효소-금속 촉매를 혼용한 1차 아민의 빠른 동적 광학 분할

Abstract

의약품들은 광학 활성을 갖는 경우가 많다. 이러한 키랄 의약품은 생체 내로 들어가게 되면 광학 이성질체에 따라 전혀 다른 성질을 나타내는 경우가 많은데, 이는 인체를 구성하는 아미노산과 대사과정에 관여하는 물질들 또한 광학 활성을 갖기 때문이다. 1960년대 임신 입덧 치료제로 사용된 Thalidomide가 대표적인 예로, D형은 약효가 있지만 L형은 팔다리가 없는 기형아 출산의 부작용이 있다. 유럽과 캐나다 등지에서 수 천명의 기형아를 낳는 부작용을 목도한 이래, 미국 FDA는 화학구조상 키랄성을 가진 분자는 광학적으로 순수한 단일 의약품으로 개발할 것을 권고하는 새로운 가이드 라인을 제시했다. 그 후 단일 광학이성질체 의약품(single enantiomer drugs) 시장은 지속적으로 증가해, 2004년 전세계 매출 10위권 안에 드는 Lipitor, Zocor, Plavix, Nexium 등이 모두 단일 광학이성질체 의약품이다. 이렇듯 원하는 형태의 광학 활성 물질을 높은 광학 순도로 합성하는 chirotechnology는 유기 합성이나 의약 화학 분야에서 중요한 과제이다.속도론적 광학분할(Kinetic Resolution, KR)은 광학이성질체간의 반응 속도차이를 이용해 분리하는 방법으로, 단백질의 독특한 3차 구조로 인해 기질 선택성과 입체 선택성이 뛰어난 효소를 이용한 Enzymatic resolution이 대표적이다. 이 방법은 값싼 효소를 이용하기 때문에 경제적이고, 반응 조건이 까다롭지 않다는 장점이 있다. 하지만 최대 수율이 50%에 불과해 반응의 경제성이 떨어지므로 합성에 응용하는데 제약이 따른다. 최근 이 문제를 해결하기 위한 방법론의 하나로 동적 속도론적 광학분할(Dynamic Kinetic Resolution, DKR)이 연구 되고 있다. 동적 속도론적 광학분할이란 속도론적 광학분할과 동시에 라세미화가 일어나는 반응을 뜻하며, 높은 수율과(~100%) 높은 광학순도의 생성물을 얻을 수 있다.우리 그룹이 연구중인 효소를 이용한 광학 분할 반응과 금속촉매의 라세미화 반응을 결합해 하나의 광학 이성질체를 선택적으로 얻는 효소/금속 촉매 혼용 반응(Enzyme/Metal Combo Reaction, EMCR)이 DKR의 대표적인 예이다. 이 방법은 2차 알코홀의 DKR에 대해서는 실용적인 측면에서 상당한 진척을 이루었으나, 아민 DKR의 경우 느린 라세미화 반응속도로 인해 아직 실용적인 수준에까지 이르지 못하였다. 따라서 본 연구에서는 라세미화 활성이 높은 촉매를 합성해 반응이 하루 이내에 종결되는 빠른 동적 속도론적 광학 분할 (Fast DKR)을 수행하고자 한다.

Since the regulation about chiral molecules by FDA, the interest in asymmetric syntheses is becoming more and more increasing due to its importance in the agricultural, food, and pharmaceutical industries. Dynamic kinetic resolution (DKR), combinations of a kinetic resolution and an in situ racemization, is one of practical methodology in preparation of optically active compounds. Moreover, DKR provides useful route for the complete transformation of racemic substrates into single enantiomeric products in contrary to conventional methods. In the last decade, the DKR by enzyme-metal combination, enzyme as a resolution catalyst together with a metal or metal complex as the racemization catalyst, have been developed by Kim-Park group and others. As a result, numerous enzyme-metal combinations are now available for the efficient DKR of secondary alcohols. However, the DKR of primary amines is rather difficult to achieve mainly due to the low activity of racemization catalyst, so few practical procedures have been developed to date. Accordingly, the amine DKRs should be performed at elevated temperature for long times (24 h or longer) to obtain satisfactory conversions. Thus, the objective of this research was to develop the highly active racemization catalyst and the practical procedure for the fast DKR of amines employing enzyme-metal combinations.I have investigated the palladium nanoparticles adsorbed on the surface of single walled carbon nanotubes (Pd on SWNTs) as a potential catalyst for racemization in the DKR of amines. Palladium nanoparticles were generated via auto-reduction by SWNTs in aqueous solution. Pd on SWNTs showed moderate activities in various palladium catalyzed reactions. However, the catalyst is poorly active in the racemization of amine. Moreover, it was proved that SWNTs are unsuitable support for amine racemization catalyst, because SWNTs are able to adsorb amines on its surface and thus leading to decrease isolated yield.I developed magnetically separable palladium nanocatalyst (Pd on Fe3O4) also for practical applications. In most of the previous studies, nanocatalysts were immobilized on the modified surface of magnetic nanoparticles (MNPs). However, the surface modifications of MNPs are time-consuming and often require non-green reagents. I thus prepared palladium nanocatalysts directly adsorbed on the unmodified surface of iron oxide MNPs via simple and straightforward synthetic procedure. The catalysts are active in the chemoselective olefin hydrogenation at room temperature. However, the catalysts are poorly active in the racemization of amine.Recently, our group employed aluminum oxyhydroxide, AlO(OH), as a support for palladium nanocatalyst utilized in amine racemization. Although the palladium nanocatalyst still needs further improvement in activity, the AlO(OH) matrix shows good compatibility in amine DKRs. After numerous efforts, I have developed the new palladium nanocatalyst, Pd on AlO(OH), showing remarkable activity toward amine racemization. As a result, I established an efficient procedure for the fast DKR of benzylic primary amines. The fast DKR employed with Pd on AlO(OH) as racemization catalyst, Novozym 435 as a resolution catalyst, isopropyl- and ethyl methoxyacetate as an acyl donor, sodium carbonate as a base for capturing acidic impurities. Under the optimized condition for fast DKR, eight benzylic amines were tested, and all of them were resolved with good yields and high optical purities within 6 hours. To the best of our knowledge, it is the fastest DKR of primary amines.I have explored the DKR of amino acid amides with enzyme-metal combination. However, it was proved that Pd on AlO(OH) is inappropriate in racemization of ？？-amino acid amide due to its electron deficient nature. I also envisaged the DKR of ？？-amino acid amide by PSL-Pd on AlO(OH) combination. Although the PSL shows a perfect enantioselectivity toward the resolution of ？？-amino acid amides, its poor thermal stability is a drawback in application. Therefore, I performed the one pot sequential reaction by adding fresh enzyme and controlling reaction temperature with good yield (90%) and excellence enantiomeric excesses (>99.5% ee).Finally, I have studied an application of Pd on AlO(OH) in the asymmetric synthesis of chiral drug. The key intermediate of calcimimetics (+)-NPS R-568 efficiently synthesized via asymmetric reductive acylation. The use of reactive palladium nanocatalyst, a dual catalyst for reduction of ketoxime and racemization of amine, reduced the reaction time more effectively, compared to the previous procedure.