1. THIOUREA-CATALYSED RING OPENING OF EPISULFONIUM IONS WITH INDOLE DERIVATIVES BY MEANS OF STABILIZING NON-COVALENT INTERACTIONS Nature Chem. 2012, 4, 817-824 Song Lin and Eric N. Jacobsen* Anne-Catherine Bédard Charette/Collins Meeting – November 27 th 2012

2. Discovery 2  Urea were originally designed as chiral ligand for Lewis acidic metal  The observation of enatioselectivity in the absence of the metal was unanticipated ! M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998, 120, 4901-4902. M.S. Sigman, P. Vachal, E.N. Jacobsen, Angew. Chem. Int. Ed. 2000, 39, 1279 – 1281 Taylor, M. S., Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543.

3. Lewis vs Br ø nsted Acid Catalysis 3 “Why did the report of Yates and Eaton, and not that of Wasserman, capture the imagination of the early practitioners of asymmetric catalysis, leading to the current situation where chiral Lewis acid catalysis, rather than chiral Br ø nsted acid catalysis, is the dominant strategy for the promotion of enantioselective additions to electrophiles ?”  Taylor, M. S. and Jacobsen, E. N. Yates, P., Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436-4437. Wassermann, A. J. Chem. Soc. 1942, 618-621. Taylor, M. S., Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543.

4.  Lewis vs Bronsted Acid  Non-covalent catalysis via H-Bonding  Mimic the mode of action of enzymes by design of small molecule  Ex : Serine protease  16 to 30 kDa H-Bonding Catalysis in Enzymes 4 Zhang, Z. G., Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187–1198.

5. Enzyme vs Small Molecule Catalysis 5  Enzymes :  Accelerate reactions and impart selectivity as they stabilize specific transition structures through networks of cooperative interactions  Chiral small-molecule :  Catalysts is rationalized typically by the steric destabilization of all but one dominant pathway.  However, stabilizing effects also play an important role in small-molecule catalysis (rare mechanistic characterization) Lin, S., Jacobsen, E. N. Nature Chem. 2012, 4, 817-824

6. Proposal  Thiourea : suitable host for an episulfonium ion formed in situ through interactions with the chiral counteranion  Friedel–Crafts-type indole alkylation reaction 6

7. Search for the Episulfonium Ion  Non-nucleophilic leaving group was required to achieve the desired reactivity  Otherwise major product is addition of chlorine atom. Hamilton, G. L., Kanai, T. & Toste, F. D. J. Am. Chem. Soc. 2008, 130, 14984–14986. 7

8. Optimization - Acid Need a non-nucleophillic anion for the acid (entry 1 major product is Cl addition) Sulfonate group work better/strong counterion effect 8

9. Optimization – Catalyst No direct correlation between size of the aromatic group and e.e. (best = phenantryl) No direct interaction of the thiourea sulfur atom (Lewis based catalysis) 9

10. Scope – Leaving Group 10 Choice of leaving group doesn’t have an effect on the enantioselectivity 1 st step is protonation of trichloroacetamide

11. Substrate Scope – Mecanism Insight 11 Benzyl is better than phenyl and alkyl

12. Rational DFT : Benzylic protons in S-Benzyl episulfonium ions partial positive charge  enhance attractive interactions with the catalyst 12

13. Substrate Scope – Indole Substitution 13 Indole N-H motif may be involved in a key interaction during e.e.-determining transition state

14. Substate Scope - Episulfonium Substitution 14 Para substitution decreases the enantioselectivity Interaction of the C-H with thiourea-bond sulfonate?

15. Proposed Mechanism 15 1.Protonation of trichloroacetamide 2.Formation of episulfonium ion (endothermic ionisation) 3. Nucleophillic attack 4. Rearomatisation

16. Kinetic Studies - in situ IR 16  Rate accelerated by chiral thiourea vs 4-NBSA alone  2.0±0.1 kcal/mol  0 th order in substrate and 1 st order in 4-NBSA  Quantitative protonation before rds  pKa 4-NBSA ≈ -7 and pKa substrate ≈ 2  1 st order in indole (present at rds)  Episulfonium-4-NBSA (covalent adduct) is the resting state of the substrate Denmark, S. E.; Vogler, T. Chem. Eur. J. 2009, 15, 11737-11745.

17. Proposed Mechanism 17 1.Protonation of trichloroacetamide 2.Formation of episulfonium ion (endothermic ionisation) 3. Nucleophillic attack 4. Rearomatisation

18. 5-Substituted Indole : Rate Comparison 18 Catalysed by 4-NBSA Catalysed by 4-NBSA and thiourea Better nucleophile = faster rate Consistent with addition being rds! No KIE when 3-D-indole is used (0.93±0.12); if rearomatisation was rds kH/kD >2.5

19. Proposed Mechanism 19 1.Protonation of trichloroacetamide 2.Formation of episulfonium ion (endothermic ionisation) 3. Nucleophillic attack 4. Rearomatisation

20. Catalyst-Substrate Interactions NMR Studies 20 NMR showed attractive interactions between the aromatic group in 3e and a-protons in 5 Shift (downfield) observed for the 2 N-H in thiourea : consistent with H-Bond Kelly, T. R.; Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072-7080. Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986-990.

21. Indole Structure N-H is important for high yield and e.e. pKa indole  rate  Rate is correlated with nucleophilicity and H-bond donor properties

22. H-Bonding with Thiourea 22

23. Aromatic Group on Thiourea 23 The arene affect may be caused by (1) acceleration of the major pathway through transition-state stabilization (2) inhibition of pathways that lead to the minor enantiomer through destabilizing interactions. Uyeda, C. & Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062–5075 Enantioselectivity increases because variations of the aryl component of the catalyst 3 are, indeed, tied to stabilization of the major transition structure

24. Proposed Model for Enantioselection 24

25. Conclusion 25  Enantioselective reaction : addition of indole to the episulfonium ion  Rate acceleration/enantioselectivity by thiourea catalyst  attractive non-covalent interactions in TS  stabilized by anion binding of the thiourea to the sulfonate  general base activation of the indole via a catalyst amide–indole N–H interaction  cation-p interaction between the arene of the catalyst and the benzylic protons of the episulfonium ion  “We anticipate that characterization of these enzyme-like non- covalent stabilizing elements with small-molecule catalysts such as 3e may enable the future design and application of such biomimetic strategies in organic asymmetric synthesis.” Lin, S.; Jacobsen, E. N. Nature Chem. 2012, 4, 817-824

26. Enzyme-Like Non-Covalent Stabilizing Elements : New Concept ? 26 Xu, H., Zuend, S. J., Woll, M. G., Tao, Y. & Jacobsen, E. N. Science 2010, 327, 986–990. Uyeda, C. & Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062–5075.

27. Thiourea Synthesis 27

28. Different Types of H-Bonding Interactions 28

29. What’s a Good H-Bond Donor ? 29 Connon, S. J. Chem. Eur. J. 2006, 12, 5418-5427. Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543. Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713-5743. Akiyama, T. Chem. Rev. 2007, 107, 5744-5758.

30. Substrate Synthesis 30

31. Catalyst Investigation 31

32. pKa Corrected 32

33. Catalyst Investigation 33

34. Use of a Chiral Phosphoric Acid 34