1. Catalytic Enantioselective Allylic Amination of Unactivated Terminal Olefins Via an Ene Reaction / [2,3]-Rearrangement Hongli Bao & Uttam K. Tambar Guillaume Benoit Charette Group– Literature meeting 02/10/2013 1 (This article was featured in the Editors’ Choice section of Science, Synfacts, Synform and Organic Highlights)

2. Allylamines compounds Allylamines compounds are key building blocks in organic chemistry 2

3. Allylic amination : previous work 3

4. Allylic amination : previous work Amination of allyl halides : Gabriel reaction Historically one of the first reaction to syntheses amines via a S N 2 or S N 2’ reactions. 4 Gabriel, S. Ber.1887, 20, 2224. Zwierzak, A.; Pilichowska, S. Synthesis 1982, 1982, 922.

5. Allylic amination : previous work Amination of allyl alcohol : Mitsunobu reaction 5 Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn 1967, 40, 2380. Sen, S. E.; Roach, S. L. Synthesis 1995, 1995, 756

6. Allylic amination : previous work Amination of allyl alcohol : Overman rearrangement Enantioselective version : 6 Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. Watson, M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031. By addition of Mercury (II) salts, the reaction can be run at rt Catalyst 5 mol% ; DCM (0.6M) ; 38°C ; 18h ­>95% ee for (E)-olefins

7. Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Trost : 7 Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427. nYield (%)ee (%) 58794 69597 78498

8. Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Hartwig : amination with iridium-phosphoramidite complex 8 Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11312. Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461.

9. Allylic amination : previous work  Amination of allyl halides, acetates, carbonates catalyzed by transition metal complexes Carreira : iridium catalyzed allylic amination of racemic allylic alcohol 9 Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew. Chem. Int. Ed. 2007, 46, 3139. Lafrance, M.; Roggen, M.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3470.

10. Allylic amination : previous work  Amination based on Ene-reaction followed by [2,3]-sigmatropic rearrangement Kresze ; Sharpless ; Katz 10 Schönberger, N.; Kresze, G. Liebigs Ann. 1975, 1975, 1725. ; Sharpless, K. B.; Hori, T. J. Org. Chem. 1976, 41, 176. Sharpless, K. B.; Hori, T.; Truesdale, L. K.; Dietrich, C. O. J. Am. Chem. Soc. 1976, 98, 269. ; Kresze, G.; Muensterer, H. J. Org. Chem. 1983, 48, 3561. ; Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 1996, 35, 454.

11. This Work Author profile : Position : Assistant Professor University of Texas Southwestern Medical Center Educational Background : A.B. Magna Cum Laude in Chemistry & Physics, Harvard University 2000 (Cynthia Friend and Stuart Schreiber) Ph.D., California Institute of Technology 2006 (Brian Stoltz) NIH Postdoctoral Fellow, Columbia University 2006-2009 (James Leighton) 11 Uttam K. Tambar

12. This Work Research Interests : Complex molecule synthesis ; new synthetic methodology ; medicinal chemistry Selected Publications : Catalytic Enantioselective [2,3]-Rearrangements of Amine N-Oxides. J. Am. Chem. Soc. 2011, 133, 1206-1208. Tandem Catalytic Allylic Amination and [2,3]-Stevens Rearrangement of Tertiary Amines. J. Am. Chem. Soc. 2011, 133, 12956-12959. 12

13. This Work Allylic amination of terminal olefins : 2 steps reaction : - Ene reaction with benzenesulfonyl sufurdiimide to provide the stable zwitterionic Ene-adduct (4) (isolated and purified by a simple filtration) - Palladium catalyzed [2,3]-rearrangement to provide eniantioenriched allylic amine 13

14. Optimization Palladium source, solvent, T°C : 14

15. Optimization Ligand screening : 15

16. Optimization Optimal conditions summary : Catalyst : Pd(TFA) 2 (10 mol%) Ligand : Bisoxazoline 6 (12 mol%) Solvent : MeOH (0.13M) T°C : -15°C Time : 2 days 16

17. Scope Linear hydrocarbon chains Branched hydrocarbons Polyunsaturated terminal olefins Protected Heteroatoms Electrophilic functional groups 17 nyield (%)ee (%) 18997 28996 38898 nyield (%)ee (%) 59796 38296 nyield (%)ee (%) 28597 38794 7 98

18. Mechanism 18

19. Vigabatrin synthesis Application of this methodology via Vigabatrin (Sabril ® ; antiepileptic drug) synthesis 19

20. Benzenesulfonyl sulfurdiimide Commercially available : Synthesis : 20 CAS : 667-20-9 Price : $26,60/gr Sigma-Aldrich

21. Summary  Improvement of the Kresze & Sharpless reaction : - 2 separated steps process which allows an enantioselective [2,3] sigmatropic rearrangement  Practical method to convert terminal olefins into chiral allylic amines  Compatible with a broad range of functional groups 21

22. Hartwig Ir 22

23. Carreira Ir 23