1. Carbenes and Nitrenes: Application to the Total Synthesis of (–)-Tetrodotoxin Effiette Sauer March 18 th 2004 Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510.

2. What are Carbenes? Nitrenes? Neutral, divalent carbon species containing six valence electrons Neutral, monovalent nitrogen species containing six valence electrons HighlyreactiveElectrondeficient 2

3. Carbene Formation Diazoalkanes Halides Sulfonylhydrazones 3

4. Reactions of Carbenes Addition reactions Ylide formation Insertion reactions 4

5. Singlet and Triplet States sp 2 hybridized carbon non-bonding electrons have opposite spin - occupy an sp 2 orbital XCY angle 100-110° sp 2 hybridized carbon (or sp?) non-bonding electrons have same spin – occupy an sp 2 and p orbital XCY angle 130-150° TripletSingletTriplet Singlet 5

6. Singlet and Triplet States TripletSingletTriplet Singlet 6

7. Relative Stability of Singlet and Triplet States Unless, added stabilization possible (X=O, N, S, halogen etc.) Triplet more stable than singlet (R=H, alkyl) 7 Triplet Singlet

8. Mode of Preparation – Singlet vs. Triplet Ionic Mechanism: Singlet Photolysis: SingletTriplet 8

9. Singlet Carbenes React Stereospecifically FMO interactions for cyclopropanation with singlet carbene: Mechanism: Concerted Stereospecific 9

10. Triplet Carbenes React Stereoselectively Cyclopropanation with triplet carbenes - radical mechanism: Two pathways Stereoselective 10

11. Nitrene Formation Azides Iminoiodanes Sulfonamides 11

12. Reactions of Nitrenes 1 Lwowski, W. Angew. Chem. Int. Ed. Engl. 1967, 6, 897. 2 Albini, A.; Bettinetti, G.; Minoli, G. J. Am. Chem. Soc., 1997, 119, 7308. Ylide formation 2 Insertion reactions 1 Addition reactions 1 12

13. Free Carbenes/Nitrenes - Too Reactive 1 Zurawski, B.; Kutzelnigg, W. J. Am. Chem. Soc. 1978, 100, 2654. 2 Richardson, D. B..; Simmons, M. C.; Dvoretzky. I. J. Am. Chem. Soc. 1961, 83, 1934. Free carbenes/nitrenes are highly reactive species → low activation energy for product formation 1 : Generally too reactive to afford useful selectivity 2 : ~ 0 kcal A.E. 25% 13% 38% 24% 13

14. Moderation of Reactivity Intramolecular, rigid systems Rearrangement reactions (e.g. Wolff, Curtius) Majerski, Z.; Hamersak, Z.; Sarac-Arneri, R. J. Org. Chem. 1988, 53, 5053. Concerted or stepwise depending on conditions 14

15. Moderation of Reactivity Binding of carbene/nitrene with a metal Carbenoid Nitrenoid Tune reactivity by changing L, M, X, Y Different species for 1) addition 2) ylide formation 3) insertion reactions 4) and more (e.g. RCM) 15

16. Generation of the Metalloid Treat carbene/nitrene precursor with transition metal ion General mechanism L n M → electrophilic → vacant coordination site 16

17. Tuning the Catalyst for CH Insertion X, Y = acceptor (EWG) donor (EDG) or H σ acceptor? π donor? Must tune electrophilicity of carbon atom to react selectively with inert CH bonds lone pair into empty d orbital d orbital into empty p orbital σ bond π back bond 17

18. Tuning the Catalyst for CH Insertion X, Y = acceptor (EWG) donor (EDG) or H σ acceptor? π donor? Must tune electrophilicity of carbon atom to react selectively with inert CH bonds 18

19. The Early Days Early investigations focus on copper catalysts (e.g. CuSO 4, CuOTf 2 ) → synthetic use confined to rigid systems 1,2 1 Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361. 2 Burns, W.; McKervey, M. A.; Mitchell, T. R. B.; Rooney, J. J. J. Am. Chem. Soc. 1978, 100, 906. 19

20. The Early Days Early investigations focus on copper catalysts (e.g. CuSO 4, CuOTf 2 ) → synthetic use confined to rigid systems 1,2 Teyssie and coworkers introduce dirhodium (II) tetraacetate 3 → Scope and utility of carbenoid insertion reactions explode 4 3 Paulissenen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, P. Tetrahedron Lett. 1973, 2233. 4 Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; Warnet, R. J.; Pellicciari, R. J. Org. Chem. 1982, 47, 3242. 20

21. Dirhodium (II) Catalysts Vacant site for carbene binding/ diazo decomposition Unique dirhodium bridge  one Rh binds carbene, other assists insertion 1,2 Electron withdrawing ligands  increase electrophilicity 1 Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181. 2 Pirrung, M. C.; Liu, H.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2002, 124, 1014. 21

22. Insertion Mechanism Doyle, M. P.; Westrum, L. J.; Wolthuis,W. N. E.; See, M. M.; Boone, W. P; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958. 22

23. Insertion Mechanism Nakamura suggests Rh-Rh cleavage occurs during diazo decomposition giving rise to two simultaneous events at the transition state → Hydride Transfer → Regeneration of the Rh-Rh bond Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181. Role of dirhodium bridge is two-fold → Enhances electrophilicity of carbon → Assists in Rh-C cleavage 23

24. Insertion Mechanism Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181. 24

25. Trends in Selectivity Build-up of positive charge in transition state → implications for selectivity 3° > 2° > 1° adjacent heteroatoms favour insertion EWGs hinder insertion 25

26. Trends in Selectivity 231 1 Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686. 2 Adams, J; Spero, D. M. Tetrahedron 1991, 47, 1765. 3 Wang, P.; Adams, J. J Am. Chem. Soc. 1994, 116, 3296. 26

27. Trends in Selectivity 1 Taber, D. F.; Ruckle, R. E. Jr. J. Am. Chem. Soc. 1986, 108, 7686. 2 Lee, E.; Choi, I.; Song, S. Y. J. Chem. Soc., Chem. Commun. 1995, 321. Five membered ring not observed → steric, electronic and conformational influences may override this preference 2 Five membered rings form preferentially Chair-like t.s. gives five membered ring product 1 27

28. Trends in Selectivity The Hammond postulate: Two species of similar energy occurring consecutively along a reaction coordinate will be similar in structure High energy intermediates → TS resembles intermediate Low energy intermediates → TS resembles the product  lower energy intermediate  later TS  more charge build-up  greater selectivity 28

29. Trends in Selectivity Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E. J. Am. Chem. Soc. 1993, 115, 958. Rh 2 (pfb) 4 32 68 Rh 2 (OAc) 4 53 47 Rh 2 (acam) 4 >99 <1 A B AB reactivity selectivity Rh 2 (pfb) 4 Rh 2 (OAc) 4 Rh 2 (acam) 4 29

30. Trends in Selectivity – in Summary Preference for most electron rich CH bond Five-membered ring formation preferred Enhanced selectivity by decreasing reactivity of carbenoid 30

31. What about those Nitrenoids? Certain Fe, Mn, and Ru porphyrin complexes catalyze CH insertion 1 1 Yu, X.; Huang, J.; Zhou, X.; Che, C. Org. Lett. 2000, 2, 2233. 2 Au, S.; Huang, J.; Yu, W.; Fung, W.; Che, C. J. Am. Chem. Soc. 1999, 121, 9120. Mechanistic studies on Ru(Por)(NTs) 2 suggest a radical intermediate 2 31

32. Good Ol’ Rhodium Rhodium was initially ignored – gave undesired insertion products (!) In 2001, Du Bois capitalizes on Rhodium’s preference for insertion 1 1 Du Bois, J.; Espino, C. G. Angew. Chem. Int. Ed. 2001, 40, 598. Reaction is stereospecific 32

33. (–)-Tetrodotoxin Isolated from the Japanese puffer fish (Sphaeroides rubripes) in 1909 1 Named after the puffer fish family Tetraodontidae LD50 = 10 ng/Kg mouse Current interest in TTX as a potent analgesic 1 Tahara, Y. J. Pharm. Soc. Jpn. 1909, 29, 587. 33

34. (–)-Tetrodotoxin Relative stereochemistry assigned in 1964 by Hiratu-Goto 1, Tsuda 2, and Woodward 3 Absolute stereochemistry established by X-ray in 1970 4 First racemic synthesis by Kishi in 1972 5 Enantioselective syntheses by Isobe 6 (Jan. 2003) and Du Bois 7 (June 2003) 1 Tetrahedron 1965, 21, 2059. 2 Chem. Pharm. Bull. 1964, 12, 1357. 3 Pure. Appl. Chem. 1964, 9, 49. 4 Bull. Chem. Soc. Jpn. 1970, 43, 3332. 5a J. Am. Chem. Soc. 1972, 94, 9217. 5b J. Am. Chem. Soc. 1972, 94, 9219. 6 J. Am. Chem. Soc. 2003, 125, 8798. 7 J. Am. Chem. Soc. 2003, 125, 11510. 34

35. Retrosynthesis 6 membered ring desired 35

36. Synthesis of (–)-Tetrodotoxin 36

37. Synthesis of (–)-Tetrodotoxin Double bond to favour six membered ring Change PG if need be 37

38. Synthesis of (–)-Tetrodotoxin AB B via: 38

39. Synthesis of (–)-Tetrodotoxin AB B via: 38

40. Synthesis of (–)-Tetrodotoxin AB 38

41. Synthesis of (–)-Tetrodotoxin AB 38

42. Synthesis of (–)-Tetrodotoxin 39

43. Synthesis of (–)-Tetrodotoxin 40

44. Synthesis of (–)-Tetrodotoxin 41

45. Synthesis of (–)-Tetrodotoxin Only product 42

46. Synthesis of (–)-Tetrodotoxin 43

47. Synthesis of (–)-Tetrodotoxin 44

48. Conclusions Completed the synthesis of (–)-TTX in 32 steps, overall yield of 0.8%, average yield of 81% Used CH insertion to stereospecifically assemble quaternary carbon centre at C6 and six-membered core ring of TTX in >95% yield Demonstrated the viability of their recently developed CH amination reaction, forming the tertiary amine in 77% yield Reinforced the utility of carbenes and nitrenes as valuable intermediates in organic synthesis 45

49. Acknowledgments Dr. Louis Barriault Patrick Ang Steve Arns Rachel Beingesser Roxanne Clément Irina Denissova Julie Farand Nathalie Goulet Christiane Grisé Roch Lavigne Louis Morency Maxime Riou Jeff Warrington Professor Justin Du Bois, Andrew Hinman