CN102127114B - Non-natural chiral amino acid derivative with di-organic phosphate group and synthesis method thereof - Google Patents

Abstract

The invention discloses a non-natural chiral a-amino acid derivative with geminal bisphosphonate and a preparation method thereof. Its synthesis method is: in an organic solvent, under the protection of inert gas or _N2 , using tetraethyl alkylidene diphosphate and 2-(benzylideneamino) methyl acetate as raw materials, copper salt/TF-BiphamPhos complex The compound is used as a catalyst, adding carbonate or an organic base, fully reacting at a temperature of -40°C to 30°C, and obtaining the target compound of the present invention after column chromatography, extraction and purification. The compound can be used as the active ingredient of the bactericide, and can also be used as the raw material for preparing the active ingredient of the drug for treating bone diseases.

Description

Unnatural chiral amino acid derivatives with geminal bisphosphate groups and their synthesis methods

technical field

The invention belongs to the technical field of amino acid synthesis, and in particular relates to a non-natural chiral amino acid and a synthesis method thereof.

Background technique

Unnatural chiral α-amino acids are an important class of compounds, mainly used in some drugs and biologically active compounds ((a) Mulzer, J., Waldmann, H., Eds.In Organic Synthesis Highlights III; Wiley-VCH: Weinheim, 1998(b) Van Hest, J.C.M.Chem.Commun.2001, 1897.(c)Wang, L.; Schultz, P.G.Chem.Commun.2002, 1.(d)Wang, L.; Shultz, P.G.Angew. Chem. Int. Ed. 2005, 44, 34.). In recent years, due to the discovery of more and more active peptides with biological functions, the demand for amino acids with special structures and their derivatives has increased. However, the existing amino acid varieties are far from meeting the demand, so more varieties of amino acids have been developed. Unnatural amino acids and their derivatives are of great interest.

Compounds containing geminal bisphosphonate groups are also an important class of compounds, which are widely used in the treatment of bone diseases, such as: osteitis deformans, bone transplantation, myeloma, osteoporosis and rheumatoid arthritis (( a) Zhang, S.; Gangal, G.; Uludag, H. Chem. Soc. Rev. 2007, 36, 507. (b) Guise, T. A. Cancer Treat. Rev. 2008, 34, S19. (c) Zhang, Y.; Leon, A.; Song, Y.; Studer, D.; Haase, C.; ; Rogers, M.J.; Barnett, B.L.; Ebetino, F H.; Russell, R.G.G.; Oppermann, U.; Segall, Y. Phosphorus, Sulfur, Silicon 2001, 173, 1.). Other studies have shown that this type of compound also has high-efficiency bactericidal activity.

The synthetic method of unnatural chiral α-amino acid compound generally has following several: (1) take ruthenium, rhodium as the asymmetric catalytic hydrogenation reaction of catalyst; (2) asymmetric Strecker (Strecker) amino acid reaction; (3) ) Asymmetric addition reaction of some electrophiles to imino esters; (4) Asymmetric alkylation of benzophenone imines of glycine esters catalyzed by phase transfer catalysts. It is difficult to obtain unnatural chiral α-amino acids with good yield and enantioselectivity by the above methods.

Contents of the invention

The object of the present invention is to overcome the problems in the background technology and provide a method for synthesizing unnatural chiral α-amino acids with geminal bisphosphate groups for the purpose of high yield and high enantioselectivity.

The non-natural chiral α-amino acid derivatives with geminal bisphosphate groups provided by the present invention have the following structural formula:

in,

R is phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-fluorophenyl, p-bromophenyl, p- Trifluoromethylphenyl, p-nitrophenyl, 2-naphthyl, 2-furyl, methyl, ethyl, propyl, cyclohexylmethyl, isobutyl, hydrogen;

R' is methyl, ethyl or tert-butyl;

R" is hydrogen or benzoyl.

The present invention also provides the synthetic method of above-mentioned compound, comprises the following steps:

1) In an organic solvent, under the protection of inert gas or _N2 , using tetraethyl alkylidene diphosphate and 2-(benzylideneamino) acetate as raw materials, copper salt/TF-BiphamPhos complex As a catalyst, add carbonate or an organic base, react fully at -40°C to 30°C, evaporate the solvent, and obtain the compound by column chromatography

其中，R”为氢基；2) The obtained compound is fully stirred in an aqueous ether solution of p-toluenesulfonic acid, purified by extraction, and the solvent is evaporated to obtain the compound

Wherein, R" is a hydrogen group;

其中，R”为苯甲酰基。3) The compound obtained in step 2) is fully stirred in a dichloromethane solution of benzoyl chloride and triethylamine, and the compound is obtained by column chromatography

Wherein, R" is benzoyl.

For above-mentioned inventive method, can carry out following optimization:

1) The molar ratio of tetraethyl alkylidene diphosphate and 2-(benzylidene amino) acetate is preferably 1: (0.52～2);

2) The copper salt/TF-BiphamPhos complex is obtained by dissolving copper salt and TF-BiphamPhos in an organic solvent at room temperature according to the number of moles of copper salt ≤ the number of moles of TF-BiphamPhos, and fully reacting;

3) The column chromatography uses silica gel as a filler, and a mixed solvent of petroleum ether and acetone as an eluent, and: the volume ratio of petroleum ether and acetone is 1:2;

4) The extraction and purification are as follows: ether extraction, the obtained aqueous phase is adjusted to weak alkalinity with saturated sodium bicarbonate, then extracted with dichloromethane, and the organic phases are combined;

A kind of intermediate that adopts above-mentioned synthetic method to obtain, structural formula is as follows:

in,

R' is methyl, ethyl or tert-butyl;

R is phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-fluorophenyl, p-bromophenyl, p- Trifluoromethylphenyl, p-nitrophenyl, 2-naphthyl, 2-furyl, methyl, ethyl, propyl, cyclohexylmethyl, isobutyl, hydrogen.

Features of the present invention:

1) The method of the present invention has the advantages of simple synthesis, low cost and high yield, and the corresponding selectivity of the obtained target compound is good, the yield is ≥ 70%, and the corresponding selectivity excess is ≥ 89%;

2) A new class of non-natural chiral α-amino acid derivatives with geminal bisphosphates synthesized by this method has fungicidal activity and can be used as an active ingredient of fungicides, especially for fusarium wilt of cotton, rhizoctonia solani, cucumber Botrytis cinerea, wheat gibberella, apple ringworm, cotton anthracnose, etc. have remarkable bactericidal effects;

3) A new class of non-natural chiral α-amino acid derivatives with geminal bisphosphates synthesized by this method has bactericidal activity, and because of the geminal bisphosphonate group, it can be used as an active ingredient for the treatment of bone diseases. raw material;

4) The catalyst copper salt/TF-BiphamPhos complex that the method of the present invention adopts has the advantages of fast catalytic reaction speed and low catalyst consumption in the reaction.

Detailed ways

In order to better understand the present invention, the present invention will be further described below in conjunction with the examples.

Example 1:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.46mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-styryl-1,1-tetraethyl diphosphate, stirred for 30 minutes, evaporated the solvent, the product After silica gel column chromatography (petroleum ether/acetone 1/2), the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was adjusted to weak with saturated sodium bicarbonate. Basic, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a white solid, the yield was 90%, the enantioselective excess of the product was 94%, HPLC (Chiralcel AD-H, i-propanol/hexane =40/60, flow rate 0.7mL/min, λ=220nm); t _r =9.89and 11.06min.) [α] ²⁵ _D +4.5 (c 0.48, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300MHz) δ7.55-7.53(m, 2H), 7.23-7.21(m, 3H), 4.54(d, J=10.8Hz, 1H), 4.19-3.91(m, 8H), 3.87-3.54(m , 2H), 3.35(s, 3H), 2.48(br, 2H), 1.34(t, J=7.2Hz, 3H), 1.23(t, J=7.2Hz, 6H), 1.11(t, J=7.2Hz , 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.73, 15.81, 15.91, 16.02, 16.15, 35.87, 37.63, 39.39, 47.75, 51.22, 56.37, 56.53, 61.94, 62.01, 62.14, 127.019, 127 , 130.30; 137.47, 175.62; IR (KBr) v 3387, 2982, 2926, 1735, 1243, 1028 cm ^-1 . HRMS calcd. For C ₁₉ H ₃₃ NO ₈ P ₂ +H ⁺ : 466.1752, found 466.1742.

Example 2:

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preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.46mmol 2-(benzylideneamino)ethyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-styryl-1,1-diphosphate tetraethyl ester, stirred for 30 minutes, evaporated the solvent, the product After silica gel column chromatography (petroleum ether/acetone 1/2), the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was adjusted to a weak base with saturated sodium bicarbonate properties, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain an oily liquid, the yield was 88%, and the enantioselectivity of the product was 94%, HPLC (Chiralcel AD-H, i-propanol/hexane= 10/90, flow rate 1.0mL/min, λ=220nm); t _r =45.39and 50.45min.) [α] ²⁵ _D +6.5 (c 0.23, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS , 300MHz) δ7.52-7.08(m, 5H), 4.54(d, J=10.8Hz, 1H), 4.19-3.91(m, 10H), 3.87-3.54(m, 2H), 3.35(s, 3H) , 2.48 (br, 2H), 1.34-1.11 (m, 15H),; ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.23, 15.31, 15.95, 16.02, 16.65, 35.77, 37.73, 39.79, 47.75, 51.22 , 56.37, 56.53, 61.94, 62.01, 62.14, 127.06, 127.19, 130.30; 137.47, 175.62; IR(KBr)v 3387, 2982, 2926, 1735, 1243, 1028cm ^-1 . HRMS calculated value. ForC ₂₀ H ₃₅ NO _{8 P2} +H ⁺ : 480.1916, measured 480.1909.

Example 3:

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preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.46 mmol 2-(benzylideneamino) tert-butyl acetate, 0.03 mmol K ₂ CO ₃ , 0.23 mmol 2-styryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent, The product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was adjusted to weak concentration with saturated sodium bicarbonate. Basic, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a white solid, the yield was 90%, the enantioselective excess of the product was 95%, HPLC (Chiralcel AD-H, i-propanol/hexane =10/90, flow rate 1.0mL/min, λ=220nm); t _r =35.89and 56.06min.) [α] ²⁵ _D +7.5 (c 0.67, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300MHz) δ7.54-7.36(m, 2H), 7.26-7.10(m, 3H), 4.55(d, J=10.8Hz, 1H), 4.16-3.97(m, 8H), 3.87-3.54(m , 2H), 3.35(s, 3H), 2.48(br, 2H), 1.34(t, J=7.2Hz, 3H), 1.23-1.11(m, 19H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.73, 15.81, 15.91, 16.02, 16.15, 28.56, 35.87, 37.63, 39.39, 47.75, 51.22, 56.37, 56.53, 61.94, 62.01, 62.14, 127.06, 127.19, 130.30; , 2982, 2926, 1735, 1243, 1028 cm ^-1 . HRMS Calc. For C ₂₂ H ₃₉ NO ₈ P ₂ +H ⁺ : 508.2229, Measured 508.2231.

Example 4:

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under nitrogen protection, add 1mL dichloromethane, stir at room temperature for 1 hour, then add 0.12 Mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-methylstyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 70%, and the enantioselectivity of the product was 99%, HPLC (Chiralcel AD-H, i- propanol/hexane=10/90, flow rate 1.0 mL/min, λ=210 nm); t _r =31.66 and 45.77 min. [α] ²⁵ _D = -6.9 (c 0.6, CH ₂ Cl ₂ ); ¹ HNMR (CDCl ₃ , TMS, 300 MHz) δ 7.42-7.39 (m, 2H), 7.05-7.02 (m, 2H), 4.49 ( d, J=11.7Hz, 1H), 4.19-3.45(m, 10H), 3.37(s, 3H), 2.40(br, 2H), 2.29(s, 3H), 1.34(t, J=7.5Hz, 3H ), 1.30-1.18 (m, 6H), 1.11 (t, J=7.2Hz, 3H); ¹³ CNMR (CDCl ₃ , TMS, 75MHz) δ16.16, 16.25, 16.37, 16.46, 16.59, 21.30, 36.40, 38.15 , 39.92, 47.58, 51.76, 56.85, 57.00, 62.43, 128.33, 128.86, 130.44, 130.79, 134.72, 137.01, 175.94; IR(KBr)v 3388, 2981, 2955, 1736, 1243, 1027cm calculated by HRMS ^-1 For _C20H35NO8P2 +H ⁺ : _{480.1911 ,} found 480.1905 _.

Example 5:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-m-methylstyryl-1,1-diphosphate tetraethyl ester, stirred for 30 minutes, evaporated solvent, the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was adjusted with saturated sodium bicarbonate to weak alkalinity, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 90%, and the enantioselective excess of the product was 95%, HPLC (Chiralcel AD-H, i -propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r =33.12and 36.22min.[α] ²⁵ _D =+5.9(c 1.5, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 75MHz) δ7.26(s, 2H), 7.07-7.02(m, 1H), 6.94-6.92(m, 1H), 4.43(d, J=11.1Hz, 1H), 4.11-3.46 (m, 10H), 3.33(s, 3H), 2.23(s, 3H), 2.19(br, 2H), 1.26(t, J=6.6Hz, 3H), 1.18-1.10(m, 6H), 1.03( t, J=6.9Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 100MHz) δ15.76, 15.86, 15.96, 16.04, 21.17, 36.05, 37.81, 39.57, 47.60, 51.30, 56.37, 56.53, 62.12, 127.16 , 127.79, 131.00, 136.51, 137.44, 138.14, 175.59; IR(KBr)v 3476, 2982, 2928, 1735, 1246, 1028cm ^-1 . HRMS calculated value. For C ₂₀ H ₃₅ NO ₈ P ₂ +H ⁺ : 480.1911 , measured 480.1904.

Embodiment 6:

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preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-methoxystyryl-1,1-tetraethyl diphosphate, stirred for 30 minutes, evaporated The solvent was removed, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was washed with saturated sodium bicarbonate Adjust to weakly alkaline, then extract 3 times with dichloromethane, combine the organic phases, evaporate the solvent to obtain a colorless oily liquid, the yield is 95%, the enantioselective excess of the product is 97%, HPLC (Chiralcel AD-H, i-propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r ＝64.95and 72.65min.[α] ²⁵ _D ＝-7.8(c 0.4, CH ₂ C1 ₂ ); ¹ H NMR (CDCl ₃ , TMS, 75MHz) δ7.47-7.44 (m, 2H), 6.78-6.75 (m, 2H), 4.48 (d, J=11.4Hz, 1H), 4.14-3.79 (m, 9H), 3.77(s, 3H), 3.64-3.45(m, 1H), 3.37(s, 3H), 2.51(br, 2H), 1.34(t, J=7.2Hz, 3H), 1.28-1.14(m, 6H) , 1.09 (t, J=7.5Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.43, 16.52, 47.03, 51.91, 55.39, 56.89, 57.06, 62.55, 112.97, 128.86, 131.84, 159.00, 175.56; IR(KBr)v 3386, 2981, ₂₉₂₇ , 1735 _, 1247 _{, 1028} , cm ^-1 . HRMS Calcd. For _C20H35NO9P2 +H ⁺ : 496.1860, found 496.1859.

Embodiment 7:

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preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-chlorostyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 85%, and the enantioselectivity of the product was 95%, HPLC (Chiralcel AD-H, i- propanol/hexane＝40/60, flow rate 0.7mL/min, λ＝220nm); t _r ＝11.53and 14.53min.[α] ²⁵ _D ＝+5.4(c 1.2, CH ₂ Cl ₂ ); ¹ H NMR ( CDCl ₃ , TMS, 300MHz) δ7.45-7.43(m, 2H), 7.15-7.13(m, 2H), 4.42(d, J=10.8Hz, 1H), 4.10-3.34(m, 10H), 3.31( s, 3H), 2.44(br, 2H), 1.27(t, J=6.6Hz, 3H), 1.22-1.13(m, 6H), 1.05(t, J=6.3 Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.12, 16.21, 25.27, 35.79, 37.55, 46.89, 51.68, 56.30, 56.45, 62.09, 62.17, 62.43, 127.46, 131.93, 133.17, 135.98, 175.07; IR (3KBr2) v 93 , 1735, 1242, 1027 cm ^-1 . HRMS Calc. For C ₁₉ H ₃₂ NO ₈ P ₂ Cl+H ⁺ : 500.1365, Measured 500.1357.

Embodiment 8:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-o-chlorostyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 90%, and the enantioselectivity of the product was 96%, HPLC (Chiralcel AD-H, i- propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r ＝44.78and 67.34min.[α] ²⁵ _D ＝+7.0(c 1.0, CH ₂ Cl ₂ ); ¹ H NMR ( CDCl ₃ , TMS, 75MHz) δ7.95-7.92(m, 1H), 7.25-7.26(m, 1H), 7.16-7.05(m, 2H), 4.41(d, J=11.1Hz, 1H), 4.19- 3.53(m, 10H), 3.32(s, 3H), 2.39(br, 2H), 1.31(t, J=7.5Hz, 3H), 1.25-1.13(m, 6H), 0.99(t, J=6.9Hz , 3H); ¹³ C NMR (CDCl ₃ , TMS, 100MHz) δ16.02, 16.23, 16.43, 36.22, 37.96, 39.72, 43.17, 51.81, 56.99, 57.13, 62.28, 62.61, 126.17, 128.40, 129.29, 1131.05 , 136.66, 174.81; IR (KBr) v 3387, 2982, 2930, 1736, 1251, 1028 cm ^-1 . HRMS calcd. For C ₁₉ H ₃₂ NO ₈ P ₂ Cl+H ⁺ : 500.1365, found 500.1358.

Embodiment 9:

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preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-m-chlorostyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 88%, the enantioselective excess of the product was 98%, HPLC (Chiralcel AD-H, i- propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r ＝38.90and 52.21min.[α] ²⁵ _D ＝+7.1(c 0.9, CH ₂ Cl ₂ ); ¹ H NMR ( CDCl ₃ , TMS, 75MHz) δ7.59-7.92(s, 1H), 7.45-7.43(m, 1H), 7.20(s, 2H), 4.51(d, J=11.1Hz, 1H), 4.18-3.44( m, 10H), 3.40(s, 3H), 2.54(br, 2H), 1.34(t, J=7.2Hz, 3H), 1.26-1.18(m, 6H), 1.13(t, J=7.2Hz, 3H ); ¹³ CNMR (CDCl ₃ , TMS, 100MHz) δ15.78, 15.88, 16.00, 16.22, 25.17, 35.55, 37.31, 39.07, 47.34, 51.50, 56.10, 56.27, 61.89, 61.99, 62.13, 62.21, 62.33, 127.29, 128.49, 128.63, 130.54, 132.94, 139.57, 175.43; IR(KBr)v 2457, 2983, 2929, 1735, 1242, 1027cm ^-1 . HRMS calculated value ForC ₁₉ H ₃₂ NO ₈ P ₂ Cl+Na ⁺ : 522.1184 , measured 522.1174.

Example 10:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-fluorostyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 90%, the enantioselective excess of the product was 99%, HPLC Chiralcel AD-H, i-propanol /hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r =43.96and 58.53min.[α] ²⁵ _D =+0.3(c 0.7, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 75MHz) δ7.57-7.53(m, 2H), 6.96-6.90(m, 2H), 4.49(d, J=11.1Hz, 1H), 4.20-3.40(m, 10H), 3.37(s , 3H), 2.46(br, 2H), 1.34(t, J=6.9Hz, 3H), 1.31-1.14(m, 6H), 1.10(t, J=7.2Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.19, 16.28, 16.39, 16.49, 36.03, 37.78, 37.31, 39.55, 47.23, 51.84, 56.75, 56.92, 62.28, 62.36, 62.53, 62.62, 62.72, 114.22, 113.48, 0 , 133.39, 160.72, 163.98, 175.75; IR(KBr)v 3387, 2983, 2929, 1736, 1241, 1028cm ^-1 . HRMS calculated ForC ₁₉ H ₃₂ NO ₈ P ₂ F+H ⁺ : 484.1660, measured 484.1654. HPLC 99%ee (Chiralcel AD-H, i-propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r =43.96a nd 58.53min.

Example 11:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-bromostyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, evaporate the solvent , the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the aqueous phase obtained was adjusted to Weakly alkaline, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 89%, the enantioselectivity of the product was over 95%, HPLC (Chiralcel AD-H, i- propanol/hexane=30/70, flow rate 0.7mL/min, λ=220nm); t _r ＝15.61and 21.27min.[α] ²⁵ _D ＝+2.5(c 1.2, CH ₂ Cl ₂ ); ¹ H NMR ( CDCl ₃ , TMS, 300MHz) δ7.40-7.37(m, 2H), 7.31-7.28(m, 2H), 4.41(d, J=10.8Hz, 1H), 4.09-3.40(m, 10H), 3.32( s, 3H), 2.46(br, 2H), 1.26(t, J=7.5Hz, 3H), 1.19-1.11(m, 6H), 1.05(t, J=6.3Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.14, 16.22, 25.29, 37.51, 46.96, 51.71, 56.24, 56.40, 62.10, 62.19, 62.37, 121.40, 130.44, 132.29, 136.50, 175.13; IR (KBr) v 38287, 29 , 1736, 1243, 1028 cm ^-1 . HRMS Calcd. For C ₁₉ H ₃₂ NO ₈ P ₂ Br+Na ⁺ : 566.0679, Measured 566.0676.

Example 12:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-trifluoromethylstyryl-1,1-diphosphate tetraethyl ester, after stirring for 30 minutes, The solvent was evaporated, the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was washed with saturated bicarbonate The sodium was adjusted to be weakly alkaline, and then extracted 3 times with dichloromethane, the organic phases were combined, the solvent was evaporated to obtain a colorless oily liquid, the yield was 88%, and the enantioselectivity of the product was 95%, HPLC (Chiralcel AD-H ₁ ^_ _{_ _ _} ^_ H NMR (CDCl ₃ , TMS, 300MHz) δ7.70-7.67(m, 2H), 7.49-7.47(m, 2H), 4.52(d, J=11.1Hz, 1H), 4.15-3.39(m, 10H) , 3.34(s, 3H), 2.43(br, 2H), 1.31(t, J=7.2Hz, 3H), 1.22-1.09(m, 6H), 1.06(t, J=7.5Hz, 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.78, 16.04, 37.53, 39.29, 47.29, 51.66, 56.19, 62.14, 62.45, 124.19, 130.92, 141.74, 174.92; IR (KBr) v 3394, 2984, 2926, 1736, 1326, 1028 cm ^-1 . HRMS Calcd. For C ₂₀ H ₃₂ NO ₈ P ₂ F ₃ +H ⁺ : 534.1628, Measured 534.1629.

Example 13:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-nitrostyryl-1,1-diphosphate tetraethyl ester, stirred for 30 minutes, evaporated solvent, the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was adjusted with saturated sodium bicarbonate to weak alkalinity, then extracted 3 times with dichloromethane, combined the organic phases, evaporated the solvent to obtain a colorless oily liquid, the yield was 91%, and the enantioselective excess of the product was 93%, HPLC (Chiralcel AD-H, i -propanol/hexane=30/70, flow rate 1.0mL/min, λ=220nm); t _r =17.34and 22.23min.[α] ²⁵ _D =+5.1 (c 1.2, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300MHz) δ8.11-8.08(m, 2H), 7.78-7.75(m, 2H), 4.53(d, J=10.2Hz, 1H), 4.17-3.45(m, 10H), 3.37 (s, 3H), 2.45(br, 2H), 1.32(t, J=6.9Hz, 3H), 1.24-1.16(m, 6H), 1.09(t, J ⁼ 6.9Hz, 3H); CDCl ₃ , TMS, 75MHz) δ15.94, 16.15, 35.46, 37.22, 39.00, 47.39, 51.63, 56.03, 56.19, 62.01, 62.09, 62.30, 62.45, 122.25, 131.54, 145.47, 146.99, 175KBrv 3388, 2983, 2927, 1735, 1347, 1243, 1027 cm ^-1 . HRMS Calcd. For C ₁₉ H ₃₂ NO ₁₀ P ₂ +H ⁺ : 511.1605, Measured 511.1606.

Example 14:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-(2-naphthylvinyl)-1,1-diphosphate tetraethyl ester, stirred for 30 minutes, evaporated The solvent was removed, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was washed with saturated sodium bicarbonate Adjust to weakly alkaline, then extract 3 times with dichloromethane, combine the organic phases, evaporate the solvent to obtain a white solid, the yield is 85%, the enantioselective excess of the product is 96%, HPLC (Chiralcel AS-H, i- propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r ＝5.07and 8.33min.[α] ²⁵ _D ＝+5.8(c 1.2, CH ₂ Cl ₂ ); ¹ H NMR ( CDCl ₃ , TMS, 300MHz) δ8.01-8.08(s, 1H), 7.81-7.72(m, 4H), 7.44-7.41(m, 2H), 4.65(d, J=11.1Hz, 1H), 4.17- 3.75(m, 10H), 3.26(s, 3H), 2.39(br, 2H), 1.32(t, J=7.2Hz, 3H), 1.26-1.15(m, 6H), 0.94(t, J=6.9Hz , 3H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.67, 15.75, 15.98, 16.07, 16.15, 16.24, 36.03, 37.77, 39.53, 47.72, 51.42, 56.40, 56.56, 61.90, 61.98, 62.10, 62.2 , 62.31, 125.51, 126.58, 127.22, 127.81, 128.44, 129.26, 132.53, 132.71, 135.13, _175.64 ; IR(KBr)v 3388, 2982, 2929, 1736, 1243, 1028cm ^-1 .HRMS3 calculation HFor C ₂₅ NO ₈ P ₂ +H ⁺ : 516.1911, measured 516.1915.

Example 15:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, add 1mL dichloromethane under nitrogen protection, stir at room temperature for 1 hour, then add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-(2-furylvinyl)-1,1-diphosphate tetraethyl ester, stirred for 30 minutes, evaporated The solvent was removed, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), and the obtained compound was stirred in an aqueous diethyl ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with diethyl ether, and the obtained aqueous phase was washed with saturated sodium bicarbonate Adjust to weakly alkaline, then extract 3 times with dichloromethane, combine the organic phases, evaporate the solvent to obtain a colorless oily liquid, the yield is 82%, the enantioselectivity of the product is over 96%, HPLC (Chiralcel AD-H, i-propanol/hexane=10/90, flow rate 1.0mL/min, λ=210nm); t _r ＝47.48and 54.62min.[α] ²⁵ _D ＝-8.0(c 0.2, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300MHz) δ7.20(s, 1H), 6.30(s, 1H), 6.21(s, 1H), 4.35(d, J=9.9Hz, 1H), 4.06-3.61(m, 10H), 3.48(s, 3H), 2.53(br, 2H), 1.28-1.16(m, 12H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.46, 29.91, 36.18, 37.06, 40.78, 52.38 , 55.96, 62.64, 62.91, 109.68, 110.52, 128.90, 141.80, 151.09, 174.84; IR(KBr) 3386, 2981, 2927, 1735, 1247, 1028cm ^-1 . HRMS calculated value For C ₁₇ H ₃₁ NO ₉ P ₂ + H ⁺ : 456.1547, measured 456.1546.

Example 16

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-methyl-1,1-tetraethyl diphosphate, stir for 30 minutes, evaporate the solvent, the product Through silica gel column chromatography (petroleum ether/acetone 1/2), a colorless oily liquid was obtained, and the obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with ether, and the obtained aqueous phase was washed with saturated Sodium bicarbonate was adjusted to weak alkalinity, and then extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of colorless oily liquid was 71%, and the enantioselectivity of the product was 95%. HPLC (Chiralcel AD-H, i-propanol/hexane=30/70, flow rate 1.0 mL/min, λ=220 nm); t _r =7.45 and 8.51 mi. [α] ²⁵ _D = +20 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ9.59 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 6.3 Hz, 2H), 7.49-7.44(m, 3H), 4.69(t, J=5.1Hz, 1H), 4.31-4.10(m, 8H), 3.78(s, 1H), 2.84-2.63(m, 1H) , 1.50 (d, J=7.2Hz, 1H), 1.41-1.34 (m, 12H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ15.98, 16.49, 16.58, 29.90, 32.89, 35.68, 37.41, 39.16 , 52.47, 58.76, 58.93, 62.88, 62.99, 63.06, 63.38, 63.45, 126.59, 127.84, 128.55, 131.65, 133.74, 168.22, 172.61; IR (KBr) 3357, 2919, 230, 2849, 1743, 165 , 972cm ^-1 . HRMS calculated for C ₂₁ H ₃₅ NO ₉ P ₂ +H ⁺ : 508.1860, measured 508.1862.

Example 17:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-ethyl-1,1-tetraethyl diphosphate, stir for 30 minutes, evaporate the solvent, the product Through silica gel column chromatography (petroleum ether/acetone 1/2), a colorless oily liquid was obtained, and the obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with ether, and the obtained aqueous phase was washed with saturated Sodium bicarbonate was adjusted to weak alkalinity, and then extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of a colorless oily liquid was 76%, and the enantioselectivity of the product was 95%. HPLC (Chiralcel OD-H, i-propanol/hexane=5/95, flow rate 0.6 mL/min, λ=220 nm); t _r =27.37 and 32.82 min. [α] ²⁵ _D = +29.0 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ 9.77 (d, J = 6.0 Hz, 1H), 8.07 (d, J = 6.3 Hz, 2H), 7.47-7.43(m, 3H), 4.86(t, J=5.1Hz, 1H), 4.29-4.08(m, 8H), 3.76(s, 1H), 2.85-2.67(m, 1H) , 2.02-1.96 (m, 2H), 1.40-1.30 (m, 12H), 1.02 (t, J=7.2Hz, 1H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ12.69, 16.51, 21.85, 29.92, 37.50 ^{, 39.66} , 52.54, 54.47, 63.07, 63.53, 127.91, 128.57, 131.66, 168.20, 173.22; HRMS Calcd. For C ₂₂ H ₃₇ NO ₉ P ₂ +H ⁺ : 522.2016, Measured 522.2008.

Example 18:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-propyl-1,1-tetraethyl diphosphate, stir for 30 minutes, evaporate the solvent, the product Through silica gel column chromatography (petroleum ether/acetone 1/2), a colorless oily liquid was obtained, and the obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with ether, and the obtained aqueous phase was washed with saturated Sodium bicarbonate was adjusted to weak alkalinity, and then extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of a colorless oily liquid was 73%, and the enantioselectivity of the product was 95%. HPLC (Chiralcel AD-H, i-propanol/hexane=20/80, flow rate 1.0 mL/min, λ=220 nm); t _r =8.29 and 10.80 min. [α] ²⁵ _D = +8.0 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ9.80 (d, J = 5.4 Hz, 1H), 8.07 (d, J = 6.3 Hz, 2H), 7.45-7.43(m, 3H), 4.80(t, J=5.1Hz, 1H), 4.30-4.07(m, 8H), 3.75(s, 1H), 2.85-2.67(m, 1H) , 2.02-1.92 (m, 2H), 1.41-1.30 (m, 12H), 0.95-0.84 (m, 5H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ13.91, 16.59, 20.96, 29.92, 30.76 , 37.43, 52.54, 54.83, 62.99, 63.46, 127.91, 128.57, 131.66, 133.68, 168.23 ^{, 173.17} ; Calculated. _{For C23H39NO9P2} +H ⁺ : _536.2172 , found 536.2177 _.

Example 19:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35 mmol 2-(benzylideneamino) methyl acetate, 0.03 mmol K ₂ CO ₃ , 0.23 mmol 2-methyl-3-cyclohexyl-1,1-diphosphate tetraethyl ester, and stir for 30 minutes, The solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2) to obtain a colorless oily liquid. The obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, and extracted 3 times with ether to obtain The aqueous organic phase was adjusted to weak alkalinity with saturated sodium bicarbonate, then extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of colorless oily liquid was 70%, and the enantioselective excess of the product was 89%. HPLC (Chiralcel AD-H, i-propanol/hexane=10/90, flowrate 1.0 mL/min, λ=220 nm); t _r =9.23 and 31.12 min. [α] ²⁵ _D = +15.0 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ9.83 (d, J = 5.4 Hz, 1H), 8.09 (d, J = 6.3 Hz, 2H), 7.49-7.44(m, 3H), 4.74(t, J=3.9Hz, 1H), 4.30-4.07(m, 8H), 3.77(s, 1H), 2.86-2.68(m, 1H) , 2.02-1.87 (m, 2H), 1.77-1.63 (m, 7H), 1.42-1.34 (m, 12H), 1.00-0.86 (m, 4H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16. 53, 26.12, 26.33, 26.77, 29.92, 31.58, 34.43, 34.87, 35.99, 52.54, 55.12, 63.10, 63.42, 127.94, 128.57, 131.65, 133.73, 168.34, 173.17, 26, 06 1744, 1661, 1253, 1218, 1023, 971 cm ^-1 . Calculated Calcd. For C ₂₇ H ₄₅ NO ₉ P ₂ +H ⁺ : 590.2642, Measured 590.2651.

Example 20:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35 mmol 2-(benzylideneamino) methyl acetate, 0.03 mmol K ₂ CO ₃ , 0.23 mmol 2-isobutyl-1,1-diphosphate tetraethyl ester, stir for 30 minutes, evaporate the solvent, The product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2) to obtain a colorless oily liquid, and the obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with ether, and the obtained aqueous organic phase was used for Saturated sodium bicarbonate was adjusted to weak alkalinity, and extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of a colorless oily liquid was 72%, and the enantioselectivity of the product was 90%. HPLC (Chiralcel AD-H, i-propanol/hexane=20/80, flow rate 1.0 mL/min, λ=220 nm); t _r =5.73 and 9.39 min. [α] ²⁵ _D = +20.0 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ9.83 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 6.6 Hz, 2H), 7.49-7.42(m, 3H), 4.78(t, J=4.8Hz, 1H), 4.32-4.00(m, 8H), 3.77(s, 1H), 2.85-2.67(m, 1H) , 1.76-1.65 (m, 2H), 1.42-1.34 (m, 12H), 1.17-0.86 (m, 7H); ¹³ C NMR (CDCl ₃ , TMS, 75MHz) δ16.51, 16.60, 20.75, 24.26, 25.21 , 25.57, 35.31, 37.34, 52.54, 55.04, 63.09, 63.53, 64.64, 127.91, 128.57, 131.66, 133.68, 168.27, 173.14; ^-1 . HRMS _calcd . _{ForC24H41NO9P2} +H ⁺ : _550.2329 , found _550.2316 .

Example 21:

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35 mmol 2-(benzylideneamino) methyl acetate, 0.03 mmol K ₂ CO ₃ , 0.23 mmol 2-methylene-1,1-diphosphate tetraethyl ester, stir for 30 minutes, and evaporate the solvent. The product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2) to obtain a colorless oily liquid, and the obtained compound was stirred in an aqueous ether solution of p-toluenesulfonic acid for 30 minutes, extracted 3 times with ether, and the obtained aqueous organic phase was used for Saturated sodium bicarbonate was adjusted to weak alkalinity, and extracted three times with dichloromethane, the organic phases were combined, and the solvent was distilled off to obtain a colorless oily liquid. The obtained colorless oily liquid was dissolved in 1 mL of dichloromethane, and 0.23 mmol of benzoyl chloride and 0.23 mmol of triethylamine were added. After stirring at room temperature for 30 minutes, the solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1 /2), the yield of colorless oily liquid was 75%, and the enantioselective excess of the product was 89%. HPLC (Chiralcel OD-H, i-propanol/hexane=10/90, flow rate 0.7 mL/min, λ=220 nm); t _r =22.27 and 25.34 min. [α] ²⁵ _D = -3.0 (c 0.3, CH ₂ Cl ₂ ); ¹ H NMR (CDCl ₃ , TMS, 300 MHz) δ8.32 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.51-7.42(m, 3H), 4.76(m, 1H), 4.24-4.12(m, 8H), 3.78(s, 1H), 2.58-2.51(m, 2H), 2.05(m, 1H), 1.40-1.26 (m, 12H); ¹³ CNMR (CDCl ₃ , TMS, 75MHz) δ16.62, 26.63, 32.98, 34.75, 52.78, 53.14, 63.38, 127.65, 128.71, 131.97, 133.43, 167.80, 171.95; IR (KBr) 3358, 2920, _2927, 1655 _, 1025 _cm ^-1 . HRMS calcd. ForC20H33NO9P2+H ⁺ : 494.1703, found _494.1709 .

Example 22

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane (1mL), stir at room temperature for 1 hour, then at -20°C Next, add 0.35mmol 2-(benzylidene amino) methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-styryl-1,1-diphosphate tetraethyl ester in turn, stir for 30 minutes, evaporate Solvent, product is through silica gel column chromatography (petroleum ether/acetone 1/2), obtains colorless oily liquid, productive rate 92%, the enantioselective excess of product 94%, HPLC (Chiralcel AD-H, i-propanol/ hexane=50/50, flowrate 1.0mL/min, λ=254nm); t _r =6.33and 18.94min.[α] ²⁵ _D -88.0 (c 1.40, CH ₂ Cl ₂ ); ¹ H NMR (C ₆ D ₆ , 300MHz) δ8.89(s, 1H), 8.21-8.18(m, 2H), 7.74-7.71(m, 2H), 7.24-7.11(m, 2H), 7.09-7.03(m, 4H), 5.90( d, J=11.7Hz, 1H), 5.06-4.92(m, 1H), 4.01-3.78(m, 8H), 3.56(t, J=28.2Hz, 1H), 3.06(s, 3H), 1.08-1.01 (m, 3H), 0.99-0.84 (m, 9H); ¹³ C NMR (C ₆ D ₆ , 75MHz) δ14.82, 14.91, 15.00, 15.05, 15.13, 36.13, 37.88, 39.61, 45.57, 50.32, 60.68, 60.73，60.78，60.82，60.88，60.93，60.96，61.00，74.31，74.50，126.20，126.28 126.39；127.62，127.65，127.68，127.75，130.22，130.49，135.16，137.51，137.57，165.85，169.52，169.49；IR(KBr ) 3463, 2983, _{1741, 1635} , 1240, 1028, 972 _cm ^-1 . HRMS Calcd. For _{C26H37NO8P2 +} H ⁺ : 554.2067, found 554.2057.

Example 23

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-methylstyryl-1,1-diphosphate tetraethyl ester, stir for 30 minutes, evaporate The solvent was removed, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), to obtain a colorless oily liquid, with a yield of 92%, and an enantioselective excess of 99% of the product, HPLC (Chiralcel AD-H, i-propanol /hexane=50/50, flowrate 1.0mL/min, λ=254nm); t _r =8.53and 19.64min.[α] ²⁵ _D -84.0 (c 1.70, CH ₂ Cl ₂ ); ¹ H NMR (C ₆ D ₆ , 300MHz) δ8.85(s, 1H), 8.24-8.16(m, 2H), 7.74-7.71(m, 2H), 7.24-7.11(m, 2H), 7.09-7.03(m, 3H), 5.90 (d, J=11.7Hz, 1H), 5.06-4.92(m, 1H), 4.01-3.78(m, 8H), 3.56(t, J=28.2Hz, 1H), 3.06(s, 3H), 2.35( s, 3H), 1.08-1.01 (m, 3H), 0.99-0.84 (m, 9H); ¹³ C NMR (C ₆ D ₆ , 75MHz) δ14.82, 14.91, 15.00, 15.05, 15.13, 35.23, 36.13, 37.88，39.61，45.57，50.32，60.68，60.73，60.78，60.82，60.88，60.93，60.96，61.00，74.31，74.50，126.20，126.28 126.39；127.62，127.65，127.68，127.75，130.22，130.49，135.16，137.51，137.57 , 165.85, 169.52 _, 169.49; IR (KBr) 3463, 2983, 1741, 1635, 1240, 1028 _, 972 cm ^-1 . HRMS calcd. For _C27H30NO8P2 + _H ⁺ : 568.2229, found 567.2233.

Example 24

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-m-methylstyryl-1,1-diphosphate tetraethyl ester, stir for 30 minutes, evaporate The solvent was removed, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2), to obtain a colorless oily liquid, with a yield of 94%, and an enantioselective excess of 95% of the product, HPLC (Chiralcel AD-H, i-propanol /hexane=50/50, flowrate 1.0mL/min, λ=254nm); t _r =8.35and 30.44min.[α] ²⁵ _D -69.0 (c 1.90, CH ₂ Cl ₂ ); ¹ H NMR (C ₆ D ₆ , 300MHz) δ8.87(s, 1H), 8.27-8.18(m, 2H), 7.74-7.70(m, 2H), 7.24-7.11(m, 2H), 7.09-7.03(m, 3H), 5.80 (d, J=11.7Hz, 1H), 5.06-4.92(m, 1H), 4.11-3.68(m, 8H), 3.76(t, J=28.2Hz, 1H), 3.06(s, 3H), 2.45( s, 3H), 1.08-1.00 (m, 3H), 0.99-0.88 (m, 9H); ¹³ C NMR (C ₆ D ₆ , 75MHz) δ14.88, 14.98, 15.00, 15.05, 15.13, 36.13, 37.88, 39.61，45.57，50.32，60.68，60.73，60.78，60.82，60.88，60.93，60.96，61.00，74.31，74.50，126.20，126.28 126.39；127.62，127.65，127.68，127.75，130.22，130.49，135.16，137.51，137.57，165.85 , 169.52, 169.49; IR(KBr) 3463 _, 2983, ₁₇₄₁ , 1635, ₁₂₄₀ , 1028, 972 cm ^-1 . HRMS Calcd. For _C27H39NO8P2 +H ⁺ : 568.2229, found 568.2234.

Example 25

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35 mmol 2-(benzylideneamino) methyl acetate, 0.03 mmol K ₂ CO ₃ , 0.23 mmol 2-p-methoxystyryl-1,1-diphosphate tetraethyl ester, and stir for 30 minutes, The solvent was evaporated, and the product was subjected to silica gel column chromatography (petroleum ether/acetone 1/2) to obtain a colorless oily liquid with a yield of 94%, and an enantioselective excess of 97% of the product, HPLC (Chiralcel AD-H, i- propanol/hexane=50/50, flowrate 1.0mL/min, λ=254nm); t _r =12.32and 27.54min.[α] ²⁵ _D -89.0 (c 1.60, CH ₂ Cl ₂ ); ¹ H NMR (C ₆ D ₆ , 300MHz) δ8.78(s, 1H), 8.24-8.08(m, 2H), 7.74-7.70(m, 2H), 7.24-7.11(m, 2H), 7.09-7.03(m, 3H), 5.80(d, J=11.7Hz, 1H), 5.06-4.92(m, 1H), 4.11-3.68(m, 8H), 3.76(t, J=28.2Hz, 1H), 3.61(s, 3H), 3.06 (s, 3H), 1.08-1.00 (m, 3H), 0.99-0.88 (m, 9H); ¹³ C NMR (C ₆ D ₆ , 75MHz) δ14.28, 14.98, 15.00, 15.05, 15.13, 36.13, 37.88 ，39.61，45.57，50.32，60.68，60.73，60.78，60.82，60.88，60.93，60.96，61.00，74.31，74.50，126.20，126.28 126.39；127.62，127.65，127.68，127.75，130.22，130.49，135.16，137.51，137.57， 165.85, 169.52 _, 169.49; IR(KBr) 3463, 2983, 1741, ₁₆₃₅ , 1240, 1028, 972 cm- ¹ . HRMS Calcd. For _C27H39NO9P2 + _H ⁺ : 584.2178, found 584.2170.

Example 26

的制备

preparation of

Add 0.007mmol Cu(CH ₃ CN) ₄ BF ₄ and 0.0075mmol TF-BiphamPhos in a 25mL reaction tube, under the protection of N ₂ , add 1mL dichloromethane, stir at room temperature for 1 hour, then at -20°C, sequentially Add 0.35mmol 2-(benzylideneamino)methyl acetate, 0.03mmol K ₂ CO ₃ , 0.23mmol 2-p-chlorostyryl-1,1-diphosphate tetraethyl ester, stir for 30 minutes, evaporate Solvent, the product is through silica gel column chromatography (petroleum ether/acetone 1/2), obtains colorless oily liquid, productive rate 94%, the enantioselectivity excess 95% of product, HPLC (Chiralcel AD-H, i-propanol/ hexane＝50/50, flow rate1.0mL/min, λ＝254nm); t _r ＝13.62and 29.54min.[α] ²⁵ _D -90.0 (c 1.30, CH ₂ Cl ₂ ); ¹ H NMR (C ₆ D ₆ , 300MHz) δ8.32(s, 1H), 8.14-8.08(m, 2H), 7.74-7.71(m, 2H), 7.24-7.11(m, 2H), 7.09-7.03(m, 3H), 5.81 (d, J=11.7Hz, 1H), 5.06-4.92(m, 1H), 4.11-3.68(m, 8H), 3.76(t, J=28.2Hz, 1H), 3.06(s, 3H), 1.08- 1.00 (m, 3H), 0.99-0.88 (m, 9H); ¹³ C NMR (C ₆ D ₆ , 75MHz) δ14.28, 14.98, 15.00, 15.05, 15.13, 36.13, 37.88, 39.61, 45.57, 50.32, 60.68 ，60.73，60.78，60.82，60.88，60.93，60.96，61.00，74.31，74.50，126.20，126.28 126.39；127.62，127.65，127.68，127.75，130.22，130.49，135.16，137.51，137.57，165.85，169.52，169.49；IR( KBr) 3463, 2983, 1741 _{, 1635} , 1240, 1028 _, 972 cm- ¹ . HRMS calcd. For _{C26H36ClNO8P2 +} H ⁺ : 588.1683, found 588.1679.

In the above examples 1-26, Cu(CH ₃ CN) ₄ BF ₄ can be replaced by Cu(OTf) ₂ , CuOTf, CuI, CuBr, CuCl, Cu(ClO) ₄ , CuOAc, Cu(OAc), etc. K ₂ CO ₃ can be replaced by Na ₂ CO ₃ , Cs ₂ CO ₃ , triethylamine, etc., dichloromethane as a solvent can be replaced by chloroform, N ₂ can be replaced by inert gas, and the reaction temperature can be any temperature within the range of -40～20℃. a temperature.

The yields and corresponding selectivity excesses of some compounds with general formula (I) structural characteristics synthesized by the present invention are shown in Table 1.

The yield and corresponding selectivity excess value of some compounds in table 1

Example 27: Bioassay of Bactericidal Activity

The concentration of the medicinal solution is 50ppm, and the prepared agar sheet is taken with a 5mm empty device, and is picked into each petri dish, and a blank control is established, and it is cultivated in a constant temperature incubator at 27°C for 48-72 hours, and the diameter of the bacterial plaque is checked, and the inhibition rate = (control plaque diameter−sample plaque diameter)/control plaque diameter×100%, and do one repetition at the same time. The measurement results are shown in Table 2.

Co-solvent: dimethylformamide; emulsifier: Tween-80; preparation solution: sterile water. Wherein, dimethylformamide/H ₂ O=1/1000; emulsifier/H ₂ O=5/1000 (weight percent).

The bacteriostasis rate of compound of the present invention in table 2

Claims (7)

1. Non-natural chiral a-amino acid derivatives with a geminal bisphosphate group, characterized by the following structural formula:

wherein,

r is phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-fluorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-nitrophenyl, 2-naphthyl, 2-furyl, methyl, ethyl, propyl, cyclohexylmethyl, isobutyl, hydrogen;

r' is methyl, ethyl or tert-butyl;

r' is benzoyl.

2. The method for the synthesis of non-natural chiral a-amino acid derivatives with a geminal bisphosphate group according to claim 1, comprising the steps of:

1) in an organic solvent, under the protection of inert gas, taking tetraethyl alkylidene diphosphate and 2- (benzylidene amino) acetate as raw materials, taking a copper salt/TF-BiphamPhos complex as a catalyst, adding carbonate or organic base, fully reacting at the temperature of-40-30 ℃, evaporating the solvent, and carrying out column chromatography to obtain a compound

2) Fully stirring the compound obtained in the step 1) in an ether water solution of p-toluenesulfonic acid, extracting and purifying, and evaporating the solvent to obtain the compound

Wherein R' is a hydrogen group;

3) fully stirring the compound obtained in the step 2) in dichloromethane solution of benzoyl chloride and triethylamine, and performing column chromatography to obtain the compound

Wherein R' is benzoyl.

3. The process for the synthesis of non-natural chiral α -amino acid derivatives with a geminal bisphosphate group according to claim 2, wherein: the mole ratio of the tetraethyl alkylidene diphosphate to the 2- (benzylidene amino) acetate is 1: 0.52 to 2.

4. The process for the synthesis of non-natural chiral α -amino acid derivatives with a geminal bisphosphate group according to claim 2 or 3, wherein: the copper salt/TF-BiphamPhos complex is obtained by dissolving copper salt and TF-BiphamPhos in an organic solvent at room temperature according to the mole number of the copper salt being less than or equal to that of the TF-BiphamPhos and fully reacting.

5. The process for the synthesis of non-natural chiral α -amino acid derivatives with a geminal bisphosphate group according to claim 2 or 3, wherein: the column chromatography takes silica gel as a filling material and a mixed solvent of petroleum ether and acetone as an eluent, and the following steps of: the volume ratio of the petroleum ether to the acetone is 1: 2.

6. the method for the synthesis of non-natural chiral α -amino acid derivatives with a geminal bisphosphate as claimed in claim 2 or 3, wherein: the extraction and purification is ether extraction, the obtained water phase is adjusted to be alkalescent by saturated sodium bicarbonate, then dichloromethane is used for extraction, and the organic phases are combined.

7. Use of the non-natural chiral α -amino acid derivative with a geminal bisphosphate group according to claim 1 for the preparation of a fungicide.