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New Tools for Organic Synthesis and Natural Product Characterization. Christina LeGay Derksen Research Group St. Francis Xavier University . Polyketides : What are they? . Secondary Metabolites Often Biologically & Pharmacologically active Erthromycin A – antibiotic .

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new tools for organic synthesis and natural product characterization

New Tools for Organic Synthesis and Natural Product Characterization

Christina LeGay

DerksenResearch Group

St. Francis Xavier University

polyketides what are they
Polyketides: What are they?
  • Secondary Metabolites
  • Often Biologically & Pharmacologically active
    • ErthromycinA – antibiotic
polyketides what are they1
Polyketides: What are they?
  • Amphotericin B – antifungal drug
  • PelorusideA – antimitotic agent
polyketide preparation
Polyketide Preparation
  • Specific stereochemistry can be achieved by the use of chiral auxiliaries: ex. Evans’ Auxiliary:
    • Advantages: popular, well-established, versatile, pre-made auxiliaries available
    • Disadvantages: adds steps, chromatography required, need stoichiometric amounts of auxiliary
organocatalysis
Organocatalysis
  • ProlineAldol:
    • Advantages: cheap, catalytic, good enantiomeric excess, avoids use of toxic transition metals
    • Disadvantages: limited substrate scope, often poor diastereomeric ratio
our approach
Our Approach
  • Subject the subunits to Asymmetricretro-aldol catalysis
    • Catalyst requirements: stereoselective, wide substrate scope, fast reaction, good yield
our approach1
Our Approach
  • Synthesis of model polyketide subunits
    • Base-catalyzed aldol addition
      • Advantages: very cheap, fairly quick, good yield
      • Disadvantages: racemic mixture, chromatography required
    • Reformatsky
      • Advantages: solvent free, very simple reaction, wide substrate scope
      • Disadvantages: chromatography required
nature s precedent
Nature’s Precedent
  • Aldolases: catalytic aldol reaction
    • Fructose Bisphosphate– catalyzes reversible retro-aldol
chemical literature precedent
Chemical Literature Precedent
  • Rapamycin: immunosuppressant drug
chemical literature precedent1
Chemical Literature Precedent
  • Rodriguez and Zweifel: Retro-Aldol of R106-1
proof of concept
Proof of Concept
  • Significant product formed using NaOH and HCl as catalysts in ethanol
our progress cont d
Our Progress (cont’d)
  • Methylene substrates – how they’re made (solvent free Reformatsky), include rxns that didn’t work, product trace <5%
our progress cont d1
Our Progress (cont’d)
  • Dimethyl substrates – no elimination, EW & ED groups
our progress cont d2
Our Progress (cont’d)
  • X groups on Darren’s aldol product – results of having EW & ED groups on either side
summary
Summary
  • Results, which substrates/solvents/acid/base works best
mechanistic insights
Mechanistic Insights
  • Groups encouraging the Retro-Aldol products (desired):
  • Groups encouraging the Elimination products (undesired):
future work
Future Work
  • Hammett Plots of aryl substituents
  • Catalyst screens with best substrate
  • Asymmetric ligands on catalysts (H3PO4 catalysts)
acknowledgments
Acknowledgments
  • St. Francis Xavier University
  • CFI
  • Merck-Frost