Preparation method of chiral dihydropyrano[3,2-c]coumarin compounds

Abstract

The present invention relates to a method for preparing chiral dihydropyrano[3,2-c]coumarin compounds. The chiral copper catalyst used in this method is generated in situ from a copper salt and a chiral P,N,N-tridentate ligand in a reaction medium. Through an asymmetric [3+3] cycloaddition reaction, a series of chiral dihydropyrano[3,2-c]coumarin compounds are synthesized with high yields and high enantioselectivities. The present invention has the characteristics of simple operation, readily available raw materials, a wide range of substrate applicability, and high enantioselectivity.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing chiral dihydropyrano[3,2-c]coumarin compounds. Background Art

[0002] The pyrano[3,2-c]coumarin skeleton widely exists in natural products and drug molecules with important biological activities. In particular, chiral dihydropyrano[3,2-c]coumarin compounds exhibit diverse biological and pharmacological activities, such as anticancer, anti-inflammatory, and antimalarial effects. [(a) F. Kuno, K. Shiomi, K. Otoguro, T. Sunazuka, S. Omura, J. Antibiot. 1996, 49, 748 - 751; (b) K. Otoguro, K. Shiomi, Y. Yamaguchi, N. Arai, T. Sunazuka, R. Masuma, Y. Iwai, S. Omura, J. Antibiot. 2000, 53, 50 - 57; (c) L. Lei, Y.-B. Xue, Z. Liu, S.-S. Peng, Y. He, Y. Zhang, R. Fang, J.-P. Wang, Z.-W. Luo, G.-M. Yao, J.-W. Zhang, G. Zhang, H.-P. Song, Y.-H. Zhang, Sci. Rep. 2015, 5, 13544.] Therefore, the synthesis of such compounds has been widely concerned by scientific researchers and is also one of the hotspots in the field of organic synthesis.The existing reports are mainly obtained by the reaction of 4-hydroxycoumarin with different nucleophiles, mainly including 1,3-diarylallyl compounds, propargyl alcohol compounds, and α,β-unsaturated carbonyl compounds [(a) X. Lin, X. Dai, Z. Mao, Y. Wang, Tetrahedron 2009, 65, 9233-9237; (b) A. Naseem, B. Venkata Babu, Synth. Commun. 2013, 43, 3044-3053; (c) S. Berger, E. Haak, Tetrahedron Lett. 2010, 51, 6630-6634; (d) Y.-K. Liu, J. Zhu, J.-Q. Qian, B. Jiang, Z.-Y. Xu, J. Org. Chem. 2011, 76, 9096-9101; (e) H. Mukut, H. Johannes, V. Tonder, C. Barend, B. Bezuidenhoudt, Tetrahedron Lett. 2013, 54, 3773-3776; (f) S. Yaragorla, O. L. Saini, G. Singh, Tetrahedron Lett. 2015, 56, 1649-1653; (g) Z. He, X. Lin, Y. Zhu, Y. Wang, Heterocycles 2010, 81, 965-976; (h) G. Appendino, G. Cravotto, S. Tagliapietra, G. M. Nano, G. Palmisano, Helv. Chem. Acta. 1990, 73, 1865-1878; (i) G. Cravotto, G. M. Nano, S. Tagliapietra, Synthesis 2001, 49-51; (j) X.-S. Wang, J.-X. Zhou, Z.-S. Zeng, Y.-L. Li, D.-Q. Shi, S.-J. Tu, ARKIVOC 2006, 107-113; (k) K. C. Majumdar, P. Debnath, P. K. Maji, Tetrahedron Lett. 2007, 48, 5265-5268; (l) R. Sarma, M. M. Sarma, K. C. Lekhok, D. Prajapati, Synlett 2010, 2847-2852.].In 2017, the Nurjamal research group reported the preparation of functionalized dihydropyrano[3,2-c]coumarin compounds via a catalyst-free "one-pot" three-component reaction of 4-hydroxycoumarin, aldehydes, and ketones [G. Brahmachari, K. Nurjamal, ChemistrySelect 2017, 2, 3695-3702.]. Although these strategies have their respective advantages, such methods require a strong acid environment, expensive catalysts, or the use of toxic reagents, etc., and are accompanied by defects such as low yields and poor chemoselectivity. Most importantly, the dihydropyrano[3,2-c]coumarin compounds prepared by such methods are all optically inactive. Therefore, it is of great significance to develop new asymmetric catalytic strategies for the simple and efficient construction of chiral dihydropyrano[3,2-c]coumarin compounds. Summary of the Invention

[0003] The object of the present invention is to provide a method for synthesizing chiral dihydropyrano[3,2-c]coumarin compounds by an asymmetric [3+3] cycloaddition reaction between 4-hydroxycoumarin compounds and propargyl compounds catalyzed by copper. The present invention has the characteristics of easily available raw materials, simple operation, mild reaction conditions, and high enantioselectivity.

[0004] The specific steps are as follows:

[0005] (1) Preparation of the chiral copper catalyst: Under nitrogen protection, a copper salt and a P,N,N-ligand are stirred in a reaction medium at a molar ratio of 1:1 to 10 for 1 to 2 hours to obtain the chiral copper catalyst;

[0006] (2) Preparation of the dihydropyrano[3,2-c]coumarin compounds: The propargyl compound, the 4-hydroxycoumarin compound, and the base additive are dissolved in a reaction medium, and then this solution is added to the above-mentioned well-stirred chiral copper catalyst solution under nitrogen protection, and stirred at 0 to 10 °C for 0.1 to 24 hours; after the reaction is completed, it is concentrated under reduced pressure until the solvent is almost gone, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain the target product;

[0007] The molar ratio of the chiral copper catalyst to the propargyl compound is 0.01 to 1:1,

[0008] The molar ratio of the base additive to the propargyl compound is 0.5 to 10:1;

[0009] The molar ratio of the 4-hydroxycoumarin compound to the propargyl compound is 1:1 to 3.

[0010] The chiral dihydropyrano[3,2-c]coumarin compounds have one of the following structures:

[0011]

[0012] I and II are enantiomers, where: R 1 , R 2 is H, a linear alkyl or alkoxy group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms in the ring, a phenyl group or a substituted phenyl group, a benzyl group or a substituted benzyl group, a naphthyl group or a substituted naphthyl group, or a five- or six-membered heteroaromatic group containing one or more of one or two or more of oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl group, substituted benzyl group, and substituted naphthyl group are each one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0013] The 4-hydroxycoumarin compound has the following structure:

[0014]

[0015] where: R 1 is the same group as R 1 in structural formulas I and II.

[0016] The propargyl compound has the following structure:

[0017]

[0018] where: R 2 is the same group as R 2 in structural formulas I and II; the leaving group X is one of fluorine, chlorine, bromine, iodine, a C1-C10 alkyl carboxylate, a C1-C10 alkyl carbonate, a C1-C10 alkyl sulfonate, a C1-C10 alkyl phosphate, a phenyl carboxylate and a substituted phenyl carboxylate, a phenyl carbonate and a substituted phenyl carbonate, a phenyl sulfonate and a substituted phenyl sulfonate, or a phenyl phosphate and a substituted phenyl phosphate; the substituent on the substituted phenyl group is one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen, a nitro group, an ester group, or a cyano group, and the number of substituents is 1 to 5.

[0019] The copper salt is Cu(OAc) 2 ·H 2 O, CuSO 4 ·H 2 O, Cu(OAc) 2 、CuSO 4 、Cu(OTf) 2 、CuCl 2 、CuOAc、CuCl、CuI、CuClO 4 、CuOTf·0.5C 6 H6 , Cu(CH 3 CN) 4 PF 6 or Cu(CH 3 CN) 4 ClO 4 or one or more of the above two kinds.

[0020] The chiral P, N, N-ligand has the following structural characteristics:

[0021]

[0022] In the formula: R 3 , R 7 is a C1-C10 linear alkyl or alkoxy group, a C3-C10 cycloalkyl group, a phenyl or substituted phenyl group, a benzyl or substituted benzyl group, a naphthyl or substituted naphthyl group, or a five- or six-membered heteroaromatic group containing one or two or more of oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are respectively one or two or more of C1-C10 alkyl groups, C1-C10 alkoxy groups, halogens, nitro groups, ester groups, or cyano groups, and the number of substituents is 1-5.

[0023] R 4 , R 5 , R 6 is H, halogen, acyl group, nitro group, C1-C10 linear alkyl or alkoxy group, a C3-C10 cycloalkyl group, a phenyl or substituted phenyl group, a benzyl or substituted benzyl group, a naphthyl or substituted naphthyl group, or a five- or six-membered heteroaromatic group containing one or two or more of oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl, substituted benzyl, and substituted naphthyl groups are respectively one or two or more of C1-C10 alkyl groups, C1-C10 alkoxy groups, halogens, nitro groups, ester groups, or cyano groups, and the number of substituents is 1-5.

[0024] The reaction medium is at least one of methanol, ethanol, toluene, benzene, xylene, dichloromethane, dichloroethane, ether, tetrahydropyran, dimethyl sulfoxide, or N, N-dimethylformamide.

[0025] The basic additive is i Pr 2 NEt, NEt 3 , DBU, t BuOK, KOH, NaOH, Na 2 CO 3 , NaHCO 3 , t BuOK, K 2 CO 3 , Cs 2 CO3 or K 3 PO 4 one or more of the above.

[0026] The preferred catalytic reaction conditions are as follows: temperature is 10 °C, the reaction medium is methanol, the pressure is atmospheric pressure, and the time is 12 hours.

[0027] The reaction equation of the present invention is:

[0028]

[0029] The present invention has the following advantages:

[0030] 1. High reaction activity, good stereoselectivity, and mild reaction conditions.

[0031] 2. The starting materials are cheap and easily available.

[0032] 3. The chiral ligand is simply synthesized, the catalyst is cheap and easily available, and the dosage is small.

[0033] 4. Compared with the traditional method, this method can conveniently synthesize various substituted dihydropyrano[3,2-c]coumarin compounds.

[0034] The chiral copper catalyst used in this method is in-situ generated from a copper salt and a chiral P,N,N-tridentate ligand in the reaction medium. Through an asymmetric [3+3] cycloaddition reaction, a series of chiral dihydropyrano[3,2-c]coumarin compounds are synthesized in high yield and high enantioselectivity. The present invention has the characteristics of simple operation, easily available raw materials, wide substrate scope, and high enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 1H NMR spectrum of (R)-4-phenyl-4H,5H-pyrano[3,2-c]chromen-5-one prepared in Example 1;

[0036] Figure 2 13C NMR spectrum of (R)-4-phenyl-4H,5H-pyrano[3,2-c]chromen-5-one prepared in Example 1; DETAILED DESCRIPTION OF THE INVENTION

[0037] The following examples will further illustrate the present invention, but do not limit the present invention thereto. Nuclear magnetic resonance was measured by a Bruker nuclear magnetic resonance spectrometer, and high performance liquid chromatography (HPLC) was measured by an Agilent 1100 series high performance liquid chromatography.

[0038] Example 1

[0039] Cu(CH 3 CN) 4PF 6 Complexes with L-2-1 and acts as a chiral catalyst for the reaction to produce the chiral dihydropyrano[3,2-c]coumarin compound (R)-4-phenyl-4H,5H-pyrano[3,2-c]chromen-5-one Ⅱ-1.

[0040] Add the metal precursor Cu(CH 3 CN) 4 PF 6 (0.015 mmol, 5.6 mg) and the chiral ligand L-2-1 (0.0165 mmol, 7.8 mg) to the reaction flask. Under nitrogen protection, add 1.0 mL of anhydrous methanol and stir at room temperature for 1 hour. Then transfer the reaction tube to a constant temperature reaction freezer at 0 °C, and dissolve propargyl alcohol ester Ⅳ-1 (0.33 mmol, 57.5 mg), 4-hydroxycoumarin compound Ⅲ-1 (0.3 mmol, 48.6 mg) and i Pr 2 NEt (0.33 mmol, 55 μL) in 2.0 mL of anhydrous methanol. Then add this solution to the above-stirred catalyst solution under nitrogen protection and stir at 0 °C for 12 h. After the reaction is completed, concentrate under reduced pressure until the solvent is almost gone, separate by silica gel column chromatography, concentrate under reduced pressure, and dry in vacuo to obtain a reddish-brown oily substance with a 90% yield and 95% ee. The 1H NMR and 13C NMR spectra of product Ⅱ-1 are as Figure 1 、 Figure 2 shown:

[0041] 1 1H NMR (700 MHz, CDCl 3 ) δ 7.83 - 7.82 (m, 1H), 7.55 - 7.52 (m, 1H), 7.39 - 7.38 (m, 2H), 7.34 - 7.28 (m, 4H), 7.24 - 7.21 (m, 1H), 6.79 (dd, J = 6.0, 1.2 Hz, 1H), 5.35 (dd, J = 6.0, 4.6 Hz, 1H), 4.54 (d, J = 4.5 Hz, 1H); 13 13C NMR (176 MHz, CDCl 3 ) δ 161.5, 155.7, 152.6, 143.6, 138.1, 131.9, 128.6, 128.4, 127.2, 124.1, 122.7, 116.7, 114.4, 108.9, 103.7, 35.3. HPLC (Chiralcel OJ-H, n-hexane / i-PrOH = 95 / 5, 0.8 mL / min, 254 nm, 40 °C): t R (major) = 30.8 min, t R(minor) = 36.9 min.

[0042] The structural formulas of Ⅲ-1, Ⅳ-1, Ⅱ-1, and L-1-1 are as follows:

[0043]

[0044] Example 2

[0045] L-1-1 reacts as a ligand to form product Ⅱ-1

[0046] Replace the ligand L-2-1 in Example 1 with ligand L-1-1, and the rest is the same as in Example 1. The reaction gives compound Ⅱ-1 in 93% yield and 89% ee.

[0047] The structural formula of L-1-1 is as follows:

[0048]

[0049] Example 3

[0050] L-2-2 reacts as a ligand to form product Ⅱ-1

[0051] Replace the ligand L-2-1 in Example 1 with ligand L-2-2, and the rest is the same as in Example 1. The reaction gives compound Ⅱ-1 in 83% yield and 85% ee.

[0052] The structural formula of L-2-2 is as follows:

[0053]

[0054] Example 4

[0055] Cu(OTf) 2 and L-2-1 catalyze the reaction to form product Ⅱ-1

[0056] Replace Cu(CH 3 CN) 4 PF 6 in Example 1 with Cu(OTf) 2 , and the rest is the same as in Example 1. Compound Ⅱ-1 is obtained in 79% yield and 86% ee.

[0057] Example 5

[0058] Cu(OAc) 2 ·H 2 O and L-2-1 catalyze the reaction to form product Ⅱ-1

[0059] Replace Cu(CH 3 CN) 4 PF 6 in Example 1 with Cu(OAc)2 ·H 2 O. The rest was the same as in Example 1, and Compound II-1 was obtained in a yield of 77% and an ee of 87%.

[0060] Example 6

[0061] NEt 3 Reacted as a base additive to form Product II-1

[0062] In Example 1 i Pr 2 Replace NEt with NEt 3 , and the rest was the same as in Example 1. Compound II-1 was obtained in a yield of 93% and an ee of 92%.

[0063] Example 7

[0064] Reacted with DBU as a base additive to form Product II-1

[0065] In Example 1 i Pr 2 Replace NEt with DBU, and the rest was the same as in Example 1. Compound II-1 was obtained in a yield of 89% and an ee of 90%.

[0066] Example 8

[0067] Reacted with absolute ethanol as the reaction solvent to form Product II-1

[0068] Replace absolute methanol in Example 1 with absolute ethanol, and the rest was the same as in Example 1. Compound II-1 was obtained in a yield of 92% and an ee of 93%.

[0069] The above-described embodiments only represent the implementation manners of the present invention, but should not be construed as limiting the scope of the present invention patent. It should be noted that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

1. A method for preparing chiral dihydropyrano[3,2-c]coumarin compounds, characterized in that: in the presence of a base additive, a chiral copper catalyst catalyzes the synthesis of chiral dihydropyrano[3,2-c]coumarin compounds from 4-hydroxycoumarin compounds and propargyl compounds through an asymmetric [3+3] cycloaddition reaction; the chiral dihydropyrano[3,2-c]coumarin compounds have one or two of the following structures: I and II are enantiomers, the 4-hydroxycoumarin compounds have the following structure: the propargyl compounds have the following structure: Wherein: R 1 is H, a C1-C10 linear alkyl group, a C1-C10 alkoxy group, a C3-C10 cycloalkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, a naphthyl group, a substituted naphthyl group, or a five- or six-membered heteroaromatic group containing one or more of one or two or more of oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl group, the substituted benzyl group, and the substituted naphthyl group are respectively one or more of a C1-C10 alkyl group, a C1-C10 alkoxy group, a halogen, a nitro group, an ester group, or a cyano group, and the number of substituents is 1-5; R 2 is phenyl and substituted phenyl, naphthyl and substituted naphthyl, or a five- or six-membered heteroaromatic group containing one or more of one or two or more of oxygen, sulfur, and nitrogen atoms; the substituents on the substituted phenyl and substituted naphthyl are respectively one or more of C1-C10 alkyl, C1-C10 alkoxy, halogen, nitro, or cyano, and the number of substituents is 1-5; the leaving group X is an alkyl carboxylate group with 1 to 10 carbon atoms; The chiral copper catalyst described above is formed in situ from a copper salt and a chiral P,N,N-tridentate ligand in a reaction medium; the copper salt is Cu(OAc) 2 ·H 2 O, Cu(OAc) 2 2, Cu(OTf) 2 2, Cu(CH 3 3CN) 4 2PF 6 6, or one or more of them; the chiral P,N,N-ligand has the following structural characteristics: In the formula: R 3 is a C1-C10 alkyl chain; R 7 is phenyl; R 4 is one of H, C1-C10 linear alkyl or phenyl; R 5 and R 6 are each H; The alkali additive described is i Pr 2 NEt, NEt 3 , DBU, t BuOK, KOH, NaOH, Na 2 CO 3 , NaHCO 3 , t BuOK, K 2 CO 3 , Cs 2 CO 3 or K 3 PO 4 one or more of the following; the reaction medium is one or both of methanol and ethanol.

2. The preparation method according to claim 1, characterized in that: the specific steps of this method are as follows: (1) Preparation of the chiral copper catalyst: Under nitrogen protection, a copper salt and a chiral P,N,N-ligand are stirred in a reaction medium at a molar ratio of 1:1 to 10 for 1 to 2 hours to obtain the chiral copper catalyst; (2) Preparation of dihydropyrano[3,2-c]coumarin compounds: The propargyl compounds, 4-hydroxycoumarin compounds and a base additive are dissolved in a reaction medium, and then this solution is added to the above-stirred solution of the chiral copper catalyst under nitrogen protection, and stirred at 0 to 10 °C for 0.1 to 24 hours; to obtain the product.

3. The preparation method according to claim 1, characterized in that: the molar ratio of the chiral copper catalyst to the propargyl compounds is 0.01 to 1:1; the molar ratio of the base additive to the propargyl compounds is 0.5 to 10:1; the molar ratio of the 4-hydroxycoumarin compounds to the propargyl compounds is 1:1 to 3.

4. According to the preparation method described in claim 1, characterized in that: the catalytic reaction conditions are: the temperature is 0 - 4 °C, the reaction medium is methanol, the pressure is normal pressure, and the time is 12 - 14 hours.

5. The preparation method according to claim 2, characterized in that: after the reaction is completed, it is concentrated under reduced pressure until the solvent is basically removed, separated by silica gel column chromatography, concentrated under reduced pressure, and dried in vacuo to obtain the target product.

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