CN104710476A - Chiral bidentate phosphite ligand and preparation method and application thereof - Google Patents

Abstract

The invention discloses a chiral bidentate phosphite ligand as well as a preparation method and application. The chiral bidentate phosphite ligand is a white foamy solid. The ligand has the characteristics of simple synthetic route, low cost, and stability in air. The 1,4-conjugated addition of its metal copper complex to cycloenone The reaction has high catalytic activity and optical selectivity.

Description

Chiral bidentate phosphite ligand, preparation method and use

technical field

The invention relates to a chiral bidentate phosphite ligand derived from tartaric acid and a synthesis method thereof, which is applied to the preparation of a ligand/Cu complex catalyst to catalyze the asymmetric 1, 4-Conjugate addition reaction to synthesize optically active β-ethyl cyclic ketones.

Background technique

The 1,4-conjugated addition of alkyl or aryl zinc reagents to α, β-unsaturated carbonyl compounds is one of the important reactions for the formation of C-C bonds. Asymmetric 1,4-conjugated addition reactions can synthesize Active drugs or intermediates, such as muscone ((R)-Muscone), anti-mycobacterial agents (erogorgiaene), anti-cancer drugs (Clavularin B), cardiovascular disease drugs (PGE1), non-competitive blockers ( (-)-pumiliotoxin C), and ibuprofen [(+)-ibuprofen]. Therefore, in recent years, this reaction has received extensive attention and in-depth research.

Designing and synthesizing chiral ligands that can form complex catalysts with metals is the key to realizing efficient asymmetric 1,4-conjugated addition reactions. In 1993, Alexakis first reported the asymmetric 1,4-conjugated addition reaction catalyzed by copper-phosphorous(Ⅲ) ligand complexes. [Alexakis, A. ; Frutos, J. ; Mangeney, P. Tetrahedron: Asymmetry 1993,4,2427-2430.] Since then, many chiral phosphorus ligands (for example: chiral phosphoramidite ligands, chiral Phosphite ligands, chiral P,O and P,N ligands, etc.) were successfully used in this reaction. [Perez H F, Etayo P, Panossian A, Ferran A V. Chem. Rev. 2011, 111, 3, 2119-2176.], these ligands have been published in multiple patent applications, such as [US 20070259774 A1, US 20090124836A1 , US7728177B2, EP 1884509 A1, CN 101565436 A, CN 101090904 A.]

At present, the existing excellent chiral ligands do not have high asymmetric induction ability for various α, β-unsaturated enone substrates; and the reaction often requires specific reaction conditions to give high enantioselectivity sex. Therefore, the design and synthesis of chiral phosphorus ligands and their application in this reaction are still of great significance.

Contents of the invention

The object of the present invention is to provide a chiral bidentate phosphite ligand derived from tartaric acid.

Another object of the present invention is to provide a method for synthesizing the above-mentioned ligands.

A further object of the present invention is to provide the use of the above-mentioned ligands.

A chiral bidentate phosphite ligand, the general structure of which is shown in formula I,

                                                 

I

Ligand The group is:

.

the

The chiral bidentate phosphite ligand of the present invention is selected from one of the formulas II to VI,

         

.

The chiral bidentate phosphite ligands described in the present invention are all white foamy solids. the

A preparation method of chiral bidentate phosphite ligand, characterized in that:

Under atmospheric nitrogen atmosphere, in tetrahydrofuran (THF) solvent, (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione, Phenol-derived phosphorous oxychloride, 4-dimethylaminopyridine (DMAP), and triethylamine (NEt ₃ ) were used as reactants, and reacted at -10°C to -15°C for 0.5 to 4 hours; after the reaction, depressurized Remove the solvent, add toluene, stir well, filter out the insoluble matter, concentrate the filtrate, separate by column chromatography, and synthesize the chiral phosphite ligand.

Reactant (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-diketone of the present invention and (R) or (S)-biphenol derived phosphorous oxychloride The molar ratio is 1: 2~4.

The molar ratio of reactant 4-dimethylaminopyridine and (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione of the present invention is 1: 4~5.

The molar ratio of the reactant (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione and triethylamine in the present invention is 1:2~4.

The chiral phosphite ligand of the present invention reacts in situ with metal copper precursors to prepare catalysts, catalyzes the asymmetric 1,4-conjugated addition reaction of organozinc to α, β-unsaturated enones, and synthesizes optically active β - substituted ketone products.

Specifically, the asymmetric 1,4-conjugated addition reaction process of organozinc to α, β-unsaturated enone is as follows:

The ligand-Cu catalyst is prepared by reacting the ligand with the Cu salt in situ in an organic solvent under a nitrogen atmosphere at normal pressure for one hour. Then add α, β-unsaturated ketene and organic zinc to it in turn, and react at -20-20°C for 4~12 hours; after the reaction, add distilled water and dilute hydrochloric acid solution to the reaction mixture to quench the reaction, and use acetic acid Extract with ethyl ester, combine the organic phases, wash with saturated NaHCO ₃ solution, saturated brine successively, dry with anhydrous Na ₂ SO ₄ , filter, concentrate, synthesize optically active β-ethyl cyclic ketone products, gas chromatography (GC ) analysis product.

The Cu salt is selected from copper trifluoromethanesulfonate [Cu(OTf) ₂ ], cuprous trifluoromethanesulfonate [(CuOTf) ₂ ·C ₆ H ₆ ] or Cu(OAc) ₂ ·H ₂ O, Wherein OTf ^-1 is trifluoromethanesulfonate; the molar ratio of Cu salt and ligand is 1:1~3; the organic solvent is selected from tetrahydrofuran, ether, toluene or methylene chloride; the reaction temperature is -20~20°C; The time is 4~12 hours.

The cyclic enone is selected from 2-cyclopentenone, 2-cyclohexenone or 2-cycloheptenone; the molar ratio of ligand/Cu catalyst, cyclic enone and organic zinc is 1:50 : 120.

The biphenol mentioned in the present invention has no chirality. Compared with the chiral binaphthol commonly used in the synthesis of phosphite ligands, the price is cheap, and its chemical modification is easy to carry out; the chiral phosphite ligand has a simple synthetic route. , low cost, stable in air, etc., and its metal copper complex has high catalytic activity and optical selectivity for the 1,4-conjugated addition reaction of cycloenone. Using this chiral ligand, asymmetric 1,4-conjugated addition reaction can be used to prepare physiologically active drugs or intermediates, which have important applications in industries such as medicine, pesticides, spices, and natural chiral product synthesis. value.

Detailed ways

Examples 1-5: Preparation of chiral bidentate phosphite ligands.

Examples 6-25: Preparation of ligand-Cu catalyst and its application in the asymmetric 1,4-addition reaction of organozinc to cycloalkenone.

Example 1: Preparation of chiral phosphite ligand, the structural formula is as follows:

 

Under normal pressure nitrogen atmosphere, add (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione (294.7mg, 1.33mmol), phosphorous oxychloride (734.6mg, 2.93 mmol) and 4-dimethylaminopyridine (35.8mg, 0.3mmol), add 10 mL tetrahydrofuran as a solvent, stir to dissolve the solid completely, cool the solution to -15°C, Add 0.56 mL of triethylamine slowly and keep it at -15°C for 0.5 h. The solvent was removed under reduced pressure, 20 mL of toluene was added and stirred thoroughly, the solid was filtered off, the filtrate was concentrated, and the ligand was separated by flash chromatography to obtain 225.2 mg, with a yield of 26.02%.

White foamy solid. ³¹ P NMR (161MHz, CDCl ₃ ): δ 143.96; ¹ HNMR (400 MHz, CDCl ₃ ): δ4.58 (d, J = 12.6 Hz, 2H), 5.06 (q, J = 3.8 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 2.2 Hz, 2H), 7.21 – 7.19 (m, 2H), 7.22 (t, J = 3.7 Hz, 3H), 7.24 (d, J = 5.2 Hz, 4H), 7.30 (td, J = 7.4, 4.4 Hz, 3H), 7.35 (dd, J = 9.8, 4.7 Hz, 4H), 7.48 – 7.41 (m, 1H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 42.03, 74.38, 121.02, 121.54, 124.27, 127.20, 128.01, 128.82, 128.99, 129.66, 133.45, 147.60, 168.74.

Example 2: Preparation of chiral phosphite ligand, the structural formula is as follows:

 

Same as the method in Example 1, (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione (201.1mg, 0.91 mmol), phosphorous oxychloride (612mg, 2.0 mmol ) and 4-dimethylaminopyridine (24.4mg, 0.15mmol), triethylamine 0.42 mL, the reaction time is 4 hours. The rest were the same as in Example 1, and 189.4 mg of the ligand was obtained, with a yield of 27.37%.

White foamy solid. ³¹ P NMR (161MHz, CDCl ₃ ): δ 146.42; ¹ HNMR (400 MHz, CDCl ₃ ): δ 2.31 (d, J = 3.0 Hz, 12H), 2.33 (s, 7H), 2.35 (s, 5H) , 4.67 (s, 2H), 5.12 – 5.07 (m, 2H), 7.00 (d, J = 11.6 Hz, 4H), 7.07 – 7.03 (m, 4H), 7.29 – 7.26 (m, 3H), 7.35 (dd , J = 6.6, 2.9 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 14.14, 20.83, 43.01, 75.90, 127.87, 128.08, 130.09, 130.45, 131.19, 131.24, 134.28, 144.434, 1 , 170.30.

Example 3: Preparation of chiral phosphite ligand, the structural formula is as follows:

 

With the method in Example 1, (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione (100.5mg, 0.45 mmol), phosphorous oxychloride (474.3mg, 1.0 mmol) and 4-dimethylaminopyridine (12.2mg, 0.1mmol), triethylamine 0.21mL, the reaction time is 0.5 hours. The rest were the same as in Example 1, and 288.7 mg of the ligand was obtained, with a yield of 15.37%.

White foamy solid. ³¹ P NMR (161MHz, CDCl ₃ ): δ146.92 ; ¹ HNMR (400 MHz, CDCl ₃ ): δ1.23 – 1.08 (m, 48H), 1.45 – 1.36 (m, 24H), 4.65 – 4.51 (m, 2H), 5.07 (d, J = 6.2 Hz, 2H), 7.10 – 7.03 (m, 6H), 7.15 (dd, J = 11.0, 4.0 Hz, 5H), 7.35 (t, J = 7.3 Hz, 2H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ28.71, 33.50, 33.65, 34.40, 41.95, 74.58, 123.21, 124.28, 125.47, 127.20, 127.67, 128.01, 136.81, 138.99, 145.430, 145.8

Embodiment 4: Preparation of chiral phosphite ligand, the structural formula is as follows:

 

With the method in Example 1, (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione (100.5mg, 0.45 mmol), phosphorous oxychloride (385.8mg, 1.0 mmol) and 4-dimethylaminopyridine (12.2mg, 0.1mmol), triethylamine 0.21 mL, the reaction time is 0.5 hours. The rest were the same as in Example 1 to obtain 268.5 mg of the ligand with a yield of 32.08%.

White foamy solid. ³¹ P NMR (161MHz, CDCl ₃ ): δ151.23; ¹ HNMR (400 MHz, CDCl ₃ ): δ4.63 (d, J = 15.2 Hz, 2H), 5.22 (d, J = 5.8 Hz, 2H), 7.10 – 7.08 (m, 3H), 7.11 (d, J = 2.3 Hz, 4H), 7.16 (d, J = 2.0 Hz, 2H), 7.23 – 7.21 (m, 4H); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 42.38, 75.15, 124.27, 127.20, 127.89, 128.01, 128.27, 128.91, 129.28, 129.35, 133.12, 146.47, 168.28.

Example 5: Preparation of chiral phosphite ligand, the structural formula is as follows:

 

Same as the method in Example 1, (3R,4R)-1-benzyl-3,4-dihydroxypyridine ring-2,5-dione (201.1mg, 0.91 mmol), phosphorous oxychloride (1.1233g, 2.0 mmol) and 4-dimethylaminopyridine (24.4mg, 0.2mmol), triethylamine 0.42 mL, the reaction time is 4 hours. The rest were the same as in Example 1, and 177.8 mg of the ligand was obtained, with a yield of 15.37%.

White foamy solid. ³¹ P NMR (161MHz, CDCl ₃ ): δ150.84; ¹ HNMR (400 MHz, CDCl ₃ ): δ4.66 (dd, J = 32.8, 13.9 Hz, 2H), 5.26 (d, J = 5.1 Hz, 2H ), 7.28 – 7.22 (m, 3H), 7.36 (dd, J = 6.3, 3.1 Hz, 2H), 7.40 (d, J = 1.3 Hz, 4H), 7.68 (dt, J = 14.3, 7.1 Hz, 4H) ; ¹³ C NMR (100 MHz, CDCl ₃ ): δ 42.40, 75.23, 116.86, 117.35, 127.20, 127.65, 127.95, 128.01, 133.10, 134,91, 134.97, 144.47, 168.48.

Embodiment 6:

Under a nitrogen atmosphere, Cu(OTf) ₂ (0.005 mmol, 1.8 mg) and the ligand described in Example 1 (0.01 mmol, 6.5 mg) were dissolved in 4 mL of toluene and stirred at room temperature for 1 h to obtain ligand-Cu Catalyst solution. Cool to 0°C, add 2-cyclohexenone (0.25 mmol, 25 μL) and diethylzinc (1 mol/L n-hexane solution, 0.6 mL) in sequence, and react at 0°C for 4 hours. Add 2 mL of distilled water and 2 mL of dilute hydrochloric acid solution (2.0 mol/L) to quench the reaction, extract with ethyl acetate (5 mL×3), combine the organic phases, wash with saturated NaHCO ₃ solution, saturated brine successively, and anhydrous Na ₂ SO ₄ was dried, filtered, concentrated, and analyzed by gas chromatography (GC). The conversion rate was 47%, the enantioselectivity was 59%, and the absolute configuration of the product was S.

Embodiment 7:

Same as Example 6, the ligands were selected from the ligands described in Example 2 (0.01 mmol, 7.6 mg), and GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 99%, and the enantioselectivity was 17%. The absolute configuration of the product is S.

Embodiment 8:

Same as in Example 6, the ligands were selected from the ligands described in Example 3 (0.01 mmol, 11.0 mg). GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 99%, and the enantioselectivity was 26%. The absolute configuration of the product is S.

Embodiment 9:

Same as Example 6, the ligand is selected from the ligand (0.01 mmol, 9.2 mg) described in Example 4, and GC analysis shows that the conversion rate of the product 3-ethylcyclohexanone is 49%, and the enantioselectivity is 5%. The absolute configuration of the product is S.

Example 10:

Same as Example 6, the ligands were selected from the ligands described in Example 5 (0.01 mmol, 12.7 mg), and GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 99%, and the enantioselectivity was 5%. The absolute configuration of the product is R.

Example 11:

Same as Example 6, the copper salt is selected from Cu(OAc) ₂ H ₂ O (0.005mmol, 1mg), GC analysis shows that the conversion rate of the product 3-ethylcyclohexanone is 99%, and the enantioselectivity is 40%, The absolute configuration of the product is S.

Example 12:

Same as Example 6, the copper salt is selected from (CuOTf) ₂ ·C ₆ H ₆ (0.0025 mmol, 1.25 mg), GC analysis shows that the conversion rate of the product 3-ethylcyclohexanone is 33%, and the enantioselectivity is 37% , the absolute configuration of the product is S.

Example 13:

With embodiment 6, solvent is selected from diethyl ether 4ml, and GC analysis shows product 3-ethyl cyclohexanone transformation rate is 92%, and enantioselectivity is 41%, and product absolute configuration is S.

Example 14:

With embodiment 6, solvent is selected from diethyl ether 4ml, and GC analysis shows product 3-ethylcyclohexanone transformation rate is 92%, and enantioselectivity is 41%, and product absolute configuration is S.

Example 15:

With embodiment 6, solvent is selected from dichloromethane 4ml, and GC analysis shows product 3-ethylcyclohexanone conversion rate is 81%, and enantioselectivity is 8%, and product absolute configuration is S.

Example 16:

With embodiment 6, solvent is selected from tetrahydrofuran 4ml, and GC analysis shows product 3-ethyl cyclohexanone conversion rate is 68%, enantioselectivity is 42%, product absolute configuration is S.

Example 17:

With embodiment 6, solvent is selected from the mixed solvent of tetrahydrofuran 2ml and diethyl ether 2ml, and GC analysis shows product 3-ethyl cyclohexanone conversion rate is 50%, enantioselectivity is 75%, product absolute configuration is S.

Example 18:

Same as Example 6, the reaction temperature was 20 ^o C, GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 99%, the enantioselectivity was 49%, and the absolute configuration of the product was S.

Example 19:

Same as in Example 6, the reaction temperature was -10 ^o C, GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 44%, the enantioselectivity was 65%, and the absolute configuration of the product was S.

Example 20:

Same as in Example 6, the reaction temperature was -20 ^o C, GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 72%, the enantioselectivity was 48%, and the absolute configuration of the product was S.

Example 21:

Same as Example 6, the reaction time was 8 hours, GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 99%, the enantioselectivity was 32%, and the absolute configuration of the product was S.

Example 22:

Same as Example 6, the reaction time was 12 hours, GC analysis showed that the conversion rate of the product 3-ethylcyclohexanone was 83%, the enantioselectivity was 69%, and the absolute configuration of the product was S.

Example 23:

Same as Example 6, the amount of ligand as described in Example 1 (0.0025mmol, 1.6mg), GC analysis shows that the conversion rate of product 3-ethylcyclohexanone is 99%, the enantioselectivity is 40%, and the product is absolutely The configuration is S.

Example 24:

Same as Example 6, with the ligand dosage (0.015mmol, 9.7mg) as described in Example 1, GC analysis shows that the conversion rate of product 3-ethylcyclohexanone is 13%, the enantioselectivity is 49%, and the product is absolutely The configuration is S.

Example 25:

As in Example 6, the cycloenone substrate was selected from 2-cyclopentenone (0.25 mmol, 0.022 mL). GC analysis showed that the conversion rate of the product 3-ethylcyclopentanone was 93%, the enantioselectivity was 50%, and the absolute configuration of the product was R.

Claims (9)

1. a chiral bidentate phosphite ligand, general structure such as formula shown in I,

I

In part group be:

。

2. part as claimed in claim 1, is characterized in that chiral bidentate phosphite ligand, is selected from the one in formula II to VI,

。

3. the preparation method of a kind of chiral bidentate phosphite ligand as claimed in claim 1 or 2, is characterized in that:

Under normal pressure nitrogen atmosphere, in tetrahydrofuran (THF) (THF) solvent, with (3R, 4R)-1-benzyl-3 that (L)-tartrate is derivative, sub-phosphoryl chloride, DMAP (DMAP) and triethylamine (NEt that 4-dihydroxy-pyridine ring-2,5-diketone, xenol are derivative ₃) be reactant, react 0.5 ~ 4 hour at-10 DEG C to-15 DEG C; After reaction terminates, removal of solvent under reduced pressure, adds toluene, after fully stirring, and elimination insolubles, after filtrate is concentrated, through column chromatography for separation, synthesis of chiral phosphite ester ligand.

4. method as claimed in claim 3, is characterized in that the mol ratio of the sub-phosphoryl chloride that reactant (3R, 4R)-1-benzyl-3,4-dihydroxy-pyridine ring-2,5-diketone derives with (R) or (S)-xenol is 1:2 ~ 4.

5. method as claimed in claim 3, is characterized in that reactant DMAP is 1:4 ~ 5 with the mol ratio of (3R, 4R)-1-benzyl-3,4-dihydroxy-pyridine ring-2,5-diketone.

6. method as claimed in claim 3, is characterized in that the mol ratio of reactant (3R, 4R)-1-benzyl-3,4-dihydroxy-pyridine ring-2,5-diketone and triethylamine is 1:2 ~ 4.

7. the application of part as claimed in claim 1 or 2, it is characterized in that chirality phosphite ester ligand and metallic copper precursor reaction in－situ Kaolinite Preparation of Catalyst, catalysis organic zinc is to asymmetric 1 of α, β-Unsaturated Alkenone, 4-conjugate addition reaction, synthesis of optically active beta substitution ketone product.

8. the application of part as claimed in claim 7, under it is characterized in that normal pressure nitrogen atmosphere, in organic solvent, described part and Cu salt reaction in－situ one hour, prepare part-Cu catalyzer; Then add α successively wherein, β-Unsaturated Alkenone and organic zinc, react 4 ~ 12 hours at-20-20 DEG C; After reaction terminates, add distilled water and dilute hydrochloric acid solution cancellation reaction in the reactive mixture, be extracted with ethyl acetate, merge organic phase, use saturated NaHCO successively ₃solution, saturated common salt water washing, anhydrous Na ₂sO ₄drying, filters, concentrated, and synthesis has optically active β-ethyl cyclic ketone product, gas-chromatography (GC) assay products.

9. the application of part as claimed in claim 8, is characterized in that described Cu salt is selected from copper trifluoromethanesulfcomposite [Cu (OTf) ₂], trifluoromethanesulfonic acid cuprous [(CuOTf) ₂c ₆h ₆] or Cu (OAc) ₂h ₂o, wherein OTf ^-1it is trifluoromethanesulfonic acid root; The mol ratio of Cu salt and part is 1:1 ~ 3; Organic solvent is selected from tetrahydrofuran (THF), ether, toluene or methylene dichloride; Temperature of reaction is-20 ~ 20 DEG C; Reaction times is 4 ~ 12 hours; Described ring-type ketenes is selected from 2-cyclopentenone, 2-cyclonene or 2-suberene ketone; The mol ratio of part/Cu catalyzer, ring-type ketenes and organic zinc is 1:50:120.