1. Radicals in Asymmetric Synthesis : Formation of Tertiary and Quaternary Carbon Centers Using Acyclic Radicals Christiane Grisé University of Ottawa November 3, 2005

2. 2 Radical Chemistry

3. 3 Outline 1. Basic concepts of radical chemistry 2. Description of asymmetric methods

4. 4 Radical Chain Reaction Mechanism

5. 5 Initiation Dibenzoyl peroxide (60-80 °C) AIBN (azoisobutyronitrile) Derivative of AIBN developed for reactions at room temperature (V-70) Et 3 B : Initiator at -78 °C Inorganic compounds : ZnCl 2, SmI 2 and other transition metals (Mn, Ni, Cu, Fe)

6. 6 Propagation – Types of Reactions Abstraction Addition Fragmentation Rearrangement

7. 7 Radical Stability Can predict radical stability by looking at the bond dissociation energy Alkyl radical : tertiary>secondary>primary Conjugating groups also stabilize radicals Both electron-withdrawing and electron- donating groups stabilize radicals

8. 8 Explanation by Frontier Molecular Orbitals Radicals have Singly Occupied Molecular Orbitals (SOMO) Most radicals are uncharged and are considered soft species

9. 9 Reactivity and Frontier Molecular Orbitals

10. 10 Radical Addition to α,β-Unsaturated Compounds Nucleophilic radical Orbital interactions are important Size of coefficient explains the regioselectivity

11. 11 Stereoselectivity and Radicals Cyclic radicals : The anti Rule Acyclic radicals : substrate controlled, chiral auxiliaries and chiral reagents

12. 12 Substrate Control : Ester Substituted Radicals

13. 13 Important Factors for Diastereoselective Reduction Delocalization of the radical with the adjacent ester Minimization of 1,3-allylic strain Dipole-dipole repulsions are decreased Stabilization by hyperconjugation Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W.W.; Delorme, D.; Renaud, J.; Robinson, G.; Lavallée, J.-F.; Slassi, A.; Rancourt, J.; Durkin, K.; Liotta, D. J. Org. Chem. 1994, 59, 1166. Guindon, Y.; Slassi, A.; Rancourt, J.; Bantle, G.; Bencheqroun, M.; Murtagh, L.; Ghiro, E.; Jung, G. J. Org. Chem. 1995, 50, 288.

14. 14 Effect of Substituents on Diastereoselectivity Guindon, Y.; Faucher, A-M.; Bourque, E.; Caron, V.; Jung, G.; Landry, S. J. Org. Chem. 1997, 62, 9276.

15. 15 The Exocyclic Effect Definition 1 : Increased diastereoselectivity demonstrated by the reactions of a radical adjacent or exo to a ring formed by tethering the β-heteroatom to the R 1 substituent in the radical shown : 1 Guindon, Y.; Faucher, A-M.; Bourque, E.; Caron, V.; Jung, G.; Landry, S. J. Org. Chem. 1997, 62, 9276.

16. 16 Lewis Acid Can Reverse Diastereoselectivity Endocyclic effect Guindon, Y.; Lavallée, J.-F.; Llinas-Brunet, M.; Horner, G.; Rancourt, J. J. Am. Chem. Soc. 1991, 113, 9701.

17. 17 Exocyclic vs Endocyclic Effect Reagent Anti:Syn Me 2 SiCl 2 100:1 Ph 2 SiCl 2 85:1 Me 2 BBr 22:1 Bu 2 BOTf 32:1 MgBr 2 -OEt 2 1:3

18. 18 Synthesis of Proprionate Motif Using Radicals Diastereoselective Mukaiyama and Free-Radical Hydrogen Transfer 1) Guindon, Y.; Houde, K.; Prévost, M.; Cardinal-David, B.; Landry, S.R.; Daoust, B.; Bencheqroun, M.; Guérin, B. J. Am. Chem. Soc. 2001, 123, 8496. 2) Guindon, Y.; Prévost, M.; Mochirian, P.; Guérin, B. Org. Lett. 2002, 4, 1019.

19. 19 Mukaiyama Reaction

20. 20 Tandem Mukaiyama/Hydrogen Transfer : Endocyclic Effect

21. 21 Tandem Mukaiyama/Hydrogen Transfer : Exocyclic Effect

22. 22 Advantages to the Mukaiyama/Hydrogen Transfer Reaction E/Z stereochemistry of the enoxysilane is unimportant With appropriate Lewis acid selection, all 4 proprionate units are accessible Conditions were found for one-pot procedure Iterative process was demonstrated with the synthesis of the polyproprionate motif : 1) Mochirian, P.; Cardinal-David, B.; Guérin, B.; Prévost, M.; Guindon, Y. Tet. Lett. 2002, 43, 7067. 2) Guindon, Y.; Brazeau, J-F.; Org. Lett. 2004, 4, 2599.

23. 23 Application to the Synthesis of Zincophorin 1)Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S.R.; Jung, G.; Bencheqroun, M.; Faucher, A.-M.; Guérin, B. J. Org. Chem. 2001, 66, 5427. 2) Guindon, Y.; Mochirian, P. Unpublished results. Bt = benzothiazole

24. 24 Can this Methodology be Applied to Other Free Radical Reactions? 76 % >100:1 75 % 1:16

25. 25 Synthesis of Tertiary and Quaternary Centers Cardinal-David, B.; Guérin, B.; Guindon, Y. J. Org. Chem. 2005, 70, 776.

26. 26 Tandem Mukaiyama and Allylation Reactions (Endocyclic Effect) 1. Cram chelate 2. Felkin-Ahn

27. 27 Future Work : 2,3-syn Products

28. 28 Summary – Substrate Control Important factors for stereoselective radical reactions: allylic strain, dipole-dipole interactions, hyperconjugation, exocyclic effect and endocyclic effect Combination of stereoselective Mukaiyama and radical reduction or allylation produced a powerful method to generate polyproprionates, tertiary and quaternary centers

29. 29 Chiral Auxiliaries 2,5-dimethylpyrrolidine : Porter and Giese (1991) Other auxiliaries : 40-70 %

30. 30 Oxazolidinone Chiral Auxiliary Yamamoto and co-workers (1994) Sibi and co-workers (1995) Lewis acidYieldRatio ZnCl 2 709:1 MgBr 2 9020:1 Yb(OTf) 3 8945:1

31. 31 Selectivity with N-Enoyloxazolidinone

32. 32 Application to the Synthesis of (-)-Enterolactone Sibi, M.P.; Liu, P.; Ji, J.; Hajra, S.; Chen, J.-x. J. Org. Chem. 2002, 67, 1738.

33. 33 Camphorsultam Auxiliary and Radical-Ionic Reactions 61 %, 2:1 Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem. Int. Ed. 2005, 44, 2. γ amino acid

34. 34 Mechanism

35. 35 Summary : Chiral Auxiliaries Chiral oxazolidinone are very useful for diastereoselective conjugate addition Camphorsultam auxiliary used for radical addition/aldol type reaction Importance of the Lewis acid

36. 36 Enantioselective Free Radical Reactions Wu, J.H.; Radinov, R.; Porter, N.A. J. Am. Chem. Soc. 1995, 117, 11029. Porter and co-workers (1995)

37. 37 Mechanism-Propagation

38. 38 Enantioselective Conjugate Addition Sibi and Porter (1996) Sibi, M.P.; Ji, J.; Wu, J.H.; Gürtler, S.; Porter, N.A. J. Am. Chem. Soc. 1996, 118, 9200. Sibi, M.P.; Ji, J. J. Org. Chem. 1997, 62, 3800. Sibi (1997)

39. 39 Application : Synthesis of (+)-Ricciocarpin A Sibi, M.P.; He, L. Org. Lett. 2004, 6, 1749.

40. 40 Scope of the Conjugate Addition Sibi, M.P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472. Sibi, M.P.; Zimmerman, J.; Rheault, T. Angew, Chem. Int. Ed. 2003, 42, 4521.

41. 41 Limitation of the Oxazolidinone Template No substituent

42. 42 New Imide Template for Conjugate Addition Sibi, M.P.; Petrovic, G.; Zimmerman, J. J. Am. Chem. Soc. 2005, 127, 2390.

43. 43 Acyclic Radicals and Asymmetric Synthesis Substrate control Chiral auxiliary Chiral lewis acids

44. 44 Acknowledgements Prof. Louis Barriault Nathalie Goulet Guillaume Tessier Steve Arns Effie Sauer Maxime Riou Rachel Beingessner Roch Lavigne Patrick Ang Louis Morency Mélina Girardin Maude Boulanger Jeff Warrington Lise-Anne Prescott Josée-Lyne Ethier Tushar Tangri Dr. Irina Denissova and Philippe Mochirian From Professor Yvan Guindon’s group

45. 45

46. 46 Ester substituted radicals and allylic strain Giese, B.; Bulliard, M.; Zeitz, H.-G. Synlett 1991, 425.

47. 47 Dipole-dipole interactions are also important

48. 48 Hyperconjugation and selectivity

49. 49 Diastereoselective Radical Addition/Allylation RXLewis acidYieldRatio MeIMgBr 2 82>100:1 i-PrIMgBr 2 85>100:1 C 6 H 11 IMgBr 2 93>100:1 MeOCH 2 BrYb(OTf) 3 7058:1 PhCOBrMgBr 2 9050:1 Sibi, M.P.; Ji, J. J. Org. Chem. 1996, 61, 6090.

50. 50 Mechanism

51. 51 Sequential Mukaiyama and Allylation Reactions – Endocyclic Effect Low yield for allylation with MgBr 2 -OEt 2 (62 %) compared to Me 2 AlCl (90 %) or AlMe 3 (80 %) Formation of both tertiary and quarternary carbon centers 73-97 % >20:1 62-90 % >20:1 76-97 % 11:1 85 % >20:1

52. 52 Ligand Modification and Enantioselectivity Sibi, M.P.; Ji, J. J. Org. Chem. 1997, 62, 3800.

53. 53 Ligand and enantioselectivity Iodine Trans Flexible Phenyl Gives S product Iodine Cis Rigid ligand Gives R product