Radicals in Asymmetric Synthesis : Formation of Tertiary and Quaternary Carbon Centers Using Acyclic Radicals

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

2. Radical Chemistry

3. Outline • Basic concepts of radical chemistry • Description of asymmetric methods

4. Radical Chain Reaction Mechanism

5. Initiation • Dibenzoyl peroxide (60-80 °C) • AIBN (azoisobutyronitrile) • Derivative of AIBN developed for reactions at room temperature (V-70) • Et3B : Initiator at -78 °C • Inorganic compounds : ZnCl2, SmI2 and other transition metals (Mn, Ni, Cu, Fe)

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

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

9. Reactivity and Frontier Molecular Orbitals

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

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

12. Substrate Control : Ester Substituted Radicals

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. 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. The Exocyclic Effect Definition1 : Increased diastereoselectivity demonstrated by the reactions of a radical adjacent or exo to a ring formed by tethering the β-heteroatom to the R1 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. 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. Exocyclic vs Endocyclic Effect Reagent Anti:Syn Me2SiCl2 100:1 Ph2SiCl2 85:1 Me2BBr 22:1 Bu2BOTf 32:1 MgBr2-OEt2 1:3

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. Mukaiyama Reaction

20. Tandem Mukaiyama/Hydrogen Transfer :Endocyclic Effect

21. Tandem Mukaiyama/Hydrogen Transfer :Exocyclic Effect

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. Application to the Synthesis of Zincophorin • 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. Can this Methodology be Applied to Other Free Radical Reactions? 76 % >100:1 75 % 1:16

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

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

27. Future Work : 2,3-syn Products

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

30. Oxazolidinone Chiral Auxiliary Yamamoto and co-workers (1994) Sibi and co-workers (1995)

31. Selectivity with N-Enoyloxazolidinone

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

34. Mechanism

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

37. Mechanism-Propagation

38. Enantioselective Conjugate Addition Sibi and Porter (1996) Sibi (1997) 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.

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

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. Limitation of the Oxazolidinone Template No substituent

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

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

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

46. Ester substituted radicals and allylic strain Giese, B.; Bulliard, M.; Zeitz, H.-G. Synlett1991, 425.

47. Dipole-dipole interactions are also important

48. Hyperconjugation and selectivity

49. Diastereoselective Radical Addition/Allylation Sibi, M.P.; Ji, J. J. Org. Chem. 1996, 61, 6090.

50. Mechanism