KR101380982B1 - Chroman-2-ol Derivatives Having Optical Avtivity and Their Preparation Methods - Google Patents

Chroman-2-ol Derivatives Having Optical Avtivity and Their Preparation Methods Download PDF

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KR101380982B1
KR101380982B1 KR1020130047506A KR20130047506A KR101380982B1 KR 101380982 B1 KR101380982 B1 KR 101380982B1 KR 1020130047506 A KR1020130047506 A KR 1020130047506A KR 20130047506 A KR20130047506 A KR 20130047506A KR 101380982 B1 KR101380982 B1 KR 101380982B1
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김성곤
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경기대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
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    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
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    • B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract

본 발명은 크로만(Chromane)과 디하이드로벤조피란(dihydrobenzopyrane)을 얻을 수 있는 제조방법에 관한 것으로, o-하이드록시신남알데하이드 유도체에 유기브롬산의 촉매 적 비대칭 1, 4-첨가 반응을 이미다졸리디논으로부터 유래한 유기촉매를 이용하여 수행한 것이다. 상기 방법은 크로만을 높은 화학적 수득률과 거울상 이성질체를 선택적으로 얻을 수 있고, 이것의 계속되는 변형을 통하여 다양한 크로만계 유도체를 제조할 수 있다. The present invention relates to a process for the production of Chromane and dihydrobenzopyrane, and to the catalytic asymmetric 1,4-addition reaction of organobromic acid to o -hydroxycinnamaldehyde derivatives. It is carried out using an organic catalyst derived from zolidinones. The process can selectively obtain high chemical yield and enantiomers of Chromman, and through its continuous modification, various chroman-based derivatives can be prepared.

Description

광학활성을 갖는 크로만-2-올 유도체 및 이의 제조방법 {Chroman-2-ol Derivatives Having Optical Avtivity and Their Preparation Methods}Chroman-2-ol Derivatives Having Optical Avtivity and Their Preparation Methods

본 발명은 유기브론산과 알데하이드의 비대칭적인 유기촉매 첨가반응에 의하여 광학활성을 갖는 크로만계 유도체 및 이의 제조방법에 관한 것이다.
The present invention relates to a Chromane derivative having optical activity by the asymmetric organic catalyst addition reaction of organobronic acid and aldehyde and a method for preparing the same.

크로만 혹은 디하이드로벤조피란은 많은 생물학적 활성 천연물에서 널리 발견된다. 이러한 크로만 작용기를 포함하는 분자들은 항바이러스성, 항종양, 항균성, 성페로몬 및 중추신경계 활성과 같은 넓은 범위의 생물활성을 나타낼 뿐만 아니라, 생분해성 농약 및 광-활성 물질로도 이용된다(참조문헌: (a) Ellis, G. P.; Lockhart, I. M. The Chemistry of Heterocyclic Compounds , Chromenes , Chromanones, and Chromones; Ellis, G. P., Ed.; Wiley-VCH; New York, 2007; Vol. 31, pp. 1-1196. (b) Geen, G. R.; Evans, J. M.; Vong, A. K. Comprehensive Heterocyclic Chemistry II : Pyrans and their Benzo Derivatives : Applications; Katritzky, A. R. ; Rees, C. W. ; Scriven, E. F. V., Eds.; Pergamon Press, Oxford, UK, 1996; Vol. 5, pp. 469-500. (c) Horton, D. A.; Boume, G. T.; Smythe, M. L. Chem . Rev . 2003, 103, 893-930).Chroman or dihydrobenzopyran is widely found in many biologically active natural products. Molecules containing these Kroman functional groups exhibit a wide range of bioactivity such as antiviral, antitumor, antimicrobial, sex pheromone and central nervous system activity, as well as biodegradable pesticides and photo-active substances (see Literature: (a) Ellis, GP; Lockhart, IM The Chemistry of Heterocyclic Compounds , Chromenes , Chromanones, and Chromones ; Ellis, GP, Ed .; Wiley-VCH; New York, 2007; Vol. 31, pp. 1-1196. (b) Geen, GR; Evans, JM; Vong, AK Comprehensive Heterocyclic Chemistry II : Pyrans and their Benzo Derivatives : Applications ; Katritzky, AR; Rees, CW; Scriven, EFV, Eds .; Pergamon Press, Oxford, UK, 1996; Vol. 5, pp. 469-500. (c) Horton, DA; Boume, GT; Smythe, ML Chem . Rev. 2003, 103 , 893-930).

이러한 구조적 중요성 때문에, 많은 크로만 합성방법이 보고되었으며, 최근에는 특히 거울상 이성질체를 선택적으로 합성하는 접근방법이 주목을 받고 있다 (참조문헌: (a) Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org . Lett. 2009, 11, 991-994. (b) Yamamoto, Y.; Itonaga, K. Org . Lett. 2009, 11, 717-720. (c) Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org . Chem. 2007, 72, 6056-6059. (d) Jagdale, A.; Sudalai, R. A. Tetrahedron Lett . 2007, 48, 4895-4898. (e) Li, K.; Vanka, K.; Thompson, W. H.; Tunge, J. A. Org . Lett. 2006, 8, 4711-4714. (f) Hedberg, C.; Andersson, P. G. Adv . Synth . Catal. 2005, 347, 662-666. (g) Li, K.; Tunge, J. A. J. Org . Chem. 2005, 70, 2881-2883. (h) Shi, Z.; He. C. J. Am . Chem . Soc. 2004, 126, 13596-13597. (i) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. J. Am . Chem . Soc. 2004, 126, 3416-3417. (j) Youn, S. W.; Pastine, S. J.; Sames, D. Org . Lett. 2004, 6, 581-584). 본 발명에서 본 발명자들은 유기촉매를 사용하여 o-하이드록시신남알데하이드와 유기브론산으로부터 크로만과 디하이드로벤조피란을 비대칭적으로 합성할 수 있는 예를 제공한다.
Because of this structural importance, a number of Kromaman synthesis methods have been reported, and in recent years, the approach of selectively synthesizing enantiomers has attracted attention (see (a) Meng, X .; Huang, Y .; Zhao, H .; Xie, P .; Ma, J .; Chen, R. Org . Lett . 2009, 11 , 991-994. (B) Yamamoto, Y .; Itonaga, K. Org . Lett . 2009, 11 , 717 (C) Ulgheri, F .; Marchetti, M .; Piccolo, O. J. Org . Chem . 2007, 72 , 6056-6059. (D) Jagdale, A .; Sudalai, RA Tetrahedron. Lett . 2007, 48 , 4895-4898. (e) Li, K .; Vanka, K .; Thompson, WH; Tunge, JA Org . Lett . 2006, 8 , 4711-4714. (f) Hedberg, C .; Andersson, PG Adv . Synth . Catal . 2005, 347 , 662-666. (g) Li, K .; Tunge, JA J. Org . Chem . 2005, 70 , 2881-2883. (h) Shi, Z .; He. C. J. Am . Chem . Soc . 2004, 126 , 13596-13597. (i) Barluenga, J .; Trincado, M .; Rubio, E .; Gonzalez, JM J. Am . Chem . Soc . 2004, 126 , 3416-3417. (j) Youn, SW; Pastine, SJ; Sames, D. Org . Lett . 2004, 6 , 581-584). In the present invention, the present inventors provide an example of asymmetric synthesis of chromman and dihydrobenzopyran from o -hydroxycinnamaldehyde and organobronic acid using an organic catalyst.

본 발명의 목적은 유기촉매를 이용하여 o-하이드록시신남알데하이드 유도체에 유기브론산의 촉매적 비대칭 1,4-첨가 반응으로 광학활성을 갖는 다양한 크로만계 유도체 및 상기 유도체를 거울상 선택적으로 순수한 형태로 만드는 제조방법을 제공하는 것이다.
An object of the present invention is to enantioselectively pure a variety of Chroma-based derivatives having optical activity by catalytic asymmetric 1,4-addition reaction of organobronic acid to o -hydroxycinnamaldehyde derivatives using an organic catalyst. It is to provide a manufacturing method.

상기 목적을 달성하기 위한 본 발명은 하기 화학식 2의 화합물을 화학식 1의 유기촉매하에서 하기 화학식 3의 화합물과 반응시키는 단계를 포함하는 화학식 4의 크로만계 유도체 제조방법을 제공한다.The present invention for achieving the above object provides a method for producing a Chroma-based derivative of the formula ( 4) comprising the step of reacting a compound of the formula ( 2) with a compound of the formula ( 3) under an organic catalyst of the formula ( 1 ).

<화학식 1>&Lt; Formula 1 >

Figure 112013037728959-pat00001

Figure 112013037728959-pat00001

<화학식 2>(2)

Figure 112013037728959-pat00002
Figure 112013037728959-pat00002

(상기 화학식 2에서, (In the formula (2)

X는 수소, 메틸기, 메톡시기, 시아노기 또는 할로젠기이다.)
X is hydrogen, methyl group, methoxy group, cyano group or halogen group.)

<화학식 3>(3)

Figure 112013037728959-pat00003
Figure 112013037728959-pat00003

(상기 화학식 3에서, (3)

R은 탄소수 은 탄소수 4 내지 8 퓨란기, 티오페닐기, 알킬 또는 알콕시기로 치환된 피롤기이다.)
R is a pyrrole group substituted with a silver carbon atom having 4 to 8 furan groups, a thiophenyl group, an alkyl or an alkoxy group.)

<화학식 4>&Lt; Formula 4 >

Figure 112013037728959-pat00004
Figure 112013037728959-pat00004

(상기 화학식 4에서, X는 수소, 메틸기, 메톡시기, 시아노기, 할로젠기로 이루어진 그룹에서 선택된 어느 하나의 작용기이고, R은 탄소수 4 내지 8 퓨란기, 티오페닐기, 알킬 또는 알콕시기로 치환된 피롤기이다.)
(In Formula 4, X is any functional group selected from the group consisting of hydrogen, methyl group, methoxy group, cyano group, halogen group, R is a blood substituted with 4 to 8 furan group, thiophenyl group, alkyl or alkoxy group) It's a roll machine.)

상기 촉매 반응은 0 내지 25 ℃의 유기용매에서 진행되고, 상기 유기 용매는 메틸렌 클로라이드, 벤젠, 디에틸 에테르, 아세톤, 아세토니트릴, 톨루엔 및 테트라하이드로퓨란으로 이루어진 군으로부터 선택된 단독 또는 이들의 혼합물일 수 있다.The catalytic reaction is carried out in an organic solvent of 0 to 25 ℃, the organic solvent may be a single or a mixture thereof selected from the group consisting of methylene chloride, benzene, diethyl ether, acetone, acetonitrile, toluene and tetrahydrofuran. have.

본 발명의 또 다른 형태는 상기 반응을 클로로포름 용매 중에 디클로로아세트산 또는 물을 가하여 수행하는 크로만계 유도체 제조방법을 제공한다. 또한, 상기 크로만계 유도체는 4-[2-(4-메톡시페닐)-비닐]-크로만-2-올, 4-[2-(4-메틸페닐)-비닐]-크로만-2-올, 4-[2-(4-클로로페닐)-비닐]-크로만-2-올, 4-[2-(4-플루오르페닐)-비닐]-크로만-2-올, 4-퓨란-2-일-크로만-2-올, 4-벤조퓨란-2-일-크로만-2-올, 4-티오펜-2-일-크로만-2-올 또는 2-(2-하이드록시-크로만-4-일)-피롤-1-카르복시산 테트라-부틸 에스테르인 것을 특징으로 하는 크로만계 유도체 제조방법을 제공한다.Another aspect of the present invention provides a method for preparing a chroman derivative, wherein the reaction is carried out by adding dichloroacetic acid or water in a chloroform solvent. In addition, the Chroma-based derivative 4- [2- (4-methoxyphenyl) -vinyl] -chroman-2-ol, 4- [2- (4-methylphenyl) -vinyl] -chroman-2-ol, 4- [2- ( 4-Chlorophenyl) -vinyl] -chroman-2-ol, 4- [2- (4-fluorophenyl) -vinyl] -chroman-2-ol, 4-furan-2-yl-chroman-2 -Ol, 4-benzofuran-2-yl-chroman-2-ol, 4-thiophen-2-yl-chroman-2-ol or 2- (2-hydroxy-chroman-4-yl) It provides a method for producing a chroman derivative, characterized in that it is -pyrrole-1-carboxylic acid tetra-butyl ester.

본 발명의 또 다른 형태는 상기 제조방법에 의하여 제조된 크로만계 유도체를 키랄셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ = 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하는 단계를 더 포함하는 것을 특징으로 하는 크로만계 유도체 제조방법을 제공한다.
In still another aspect of the present invention, the Chromane derivatives prepared according to the above-described method are used in a Chiralcel AD-H column and an AD-H guard column (5% i −). PrOH: hexane, 1.0 mL / min flow rate, λ = 220 nm) to provide a method for producing a chromamann derivative characterized in that it further comprises the step of determining the enantiomer selectivity.

유기촉매를 이용하여 o-하이드록시신남알데하이드에 유기브론산의 촉매적 비대칭 1,4-첨가 반응으로 광학활성을 갖는 다양한 크로만-2-올 유도체를 합성할 수 있다. 본 발명의 방법은 상기 크로만의 높은 화학적 수득률과 거울상 이성질체를 선택적으로 얻을 수 있으며, 이의 계속되는 변형을 통하여 다양한 크로만-2-올 유도체를 합성할 수 있다.
The organic catalyst can be used to synthesize various chroman-2-ol derivatives having optical activity by the catalytic asymmetric 1,4-addition reaction of organobromic acid to o -hydroxycinnamaldehyde. The method of the present invention can selectively obtain the high chemical yield and enantiomer of the chroman, and through its continuous modification, various chroman-2-ol derivatives can be synthesized.

이하, 당업자가 용이하게 실시할 수 있도록 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail so that those skilled in the art can easily practice.

본 발명의 광학 활성을 가지는 크로만-2-올 유도체 및 이의 제조방법은 촉매 반응 단계를 포함한다. 상기 방법에 의해 중금속 촉매를 사용하지 않고 종래보다 간단한 공정으로 거울상 선택성이 높은 키랄 크로만-2-올 유도체를 높은 수율로 합성할 수 있다.Chromman-2-ol derivative having optical activity of the present invention and a method for preparing the same include a catalytic reaction step. By the above method, a chiral chroman-2-ol derivative having high enantioselectivity can be synthesized in a high yield by a simpler process without using a heavy metal catalyst.

상기 촉매 반응 단계는 유기브론산을 o-하이드록시신남알데하이드 유도체에 키랄 아민 촉매의 존재하에 1,4-첨가반응시키는 단계이다.
The catalytic reaction step is a step of reacting organobronic acid with 1,4-addition of an o -hydroxycinnamaldehyde derivative in the presence of a chiral amine catalyst.

상기 키랄 아민 촉매는 하기 화학식 1로 표현될 수 있다. The chiral amine catalyst may be represented by the following formula (1).

<화학식 1>&Lt; Formula 1 >

Figure 112013037728959-pat00005

Figure 112013037728959-pat00005

상기 o-하이드록시신남알데하이드 유도체는 하기 화학식 2로 표현될 수 있다.The o -hydroxycinnamaldehyde derivative may be represented by the following Chemical Formula 2 .

<화학식 2>(2)

Figure 112013037728959-pat00006
Figure 112013037728959-pat00006

(상기 화학식 2에서, (In the formula (2)

X는 수소, 메틸기, 메톡시기, 시아노기 또는 할로젠기이다.
X is hydrogen, a methyl group, a methoxy group, a cyano group, or a halogen group.

상기 유기브론산은 하기 화학식 3으로 표현될 수 있다.The organobronic acid may be represented by the following Chemical Formula 3 .

<화학식 3>(3)

Figure 112013037728959-pat00007
Figure 112013037728959-pat00007

(상기 화학식 3에서,(3)

R은 탄소수 은 탄소수 4 내지 8 퓨란기, 티오페닐기, 알킬 또는 알콕시기로 치환된 피롤기이다.)
R is a pyrrole group substituted with a C4 to C8 furan group, a thiophenyl group, an alkyl or an alkoxy group.)

상기 키랄 크로만-2-올 유도체는 하기 화학식 4로 표현될 수 있다.The chiral chroman-2-ol derivative may be represented by the following formula (4).

<화학식 4>&Lt; Formula 4 >

Figure 112013037728959-pat00008
Figure 112013037728959-pat00008

(상기 화학식 4에서,X는 수소, 메틸기, 메톡시기, 시아노기, 할로젠기로 이루어진 그룹에서 선택된 어느 하나의 작용기이고, R은 탄소수 4 내지 8 퓨란기, 티오페닐기, 알킬 또는 알콕시기로 치환된 피롤기이다.)
(In Formula 4, X is any functional group selected from the group consisting of hydrogen, methyl group, methoxy group, cyano group, halogen group, R is a blood substituted with 4 to 8 furan group, thiophenyl group, alkyl or alkoxy group It's a roll machine.)

상기 유기브론산과 상기 o-하이드록시신남알데하이드 유도체는 1:1 내지 1:3의 몰비로 반응시킬 수 있다. 1:1 보다 낮은 비율로 반응시키는 경우 아릴브론산 또는 아릴비닐브론산의 1,4-첨가반응이 제대로 일어나지 않아 수율이 낮으며, 1:3 을 초과하는 경우 수율의 향상이 크지 않아 효율적이지 못하다.The organobronic acid and the o -hydroxycinnamaldehyde derivative may be reacted in a molar ratio of 1: 1 to 1: 3. When reacting at a ratio lower than 1: 1, the yield is low because 1,4-addition reaction of arylbronic acid or arylvinylbronic acid does not occur properly, and when the ratio is greater than 1: 3, the yield is not large and is not efficient. .

상기 키랄 아민 촉매는 유기브론산에 대하여 10 내지 30 몰% 로 첨가할 수 있다. 10몰% 미만으로 첨가되면 촉매 반응이 제대로 일어나지 않아 반응의 수율이 낮으며, 30몰% 를 초과하여 첨가되는 경우 반응의 수율의 증가가 미미하여 효율적이지 못하다.
The chiral amine catalyst may be added in an amount of 10 to 30 mol% based on the organobronic acid. If the amount is less than 10 mol%, the catalytic reaction does not occur properly, and the yield of the reaction is low. When the amount is added more than 30 mol%, the increase in the yield of the reaction is inefficient and inefficient.

하기 반응식 1은 상기 촉매 반응을 간략히 나타낸 것이다:Scheme 1 below outlines the catalytic reaction:

[반응식 1][Reaction Scheme 1]

Figure 112013037728959-pat00009

Figure 112013037728959-pat00009

상기 반응식 1을 참조하면, 상기 유기브론산은 상기 키랄 아민 촉매 존재하에 o-하이드록시신남알데하이드 유도체에 1,4-첨가반응을 하여 키랄 크로만-2-올 유도체를 생성된다. Referring to Scheme 1, the organobronic acid is subjected to 1,4-addition reaction to o -hydroxycinnamaldehyde derivative in the presence of the chiral amine catalyst to generate a chiral chroman-2-ol derivative.

상기 촉매 반응은 -10℃ 내지 25℃에서 유기용매하에서 진행된다. 바람직하게는 상온에서 진행될 수 있다. -10℃보다 낮은 온도에서 진행될 경우 반응 속도가 느려 반응시간이 길어지며, 25℃보다 높은 온도에서 진행될 경우 반응이 조기에 종결되어 반응 수율이 감소할 수 있다. The catalytic reaction proceeds under an organic solvent at -10 ° C to 25 ° C. Preferably it can be carried out at room temperature. When the reaction temperature is lower than -10 ° C, the reaction rate is slow and the reaction time is long. When the reaction temperature is higher than 25 ° C, the reaction may be terminated prematurely and the reaction yield may decrease.

상기 유기용매는 메틸렌 클로라이드, 클로로포름, 벤젠, 디에틸 에테르, 아세톤, 아세토니트릴, 톨루엔 및 테트라히드로푸란으로 이루어진 군으로부터 선택된 단독 또는 이들의 혼합물일 수 있다. 바람직하게는, 클로로포름이 사용될 수 있다. 상기 유기용매의 농도는 0.1 내지 1.0 M일 수 있으며, 바람직하게는 0.3 M일 수 있다. 0.1 M미만이면 반응속도가 느려질 수 있고, 1.0 M을 초과하면 반응물의 용해가 제대로 일어나지 않을 수 있다.The organic solvent may be alone or a mixture thereof selected from the group consisting of methylene chloride, chloroform, benzene, diethyl ether, acetone, acetonitrile, toluene and tetrahydrofuran. Preferably, chloroform can be used. The concentration of the organic solvent may be 0.1 to 1.0 M, preferably 0.3 M. If it is less than 0.1 M may slow down the reaction rate, if it exceeds 1.0 M may not properly dissolve the reactants.

상기 촉매 반응의 반응 시간은 반응물의 종류에 따라 당업자가 적절하게 선택할 수 있으나, 바람직하게는 24 내지 80시간 동안 반응시킬 수 있다. 24시간 미만으로 반응시키면 반응이 완결되지 않으며, 80시간을 초과하여 반응시키면 반응이 이전에 완결되는데 반해 반응시간만 길어지는 단점이 있다.The reaction time of the catalytic reaction can be appropriately selected by those skilled in the art according to the kind of reactant, but preferably can be reacted for 24 to 80 hours. If the reaction is less than 24 hours, the reaction is not completed, if the reaction is more than 80 hours, the reaction is completed before, but the reaction time is long.

상기 촉매 반응에 산을 첨가할 수 있다. 산을 첨가하는 경우 거울상 선택성이 증가된다. 상기 산은 당업계에 공지된 것이 제한없이 사용될 수 있으며, 구체적으로는 황산, 염산, 질산, 아세트산, 트리플루오르아세트산, 트리클로로아세트산, 디클로로아세트산, 벤조산 등이 있으며, 바람직하게는 디클로로아세트산을 사용할 수 있다. 상기 산의 농도는 당업자가 임의적으로 조절할 수 있으나, 사용되는 o-하이드록시신남알데하이드 유도체 양의 2 몰%로 첨가될 수 있다. 2 몰%보다 적은 양이 첨가되면 반응의 수율이 감소하며, 2몰%보다 많은 양이 첨가될 경우 부반응이 일어날 수 있다.
An acid may be added to the catalytic reaction. The addition of acid increases the enantioselectivity. The acid may be used without limitation as is known in the art, specifically, sulfuric acid, hydrochloric acid, nitric acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid, benzoic acid, and the like, preferably dichloroacetic acid may be used. . The concentration of the acid may be arbitrarily adjusted by those skilled in the art, but may be added in 2 mol% of the amount of o -hydroxycinnamaldehyde derivative used. If an amount of less than 2 mol% is added, the yield of the reaction is reduced, and if an amount of more than 2 mol% is added, side reactions may occur.

이하 실시예에 의하여 본 발명을 더욱 상세히 설명한다. 하기 실시예는 본 발명을 예시하는 것으로서 본 발명의 범위를 제한하는 것으로 해석해서는 안 될 것이다.
The present invention will be described in more detail with reference to the following examples. The following examples are illustrative of the invention and should not be construed as limiting the scope of the invention.

실시예Example 1 One

(4R)-4-스티릴-크로만-2-올((4R)-4-Styryl-chroman-2-ol)(4a)의 합성 (4R) -4- styryl-chroman-2-ol Synthesis of the ((4R) -4-Styryl- chroman-2-ol) (4a)

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 o-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (52 mg, 83% 수득률, 92:8 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. At 0 o C o - hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added 72 hours after 25% EtOAc / the title compound by silica gel chromatography in hexane to a white solid (52 mg, 83% yield stirred , 92: 8 er).

mp 127-128 oC ;mp 127-128 o C;

1H NMR (300 MHz, CDCl3) δ7.16-7.45 (m, 7H), 6.87-6.97 (m, 2H), 6.63 (d, J= 11.7 Hz, 0.75H), 6.59 (d, J= 12.0 Hz, 0.25H), 6.34 (dd, J = 6.0, 12.0 Hz, 0.25H), 6.21 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.72 (brs, 0.75H), 5.60 (dt, J = 5.1, 10.2 Hz, 0.25H), 3.93 (dt, J = 4.5, 7.5 Hz, 0.75H), 3.80 (dt, J = 4.8, 6.3 Hz, 0.25H), 3.24 (d, J = 5.1 Hz, 0.25H), 3.12 (brs, 0.75H), 2.37 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.25H), 2.21 (ddd, J = 2.7, 4.5, 10.2 Hz, 0.75H), 1.97-2.07 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ7.16-7.45 (m, 7H), 6.87-6.97 (m, 2H), 6.63 (d, J = 11.7 Hz, 0.75H), 6.59 (d, J = 12.0 Hz, 0.25H), 6.34 (dd, J = 6.0, 12.0 Hz, 0.25H), 6.21 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.72 (brs, 0.75H), 5.60 (dt, J = 5.1, 10.2 Hz, 0.25H), 3.93 (dt, J = 4.5, 7.5 Hz, 0.75H), 3.80 (dt, J = 4.8, 6.3 Hz, 0.25H), 3.24 (d, J = 5.1 Hz, 0.25H ), 3.12 (brs, 0.75H), 2.37 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.25H), 2.21 (ddd, J = 2.7, 4.5, 10.2 Hz, 0.75H), 1.97-2.07 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 152.4 (minor), 151.4 (major), 137.0 (major), 136.9 (minor), 132.5 (minor), 132.4 (major), 131.7 (major), 131.5 (minor), 129.3 (minor), 129.1 (major), 128.6 (major), 128.3 (minor), 128.1 (major), 127.5 (minor), 127.4 (major), 126.3 (minor), 126.2 (major), 124.1 (major), 123.5 (minor), 121.1 (major), 121.0 (minor), 117.1 (major), 117.0 (minor), 93.6 (minor), 91.3 (major), 38.3 (minor), 35.5 (minor), 34.3 (major), 33.8 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 152.4 (minor), 151.4 (major), 137.0 (major), 136.9 (minor), 132.5 (minor), 132.4 (major), 131.7 (major), 131.5 (minor) , 129.3 (minor), 129.1 (major), 128.6 (major), 128.3 (minor), 128.1 (major), 127.5 (minor), 127.4 (major), 126.3 (minor), 126.2 (major), 124.1 (major) , 123.5 (minor), 121.1 (major), 121.0 (minor), 117.1 (major), 117.0 (minor), 93.6 (minor), 91.3 (major), 38.3 (minor), 35.5 (minor), 34.3 (major) , 33.8 (major);

IR (KBr) 3436, 1584, 1492, 1448, 1229, 1204, 1175, 1100, 1011 cm-1; IR (KBr) 3436, 1584, 1492, 1448, 1229, 1204, 1175, 1100, 1011 cm −1 ;

MS m/z (%) 252 (M+, 50), 234 (100), 207 (74), 178 (28), 131 (51), 91 (40); MS m / z (%) 252 (M + , 50), 234 (100), 207 (74), 178 (28), 131 (51), 91 (40);

원소분석: C17H16O2: 계산상 C 80.93, H 6.39 측정상 C 81.22, H 6.37;Elemental Analysis: C 17 H 16 O 2 : Calcd for C 80.93, H 6.39 Calcd for C 81.22, H 6.37;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 15.5 분 및 S- 이성질체 tr = 19.6 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 15.5 min and S- isomer t r = 19.6 min.

실시예Example 2 2

(R)-6-메톡시-4-스티릴-크로만-2-올 ((R)-6-Methoxy-4-styryl-chroman-2-ol (4b))의 합성 ( R ) -6-methoxy-4-styryl-chroman-2-ol (( R ) -6-Methoxy-4-styryl-chroman-2-ol (4b)) synthesis

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 2-하이드록시-5-메톡시신남알데하이드 2b (45 mg, 0.25 mmol)를 가하고 상온에서 72 시간 동안 교반한 후 30% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (46 mg, 65% 수득률, 80:20 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. 2-hydroxy-5-methoxycinnaaldehyde 2b (45 mg, 0.25 mmol) was added and stirred at room temperature for 72 hours, followed by silica gel chromatography on 30% EtOAc / hexanes to give the desired compound as a white solid (46 mg, 65% yield, 80:20 er).

mp 130-131 oC;mp 130-131 o C;

1H NMR (300 MHz, CDCl3) δ 7.25-7.46 (m, 6H), 6.57-6.87 (m, 3H), 6.33 (dd, J = 6.6, 11.7 Hz, 0.23H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.77H), 5.69 (dd, J = 2.4, 4.5 Hz, 0.77H), 5.55 (dt, 0.23H), 3.74 (s, 3H), 3.86-3.96 (m, 1H), 3.12 (d, J = 5.1 Hz, 0.23H), 2.99 (dd, J = 1.2, 2.7 Hz, 0.77H), 2.36 (ddd, 0.23H), 2.19 (ddd, J = 2.7, 4.5, 10.2 Hz, 0.75H), 1.94-2.05 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.25-7.46 (m, 6H), 6.57-6.87 (m, 3H), 6.33 (dd, J = 6.6, 11.7 Hz, 0.23H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.77H), 5.69 (dd, J = 2.4, 4.5 Hz, 0.77H), 5.55 (dt, 0.23H), 3.74 (s, 3H), 3.86-3.96 (m, 1H), 3.12 ( d, J = 5.1 Hz, 0.23H), 2.99 (dd, J = 1.2, 2.7 Hz, 0.77H), 2.36 (ddd, 0.23H), 2.19 (ddd, J = 2.7, 4.5, 10.2 Hz, 0.75H) , 1.94-2.05 (m, 1 H);

13H NMR (75 MHz, CDCl3) δ 153.8 (major), 145.0 (minor), 137.0 (major), 132.5 (major), 131.5 (major), 128.6 (major), 127.5 (major), 126.4 (major), 126.3 (major), 124.8 (major), 117.8 (minor), 117.6 (major), 114.1 (minor), 113.9 (major), 113.8 (major), 93.5 (minor), 91.1 (major), 55.8 (major), 35.5 (minor), 34.6 (major), 33.8 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 153.8 (major), 145.0 (minor), 137.0 (major), 132.5 (major), 131.5 (major), 128.6 (major), 127.5 (major), 126.4 (major) , 126.3 (major), 124.8 (major), 117.8 (minor), 117.6 (major), 114.1 (minor), 113.9 (major), 113.8 (major), 93.5 (minor), 91.1 (major), 55.8 (major) , 35.5 (minor), 34.6 (major), 33.8 (major);

IR (KBr) 3468, 1654, 1473, 1264, 1100, 1017 cm-1; IR (KBr) 3468, 1654, 1473, 1264, 1100, 1017 cm −1 ;

MS m/z (%) 282 (M+, 100), 264 (42), 237 (60), 161 (38), 115 (27), 91 (29); MS m / z (%) 282 (M + , 100), 264 (42), 237 (60), 161 (38), 115 (27), 91 (29);

원소분석: C18H18O3?1/3H2O: 계산상 C 74.98, H 6.53 측정상 C 75.08, H 6.45;Elemental Analysis: C 18 H 18 O 3 1 1/3 H 2 O: Calcd for C 74.98, H 6.53 Calibrated C 75.08, H 6.45;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 21.7 분 및 S- 이성질체 tr = 26.5 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 21.7 min and S- isomer t r = 26.5 min.

실시예Example 3 3

(R)-8-메톡시-4-스티릴-크로만-2-올 ((R)-8-Methoxy-4-styryl-chroman-2-ol (4c))의 합성( R ) -8-methoxy-4-styryl-chroman-2-ol (( R ) -8-Methoxy-4-styryl-chroman-2-ol (4c)) synthesis

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시-3-메톡시신남알데하이드 2c (45 mg, 0.25 mmol)를 가하고 0℃에서 48 시간 동안 교반한 후 30% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (66 mg, 93% 수득률, 93:7 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. From 0 o C 2- hydroxy-3-methoxy cinnamaldehyde 2c (45 mg, 0.25 mmol) was added to a silica gel chromatography from the mixture was stirred at 0 ℃ for 48 hours, 30% EtOAc / hexane white of the desired compound Obtained as a solid (66 mg, 93% yield, 93: 7 er).

mp 143-145 oC; mp 143-145 o C;

1H NMR (300 MHz, CDCl3) δ 7.25-7.45 (m, 6H), 6.81-6.92 (m, 2H), 6.64 (d, J = 12.0 Hz, 0.78H), 6.58 (d, J = 12.0 Hz, 0.22H), 6.38 (dd, J = 6.0, 11.7 Hz, 0.22H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.78H), 5.85 (dd, J = 2.1, 4.5 0.78H), 5.71 (dt, 0.22H), 3.92 (s, 3H), 3.67-4.00(m, 1H), 3.52 (d, J = 5.1 Hz, 0.22H), 3.42 (dd, J = 1.5, 2.7, 0.78H), 2.37 (ddd, 0.22H), 2.19 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.97-2.12 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.25-7.45 (m, 6H), 6.81-6.92 (m, 2H), 6.64 (d, J = 12.0 Hz, 0.78H), 6.58 (d, J = 12.0 Hz , 0.22H), 6.38 (dd, J = 6.0, 11.7 Hz, 0.22H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.78H), 5.85 (dd, J = 2.1, 4.5 0.78H), 5.71 ( dt, 0.22H), 3.92 (s, 3H), 3.67-4.00 (m, 1H), 3.52 (d, J = 5.1 Hz, 0.22H), 3.42 (dd, J = 1.5, 2.7, 0.78H), 2.37 (ddd, 0.22H), 2.19 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.97-2.12 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 148.3 (major), 140.8 (minor), 137.0 (major), 132.8 (minor), 132.4 (major), 131.6 (major), 131.0 (minor), 128.6 (major), 127.5 (major), 126.3 (major x2), 125.0 (major), 121.2 (minor), 120.9 (major), 120.5 (minor), 120.4 (major), 109.8 (major), 93.6 (minor), 91.3 (major), 55.9 (major), 38.1 (minor), 35.0 (minor), 34.2 (major), 33.5 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 148.3 (major), 140.8 (minor), 137.0 (major), 132.8 (minor), 132.4 (major), 131.6 (major), 131.0 (minor), 128.6 (major) , 127.5 (major), 126.3 (major x2), 125.0 (major), 121.2 (minor), 120.9 (major), 120.5 (minor), 120.4 (major), 109.8 (major), 93.6 (minor), 91.3 (major) ), 55.9 (major), 38.1 (minor), 35.0 (minor), 34.2 (major), 33.5 (major);

IR (KBr) 3460, 1648, 1465, 1230, 1021 cm-1; IR (KBr) 3460, 1648, 1465, 1230, 1021 cm −1 ;

MS m/z (%) 282 (M+, 56), 264 (100), 239 (51), 207 (34), 178 (34), 115 (39), 91 (38); MS m / z (%) 282 (M + , 56), 264 (100), 239 (51), 207 (34), 178 (34), 115 (39), 91 (38);

원소분석: C18H18O3: 계산상 C 76.57, H 6.43 측정상 C 76.43, H 6.54;Elemental Analysis: C 18 H 18 O 3 : Calculated C 76.57, H 6.43 Measuring Phase C 76.43, H 6.54;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 0.5 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 55.1 분 및 S- 이성질체 tr = 59.3 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantiomeric selectivity was determined by HPLC analysis using 0.5 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 55.1 min and S- isomer t r = 59.3 min.

실시예Example 4 4

(R)-6-클로로-4-스티릴-크로만-2-올 ((R)-6-Chloro-4-styryl-chroman-2-ol (4d))의 합성( R ) -6-chloro-4-styryl-chroman-2-ol (( R ) -6-Chloro-4-styryl-chroman-2-ol (4d)) synthesis

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 5-클로로-2-하이드록시신남알데하이드 2d (46 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (57 mg, 85% 수득률, 85:15 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. At 0 o C 5- chloro-2-hydroxy-cinnamaldehyde 2d (46 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 20% EtOAc / hexanes was purified by silica gel chromatography as a white solid (57 mg, 85% yield, 85:15 er).

mp 137-138 oC; mp 137-138 o C;

1H NMR (300 MHz, CDCl3) δ 7.12-7.44 (m, 7H), 6.81 (d, J = 6.6 Hz, 1H), 6.64 (d, J = 12.0 Hz, 0.78H), 6.60 (d, J = 11.7 Hz, 0.22H), 6.30 (dd, J = 6.6, 11.7 Hz, 0.22H), 6.15 (dd, J = 6.9, 12.0 Hz, 0.78H), 5.71 (brd, J = 1.8 Hz, 0.78H), 5.59 (brs, 0.22H), 3.90 (dt, J = 4.2, 7.8 Hz, 0.78H), 3.74 (dt, J = 4.8, 6.6 Hz, 0.22H), 3.13 (brd, J = 4.2 Hz, 0.22H), 3.13 (brs, 0.78H), 2.35 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.22H), 2.20 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.93-2.07 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.12-7.44 (m, 7H), 6.81 (d, J = 6.6 Hz, 1H), 6.64 (d, J = 12.0 Hz, 0.78H), 6.60 (d, J = 11.7 Hz, 0.22H), 6.30 (dd, J = 6.6, 11.7 Hz, 0.22H), 6.15 (dd, J = 6.9, 12.0 Hz, 0.78H), 5.71 (brd, J = 1.8 Hz, 0.78H) , 5.59 (brs, 0.22H), 3.90 (dt, J = 4.2, 7.8 Hz, 0.78H), 3.74 (dt, J = 4.8, 6.6 Hz, 0.22H), 3.13 (brd, J = 4.2 Hz, 0.22H ), 3.13 (brs, 0.78H), 2.35 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.22H), 2.20 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.93-2.07 (m, 1H);

13H NMR (75 MHz, CDCl3) d 151.0 (minor), 150.0 (major), 136.7 (major), 133.1 (major), 132.1 (minor), 131.5 (minor), 130.6 (major), 128.9 (minor), 128.7 (major), 128.6 (major), 128.3 (minor), 128.1 (major), 127.7 (major), 126.4 (major x2), 125.9 (major), 115.5 (minor), 118.4 (major), 93.6 (minor), 91.3 (major), 38.2 (minor), 35.1 (minor), 34.3 (major), 33.4 (major); 13 H NMR (75 MHz, CDCl 3 ) d 151.0 (minor), 150.0 (major), 136.7 (major), 133.1 (major), 132.1 (minor), 131.5 (minor), 130.6 (major), 128.9 (minor) , 128.7 (major), 128.6 (major), 128.3 (minor), 128.1 (major), 127.7 (major), 126.4 (major x2), 125.9 (major), 115.5 (minor), 118.4 (major), 93.6 (minor) ), 91.3 (major), 38.2 (minor), 35.1 (minor), 34.3 (major), 33.4 (major);

IR (KBr) 3480, 1611, 1515, 1240, 1170, 1009 cm-1; IR (KBr) 3480, 1611, 1515, 1240, 1170, 1009 cm −1 ;

MS m/z (%) 286 (M+, 62), 268 (100), 241 (75), 207 (24), 181 (52), 165 (51), 91 (53);MS m / z (%) 286 (M + , 62), 268 (100), 241 (75), 207 (24), 181 (52), 165 (51), 91 (53);

원소분석: C17H15ClO2: 계산상 C 71.20, H 5.27 측정상 C 70.89, H 5.46; Elemental Analysis: C 17 H 15 ClO 2 : Calcd for C 71.20, H 5.27 Calibrated C 70.89, H 5.46;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 16.6 분 및 S- 이성질체 tr = 21.0 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 16.6 min and S- isomer t r = 21.0 min.

실시예Example 5 5

(R)-6,8-디클로로-4-스티릴-크로만-2-올 ((R)-6,8-Dichloro-4-styryl-chroman-2-ol (4e))의 합성( R ) -6,8-dichloro-4-styryl-chroman-2-ol (( R ) -6,8-Dichloro-4-styryl-chroman-2-ol (4e)) synthesis

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 3,5-디클로로-2-하이드록시신남알데하이드 2e (55 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (90 mg, 99% 수득률, 85:15 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. And the 3,5-dichloro-2-hydroxy cinnamic aldehyde 2e (55 mg, 0.25 mmol) was added at 0 ℃ silica 72 hours a 20% EtOAc / hexane and then stirred at 0 o C gel chromatography, the desired compound Obtained as a white solid (90 mg, 99% yield, 85:15 er).

1H NMR (300 MHz, CDCl3) δ 7.27-7.47 (m, 6H), 7.11 (dd, J = 0.6, 1.8 Hz, 0.80H), 7.07 (dd, J = 0.9, 2.1 Hz, 0.20H), 6.66 (d, J = 12.0 Hz, 0.80H), 6.60 (d, J = 12.0 Hz, 0.80H), 6.32 (dd, J = 6.6, 11.7 Hz, 0.20H), 6.11 (dd, J = 6.9, 11.7 Hz, 0.80H), 5.86 (brs, 0.80H), 5.72 (brs, 0.20H), 3.92 (dt, J = 4.5, 8.4 Hz, 0.80H), 3.64 (dt, J = 4.8, 6.6 Hz, 0.20H), 3.40 (brs, 1H), 2.38 (ddd, J = 1.8, 4.5, 10.2 Hz, 0.20H), 2.23 (ddd, J = 2.1, 4.2, 10.2 Hz, 0.80H), 1.93-2.11 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.27-7.47 (m, 6H), 7.11 (dd, J = 0.6, 1.8 Hz, 0.80H), 7.07 (dd, J = 0.9, 2.1 Hz, 0.20H), 6.66 (d, J = 12.0 Hz, 0.80H), 6.60 (d, J = 12.0 Hz, 0.80H), 6.32 (dd, J = 6.6, 11.7 Hz, 0.20H), 6.11 (dd, J = 6.9, 11.7 Hz, 0.80H), 5.86 (brs, 0.80H), 5.72 (brs, 0.20H), 3.92 (dt, J = 4.5, 8.4 Hz, 0.80H), 3.64 (dt, J = 4.8, 6.6 Hz, 0.20H ), 3.40 (brs, 1H), 2.38 (ddd, J = 1.8, 4.5, 10.2 Hz, 0.20H), 2.23 (ddd, J = 2.1, 4.2, 10.2 Hz, 0.80H), 1.93-2.11 (m, 1H );

13H NMR (75 MHz, CDCl3) δ 146.1 (major), 136.5 (major), 133.6 (major), 132.2 (minor), 131.1 (minor), 129.9 (major), 128.7 (major), 128.5 (minor), 128.4 (major), 127.9 (major), 127.6 (minor), 127.4 (major), 127.3 (major), 126.4 (minor), 126.4 (major), 125.6 (major), 122.6 (major), 94.1 (minor), 91.8 (major), 38.4 (minor), 34.5 (minor), 34.4 (major), 33.1 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 146.1 (major), 136.5 (major), 133.6 (major), 132.2 (minor), 131.1 (minor), 129.9 (major), 128.7 (major), 128.5 (minor) , 128.4 (major), 127.9 (major), 127.6 (minor), 127.4 (major), 127.3 (major), 126.4 (minor), 126.4 (major), 125.6 (major), 122.6 (major), 94.1 (minor) 91.8 (major), 38.4 (minor), 34.5 (minor), 34.4 (major), 33.1 (major);

IR (KBr) 3417, 1454, 1242, 1175, 1021 cm-1; IR (KBr) 3417, 1454, 1242, 1175, 1021 cm −1 ;

HRMS: [M+] C17H14Cl2O2: 계산상 320.0371 측정상 320.0367; HRMS: [M + ] C 17 H 14 Cl 2 O 2 : computationally 320.0371 measurement 320.0367;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; S- 이성질체 tr = 13.9 분 및 R- 이성질체 tr = 14.8 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; S- isomer t r = 13.9 min and R- isomer t r = 14.8 min.

실시예Example 6 6

(R)-6,8-디브로모-4-스티릴-크로만-2-올 ((R)-6,8-Dibromo-4-styryl-chroman-2-ol (4f))의 합성( R ) -6,8-Dibromo-4-styryl-chroman-2-ol (( R ) -6,8-Dibromo-4-styryl-chroman-2-ol (4f)) synthesis

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 3,5-디브로모-2-하이드록시신남알데하이드 2f (77 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (93 mg, 91% 수득률, 85:15 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. And the 3,5-dibromo-2-hydroxy-cinnamaldehyde 2f (77 mg, 0.25 mmol) was added silica 72 hours a 20% EtOAc / hexane and then stirred at 0 ℃ gel chromatography at 0 o C purpose The compound was obtained as a white solid (93 mg, 91% yield, 85:15 er).

1H NMR (300 MHz, CDCl3) δ 7.23-7.58 (m, 7H), 6.66 (d, J = 11.7 Hz, 0.80H), 6.60 (d, J = 11.7 Hz, 0.20H), 6.32 (dd, J = 6.6, 11.7 Hz, 0.20H), 6.11 (dd, J = 6.6, 11.7 Hz, 0.80H), 5.85 (brs, 0.80H), 5.71 (brs, 0.20H), 3.93 (dt, J = 4.5, 8.4 Hz, 0.80H), 3.75 (dt, J = 4.8, 6.6 Hz, 0.20H), 3.43 (brs, 0.20H), 3.37 (brs, 0.80H), 2.36 (ddd, J = 1.8, 4.5, 10.2 Hz, 0.20H), 2.21 (ddd, J = 2.1, 4.2, 10.2 Hz, 0.80H), 1.93-2.11 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.23-7.58 (m, 7H), 6.66 (d, J = 11.7 Hz, 0.80H), 6.60 (d, J = 11.7 Hz, 0.20H), 6.32 (dd, J = 6.6, 11.7 Hz, 0.20H), 6.11 (dd, J = 6.6, 11.7 Hz, 0.80H), 5.85 (brs, 0.80H), 5.71 (brs, 0.20H), 3.93 (dt, J = 4.5, 8.4 Hz, 0.80H), 3.75 (dt, J = 4.8, 6.6 Hz, 0.20H), 3.43 (brs, 0.20H), 3.37 (brs, 0.80H), 2.36 (ddd, J = 1.8, 4.5, 10.2 Hz , 0.20H), 2.21 (ddd, J = 2.1, 4.2, 10.2 Hz, 0.80H), 1.93-2.11 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 147.5 (major), 136.5 (major), 134.0 (minor), 133.9 (major), 133.6 (major), 132.5 (minor), 131.4 (minor), 131.2 (minor), 130.9 (major), 129.8 (major), 128.7 (major), 127.9 (major), 126.5 (major), 126.4 (major), 113.0 (major), 112.0 (major), 94.0 (minor), 91.8 (major), 38.5 (minor), 34.5 (minor), 34.4 (major), 33.2 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 147.5 (major), 136.5 (major), 134.0 (minor), 133.9 (major), 133.6 (major), 132.5 (minor), 131.4 (minor), 131.2 (minor) , 130.9 (major), 129.8 (major), 128.7 (major), 127.9 (major), 126.5 (major), 126.4 (major), 113.0 (major), 112.0 (major), 94.0 (minor), 91.8 (major) , 38.5 (minor), 34.5 (minor), 34.4 (major), 33.2 (major);

IR (KBr) 3420, 1448, 1233, 1163, 1017 cm-1; IR (KBr) 3420, 1448, 1233, 1163, 1017 cm −1 ;

HRMS: [M+] C17H14Br2O2 : 계산상 407.9361 측정상 407.9360; HRMS: [M + ] C 17 H 14 Br 2 O 2 : Calculated 407.9361 measured 407.9360;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; S- 이성질체 tr = 14.8 분 및 R- 이성질체 tr = 15.8 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; S- isomer t r = 14.8 min and R- isomer t r = 15.8 min.

실시예Example 7 7

(R)-6-메틸-4-스티릴-크로만-2-올 ((R)-6-Methyl-4-styryl-chroman-2-ol (4g))의 합성( R ) -6-methyl-4-styryl-chroman-2-ol (( R ) -6-Methyl-4-styryl-chroman-2-ol Synthesis of ( 4g ))

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시-5-메틸신남알데하이드 2g (41 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (44 mg, 66% 수득률, 86:14 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. At 0 o C 2- hydroxy-5-methyl cinnamaldehyde 2g (41 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 25% EtOAc / hexanes was purified by silica gel chromatography as a white solid (44 mg, 66% yield, 86:14 er).

1H NMR (300 MHz, CDCl3) δ 7.24-7.47 (m, 5H), 6.96-7.02 (m, 2H), 6.76-6.83 (m, 1H), 6.63 (d, J = 12.0 Hz, 0.75H), 6.59 (d, J = 12.9 Hz, 0.25H), 6.33 (dd, J = 6.3, 12.0 Hz, 0.25H), 6.20 (dd, J = 6.9, 11.7 Hz, 0.75H), 5.70 (brs, 0.75H), 5.57 (brs, 0.25H), 3.89 (m, 0.75H), 3.75 (m, 0.25H), 3.13 (d, J = 4.8 Hz, 0.75H), 3.00 (brs, 0.75H), 2.26 (s, 3H), 1.92-2.42 (m, 2H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.24-7.47 (m, 5H), 6.96-7.02 (m, 2H), 6.76-6.83 (m, 1H), 6.63 (d, J = 12.0 Hz, 0.75H) , 6.59 (d, J = 12.9 Hz, 0.25H), 6.33 (dd, J = 6.3, 12.0 Hz, 0.25H), 6.20 (dd, J = 6.9, 11.7 Hz, 0.75H), 5.70 (brs, 0.75H ), 5.57 (brs, 0.25H), 3.89 (m, 0.75H), 3.75 (m, 0.25H), 3.13 (d, J = 4.8 Hz, 0.75H), 3.00 (brs, 0.75H), 2.26 (s , 3H), 1.92-2.42 (m, 2H);

13H NMR (75 MHz, CDCl3) δ 150.1 (minor), 149.0 (major), 137.0 (major), 132.6 (minor), 132.3 (major), 131.8 (major), 131.4 (minor), 130.3 (major), 129.5 (minor), 129.3 (major), 129.0 (minor), 128.8 (major), 128.6 (major), 127.5 (major), 126.4 (minor), 126.3 (major), 123.7 (major), 116.9 (minor), 116.8 (major), 93.5 (minor), 91.2 (major), 38.3 (minor), 35.5 (minor), 34.4 (major), 33.8 (major), 20.6 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 150.1 (minor), 149.0 (major), 137.0 (major), 132.6 (minor), 132.3 (major), 131.8 (major), 131.4 (minor), 130.3 (major) , 129.5 (minor), 129.3 (major), 129.0 (minor), 128.8 (major), 128.6 (major), 127.5 (major), 126.4 (minor), 126.3 (major), 123.7 (major), 116.9 (minor) , 116.8 (major), 93.5 (minor), 91.2 (major), 38.3 (minor), 35.5 (minor), 34.4 (major), 33.8 (major), 20.6 (major);

IR (KBr) 3445, 1580, 1495, 1430, 1228, 1200, 1168, 1101 cm-1; IR (KBr) 3445, 1580, 1495, 1430, 1228, 1200, 1168, 1101 cm −1 ;

HRMS: [M+] C18H18O2: 계산상 266.1307 측정상 266.1305; HRMS: [M + ] C 18 H 18 O 2 : Calculated 266.1307 Measuring 266.1305;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 14.2 분 및 S- 이성질체 tr = 18.3 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 14.2 min and S- isomer t r = 18.3 min.

실시예Example 8 8

(R)-6-니트로-4-스티릴-크로만-2-올 ((R)-6-Nitro-4-styryl-chroman-2-ol (4h))의 합성( R) -6-nitro-4-styryl-chroman-2-ol (( R ) -6-Nitro-4-styryl-chroman-2-ol Synthesis of ( 4h ))

트랜스-2-페닐비닐브론산 3a (42 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시-5-니트로신남알데하이드 2h (49 mg, 0.25 mmol)를 가하고 상온에서 72 시간 동안 교반한 후 40% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (60 mg, 81% 수득률, 84:16 er)로 얻었다. To trans-2-phenylvinylbronic acid 3a (42 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H. 2 0 (4.5 μL, 0.25 mmol) is added dropwise. 2-hydroxy-5-nitrosinnamaldehyde 2h (49 mg, 0.25 mmol) was added at 0 ° C., stirred at room temperature for 72 hours, and silica gel chromatography at 40% EtOAc / hexanes gave the target compound as a white solid ( 60 mg, 81% yield, 84:16 er).

mp 148-149 oC; mp 148-149 o C;

1H NMR (300 MHz, CDCl3) δ 8.07-8.15 (m, 2H), 7.26-7.47 (m, 5H), 6.97 (d, J = 5.4 Hz, 0.22H), 6.95 (d, J = 5.4 Hz, 0.78H), 6.70 (d, J = 12.0 Hz, 0.78H), 6.66 (d, J = 12.0 Hz, 0.22H), 6.42 (dd, J = 5.4, 11.7 Hz, 0.22H), 6.17 (dd, J = 5.4, 11.7 Hz, 0.78H), 5.81 (dd, J = 2.4, 4.5 Hz, 0.78H), 5.72 (dt, 0.22H), 3.80-4.02 (m, 1H), 3.67 (brd, J = 4.5 Hz, 0.22H), 3.11 (brs, 0.78H), 2.42 (ddd, 0.22H), 2.27 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.97-2.13 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 8.07-8.15 (m, 2H), 7.26-7.47 (m, 5H), 6.97 (d, J = 5.4 Hz, 0.22H), 6.95 (d, J = 5.4 Hz , 0.78H), 6.70 (d, J = 12.0 Hz, 0.78H), 6.66 (d, J = 12.0 Hz, 0.22H), 6.42 (dd, J = 5.4, 11.7 Hz, 0.22H), 6.17 (dd, J = 5.4, 11.7 Hz, 0.78H), 5.81 (dd, J = 2.4, 4.5 Hz, 0.78H), 5.72 (dt, 0.22H), 3.80-4.02 (m, 1H), 3.67 (brd, J = 4.5 Hz, 0.22H), 3.11 (brs, 0.78H), 2.42 (ddd, 0.22H), 2.27 (ddd, J = 2.4, 4.2, 10.2 Hz, 0.78H), 1.97-2.13 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 157.1 (major), 141.8 (major), 136.4 (major), 134.0 (major), 133.7 (minor), 133.0 (minor), 131.0 (minor), 130.5 (minor), 129.4 (major), 128.7 (major), 127.9 (major), 127.8 (minor), 126.5 (major), 126.4 (major), 125.6 (minor), 125.2 (major), 124.4 (minor), 124.2 (major), 117.7 (major), 94.2 (minor), 91.9 (major), 38.0 (minor), 34.6 (minor), 34.1 (major), 33.1 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 157.1 (major), 141.8 (major), 136.4 (major), 134.0 (major), 133.7 (minor), 133.0 (minor), 131.0 (minor), 130.5 (minor) , 129.4 (major), 128.7 (major), 127.9 (major), 127.8 (minor), 126.5 (major), 126.4 (major), 125.6 (minor), 125.2 (major), 124.4 (minor), 124.2 (major) , 117.7 (major), 94.2 (minor), 91.9 (major), 38.0 (minor), 34.6 (minor), 34.1 (major), 33.1 (major);

IR (KBr) 3547, 3485, 1557, 1511, 1479, 1334, 1254, 1235, 1090, 1011 cm-1; IR (KBr) 3547, 3485, 1557, 1511, 1479, 1334, 1254, 1235, 1090, 1011 cm - 1;

MS m/z (%) 297 (M+, 57), 279 (100), 263 (81), 234 (32), 176 (55), 91 (27); MS m / z (%) 297 (M + , 57), 279 (100), 263 (81), 234 (32), 176 (55), 91 (27);

원소분석: C17H15NO4: 계산상 C 68.68, H 5.09, N 4.71 측정상 C 68.37, H 5.17, N 4.69; Elemental Analysis: C 17 H 15 NO 4 : Calcd for C 68.68, H 5.09, N 4.71 Calibrated C 68.37, H 5.17, N 4.69;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 43.1 분 및 S- 이성질체 tr = 54.8분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 43.1 min and S- isomer t r = 54.8 min.

실시예Example 9 9

(R)-4-[2-(4-메톡시페닐)-비닐]-크로만-2-올 ((R)-4-[2-(4-Methoxyphenyl)-vinyl]-chroman-2-ol (4i))의 합성( R ) -4- [2- (4-methoxyphenyl) -vinyl] -chroman-2-ol (( R ) -4- [2- (4-Methoxyphenyl) -vinyl] -chroman-2-ol Synthesis of ( 4i ))

트랜스-2-(4-메톡시)페닐비닐브론산 3b (54 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (56 mg, 80% 수득률, 93:7 er)로 얻었다. To trans-2- (4-methoxy) phenylvinylbronic acid 3b (54 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL). , 0.005 mmol) and H 2 O (4.5 μL, 0.25 mmol) are added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 25% EtOAc / hexanes was purified by silica gel chromatography as a white solid (56 mg, 80% yield, 93: 7 er).

mp 115-116 oC; mp 115-116 o C;

1H NMR (300 MHz, CDCl3) δ 7.33-7.38 (m, 2H), 7.16-7.24 (m, 2H), 6.87-6.95 (m, 4H), 6.56 (d, J = 11.7 Hz, 0.70H), 6.52 (d, J = 11.7 Hz, 0.30H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.30H), 6.05 (dd, J = 6.6, 11.7 Hz, 0.70H), 5.71 (brd, J = 2.1 Hz, 0.70H), 5.57 (dt, J = 1.5, 6.6 Hz, 0.70H), 3.84 (s, 3H), 3.73-3.92 (m, 1H), 3.43 (dd, J = 5.1 Hz, 0.30H), 3.27 (dd, J = 2.1 Hz, 0.70H), 2.32-2.41 (m, 0.3H), 2.17-2.22 (m, 0.70H), 1.95-2.07 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.33-7.38 (m, 2H), 7.16-7.24 (m, 2H), 6.87-6.95 (m, 4H), 6.56 (d, J = 11.7 Hz, 0.70H) , 6.52 (d, J = 11.7 Hz, 0.30H), 6.19 (dd, J = 6.6, 11.7 Hz, 0.30H), 6.05 (dd, J = 6.6, 11.7 Hz, 0.70H), 5.71 (brd, J = 2.1 Hz, 0.70H), 5.57 (dt, J = 1.5, 6.6 Hz, 0.70H), 3.84 (s, 3H), 3.73-3.92 (m, 1H), 3.43 (dd, J = 5.1 Hz, 0.30H) , 3.27 (dd, J = 2.1 Hz, 0.70H), 2.32-2.41 (m, 0.3H), 2.17-2.22 (m, 0.70H), 1.95-2.07 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 159.1 (major), 153.5 (minor), 151.4 (major), 131.8 (major), 131.0 (minor), 130.2 (minor), 129.8 (minor), 129.5 (major), 129.3 (minor), 129.1 (major), 128.3 (minor), 128.1 (major), 127.5 (major), 127.4 (major), 124.4 (major), 123.7 (minor), 121.0 (major), 117.1 (minor), 117.0 (major), 114.0 (major), 93.7 (minor), 91.3 (major), 55.4 (major), 38.3 (minor), 35.6 (minor), 34.3 (major), 33.9 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 159.1 (major), 153.5 (minor), 151.4 (major), 131.8 (major), 131.0 (minor), 130.2 (minor), 129.8 (minor), 129.5 (major) , 129.3 (minor), 129.1 (major), 128.3 (minor), 128.1 (major), 127.5 (major), 127.4 (major), 124.4 (major), 123.7 (minor), 121.0 (major), 117.1 (minor) , 117.0 (major), 114.0 (major), 93.7 (minor), 91.3 (major), 55.4 (major), 38.3 (minor), 35.6 (minor), 34.3 (major), 33.9 (major);

IR (KBr) 3500, 1609, 1578, 1514, 1489, 1245, 1179, 1100, 1014 cm-1; IR (KBr) 3500, 1609, 1578, 1514, 1489, 1245, 1179, 1100, 1014 cm −1 ;

MS m/z (%) 282 (M+, 100), 264 (73), 237 (75), 147 (59), 121 (82), 91 (21); MS m / z (%) 282 (M + , 100), 264 (73), 237 (75), 147 (59), 121 (82), 91 (21);

원소분석: C18H18O3: 계산상 C 76.57, H 6.43 측정상 C 76.67, H 6.57; Elemental Analysis: C 18 H 18 O 3 : Calculated C 76.57, H 6.43 Measuring Phase C 76.67, H 6.57;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 34.6 분 및 S- 이성질체 tr = 42.2분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 34.6 min and S- isomer t r = 42.2 min.

실시예Example 10 10

(R)-4-[2-(4-메틸페닐)-비닐]-크로만-2-올 ((R)-4-[2-(4-Methylphenyl)-vinyl]-chroman-2-ol (4j))의 합성( R ) -4- [2- (4-methylphenyl) -vinyl] -chroman-2-ol (( R ) -4- [2- (4-Methylphenyl) -vinyl] -chroman-2-ol Synthesis of ( 4j ))

트랜스-2-(4-메틸)페닐비닐브론산 3c (49 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (42 mg, 63% 수득률, 92:8 er)로 얻었다. To trans-2- (4-methyl) phenylvinylbronic acid 3c (49 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O (4.5 μL, 0.25 mmol) are added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 25% EtOAc / hexanes was purified by silica gel chromatography as a white solid (42 mg, 63% yield, 92: 8 er).

mp 120-121 oC; mp 120-121 o C;

1H NMR (300 MHz, CDCl3) δ 7.17-7.35 (m, 6H), 6.88-6.97 (m, 2H), 6.60 (d, J = 11.7 Hz, 0.75H), 6.57 (d, J = 9.9 Hz, 0.25H), 6.29 (dd, J = 6.6, 12.0 Hz, 0.25H), 6.16 (dd, J = 6.6, 12.0 Hz, 0.75H), 5.72 (brs, 0.75H), 5.57 (brs, 0.25H), 3.92 (dd, J = 4.2, 11.2 Hz, 0.75H), 3.79 (dd, J = 3.9, 11.2 Hz, 0.25H), 3.44 (brs, 0.25H), 3.31 (brs, 0.75H), 2.39 (s, 3H), 2.19-2.24 (m, 1H), 1.96-2.06 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.17-7.35 (m, 6H), 6.88-6.97 (m, 2H), 6.60 (d, J = 11.7 Hz, 0.75H), 6.57 (d, J = 9.9 Hz , 0.25H), 6.29 (dd, J = 6.6, 12.0 Hz, 0.25H), 6.16 (dd, J = 6.6, 12.0 Hz, 0.75H), 5.72 (brs, 0.75H), 5.57 (brs, 0.25H) , 3.92 (dd, J = 4.2, 11.2 Hz, 0.75H), 3.79 (dd, J = 3.9, 11.2 Hz, 0.25H), 3.44 (brs, 0.25H), 3.31 (brs, 0.75H), 2.39 (s , 3H), 2.19-2.24 (m, 1 H), 1.96-2.06 (m, 1 H);

13H NMR (75 MHz, CDCl3) δ 152.4 (minor), 151.3 (major), 137.4 (minor), 137.3 (major), 134.2 (minor), 134.1 (major), 132.3 (major), 131.5 (minor), 131.3 (minor), 130.6 (major), 129.3 (major), 129.2 (major), 128.3 (minor), 128.1 (major), 126.3 (major), 126.2 (major), 124.3 (minor), 123.6 (minor), 121.1 (major), 117.1 (minor), 117.0 (major), 93.7 (minor), 91.3 (major), 38.3 (minor), 35.6 (minor), 34.3 (major), 33.8 (major), 21.2 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 152.4 (minor), 151.3 (major), 137.4 (minor), 137.3 (major), 134.2 (minor), 134.1 (major), 132.3 (major), 131.5 (minor) , 131.3 (minor), 130.6 (major), 129.3 (major), 129.2 (major), 128.3 (minor), 128.1 (major), 126.3 (major), 126.2 (major), 124.3 (minor), 123.6 (minor) , 121.1 (major), 117.1 (minor), 117.0 (major), 93.7 (minor), 91.3 (major), 38.3 (minor), 35.6 (minor), 34.3 (major), 33.8 (major), 21.2 (major) ;

IR (KBr) 3436, 1584, 1492, 1448, 1230, 1204, 1176, 1100, 1011 cm-1; IR (KBr) 3436, 1584, 1492, 1448, 1230, 1204, 1176, 1100, 1011 cm −1 ;

MS m/z (%) 266 (M+, 64), 248 (82), 221 (100), 178 (22), 145 (47), 115 (18), 91 (28); MS m / z (%) 266 (M + , 64), 248 (82), 221 (100), 178 (22), 145 (47), 115 (18), 91 (28);

원소분석: C18H18O2: 계산상 C 81.17, H 6.81 측정상 C 80.66, H 6.95; Elemental Analysis: C 18 H 18 O 2 : Calculated C 81.17, H 6.81 Measuring C 80.66, H 6.95;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 15.1 분 및 S- 이성질체 tr = 20.8 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 15.1 min and S- isomer t r = 20.8 min.

실시예Example 11 11

(R)-4-[2-(4-클로로페닐)-비닐]-크로만-2-올 ((R)-4-[2-(4-Chlorophenyl)-vinyl]-chroman-2-ol (4k))의 합성( R ) -4- [2- (4-chlorophenyl) -vinyl] -chroman-2-ol (( R ) -4- [2- (4-Chlorophenyl) -vinyl] -chroman-2-ol Synthesis of ( 4k ))

트랜스-2-(4-클로로)페닐비닐브론산 3d (49 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (39 mg, 55% 수득률, 91:9 er)로 얻었다. To trans-2- (4-chloro) phenylvinylbronic acid 3d (49 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O (4.5 μL, 0.25 mmol) are added dropwise. 0 o C in the 2-hydroxy-cinnamaldehyde 2a (37 mg, 0.25 mmol) was added and after stirring at 0 ℃ for 72 hours and purified by silica gel chromatography in 25% EtOAc / hexane the title compound as a white solid (39 mg, 55% yield, 91: 9 er).

mp 100-101 oC; mp 100-101 o C;

1H NMR (300 MHz, CDCl3) δ 7.29-7.36 (m, 4H), 7.16-7.23 (m, 2H), 6.88-6.96 (m, 2H), 6.57 (d, J = 11.7 Hz, 0.75H), 6.53 (d, J = 11.7 Hz, 0.25H), 6.33 (dd, J = 6.3, 11.7 Hz, 0.25H), 6.18 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.71 (dd, J = 2.4, 4.2 Hz, 0.75H), 5.60 (dt, J = 1.5, 4.8 Hz, 0.75H), 3.92 (dd, J = 7.5, 11.7 Hz, 0.75H), 3.78 (dd, J = 7.2, 11.7 Hz, 0.25H), 3.26 (d, J = 4.8 Hz, 0.25H), 3.17 (d, J = 3.0 Hz, 0.75H), 2.36 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.25H), 2.20 (ddd, J = 2.7, 4.5, 10.2 Hz, 0.75H), 1.97-2.03 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.29-7.36 (m, 4H), 7.16-7.23 (m, 2H), 6.88-6.96 (m, 2H), 6.57 (d, J = 11.7 Hz, 0.75H) , 6.53 (d, J = 11.7 Hz, 0.25H), 6.33 (dd, J = 6.3, 11.7 Hz, 0.25H), 6.18 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.71 (dd, J = 2.4, 4.2 Hz, 0.75H), 5.60 (dt, J = 1.5, 4.8 Hz, 0.75H), 3.92 (dd, J = 7.5, 11.7 Hz, 0.75H), 3.78 (dd, J = 7.2, 11.7 Hz, 0.25H), 3.26 (d, J = 4.8 Hz, 0.25H), 3.17 (d, J = 3.0 Hz, 0.75H), 2.36 (ddd, J = 1.8, 4.8, 10.2 Hz, 0.25H), 2.20 (ddd , J = 2.7, 4.5, 10.2 Hz, 0.75H), 1.97-2.03 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 152.2 (minor), 151.3 (major), 135.5 (major), 135.4 (minor), 133.3 (minor), 133.1 (minor), 132.4 (major), 131.2 (major), 130.1 (minor), 129.3 (minor), 129.0 (major), 128.8 (major), 128.4 (minor), 128.2 (major), 127.5 (major), 127.4 (major), 123.9 (major), 123.3 (minor), 121.2 (minor), 121.1 (major), 117.2 (minor), 117.1 (major), 93.4 (minor), 91.2 (major), 38.1 (minor), 35.2 (minor), 34.3 (major), 33.7 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 152.2 (minor), 151.3 (major), 135.5 (major), 135.4 (minor), 133.3 (minor), 133.1 (minor), 132.4 (major), 131.2 (major) , 130.1 (minor), 129.3 (minor), 129.0 (major), 128.8 (major), 128.4 (minor), 128.2 (major), 127.5 (major), 127.4 (major), 123.9 (major), 123.3 (minor) , 121.2 (minor), 121.1 (major), 117.2 (minor), 117.1 (major), 93.4 (minor), 91.2 (major), 38.1 (minor), 35.2 (minor), 34.3 (major), 33.7 (major) ;

IR (KBr) 3443, 1584, 1489, 1450, 1229, 1207, 1176, 1090, 1011 cm-1; IR (KBr) 3443, 1584, 1489, 1450, 1229, 1207, 1176, 1090, 1011 cm −1 ;

MS m/z (%) 286 (M+, 49), 268 (100), 241 (68), 207 (28), 178 (40), 147 (72), 125 (40); MS m / z (%) 286 (M + , 49), 268 (100), 241 (68), 207 (28), 178 (40), 147 (72), 125 (40);

원소분석: C17H15ClO2: 계산상 C 71.20, H 5.27 측정상 C 70.91, H 5.43;Elemental Analysis: C 17 H 15 ClO 2 : Calcd for C 71.20, H 5.27 Calibrated C 70.91, H 5.43;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 24.7 분 및 S- 이성질체 tr = 28.8 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 24.7 min and S- isomer t r = 28.8 min.

실시예Example 12 12

(R)-4-[2-(4-플루오르페닐)-비닐]-크로만-2-올 ((R)-4-[2-(4-fluorophenyl)-vinyl]-chroman-2-ol (4l)의 합성( R ) -4- [2- (4-fluorophenyl) -vinyl] -chroman-2-ol (( R ) -4- [2- (4-fluorophenyl) -vinyl] -chroman-2-ol Synthesis of ( 4l )

트랜스-2-(4-플루오르)페닐비닐브론산 3e (43 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 25% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (38 mg, 57% 수득률, 90:10 er)로 얻었다. To trans-2- (4-fluoro) phenylvinylbronic acid 3e (43 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O (4.5 μL, 0.25 mmol) are added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 25% EtOAc / hexanes was purified by silica gel chromatography as a white solid (38 mg, 57% yield, 90:10 er).

mp 115-116 oC; mp 115-116 o C;

1H NMR (300 MHz, CDCl3) δ 6.87-7.42 (m, 8H), 6.58 (d, J = 11.7 Hz, 0.75H), 6.54 (d, J = 11.7 Hz, 0.25H), 6.26 (dd, J = 6.6, 12.0 Hz, 0.25H), 6.12 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.72 (brs, 0.75H), 5.60 (brd, J = 4.8 Hz, 0.75H), 3.91 (dd, J = 7.2, 11.7 Hz, 0.75H), 3.77 (dd, J = 6.6, 11.7 Hz, 0.25H), 3.24 (brs, 0.25H), 3.13 (brs, 0.75H), 2.35 (ddd, J = 0.9, 4.2, 9.9 Hz, 0.25H), 2.20 (ddd, J = 2.7, 7.2, 12.9 Hz, 0.75H), 1.96-2.08 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.87-7.42 (m, 8H), 6.58 (d, J = 11.7 Hz, 0.75H), 6.54 (d, J = 11.7 Hz, 0.25H), 6.26 (dd, J = 6.6, 12.0 Hz, 0.25H), 6.12 (dd, J = 6.6, 11.7 Hz, 0.75H), 5.72 (brs, 0.75H), 5.60 (brd, J = 4.8 Hz, 0.75H), 3.91 (dd , J = 7.2, 11.7 Hz, 0.75H), 3.77 (dd, J = 6.6, 11.7 Hz, 0.25H), 3.24 (brs, 0.25H), 3.13 (brs, 0.75H), 2.35 (ddd, J = 0.9 , 4.2, 9.9 Hz, 0.25H), 2.20 (ddd, J = 2.7, 7.2, 12.9 Hz, 0.75H), 1.96-2.08 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 163.5 (major), 152.3 (minor), 151.4 (major), 133.2 (minor), 131.4 (major), 131.2 (major), 130.2 (minor), 129.3 (minor), 129.0 (major), 128.3 (minor), 128.2 (major), 127.9 (minor), 127.8 (major), 127.7 (major), 124.0 (major), 121.1 (major), 117.2 (minor), 117.1 (major), 115.6 (major), 115.4 (major), 93.5 (minor), 91.2 (major), 38.1 (minor), 35.4 (minor), 34.3 (major), 33.8 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 163.5 (major), 152.3 (minor), 151.4 (major), 133.2 (minor), 131.4 (major), 131.2 (major), 130.2 (minor), 129.3 (minor) , 129.0 (major), 128.3 (minor), 128.2 (major), 127.9 (minor), 127.8 (major), 127.7 (major), 124.0 (major), 121.1 (major), 117.2 (minor), 117.1 (major) 115.6 (major), 115.4 (major), 93.5 (minor), 91.2 (major), 38.1 (minor), 35.4 (minor), 34.3 (major), 33.8 (major);

IR (KBr) 3429, 1511, 1486, 1226, 1179, 1100, 1017 cm-1; IR (KBr) 3429, 1511, 1486, 1226, 1179, 1100, 1017 cm −1 ;

HRMS: [M+] C17H15FO2 계산상 270.1056 측정상 270.1058; HRMS: [M + ] C 17 H 15 FO 2 Calculated 270.1056 measured 270.1058;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 20.2 분 및 S- 이성질체 tr = 27.0 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 20.2 min and S- isomer t r = 27.0 min.

실시예Example 13 13

(R)-4-퓨란-2-일-크로만-2-올 ((R)-4-Furan-2-yl-chroman-2-ol (4m))의 합성( R ) -4-furan-2-yl-chroman-2-ol (( R ) -4-Furan-2-yl-chroman-2-ol Synthesis of ( 4m ))

2-퓨란브론산 3f (34 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (49 mg, 90% 수득률, 78:22 er)로 얻었다. To 1f (34 mg, 0.30 mmol) of 2-furanbromic acid, catalyst 1 (0.05 mmol) was added and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O ( 4.5 μL, 0.25 mmol) is added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added for 72 hours the desired compound by silica gel chromatography in a stirring 20% EtOAc / hexane over from 0 ℃ white solid (49 mg, 90% yield, 78:22 er).

mp 68-69 oC; mp 68-69 o C;

1H NMR (300 MHz, CDCl3) δ 6.87-7.42 (m, 5H), 6.36 (dd, J = 1.8, 2.4 Hz, 1H), 6.15 (d, J = 2.4 Hz, 0.83H), 6.11 (d, J = 2.4 Hz, 0.17H), 5.68 (dd, J = 3.3, 4.8 Hz, 0.83H), 5.60 (m, 0.17H), 4.45 (dd, J = 4.2, 10.5 Hz, 0.83H), 4.35 (dd, J = 4.5, 10.2 Hz, 0.17H), 3.53 (d, J = 6.3 Hz, 0.17H), 3.30 (d, J = 3.0 Hz, 0.83H), 2.20-2.46 (m, 2H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.87-7.42 (m, 5H), 6.36 (dd, J = 1.8, 2.4 Hz, 1H), 6.15 (d, J = 2.4 Hz, 0.83H), 6.11 (d , J = 2.4 Hz, 0.17H), 5.68 (dd, J = 3.3, 4.8 Hz, 0.83H), 5.60 (m, 0.17H), 4.45 (dd, J = 4.2, 10.5 Hz, 0.83H), 4.35 ( dd, J = 4.5, 10.2 Hz, 0.17H), 3.53 (d, J = 6.3 Hz, 0.17H), 3.30 (d, J = 3.0 Hz, 0.83H), 2.20-2.46 (m, 2H);

13H NMR (75 MHz, CDCl3) δ 156.2 (minor), 156.0 (major), 151.7 (major), 142.1 (minor), 141.9 (major), 129.2 (minor), 128.8 (major), 128.6 (minor), 128.3 (major), 122.5 (major), 121.2 (minor), 121.1 (major), 117.5 (minor), 117.1 (major), 110.3 (minor), 110.1 (major), 107.3 (major), 106.8 (minor), 93.2 (minor), 91.4 (major), 33.6 (minor), 33.1 (minor), 32.6 (major), 31.1 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 156.2 (minor), 156.0 (major), 151.7 (major), 142.1 (minor), 141.9 (major), 129.2 (minor), 128.8 (major), 128.6 (minor) , 128.3 (major), 122.5 (major), 121.2 (minor), 121.1 (major), 117.5 (minor), 117.1 (major), 110.3 (minor), 110.1 (major), 107.3 (major), 106.8 (minor) , 93.2 (minor), 91.4 (major), 33.6 (minor), 33.1 (minor), 32.6 (major), 31.1 (major);

IR (KBr) 3448, 1582, 1489, 1452, 1248, 1212, 1175, 1090, 1009 cm-1; IR (KBr) 3448, 1582, 1489, 1452, 1248, 1212, 1175, 1090, 1009 cm −1 ;

MS m/z (%) 216 (M+, 58), 198 (100), 165 (52), 131 (28), 91 (38); MS m / z (%) 216 (M + , 58), 198 (100), 165 (52), 131 (28), 91 (38);

원소분석: C13H12O3: 계산상 C 72.21, H 5.59 측정상 C 71.96, H 5.63;Elemental Analysis: C 13 H 12 O 3 : Calcd for C 72.21, H 5.59 Calibrated C 71.96, H 5.63;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 12.3 분 및 S- 이성질체 tr = 13.0 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 12.3 min and S- isomer t r = 13.0 min.

실시예Example 14 14

(R)-4-벤조퓨란-2-일-크로만-2-올 ((R)-4-Benzofuran-2-yl-chroman-2-ol (4n))의 합성( R ) -4-benzofuran-2-yl-chroman-2-ol (( R ) -4-Benzofuran-2-yl-chroman-2-ol Synthesis of ( 4n ))

2-벤조퓨란브론산 3g (49 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (62 mg, 93% 수득률, 78:22 er)로 얻었다. To 3 g (49 mg, 0.30 mmol) of 2-benzofuranbromic acid was added catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O. (4.5 μL, 0.25 mmol) is added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 20% EtOAc / hexanes was purified by silica gel chromatography as a white solid (62 mg, 93% yield, 78:22 er).

mp 146-147 oC; mp 146-147 o C;

1H NMR (300 MHz, CDCl3) δ 6.85-7.56 (m, 9H), 6.56 (s, 0.87H), 6.52 (s, 0.13H), 5.74 (brs, 0.87H), 5.64 (brs, 0.13H), 4.60 (dd, J = 3.3, 7.5 Hz, 0.87H), 4.48 (dd, J = 3.6, 7.2 Hz, 0.13H), 3.44 (d, J = 5.7 Hz, 0.13H), 3.22 (d, J = 3.0 Hz, 0.87H), 2.31-2.62 (m, 2H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.85-7.56 (m, 9H), 6.56 (s, 0.87H), 6.52 (s, 0.13H), 5.74 (brs, 0.87H), 5.64 (brs, 0.13H ), 4.60 (dd, J = 3.3, 7.5 Hz, 0.87H), 4.48 (dd, J = 3.6, 7.2 Hz, 0.13H), 3.44 (d, J = 5.7 Hz, 0.13H), 3.22 (d, J = 3.0 Hz, 0.87H), 2.31-2.62 (m, 2H);

13H NMR (75 MHz, CDCl3) δ 159.3 (minor), 159.1 (major), 155.0 (major), 151.8 (major), 129.3 (minor), 123.0 (major), 128.9 (minor), 128.6 (major), 128.4 (major), 124.0 (minor), 123.8 (major), 122.9 (minor), 122.7 (major), 121.7 (major), 121.3 (minor), 121.2 (major), 120.8 (minor), 120.7 (major), 117.6 (minor), 117.3 (major), 111.2 (major), 104.7 (major), 103.8 (minor), 93.1 (minor), 91.3 (major), 33.6 (minor), 33.3 (minor), 32.4 (major), 31.7 (major); 13 H NMR (75 MHz, CDCl 3 ) δ 159.3 (minor), 159.1 (major), 155.0 (major), 151.8 (major), 129.3 (minor), 123.0 (major), 128.9 (minor), 128.6 (major) , 128.4 (major), 124.0 (minor), 123.8 (major), 122.9 (minor), 122.7 (major), 121.7 (major), 121.3 (minor), 121.2 (major), 120.8 (minor), 120.7 (major) , 117.6 (minor), 117.3 (major), 111.2 (major), 104.7 (major), 103.8 (minor), 93.1 (minor), 91.3 (major), 33.6 (minor), 33.3 (minor), 32.4 (major) , 31.7 (major);

IR (KBr) 3452, 1584, 1492, 1451, 1252, 1214, 1182, 1090, 1008 cm-1; IR (KBr) 3452, 1584, 1492, 1451, 1252, 1214, 1182, 1090, 1008 cm −1 ;

MS m/z (%) 266 (M+, 62), 248 (84), 223 (100), 165 (42), 131 (22); MS m / z (%) 266 (M + , 62), 248 (84), 223 (100), 165 (42), 131 (22);

원소분석: C17H14O3: 계산상 C 76.68, H 5.30 측정상 C 76.29, H 5.41; Elemental Analysis: C 17 H 14 O 3 : C 76.68, H 5.30 on calculation C 76.29, H 5.41;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 17.1 분 및 S- 이성질체 tr = 22.4 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 17.1 min and S- isomer t r = 22.4 min.

실시예Example 15 15

*(R)-4-티오펜-2-일-크로만-2-올 ((R)-4-Thiophen-2-yl-chroman-2-ol (4o))의 합성* ( R ) -4-thiophen-2-yl-chroman-2-ol (( R ) -4-Thiophen-2-yl-chroman-2-ol Synthesis of ( 4o ))

2-티에닐브론산 3h (45 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 20% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (37 mg, 64% 수득률, 78:22 er)로 얻었다. To 3 -thienylbronic acid 3h (45 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O. (4.5 μL, 0.25 mmol) is added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 20% EtOAc / hexanes was purified by silica gel chromatography as a white solid (37 mg, 64% yield, 78:22 er).

mp 109-110 oC; mp 109-110 o C;

1H NMR (300 MHz, CDCl3) δ 7.16-7.27 (m, 2H), 6.86-7.02 (m, 5H), 5.69 (dt, J = 2.1, 3.0 Hz, 0.90H), 5.60 (dt, 0.10H), 4.69 (dd, J = 4.2, 7.8 Hz, 0.90H), 4.58 (dd, 0.10H), 3.04 (brs, 0.10H), 3.22 (brs, 0.90H), 2.60 (ddd, 0.10H), 2.39 (ddd, J = 3.0, 4.2, 10.8 Hz, 0.90H), 2.20-2.31 (m, 1H); 1 H NMR (300 MHz, CDCl 3 ) δ 7.16-7.27 (m, 2H), 6.86-7.02 (m, 5H), 5.69 (dt, J = 2.1, 3.0 Hz, 0.90H), 5.60 (dt, 0.10H ), 4.69 (dd, J = 4.2, 7.8 Hz, 0.90H), 4.58 (dd, 0.10H), 3.04 (brs, 0.10H), 3.22 (brs, 0.90H), 2.60 (ddd, 0.10H), 2.39 (ddd, J = 3.0, 4.2, 10.8 Hz, 0.90H), 2.20-2.31 (m, 1H);

13H NMR (75 MHz, CDCl3) δ 151.4, 147.5, 129.2, 128.3, 126.7, 126.0, 124.8, 124.3, 121.1, 116.9. 91.3, 36.7, 32.5; 13 H NMR (75 MHz, CDCl 3 ) δ 151.4, 147.5, 129.2, 128.3, 126.7, 126.0, 124.8, 124.3, 121.1, 116.9. 91.3, 36.7, 32.5;

IR (KBr) 3452, 1579, 1479, 1448, 1252, 1175, 1092, 1010 cm-1; IR (KBr) 3452, 1579, 1479, 1448, 1252, 1175, 1092, 1010 cm −1 ;

HRMS: [M+] C13H12O2S: 계산상 232.0558 측정상 232.0561; HRMS: [M + ] C 13 H 12 O 2 S: calc. 232.0558. Calc. 232.0561;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 14.5 분 및 S- 이성질체 tr = 15.7 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 14.5 min and S- isomer t r = 15.7 min.

실시예Example 16 16

(R)-2-(2-하이드록시-크로만-4-일)-피롤-1-카르복시산 테트라-부틸 에스테르 ((R)-2-(2-Hydroxy-chroman-4-yl)-pyrrole-1-carboxylic acid tert-butyl ester (4p))의 합성( R) -2- (2-hydroxy-chroman-4-yl) -pyrrole-1-carboxylic acid tetra-butyl ester (( R ) -2- (2-Hydroxy-chroman-4-yl) -pyrrole- Synthesis of 1-carboxylic acid tert -butyl ester ( 4p ))

2-N-복(Boc)-피롤브론산 3i (53 mg, 0.30 mmol)에 촉매 1 (0.05 mmol)를 첨가하고 클로로포름 (0.8 mL)를 가한 후, 0.5 N CHCl2CO2H (10μＬ , 0.005 mmol)과 H2O (4.5 μＬ, 0.25 mmol)를 적가한다. 0 oC에서 2-하이드록시신남알데하이드 2a (37 mg, 0.25 mmol)를 가하고 0℃에서 72 시간 동안 교반한 후 15% EtOAc/헥산에서 실리카 겔 크로마토그래피를 하여 목적 화합물을 백색 고체 (69 mg, 88% 수득률, 92:8 er)로 얻었다. To 2-N-Boc-pyrrobromic acid 3i (53 mg, 0.30 mmol) was added Catalyst 1 (0.05 mmol) and chloroform (0.8 mL) was added, followed by 0.5 N CHCl 2 CO 2 H (10 μL, 0.005 mmol) and H 2 O (4.5 μL, 0.25 mmol) are added dropwise. From 0 o C 2- hydroxy cinnamic aldehyde 2a (37 mg, 0.25 mmol) was added and the desired compound was obtained and then stirred at 0 ℃ for 72 hours in 15% EtOAc / hexanes was purified by silica gel chromatography as a white solid (69 mg, 88% yield, 92: 8 er).

1H NMR (300 MHz, CDCl3) δ 6.84-7.32 (m, 5H), 6.08 (t, J = 2.4 Hz, 1H), 5.45-5.81 (m, 2H), 5.01 (t, J = 3.6 Hz, 0.75H), 4.93 (brs, 0.25H), 3.52 (brs, 0.25H), 3.43 (brs, 0.75H), 2.19-2.51 (m, 2H), 1.62 (s, 9H); 1 H NMR (300 MHz, CDCl 3 ) δ 6.84-7.32 (m, 5H), 6.08 (t, J = 2.4 Hz, 1H), 5.45-5.81 (m, 2H), 5.01 (t, J = 3.6 Hz, 0.75H), 4.93 (brs, 0.25H), 3.52 (brs, 0.25H), 3.43 (brs, 0.75H), 2.19-2.51 (m, 2H), 1.62 (s, 9H);

13H NMR (75 MHz, CDCl3) δ 152.7 (major), 152.4 (minor), 149.4 (major), 129.8 (major), 128.4 (minor), 128.0 (major), 123.7 (major), 122.3 (minor), 121.7 (major), 121.0 (major), 120.8 (major), 117.4 (minor), 116.8 (major), 113.9 (major), 110.3 (minor), 110.0 (major), 94.0 (minor), 91.9 (major), 84.2 (minor), 84.1 (major), 34.7 (major), 32.4 (major), 28.0 (major);
13 H NMR (75 MHz, CDCl 3 ) δ 152.7 (major), 152.4 (minor), 149.4 (major), 129.8 (major), 128.4 (minor), 128.0 (major), 123.7 (major), 122.3 (minor) , 121.7 (major), 121.0 (major), 120.8 (major), 117.4 (minor), 116.8 (major), 113.9 (major), 110.3 (minor), 110.0 (major), 94.0 (minor), 91.9 (major) 84.2 (minor), 84.1 (major), 34.7 (major), 32.4 (major), 28.0 (major);

*IR (KBr) 3443, 1736, 1492, 1372, 1318, 1160, 1119, 1068, 1005 cm-1; * IR (KBr) 3443, 1736, 1492, 1372, 1318, 1160, 1119, 1068, 1005 cm -1 ;

HRMS: [M+] C18H21NO4: 계산상 315.1471 측정상 315.1474; HRMS: [M + ] C 18 H 21 NO 4 : calcd for 315.1471 calcd for 315.1474;

산화(PCC, CH2Cl2)되어진 상기 크로만 생성물을 카이럴셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, λ= 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하였다. ; R- 이성질체 tr = 7.3 분 및 S- 이성질체 tr = 8.6 분.
The Croman product, oxidized (PCC, CH 2 Cl 2 ), was subjected to a Chiralcel AD-H column and an AD-H guard column (5% i-PrOH: hexane , Enantioselectivity was determined by HPLC analysis using 1.0 mL / min flow rate, λ = 220 nm). ; R- isomer t r = 7.3 min and S- isomer t r = 8.6 min.

상기 실시예 1 내지 16에 사용되는 촉매 1은 하기 화학식 1로 표현될 수 있다.Catalyst 1 used in Examples 1 to 16 may be represented by the following formula (1).

<화학식 1>&Lt; Formula 1 >

Figure 112013037728959-pat00010

Figure 112013037728959-pat00010

상기 실시예 1 내지 16에 의해 합성된 키랄 크로만-2-올 유도체를 하기 표 1에 나타내었다. The chiral chroman-2-ol derivatives synthesized in Examples 1 to 16 are shown in Table 1 below.

구분division 실시예 1(4a)Example 1 (4a) 실시예 2(4b)Example 2 (4b) 실시예 3(4c)Example 3 (4c) 실시예 4(4d)Example 4 (4d) 생성물product

Figure 112013037728959-pat00011
Figure 112013037728959-pat00011
Figure 112013037728959-pat00012
Figure 112013037728959-pat00012
Figure 112013037728959-pat00013
Figure 112013037728959-pat00013
Figure 112013037728959-pat00014
Figure 112013037728959-pat00014
 구분division 실시예 5(4e)Example 5 (4e) 실시예 6(4f)Example 6 (4f) 실시예 7(4g)Example 7 (4 g) 실시예 8(4h)Example 8 (4h) 생성물product
Figure 112013037728959-pat00015
Figure 112013037728959-pat00015
Figure 112013037728959-pat00016
Figure 112013037728959-pat00016
Figure 112013037728959-pat00017
Figure 112013037728959-pat00017
Figure 112013037728959-pat00018
Figure 112013037728959-pat00018
 구분division 실시예 9(4i)Example 9 (4i) 실시예 10(4j)Example 10 (4j) 실시예 11(4k)Example 11 (4k) 실시예 12(4l)Example 12 (4l) 생성물product
Figure 112013037728959-pat00019
Figure 112013037728959-pat00019
Figure 112013037728959-pat00020
Figure 112013037728959-pat00020
Figure 112013037728959-pat00021
Figure 112013037728959-pat00021
Figure 112013037728959-pat00022
Figure 112013037728959-pat00022
 구분division 실시예 13(4m)Example 13 (4 m) 실시예 14(4n)Example 14 (4n) 실시예 15(4o)Example 15 (4o) 실시예 16(4p)Example 16 (4p) 생성물product
Figure 112013037728959-pat00023
Figure 112013037728959-pat00023
Figure 112013037728959-pat00024
Figure 112013037728959-pat00024
Figure 112013037728959-pat00025
Figure 112013037728959-pat00025
Figure 112013037728959-pat00026
Figure 112013037728959-pat00026

Claims (5)

하기 화학식 2의 화합물을 화학식 1의 유기촉매하에서 하기 화학식 3의 화합물과 반응시키는 단계를 포함하는 화학식 4의 화합물 제조방법.
<화학식 1>
Figure 112013086746076-pat00027


<화학식 2>
Figure 112013086746076-pat00028

(상기 화학식 2에서, X는 수소, 메틸기, 메톡시기, 시아노기, 할로젠기로 이루어진 그룹에서 선택된 어느 하나의 작용기이다.)
<화학식 3>
Figure 112013086746076-pat00029

(상기 화학식 3에서, R은 퓨란기, 티오페닐기, 부톡시기로 치환된 피롤기로 이루어진 그룹에서 선택된 어느 하나의 작용기이다.)
<화학식 4>
Figure 112013086746076-pat00030

(상기 화학식 4에서, X는 수소, 메틸기, 메톡시기, 시아노기, 할로젠기로 이루어진 그룹에서 선택된 어느 하나의 작용기이고, R은 퓨란기, 티오페닐기, 부톡시기로 치환된 피롤기로 이루어진 그룹에서 선택된 어느 하나의 작용기이다.)A method for preparing a compound of Formula 4 comprising reacting a compound of Formula 2 with a compound of Formula 3 under an organic catalyst of Formula 1.
&Lt; Formula 1 >
Figure 112013086746076-pat00027


(2)
Figure 112013086746076-pat00028

(In Formula 2, X is any functional group selected from the group consisting of hydrogen, methyl group, methoxy group, cyano group, halogen group.)
(3)
Figure 112013086746076-pat00029

(In Formula 3, R is any functional group selected from the group consisting of a furan group, a thiophenyl group, a pyrrole group substituted with a butoxy group.)
&Lt; Formula 4 >
Figure 112013086746076-pat00030

(In Formula 4, X is any one selected from the group consisting of hydrogen, methyl, methoxy, cyano, halogen group, R is selected from the group consisting of a pyrrole group substituted with a furan group, thiophenyl group, butoxy group) It is either functional group.) 제 1 항에 있어서, 상기 반응은 클로로포름 용매 중에 디클로로아세트산을 가하여 수행되는 것을 특징으로 하는 화학식 4의 화합물 제조방법.The method of claim 1, wherein the reaction is performed by adding dichloroacetic acid in a chloroform solvent. 제 1 항에 있어서, 상기 화학식 4의 화합물은 4-퓨란-2-일-크로만-2-올, 4-벤조퓨란-2-일-크로만-2-올, 4-티오펜-2-일-크로만-2-올 또는 2-(2-하이드록시-크로만-4-일)-피롤-1-카르복시산 테트라-부틸 에스테르로 이루어진 그룹에서 선택된 어느 하나의 화합물인 것을 특징으로 하는 화학식 4의 화합물 제조방법. According to claim 1, wherein the compound of formula 4 is 4-furan-2-yl-chroman-2-ol, 4-benzofuran-2-yl-chroman-2-ol, 4-thiophene-2- Formula 4, characterized in that the compound of any one selected from the group consisting of 1-chroman-2-ol or 2- (2-hydroxy-chromen-4-yl) -pyrrole-1-carboxylic acid tetra-butyl ester Method for preparing a compound. 제 3 항에 있어서, 상기 화학식 4의 화합물은 R-이성질체인 것을 특징으로 하는 화학식 4의 화합물 제조방법. The method of claim 3, wherein the compound of Formula 4 is an R-isomer. 제 1 항 내지 제 4 항 중 어느 항에 있어서, 상기 화학식 4의 화합물을 키랄셀 AD-H 칼럼(Chiralcel AD-H column) 및 AD-H 가드 칼럼(AD-H guard column) (5% i-PrOH:헥산, 1.0 mL/min 유속, = 220 nm)을 이용한 HPLC 분석하여 거울상 이성질체 선택성을 결정하는 단계를 더 포함하는 것을 특징으로 하는 화학식 4의 화합물 제조방법.The compound according to any one of claims 1 to 4, wherein the compound of formula 4 is used in a chiralcel AD-H column and an AD-H guard column (5% i-). PrOH: hexane, 1.0 mL / min flow rate, = 220 nm) method of preparing a compound of formula 4 characterized in that it further comprises the step of determining the enantiomer selectivity by HPLC analysis.
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