LU600467B1 - A novel chiral tertiary amine-hydroxyl ligand and preparation method, application - Google Patents
A novel chiral tertiary amine-hydroxyl ligand and preparation method, applicationInfo
- Publication number
- LU600467B1 LU600467B1 LU600467A LU600467A LU600467B1 LU 600467 B1 LU600467 B1 LU 600467B1 LU 600467 A LU600467 A LU 600467A LU 600467 A LU600467 A LU 600467A LU 600467 B1 LU600467 B1 LU 600467B1
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- Luxembourg
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- ligand
- tertiary amine
- chiral
- group
- mmol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel chiral tertiary amine-hydroxyl ligand, having a chemical structural formula shown in general Formula : , where R1 represents any one of hydrogen, methyl group , benzyl group and Boc group; R2 represents aryl group or alkyl group; R3 represents aryl group or hydrogen. The ligand is a compound represented by Formula 1, their racemates, optical isomers, or catalytically acceptable salts thereof. The complex formed by the ligand and copper trifluoromethanesulfonate has good catalytic activity for catalyzing asymmetric addition of diethyl zinc to aldehyde. The invention provides a preparation method of the novel chiral tertiary amine-hydroxyl ligand, which comprises the following steps: chiral amino alcohol is condensed with a chiral N-substituted amino acid to obtain a target ligand. The preparation method is simple, and the yield of ligand is high.
Description
A novel chiral tertiary amine-hydroxyl ligand and preparation method, 600467 application
The invention relates to the field of chemistry. More specifically, the invention relates to a novel chiral tertiary amine-hydroxyl ligand and preparation method, application.
Metal-catalyzed asymmetric synthesis is an important method for the preparation of optically active chemicals, which requires the coordination of chiral ligands to metals to form highly active metal complex catalysts. However, the synthesis route of chiral ligands is often long, and the applicable reaction types are limited, so the development of chiral ligands with new coordinating atom or new skeleton is of great significance.
Due to the diverse structure and stable properties, chiral amino alcohols have become important raw materials for the development of chiral catalysts or ligands.
The disadvantages of long synthesis routes or insufficient structure restricted the flexible development of the existing tertiary amine-alcohol ligands. In addition,
Lewis acid catalysts formed by metal-ligands complex often have the problem of imperfect stereoscopic control effect or low catalytic efficiency.
It is an object of the present invention to solve at least the above problems and propose a novel chiral tertiary amine-hydroxyl ligand and preparation method, application.
According to an aspect of the present disclosure, a novel chiral tertiary amine- hydroxyl ligand is provided, having a chemical structural formula shown:
0 NL LUB00467 „NH OH ar wherein, R! represents any one of hydrogen, methyl group, benzyl group and
Boc group; R? represents aryl group or alkyl group; R* represents phenyl group or
Hydrogen.
According to an aspect of the present disclosure, a method for preparing the novel chiral tertiary amine-hydroxyl ligand is provided, comprises: chiral amino alcohol is condensed with a chiral N-substituted amino acid to obtain the novel chiral tertiary amine-hydroxyl ligand; the chemical reaction equation is as follows:
RZ RS
A OH 3 “on a , Da EDCI, DMAP —
N HN OH [N-rt HCl SAR
Optionally, further, the chiral amino alcohol is condensed with a chiral N- substituted amino acid comprises: 1.0 equivalents of N-substituted amino acids, 1.0 equivalents of EDCI and 0.1 equivalent of DMAP are stirred in CH,Cl; to obtain a primary solution.; then this primary solution is added 1.0 equivalent of chiral amino alcohol and reacted at room temperature for 24-48 h; after the reaction is completed to obtain a mixture solution, using petroleum ether-ethyl acetate-CH,Cl, as eluent, this mixture solution is purified by column chromatography, so as to obtain the novel chiral tertiary amine- hydroxyl ligand.
Optionally, further, the volume ratio of petroleum ether to ethyl acetate to
CH:CL of the eluent is 1 to the ratio of (5~2): 1:1.
Application of a novel chiral tertiary amine-hydroxy ligand as a catalyst for the | U600467 asymmetric addition of diethylzinc to aldehydes.
The invention at least includes the following beneficial effects.
Firstly, the complex formed by the novel chiral amino amide-selenide ligand and copper trifluoromethanesulfonate has good catalytic activity for catalysing the asymmetric addition of diethyl zinc to aldehyde. Among them, the compound of
Formulas 1-4 has the best effect.
Secondly, the compounds (novel chiral tertiary amine-hydroxyl ligands) can be directly used to prepare various chiral secondary alcohols as ligands for copper- catalyzed asymmetric asymmetric addition of diethyl zinc to aldehyde.
In the following, the invention will be further described in detail with examples, so that chemical workers can implement it with reference to the text of the specification.
It should be noted that the experimental methods described in the following embodiments are all conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified. < example 1 > 10 mL of dichloromethane was added to a round-bottom flask, then N-methyl-
L-proline 3-1 (026 g 2.0 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 20 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1R,2S)-2-amino-1,2-diphenylethan-1-ol 2-1(0.42 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH2CL (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula | U600467 1-1, which is a white solid with a yield coefficient of 65%. © pa Ph
A OH 4
N—
NMR data of target compound 1-1: 'H NMR (400 MHz, CDCl) 5 8.04 (S, 1H), 7.34 — 7.20 (m, 6H), 7.11-7.03(m, 4H), 5.29 (dd, J = 7.3, 5.5 Hz, 1H), 5.01(d, J = 4.0 Hz, 1H), 3.03-3.10 (m, 1H), 2.85-2.92 (m, 1H), 2.27-3.35 (m, 1 H), 2.26(s, 3 H), 2.08-2.18 (m, 1H), 1.60 (s, 3H). PC NMR (100 MHz, CDCI;) & 174.81, 139.67, 137.90, 128.32, 127.90, 127.83, 127.66, 127.43, 126.92, 68.76, 61.84, 59.18, 56.65, 41.61, 30.78, 24.32. [a] TS -66.37 (c=0.1, CHCIs). melting point: 167.1-168.6°C < example 2 > 10 mL of dichloromethane was added to a round-bottom flask, then N-benzyl-
L-proline 3-2 (041g, 20 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 2.0 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1R,2S)-2-amino-1,2-diphenylethan-1-ol 2-1(0.42 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH2CL (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-2, which is a white solid with a yield coefficient of 72%.
0 NL LU600467
NH OH
L
5 1-2
NMR data of target compound 1-2:
TH NMR (400 MHz, CDCl3) 6 8.31 (d, J = 7.8 Hz, 1H), 7.36 — 7.18 (m, 9H), 7.15 (s, 3H), 6.99 (s, 4H), 5.32 — 5.17 (m, 1H), 4.95 (s, 1H), 3.83 (d, J = 13.7 Hz, 1H), 5 3.46 (q,J= 13.6, 13.2 Hz, 2H), 3.24 (d, J = 10.0 Hz, 1H), 2.99 (s, 1H), 2.32 (d, J = 10.2 Hz, 1H), 2.15 (t, J = 10.8 Hz, 1H), 1.84 — 1.51 (m, 3H). PC NMR (100 MHz,
CDCIs) 6 174.79, 139.88, 138.56, 137.28, 128.72, 128.40, 128.13, 127.83, 127.66, 127.58, 127.24, 126.64, 77.48, 67.29, 59.81, 59.17, 53.83, 30.46, 24.12. [o]T9 -56.88 (c=0.1, CHCI;). melting point:158.6-159.3°C < example 3 > 10 mL of dichloromethane was added to a round-bottom flask, then N-benzyl-
L-proline 3-2 (041g, 20 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 20 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1S,2R)-2-amino-1,2-diphenylethan-1-ol 2-2(0.42 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH»CL (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-3, which is a white solid with a yield coefficient of 72%.
Ph Ph 0 SX LU600467
NH OH
L
1-3
NMR data of target compound 1-3:
TH NMR (400 MHz, CDCI;) 5 8.14(d, J = 4.0Hz, 1H) , 7.41-7.12 (m, 6 H), 7.10 — 6.91 (m, 4H), 5.27 (dd, J = 8.0, 4.4 Hz, 1H), 4.96(d, J = 4.3 Hz, 1H), 3.74 (d, J = 5 12.9 Hz, 1H), 3.41 (d, J= 13.0 Hz, 1H), 3.20 (dd, J = 11.8, 3.0 Hz), 2.98 (t, J = 7.9
Hz), 2.40 — 2.28 (m, 2H), 2.25 — 2.14 (m, 1H), 1.94-1.69 (m, 2H), 1.57-1.68 (m, 2H).BC NMR (100 MHz, CDCIs) 8 175.41, 141.41, 139.42,128.55, 128.46, 128.38, 128.33, 128.28, 128.11,127.80, 127.54, 127.06, 126.92, 78.35, 67.12, 61.83, 59.93, 54.05, 30.67, 24.26. [a]? -3.00 (c=0.1, CHCl). melting point:110.6-111.5°C < example 4 > 10 mL of dichloromethane was added to a round-bottom flask, then N-benzyl-
L-proline 3-2 (041g, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 2.0 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol 2-3(0.30 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature.
After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH2CL (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-4, which is a white solid with a yield coefficient of 75%.
(A LU600467 3 NH OH 1-4
NMR data of target compound 1-4: 'H NMR (400 MHz, CDCl;) 6 8.02 (d, J = 9.2 Hz, 1H), 7.34 — 7.21 (m, 9H), 7.19- 7.14 (m, 1H), 5.35 (dd, J = 9.2, 4.9 Hz, 1H), 4.50 (qd, J = 5.5, 1.6 Hz, 1H), 3.93 (d, 5 J=12.7Hz, 1H), 3.52 (d, J=12.7 Hz, 1H), 3.35 (dd, J= 10,3, 4.7, 1H), 3.15 (dd, J = 16.6, 5.0 Hz, 1H), 3.02 (t, J = 7.9 Hz, 1H), 2.92 (d, J = 16.5 Hz, 1H), 2.50 — 2.27 (m, 2H), 2.11-2.05 (m, 1H), 1.90 — 1.51 (m, 4H).5C NMR (100MHz, CDCI) 8 175.56, 140.98, 139.86, 138.74, 128.93, 128.45, 128.09, 127.31, 127.18, 125.35, 124.13, 73.99, 67.54, 60.16, 56.77, 54.34, 39.79, 31.34, 24.22. [a] TS -48.30 (c=0.1, CHCIs). melting point:170.3-171.0°C < example 5 > 10 mL of dichloromethane was added to a round-bottom flask, then N-benzyl-
L-proline 3-2 (041g, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 2.0 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (S)-2-amino-2-phenylethan-1-ol 2-4 (0.27 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether- ethyl acetate-CH,Cl; (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-5, which is a white solid with a yield coefficient of 69%.
4 LU600467 3 NH OH 4,
NMR data of target compound 1-5: 'H NMR (400 MHz, CDCIs) 6 8.13 (d, J= 6.8 Hz, 1H), 7.43 — 7.13 (m, 9H), 7.10 — 7.01 (m, 2H), 5.0-4.85 (m, 1H), 3.95 — 3.76 (m, 3H), 3.5-3.3 (m, 2H), 3.25 (dd, J = 10.3, 4.7 Hz, 1H), 3.08-2.95 (m, 1H), 2.44 — 2.19 (m, 2H), 2.09 — 1.94 (m, 1H), 1.7- 1.85 (m, 2H).1°C NMR (100MHz, CDCIs) § 175.91, 138.70, 138.33, 128.93, 128.62, 128.41, 127.95, 127.22, 126.75, 67.43, 67.16, 59.98, 56.38, 54.02, 30.84, 24.20.
[0]15 -34.87 (c=0.1, CHC). melting point: 72.1-73.3°C < example 6 > 10 mL of dichloromethane was added to a round-bottom flask, then N-benzyl-
L-proline 3-2 (0.4lg, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (0.38 g 20 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (S)-2-amino-3,3-dimethylbutan-1-ol 2-5 (0.23 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH,Cl, (the volume ratio of petroleum ether to ethyl acetate to CH:CL is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-6, which is a white solid with a yield coefficient of 63%.
I LU600467 + +
NMR data of target compound 1-6: 'H NMR (400 MHz, CDCI) § 7.73 (d, J = 9.0 Hz, 1H), 7.41 — 7.23 (m, 5H), 3.89 (d, J = 12.8 Hz, 1H), 3.82 — 3.72 (m, 1H), 3.68 (ddd, J = 9.1, 8.1, 3.1 Hz, 1H), 3.58 (dd, J= 12.9, 1.4 Hz, 1H), 3.38 — 3.24 (m, 2H), 3.12 (t, J = 9.0 Hz, 1H), 2.56 — 2.38 (m, 2H), 2.17 — 2.30 (m, 1H), 1.97 — 1.87 (m, 1H), 1.86 — 1.76 (m, 1H), 1.75 — 1.61 (m, 1H), 0.94 (s, 9H).°C NMR (100 MHz, CDCIs) 3 175.98, 138.73, 128.72, 128.54, 127.39, 67.30, 63.73, 63.72, 60.10, 59.68, 59.67, 54.49, 54.48, 33.26, 30.86, 26.88, 26.86, 24.39. [o]29 -50.55 (c=0.1, CHCI;). melting point:115.0-116.5°C < example 7 > 10 mL of dichloromethane was added to a round-bottom flask, then (25,3aR,7aR)-1-benzyloctahydro-1H-indole-2-carboxylic acid 3-3 (0.52g, 2.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.38 g, 2.0 mmol) and 4-dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1R,2S)-2-amino-1,2-diphenylethan-1-ol 2-1(0.42 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature. After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH»CL (the volume ratio of petroleum ether to ethyl acetate to CH:CL> is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by
Formula 1-7, which is a white solid with a yield coefficient of 70%.
0 pd LU600467
NH OH ol 1-7 ©
NMR data of target compound 1-7: 'H NMR (400 MHz, CDCIz) § 8.29 (d, J = 8.2 Hz, 1H), 7.41-7.36 (m, 2H), 7.27- 7.33 (m, 3H), 7.25-7.27 (m, 1H), 7.22 — 7.13 (m, 6H), 7.00 — 6.93 (m, 4H), 5.04 (dd,
J=8,, 3.7Hz, 1H), 4.64 (d, J = 4.0 Hz, 1H), 3.79 (d, J = 13.3 Hz, 1H), 3.59 (d, J = 13.3 Hz, 1H), 3.47 — 3.40 (m, 1H), 2.82 — 2.95 (m, 1H), 2.55 — 2.7 (m, 1H), 2.15 — 2.25(m, 1H), 2.10 — 1.91 (m, 1H), 1.7-1.81 (m, 1H), 1.70 — 1.54 (m, 2H), 1.51 — 1.03 (m, 4H), 0.96 — 0.71 (m, 2H). PC NMR (100MHz, CDCIs) § 174.99, 140.06, 138.41, 136.89, 129.72, 128.51, 127.99, 127.93, 127.80, 127.54, 127.47, 126.46, 76.85, 67.03, 63.30, 59.19, 58.85, 36.92, 35.06, 27.77, 27.62, 24.07, 21.18.
[0] F9 -47.52 (c=0.1, CHC). melting point:169.5-170.5°C < example 8 > 10 mL of dichloromethane was added to a round-bottom flask, then (tert- butoxycarbonyl)-D-proline 3-4 (0.43g, 2.0 mmol) and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI) (0.38 g, 2.0 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol 2-3(0.30 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature.
After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH2CL (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-8, which is a white solid with a yield coefficient of 82%.
UN LU600467
Ah OH (nv 1-8
N
NMR data of target compound 1-8: 'H NMR (400 MHz, CDCl;) § 7.33 — 7.17 (m, 4H), 6.68 (d, J = 8.7 Hz, 1H), 5.34 (d, /= 8.1 Hz, 1H), 4.69 (s, 1H), 4.23 — 4.05 (m, 1H), 3.35 — 3.58 (m, 3H), 3.13 (d,
J= 16.7 Hz, 1H), 2.97 (d, J = 16.4 Hz, 1H), 2.32 — 2.08 (m, 3H), 1.96 — 1.81 (m, 2H), 1.43 (s, 9H).1°C NMR (100MHz, CDCls) § 173.36, 140.93, 140.91, 128.13, 128.10, 126.88, 126.86, 126.84, 126.83, 125.30, 125.27, 125.25, 124.06, 124.03, 80.63, 72.84, 60.65, 58.55, 47.10, 39.08, 29.34, 28.31, 24.80. [a] f$ -4.68 (c=0.1, CHCl). melting point: 147.6-148.3°C < example 9 > 10 mL of dichloromethane was added to a round-bottom flask, then (tert- butoxycarbonyl)-L-proline 3-5 (0.43g, 2.0 mmol) and 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI) (0.38 g, 2.0 mmol) and 4- dimethylaminopyridine (DMAP) (12.2 mg, 0.1 mmol) were added and stirred therein. Then (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol 2-3(0.30 g, 2.0 mmol) was added into the reaction system to continue the reaction at room temperature.
After the reaction is completed, silica gel powder is directly added into the reaction solution and stirred; then desolventized and concentrated under reduced pressure, using petroleum ether-ethyl acetate-CH,Cl, (the volume ratio of petroleum ether to ethyl acetate to CHCl, is 2:1:1) as eluent, this crude product was purified by column chromatography separation to obtain the target compound represented by Formula 1-9, which is a white solid with a yield coefficient of 75%.
UN LU600467 ° NH OH de 1
N
NMR data of target compound 1-9:
TH NMR (400 MHz, CDChs) 5 7.35 — 7.12 (m, 4H), 6.83 (d, J = 10.1 Hz, 1H), 5.40 (dd, J = 9.7, 4.9 Hz, 1H), 4.63 (t, J = 4.9 Hz, 1H), 4.43 — 4.23 (m, 1H), 3.31 — 3.54 (m, 2H), 3.15 — 3.25 (m, 1H), 2.94 (d, J = 16.7 Hz, 1H), 2.15 — 2.35(m, 2H), 1.85 — 2.01 (s, 2H), 1.43 (s, 9H).5C NMR (100 MHz, CDCI;) § 172.83, 140.79, 140.35, 128.08, 126.82, 125.31, 124.07, 80.99, 73.08, 61.19, 57.51, 47.34, 39.14, 29.67, 28.27, 24.60.
[0] F9 -112.83 (c=0.1, CHCI-). melting point: 147.1-147.7°C < example 10 >
Asymmetric addition reaction of diethyl zinc to aldehyde. under the atmosphere of nitrogen, 0.01 mmol of copper trifluoromethanesulfonate (Cu(OTf)z) and 0.01 mmol of the target compounds (ligands) prepared in Examples 1 to 9 were dissolved in 2 mL of anhydrous toluene, and stirred at room temperature for 1 h, then 0.2 mmol p-bromobenzaldehyde was added to the system and stirred for 10 min. Then added 0.3 mmol diethyl zinc to this system and stirred until the reaction is complete; 10% HCI was added drop wisely, then extracted with DCM, combined the organic solvent and dried over Na:SO4, filtered, then added silica gel powder into the filtrate, desolventized and concentrated under reduced pressure; using petroleum ether-ethyl acetate (the volume ratio of petroleum ether to ethyl acetate is 5:1) as eluent, the crude product was purified by column chromatography to obtain the target product. Table 1 shows the results of asymmetric addition reaction of diethyl zinc to aldehyde catalyzed by copper. It can be seen from the following experimental data that the complexes formed by the target ligand compounds that were prepared in Examples 1 to 9 of the present | U600467 invention and copper trifluoromethanesulfonate have good catalytic activity for addition reaction of diethyl zinc to aldehyde. Among them, the compounds of
Formulas 1-4 have the best effect. The target ligand compounds prepared in
Examples 1-9 of the present invention can be directly used to prepare various secondary alcohol compounds via copper-catalyzed asymmetric addition reaction of diethyl zinc to aldehyde. 0 OH
Cu(OTf),, Ligand jon
Zn(Et), + ( J _ toluene
Br Br
A B
Table 1 Influence of ligand effect on addition reaction *
Product Ligand Reaction time Yield Enantiomeric number coefficient excess value (%)° (%)°
IE LL I | 7
Cw [ww ow | 5 pu | #5 ow ow ow [ow | ww | & _
Note: “ reaction conditions: compound A (diethyl zince) is 0.3 mmol, compound
B aldehyde is 0.2 mmol, Cu(OTf)z is 0.01 mmol, Ligand is 0.01 mmol, toluene is 2 mL, and the reaction is carried out at room temperature; ” isolated yield; ¢ the enantiomeric excess of was determined by chiral HPLC.
Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and the implementation but can be applied to various suitable fields.
For those familiar with | U600467 the field, other modifications can be easily realized, so the present invention is not limited to the specific details and the embodiments, which have been shown and described here without departing from the general concepts defined by the claims and their equivalents.
Claims (5)
1. A novel chiral tertiary amine-hydroxyl ligand, wherein having a chemical structural formula shown: R2 RS 9 8 NH OH [Nw wherein, R! represents any one of hydrogen, methyl group, benzyl group and Boc group; R? represents aryl group or alkyl group; R* represents phenyl group or Hydrogen.
2. A method for preparing the novel chiral tertiary amine-hydroxyl ligand according to claim 1, comprises: chiral amino alcohol is condensed with a chiral N-substituted amino acid to obtain the novel chiral tertiary amine-hydroxyl ligand; the chemical reaction equation is as follows: RR RS oO $- A N NH OH R2 RS JOH y FX ew Tae Law HN OH (NR 2-2 >
3. The method for preparing the novel chiral tertiary amine-hydroxyl ligand according to claim 2, wherein the chiral amino alcohol is condensed with a chiral N- substituted amino acid comprises:
1.0 equivalents of N-substituted amino acids, 1.0 equivalents of EDCI and 0.1 equivalent of DMAP are stirred in CHCl, to obtain a primary solution.; then this primary solution is added 1.0 equivalent of chiral amino alcohol and reacted at room temperature for 24-48 h; after the reaction is completed to obtain a mixture solution, using petroleum ether-ethyl acetate-CH,Cl, as eluent, this mixture solution is purified by column chromatography, so as to obtain the novel chiral tertiary amine- | 500467 hydroxyl ligand.
4. The method for preparing the novel chiral tertiary amine-hydroxyl ligand ; according to claim 3, whereinthe volume ratio of petroleum ether to ethyl acetate to CH:CL of the eluent is 1 to the ratio of (5-2): 1:1.
5. Application of a novel chiral tertiary amine-hydroxy ligand as a catalyst for the asymmetric addition of diethylzinc to aldehydes.
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