Steven L. Castle, Department of Chemistry and Biochemistry

Introduction

This report summarizes the results of the mentoring environment in my laboratory that were generated from January 2012 to present. During this period, a total of seven undergraduates performed research in my laboratory. Their names and accomplishments are listed below.

Evaluation of Academic Objectives

Our academic goals were to synthesize the organic compounds rimantadine thiol (1, Figure 1), cranomycin (2), and yaku’amide A (3). Compounds 1 is an analogue of rimantadine, an influenza drug that has recently lost its potency due to mutation of the virus. We targeted 1 as part of a collaboration with Physiology and Developmental Biology Professor David Busath, and our goal was to attach 1 covalently to the M2 proton channel, thereby providing more information regarding the nature of its binding site within the channel. Compounds 2 and 3 are natural products with antimalarial and anticancer activity, respectively. Our goals in synthesizing 2 and 3 were to (1) develop new reactions that would be of broad utility to the organic synthesis community, and (2) use our synthetic route to prepare analogues for use in chemical biology studies designed to reveal the mode of action of the natural products. We are currently in the final stages of synthesizing 1. We successfully fashioned the core structure of 2, but have been unable to elaborate this core into the natural product. We have made great strides toward the synthesis of 3 and are optimistic of success in the near future. To date, these efforts have resulted in the publication of two papers with a total of four undergraduate co-authors and the presentation of one poster at a national scientific meeting by an undergraduate. While we are still working towards accomplishing our academic objectives, we are pleased with the scientific achievements that have resulted so far from this work.

Evaluation of Mentoring Environment

Our mentoring goals are to train students in the techniques of organic synthesis, provide them with independent research projects, and prepare them for postgraduate education or employment. We have been successful in all three phases. During 2012 and 2013, three students who participated in this mentoring environment graduated from BYU. Two are currently Ph.D. students in graduate school, and the third is engaged in a prestigious internship at the National Institutes of Health while going through the medical school application process. Two undergraduates who are still a part of the mentoring environment will be graduating in 2014. One plans to attend graduate school, and the other is applying to medical school. Two new students joined the mentoring environment in 2013, and both have completed the training phase and assumed responsibility for their own independent research projects. Thus, students who graduate from this environment are on track to achieve their postgraduate educational goals. Moreover, promising new students are joining the environment, replacing the talented researchers who have graduated. As a result, we believe that our mentoring goals are being achieved.

List of Students and Academic Deliverables

1. Aaron Clark. Unfortunately, Aaron’s project did not pan out, leaving him unable to present a poster or publish a paper. This is an extremely rare occurrence for this mentoring environment, as the vast majority of students end up publishing papers and/or giving presentations at scientific meetings. Fortunately, Aaron overcame this challenge and was admitted as a Ph.D. student to the Department of Chemistry and Biochemistry at the University of Oklahoma.
2. Bradley Naylor. Bradley successfully accomplished the synthesis of -hydroxy amino acids via base-free aminohydroxylation. These compounds are key intermediates in the synthesis of yaku’amide A. He was a co-author of a paper that was published in a high-impact journal (J. Org. Chem. 2012, 77, 1208). Currently, he is a Biochemistry Ph.D. student at BYU.
3. Phil Young. Phil assisted in the synthesis of the core structure of cranomycin. He was a co-author of a paper that was published in a high-impact journal (Org. Lett. 2013, 15, 1930). Currently, he is involved in an internship at the National Institutes of Health.
4. Joseph Cardon. Joseph is working toward the total synthesis of yaku’amide A. He presented a poster outlining his research at the National Organic Symposium, which was held in June 2013 at the University of Washington. Joseph will graduate in December 2013 and enter graduate school in the fall of 2014.
5. Patrick Evans. Patrick worked with Phil on the cranomycin project, and was a co-author of the paper cited above. Patrick will graduate in April 2014 and hopes to attend medical school in the fall.
6. Shi Luo. Shi joined the mentoring environment in Spring 2013. He is currently working toward the synthesis of yaku’amide A.
7. Patrick Asay. Patrick joined the mentoring environment in Summer 2013. He is currently finishing up the synthesis of rimantadine thiol.

Description of Results

After several failed approaches toward rimantadine thiol (1), Patrick Asay has found what appears to be a viable route involving a thiocyanate precursor. Upon heating this compound in refluxing toluene, a product is formed that has the expected spectral data for 1. Now, Patrick is attempting to purify this compound so that we can precisely determine its structure. Our synthesis of cranomycin (2) is currently on hold due to problems with an aziridination reaction. Despite these difficulties, Phil Young and Patrick Evans were able to work with graduate student Brad Loertscher to develop a method for the highly stereoselective formation of vicinal tertiary diols, a process with applications that go beyone the synthesis of cranomycin. This result is described more fully in the Organic Letters paper cited above. The total synthesis of yaku’amide A (3) is ongoing, with successes being achieved in the synthesis of the unusual -hydroxy amino acids and dehydroamino acids. Our use of base-free aminohydroxylation to prepare both of these types of unusual amino acids is outlined in the J. Org. Chem. paper cited above. A manuscript describing our most recent results in this area is currently in preparation for submission to the journal Chemical Science.

Summary of How Funds Were Used

The majority of MEG funds were used to pay salaries to the undergraduates involved in the research. Some MEG funds were used to support Jintao Jiang, a graduate student who has mentored Joseph Cardon. Some MEG funds were also used to purchase chemicals and other consumable supplies.

Conclusion

2012 and 2013 were productive years for our mentoring environment. We have yet to achieve everything that we set out to accomplish. Nevertheless, we have published papers, presented posters, and laid the groundwork for more publications and presentations next year. We have learned much from the research funded by this MEG. Importantly, each of the seven students who participated in this environment has experienced personal growth and development as a scientist. It is extremely gratifying to have the opportunity to work with dedicated students and to help them reach their goals. I am very grateful for the Mentoring Environment Grant program and the opportunities it has provided for me to work with outstanding undergraduates.