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D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Tota

D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Total Synthesis. Supervisor: Professor Yang Zhen Chen Jiahua Reporter: Lin Guang. Introduction. CV of David A. Evans

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D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Tota

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  1. D. A. Evans’ Asymmetric Synthesis — From 80’s Chiral Auxiliary to 90’s Copper Complexes and Their Applications in Total Synthesis Supervisor: Professor Yang Zhen Chen Jiahua Reporter: Lin Guang

  2. Introduction CV of David A. Evans David A. Evans was born in Washington D.C, He received his A.B. degree from Oberlin College in 1963. He obtained Ph.D. at the California Institute of Technology in 1967, where he worked under the direction of Professor Robert E. Ireland. In that year he joined the faculty at the University of California, Los Angeles. In 1973 he was promoted to the rank of Full Professor and shortly there after returned to Caltech where he remained until 1983. He then joined the Faculty at Harvard University and in 1990 he was appointed as the Abbott and James Lawrence Professor of Chemistry.

  3. Outline Part 1: Enantioselective reactions using chiral auxiliary Part 2: Catalysis of enantioselective reactions using chiral copper complexes Part 3: The application of Evans’ asymmetric methodologies in his total syntheses

  4. Part 1:Enantioselective Reactions Induced by Chiral Auxiliary • Initial reports of asymmetric induction from chiral imides • The Optimization of the Chiral Imide Auxiliary • Asymmetric Aldol Reaction • Asymmetric Alkylation • Asymmetric Diels-Alder Reaction

  5. Initial Reports of Asymmetric Induction from Chiral Imides

  6. The Optimization of the Chiral Imide Auxiliary Stereoselective Aldol Condensation via Boron Enolates (1979) Why boron? M = Li, MgL, ZnL, AIL2 Metal-oxygen bond lengths: (1.9-2.2Å ) M-L bond lengths: ( 2-2.2Å ) M = BR2 Metal-oxygen bond lengths:(1.36-1.47Å) M-L bond lengths:(1.5-1.6Å) Result: the boron enolates are superior to the corresponding lithium enolates in stereoselective bond construction. Stereoselective Aldol Condensation via Zirconium Enolates (1980) 1. From Li to Zr the loss of enolate geometry was not significant 2. Product selective aldol condensations independent of enolate geometry 3. Pseudo-boat VS pseudo-chair D. A. Evans et al,J. Am. Chem. Soc., 1979,101,6120 D. A. Evans et al,Tetrahedron Lett.,1980,21,7975

  7. The Optimization of the Chiral Imide Auxiliary Transition states and relative products: D. A. Evans et al, J. Am. Chem. Soc., 1979, 101, 6120

  8. The Optimization of the Chiral Imide Auxiliary Approach to enatioselective alkylation via initial chiral auxiliary (1980) 3 4 R2=Li Major product is 3; 3:4 high selective ratio R2=alkyl Major product is 4; 4:3 moderate selective ratio Easy to hydrolysis D. A. Evans et al, Tetrahedron Letters, 1980, 31, 7975

  9. The Optimization of the Chiral Imide Auxiliary Approach to enatioselective aldol condensation via initial chiral auxiliary (1980) Seebach: M=Li, RL=Et, RS=Me, R1=H (1976) Heathcock: M=Li, RL=t-Bu, RS=OSiMe3, R1=Me (1979) Evans: M=B, RL=Et, Rs=Me, R1=H or Me (1980) M=BBu2; R1=Me or H; R2=Ph or i-Pr, D.A Evans et al, Tetrahedron Lett.,1980,21, 4675

  10. The Optimization of the Chiral Imide Auxiliary The completion of the Evans’ auxiliary (1981) A B D C D. A. Evans et al, Pure and Applied Chemistry, 1981,53,1109

  11. Asymmetric Aldol Reaction 2 1 Metal=B(Bu)2 a, R=H b, R=C(O)Et c, R=C(O)Me d, R=C(O)CH2SMe D. A. Evans et al, J. Am. Chem. Soc., 1981,103, 8

  12. Asymmetric Aldol Reaction Sn(II) Aldol and Ti(IV) Aldol Anti-Syn Syn-Syn D. A. Evans et al,J. Am. Chem. Soc.,1990, 112,866

  13. Asymmetric Aldol Reaction D. A. Evans et al, J. Am. Chem. Soc., 2002, 124, 392

  14. Asymmetric Aldol Reaction

  15. Asymmetric Aldol Reaction D.A. Evans et al, Org. Lett., 2002, 4, 1127

  16. Asymmetric Alkylation D. A. Evans et al, J. Am. Chem. Soc.,1982, 104,1737

  17. Asymmetric Diels-Alder Reaction D. A. Evans et al, J. Am. Chem. Soc., 1984,106,4261 D. A. Evans et al, J. Am. Chem. Soc., 1988, 110,1238

  18. Conclusion of Part 1 The gradual approach to the enantioselectivity The variety of aldol reactions Applications in other reactions such as alkylation and D-A reaction Transition states

  19. Part 2: Catalysis of Enantioselective Reactions Using Chiral Copper Complexes • Enantioselective Cycloaddition • Enantioselective Carbonyl Ene Reactions • Enantioselective Aldol • Enantioselective Michael Addition

  20. Basic Knowledge Metal center:Cu, Mg, Zn, Sc, Ni…… Why copper? 1.Cu(II) forms the most stable ligand-metal complexes (Mn < Fe < Co <Ni < Cu > Zn) 2.The exchange rate is greater than those of other first row divalent transition metal Some Bis(oxazo1ines) Ligands D.A.Evans et al, Acc. Chem. Res. 2000, 33, 325

  21. Enantioselective Cycloaddition Diels-Alder Reactions A, R=Ph B, R=α-Np C, R=CHMe2 D, R=CMe3 D R=CMe3 is the best: 1. endo:exo=98:2 2. Endo e.e.>98% Cu: Square-planar Zn & Mg: Tetrahedral X=SbF6 is the best D. A. Evans et al, J. Am. Chem. Soc.,1999, 121,7559

  22. Enantioselective Cycloaddition Hetero Diels-Alder Reactions D.A. Evans et al,J. Am. Chem. Soc.,2000,122,1635 D.A. Evans et al, J. Am. Chem. Soc., 1998,120,4895

  23. Practical utility: Low catalyst loading (0.2-10 mol %) Moderate temperatures (0-25 ℃) Commercially available undistilled glyoxylate Enantioselective Carbonyl Ene Reactions Ene Reactions of Glyoxylate Esters D.A. Evans et al, J. Am. Chem. Soc.,2000, 122,7936

  24. Enantioselective Carbonyl Ene Reactions Ene Reaction of Pyruvate Esters D.A. Evans et al, J. Am. Chem. Soc.,2000,122, 7936

  25. Enantioselective Aldol Reactions Some incorporate additional stabilizing interactions: hydrogen, bonding, chelation D.A. Evans, et al,J. Am. Chem. Soc.,1999, 121,669

  26. Enantioselective Aldol Reactions D. A. Evans et al, J. Am. Chem. Soc.,1999,121,686

  27. Enantioselective Michael Addition Alkylidene Malonates D. A. Evans et al, J. Am. Chem. Soc.,2001,123,4480

  28. Enantioselective Michael Addition Alkylidene Malonates D.A. Evans et al, J. Am. Chem. Soc., 2001,123,4480

  29. Enantioselective Michael Addition Fumaroyl Oxazolidinone David A. Evans et al,Org. Lett., 1999, 1, 865

  30. Conclusion of Part 2 The character and advantage of catalytic reactions The character of these Cu(II) complexes Different reactions catalyzed by Cu(II) complexes

  31. Part 3:The applications of Evans’ asymmetric methodologies in his total synthesis • Cytovaricin (1990) • 6-Deoxyerythronolide B (1998) • Callipeltoside A (2002) • Oasomycin A (2006)

  32. Cytovaricin (1990) D.A. Evans et al, J. Am. Chem. Soc.,1990, 112,7001

  33. Cytovaricin (1990) D.A. Evans et al, J. Am. Chem. Soc.,1990, 112, 7001

  34. Cytovaricin (1990) D.A. Evans et al, J. Am. Chem. Soc.,1990, 112,7001

  35. 6-Deoxyerythronolide B (1998) Erythromycins A R=OH Erythromycins B R=H D.A. Evans et al, J. Am. Chem. Soc.,1990, 112,7001

  36. 6-Deoxyerythronolide B (1998) D.A. Evans et al, J. Am. Chem. Soc., 1990, 112,7001

  37. Callipeltoside A (2002) D. A. Evans et al, J. Am. Chem. Soc., 2002, 124, 5654

  38. Callipeltoside A (2002) D. A. Evans et al, J. Am. Chem. Soc.,2002,124, 5654

  39. Oasomycin A (2006) D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537

  40. Oasomycin A (2006) D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537

  41. Oasomycin A (2006) D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537

  42. Summary 1.Chiral auxiliary The Key Point: How to control the transition states!!! 2.Copper complexes 3. Total syntheses

  43. Acknowledgement Professor Yang Zhen and Chen Jiahua All the members in our group Professor Yu and Shi All the members of IOC

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