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 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 He then joined the Faculty at Harvard University and in 1990 he was appointed as the Abbott and James Lawrence Professor of Chemistry.

3 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 Outline

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

5 Initial Reports of Asymmetric Induction from Chiral Imides

6 The Optimization of the Chiral Imide Auxiliary Stereoselective Aldol Condensation via Boron Enolates (1979) Stereoselective Aldol Condensation via Zirconium Enolates (1980) Why boron? M = Li, MgL, ZnL, AIL 2 Metal-oxygen bond lengths: ( Å ) M-L bond lengths: ( 2-2.2Å ) M = BR 2 Metal-oxygen bond lengths:( Å) M-L bond lengths:( Å) Result: the boron enolates are superior to the corresponding lithium enolates in stereoselective bond construction. 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 Transition states and relative products: The Optimization of the Chiral Imide Auxiliary D. A. Evans et al, J. Am. Chem. Soc., 1979, 101, 6120

8 Approach to enatioselective alkylation via initial chiral auxiliary (1980) 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 The Optimization of the Chiral Imide Auxiliary D. A. Evans et al, Tetrahedron Letters, 1980, 31,

9 Approach to enatioselective aldol condensation via initial chiral auxiliary (1980) Seebach: M=Li, R L =Et, R S =Me, R 1 =H (1976) Heathcock: M=Li, R L =t-Bu, R S =OSiMe 3, R 1 =Me (1979) Evans: M=B, R L =Et, R s =Me, R 1 =H or Me (1980) M=BBu 2 ; R 1 =Me or H; R 2 =Ph or i-Pr, The Optimization of the Chiral Imide Auxiliary D.A Evans et al, Tetrahedron Lett., 1980, 21, 4675

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

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

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

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

20 Metal center: Cu, Mg, Zn, Sc, Ni…… Why copper? 1.Cu(II) forms the most stable ligand-metal complexes (Mn 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 Basic Knowledge

21 A, R=Ph B, R=α-Np C, R=CHMe 2 D, R=CMe 3 D R=CMe 3 is the best: 1. endo:exo=98:2 2. Endo e.e.>98% Enantioselective Cycloaddition X=SbF 6 is the best Diels-Alder Reactions Cu: Square-planar Zn & Mg: Tetrahedral 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 Ene Reactions of Glyoxylate Esters Enantioselective Carbonyl Ene Reactions Low catalyst loading ( mol %) Moderate temperatures (0-25 ℃ ) Practical utility: Commercially available undistilled glyoxylate D.A. Evans et al, J. Am. Chem. Soc., 2000, 122, 7936

24 Ene Reaction of Pyruvate Esters Enantioselective Carbonyl Ene Reactions 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 Alkylidene Malonates D. A. Evans et al, J. Am. Chem. Soc., 2001, 123, 4480 Enantioselective Michael Addition

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

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

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  6-Deoxyerythronolide B (1998)  Cytovaricin (1990)  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 D. A. Evans et al, Angew. Chem. Int. Ed., 2007, 46, 537 Oasomycin A (2006)

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

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

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

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