Lessons Learned from Organic Synthesis

1
Lessons Learned from Organic Synthesis
Joshua J. Nyman Howard Hughes Medical Institute
Summer Scholar Research Project
Mentor Dr. Yan Zhang, Department of Medicinal
Chemistry, VCU School of Pharmacy
2
Background

• Anibamine is a natural product, but recently it
  has been successfully synthesized in the
  laboratory.
• Anibamine can be used as an anti-HIV drug
• It has a unique chemical structure.

_
TFA
Anibamine
3
The Research Project

• The objective of the research project was to
  synthesize the ring system of anibamine and then
  to alter the stereochemistry of its side-chains.

_
TFA
Anibamine
4
My Synthesis Route
K2CO3
acetylacetone

3-cyano-4,6-dimethyl-2-hydroxypyridine (2-hydroxy-
4,6-dimethyl-nicotinonitrile)
, TFA, H2SO4
cyanoacetamide
CuCN, DMF
under nitrogen gas
5-bromo-2-hydroxy-4,6-dimethyl-nicotinonitrile
1,2-dihydro-4,6-dimethyl-2-oxopyridine-3,5-dicarbo
nitrile
Tetrabutylammonium bromide, P2O5
2-bromo-4,6-dimethylpyridine-3,5-dicarbonitrile
5
Forming the Pyridine Ring
K2CO3
acetylacetone
cyanoacetamide
3-cyano-4,6-dimethyl-2-hydroxypyridine

• An aqueous solution of potassium carbonate was
  prepared.
• Acetylacetone and cyanoacetamide were added to
  the solution.
• A stir bar was placed into the resulting mixture
  and the mixture was allowed to stir at room
  temperature for 24 hours.

6
Forming the Pyridine Ring

• After 24 hours of stirring, the mixture was
  vacuum filtrated, yielding a white powder.
• Melting point was on the high end of the
  literature melting point, and the thin-layer
  chromatography provided a positive presumptive
  test for the pyridine ring product.
• A proton-NMR was also done on the resultant
  compound, but was later to found to be of little
  value based on the solvent used to dissolve the
  sample.

Images Barnard College Organic Chemistry Lab
7
Brominating the Pyridine Ring
, TFA, H2SO4

• The product of the previous reaction was
  dissolved in concentrated sulfuric acid and
  trifluoracetic acid, while in an ice bath.
  N-bromosuccinimide was then added.
• This reaction was run multiple times with varying
  degrees of purity.
• Melting points taken of the product(s) were 10
  to 15 degrees too high in a couple of cases.
• Thin-layer chromatography suggested some
  compounds were impure.
• Product appeared to be a light yellow in the more
  impure products and white in the purer products.

8
Brominating the Pyridine Ring
, TFA, H2SO4

• It seems the purity of this reaction could have
  been affected by certain techniques.
• For example
• Removing the reaction mixture from the ice bath
  Exothermic reaction
• Rate of addition Adding the NBS too quickly
  likely resulted in an undesired side reaction.
• Acid-Base reaction.

9
Adding a Cyano- Group to the Pyridine Ring
CuCN, DMF
under nitrogen gas

• This reaction had some special considerations
• One of the chemicals used in this reaction is a
  highly toxic compound called cuprous cyanide
  (a.k.a. copper (I) cyanide).
• Handling the cyanide required great care

10
Adding a Cyano- Group to the Pyridine Ring
Oil Pump

• All reactants had to be very dry!!!

11
Adding a Cyano- Group to the Pyridine Ring
CuCN, DMF
under nitrogen gas

• The cuprous cyanide was dissolved in
  dimethylformamide along with the product from the
  previous reaction.
• The mixture was then refluxed for 48 hours under
  nitrogen gas.

12
Adding a Cyano- Group to the Pyridine Ring

• My compound being refluxed under nitrogen
  protection

13
Adding a Cyano- Group to the Pyridine Ring
CuCN, DMF
under nitrogen gas

• This reaction gave me multiple problems
• Proton NMR, Thin-Layer Chromatograhy tests, and
  melting point tests impure.
• Because of this, I wasnt able to proceed further
  before the end of this program.

14
Lessons Learned

• Organic synthesis can be very tricky, especially
  when trying to form natural products.
• I learned not only to think about the products I
  am trying to synthesize, but also about which
  products I do not want to synthesize (i.e.
  impurities) and how to prevent them.
• Its not just what chemicals you add, but how you
  add them. Temperature, rate of addition, and
  other factors can have a considerable impact on
  the overall synthesis.

15
References and Acknowledgements

• A special thanks to Dr. Yan Zhang (my mentor) for
  sharing his expertise, his laboratory, and for
  making this an exceptional research learning
  experience.
• Also a special thanks to Dr. Guo Li and Kendra
  Haney, for generously sharing their time and for
  their guidance.
• And to all of the others brilliant individuals
  in Dr. Zhangs lab whose efforts contributed to
  my learning experience.

16
References and Acknowledgements

• Literature (the primary source for my research
  project and background information presented in
  this presentation)
• Guo Li, Karen Watson, Robert W. Buckheit, and Yan
  Zhang Total Synthesis of Anibamine, a Novel
  Natural Product as a Chemokine Receptor CCR5
  Antagonist Organic Letters 2007. Vol 9. 10
  2043-2046.

17
References and Acknowledgements

• Pictures and Graphics
• Title Slide Erlenmeyer Flasks
• Department of Chemistry BiochemistryNorthern
  Arizona University
• www.nau.edu/chem/Images/flasks.jpg
• Slide 10 Reflux Apparatus and White Compound in
  Erlenmeyer Flask
• Barnard College Organic Chemistry Lab
• http//www.barnard.edu/chem/orgolab/lab2.htm