본 발명은 미생물에 의한 광학활성 2-페닐-1-프로파놀의 제조 방법에 관한 것이다. 좀 더 상세하게는 알코올탈수소 효소 생산능을 갖는 미생물 중에서 2-페닐프로피온알데히드를 2-페닐-1-프로파놀로 환원하는 미생물을 스크리닝 (screening)하고, 이를 이용하여 [반응식 1]에서 일반식 1로 표시되는 라세믹 2-페닐프로피온알데히드를 (S)-2-페닐-1-프로파놀 또는 (R)-2-페닐-1-프로파놀로 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing optically active 2-phenyl-1-propanol by microorganisms. More specifically, screening microorganisms that reduce 2-phenylpropionaldehyde to 2-phenyl-1-propanol among microorganisms having an alcohol dehydrogenase-producing ability, and screening the microorganisms using the formula 1 in Scheme 1 A method for producing racemic 2-phenylpropionaldehyde represented by (S) -2-phenyl-1-propanol or (R) -2-phenyl-1-propanol.
현재까지 광학활성 2-페닐-1-프로파놀의 제조방법은 리파제(lipase) 효소를 이용하여 라세믹 2-페닐-1-프로파놀을 에스테르 반응(transesterification)하거나 라세믹 2-페닐-1-프로파놀의 에스테르를 가수분해 반응(hydrolysis)하여 광학활성 2-페닐-1-프로파놀과 이의 에스테르 유도체를 얻는 방법이 보고되고 있다.Until now, the method for preparing optically active 2-phenyl-1-propanol has been performed by transesterification of racemic 2-phenyl-1-propanol using lipase enzyme or by racemic 2-phenyl-1-propanol. It has been reported to hydrolyze esters of panol to obtain optically active 2-phenyl-1-propanol and ester derivatives thereof.
Bianchi 등(Journal of Organic Chemistry, 1988, 53:5531-5534)은 벤젠 상에서 리파제 P(아마노사)를 촉매로, 무수초산(acetic anhydride)을 아실공여체( acyl donor)로 사용하여 에스테르 반응하여, 라세믹 2-페닐-1-프로파놀로부터 (R)-2- 페닐-1-프로파놀(28 % ee)과 (S)-2-페닐-1-프로파놀의 에스테르(8 % ee)를 얻었다. 또 헥산 상에서 아실공여체로 초산비닐(vinyl acetate)을 사용하고 촉매로는 PPL (porcine pancreatic lipase) 효소를 사용하여 라세믹 2-페닐-1-프로파놀로부터 (R)-2-페닐-1-프로파놀(95 % ee)과 (S)-2-페닐-1-프로파놀의 에스테르 유도체(48 % ee)를 제조하는 방법이 Chen 등(Journal of Organic Chemistry, 1991, 56:1966-1968)에 의해 보고된 바 있다. Kawasaki 등(Tetrahedron Letters, 1999, 40:5223-5226)은 시클로헥산 상에서 아실공여체로 3-(2-나프틸)-프로피온산비닐 (vinyl 3-(2-naphthy)propanoate)과 촉매로 PPL 효소를 사용하여 에르테르 반응을 수행하여 라세믹 2-페닐-1-프로파놀에서 96.3 % ee의 (S)-2-페닐-1-프로파놀 에스테르 유도체와 28.8 % ee의 (R)-2-페닐-1-프로파놀을 제조하였다. 또한 같은 공정하에서 아실공여체로 3-(파라토릴) 프로피온산비닐(vinyl 3-(ｐ-tolyl) propanoate)과 리파제 PS(아마노사) 효소를 사용하여 (R)-알코올(23.6 % ee)과 이의 (R)-에스테르 유도체(95.8 % ee)를 제조하였다. 또 Goto 등(Journal of Molecular Catalysis B:Enzymatic, 2000, 9:245-250)은 2-페닐-1-(3-페닐프로피오닐옥시)-프로판(2-phenyl-1-(3-phenylpropionyloxy)-propane)을 PPL(시그마사)효소로 가수분해하여 전환율 35 %, 97 % ee를 갖는 (S)-2-페닐-1-프로파놀을 제조하였다.Bianchi et al. (Journal of Organic Chemistry, 1988, 53: 5531-5534) catalyzed esterification using lipase P (amanosa) on benzene and acetic anhydride as acyl donor. (R) -2-phenyl-1-propanol (28% ee) and ester (S) -2-phenyl-1-propanol (8% ee) were obtained from Mic 2-phenyl-1-propanol. In addition, (R) -2-phenyl-1-prop from racemic 2-phenyl-1-propanol using vinyl acetate as acyl donor on hexane and porcine pancreatic lipase (PPL) enzyme as catalyst. Preparation of ester derivatives of panol (95% ee) and (S) -2-phenyl-1-propanol (48% ee) is described by Chen et al. (Journal of Organic Chemistry, 1991, 56: 1966-1968). It has been reported. Kawasaki et al. (Tetrahedron Letters, 1999, 40: 5223-5226) use PPL enzyme as a catalyst with 3- (2-naphthyl) -vinyl propionate as an acyl donor on cyclohexane The ether reaction was carried out to obtain 96.3% ee (S) -2-phenyl-1-propanol ester derivative and 28.8% ee (R) -2-phenyl-1 in racemic 2-phenyl-1-propanol. Propanol was prepared. Also, under the same process, (R) -alcohol (23.6% ee) and its (I) using acyl donor 3- (paratoryl) vinyl propionate and lipase PS (Amanosa) enzymes R) -ester derivative (95.8% ee) was prepared. Goto et al. (Journal of Molecular Catalysis B: Enzymatic, 2000, 9: 245-250) are also known as 2-phenyl-1- (3-phenylpropionyloxy) -propane (2-phenyl-1- (3-phenylpropionyloxy)- propane) was hydrolyzed with PPL (Sigma) enzyme to prepare (S) -2-phenyl-1-propanol having a conversion of 35% and 97% ee.
한편 효소에 의한 환원반응에 의해 2-페닐프로피온알데히드에서 광학활성 2-페닐-1-프로파놀을 제조하는 공정이 보고되었는데 Yuan 등(Journal of Organic Chemistry, 1997, 62:2494-2499)은 말의 간에 있는 알코올탈수소효소(Equine liver alcohol dehydrogenase)와 전자 중개물질(electron mediator)인 메틸 비올로겐(methyl viologen)을 보조 물질(assistant)로 사용하여 98 % ee의 (S)-2-페닐-1-프로파놀을 얻었다. Kelemen-Horvath 등(Chemicke Zvesti,2002,6:52-56)등은 같은 효소를 이용하여 2-페닐프로피온알데히드에서 96 % ee의 (S)-2-페닐-1-프로파놀을 얻었다. 두 반응 모두 조효소(cofactor)로 β-nicotinamide adenine dinucleotide(NAD)를 사용하는 특징을 갖는다.
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이에 본 발명자들은 말의 간에 있는 알코올탈수소효소와 조효소로 NAD를 사용한 기존의 방법과는 달리, 알코올탈수소효소와 조효소가 함께 존재하는 환원반응이 가능한 미생물을 사용하여 2-페닐프로피온알데히드에서 광학활성 2-페닐-1-프로파놀을 합성하고자 하였다.Therefore, the present inventors, unlike the conventional method using NAD as the alcohol dehydrogenase and coenzyme in the liver of the liver, using the microorganism capable of the reduction reaction with the alcohol dehydrogenase and the coenzyme together optical activity in 2-phenylpropionaldehyde 2 It was intended to synthesize -phenyl-1-propanol.
앞서 말한 Yuan 등의 연구를 보면, 광학활성 2-페닐-1-프로파놀의 제조에 있어서 말의 간으로부터 얻은 알코올탈수소 효소와 조효소만으로 반응을 수행할 경우 입체선택적 환원반응이 이루어지지 않는다. 이 경우 보조 물질로 메틸 비올로겐(methyl viologen)을 첨가해주어야만 광학활성 2-페닐-1-프로파놀을 제조할 수 있다. 또한 Kelemen-Horvath 등의 경우도 효소의 작용을 도울 조효소 β-nicotinamide adenine dinucleotide(NAD)를 첨가해주는 반응이다.알코올탈수소 효소의 경우처럼 산화 환원반응과 관련하여 수행하는 효소들은 수소 이온의 수송을 위한 NAD+/NADH 체계가 필수적인 NADH 의존적(NADH-dependent)효소이다. 따라서 광학활성 2-페닐-1-프로파놀을 알코올탈수소 효소를 이용한 환원 반응으로 제조할 경우 반드시 조효소를 따로 공급해 주거나 조효소와 함께 보조물질까지 공급해 주어야하는 단점이 있다. 하지만 본 발명에 의한 방법을 기존의 단점을 극복할 수 있는 기술로 반응에 적합한 효소와 환원 반응시 반드시 필요한 조효소를 함께 보유하고 있는 미생물을 이용함으로써 추가적인 고가의 조효소 첨가가 불필요하여 공정이 간단하고 경제적인 장점을 갖는다. 또한 미생물 또는 미생물 유래의 효소를 이용하여 광학활성 2-페닐-1-프로파놀을 제조한 경우는 보고되어 있지 않다.따라서, 본 발명의 목적은 미생물을 생촉매로 사용하여 라세믹 2-페닐프로피온알데히드로부터 높은 광학순도와 수율의 (R)-또는 (S)-2-페닐-1-프로파놀을 제조하는 공정을 제공하는데 있다.According to the aforementioned research by Yuan et al., In the preparation of optically active 2-phenyl-1-propanol, the stereoselective reduction reaction does not occur when the reaction is performed only with alcohol dehydrogenase and coenzyme obtained from horse liver. In this case, methyl viologen should be added as an auxiliary material to prepare optically active 2-phenyl-1-propanol. Kelemen-Horvath also adds coenzyme β-nicotinamide adenine dinucleotide (NAD) to help the enzyme's action. As in the case of alcohol dehydrogenase, enzymes involved in redox reactions are used to transport hydrogen ions. The NAD+ / NADH system is an essential NADH-dependent enzyme. Therefore, when the optically active 2-phenyl-1-propanol is prepared by a reduction reaction using an alcohol dehydrogenase, a coenzyme must be supplied separately or an auxiliary material must be supplied together with the coenzyme. However, the method according to the present invention is a technology that can overcome the existing disadvantages by using a microorganism having both the enzyme suitable for the reaction and the coenzyme necessary for the reduction reaction, the addition of additional expensive coenzyme is unnecessary and the process is simple and economical Has the advantage. In addition, there have been no reports on the preparation of optically active 2-phenyl-1-propanol using microorganisms or enzymes derived from microorganisms. Accordingly, an object of the present invention is to provide a racemic 2-phenylpropion using a microorganism as a biocatalyst. To provide a process for preparing (R)-or (S) -2-phenyl-1-propanol of high optical purity and yield from aldehyde.
상기 목적을 달성하기 위한 본 발명의 방법은 페닐프로피온알데히드에서 광학활성 2-페닐-1-프로파놀 생성능을 갖는 미생물을 스크리닝하여 배양하고, 이를 촉매로 사용하여 반응시키는 것으로 이루어진다.The method of the present invention for achieving the above object consists of screening and culturing a microorganism having an optically active 2-phenyl-1-propanole generating ability in phenyl propionaldehyde, and reacting using it as a catalyst.
이하 본 발명을 좀 더 상세히 설명하면 다음과 같다. 전술한 바와 같이, 본 발명은 라세믹 2-페닐프로피온알데히드로부터 미생물을 이용하여 광학활성 2-페닐-1-프로파놀을 제조하는 공정에 관한 것이다.Hereinafter, the present invention will be described in more detail. As described above, the present invention relates to a process for preparing optically active 2-phenyl-1-propanol from racemic 2-phenylpropionaldehyde using microorganisms.
본 발명에 사용되는 미생물은 박테리아로서Enterobacter cloacae,Erwinia herbicolar,Klebsiella pneumoiae,Micrococcus luteus,Pseudomonas putida,Rhodococcus erythropolis와 효모로서Candida parapsilosis와Candida rugosa 등을 포함하는Candida 속 미생물들,Geotrichum candidum,Kluyveromyces lactis와Kluyveromyces marxianus 등을 포함하는Kluyveromyces 속 미생물들,Mucor racemosus,Mortierella ramanniana var.,Penicillium pinophilum,Pichia pastoris,Rhodotorula mucilaginosa,Saccharomyces cerevisiae,Trigonopsis variabilis 등 알코올탈수소효소 생산능을 갖는 여러 종의 미생물에 해당되나 이에 한정되는 것은 아니다.As the microorganism bacteria used in the present invention,Enterobacter cloacae, Erwinia herbicolar, Klebsiella pneumoiae , Micrococcus luteus, Pseudomonas putida, Rhodococcus aserythropolis and yeasts ofCandida spp, or the likeCandida parapsilosis andCandida rugosa,Geotrichum candidum,Kluyveromyces lactis andKluyveromyces Microorganisms of the genusKluyveromyces , includingmarxianus ,Mucor racemosus ,Mortierella ramanniana var.,Penicillium pinophilum ,Pichia pastoris ,Rhodotorula mucilaginosa ,Saccharomyces cerevisiae ,Trigonopsis variabili s, etc. It doesn't happen.
본 발명에 있어서, 미생물에 의해 생성된 화합물은 모세관 칼럼인 BP-5(SGE사, 0.53 mm X 30 m)가 장착된 기체크로마토그래피(도남인스트루먼트사, 모델 DS 6200)를 이용하여 정량하였다. 분석 조건으로는 60 ℃에서 5 분간 가열하고 분당 7 ℃씩 200 ℃까지 증가시킨 후 200 ℃에서 5 분간 유지시켰다. 담체(carrier gas)로는 헬륨 기체를 분당 2 ml의 속도로 흘리고 230 ℃에서 FID(flame ionization detector)를 사용하여 검출하였다. 이 때 라세믹 2-페닐 프로피온알데히드는 13.8 분, 2-페닐-1-프로파놀은 16.2 분에서 각각 검출되었다. 광학활성 2-페닐-1-프로파놀은 키랄 칼럼 G-TA(Alltech사, 0.32 mm X 30 m)가 장착된 기체크로마토그래피(도남인스트루먼트사, 모델 DS 6200)를 이용하여 분석하였다. 온도를 80 ℃로 헤드 압력(head pressure)을 22 psi로 유지하였고, 200 ℃에서 FID(flame ionization detector)를 사용하여 검출하였다. 이 때 (R)-2-페닐-1-프로파놀은 30.8 분에서 검출되었고, (S)-2-페닐-1-프로파놀은 29.8 분에서 검출되었다.In the present invention, the compound produced by the microorganism was quantified using gas chromatography (Donam Instruments, Model DS 6200) equipped with a capillary column BP-5 (SGE, 0.53 mm X 30 m). Analytical conditions were heated at 60 ° C. for 5 minutes, increased 7 ° C. per minute to 200 ° C., and maintained at 200 ° C. for 5 minutes. As a carrier gas, helium gas was flowed at a rate of 2 ml / min and detected using a flame ionization detector (FID) at 230 ° C. At this time, racemic 2-phenyl propionaldehyde was detected at 13.8 minutes and 2-phenyl-1-propanol at 16.2 minutes, respectively. Optically active 2-phenyl-1-propanol was analyzed using gas chromatography (Cheonnam Instruments, Model DS 6200) equipped with chiral column G-TA (Alltech, 0.32 mm × 30 m). The temperature was maintained at 80 ° C., head pressure at 22 psi, and detected at 200 ° C. using a flame ionization detector (FID). At this time, (R) -2-phenyl-1-propanol was detected at 30.8 minutes, and (S) -2-phenyl-1-propanol was detected at 29.8 minutes.
이하 실시예를 통하여 본 발명을 좀 더 구체적으로 설명하지만, 하기 예에 본 발명의 범주가 한정되는 것은 아니다.실시예 1-9The present invention will be described in more detail with reference to the following Examples, but the scope of the present invention is not limited to the following Examples.
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1 L 플라스크에서 포도당을 첨가한 LB 배지액 200 ml에 36 시간동안 하기 표1에 명시한 박테리아를 배양한 다음, 배양된 균체를 원심분리하였다. 15 ml 바이알에 50 mM 인산완충용액(potassium phosphate buffer, pH 7.0) 4.45 ml, 1M 포도당 500 ㎕ 및 2-페닐프로피온알데히드 50 ㎕ 를 넣은 뒤, 분리된 균체를 주입한 후 30 ℃에서 반응을 수행하였다. 일정 시간 반응 후 반응액을 초산에틸(ethyl acetate)로 추출하여 상기의 분석방법에 따라 분석하였다. 2-페닐-프로파놀의 반응전환율 및 광학순도는 표1과 같다.In a 1 L flask, the bacteria specified in Table 1 were incubated in 200 ml of glucose-added LB medium for 36 hours, followed by centrifugation of the cultured cells. In a 15 ml vial, 4.45 ml of 50 mM phosphate buffer (pH 7.0), 500 μl of 1M glucose and 50 μl of 2-phenylpropionaldehyde were injected, and then the separated cells were injected. . After reaction for a certain time, the reaction solution was extracted with ethyl acetate and analyzed according to the above analysis method. Reaction conversion and optical purity of 2-phenyl-propanol are shown in Table 1.
실시예 10-26Example 10-26
실시예1 과 같은 조건으로 표2에 명시한 효모를 GYP배지를 사용하여 배양하였고, 실시예1과 동일한 방법으로 반응을 수행하여 그 결과를 표2에 나타내었다.
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상기 실시예에서 알 수 있는바와 같이, (R)-2-페닐-1-프로파놀 및 (S)-2-페닐-1-프로파놀을 제조함에 있어서 알코올탈수소 효소와 조효소 생산능을 갖는 미생물이 이용될 수 있으며, 미생물마다 광학활성이 다르게 나타나는 특징을 이용하여 반응을 수행하여 각각 (R)-및 (S)-2-페닐-1-프로파놀을 제조할 수 있다. 또한 비대칭 합성법(asymmetric synthesis)이 아닌 미생물을 이용한다는 점에서 본 발명은 환경친화적이라 할 수 있다.As can be seen in the above examples, in the preparation of (R) -2-phenyl-1-propanol and (S) -2-phenyl-1-propanol, microorganisms having an alcohol dehydrogenase and coenzyme-producing ability (R)-and (S) -2-phenyl-1-propanol can be prepared by carrying out the reaction using the characteristic that the optical activity is different for each microorganism. In addition, the present invention is environmentally friendly in that it uses microorganisms rather than asymmetric synthesis.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2003-0033596AKR100532627B1 (en) | 2003-05-27 | 2003-05-27 | Alcohol dehydrogenase -producing microorganisms and the method of making optically active 2-phenyl-1-propanol by these microorganisms |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2003-0033596AKR100532627B1 (en) | 2003-05-27 | 2003-05-27 | Alcohol dehydrogenase -producing microorganisms and the method of making optically active 2-phenyl-1-propanol by these microorganisms |
| Publication Number | Publication Date |
|---|---|
| KR20040101797A KR20040101797A (en) | 2004-12-03 |
| KR100532627B1true KR100532627B1 (en) | 2005-12-02 |
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| KR10-2003-0033596AExpired - Fee RelatedKR100532627B1 (en) | 2003-05-27 | 2003-05-27 | Alcohol dehydrogenase -producing microorganisms and the method of making optically active 2-phenyl-1-propanol by these microorganisms |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP5947219B2 (en) | 2009-12-29 | 2016-07-06 | ビュータマックス・アドバンスド・バイオフューエルズ・エルエルシー | Alcohol dehydrogenase (ADH) useful for fermentative production of lower alkyl alcohols |
| CN103484404A (en)* | 2013-09-22 | 2014-01-01 | 中国环境科学研究院 | Efficient repairing complex inoculant and application thereof |
| EP3180437A2 (en)* | 2014-08-14 | 2017-06-21 | Repsol, S.A. | Process for production of branched chain alcohols |
| CN111778198B (en)* | 2020-08-18 | 2021-12-10 | 杭州医学院 | A kind of Bacillus luteus HMC01 and its application in the preparation of chiral alcohol by asymmetric reduction |
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| KR20040101797A (en) | 2004-12-03 |
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