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Progress

During the 2009-2010 grant year, we continued to develop the poly(ethylene glycol) (PEG) tethered guanidnylation reagents (Figure 1).  We have made progress in exploring the preparation and usability of activated poly(ethylene glycol) polymers and began coupling those PEGs to our guanidinylation reagents.  Our institution now has a high field NMR, which will greatly facilitate the characterization of these molecules. 

Figure 1.  Proposed guanidinlation reagents.

We are using two commercially available PEGs for our research:  a difunctional PEG with an average weight of 3350 (PEG 3350) and a monofunctional PEG monomethyl ether with average molecular weight of 2000 (PEG-2000).  PEG-3500-dinitrophenyl carbonate, 3, has been prepared in 60.3% yield using traditional methods, and in 20.3% unoptimized yield under solvent free, microwave conditions.  These preliminary microwave results are encouraging, as they support our hypothesis that our PEG based protective group may not only allow for the use of liquid phase organic synthesis techniques, but also allow for microwave based solvent free techniques. 

Figure 2.  Activated poly(ethylene glycol) carbonates.

Succimidiyl carbonate activated PEGs were also prepared. In these reactions, there were difficulties in the solubilities of the reagents, and several different literature preparations were attempted.^1,2  At this point, we have synthesized the difunctional succimidyl carbonate PEG-3350, 4, and monofunctional succimidyl carbonate PEG-2000, 5, in 32.1% and 22% unoptimized yields, respectively.  During preparation of these compounds, we learned a great deal about the nature of PEG based reagents.  For liquid phase organic synthesis reactions to work well, the polymer-based reagent must be soluble enough in the reaction solvent for the desired reactions to take place, but insoluble enough in a different solvent for product isolation upon precipitation.³ It appears that most of the product loss was in purification steps, and we are currently working to improve those yields 

Undergraduate Researcher Katie Strong focused on preparation of the guanylpyrazole based guanidinylation reagent, 5, as its UV activity makes the reactions much easier to follow using TLC.  The reaction of guanylpyrazole hydrochloride with the nitrophenyl carbonate activated PEG resulted in cleavage of the activating group.  Reaction with the succimidyl carbonate activated PEG, afforded unreacted activated PEG as the only polymeric product.  These reactions will continue to be studied next year. Characterization of these large compounds with our 60 MHz NMR was very difficult, but with our new 300 MHz NMR, we anticipate making great progress during our grant extension.

Figure 3.  Synthesis of guanidinylation reagents.

Impact

The impact of the PRF grant on my career and on my students has been so great that it is almost impossible to measure.  Although UMW is a teaching institution, it is a requirement for tenure that faculty have demonstrated a pattern of scholarly activity that contributes to our discipline beyond the campus.  Two of the activities that are considered "significant" in building that pattern are winning a grant and participation in programming at a professional meeting. Winning this grant, and using the funds to travel to and present at the ACS National Meeting in San Francisco were recognized as significant contributions to my pattern of professional activity.  I have been recommended for tenure by the Promotion and Tenure Committee at UMW, and am awaiting recommendations from the Dean, Provost, President and Board of Visitors. 

In 2009, UMW entered into an educational partnership agreement with chemists at the Naval Surface Warfare Center, Dahlgren, VA.  The main component of this agreement is that UMW houses and maintains a 300 MHz NMR owned by the Navy.  I believe that my success in obtaining the PRF Grant helped me to convince the UMW administration that partnering with the Navy was a good idea, and prove that I am capable of obtaining and maintaining the agreement and the instrument.  The NMR was installed in July of 2010, and has accelerated progress on this project this year. 

During the 2009 - 2010 grant year, I used PRF funds to take my undergraduate researcher, Katie Strong, to the ACS National Meeting in San Francisco and present at her work in the undergraduate poster session. Katie was very excited by the scope of the meeting, all of the chemistry that she saw, and the students that she met during the undergraduate activities.  In addition, Katie's work on this project was the core of her Honors Thesis, which she successfully defended in April of 2010. She applied to several graduate schools, and was accepted to her first choice, Emory University.  Katie keeps in touch, and is always telling me how the experience that she gained presenting at the national meeting and preparing a honors thesis make her feel "ahead of the curve" in her research and presentation experiences in her first year of graduate school. 

¹  Miron, T.; Wichek, M.  Bioconj. Chem 1993, 4, 568-569.

²  Sarvi, F.; Vasheghani-Farahani, E.; Shojaosadti, S.A.; Hashemi-Najafabadi, S.; Moin, M.; Pourpak, Z.  Iranian Polymer Journal 2006, 4, 525.534.

³ Gravert, D. J.; Janda, K. D.  Chem. Rev. 1997, 97, 489-510.