Lessons learned from organic synthesis
Download
1 / 17

Lessons Learned from Organic Synthesis - PowerPoint PPT Presentation


  • 61 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Lessons Learned from Organic Synthesis' - leigh


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Lessons learned from organic synthesis

Joshua J. Nyman

Howard Hughes Medical Institute Summer Scholar Research Project

Lessons Learned from Organic Synthesis

Mentor: Dr. Yan Zhang, Department of Medicinal Chemistry,

VCU School of Pharmacy


Background
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


The research project
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


My synthesis route
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-dicarbonitrile

Tetrabutylammonium

bromide,

P2O5

2-bromo-4,6-dimethylpyridine-3,5-dicarbonitrile


Forming the pyridine ring
Forming the Pyridine Ring

  • 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.

K2CO3

acetylacetone

cyanoacetamide

3-cyano-4,6-dimethyl-2-hydroxypyridine


Forming the pyridine ring1
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


Brominating the pyridine ring
Brominating the Pyridine Ring

  • 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.

, TFA, H2SO4


Brominating the pyridine ring1
Brominating the Pyridine Ring

  • 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.

, TFA, H2SO4


Adding a cyano group to the pyridine ring
Adding a Cyano- Group to the Pyridine Ring

  • 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

CuCN, DMF

under nitrogen gas


Adding a cyano group to the pyridine ring1
Adding a Cyano- Group to the Pyridine Ring

  • All reactants had to be very dry!!!

Oil Pump


Adding a cyano group to the pyridine ring2
Adding a Cyano- Group to the Pyridine Ring

  • 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.

CuCN, DMF

under nitrogen gas


Adding a cyano group to the pyridine ring3
Adding a Cyano- Group to the Pyridine Ring

  • My compound being refluxed under nitrogen protection


Adding a cyano group to the pyridine ring4
Adding a Cyano- Group to the Pyridine Ring

  • This reaction gave me multiple problems

  • Proton NMR, Thin-Layer Chromatograhy tests, and melting point tests = impure.

  • Because of this, I wasn’t able to proceed further before the end of this program.

CuCN, DMF

under nitrogen gas


Lessons learned
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.

  • It’s 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.


References and acknowledgements
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. Zhang’s lab whose efforts contributed to my learning experience.


References and acknowledgements1
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.


References and acknowledgements2
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


ad