Cycloaddition reaction for making nitrogen-containing 7-membered heterocyclic compounds


Research in the Jeffrey laboratory at UNR is focused on addressing important, unmet challenges in target directed synthesis. Areas of research are identified using a synergistic approach where (1) inspiration from structurally and biologically interesting molecular targets drives reaction discovery, and (2) innovation in methodology enables new strategies for target-directed synthesis.

Areas of research in the Jeffrey laboratory are focused on the development of new methods/strategies to generate and control electrophilic nitrogen species that will enable the direct functionalization of alkenes and C-H bonds-the two most ubiquitous functional groups in organic molecules. These research interests are focused on the development of: (i) new hetero-cycloaddition reactions, (ii) a concise and general synthesis of a family of biologically active alkaloids, and (iii) new methods of metal-mediated amination.

Technology Summary
Nitrogen based heterocyclic compounds are widely represented in natural products, pharmaceuticals, peptidomimetics, and monomers for polymerization. This technology is a [4+3] cycloaddition reaction having an intermediate aza-oxyallylcation which can react with an appropriate second reactant to synthesize 7-membered nitrogen containing heterocyclic compounds. These compounds can then be used as a novel scaffold in drug development.

The reaction will produce nitrogen-based seven membered heterocycles (also referred to as azepanes) which have been proven as both intermediates and compounds that exhibit useful biological activity. An aza-oxallyl cation is generated by the dehydrohalogenation of α-halo N-alkoxyamides as an intermediate of the cycloaddition reaction. This intermediate is a suitable compound which allows for several direct synthesization targets in carbocyclic nucleosides and their analogs, polyhydroxylated alkaloids, and polyhydroxylated azepanes.

Example Applications
The compounds listed below have the potential to or have been used as an intermediate in drug systhesis. These are examples of the type of compunds that can be produced using the [4+3] cycloaddition reaction.

  • Carbovir (C11H13N5O2) CAS # 118353-02, carbocylic nucleoside with potent in-vitro activity against HIV
  • Aristeromycin (C11H15N5O3) CAS # 19186-33-5, carbocyclic analogue of adenosine with anti-viral properties
  • Entecavir CAS # 142217-69-4, guanosin analogue with potent anti-viral capabilities
  • Deoxynojirimycin CAS # 19130-96-2, inhibitor of glucosidase
  • Miglitol CAS # 72432-03-2, oral anti-diabetic

Intellectual Property
UNR ID#: UNR11-011
Title: Nitrogen-Containing Heterocyclic Compounds and Methods of Making the same
Appl. No.: 61/476,933

Patent Information:
For Information, Contact:
April Sferrazzo
Account Tech
University of Nevada, Reno and Desert Research Institute
Christopher Jeffrey
Korry Barnes
John Eickhoff
Christopher Carson