Carbenes and Nitrenes: Application to the Total Synthesis of (

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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.
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What are Carbenes? Nitrenes?

• Neutral, divalent carbon species containing six
  valence electrons

• Neutral, monovalent nitrogen species containing
  six valence electrons

Highly reactive
Electron deficient
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Carbene Formation

• Diazoalkanes

• Sulfonylhydrazones

• Halides

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Reactions of Carbenes

• Addition reactions

• Ylide formation

• Insertion reactions

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Singlet and Triplet States
Triplet
Singlet
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

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Singlet and Triplet States
Triplet
Singlet
Triplet
Singlet
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Relative Stability of Singlet and Triplet States

• Triplet more stable than singlet (RH, alkyl)

Singlet
Triplet

• Unless, added stabilization possible (XO, N, S,
  halogen etc.)

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Mode of Preparation Singlet vs. Triplet
Ionic Mechanism
Singlet
Photolysis
Singlet
Triplet
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Singlet Carbenes React Stereospecifically
FMO interactions for cyclopropanation with
singlet carbene
Mechanism
Concerted
Stereospecific
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Triplet Carbenes React Stereoselectively
Cyclopropanation with triplet carbenes - radical
mechanism
Two pathways
Stereoselective
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Nitrene Formation

• Azides

• Iminoiodanes

• Sulfonamides

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Reactions of Nitrenes

• Addition reactions1

• Ylide formation2

• Insertion reactions1

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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.
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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.
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Moderation of Reactivity

• Intramolecular, rigid systems

• Rearrangement reactions (e.g. Wolff, Curtius)

Concerted or stepwise depending on conditions
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Majerski, Z. Hamersak, Z. Sarac-Arneri, R. J.
Org. Chem. 1988, 53, 5053.
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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)

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Generation of the Metalloid

• Treat carbene/nitrene precursor with transition
  metal ion

• General mechanism

LnM ? electrophilic ? vacant
coordination site
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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
s acceptor? p donor?
p back bond
s bond
lone pair into empty d orbital
d orbital into empty p orbital
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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
s acceptor? p donor?
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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.
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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.
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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.
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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.
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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

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Nakamura, E. Yoshikai, N. Yamanaka, M. J. Am.
Chem. Soc. 2002, 124, 7181.
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Insertion Mechanism
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Nakamura, E. Yoshikai, N. Yamanaka, M. J. Am.
Chem. Soc. 2002, 124, 7181.
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Trends in Selectivity
Build-up of positive charge in transition state ?
implications for selectivity

• 3 gt 2 gt 1
• adjacent heteroatoms favour insertion
• EWGs hinder insertion

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Trends in Selectivity
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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.
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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.
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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
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Trends in Selectivity
B
A
A
B
Rh2(pfb)4 32
68 Rh2(OAc)4 53
47 Rh2(acam)4
gt99 lt1
reactivity
Rh2(pfb)4
Rh2(OAc)4
Rh2(acam)4
selectivity
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Doyle, M. P. Westrum, L. J. Wolthuis, W. N. E.
J. Am. Chem. Soc. 1993, 115, 958.
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Trends in Selectivity in Summary

• Preference for most electron rich CH bond
• Five-membered ring formation preferred
• Enhanced selectivity by decreasing reactivity of
  carbenoid

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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.
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Good Ol Rhodium

• Rhodium was initially ignored gave undesired
  insertion products (!)

• In 2001, Du Bois capitalizes on Rhodiums
  preference for insertion1

• Reaction is stereospecific

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1 Du Bois, J. Espino, C. G. Angew. Chem. Int.
Ed. 2001, 40, 598.
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()-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

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1 Tahara, Y. J. Pharm. Soc. Jpn. 1909, 29, 587.
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()-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)

1Tetrahedron 1965, 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.
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Retrosynthesis
6 membered ring desired
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Synthesis of ()-Tetrodotoxin
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Synthesis of ()-Tetrodotoxin
Change PG if need be
Double bond to favour six membered ring
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Synthesis of ()-Tetrodotoxin
A
B
B via
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Synthesis of ()-Tetrodotoxin
A
B
B via
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Synthesis of ()-Tetrodotoxin
A
B
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Synthesis of ()-Tetrodotoxin
A
B
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Synthesis of ()-Tetrodotoxin
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Synthesis of ()-Tetrodotoxin
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Synthesis of ()-Tetrodotoxin
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Synthesis of ()-Tetrodotoxin
Only product
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Synthesis of ()-Tetrodotoxin
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Synthesis of ()-Tetrodotoxin
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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 gt95 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

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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