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1、Recent Progress on Catalytic Asymmetric Synthesis,Albert S. C. Chan The Hong Kong Polytechnic University,Louis Pasteur Chemist 1822 - 1895,“Chance favors only the prepared mind.”,从酒石中结晶出来的酒石酸有两种形态，借助于放大镜和镊子可以分开。,威廉诺尔斯 William S, Knowles, Nobel Laureate 2001,Our book published in 2000!,Starting mater
2、ial,Hydrogen,Hydrogen,A: (S)-product, hydrolysis makes L-DOPA.,B: (R)-product,ee% = (A-B)/(A+B) 100%,Without chiral catalyst: ee = 0; With good chiral catalyst: ee 99%,Monsanto L-Dopa Process,Without chiral catalyst: (S)-alanine = (R)-alanine; ee = 0 With chiral catalyst: (S)-alanine (R)-alanine; ee
3、 99% ee% = (A-B)/(A+B) 100%,Production of L-alanine,A,B,野依良治 Ryoji Noyori, Nobel Laureate 2001,P-Phos (PolyU-invented Phosophine) 含吡啶基的新颖手性膦配体的设计、合成及应用,Chan, A. S. C.; Pai, C.-C. US Patent 5 886 182, 1999. Technology licensed to Johnson Matthey. Pai, C.-C.; Chan, A. S. C; et al. J. Am. Chem. Soc. 20
4、00, 122, 11513. Chemtract 杂志进行了专题评述，Chemtract Inorg. Chem., 14: 278-281, 2001.,R1 = Ph, R2 = Et: 95% ee (BINAP: 85% ee),P-Phos类手性配体在不对称催化反应中的应用,up to 99% ee,up to 99% ee,up to 96% ee,up to 98% ee,up to 95% ee,up to 99.9% ee,up to 99.7% ee,up to 92% ee,P-Phos 适用范围广（C=C，C=O和C=N键的氢化，C-C键的形成），对空气稳定，立体选择
5、性能优于或与BINAP性能相当。,P-Phos 类催化剂,BINAP催化剂,无氧条件,反应前体系在空气中暴露10小时,含P-Phos类手性配体的钌催化剂RuL*(C6H6)Cl2的空气稳定性,100% conv. 96.2% ee,100% conv. 92.0% ee,100% conv. 95.7% ee,94.1% conv. 66.6% ee,P-Phos类手性金属催化剂是目前报道的唯一不怕氧，可在空气中操作的高效不对称氢化催化剂。,含吡啶基手性膦配体铜配合物催化下芳香酮的不对称硅氢化反应,催化剂与底物的比率高于100,000； 产物的对映体过量高达97%； 空气中进行，操作方便； 与
6、Novartis达成技术转让协议。,Wu, J.; Chan, A. S. C.; et al. PNAS, 2005, 102, 3570-3575. Special lightlight by This Week in PNAS (March 8, 2005) ； Also reported by C&En News (Feb., 28, 2005).,Wu, J.; Chan, A. S. C.; et al. J. Org. Chem., 2002, 67, 7908. Wu, J.; Chan, A. S. C.; et al. Chem. Eur J., 2003, 9, 2963
7、.,P-Phos-钌配合物催化下芳香酮的不对称氢化反应,香港理工大学与英国ICI公司签订技术转让协议,第五部分香港理工大学的手性科技实验室,香港理工大学与英国ICI公司签订技术转让协议,新型手性膦配体：手性膦配体的新合成方法,高对映选择性反应 得到单一组分配体,PNAS, 2004, 101, 5815-5820.,钌催化的酮酸酯的不对称氢化反应,JACS, 2006, 128(17), 5955-5965.,Enantioselective hydrogenation of -aminomethylacrylates containing a free N-H group for the s
8、ynthesis of -amino acid derivatives,HK PolyU,Novartis,BackgroundVery important constituents of molecules with interesting biological and pharmacological activities for example,found by Merck against fungi,Scheme 1. Synthesis of -aminomethylacrylates and the asymmetric hydrogenation process,Some liga
9、nds used in this study,Screening of catalysts for the asymmetric hydrogenation of E-2a,T = r.t.,P = 1000psi, T = r.t., S/C = 100 solvent: MeOH,L= Et-DuPhos, T = r.t., S/C = 100 *No further optimization,Effects of ligands and solvents for the hydrogenation of E-2a,*E:Z = 80:20 T = r.t.,L=,Asymmetric
10、hydrogenation of -aminomethylacrylates,*2b: E/Z = 1,L=,Asymmetric hydrogenation of -aminomethylacrylates,PNAS 2007, 104, 16787-16792,The catalytic asymmetric hydrogenation is a great success both in scientific discovery and in commercial application. An important challenge for organic chemists is to
11、 make catalytic asymmetric formation of C-C, C-O, C-N bonds equally successful.,Catalytic Asymmetric Alkenyl Transfer to Aldehydes Promoted by Optically Active Tertiary Aminonaphthol,Importance of chiral (E) -allyl alcohols: key intermediates for a large number of natural products and biological act
12、ive compounds substrates for various useful reactions, such as allylic substitution, cyclopropanation, aziridination, epoxidations and ene-reactions,Asymmetric (E)-alkenylzinc addition to aldehydes afford chiral (E) - allyl alcohols,Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1 1994, 1257.,
13、Examples of alkenyl transfer to aldehydes by alkyne-BH3-ZnMe2-aldehyde system,Using alkyne-BH3-ZnMe2 method to generate alkenylzinc reagent A new and one-step method for the practical synthesis of optically active tertiary aminonaphthol ligand High activities and enentioselectivities (up to 99% ee),
14、J.-X. Ji.; L.-Q. Qiu.; C. W. Yip,; A. S. C. Chan, J. Org. Chem. 2003, 68(4), 1589-1590.,C & E N, April 7. 2003, 81(14), 28-31.,Firstly using commercial (S)-(-)-N-dimethylbenzylamine in this Mannich type reaction, direct condensation, solvent free, completely stereoselective Optically pure product wa
15、s easily obtained by adding methanol to the crude reaction mixture, and could be used directly in the asymmetric alkenylzinc addition reactions without any further purification,One step synthesis of optically active tertiary aminonaphthol,J.-X. Ji.; L.-Q. Qiu.; C. W. Yip,; A. S. C. Chan, J. Org. Che
16、m. 2003, 68(4), 1589-1590.,Ligand A,Alkenylzinc addition to aldehydes catalyzed by ligand A,Examples of aliphatic aldehydes,Examples of substituted benzaldehydes:,The best ees in the catalytic asymmetric alkenylation of ortho-substituted benzaldehydes were achieved,Catalytic Asymmetric Phenyl Transfer to Aldehydes Promoted by Optically Active Tertiary Aminonaphthol,(S)-cetirizine,(S)-carbinoxamine,(R)-orphenadrine,Some pharmacologically active diarylmethol derivatives,
