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

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slide1

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

introduction
Introduction
  • Methods of generating allylic alcohols
  • Nickel-catalyzed coupling between
    • alkynes and aldehydes
    • alkynes and epoxides
    • alkynes and imines
  • Jamison’s methodology applied towards
  • the total synthesis of amphidinolide T1
preparation of allylic alcohols
Preparation of Allylic Alcohols
  • Reductions, organomagnesium and organolithium reagents
  • Reactive allylic sulfoxides via a [2,3]-sigmatropic rearrangement
preparation of allylic and homoallylic alcohols
Preparation of Allylic and Homoallylic Alcohols
  • Allylic oxidation with selenium dioxide
  • Homoallylic alcohols via chiral or achiral crotyl and allyl metals
slide5

Preparation of Allylic Alcohols : The Nozaki-Hiyama-Kishi Reaction

Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048

slide6

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 CrCl2free 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

synthesis of enantioselective e allylic alcohols
Synthesis of Enantioselective (E)-Allylic Alcohols

Oppolzer, W.; Radinov, N. J. Am. Chem. Soc., 1993, 115, 1593

slide8

Synthesis of Macrocyclic (E)-Allylic Alcohols

Oppolzer et al, J. Org. Chem., 2001, 66, 4766

slide9

Addition to RCHO by Zirconocene-Zinc Transmetallation

Wipf, P.; Ribe, S. J. Org. Chem., 1998, 63, 6454

slide10

Intramolecular Ni-Catalyzed Alkylative Cyclizations

Montgomery, J.; Oblinger, E. J. Am. Chem. Soc., 1997, 119, 9065

slide11

Nickel-Catalyzed Alkylative and Reductive Coupling

Montgomery, J.; Oblinger, E.; J. Am. Chem. Soc, 1997, 119, 9065

slide12

Choice of Ligand

Phosphine Ligands with EDG

  • Soft neutral 2e-donor ligand
  • σ-donor ability :
  • (t-Bu)3P > Cy3P > (n-Bu)3P > Et3P > Ph3P

Tolman, C. Chem. Rev.1977, 77, 313

slide13

Reductive vs β-Hydride Elimination : Additive Effect?

  • Direct reductive elimination is
  • accompanied by a 2e- reduction
  • of Ni
  • Process disfavored by the
  • coordination of good σ-donor (n-Bu)3P
  • π-acidic ligands (aldehyde) accelerate
  • reductive elimination
  • In the absence of (n-Bu)3P, unreacted RCHO
  • can coordinate to Ni
slide14

Catalytic Intermolecular Reductive Coupling

of Alkynes and Aldehydes

Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

slide16

Jamison, T.F. et al, Org. Lett., 2000, 26, 4221

Choosing the Reducing Agent

Montgomery, J.; Tang, X-Q. J. Am. Chem. Soc., 1999, 121, 6098

slide18

Asymmetric Reductive Coupling with NMDPP

Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442

slide24

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
slide25

Intermolecular Reductive Coupling of Alkynes andEpoxides

Jamison, T.F.; Molinaro, C. J. Am. Chem. Soc, 2003, 125, 8076

slide27

Summary of Nickel-Catalyzed Reaction

  • Racemic and enantioselective allylic alcohols
  • Allylic amines via three-component coupling
  • Homoallylic alcohols
slide28

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

slide29

Ghosh’s Enantioselective Synthesis of Amphidinolide T1

via Macrolactonization

Ghosh, A.K.; Liu, C. J. Am. Chem. Soc., 2003, 125, 2374

slide30

Fürstner’s Synthesis of Amphidinolide T1

viaRCM Macrocyclization

Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125, 15512

slide31

Jamison’s Approach to Amphidinolide T1

  • Jamison’s Approach : Ni-catalyzed reductive rxn
  • alkyne-epoxide
  • alkyne-aldehyde

Jamison et al, J. Am. Chem. Soc., 2004, 126, 998

slide34

Enantioselective Brown (Z)-Crotyl Addition

Brown, H.C.; Bhat, K. J. Am. Chem. Soc.,1986, 108, 5919

slide39

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.
slide40

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

Premier’s Research Excellence Award

Merck Frosst Canada

Astra Zeneca

Bristol Myers Squibb

Boerhinger Ingelheim

University of Ottawa

NSERC

OGS