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Rh-Catalyzed Asymmetric Additions: The Rise of Chiral Dienes. Tamio Hayashi. Erick Carreira. Daniela Sustac February 16, 2010. Outline. Transition Metal – Olefin Complexes. Alkenes not very basic, backbonding necessary to stabilize M-olefin bond;

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rh catalyzed asymmetric additions the rise of chiral dienes

Rh-Catalyzed Asymmetric Additions: The Rise of Chiral Dienes

Tamio Hayashi

Erick Carreira

Daniela Sustac

February 16, 2010

transition metal olefin complexes
Transition Metal – Olefin Complexes
  • Alkenes not very basic, backbonding necessary to stabilize M-olefin bond;
  • Olefins considered labile, easily displaced from M center.

Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

transition metal strained alkene complexes
Transition Metal – Strained Alkene Complexes
  • Strained alkenes (cyclopropene, norbornene) bind very strongly to metals;
  • Rehybridization on binding relieves ring strain.

Crabtree, H.R. The Organometallic Chemistry of Transition Metals. Wiley: New Jersey, 2005.

examples of olefins in complexes and catalysis
Examples of Olefins in Complexes and Catalysis
  • Prepared by Zeise in 1827;
  • Structure elucidated in the 1950’s;
  • Norbornene in the Catellani reaction: “a sort of scaffold to be removed after the building of the molecule is complete; behaves as catalyst, excess necessary to push the reaction”

Wunderlich, A.J.; Mellor, D.P. Acta Crystallogr. 1955, 8, 57.

Catellani, M; Frignani, F.; Rangoni, A. Angew. Chem. Int. Ed. 2007, 36, 119.

who binds the strongest
Who Binds the Strongest?
  • Electron deficient alkenes bind tighter;
  • Stronger binding with strained alkenes.

Tolman, A.C. Organometallics 1983, 2, 614.

rh catalyzed 1 4 addition before chiral dienes
Rh-Catalyzed 1,4-Addition (before chiral dienes)

Consequently, the reaction can be done using directly [Rh(OH)(S-binap)]2 at 35 ºC.

Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.

chiral dienes first contact
Chiral Dienes: First Contact

Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

Hydrosylilation: Uozumi, Y.; Lee, S.-Y.; Hayashi, T. Tetrahedron Lett. 1992, 33, 7185.

the only one with a lot of scope
The (Only) One with A Lot of Scope

Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

explaining stereochemistry
Explaining Stereochemistry

Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

chiral dienes first contact1
Chiral Dienes: First Contact
  • Advantages
  • Highest catalytic activity of all rhodium catalysts used for 1,4-addition;
  • Among the highest enantioselectivities (most over 90% ee);
  • Disadvantages
  • Long synthesis of chiral diene;
  • Bistriflate intermediate hard to isolate.

Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508.

new route to chiral dienes
New Route to Chiral Dienes

Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.

Vandyck, K.; Matthys, B.; Willen, M.; Robeyns, K.; Van Meervelt, L.; Van der Eycken, J. Org. Lett. 2006, 8, 363.

one unstable chiral diene one stable rh complex
One Unstable Chiral Diene, One Stable Rh Complex

Berthon-Gelloz, G.; Hayashi, T. J. Org. Chem. 2006, 71, 8957.

one more carbon
One More Carbon
  • Optical resolution by recrystallization inefficient route;
  • Alternatively, can do racemic synthesis and separate by chiral HPLC, either intermediate or final product.

Otomaru, Y.; Okamoto, K.; Shintani, R.; Hayashi, T. J. Org. Chem. 2005, 70, 2503.

the one with imean arylation
The One with iMean Arylation

Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

stereochemistry is explained
Stereochemistry is Explained

Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

the one with a bit of scope
The One with (a Bit) of Scope

Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584.

the one where they do it better
The One where They Do It Better?

Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.

the one with the imean mechanism
The One with the iMean Mechanism

Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

more stereochemistry explained
More Stereochemistry Explained

Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

is nine the lucky number
Is Nine the Lucky Number?

Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

the one with the deprotection
The One with the Deprotection

By far the mildest approach!

Boezio, A.A; Pytkowicz, J.; Cote, A.; Charette, A.B. J. Am. Chem. Soc. 2003, 125, 14260.

Nishimura, T; Yasuhara, Y.; Hayashi, T. Org. Lett. 2006, 8, 979.

Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307.

the one with the cyclization of alkynals
The One with the Cyclization of Alkynals

*[Rh(OH)(cod)]2 used directly

Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

the one with the mechanism
The One with the Mechanism

Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

the one with the cyclization of alkynals1
The One with the Cyclization of Alkynals

*Et instead of Me.

Shintani, R.; Okamoto, K.; Otomaru, Y; Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54.

let s do some cycloadditions
Let’s Do Some Cycloadditions

Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

slide28
[4+2]

Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

cycloaddition mechanism
Cycloaddition Mechanism

Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

stereochemistry explained
Stereochemistry Explained

Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi, T. Angew. Chem. Int. Ed. 2007, 46, 7277.

1 6 enynes cycloisomerization
1,6-Enynes Cycloisomerization

Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

tfb tetrafluorobenzobarrelene diene synthesis
Tfb (tetrafluorobenzobarrelene) Diene Synthesis
  • Chiral HPLC to separate enantiomers;
  • Low yielding steps.

Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem. Commun. 2009, 5713.

the one with the catalyst design
The One with the Catalyst Design

A chiral diene and a phosphine on the same catalyst!

Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

dig the mechanism
“Dig” the Mechanism

Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

stereochemistry explained1
Stereochemistry Explained

Nishimura, T.; Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem. Int. Ed. 2010, 49, In Press.

more chiral dienes
More Chiral Dienes

Most effective ligands reported so far for Rh-catalyzed asymmetric addition!

Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.

last stereochemistry picture
Last Stereochemistry Picture

Okamoto, K.; Hayashi, T.; Rawal, H.V. Org. Lett. 2008, 10, 4387.

ir catalyzed allylic displacement
Ir-Catalyzed Allylic Displacement

Potential for the diene to be synthesized asymmetrically from cheap (R) or (S)-carvone.

Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

spin off carreira s diene
Spin-Off: Carreira’s Diene

Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

carreira s dienes generation ii the long way home
Carreira’s Dienes Generation II“The Long Way Home”

Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.

again with the enones
Again with the Enones?
  • Additional substrates in the scope (not covered by Hayashi)

Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E.M. Org. Lett. 2004, 6, 3873.

the short way home
The Short Way Home

Carreira

Darses

  • Ortho substituted boronic acids a challenge;
  • Most accessible route;
  • Library of 14 ligands;
  • High enantioselectivities (over 90%).

Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem. Int. Ed. 2008, 47, 7669.

Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E.M. J. Am. Chem. Soc. 2004, 126, 1628.

enantioselective diene synthesis
Enantioselective Diene Synthesis

Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

order of addition is important
Order of Addition Is Important
  • Diene is inhibited
  • Less strained system necessary

Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

adding one more carbon
Adding One More Carbon

Brown, K.M.; Corey, E.J. Org. Lett. 2010, 12, 172.

summary
Summary

Reviews:

Defieber, C.; Grutzmacher, H.; Carreira, E.M. Angew. Chem. Int. Ed. 2008, 47, 4482.

Johnson, B.J.; Rovis, T. Angew. Chem. Int. Ed. 2008, 47, 840.

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