1. Trost’s Palladium Catalysed Asymmetric Allylic Alkylation (Pd-AAA) 1 Literature Meeting Charette’s group Miguel St-Onge October 9 th, 2007

2. Presentation 1.Trost and Palladium  -allyl complexes i.Stereochemistry of oxidative addition and nucleophilic attack ii.Counter anion effects iii.Syn vs anti complexes iv.Nucleophilic approach on allyl terminus 3.Ligands and cartoon model 4.Classes of enantiodiscrimination processes 5.Types of nucleophiles and their application to total synthesis 6.Exceptions to the model 7.AAA with other metals 8.Total synthesis of Tipranavir 9.Conclusion 2

3. Pr. Barry M. Trost 3  Born in 1941 in Philadelphia  Received B.A. From University of Pennsylvania (1962)  Received Ph.D. at MIT under H.O. House’s supervision (1965)  Professor of chemistry at University of Wisconsin (1969) Vilas research professor of chemistry (1982)  Professor of chemistry at Standford University (1987) Takami professor of humanities and sciences (1990)  803 publications (2006)  38 honors and awards  14 Patents Barry Trost web page at www.stanford.edu/group/bmtrost

4. Palladium 4 Discovered in 1803 by William Hyde Wollaston Isolated from (NH 4 ) 2 PtCl 6 Name comes from Greek goddess of wisdom, Pallas or Palladion Atomic number 46 [Kr] 4d 10 Pd 0 = 18e square planar complexes Pd (II) = 14e square planar complexes

5.  -Allyl Palladium Complex and C-C Bond Formation 5 Trost, B. M.*; Weber, L. J.Am.Chem.Soc. 1975, 97, 1611-1612.

6. Trost’s Study 6 Trost, B.M; Weber, L. J. Am. Chem. Soc. 1975, 97, 1611-1612

7. Study conclusion 7 Conclusions: -Stereospecificity of allylic alkylation has potentially important consequences in the application of the method for the creation of stereochemistry in acyclic and macrocyclic systems. - Alkylation occurs on the face of the  -allyl unit opposite to that of the palladium and use of soft nucleophiles are required for successful alkylation

8. Stereochemistry of Oxidative Addition 8 Hayashi, T.*; Hagihara, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1983, 105, 7768-7770.

9. Stoichiometric vs Catalytic 9 Conclusions: - Oxidative addition of palladium proceed with inversion of configuration and addition on  -allyl palladium proceed also with inversion of configuration. - Net retention of configuration also occurs in enantiomeric catalytic system

10. Catalytic Cycle 10

11. Counter Anion Effects 11 Amatore, C.; Jutand, A.; M’Barki, M. A.; Meyer, G.; Mottier, L. Eur. J. Inorg. Chem. 2001, 873. Cantat, T.; Génin, É.; Giroud, C.; Meyer, G.; Jutand, A.* J. Org. Chem. 2003, 687, 365-376.

12. Syn Complex vs Anti Complex (  equilibration) 12 Trost, B.M.; Machacek, M.R.; Aponik, A. Acc. Chem. Res. 2006, 39, 747-760.

13. Nucleophile Approach 13 Nucleophile addition is considered as a SN 2 -like displacement Attack must be anti to the Pd leaving group (180 o ) High impact for ligand working model analysis

14. Allyl Terminus Less substituted terminus Small and  -donating ligands Metal at higher oxidation state More substituted terminus Bulky ligands Good  -acid ligands Pd coordination with more electron poor olefins 14 Trost, B.M.; Machacek, M.R.; Aponik, A. Acc. Chem. Res. 2006, 39, 747-760.

15. Redesign Catalytic Cycle 15

16. Successful Ligands 16 Tognie, A.; Breutel., C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A J. Am. Chem. Soc. 1994, 116, 4062-4066. Pfaltz, A Acc. Chem. Res. 1993, 26, 339-345. Evans, D.A.; Campos, K.R.; Tedros, J.S.; Michael, F.E.; Gagné, M.R. J. Am. Chem. Soc. 2000, 122, 7905-7920. Faller, J.W.; Wilt, J.C. Organometallics, 2005, 24, 5076-5083. Morimoto, T.; Tachibana, K.; Achiwa, K. Synlett, 1997, 783-785.

17. Trost’s Classic Ligands 17

18. Cartoon Model 18 Trost, B.M.; Toste, F.D. J. Am. Chem. Soc., 1999, 121, 4545-4554. Lloyd-Jones G.C. Et. Al. Pure Appl. Chem., 2004, 76, 589-601.

19. Classes of Enantiodiscriminating Processes Ionization of the leaving group Class A- Desymmetrization of meso diester Class B- Desymmetrization of prochiral leaving group on the same carbon Class C- Unsymmetrical  -allyl Pd complexes (achiral) Addition of the nucleophile Class D- Meso-like  -allyl Pd complex Class E- Unsymmetrical  -allyl Pd complexes (chiral) 19

20. Class A- Desymmetrization of meso Diester 20 Trost, B.M.; Dudash, J., Jr.; Dirat, O. Chem-Eur. J. 2002, I81, 259-268. Trost, B.M.; Patterson, D.E., J. Org. Chem., 1998, 63, 1339-1341.

21. Class B- Desymetrisation of Prochiral Leaving Group on the Same Carbon 21 Trost, B.M.; Lee, C.B. J. Am. Chem. Soc. 1998, 120, 6818-6819.

22. 22 Class B- Desymmetrization of Prochiral Leaving Group on the Same Carbon Trost, B.M.; Lee, C.B. J. Am. Chem. Soc. 1998, 120, 6818-6819.

23. Class C- Unsymmetrical  -Allyl Pd Complexes (Achiral) 23 Trost, B.M.; Machacek, M.R. Angew. Chem., Int. Ed. 2002, 41, 4693-4697.

24. Class C- Unsymmetrical  -Allyl Pd Complexes (Achiral) 24 Trost, B.M.; Machacek, M.R. Angew. Chem., Int. Ed. 2002, 41, 4693-4697.

25. Class D- Meso-like  -Allyl Pd Complex 25 Trost, B.M.; Dudash, J., Jr.; Hembre, E.J. Chem.-Eur. J. 2001, 16, 1619-1629.

26. Class D- Meso-like  -Allyl Pd Complex 26 Trost, B.M.; Dudash, J., Jr.; Hembre, E.J. Chem.-Eur. J. 2001, 16, 1619-1629.

27. Class E- Unsymmetrical  -Allyl Pd Complexes (Chiral Acyclic Substrate) 27 Trost, B.M.; Bunt, R.C.; Lemoine, R.C.; Calkins, T.L. J. Am. Chem. Soc. 2000, 122, 5968-5976.

28. Class E- Unsymmetrical  -Allyl Pd Complexes (Chiral Cyclic Substrate) 28 Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090-3100.

29. Lactone Isomerization 29 Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090-3100.

30. Chirality at the Nucleophile 30 Trost, B.M.; Radinov, R.; Grenzer, H.M. J. Am. Chem. Soc. 1997, 119, 7879-7880. Trost, B.M.; Schroeder, G.M.; Kristensen, J Angew. Chem., Int. Ed. 2002, 41, 3492-3495.

31. Carbon Nucleophiles in Total Synthesis 31 Chapsal, B.D.; Ojima, I. Org. Lett., 2006, 8, 1395-1398. Malonate type:

32. Carbon Nucleophiles in Total Synthesis 32 Sulfone Type: Trost, B. M.; Chupak, L. S.; Lubbers J. Am. Chem. Soc. 1998, 120, 1732-1740. Trost, B. M.; Surivet, J.-P. Angew. Chem., Int. Ed. 2000, 39, 3122-3124. Nitro type:

33. Oxygen Nucleophiles in Total Synthesis 33 Primary alcohols: Trost, B. M.; Weiping, T.; Schulte, J. L. Org. Lett. 2000, 2, 4013-4015. Trost, B. M.; Kondo, Y. Tet. Let. 1991, 32, 1613. Carboxylates:

34. Oxygen Nucleophiles in Total Synthesis 34 Phenols Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074-9075. Trost, B. M., Tang, W. J. Am. Chem. Soc., 2002, 124, 14542-14543.

35. Nitrogen Nucleophiles 35 Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996, 118, 6297-6298. You, S. L.; Zhu, X. Z.; Luo, Y. M.; Hou, X. L.; Dai, L. X. J. Am. Chem. Soc. 2001, 123, 7471-7472. Mono versus bisalkylation of primary amines Regioselectivity on Pd  -allyl system Speed of nucleophile versus  equilibration Amines

36. Nitrogen Nucleophiles in Total Synthesis 36 Azides Trost, B. M.; Pulley, S.R. J. Am. Chem. Soc 1995, 117, 10143-10144. Trost, B. M.; Cook, G. R. Tet. Lett., 1996, 37, 7485-7488.

37. Nitrogen Nucleophiles in Total Synthesis 37 Sulfonamide Trost, B. M.,; Oslob, J. D.; J. Am. Chem. Soc. 1999, 121, 3057-3064. Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. Org. Lett. 2001, 3, 1913-1916.

38. Nitrogen Nucleophiles in Total Synthesis 38 Imides Trost, B. M.,; Patterson, D. E.; Chem. Eur. J. 1999, 5, 3279 Buschmann, N.; Rueckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-4329.

39. Nitrogen Nucleophiles in Total Synthesis 39 Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037-3038. Trost, B. M.; Madsen, R.; Guile, S. D.; Tet. Lett., 1997, 38, 1707-1710.

40. Sulfur Nucleophiles Pd -AAA 40 Trost, B. M.; Organ, M. G.; O’Doherty, G. A. J. Am. Chem. Soc. 1995, 117, 9662-9670. Trost, B. M.; Crawley, M. L.; Lee, C. B. J. Am. Chem. Soc. 2000, 122,6120-6121.

41. Exceptions 41 Trost, B. M.; Toste, D. F. J. Am. Chem. Soc. 2000, 122, 11262-11263. Trost, B.M.; Machacek, M.R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747-760.

42. Exceptions 42 Trost, B.M.; Machacek, M.R.; Aponick, A. Acc. Chem. Rev. 2006, 39, 747-760.

43. Exceptions 43 Trost, B.M.; Gunzner, J.L.; Dirat, O.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 10396-10415.

44. AAA with Other Metals: Tungsten 44 Lloyd-Jones, G.C.; Pfaltz, A. Angew.Chem., Int. Ed., 1995, 34, 462. Co, T.T.; Paek, S.W.; Shim, S.C.; Cho, C.S.; Kim, T.-J.; Choi, D.W.; Kang, S.O.; Jeong, J.H Organometallics, 2002, 22, 1475-1482.

45. AAA with Other Metals: Iridium 45 Ohmura, T.; Hartwig J.F. J. Am. Chem. Soc. 2002, 124, 15164-15165. Kiener, C.A.; Shu, C.; Incarvito, C.; Hatrwig, J.F. J. Am. Chem. Soc. 2003, 125, 14272-14273.

46. Novel Iridium Utilisation Preparation of -Substituted Allylboronates by Chemoselective Iridium- Catalyzed Asymmetric Allylic Alkylation of 1-Propenylboronates - Peng, F.; Hall*, D. G. Tet. Lett. 2007, 18, 3305-3309 Salt-Free Iridium-Catalyzed Asymmetric Allylic Aminations with N,N- Diacylamines and ortho-Nosylamide as Ammonia Equivalents - Weihofen, R.; Tverskoy, O.; Helmchen, G.; Angew. Chem., Int. Ed. 2006, 33, 5546-5549 Very Efficient Phosphoramidite Ligand for Asymmetric Iridium-Catalyzed Allylic Alkylation - Alexakis*, A.; Polet, D.; Org. Lett. 2004, 20, 3529-3532 Regio- and Enantioselective Iridium-Catalyzed Allylic Alkylation with In Situ Activated P,C-Chelate Complexes - Lipowsky, G.; Miller, N.; Helmchen, G. Angew. Chem., Int. Ed. 2004, 43, 4595 –4597 46

47. AAA with Other Metals: Molybdenum 47 Trost, B.M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256-7257.

48. Molybdenum AAA Transition State 48 Krska, S. W.; Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Sun, Y.; Trost, B. M. J. Am. Chem. Soc. 2002, 124 (43), 12656-12657.

49. Synthesis of Tipranavir (Aptivus) 49 Trost, B.M.; Andersen, N.G. J. Am. Chem. Soc. 2002, 124, 14320-14321.

50. Synthesis of Tipranavir (Aptivus) 50 Trost, B.M.; Andersen, N.G. J. Am. Chem. Soc. 2002, 124, 14320-14321. 15 steps, 25%yield

51. Conclusion High yields and enantioselectivities are obtain 5 mechanisms for enantiodiscrimination Diversity of bond type (C-C, C-O, C-N, C-S) Chirality can be set at substrates, nucleophiles or both AAA react with sp 3 instead of sp 2 centers Transforms achiral, prochiral and more importantly chiral racemic substrates into enantiopure compounds (through DYKAT) Cartoon model developped to predict final stereochemistry (almost no exceptions) Versatile method using mild conditions Usefull central strategy for total synthesis Scope have been expanded to other metals 51