카이랄 2-aminobenzimidazole계 유기 촉매의 개발과 CF3 작용기의 전자적 영향에 관한 연구

Abstract

1998년 Jacobsen group에서 유기 금속을 사용하지 않는 비대칭thiourea 유기 촉매 Strecker reaction을 처음으로 발표한 후, 수소 결합을 이용한 비대칭 thiourea 유기 촉매 반응은 급격하게 증가하여 다양한 화학 반응에 널리 적용되고 있다. 특히 카이랄 bifunctional 유기 촉매는 nucleophile와 electrophile을 동시에 활성화시킬 수 있어서 특정 반응을 높은 입체선택적으로 진행하기 위해 유용하게 사용되고 있다. 2002년 Schreiner group에서는 thiourea 유기 촉매에 CF3 작용기를 도입해 amine에 위치한 수소의 acidity를 높였으며 그 결과 수소 결합의 세기도 증가시킬 수 있었다. 또한 meta 위치에 CF3가 치환된 촉매는 ortho 위치의 수소와 thiourea의 황 사이에서 인력 상호 작용이 일어나, 유기 촉매가 적절한 conformer로 고정될 수 있어서 촉매 반응이 크게 개선시킬 수 있었다. 2005년 Göbel group에서는 RNA를 자르기 위한 촉매로 tris[2-(benzimidazol-2-ylamino)ethyl]amine을 도입하였다. 여기서 도입한 2-aminobenzimidazole 구조는 thiourea와 유사하면서도 좀 더 견고한 수소 결합 donor로 작용할 수 있어 새로운 Lewis acid 촉매로 활용될 수 있으며, 본 연구에서는 이 구조를 도입한 새로운 카이랄 2-aminobenzimidazole bifunctional 유기 촉매를 설계하여 촉매의 구조가 반응성에 어떤 변화를 가져오는지 연구하였다. 다양한 카이랄 2-aminobenzimidazole bifunctional 유기 촉매를 합성하여 점검해 본 결과, 성공적으로 합성된 카이랄 (S,S)-trans-cyclohexanediamine-5,7-di-CF3-benzimidazole 유기 촉매가 Michael reaction에서 뛰어난 결과를 나타냈다. 또한 이 유기 촉매에 치환된 두 개의 CF3 작용기는 2-aminobenzimidazole 구조의 전자 밀도를 감소시켜 acidity가 큰 촉매로 작용한다는 사실도 확인할 수 있었다. 특히 2-aminobenzimidazole 구조의 유기 촉매는 중성 조건과 산성 조건에서 각각 다른 반응 과정으로 작동한다는 사실도 확인하였으며, 이를 바탕으로 새로운 비대칭 2-aminobenzimidazole 유기 촉매 Michael reaction의 입체선택적인 반응 과정을 제시할 수 있었다. 새로운 카이랄 2-aminobenzimidazole bifunctional 유기 촉매는 aza-Michael type reaction에도 적용되어 좋은 입체선택성을 나타냈고, 입체선택성을 더욱 개선하기 위해 계속 연구중이다. 이 결과가 개선된다면 (+)-(S)-Dapoxetine의 합성에 응용될 수 있을 것으로 생각된다.

Since the Jacobsen group reported the metal-free Strecker reaction by using the first thiourea-based chiral ligands as hydrogen bond donors in 1998, thioureas have been extensively developed as Lewis acid organocatalysts, and successfully applied to various useful organic reactions thus far. Especially, chiral amine conjugated thioureas have been used as chiral bifunctional organocatalysts capable of simultaneously activating both nucleophiles and electrophiles in asymmetric reactions due to their Lewis acidic (thiourea moiety) and basic (chiral amine moiety) functionalities. Among the disclosed thiourea based catalysts, the N-5,7-bis(trifluoromethyl)phenyl group substituted catalysts, which was first introduced by the Schreiner group in 2002, have been widely used as chiral bifunctional catalysts. The electron-withdrawing CF3 group not only increases N–H acidity, which in turn facilitates a stronger hydrogen bonding interaction, but also contributes to the conformational rigidity of the catalyst by polarizing the adjacent H atoms and inducing an intramolecular hydrogen bonding interaction with the sulfur atom in the thioureas. In 2005, the Göbel group reported that the cleavage of RNA could be catalyzed by tris[2-(benzimidazol-2-ylamino)ethyl]amine under neutral conditions (pH 7.0). The guanidine moiety in 2-aminobenzimidazoles efficiently activated phosphates by hydrogen bonding, which could facilitate the cleavage of phosphate esters to cyclic phosphate and the corresponding alcohol. Since the 2-aminobenzimidazole group is conformationally more rigid and can potentially serve as new Lewis acid catalysts, we recently reported new 2-aminobenzimidazoles conjugated with cinchona alkaloid and successfully applied to enantioselective Michael additions. In this study, the synthesis and application of (S,S)-trans-cyclohexanediamine-5,7-di-CF3-benzimidazole as new efficient chiral bifunctional organocatalysts are reported and also investigated the catalytic mechanism of chiral 2-aminobenzimidazole type bifunctional organocatalysts at different reaction conditions. (S,S)-trans-cyclohexanediamine-5,7-di-CF3-benzimidazole was prepared as an efficient chiral bifunctional organocatalysts by the incorporation of the electron-withdrawing di-CF3 groups on the benzimidazole moiety and successfully applied to Michael additions of diethylmalonate to nitroolefins. The catalytic mechanism of 2-aminobenzimidazole bifunctional organocatalysts under different reaction conditions was also investigated. Under a neutral condition, the dimethylamine moiety and guanidine moiety play the role of base to abstract the alpha-hydrogen of malonate and Lewis acid to activate nitroolefin, respectively. However, the dimethylamine moiety, which is protonated under TFA additive condition, serves to form hydrogen bonds with nitroolefin as a Lewis acid, and the 2-aminobenzimidazole moiety then functions as a weak base to abstract the alpha-hydrogen of malonate, which in turn forms an ion pair between the guanidinium cation and malonate anion. The role of guanidine moiety and dimethylamine moiety might be reversed depending on the two reaction conditions. The positive basic role of 2-aminobenzimidazoles, compared to thioureas, might be applied to design new efficient bifunctional organocatalysts. Chiral (S,S)-trans-cyclohexanediamine-5,7-di-CF3-benzimidazole bifunctional organocatalyst was also applied to asymmetric aza-Michael type reaction and showed good enantiomeric excess. Further investigations into the stereoselectivity and mechanism of this reaction are underway and these enantiomeric rich products can be introduced to total synthesis of (+)-(S)-Dapoxetine.