KR101459184B1 - SYNTHESIS OF 4-SUBSTITUTED CHIRAL CHROMANOLS BY USING MALONIC ESTER AND O-HYDROXYAROMATIC α,β-UNSATURATED ALDEHYDES - Google Patents

Abstract

A method for preparing cromanols having an excellent yield and a high enantioselectivity by conducting a conjugate addition reaction in the presence of a specific catalyst by selecting a specific nucleophilic agent for ortho-hydroxyaromatic?,? -Unsaturated aldehyde, and a method for producing ≪ / RTI > The present invention relates to a catalyst reaction step in which malonate is subjected to conjugate addition reaction with o-hydroxycinnamaldehyde in the presence of diphenylprolinol TMS ether catalyst (Chroman-2-ol), which is substituted at the 4-position, and chroman-2-ol prepared by this method.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for preparing chiral chromanols substituted with 4-position using a malonic acid ester and ortho-hydroxyaromatic alpha, beta-unsaturated aldehyde -UNSATURATED ALDEHYDES}

The present invention relates to a method for producing optically active cromanols, and more particularly, to a method for producing optically active croman-2-ol substituted at the 4-position with high enantioselectivity using a specific nucleophile and a catalyst .

Croman structural units are frequently present in natural products with many medicinal and biological activities, and molecules containing chroman skeleton exhibit activities of central nervous system activity such as antiviral, anticancer, antimicrobial and sex pheromone, It is also used as a sex pesticide. Due to the importance of the chroman structure, various chroman synthesis methods have recently been disclosed in terms of the selectivity of the enantiomer (Non-Patent Documents 1 to 13).

The present inventors have recently proposed a method for asymmetrically synthesizing chromium from ortho-hydroxycinnamaldehyde and organoboronic acid using an organic catalyst derived from imidazolidinone 1) (Non-Patent Documents 14 to 15).

[Reaction Scheme 1]

In the above report, when arylvinylboronic acid is used in the organic catalytic reaction, it shows an excellent yield of 99% and a high enantioselectivity of 86%. However, when arylboronic acid is used, low enantioselectivity Respectively.

From these findings it is necessary to develop a method for the catalytic production of chroman derivatives with better enantioselectivity using other nucleophiles instead of organic bromates.

[Non-Patent Document]

Non-Patent Document 1: X. Meng, Y. Huang, H. Zhao, P. Xie, J. Ma, R. Chen, Org . Lett . 2009, 11 , 991.

Non-Patent Document 2: Y. Yamamoto, K. Itonaga, Org . Lett . 2009, 11 , 717.

Non-Patent Document 3: F. Ulgheri, M. Marchetti, O. Piccolo, J. Org . Chem . 2007, 72 , 6056.

Non-Patent Document 4: A. Jagdale, RA Sudalai, Tetrahedron Lett . 2007, 48 , 4895.

Non-Patent Document 5: K. Li, K. Vanka, WH Thompson, JA Tunge, Org . Lett . 2006, 8 , 4711.

Non-Patent Document 6: C. Hedberg, PG Andersson, Adv . Synth . Catal . 2005, 347 , 662.

Non-Patent Document 7: Z. Shi, C. He. J. Am . Chem . Soc . 2004, 126 , 13596.

Non-Patent Document 8: H.-H. Lu, H. Liu, W. Wu, X.-F. Wang, L.-Q. Lu, W.-J. Xiao, Chem . Eur . J. 2009, 15 , 2742.

Non-Patent Document 9: M. Yoshida, M. Higuchi, K. Shishido, Org . Lett . 2009, 11 , 4752.

Non-Patent Document 10: L. Zu, S. Zhang, H. Xie, W. Wang, Org . Lett . 2009, 11 , 1627.

Non-Patent Document 11: L. Hong, L. Wang, W. Sun, K. Wong, R. Wang, J. Org . Chem . 2009, 74 , 6881.

Non-Patent Document 12: M. Rueping, E. Sugiono, E. Merino, Chem . Eur . J. 2008, 14 , 6329.

Non-patent document 13: PT Franke, B. Richter, KA Jorgensen, Chem .- Eur . J. 2008, 14 , 6317.

Non-Patent Document 14: K.-S. Choi, S.-G. Kim, Tetrahedron Lett . 2010, 51 , 5203.

Non-Patent Document 15: K.-S. Choi, S.-G. Kim, Synthesis 2010, 3999.

In order to solve the above problems, the present invention provides a method for preparing cromanols having excellent yield and high enantioselectivity by preparing a specific nucleophilic agent for ortho-hydroxyaromatic?,? -Unsaturated aldehyde by conjugate addition reaction in the presence of a specific catalyst And to provide cromanols prepared using such methods.

In order to solve the above-mentioned problems, the present invention provides a process for preparing a conjugate addition (hereinafter referred to as "conjugate addition") by adding malonate to o-hydroxycinnamaldehyde in the presence of diphenylprolinol TMS ether catalyst ), Wherein the chroman-2-ol is substituted with the 4-position.

The present invention also provides a process for preparing optically active chroman-2-ol substituted at the 4-position, wherein the malonic acid is represented by the following formula (1).

[Chemical Formula 1]

(R is H or an alkyl or aryl group having 1 to 14 carbon atoms)

Also, the present invention provides an optically active chroman-2-ol substituted at the 4-position, wherein the ortho-hydroxycinnamaldehyde is represented by the following general formula (2).

(2)

(X is H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3, 4-MeO or 6-MeO)

The optically active chroman-2-ol substituted with 4-position is characterized in that the catalytic reaction proceeds in at least one solvent selected from the group consisting of dichloromethane, toluene, methanol and chloroform. ol. < / RTI >

In order to solve the above-mentioned problem, the present invention provides optically active chroman-2-ol substituted by 4-position represented by the following formula (3) prepared by the above method.

(3)

(R is an alkyl group or an aryl group, X a H or C 1 -C 14 H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3 , 4-MeO or 6-MeO)

The present invention includes a step of selecting malonic acid as a nucleophilic agent for ortho-hydroxycinnamic aldehyde and selecting conjugated diphenylpyrrolinol thiosulfate ether as an organic catalyst, thereby obtaining 4 An optically active croman-2-ol in which the position is substituted and a croman-2-ol prepared by this method can be provided.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately The present invention should be construed in accordance with the meaning and concept consistent with the technical idea of the present invention. Accordingly, it is to be understood that the constituent features of the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the inventive concepts of the present invention, so that various equivalents, And the like.

As a result of intensive studies on an effective method for synthesizing an enantioselective compound for obtaining a chroman skeleton, the present inventors have found that malonic acid is selected as a nucleophilic agent for ortho-hydroxycinnamic aldehyde, It has been found that a chroman derivative substituted at the 4-position which is enantiomerically enriched in the catalytic asymmetric addition-cyclization reaction can be easily produced, leading to the present invention.

Accordingly, the present invention relates to a process for the catalytic reaction of conjugating malonate to ortho-hydroxycinnamaldehyde in the presence of diphenylprolinol TMS ether catalyst, (Chroman-2-ol) in which the 4-position is substituted.

The following Reaction Scheme 2 briefly shows the organic catalytic conjugate addition-cyclization continuous reaction of malonic acid and ortho-hydroxycinnamaldehyde in the preparation of optically active chroman-2-ol substituted at the 4-position according to the present invention .

[Reaction Scheme 2]

As in Scheme 2, when malonic acid is selected as the nucleophile and the appropriate organic catalyst is selected for the ortho-hydroxycinnamaldehyde, it is possible to generate chroman-2-ol substituted at position 4 with high enantioselectivity . In the above reaction, malonic acid is conjugated to ortho-hydroxycinnamaldehyde in a conjugate reaction to produce a substituted aldehyde in the beta-position of chirality, followed by hemiacetalation to form chroman-2-ol substituted with the 4-position of chirality do. This is because the malonic acid is provided as a nucleophilic agent rather than the hydroxyl group of the ortho-hydroxycinnamic aldehyde in the conjugate addition reaction.

The malonic acid may be represented by the following formula (1).

[Chemical Formula 1]

In formula (1), R may be selected from H or an alkyl or aryl group having 1 to 14 carbon atoms, preferably a methyl group, an ethyl group, an isopropyl group or a phenyl group, and more preferably a phenyl group.

The ortho-hydroxycinnamaldehyde may be represented by the following general formula (2).

(2)

X in formula 2 is H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3, 4-MeO MeO-or 6 may be selected from , Preferably 4,6-Br ₂ or 6-MeO.

In the conjugate addition reaction, malonic acid and ortho-hydroxycinnamaldehyde can be reacted at a molar ratio of 1: 1 to 1: 3. When the reaction is carried out at a molar ratio of less than 1: 1, the conjugation reaction of malonic acid is unsatisfactory and the yield may be lowered. When the reaction is carried out at a molar ratio exceeding 1: 3, The degree of improvement may not be large.

In the present invention, a diphenylprolinol TMS ether catalyst represented by the following general formula (4) is selected as the organic catalyst, and the yield of the conjugate addition reaction of malonic acid with ortho-hydroxycinnamaldehyde is To yield chroman-2-ol substituted at position 4 with maximal and high enantioselectivity.

[Chemical Formula 4]

The diphenylpyrrololinium thiosulfate catalyst may be added in an amount of 5 to 20 mol%, preferably 10 to 20 mol%, based on the reaction mixture. When the amount of the malonic acid is less than 5 mol%, the catalytic reaction does not occur satisfactorily and the yield may be lowered. If the amount exceeds 20 mol%, the degree of increase in the yield may not be large.

The catalytic reaction proceeds at room temperature in an organic solvent. Examples of the organic solvent include dichloromethane, benzene, diethyl ether, acetone, acetonitrile, toluene, tetrahydrofuran, methanol, isopropanol, chloroform and the like, and dichloromethane, toluene, It is preferable to use chloroform.

In addition, the catalytic reaction can be carried out for 2 to 50 hours, preferably 24 to 48 hours. If the reaction time is less than 2 hours, the yield of chroman-2-ol may be lowered, and if it exceeds 50 hours, the reaction time may be prolonged without improving the yield.

The optically active chroman-2-ol substituted at the 4-position having an excellent yield and high enantioselectivity represented by the following formula (3) can be prepared by the above-described method.

(3)

In formula (3), R may be H or an alkyl or aryl group having 1 to 14 carbon atoms, preferably a methyl group, an ethyl group, an isopropyl group or a phenyl group, and more preferably a phenyl group. Also, X may be a H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3, 4-MeO or 6-MeO, preferably it may be a 4,6-Br ₂ or 6-MeO.

Manufacturing example

37 mg (0.25 mmol) of the catalyst 16 mg (0.05 mmol) and ortho-hydroxycinnamaldehyde (1a, see Scheme 3) are placed in a flask and 0.8 ml of 0.3 M organic solvent is added dropwise at room temperature. After stirring for 5 minutes, 34 말 (0.30 mmol) of malonic acid is added. The solution is stirred until the ortho-hydroxycinnamaldehyde is completely reacted, and the completion of the reaction is confirmed by thin-layer chromatography (TLC). The reaction product is then purified by a forced-flow chromatograph using ICN 60 silica gel 63 (32-64 mesh) with 20% ethyl acetate / hexanes to give the compound.

Comparative Example  1, 2, and Example  1 to 7

In the above preparation example, dimethyl malonic acid (2a) was used as the malonic acid, the catalyst, the additive (added with the catalyst in an amount of 20 mol% to the reaction mixture) and the solvent were reacted as shown in the following reaction formula 3, (Dimethyl 2 - (( 4R ) -3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (3a) was obtained. The reaction composition according to each of Comparative Examples and Examples is shown in Table 1 together with the yield of the obtained chroman-2-ol.

_{^{[α] 22 D -58.8 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.03-7.20 (m, 2H), 6.83-6.92 (m, 2H), 5.69 (dd, J = 3.2 , 5.2 Hz, 0.6H), 5.64 (brs, 0.4H), 4.37 (d, J = 9.6 Hz, 0.4H), 4.02 (d, J = 7.6 Hz, 0.6H), 3.64-3.87 , 3.76 (s, 2H), 3.76 (s, 2H), 3.76 (s, -2.38 (m, 1 H), 2.01-2.19 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.5 (minor), 168.8 (minor), 168.7 (major), 168.3 (major), 152.1 (major), 152.0 (minor), 128.8 (minor), 128.5 (major), Minor, 127.4 (major), 122.3 (major), 121.5 (minor), 121.0 (major), 120.9 (minor), 117.5 (major), 117.4 (minor), 92.6 (minor), 91.4 52.5 (minor), 52.5 (minor), 52.3 (major), 32.5 (minor), 31.3 (major), 30.5 (major), 30.0 (minor) ; ^{HRMS: [M +] Calcd for} C 14 H 16 O 6: 280.0947 Found: 280.0945.

[Reaction Scheme 3]

In Table 1, the catalysts I and III are represented by the following formulas (5) and (6).

[Chemical Formula 5]

[Chemical Formula 6]

Experimental Example  One

Reduction (Et ₃ SiH / BF ₃ .Et ₂ O with CH ₂ Cl ₂ ) of the chroman-2-ol obtained according to Comparative Examples 1 and 2 and Examples 1 to 7 was performed and the enantioselectivity And the results are shown in Table 2 below. Columns were of Chiralcel columns (AD-H (25 cm) and AD-H guard (5 cm) 1.0 ml / min flow, [lambda] = 220 nm); minor- isomer t _r = 12.6 min and major- isomer t _r = 26.9 min.

Referring to Table 1, when the catalyst I was used (Comparative Example 1), the corresponding chroman-2-ol was not generated and the starting material was almost recovered. When the catalyst II was used (Example 1), 77% And 92% of the selectivity for the enantioselectivity. However, when the catalyst III was used under the same conditions as in Example 1 (Comparative Example 2), the yield was as low as 13% and no enantioselectivity was measured. On the other hand, even when an acid or base additive known to improve the reaction activity and enantioselectivity in the organic catalytic conjugate addition reaction is added, the catalytic reaction of the present invention does not show any significant effect (Comparative Examples 1 and 2, Examples 1 and 2 ) In the case where the additive is not added (Examples 3 to 7), it can be seen that it is more effective in terms of the reaction activity and the image selectivity. Further, in the case of using organic solvent, dichloromethane, toluene, methanol and chloroform were used (Examples 3 to 7), both yield and mirror image selectivity were good in the conjugation addition reaction, and chloroform was used However, it was confirmed that when the catalyst was added in an amount of ½ of that of the other examples (Example 7), the selectivity to the enantioselectivity was slightly increased but the reaction activity was somewhat lowered.

Example  8 to 10 and Comparative Example  3

(Examples 8 to 10) obtained by catalytic reaction using various malonic acids (2) under the same conditions as in Example 6 showing the best reaction activity and enantioselectivity in Experimental Example 1 To investigate the reaction activity and enantioselectivity, the reaction was carried out as shown in the following Reaction Scheme 4 to obtain colorless chroman-2-ol (3). For comparison, chroman-2-ol (Comparative Example 3) was obtained using malonitrile as a nucleophilic agent. The reaction compositions and conditions according to each Example (including Example 6) and Comparative Example are shown in Table 3 together with the yield of the obtained chroman-2-ol.

Example 8: Diethyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (3b)

_{^{[α] 22 D -42.5 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.09-7.28 (m, 2H), 6.84-6.91 (m, 2H), 5.71 (brs, 0.6H) , 5.62 (brs, 0.4H), 4.28 (d, J = 9.2 Hz, 0.4H), 4.12-4.22 (m, 4H), 3.97 (d, J = 7.2 Hz, 0.6H), 3.71-3.88 1H), 3.53 (d, J = 4.8 Hz, 0.4H), 3.20 (d, J = 4.0 Hz, 0.6H), 2.29-2.42 (m, 6 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.9 (minor), 168.5 (minor), 168.4 (major), 167.9 (major), 152.3 (minor), 152.1 (major), 128.6 (minor), 128.4 (major), Minor, 127.3, major, 121.9, major, 120.9, major, 117.3 minor, 92.8 major, 91.5 minor, 61.7 minor, 61.5 minor, 61.4 major, 56.0 minor, 54.7 major, 32.4 minor, 31.1 major, 30.5 major, 30.4 minor, 14.0; ^{HRMS: [M +] Calcd for} C 16 H 20 O 6: 308.1260 Found: 308.1264.

Example 9: Diisopropyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (3c)

_{^{[α] 22 D -34.1 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.12-7.28 (m, 2H), 6.82-6.90 (m, 2H), 5.70 (dd, J = 4.4 , 7.2 Hz, 0.6H), 5.57 (dd, J = 4.8, 8.0 Hz, 0.4H), 4.98-5.09 (m, 2H), 4.16 (d, J = 8.4 Hz, 0.4H), 3.92 (d, J = 7.2 Hz, 0.6H), 3.71-3.87 (m, 1.4H), 3.41 (d, J = 4.0 Hz, 0.6H), 2.30-2.42 -1.30 (m, 12H); ^{13 C NMR (100 MHz, CDCl} 3) 169.6 (minor), 169.0 (minor), 168.0 (major), 167.5 (major), 128.5 (minor), 128.3 (major), 128.2 (minor), 127.3 (major), (Major), 122.1 (minor), 120.9 (major), 117.3 (minor), 93.0 (minor), 91.5 (major), 69.4 (major), 69.3 (minor), 69.1 (minor), 69.0 Minor, 55.0, minor, 30.8 major, 30.7 minor, 21.43 minor, 21.61 major, 21.57 minor, 21.5 major; ^{HRMS: [M +] Calcd for} C 18 H 24 O 6: 336.1573 Found: 336.1577.

Example 10: Dibenzyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (3d)

(m, 2H), 5.64 (brs, 0.6H), [delta] ²² _D -28.2 (c 1.0, CHCl ₃ ), ¹ H NMR (400 MHz, CDCl ₃ ) 7.02-7.36 , 5.59 (brs, 0.4H), 5.06-5.18 (m, 4H), 4.45 (d, J = 9.2 Hz, 0.4H), 4.13 (d, J = 7.2 Hz, 0.6H), 3.74-3.92 1H), 3.56 (d, J = 4.0 Hz, 0.4H), 3.34 (d, J = 4.0 Hz, 0.6H), 2.27-2.36 (m, 1H), 2.00-2.17 (m, 1H); ^{13 C NMR (100 MHz, CDCl} 3) 168.8 (minor), 168.2 (minor), 168.1 (major), 167.7 (major), 152.2 (minor), 152.1 (major), 135.1 (minor), 135.0 (major), (Major), 127.1 (minor), 122.2 (major), 121.6 (minor), 120.1 (major), 120.0 (minor), 128.0, 128.7, 128.61, 128.57, 128.55, 128.49, 128.42, 128.39, 128.35, 128.3, 128.2, (Major), 117.4 (minor), 92.7 (minor), 91.4 (major), 124.1 (major), 121.1 (major), 121.0 (minor), 117.1 (major), 117.0 (Major), 67.5 (major), 67.4 (minor), 67.3 (major), 67.2 (minor), 56.0 (major), 54.5 (minor), 32.6 (minor), 31.2 (major), 30.2 30.1 (minor); HRMS: [M ⁺ ] ^Calcd for C ₂₆ H ₂₄ O ₆ : 432.1573 Found: 432.1580.

[Reaction Scheme 4]

Experimental Example  2

The chroman-2-ol obtained in Examples 8 to 10 was measured for its enantioselectivity by the same method as Experimental Example 1, and the results are shown in Table 4 below. The HPLC conditions in each example are as follows.

Example 8: AD-H column and AD-H guard column, 5% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 6.1 min and major- isomer t _r = 26.4 min.

Example 9: AD-H column and AD-H guard column, 5% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 5.4 min and major- isomer t _r = 13.9 min.

Example 10: AD-H column and AD-H guard column, 5% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 27.9 min and major- isomer t _r = 45.8 min.

Referring to Table 4, it can be seen that when various malonic acids including dimethyl, diethyl, diisopropyl and dibenzyl esters are used, they show high reactivity and excellent enantioselectivity. In the case of malonic acid containing benzyl ester (Example 10) It can be seen that the most excellent mirror image selectivity is exhibited. On the other hand, referring to Table 3, it can be seen that when malononitrile is used as the nucleophilic agent, the yield is as low as 23%.

Example  11 to 18

The reaction activity of the resulting chroman-2-ol obtained by catalytic reaction using various ortho-hydroxycinnamaldehyde (1) under the same conditions as in Example 6 showing the most excellent reaction activity and enantioselectivity in Experimental Example 1 (4) to obtain colorless chroman-2-ol (4). The reaction composition and conditions according to each example are shown in Table 5 together with the yield of the obtained chroman-2-ol.

Example 11: Dimethyl 2 - ((4R ) -6-chloro-3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (4a)

_{^{[α] 22 D -9.1 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.03-7.15 (m, 2H), 6.75-6.81 (m, 1H), 5.68 (dd, J = 3.2 , 5.2 Hz, 0.6H), 5.63 (dd, J = 2.8, 6.0 Hz, 0.4H), 4.35 (d, J = 9.6 Hz, 0.4H), 3.98 (d, J = 7.2 Hz, 0.6H), 3.65 (S, 3H), 3.58 (brs, 0.4H), 3.39 (brs, 0.6H), 2.28-2.37 (m, 1H), 2.01-2.16 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.4 (minor), 168.6 (minor), 168.5 (major), 168.0 (major), 150.8 (minor), 150.6 (major), 128.8 (minor), 128.5 (major), Minor, 126.8 major, 125.6 major, 125.6 minor, 123.9 major, 123.0 minor, 118.9 major, 118.8 minor, 92.5 minor, 91.5 major, 55.8 (minor), 54.1 (major), 53.5 (minor), 52.9 (minor), 52.8 (major), 52.7 (major), 32.3 (minor), 31.0 (major), 30.0 (major), 29.5 (minor); ^{HRMS: [M +] Calcd for} C 14 H 15 ClO 6: 314.0557 Found: 314.0562.

Example 12: Dimethyl 2 - ((4R ) -6-bromo-3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (4b).

_{^{[α] 22 D 11.3 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.17-7.27 (m, 2H), 6.75 (d, J = 4.4 Hz, 0.6H), 6.73 (d, J = 4.4 Hz, 0.4H), 5.67 (dd, J = 2.8, 5.2 Hz, 0.6H), 5.64 (brs, 0.4H), 4.35 (d, J = 9.6 Hz, 0.4H), 3.96 (d, J 2H), 3.76 (s, 2H), 3.76 (s, 2H), 3.76 (brs, 0.4H), 3.42 (brs, 0.6H), 2.27-2.36 (m, 1H), 2.02-2.36 (m, 1H); ^{13 C NMR (100 MHz, CDCl} 3) 169.4 (minor), 168.6 (major), 168.5 (major), 168.0 (minor), 151.3 (major), 151.1 (minor), 131.6 (minor), 131.4 (major), Major, 129.5, Major, 123.6, Major, 119.2, 113.1 Major, 112.9 Minor, 92.5 Major, 91.4 Major, 55.8 (minor), 54.2 (major), 52.8 (major), 52.7 (minor), 52.6, 32.2 (minor), 31.1 (major), 30.0 (major), 29.5 (minor); ^{HRMS: [M +] Calcd for} C 14 H 15 BrO 6: 358.0052 Found: 358.0057.

Example 13: Dimethyl 2 - ((4R ) -6,8-dichloro-3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (4c)

_{^{[α] 22 D -24.8 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 7.25-7.33 (m, 1H), 7.06 (d, J = 2.4 Hz, 0.6H), 6.97 (d , J = 2.0 Hz, 0.4H) , 5.83 (dd, J = 3.2, 4.4 Hz, 0.6H), 5.79 (dd, J = 2.8, 5.6 Hz, 0.4H), 4.38 (d, J = 10.4 Hz, 0.4 H), 3.99 (d, J = 6.8 Hz, 0.6H), 3.58-3.85 (m, 2H), 3.78 (s, 1.2H), 2.33 - 2.42 (m, 1H), 2.05 - 2.16 (m, 1H); ^{13 C NMR (100 MHz, CDCl} 3) 169.2, 168.4, 168.3, 167.9, 146.9, 146.7, 129.7, 129.4, 129.1, 128.8, 127.2, 127.0, 125.6, 125.4, 123.2, 123.0, 93.0, 92.0, 55.7, 53.4, 53.0, 52.9, 52.8, 52.7, 32.3, 31.0, 29.6, 29.1; ^{HRMS: [M +] Calcd for} C 14 H 14 Cl 2 O 6: 348.0167 Found: 348.0175.

Example 14: Dimethyl 2 - ((4R ) -6,8-dibromo-3,4-dihydro-2-hydroxy-2 H -chromen-4-yl) malonate (4d)

J = 2.4 Hz, 0.4H), 7.55 (d, J = 2.0 Hz, 0.6H), [?] ²² _D -18.2 (c 1.0, CHCl ₃ ), ¹ H NMR (400 MHz, CDCl ₃ ) 7.58 , 7.23 (d, J = 2.0 Hz, 0.6H), 7.14 (d, J = 1.6 Hz, 0.4H), 5.77-5.87 (m, 1H), 4.13 (d, J = 6.8 Hz, 0.4H), 3.98 (d, J = 7.2 Hz, 0.6H), 3.66-3.91 (m, 2H), 3.78 (s, 1.2H), 3.76 H), 2.31-2.39 (m, 1 H), 2.03-2.14 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.3 (minor), 168.4 (minor), 168.3 (major), 167.9 (major), 148.3 (major), 148.1 (minor), 134.6 (minor), 134.3 (major), (Minor), 129.1 (major), 126.0 (major), 124.8 (minor), 112.9 (minor), 112.6 (minor), 112.5 (major), 112.4 (major), 93.1 (minor), 92.2 55.8 (minor), 53.8 (major), 53.0 (major), 52.9 (minor), 52.8 (major), 52.7 (minor), 32.5 (minor), 31.2 (major), 29.7 (major), 29.1 (minor); ^{HRMS: [M +] Calcd for} C 14 H 14 Br 2 O 6: 435.9157 Found: 435.9178.

Example 15: Dimethyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-6-nitro-2 H -chromen-4-yl) malonate (4e)

_{^{[α] 22 D 25.4 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 8.00-8.10 (m, 2H), 6.92 (d, J = 9.2 Hz, 0.4H), 6.91 (d, J = 8.8 Hz, 0.6H), 5.77 (brs, 0.6 H), 5.74 (brs, 0.4H), 4.39 (d, J = 10.0 Hz, 0.4H), 4.08 (d, J = 6.8 Hz, 0.6H) (M, 2H), 3.79 (s, 2H), 3.79 (s, , 2.06-2.20 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.0 (minor), 168.4 (minor), 168.3 (major), 167.9 (major), 157.9 (major), 157.7 (minor), 141.4 (major), 141.2 (minor), (Minor), 124.8 (minor), 124.5 (major), 123.3 (major), 123.0 (major), 122.0 (minor), 118.2 (major), 118.1 (minor), 93.2 (minor), 92.0 55.6 minor, 53.7 major, 53.1 major, 53.0 minor, 52.9 minor, 52.8 major, 32.2 minor, 30.6 major, 29.4 major, 29.1 minor; ^{HRMS: [M +] Calcd for} C 14 H 15 NO 8: 325.0798 Found: 325.0795.

Example 16: Dimethyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-6-methyl-2 H -chromen-4-yl) malonate (4f)

_{^{[α] 22 D -23.6 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 6.73-6.99 (m, 3H), 5.65 (dd, J = 4.8, 7.2 Hz, 0.6H), 5.60 (d, J = 3.6,6.8 Hz, 0.4H), 4.36 (d, J = 9.6 Hz, 0.4H), 3.99 (d, J = 7.6 Hz, 0.6H), 3.64-3.81 3.75 (s, 1.2H), 3.73 (s, 1.8H), 3.71 (s, 1.8H), 3.69 (s, 1.2H), 3.55 (d, J = 4.8 Hz, 0.6H), 2.21-2.37 (m , ≪ / RTI > 1H), 2.25 (s, 3H), 1.98-2.16 (m, 1H); ^{13 C NMR (100 MHz, CDCl} 3) 169.6 (minor), 168.9 (major), 168.8 (minor), 168.3 (major), 149.9 (major), 149.7 (minor), 130.2 (major), 130.1 (minor), 129.4 minor, 129.1 major, 128.7 minor, 127.5 major, 121.9 major, 121.2 minor, 117.2 major, 117.1 minor, 92.6 minor, 91.4 major, Major, 52.6, minor, 52.4, minor, 32.5, major, 30.6, major, minor, minor, 52.6, 20.7 (major), 20.6 (minor); ^{HRMS: [M +] Calcd for} C 15 H 18 O 6: 294.1103 Found: 294.1105.

Example 17: Dimethyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-6-methoxy-2 H -chromen-4-yl) malonate (4g)

_{^{[α] 22 D -22.5 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 6.72-6.81 (m, 2H), 6.69 (d, J = 2.8 Hz, 0.6H), 6.62 (d , J = 2.8 Hz, 0.4H) , 5.66 (dd, J = 4.0, 7.2 Hz, 0.6H), 5.60 (dd, J = 3.6, 6.8 Hz, 0.4H), 4.35 (d, J = 9.6 Hz, 0.4 H), 4.00 (d, J = 7.2 Hz, 0.6H), 3.67-3.81 (m, 1H), 3.79 (s, 3H), 3.74 (s, 1.8H), 3.73 (s, 1.2H), 3.72 ( s, 1.8H), 3.71 (s , 1.2H), 3.46 (d, J = 3.6 Hz, 0.4H), 3.22 (d, J = 4.0 Hz, 0.6H), 2.24-2.37 (m, 1H), 1.99 -2.17 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.5 (minor), 168.8 (minor), 168.7 (major), 168.2 (major), 153.7 (major), 153.6 (minor), 146.0 (major), 145.9 (minor), Major, 122.2 (minor), 118.1 (major), 118.0 (minor), 114.9 (minor), 114.3 (major), 112.9 (minor), 112.1 (major), 92.6 (minor), 91.4 55.9 (major), 52.8 (major), 52.7 (minor), 52.6 (minor), 52.5 (major), 32.7 (minor), 31.6 (major), 30.5 (major), 30.1 ); ^{HRMS: [M +] Calcd for} C 15 H 18 O 7: 310.1053 Found: 310.1055.

Example 18: Dimethyl 2 - ((4R ) -3,4-dihydro-2-hydroxy-8-methoxy-2 H -chromen-4-yl) malonate (4h)

_{^{[α] 22 D -51.9 (c}} 1.0, CHCl 3), 1 H NMR (400 MHz, CDCl 3) 6.64-7.28 (m, 4H), 5.82 (brs, 0.6H), 5.77 (d, J = 2.8 Hz , 0.4H), 4.42 (d, J = 10.0Hz, 0.4H), 4.04 (d, J = 7.2Hz, 0.6H), 3.81-3.93 2H), 3.76 (s, 1H), 3.76 (s, 2H), 3.74 (m, 1 H), 2.03-2.17 (m, 1 H); ^{13 C NMR (100 MHz, CDCl} 3) 169.6 (minor), 168.8, 168.2 (major), 148.5 (major), 148.3 (minor), 141.4 (major), 141.3 (minor), 123.2 (major), 122.3 (minor ), 120.5 (major), 120.4 (minor), 120.3 (minor), 118.7 (major), 110.3 (minor), 110.2 (major), 92.7 (minor), 91.6 (major), 56.0 (major), 52.7 (major), 52.6 (minor), 52.50 (minor), 52.48 (major), 32.3 (minor), 31.0 (major), 30.0 (major), 29.5 (minor); ^{HRMS: [M +] Calcd for} C 15 H 18 O 7: 310.1053 Found: 310.1051.

[Reaction Scheme 5]

Experimental Example  3

The chroman-2-ol obtained in Examples 11 to 18 was measured for its enantioselectivity in the same manner as in Experimental Example 1, and the results are shown in Table 6 below. The HPLC conditions in each example are as follows.

Example 11: AD-H column and AD-H guard column, 10% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 31.8 min and major- isomer t _r = 41.4 min.

Example 12: AD-H column and AD-H guard column, 20% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); major- isomer t _r = 29.5 min and minor minor t _r = 43.5 min.

Example 13: AD-H column and AD-H guard column, 20% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); major- isomer t _r = 23.3 min and minor minor is t _r = 46.3 min.

Example 14: AD-H column and AD-H guard column, 10% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); major- isomer t _r = 35.3 min and minor minor t _r = 51.3 min.

Example 15: AD-H column and AD-H guard column, 2% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 40.8 min and major- isomer t _r = 43.8 min.

Example 16: AD-H column and AD-H guard column, 5% EtOH: hexanes, 1.0 ml / min flow, λ = 220 nm); minor- isomer t _r = 23.8 min and major- isomer t _r = 28.4 min.

Example 17: AD-H column and AD-H guard column, 2% EtOH: hexanes, 0.5 ml / min flow, λ = 220 nm); major- isomer t _r = 71.7 min and minor minor is t _r = 78.9 min.

Example 18: AD-H column and AD-H guard column, 5% EtOH: hexanes, 0.5 ml / min flow, λ = 220 nm); major- isomer t _r = 43.0 min and minor minor is t _r = 48.4 min.

Referring to Table 6, it can be seen that asymmetric catalytic reaction of dimethyl malonic acid with various ortho-hydroxycinnamaldehydes resulted in good yield and excellent enantioselectivity for the selected ortho-hydroxycinnamaldehyde. In Examples 12 and 13, it exhibited an enantioselectivity of 99% or more. Specifically, the phenyl group substituent of ortho-hydroxycinnamic aldehyde has a high (e. G., High or low) electron donating property regardless of the electron-withdrawing properties (Examples 11 to 15) or the electron-donating properties (Examples 16 to 18) Indicating the mirror image selectivity. It is also noted that this reaction is not affected by steric hindrance (see Examples 13, 14 and 18).

Suggested Organization ( proposed mechanism )

The proposed mechanism of the organic catalytic conjugate addition-cyclization continuous reaction in the presence of the organic catalyst of malonic acid and ortho-hydroxycinnamaldehyde according to the present invention is shown in the following Reaction Scheme 6 Respectively.

[Reaction Scheme 6]

As shown in Reaction Scheme 6, the reaction sequence is a reaction in which ortho-hydroxycinnamaldehyde (1a) as an alpha, beta -unsaturated aldehyde forms an iminium ion (5) starting from the reaction with catalyst And iminium ions 5 are formed through enamine 6 formation through 1,4-addition reaction with dimethyl malonic acid 2a to form intermediate 7. Then, hydrolysis and cyclization are performed to produce chroman-2-ol (3a) and catalyst (II) is regenerated. Here, the non-patent literature 16 (L. Zu, S. Zhang , H. Xie, W. Wang, Org. Lett. 2009, 11, 1627) and a continuous ring which is isomerized in the already-carbon double bond from the hydronium ions (5) (8) is produced through the reaction of aminol (8) and aminal (8) acts as an active nucleophile in a Michael reaction with nitroolefin. However, in the present invention, The formation of aminals (8) was excluded from the reaction mechanism due to the reduced electrophilicity compared to the ion (5).

Modifications

The following Reaction Scheme 7 shows several modifications of the chroman-2-ol (3a) substituted at the 4-position according to Example 6 above.

[Reaction Scheme 7]

As shown in Reaction Scheme 7, the chroman-2-ol (3a) according to the present invention can be obtained by subjecting chroman-2-ol (3a) substituted at the 4-position of chirality through oxidation, reduction and Wittig reaction 9), chroman 10 substituted at the 4-position, and 2-hydroxyphenyl compound 11 can be obtained in high yield.

Absolute placement decisions ( determination of absolute configuration )

The following Reaction Scheme 8 shows absolute arrangement of croman-2-ol (3d) substituted at position 4 according to Example 10 above.

[Reaction Scheme 8]

As shown in Reaction Scheme 8, the absolute arrangement of the chroman-2-ol (3d) according to the present invention was determined as follows. Methylation of the alcoholic compound (12) yields the methyl ether compound (13), and the methyl ether compound (13) has a reliable sample derived from the compound (14) whose optical rotation determined by polarization analysis is known (-) - value in the same way.

The preferred embodiments of the present invention have been described in detail above. It will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.

Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing detailed description, and all changes or modifications derived from the meaning, range, and equivalence of the claims are included in the scope of the present invention Should be interpreted.

Claims (5)

A catalyst for conjugate addition reaction of malonate to ortho-hydroxycinnamaldehyde in the presence of diphenylprolinol TMS ether catalyst represented by the following formula 4 A process for producing optically active chroman-2-ol substituted at the 4-position represented by the following formula (3), which comprises a reaction step.
[Chemical Formula 4]

(3)

(R is an alkyl group or an aryl group, X a H or C 1 -C 14 H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3 , 4-MeO or 6-MeO) The method according to claim 1,
Wherein the malonic acid is represented by the following formula (1). ≪ / RTI >
[Chemical Formula 1]

(R is H or an alkyl or aryl group having 1 to 14 carbon atoms) The method according to claim 1,
Wherein the ortho-hydroxycinnamaldehyde is represented by the following general formula (2). ≪ / RTI >
(2)

(X is H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3, 4-MeO or 6-MeO) The method according to claim 1,
The optically active chroman-2-ol substituted at the 4-position is characterized in that the catalytic reaction proceeds in at least one solvent selected from the group consisting of dichloromethane, toluene, methanol and chloroform. Gt; An optically active chroman-2-ol substituted by 4-position represented by the following formula (3), prepared by the method of any one of claims 1 to 4.
(3)

(R is an alkyl group or an aryl group, X a H or C 1 -C 14 H, 4-Cl, 4- Br, 4,6-Cl 2, 4,6-Br 2, 4-NO 2, 4-CH 3 , 4-MeO or 6-MeO)