1. 1 Rh-Catalyzed Asymmetric Additions: The Rise of Chiral Dienes Daniela Sustac February 16, 2010 Tamio HayashiErick Carreira

2. 2 Outline

3. 3 Transition Metal – Olefin Complexes Alkenes not very basic, backbonding necessary to stabilize M-olefin bond; Olefins considered labile, easily displaced from M center. Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

4. 4 Transition Metal – Strained Alkene Complexes Strained alkenes (cyclopropene, norbornene) bind very strongly to metals; Rehybridization on binding relieves ring strain. Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

5. 5 Examples of Olefins in Complexes and Catalysis Prepared by Zeise in 1827; Structure elucidated in the 1950’s; Norbornene in the Catellani reaction: “a sort of scaffold to be removed after the building of the molecule is complete; behaves as catalyst, excess necessary to push the reaction” Wunderlich, A.J.; Mellor, D.P. Acta Crystallogr. 1955, 8, 57. Catellani, M; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. 2007, 36, 119.

6. 6 Who Binds the Strongest? Electron deficient alkenes bind tighter; Stronger binding with strained alkenes. Tolman, A.C. Organometallics 1983, 2, 614.

7. 7 Rh-Catalyzed 1,4-Addition (before chiral dienes) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052. Consequently, the reaction can be done using directly [Rh(OH)(S-binap)] 2 at 35 ºC.

8. 8 Chiral Dienes: First Contact Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. Hydrosylilation: Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.

9. 9 The (Only) One with A Lot of Scope Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

10. 10 Explaining Stereochemistry Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

11. 11 Chiral Dienes: First Contact Advantages Highest catalytic activity of all rhodium catalysts used for 1,4- addition; Among the highest enantioselectivities (most over 90% ee); Disadvantages Long synthesis of chiral diene; Bistriflate intermediate hard to isolate. Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

12. 12 New Route to Chiral Dienes Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957. Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363.

13. 13 One Unstable Chiral Diene, One Stable Rh Complex Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.

14. 14 One More Carbon Optical resolution by recrystallization inefficient route; Alternatively, can do racemic synthesis and separate by chiral HPLC, either intermediate or final product. Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503.

15. 15 To Be Stable or Not to Be Stable

16. 16 The One with iMean Arylation Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

17. 17 Stereochemistry is Explained Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

18. 18 The One with (a Bit) of Scope Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

19. 19 The One where They Do It Better? Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260. Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

20. 20 The One with the iMean Mechanism Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

21. 21 More Stereochemistry Explained Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

22. 22 Is Nine the Lucky Number? Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

23. 23 The One with the Deprotection Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260. Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979. Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307. By far the mildest approach!

24. 24 The One with the Cyclization of Alkynals EntryLigandYield (%) 1(S)-binap24 2Dppp23 3Dppb20 4Dppf27 5PPh 3 20 6Cod73 7*Cod76 *[Rh(OH)(cod)] 2 used directly Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

25. 25 The One with the Mechanism Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

26. 26 The One with the Cyclization of Alkynals EntryArYield (%) ee (%) 1*Ph8994 24-MeOPh7193 34-FPh7793 43-ClPh7196 52-naphtyl7896 *Et instead of Me. Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

27. 27 Let’s Do Some Cycloadditions Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

28. 28 [4+2] Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

29. 29 Cycloaddition Mechanism Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

30. 30 Stereochemistry Explained Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

31. 31 1,6-Enynes Cycloisomerization Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

32. 32 Tfb (tetrafluorobenzobarrelene) Diene Synthesis Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun. 2009, 5713. Chiral HPLC to separate enantiomers; Low yielding steps.

33. 33 The One with the Catalyst Design Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press. A chiral diene and a phosphine on the same catalyst!

34. 34 “Dig” the Mechanism Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

35. 35 Stereochemistry Explained Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

36. 36 More Chiral Dienes Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387. Most effective ligands reported so far for Rh-catalyzed asymmetric addition!

37. 37 Last Stereochemistry Picture Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.

38. 38 Hayashi’s Dienes: Summary

39. 39 Ir-Catalyzed Allylic Displacement Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628. Potential for the diene to be synthesized asymmetrically from cheap (R) or (S)-carvone.

40. 40 Spin-Off: Carreira’s Diene Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

41. 41 Carreira’s Dienes Generation II “The Long Way Home” Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.

42. 42 Again with the Enones? Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873. Additional substrates in the scope (not covered by Hayashi)

43. 43 One Ligand, One Day, Two Papers

44. 44 The Short Way Home Ortho substituted boronic acids a challenge; Most accessible route; Library of 14 ligands; High enantioselectivities (over 90%). Carreira Darses Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem. Int. Ed. 2008, 47, 7669. Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

45. 45 Enantioselective Diene Synthesis Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

46. 46 Order of Addition Is Important Diene is inhibited Less strained system necessary Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

47. 47 Adding One More Carbon Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

48. 48 Summary Reviews: Defieber, C.; Grutzmacher, H.; Carreira, E.M. Angew. Chem. Int. Ed. 2008, 47, 4482. Johnson, B.J.; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840.

49. 49 A Bit of Shopping: Chiral Dienes at Aldrich