 Hz), 52.2 (d, J = 6.9 Hz), 39.8, 38.7, 28.5 (d, J =16.0 Hz), 17.8 (d, J = 3.5 Hz).

[0315] HRMS (ESI) m / z: [M + Na] + Calcd for C 14 H 21 NaO6P 339.0968 Found 339.0970

[0316] Preparation Example 2-12 Synthesis of diisopropyl((1S,2R)-1-hydroxy-6,7-dimethoxy-1,2,3,4-tetrahydronaphthyl-2-yl)phosphonate (II-l):

[0317] An α-phosphonate-substituted benzocycloone derivative, II (111 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-l, which was then purified by column chromatography to obtain clean product II-l. The product yield was 98%, >20:1 dr, >99% ee, and it was a pale yellow oil.

[0318] 1 H NMR (500 MHz, CDCl3) δ 6.85 (s, 1H), 6.51 (s, 1H), 4.97 – 4.90 (m,1H), 4.71 (dt, J = 12.6, 6.4 Hz, 2H), 4.16 (d, J = 3.3 Hz, 1H), 3.78 (d, J =16.4 Hz, 6H), 2.84 – 2.75 (m, 1H), 2.70 – 2.60 (m, 1H), 2.16 – 2.01 (m, 2H), 1.99 – 1.91 (m, 1H), 1.28 (td, J = 11.9, 11.1, 6.2 Hz, 12H).

[0319] 31 P NMR (203 MHz, CDCl3) δ 29.4.

[0320] 13 C NMR (126 MHz, CDCl3) δ 148.7, 147.4, 129.2 (d, J= 15.2 Hz), 127.9, 112.3 (d, J = 2.2 Hz), 111.2, 70.7 (d, J = 6.7 Hz), 70.1 (d, J = 7.0Hz), 65.8 (d, J = 5.4 Hz), 55.7, 40.2, 39.1, 28.7, 28.5, 24.2 (d, J = 2.8Hz), 24.0 (d, J = 4.2 Hz), 23.8 (d, J = 5.6 Hz), 17.6 (d, J = 3.1 Hz).

[0321] HRMS (ESI) m / z: [M + Na] + Calcd for C 18 H 29 NaO6P 395.1594 Found 395.1593

[0322] Preparation Example 2-13 Synthesis of dimethyl((1S,2R)-7-bromo-1-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (II-m):

[0323] An α-phosphonate-substituted benzocycloketone derivative, Im (100 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-m, which was then purified by column chromatography to obtain clean product II-m. The product yield was 88%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0324] 1 H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 2.1 Hz, 1H), 7.32 – 7.26 (m,1H), 6.96 (d, J = 8.2 Hz, 1H), 5.02 – 4.93 (m, 1H), 4.27 (d, J = 4.5 Hz, 1H), 3.76 (dd,J = 13.1, 10.7 Hz, 6H), 2.92 – 2.83 (m, 1H), 2.71 – 2.61 (m, 1H), 2.27 – 2.13 (m, 2H), 2.04 – 1.96 (m, 1H).

[0325] 31 P NMR (203 MHz, CDCl3) δ 33.0.

[0326] 13 C NMR (126 MHz, CDCl3) δ 139.3 (d, J = 14.6 Hz), 134.6, 132.7 (d, J = 1.8 Hz), 131.1, 130.7, 119.7 (d, J = 1.6 Hz), 65.5 (d, J = 5.5 Hz), 52.8 (dd, J = 98.9, 6.7 Hz), 39.5, 38.3, 28.3 (d, J = 15.4 Hz), 17.6 (d, J = 3.3Hz).

[0327] HRMS (ESI) m / z: [M + Na] + Calcd for C 12 H 16 BrNaO4P 356.9862; Found356.9862

[0328] Preparation Example 2-14 Synthesis of diisopropyl((1S,2R)-7-bromo-1-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (II-n):

[0329] An α-phosphonate-substituted benzocycloketone derivative, In (116 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-n, which was subsequently purified by column chromatography to obtain clean product II-n. The product yield was 90%, >20:1 dr, >99% ee, and it was a white solid.

[0330] 1 H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.2,2.1 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 5.02 – 4.96 (m, 1H), 4.79 – 4.69 (m,3H), 2.92 – 2.82 (m, 1H), 2.72 – 2.60 (m, 1H), 2.24 – 2.14 (m, 1H), 2.12 –1.96 (m, 2H), 1.36 – 1.26 (m, 12H).

[0331] 31 P NMR (162 MHz, CDCl3) δ 28.9.

[0332] 13 C NMR (101 MHz, CDCl3) δ 139.5 (d, J = 14.9 Hz), 134.7, 132.8 (d, J = 1.8 Hz), 130.9, 130.6, 119.5 (d, J = 1.7 Hz), 70.9 (d, J = 6.8 Hz), 70.4(d, J = 6.9 Hz), 65.7 (d, J = 5.4 Hz), 40.0, 38.6, 28.5 (d, J = 15.5 Hz),24.3 (d, J = 2.9 Hz), 24.1 (d, J = 4.3 Hz), 23.8 (d, J = 5.8 Hz), 17.6 (d, J = 3.1 Hz).

[0333] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 25 BrO4P 391.0669; Found391.0668

[0334] Preparation Example 2-15 Synthesis of diisopropyl((1S,2R)-8-bromo-1-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)phosphonate (II-o):

[0335] An α-phosphonate-substituted benzocycloketone derivative, Io (116 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-o, which was then purified by column chromatography to obtain clean product II-o. The product yield was 84%, >20:1 dr, >99% ee, and it was a white solid.

[0336] 1 H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 7.9, 1.3 Hz, 1H), 7.34 (dd, J = 7.7, 1.3 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 5.04 – 4.97 (m, 1H), 4.81 –4.72 (m, 2H), 4.09 (d, J = 2.9 Hz, 1H), 3.09 – 3.01 (m, 1H), 2.64 – 2.54 (m,1H), 2.31 – 2.19 (m, 1H), 2.13 – 2.04 (m, 2H), 1.37 – 1.30 (m, 12H).

[0337] 31 P NMR (162 MHz, CDCl3) δ 28.8.

[0338] 13 C NMR (101 MHz, CDCl3) δ 139.4 (dd, J = 15.1, 7.5 Hz), 135.7, 132.4(d, J = 2.4 Hz), 129.3, 127.6, 125.5, 71.2 (d, J = 6.9 Hz), 70.8 (d, J = 4.0Hz), 66.7 (d, J= 5.5 Hz), 39.5 (d, J = 2.9 Hz), 38.1 (d, J = 3.0 Hz), 29.9(d, J = 15.0 Hz), 24.4 (d, J = 3.2 Hz), 24.2 (t, J = 3.7 Hz), 24.0 (d, J =5.4 Hz), 17.5.

[0339] HRMS (ESI) m / z: [M + H] + Calcd for C 16 H 25 BrO4P 391.0669; Found 391.0671

[0340] Preparation Example 2-16 Synthesis of dimethyl((3R,4S)-4-hydroxybenzodihydropyran-3-yl)phosphonate (II-p):

[0341] An α-phosphonate-substituted benzocycloketone derivative, Ip (77 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-p, which was then purified by column chromatography to obtain clean product II-p. The product yield was 91%, >20:1 dr, >99% ee, and it was a white solid.

[0342] 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.29 (m, 1H), 7.20 – 7.14 (m, 1H), 6.92 – 6.87 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.98 (q, J = 3.9 Hz, 1H), 4.51(d, J = 2.8 Hz, 1H), 4.37 – 4.29 (m, 2H), 3.78 – 3.75 (m, 3H), 3.75 – 3.71(m, 3H), 2.59 – 2.48 (m, 1H).

[0343] 31 P NMR (162 MHz, CDCl3) δ 28.9.

[0344] 13 C NMR (101 MHz, CDCl3) δ 153.7, 130.4 (d, J = 2.0 Hz), 129.9, 123.4 (d, J = 13.0 Hz), 121.0, 117.0, 62.4 (d, J = 6.4 Hz), 60.7 (d, J = 3.8 Hz), 52.9 (dd, J = 78.1, 6.5 Hz), 39.6, 38.2.

[0345] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 15 NaO5P 281.0550; Found 281.0548

[0346] Preparation Example 2-17 Synthesis of diisopropyl((3R,4S)-4-hydroxybenzodihydropyran-3-yl)phosphonate (II-q):

[0347] An α-phosphonate-substituted benzocycloketone derivative, Iq (94 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-q, which was subsequently purified by column chromatography to obtain clean product II-q. The product yield was 90%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0348] 1 H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 7.7, 1.7 Hz, 1H), 7.22 – 7.17(m, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.83 (d, J= 8.2 Hz, 1H), 5.03 – 4.98 (m,1H), 4.81 – 4.72 (m, 2H), 4.36 (dd, J = 8.6, 2.5 Hz, 2H), 3.96 (s, 1H), 2.53– 2.40 (m, 1H), 1.37 – 1.30 (m, 12H).

[0349] 31 P NMR (162 MHz, CDCl3) δ 24.1.

[0350] 13 C NMR (101 MHz, CDCl3) δ 153.9, 130.6 (d, J = 1.8 Hz), 130.0, 123.2 (d, J = 13.2 Hz), 120.9, 117.1, 71.3 (dd, J = 38.0, 6.9 Hz), 62.9 (d, J = 6.2Hz), 60.9 (d, J = 4.4 Hz), 40.1, 38.7, 29.8, 24.4 (d, J = 3.0 Hz), 24.2 (d, J = 7.6 Hz), 24.0 (d, J = 5.6 Hz).

[0351] HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 23 NaO5P 337.1175; Found 337.1178

[0352] Preparation Example 2-18 Synthesis of dimethyl((3R,4S)-4-hydroxy-6-methylbenzodihydropyran-3-yl)phosphonate (II-r):

[0353] An α-phosphonate-substituted benzocycloketone derivative, Ir (81 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-r, which was then purified by column chromatography to obtain clean product II-r. The product yield was 75%, >20:1 dr, >99% ee, and it was a white solid.

[0354] 1 H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.73(d, J = 8.4 Hz, 1H), 4.95 (q, J = 4.1 Hz, 1H), 4.37 – 4.26 (m, 2H), 4.04 (d, J = 4.5 Hz, 1H), 3.78 (dd, J = 7.8, 1.6 Hz, 3H), 3.77 – 3.74 (m, 3H), 2.53(ddt, J = 21.9, 11.5, 3.7 Hz, 1H), 2.25 (s, 3H).

[0355] 31 P NMR (203 MHz, CDCl3) δ 28.9.

[0356] 13 C NMR (126 MHz, CDCl3) δ 151.5, 130.7, 130.5 (d, J = 2.1 Hz), 130.2,122.9 (d, J = 12.9 Hz), 116.8, 62.6 (d, J = 6.4 Hz), 60.6 (d, J = 3.7 Hz), 52.8 (dd, J = 93.4, 6.6 Hz), 39.6, 38.4, 20.5.

[0357] HRMS (ESI) m / z: [M + Na] +Calcd for C 12 H 17 NaO5P 295.0706; Found 295.0708

[0358] Preparation Example 2-19 Synthesis of diisopropyl((3R,4S)-4-hydroxy-6-methylbenzodihydropyran-3-yl)phosphonate (II-s):

[0359] An α-phosphonate-substituted benzocycloketone derivative, Is (98 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-s, which was then purified by column chromatography to obtain clean product II-s. The product yield was 70%, >20:1 dr, >99% ee, and it was a white solid.

[0360] 1 H NMR (500 MHz, CDCl3) δ 7.12 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.72(d, J = 8.3 Hz, 1H), 4.96 (t, J = 3.7 Hz, 1H), 4.76 (dt, J = 13.2, 6.6 Hz,2H), 4.35 – 4.29 (m, 2H), 2.49 – 2.40 (m, 1H), 2.24 (s, 3H), 1.37 – 1.29 (m,12H), 1.24 (s, 1H).

[0361] 31 P NMR (203 MHz, CDCl3) δ 24.5.

[0362] 13 C NMR (126 MHz, CDCl3) δ 151.6, 130.7 (d, J = 2.0 Hz), 130.6, 130.0,123.1 (d, J = 13.3 Hz), 116.7, 71.4 (d, J = 6.8 Hz), 70.9 (d, J= 6.8 Hz), 62.7 (d, J = 6.1 Hz), 60.9 (d, J = 4.2 Hz), 40.3, 39.1, 24.3 (d, J = 2.7 Hz), 24.1 (dd, J = 6.4, 4.2 Hz), 23.8 (d, J = 5.8 Hz), 20.5.

[0363] HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 25 NaO5P 351.1332; Found 351.1331

[0364] Preparation Example 2-20 Synthesis of dimethyl((3R,4S)-4-hydroxy-6-methylbenzodihydropyran-3-yl)phosphonate (II-t):

[0365] An α-phosphonate-substituted benzocycloketone derivative, It (100 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-t, which was subsequently purified by column chromatography to obtain clean product II-t. The product yield was 91%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0366] 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 2.5 Hz, 1H), 7.29 – 7.23 (m,1H), 6.72 (d, J = 8.8 Hz, 1H), 4.96 (q, J = 4.1 Hz, 1H), 4.53 (d, J = 4.4 Hz,1H), 4.36 – 4.25 (m, 2H), 3.80 – 3.73 (m, 6H), 2.53 (ddt, J = 21.8, 11.5, 3.6Hz, 1H).

[0367] 31 P NMR (162 MHz, CDCl3) δ 28.4.

[0368] 13 C NMR (101 MHz, CDCl3) δ 152.9, 133.0 (d, J = 2.2 Hz), 132.8, 125.5 (d, J = 13.2 Hz), 119.0, 112.9, 62.2 (d, J = 6.3 Hz), 61.0 (d, J = 3.7 Hz), 53.0 (dd, J = 75.7, 6.5 Hz), 39.4, 37.9.

[0369] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 14 BrNaO5P 358.9654; Found358.9657

[0370] Preparation Example 2-21 Synthesis of dimethyl((3R,4S)-4-hydroxy-6-methylbenzodihydropyran-3-yl)phosphonate (II-u):

[0371] An α-phosphonate-substituted benzocycloketone derivative, Iu (87 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-u, which was then purified by column chromatography to obtain clean product II-u. The product yield was 80%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0372] 1 H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 2.6 Hz, 1H), 7.14 (dt, J = 9.0, 1.7 Hz, 1H), 6.78 (d, J= 8.7 Hz, 1H), 4.97 (s, 1H), 4.50 (s, 1H), 4.41 –4.34 (m, 1H), 4.35 – 4.26 (m, 1H), 3.82 – 3.79 (m, 3H), 3.77 (dd, J = 11.0,1.2 Hz, 3H), 2.62 – 2.48 (m, 1H).

[0373] 31 P NMR (203 MHz, CDCl3) δ 28.4.

[0374] 13 C NMR (126 MHz, CDCl3) δ 152.4, 130.0 (d, J = 2.1 Hz), 130.0, 125.7,124.9 (d, J = 13.1 Hz), 118.6, 62.2 (d, J = 6.3 Hz), 61.0 (d, J = 3.7 Hz), 53.0 (dd, J = 95.3, 6.6 Hz), 39.3, 38.1.

[0375] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 14 ClNaO5P 315.0160; Found315.0161

[0376] Preparation Example 2-22 Synthesis of dimethyl((3R,4S)-6-fluoro-4-hydroxybenzodihydropyran-3-yl)phosphonate (II-v):

[0377] An α-phosphonate-substituted benzocycloketone derivative, IIv (82 mg, 0.3 mmol), was added to a reaction flask along with a catalyst (Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product IIv, which was then purified by column chromatography to obtain clean product IIv. The product yield was 90%, >20:1 dr, >99% ee, and it was a white solid.

[0378] 1H NMR (400 MHz, CDCl3) δ 7.08 (dd, J = 8.6, 3.1 Hz, 1H), 6.93 – 6.86(m, 1H), 6.78 (dd, J = 9.0, 4.6 Hz, 1H), 4.95 (dd, J = 8.5, 4.9 Hz, 2H), 4.37– 4.30 (m, 1H), 4.27 (td, J = 11.2, 1.9 Hz, 1H), 3.78 (d, J = 10.9 Hz, 3H),3.75 (d, J = 11.1 Hz, 3H), 2.62 – 2.50 (m, 1H).

[0379] 31 P NMR (162 MHz, CDCl3) δ 21.4.

[0380] 19 F NMR (376 MHz, CDCl3) δ -130.4.

[0381] 13 C NMR (101 MHz, CDCl3) δ 157.0 (d, J = 239.3 Hz), 149.8 (d, J = 2.1Hz), 124.6 (dd, J = 14.1, 7.1 Hz), 118.1 (d, J = 7.9 Hz), 116.8 (d, J = 23.4Hz), 116.1 (dd, J = 22.8, 2.2 Hz), 62.2 (d, J = 6.1 Hz), 61.0 (d, J = 3.5Hz), 52.9 (dd, J = 86.7, 6.6 Hz), 39.6, 38.2.

[0382] HRMS (ESI) m / z: [M + NH4] + Calcd for C 11 H 18FNO5P 294.0902; Found294.0901

[0383] Preparation Example 2-23 Synthesis of tert-butyl(3R,4S)-3-(dimethoxyphosphoryl)-4-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylic acid ester (II-w):

[0384] An α-phosphonate-substituted benzocycloketone derivative, Iw (107 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-w, which was subsequently purified by column chromatography to obtain clean product II-w. The product yield was 94%, >20:1 dr, >99% ee, and it was a white solid.

[0385] 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 7.7,1.7 Hz, 1H), 7.24 – 7.17 (m, 1H), 7.07 – 7.00 (m, 1H), 4.97 (q, J = 4.9, 4.3Hz, 1H), 4.51 (d, J = 5.8 Hz, 1H), 4.42 – 4.33 (m, 1H), 3.75 (d, J = 10.9 Hz, 3H), 3.69 (d, J = 10.9 Hz, 3H), 3.55 – 3.45 (m, 1H), 2.47 – 2.36 (m, 1H), 1.49 (s, 9H).

[0386] 31 P NMR (203 MHz, CDCl3) δ 29.4.

[0387] 13 C NMR (126 MHz, CDCl3) δ 153.2, 137.1, 129.5, 129.4, 129.3 (d, J =1.8 Hz), 128.1, 123.6 (d, J= 17.6 Hz), 81.6, 64.5 (d, J = 6.1 Hz), 52.7 (dd, J = 117.0, 6.6 Hz), 40.4, 39.8 (d, J = 2.3 Hz), 39.3, 28.3.

[0388] HRMS (ESI) m / z: [M + Na] + Calcd for C 16 H 24 NNaO6P 380.1233 Found380.1230

[0389] Preparation Example 2-24 Synthesis of dimethyl((3S,4S)-4-hydroxybenzodihydrothiaran-3-yl)phosphonate (II-x):

[0390] An α-phosphonate-substituted benzocycloketone derivative, Ix (82 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-x. Subsequent purification by column chromatography yielded clean product II-x. The product yield was 96%, >20:1 dr, >99% ee, and was a white solid.

[0391] 1 H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 7.7 Hz, 1H), 7.12 (t, J = 7.5Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 5.07 (d, J = 7.7Hz, 1H), 4.10 (s, 1H), 3.75 (t, J = 1.8 Hz, 3H), 3.73 (t, J = 1.8 Hz, 3H), 3.54 – 3.45 (m, 1H), 2.93 – 2.84 (m, 1H), 2.43 – 2.32 (m, 1H).

[0392] 31 P NMR (203 MHz, CDCl3) δ 30.9.

[0393] 13 C NMR (126 MHz, CDCl3) δ 133.5 (d, J = 14.4 Hz), 132.2, 131.5,128.7, 126.4, 124.4, 65.1 (d, J = 5.0 Hz), 53.0 (dd, J = 106.4, 6.6 Hz),38.9, 37.7, 20.5.

[0394] HRMS (ESI) m / z: [M + Na] + Calcd for C 11 H 15 NaO4PS 297.0321 Found 297.0323

[0395] Preparation Example 2-25 Synthesis of dimethyl((3S,4S)-4-hydroxy-6-methylbenzodihydrothiaran-3-yl)phosphonate (II-y):

[0396] An α-phosphonate-substituted benzocycloketone derivative, Iy (86 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-y, which was then purified by column chromatography to obtain clean product II-y. The product yield was 96%, >20:1 dr, >99% ee, and was a pale yellow oil.

[0397] 1 H NMR (500 MHz, CDCl3) δ 7.11 (d, J = 1.9 Hz, 1H), 7.01 – 6.94 (m,2H), 5.04 (d, J = 7.8 Hz, 1H), 3.85 (d, J = 3.9 Hz, 1H), 3.77 (d, J = 3.5 Hz, 3H), 3.75 (d, J= 3.5 Hz, 3H), 3.54 – 3.45 (m, 1H), 2.93 – 2.84 (m, 1H), 2.44– 2.33 (m, 1H), 2.24 (s, 3H).

[0398] 31 P NMR (203 MHz, CDCl3) δ 31.0.

[0399] 13 C NMR (126 MHz, CDCl3) δ 134.1, 133.3 (d, J = 14.2 Hz), 132.0,129.8, 128.5, 126.3, 65.3 (d, J = 5.0 Hz), 53.4 (d, J = 6.4 Hz), 52.6 (d, J =6.9 Hz), 39.0, 37.9, 20.6 (d, J = 29.4 Hz).

[0400] HRMS (ESI) m / z: [M + Na] + Calcd for C 12 H 17 NaO4PS 311.0477 Found 311.0479

[0401] Preparation Example 2-26 Synthesis of tert-butyl(4S,5R)-5-(dimethoxyphosphoryl)-4-hydroxy-4,5,6,7-tetrahydro-1H-indole-1-carboxylic acid ester (II-z):

[0402] An α-phosphonate-substituted benzocycloketone derivative, Iz (103 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-z, which was then purified by column chromatography to obtain clean product II-z. The product yield was 78%, >20:1 dr, >99% ee, and it was a white solid.

[0403] 1 H NMR (500 MHz, CDCl3) δ 7.11 (d, J= 3.5 Hz, 1H), 6.16 (d, J = 3.4Hz, 1H), 4.94 (d, J = 3.2 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.31 (d, J =4.7 Hz, 1H), 3.13 (dd, J = 16.3, 5.0 Hz, 1H), 2.72 – 2.60 (m, 1H), 2.16 –2.03 (m, 3H), 1.54 (s, 9H).

[0404] 31 P NMR (203 MHz, CDCl3) δ 33.7.

[0405] 13 C NMR (126 MHz, CDCl3) δ 149.4, 130.5 (d, J = 1.7 Hz), 123.5 (d, J =15.7 Hz), 120.4, 110.1 (d, J = 2.6 Hz), 83.7, 62.2 (d, J = 5.2 Hz), 52.7 (dd, J = 65.0, 6.7 Hz), 39.8, 38.7, 28.1, 24.7 (d, J = 16.1 Hz), 18.1 (d, J = 2.7Hz).

[0406] HRMS (ESI) m / z: [M + Na] + Calcd for C 15 H 24 NNaO6P 368.1233; Found368.1235

[0407] Preparation Example 2-27 Synthesis of dimethyl((4S,5R)-4-hydroxy-4,5,6,7-tetrahydrobenzofuran-5-yl)phosphonate (II-aa):

[0408] An α-phosphonate-substituted benzocycloketone derivative, I-aa (73 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude product II-aa, which was then purified by column chromatography to obtain clean product II-aa. The product yield was 80%, >20:1 dr, >99% ee, and it was a white solid.

[0409] 1 H NMR (500 MHz, CDCl3) δ 7.23 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 1.9Hz, 1H), 4.96 (t, J = 3.4 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.74 (dd, J =16.4, 5.0 Hz, 1H), 2.58 – 2.47 (m, 1H), 2.20 – 2.14 (m, 2H), 2.10 – 2.04 (m,1H), 1.22 (s, 1H).

[0410] 31 P NMR (203 MHz, CDCl3) δ 33.3.

[0411] 13 C NMR (126 MHz, CDCl3) δ 151.7 (d, J = 1.7 Hz), 141.4, 119.1 (d, J =16.6 Hz), 109.5 (d, J = 2.3 Hz), 61.9 (d, J = 5.0 Hz), 52.8 (dd, J = 71.0,6.7 Hz), 40.5, 39.3, 23.1 (d, J = 16.6 Hz), 18.4 (d, J = 2.4 Hz).

[0412] HRMS (ESI) m / z: [M + Na] + Calcd for C10 H 15 NaO5P 269.0549; Found 269.0550

[0413] Preparation Example 2-28 Synthesis of dimethyl((4S,5R)-4-hydroxy-4,5,6,7-tetrahydrobenzo[b]thiophene-5-yl)phosphonate (II-ab):

[0414] An α-phosphonate-substituted benzocycloketone derivative, I-ab (78 mg, 0.3 mmol), was added to a reaction flask along with a catalyst, Cat.E (0.2 mg, 0.003 mmol), HCOOH / Et3N (molar ratio 5:2) (76 μL, 0.6 mmol), and methanol (1 mL). The reaction was carried out at 25 °C for 16 h. After the reaction was complete, the solvent was evaporated to obtain crude II-ab, which was then purified by column chromatography to obtain clean product II-ab. The product yield was 86%, >20:1 dr, >99% ee, and it was a white solid.

[0415] 1 H NMR (500 MHz, CDCl3) δ 7.08 (d, J = 5.2 Hz, 1H), 6.98 (d, J = 5.2Hz, 1H), 5.04 (d, J = 4.6 Hz, 1H), 3.78 (d, J = 3.1 Hz, 3H), 3.76 (d, J = 2.9Hz, 6H), 3.67 (d, J = 5.0 Hz, 1H), 2.97 (dd, J = 16.9, 4.6 Hz, 1H), 2.76 –2.65 (m, 1H), 2.28 – 2.10 (m, 4H).

[0416] 31 P NMR (203 MHz, CDCl3) δ 33.3.

[0417] 13 C NMR (126 MHz, CDCl3) δ 138.0 (d, J = 1.7 Hz), 136.5 (d, J = 15.1Hz), 127.2 (d, J = 2.5 Hz), 123.2, 62.7 (d,J = 5.4 Hz), 52.8 (dd, J = 79.9,6.7 Hz), 40.1, 38.9, 25.1 (d, J = 16.6 Hz), 18.9 (d, J = 2.8 Hz).

[0418] HRMS (ESI) m / z: [M + Na] + Calcd for C 10 H 15 NaO4PS 285.0321 Found 285.0323

[0419] Effect Example

[0420] To analyze the activity of chiral hydroxyphosphate compounds on cell migration and repair, a scratch assay was performed using human keratinocytes (HaCaT cells). First, HaCaT cells in logarithmic growth phase were passaged and seeded into 12-well plates, then incubated statically at 37°C with 5% CO2. When the cell density reached 60%-70%, scratching was performed, drawing two perpendicular lines in each well. After scratching, the cells were gently rinsed 2-3 times with PBS to remove cell debris. Fresh culture medium was then added. Following scratching, the corresponding concentration of the compound was added to each well. Data was collected at 0 h and 24 h post-scratching. The scratch area of ​​keratinocytes in the control group and the sample group was measured, and the healing rate was calculated to analyze the effect of different compound concentrations on cell migration and repair activity. The healing rate was calculated using the following formula:

[0421]

[0422] The results are as follows Figure 1 The chemical structures of the compounds shown (II-v, II-ab) exhibit strong biological activity in promoting keratinocyte migration and repair. Figure 1The study shows the scratch healing rates of keratinocytes at 0 and 24 hours after treatment with different compounds (II-v, II-ab). Compared to the control group (marked as BC in the figure), the experimentally treated HaCaT cells exhibited significantly enhanced migration ability after the addition of these compounds. Over time, the cells gradually migrated and merged, leading to a significant reduction in the scratch area. Specifically, the healing rate of II-v (marked as 2v in the figure) at a concentration of 0.5 μg / mL was 45.4%, and the healing rate of II-ab (marked as 2ab in the figure) at a concentration of 1 μg / mL was 46%, both significantly promoting HaCaT cell migration. Calculations of scratch area changes and healing rates showed a significantly increased healing rate for IaCaT cells in the treated groups, accelerating scratch repair (*P<0.05).

[0423] The stratum corneum, the outermost layer of the skin, is mainly composed of multiple layers of keratinocytes. This structure plays a fundamental role in maintaining the skin barrier function. When the skin is damaged, stress responses such as inflammation are activated, and the regeneration and migration capabilities of keratinocytes play a crucial role in the repair of skin wounds. Studies have found that compounds such as II-v and II-ab have significant promoting effects on keratinocyte migration and repair, demonstrating broad application potential and value in wound healing, skin tissue soothing, repair, and anti-aging.

[0424] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A chiral hydroxyphosphonate, characterized in that, It has the structure shown in Equation II: ； Each R is independently H and C. 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; X represents the bond, -O-, -(C(R) 2 )2) q -、-S(=O) m -; m is 0; q is 1; Each R 2 H stands alone; When X is a key or -(C(R) 2 )2) q -;Ar is or ; When X is -O- or -S (=O) m -; Ar represents phenyl; The alkyl, alkenyl, ynyl, phenyl, and Further, each optionally and independently, is replaced by the same or different substituents R. 3 Mono- or poly-substituted; the substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, or C. 1-6 alkyl.

2. The chiral hydroxyphosphonate according to claim 1, characterized in that, Each R is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, vinyl, or ethynyl; Each R 2 H stands alone; The substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, n-propyl, isopropyl, n-butyl, or n-pentyl; When X is a key or -(C(R) 2 )2) q -;Ar is or ; When X is -O- or -S (=O) m -; Ar is selected from one of the following groups: 、 、 、 、 、 、。 3. The chiral hydroxyphosphonate according to claim 1, characterized in that, Choose from one of the following structures: 。 4. A method for preparing the chiral hydroxyphosphonate according to any one of claims 1-3, characterized in that, include: In the presence of a rhodium catalyst, the α-phosphonate-substituted benzocycloketone compound of Formula I is reacted with a hydrogen source to prepare the chiral hydroxyphosphonate of Formula II. ； in, Each R is independently H, C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; X represents the bond, -O-, -(C(R) 2 )2) q -、-S(=O) m -; m is 0; q is 1; Each R 2 H stands alone; When X is a key or -(C(R) 2 )2) q -;Ar is or ; When X is -O- or -S (=O) m -; Ar represents phenyl; The alkyl, alkenyl, ynyl, phenyl, and Further, each optionally and independently, is replaced by the same or different substituents R. 3 Mono- or poly-substituted; the substituent R 3 It can be hydrogen, -F, -Cl, -Br, -I, or C. 1-6 alkyl.

5. The preparation method according to claim 4, characterized in that, The rhodium catalyst is ; The hydrogen source is at least one of the following: a mixture of HCOOH / Et3N, a mixture of HCOOH / DABCO, a mixture of HCOOH / DBU, HCO2NH4, and HCO2Na; wherein, in the HCOOH / Et3N mixture, the molar ratio of HCOOH to Et3N is 5:2, 3:2, or 1:1; in the HCOOH / DABCO mixture, the molar ratio of HCOOH to DABCO is 2:1; and in the HCOOH / DBU mixture, the molar ratio of HCOOH to DBU is 2:

1.

6. The preparation method according to claim 4, characterized in that, The reaction is carried out in an air atmosphere; The reaction temperature is 10-40℃; The solvent used in the reaction includes at least one of methanol, ethanol, isopropanol, ethyl acetate, and tetrahydrofuran; The molar ratio of the hydrogen source to the compound shown in Formula I is (1-3):1; The molar ratio of the catalyst to the compound shown in Formula I is (0.00005~0.05):

1.

7. The preparation method according to claim 4, characterized in that, The α-phosphonate-substituted benzocycloketone compound shown in Formula I is prepared by reacting compound III with compound IV after treatment with lithium reagent. ； in, Y is -Cl, -Br, or -I; The lithium reagent is at least one of lithium diisopropylaminolithium, methyllithium reagent, n-butyllithium, or 2,2,4,4-tetramethylpiperidine.

8. The preparation method according to claim 4, characterized in that, The α-phosphonate-substituted benzocycloketone compounds are selected from one of the following structures: 。 9. Use of the chiral hydroxyphosphonate of claim 1 or the chiral hydroxyphosphonate prepared by the method of claim 4 in the preparation of medicaments for skin wound repair and anti-aging.

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