催化劑與諾貝爾獎的故事
關於Kanto Chemical
日本關東化學，成立於1944年，一直致力於化學試劑、電子產業化學品、診斷及精細化工產品的研發和生產，其產品新穎性以及質量標準一直是行業標杆。通過覽博網，關東化學催化劑產品首次面向中國供應，為中國研究人員帶來更多優質選擇。
立體選擇性不對稱加氫催化劑
本次介紹的催化劑由日本科技振興會（JST）支持的先進技術探索研究計劃（ERATO）-- NOYORI分子催化項目研究，開發與應用研究項目開發。關東化學推出了一系列具有雙膦和雙胺配體的不對稱加氫催化劑。其中，耦合BINAP配體的手性釕催化劑對酮類化合物具有非常不錯的反應活性和更好的對映選擇性[1]。
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手性釕催化劑的運用
1. 芳香酮的氫化
XylSKEWPHOS catalysts hydrogenate aromatic ketones effectively with high enantioselectivity to yield optically active alcohols[2]. For example, acetophenone is hydrogenated with RuCl2(tolbinap)(daipen) to afford 1-phenylethanol in 91% ee and RuBr2(xylskewphos)(daipen) gives 98% ee for the same substrate.
Aromatic ketones with several substituents on aromatic rings are also hydrogenated efficiently to give optically active alcohols in high ee. To obtain high enantioselectivity, proper selection of the catalysts is necessary. The DPEN catalyst usually gives higher enantioselectivity than the DAIPEN catalyst for the reaction of o-substituted aromatic ketones. For example, o-chloroacetophenone is hydrogenated with the DPEN and the DAIPEN catalyst in 97% ee and 94% ee, respectively. o-Bromoacetophenone is hydrogenated in >99% ee with both of the DPEN and the DAIPEN catalyst. For the reaction of m- and p-substututed-aromatic ketones, the DAIPEN catalyst is assumed to have better enantioselectivity than the DPEN catalyst. For example, m-chloro and m-bromoacetophenone are hydrogenated with the DAIPEN catalyst in 97% ee and 99% ee, respectively. p-Fluoro, p-chloro and p-bromoacetophenone are also hydrogenated with the DAIPEN catalyst in 97% ee, 97% ee and 99% ee, respectively.
2. 雜環酮的氫化
RuCl2(binap)(diamine) catalysts don’t have high enantio-selectivity for the asymmetric hydrogenation of hetero aromatic ketones. RuBr2(xylskewphos)(daipen) has higher enantio-selectivity for these ketones. For example, 2-acetylfuran and 2-acetylthiophene are hydrogenated efficiently to give optically active 1-(2-furanyl) ethanol in 97% ee and 1-(2-thienyl) ethanol in 96% ee.
3. 其他酮的氫化
Carbonyl compounds with conjugatedor unconjugated carbon-carbon multiple bonds can be converted effectively to the corresponding unsaturated alcohols. Cyclohexyl ketone, which is a difficultsubstrate to obtain with high enantioselectivity, can be hydrogenated in 94% eewith this catalyst. a-N,N-Dimethyl-aminoacetophenone is also hydrogenated enantioselectively with 97% ee.
4. 亞胺的氫化
Catalytic asymmetric hydrogenation ofimines is one of the most efficient and convenient method for the preparationof optically active amines. We foundthat RuBr2(xylskewphos)(dpen) is an excellent catalyst for theasymmetric hydrogenation of imines[3] in the joint research project with Prof. Ohkuma in Hokkaido University . Various iminescan be hydrogenated efficiently with this catalyst to afford the amine productsin high ee’s.
Reactions can be conducted in a varietyof aprotic slovents suchas toluene (hydrocarbon solvent) and THF (ether solvent). For example, hydrogenation of N-2-methoxyphenyl (OMP) acetophenone imine is completed within 15 h in various aprotic solventsin the presence of potassium tert-butoxide at a substrate-to-catalystmolar ratio (S/C) of 1,000 under 10 atm of hydrogen pressure, leading to theoptically active phenetylamine in 99% ee.
The reaction of N-substitutedimines, where the N-substituent is the phenyl group,electron-donating methoxyphenyl group, or electron-withdrawing halogenatedphenyl group, also proceed efficiently. For example, N-OMPacetophenone imine is hydrogenated at a S/C of 5,000 under 10 atm of H2 to afford the optically active amine in99% eequantitatively. The methoxyphenyl groupis readily deprotected to give the optically active primary amines[4]. Although the reactivity of N-alkyl imines is relatively low, the enantioselectivity is maintained high. For example, N-n-Bu imine is reduced at a S/C of 2,000 toafford the amine product in 97% ee with 85% yield. The ee value of product from N-Benzylimines is low.
This catalyst system is applicable to avariety of N-arylimines. N-OMP imines derived from acetophenoneswith an electron-donating or an electron-withdrawing group on the phenyl ringare hydrogenated at a S/C of 1,500-3,000 under 10 atm of H2 to afford the optically active amines inup to 99% eequantitatively. The reaction of iminewith naphthalene ring, propiophenone imine and butyrophenone imine proceedefficiently. Heteroaromatic imines, suchas pyridyl imines, ferrocenyl imine and a,b-unsaturated imine, are also hydrogenatedin high ee’s. The hydrogenation of diiminederived from 1,3-diacetylbenzene affords the diamine product with a high diastereo (dl:meso= 96:4) and high enantioselectivity (>99% ee) in 99% yield.
The N-substituted imine with 3-bromophenylgroup or 4-Boc-aminopheny group is converted to the corresponding chiral aminein 96% ee or 93% ee,respectively. These chiral amines areenable to the synthetic intermediates of biologically active compounds[5,6].
1) R. Noyori, T. Ohkuma, Asymmetric Catalysis byArchitectural and Functional Molecular Engineerig: Practical Chemo- and Stereoselective Hydrogenation of Ketones, Angew. Chem. Int. Ed.2001,40,40.
2) Novel Ruthenium complexes and preparation ofalcohols with these Ruthenium catalysts. Patent 3566955 (Japan).
3) N. Arai, N. Utsumi, Y. Matsumoto, K. Murata, K. Tsutsumi, T. Ohkuma, Adv. Synth. Catal.2012, 354, 2089.
4) a) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg, P. L. Alsters, F. L. van Delft, F. P. J. T. Rutjes, Tetrahedron Lett.2006,47,8109. b) N. Mršić,A. J. Minnaard, B. L. Feringa, J. G. de Vries, J. Am. Chem. Soc.2009, 131, 8358. c) D. Xiao, X. Zhang, Angew. Chem. Int. Ed.2001,40,3425. d) J. M. M. Verkade, F. van der Pijl, M. M. J. H. P. Willems, P. J. L.M. Quaedflieg, F. L. van Delft, F. P. J. T. Rutjes, J. Org. Chem.2009,74,3207. e) J. R. Porter, J. F. Traverse, A. H. Hoveyda, M. L. Snapper, J. Am. Chem. Soc.2001, 123, 984. f) M. Ohara,S. Nakamura, N. Shibata, Adv. Synth. Catal.2011, 353, 3285.
5) D. Angst, B. Bollbuck, P. Janser, J. Quancard, (Novartis AG.), PCT Int.WO2010/072712 A1, 2010.
6) K. Schnatbaum, D. Scharn, E. Locardi, T. Polaakowski, U. Richter, U. Reineke, G. Hummel, (Jerini AG.), PCT Int. WO2006/128670 A1, 2006.
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