Applications of a Novel NickelCatalyzed Reductive Coupling Reaction Towards the Total Synthesis of A

1
Applications of a Novel Nickel-Catalyzed
Reductive Coupling Reaction Towards the Total
Synthesis of Amphidinolide T1
Julie Farand April 1st, 2004
Jamison et al, J. Am. Chem. Soc., 2004, 126, 998
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
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Introduction

• Methods of generating allylic alcohols
• Nickel-catalyzed coupling between
• alkynes and aldehydes
• alkynes and epoxides
• alkynes and imines
• Jamisons methodology applied towards
• the total synthesis of amphidinolide T1

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Preparation of Allylic Alcohols

• Reductions, organomagnesium and organolithium
  reagents

• Reactive allylic sulfoxides via a
  2,3-sigmatropic rearrangement

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Preparation of Allylic and Homoallylic Alcohols

• Allylic oxidation with selenium dioxide

• Homoallylic alcohols via chiral or achiral
  crotyl and allyl metals

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Preparation of Allylic Alcohols The
Nozaki-Hiyama-Kishi Reaction
Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048
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Nozaki-Hiyama-Kishi Mechanism
The success of this reaction heavily depended on
the nature of the CrCl2!

• In 1983, anhydrous CrCl2 from ROC/RIC Corp (New
  Jersey) proved to
• contain ca. 0.5 mol of Ni on the basis of Cr
• Aldrich Co. (90 purity) and Rare Metallic Co.
  (99.99 purity) offers
• anhydrous CrCl2 free from Ni salts

Hiyama, T. Nozaki, H. et al, Tetrahedron
Letters, 1983, 24, 5281 Kishi Y. et al, J. Am.
Chem. Soc, 1986, 108, 5644 Nozaki, H. et al, J.
Am. Chem. Soc, 1986, 108, 6048
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Synthesis of Enantioselective (E)-Allylic Alcohols
Oppolzer, W. Radinov, N. J. Am. Chem. Soc.,
1993, 115, 1593
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Synthesis of Macrocyclic (E)-Allylic Alcohols
Oppolzer et al, J. Org. Chem., 2001, 66, 4766
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Addition to RCHO by Zirconocene-Zinc
Transmetallation
Wipf, P. Ribe, S. J. Org. Chem., 1998, 63, 6454
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Intramolecular Ni-Catalyzed Alkylative
Cyclizations
Montgomery, J. Oblinger, E. J. Am. Chem. Soc.,
1997, 119, 9065
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Nickel-Catalyzed Alkylative and Reductive Coupling
Montgomery, J. Oblinger, E. J. Am. Chem. Soc,
1997, 119, 9065
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Choice of Ligand
Phosphine Ligands with EDG

• Soft neutral 2e-donor ligand
• s-donor ability
• (t-Bu)3P gt Cy3P gt (n-Bu)3P gt Et3P gt Ph3P

Tolman, C. Chem. Rev. 1977, 77, 313
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Reductive vs ß-Hydride Elimination Additive
Effect?

• Direct reductive elimination is
• accompanied by a 2e- reduction
• of Ni
• Process disfavored by the
• coordination of good s-donor (n-Bu)3P

• p-acidic ligands (aldehyde) accelerate
• reductive elimination
• In the absence of (n-Bu)3P, unreacted RCHO
• can coordinate to Ni

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Catalytic Intermolecular Reductive Coupling of
Alkynes and Aldehydes
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
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Proposed Mechanism via an Oxametallacyle
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Choosing the Reducing Agent
Montgomery, J. Tang, X-Q. J. Am. Chem. Soc.,
1999, 121, 6098
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Catalytic Intermolecular Reductive Coupling of
Alkynes and Aldehydes
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Asymmetric Reductive Coupling with NMDPP
Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442
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Proposed Steric and Electronic Control
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Proposed Mechanism for Asymetric Reductive
Coupling
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Catalytic Three-Component Coupling
Reaction Allylic Amines
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Boronic Acids in Catalytic Three-Component
Couplings
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Enantioselectivities for Alkylative and Reductive
Coupling Using (S)-()-NMDPP
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Proposed Mechanism for the Ni-catalyzed Coupling
Reaction Between Alkynes and Imines

• Enantioselectivity and regioselectivity are
  determined in the same step
• and before the azametallacyclopentene
• Highly selective for alkylative coupling in MeOH

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Intermolecular Reductive Coupling of Alkynes and
Epoxides
Jamison, T.F. Molinaro, C. J. Am. Chem. Soc,
2003, 125, 8076
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Reductive Cyclization via a Proposed
Nickella(II)oxetane
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Summary of Nickel-Catalyzed Reaction

• Racemic and enantioselective allylic alcohols

• Allylic amines via three-component coupling

• Homoallylic alcohols

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Synthesis of Amphidinolide T1

• The amphidinolides are a family of macrolides
• produced by marine dinoflagellates of the genus
• Amphidinium
• The marine algae live in symbiosis with the
  Okinawan
• flatworm
• Amphidinolide T1, a 19-membered macrolide, is
• cytotoxic against human epidermoid carcinoma KB
• and murine lymphoma L1210 cell lines

Total Synthesis of Amphidinolide T1

• Ghosh (2003)
• Fürstner (2003)
• Jamison (2004)

Amphidinium carterae
Amphidinium lactum
Kobayashi, J. et al, J. Org. Chem., 2001, 66, 134
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Ghoshs Enantioselective Synthesis of
Amphidinolide T1 via Macrolactonization
Ghosh, A.K. Liu, C. J. Am. Chem. Soc., 2003,
125, 2374
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Fürstners Synthesis of Amphidinolide T1 via RCM
Macrocyclization
Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125,
15512
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Jamisons Approach to Amphidinolide T1

• Jamisons Approach Ni-catalyzed reductive rxn
• alkyne-epoxide
• alkyne-aldehyde

Jamison et al, J. Am. Chem. Soc., 2004, 126, 998
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Synthesis of Amphidinolide T1
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Mechanism Revisited
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Enantioselective Brown (Z)-Crotyl Addition
Brown, H.C. Bhat, K. J. Am. Chem. Soc.,1986,
108, 5919
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Synthesis of Amphidinolide T1
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Synthesis of Amphidinolide T1
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Synthesis of Amphidinolide T1
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Synthesis of Amphidinolide T1
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Conclusion

• Two nickel-catalyzed carbon-carbon bond
• forming reactions were utilized during the
• synthesis of Amphidinolide T1

• catalytic intermolecular alkyne-epoxide
• reductive coupling
• catalytic intramolecular alkyne-aldehyde
• reductive coupling

• This is the most direct synthesis of
• Amphidinolide T1 with 20 synthetic operations.

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Aknowledgements
Prof Louis Barriault Irina Denissova Steve
Arns Effie Sauer Jeff Warrington Roxanne
Clément Patrick Ang Louis Morency Rachel
Beingessner Gerardo Ulibarri Danny Gauvreau Ross
MacLean Jermaine Thomas Roch Lavigne Nathalie
Goulet Christiane Grisé
Financial Support
Canada Foundation for Innovation Ontario
Innovation Trust Premiers Research Excellence
Award
Merck Frosst Canada Astra Zeneca Bristol Myers
Squibb Boerhinger Ingelheim
University of Ottawa NSERC OGS