Carbenes and Nitrenes: Application to the Total Synthesis of (–)-Tetrodotoxin

1. Carbenes and Nitrenes: Application to the Total Synthesis of (–)-Tetrodotoxin Effiette Sauer March 18th 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 Electron deficient Highly reactive 2

3. Carbene Formation • Diazoalkanes • Sulfonylhydrazones • Halides 3

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

5. Singlet and Triplet States Singlet Triplet Triplet Singlet • sp2 hybridized carbon • non-bonding electrons have opposite spin - occupy an sp2 orbital • XCY angle 100-110° • sp2 hybridized carbon (or sp?) • non-bonding electrons have same spin – occupy an sp2 and p orbital • XCY angle 130-150° 5

6. Singlet and Triplet States Singlet Triplet Triplet Singlet 6

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

8. Mode of Preparation – Singlet vs. Triplet Ionic Mechanism: Singlet Photolysis: Singlet Triplet 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 • Addition reactions1 • Ylide formation2 • Insertion reactions1 12 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.

13. Free Carbenes/Nitrenes - Too Reactive • Free carbenes/nitrenes are highly reactive species → low activation energy for product formation1: ~ 0 kcal A.E. • Generally too reactive to afford useful selectivity2: 25% 13% 38% 24% 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. 13

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

15. Moderation of Reactivity • Binding of carbene/nitrene with a metal Nitrenoid Carbenoid • 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 LnM → electrophilic → vacant coordination site 16

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

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

19. The Early Days • Early investigations focus on copper catalysts (e.g. CuSO4, CuOTf2) • synthetic use confined to rigid systems1,2 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. CuSO4, CuOTf2) • synthetic use confined to rigid systems1,2 • Teyssie and coworkers introduce dirhodium (II) tetraacetate3 • Scope and utility of carbenoid insertion reactions explode4 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 Electron withdrawing ligands  increase electrophilicity Vacant site for carbene binding/ diazo decomposition Unique dirhodium bridge  one Rh binds carbene, other assists insertion1,2 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 • Role of dirhodium bridge is two-fold • Enhances electrophilicity of carbon • Assists in Rh-C cleavage 23 Nakamura, E.; Yoshikai, N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.

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

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 23 1 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 • Five membered rings form preferentially Chair-like t.s. gives five membered ring product1 → steric, electronic and conformational influences may override this preference2 Five membered ring not observed 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. 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 B A A B Rh2(pfb)4 32 68 Rh2(OAc)4 53 47 Rh2(acam)4 >99 <1 reactivity Rh2(pfb)4 Rh2(OAc)4 Rh2(acam)4 selectivity 29 Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E. J. Am. Chem. Soc. 1993, 115, 958.

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 insertion1 • Mechanistic studies on Ru(Por)(NTs)2 suggest a radical intermediate2 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. 31

32. Good Ol’ Rhodium • Rhodium was initially ignored – gave undesired insertion products (!) • In 2001, Du Bois capitalizes on Rhodium’s preference for insertion1 • Reaction is stereospecific 32 1 Du Bois, J.; Espino, C. G. Angew. Chem. Int. Ed. 2001, 40, 598.

33. (–)-Tetrodotoxin • Isolated from the Japanese puffer • fish (Sphaeroides rubripes) in 19091 • Named after the puffer fish • family Tetraodontidae • LD50 = 10 ng/Kg mouse • Current interest in TTX as a • potent analgesic 33 1 Tahara, Y. J. Pharm. Soc. Jpn. 1909, 29, 587.

34. (–)-Tetrodotoxin • Relative stereochemistry assigned in 1964 by Hiratu-Goto1, Tsuda2, and Woodward3 • Absolute stereochemistry established by X-ray in 19704 • First racemic synthesis by Kishi in 19725 • Enantioselective syntheses by Isobe6 (Jan. 2003) and Du Bois7 (June 2003) 1Tetrahedron1965, 21, 2059. 2Chem. Pharm. Bull. 1964, 12, 1357. 3Pure. Appl. Chem. 1964, 9, 49. 4Bull. Chem. Soc. Jpn. 1970, 43, 3332. 5aJ. Am. Chem. Soc. 1972, 94, 9217. 5bJ. Am. Chem. Soc. 1972, 94, 9219. 6J. Am. Chem. Soc. 2003, 125, 8798. 7J. Am. Chem. Soc. 2003, 125, 11510. 34

35. Retrosynthesis 6 membered ring desired 35

36. Synthesis of (–)-Tetrodotoxin 36

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

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

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

40. Synthesis of (–)-Tetrodotoxin A B 38

41. Synthesis of (–)-Tetrodotoxin A B 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