Steven L. Castle, Department of Chemistry and Biochemistry
This report summarizes the results that were generated under the auspices of the mentoring environment in my laboratory from January 2014 to the present. A total of six undergraduates participated in the mentoring environment during this period. Their names and accomplishments are listed below.
Evaluation of Academic Objectives
Our academic goals were twofold. First, we aimed to synthesize building blocks that could be used to assemble the anticancer peptide yaku’amide A (YA, Figure 1). Our purposes in synthesizing YA were to (1) develop new chemical reactions suitable for efficiently constructing its unusual amino acids (shown in red in Figure 1), and (2) prepare simplified analogues for use in studies designed to reveal its biological target and mode of action. Our second academic goal involved developing straightforward and efficient methods of preparing the pyrrolidine ring system, which is present in several top-selling pharmaceuticals and biologically active natural products (Figure 1). We have achieved three important milestones related to these goals. First, we have synthesized two key subunits of YA: a nonapeptide representing two-thirds of its structure, and its N-terminal acyl group (the latter is shown in blue in Figure 1). Second, we have begun applying our method for constructing the bulky dehydroamino acids present in YA to the synthesis of other important biologically active peptides. Third, we have found that microwave-promoted iminyl radical cyclizations offer a direct and practical route to substituted pyrroles and pyrrolidines. To date, this work has resulted in the publication of three papers with undergraduate co-authors and one poster presentation by an undergraduate at a national scientific meeting. Thus, we are pleased with our progress and the achievements that have resulted 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 that require problem-solving and troubleshooting, and prepare them for postgraduate education or employment. We have been successful, as evidenced by the fact that undergraduates have been co-authors on scientific papers and have given presentations at scientific conferences (see below). All six students who were a part of the mentoring environment during 2014 and 2015 have plans to attend either graduate school or medical school. They will join a growing list of alumni from this mentoring environment who work in scientific or medical careers. Thus, we believe that our mentoring goals are being achieved.
List of Students and Academic Deliverables
- Shi Luo. Shi joined the mentoring environment in Spring 2013. He is working toward the synthesis of yaku’amide A. He has been a co-author of two papers (Org. Lett. 2014, 16, 4044; Tetrahedron Lett. 2015, 56, 3311). He also presented a poster at the National Organic Symposium (sponsored by the Organic Division of the American Chemical Society), held June 28–July 2, 2015 at the University of Maryland.
- Patrick Asay. Patrick joined the mentoring environment in Summer 2013. He explored the synthesis of the pyrrolidine-containing natural product hyacinthacine A2, graduated in Spring 2015, and is currently working while applying to medical school.
- Brock Davis. Brock joined the mentoring environment in Winter 2014. He is working with Shi on the synthesis of yaku’amide A.
- Aaron Kubosumi. Aaron joined the mentoring environment in Winter 2014. He is developing new iminyl radical cyclizations suitable for preparing pyrrole- and pyrrolidine-containing compounds. He has been a co-author of one paper (Org. Lett. 2015, 17, 488).
- Zach Gibson. Zach joined the mentoring environment in Summer 2015. He is working with Aaron on the development of new iminyl radical cyclizations.
- Kei Webber. Kei joined the mentoring environment in Summer 2015. He is working on the synthesis of amino acids related to yaku’amide A.
Description of Results
Shi Luo and Brock Davis have worked together with graduate students Zhiwei Ma and Yu Cai to prepare the right-central nonapeptide subunit of YA. The challenging β-hydroxy amino acids required for this endeavor were synthesized using an Os-catalyzed aminohydroxylation reaction developed previously in our laboratory. The bulky tetrasubstituted dehydroamino acids were constructed via a sequence of reactions described in the Organic Letters paper cited above. Shi and Yu have also synthesized the N-terminal acyl group of YA using a variant of an aldol reaction. Currently, Kei Webber is working with graduate student Jintao Jiang to determine the role of bulky tetrasubstituted dehydroamino acids on the structure and mode of action of therapeutic peptides such as enfuvirtide, an FDA-approved anti-HIV drug. Shi Luo was involved in the preliminary efforts on this project, which were published earlier this year in Tetrahedron Letters. In collaboration with Yu Cai and another graduate student, Ankur Jalan, Aaron Kubosumi discovered that microwave-promoted iminyl radical cyclizations with TEMPO trapping provide a safe and high-yielding route to 2-acylpyrroles. This finding was published in Organic Letters earlier this year. We anticipate making further progress in all of these areas during 2016, which should result in 1–3 additional publications.
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 provide partial support to Yu Cai and Jintao Jiang, graduate students who have participated in the mentoring of the students listed above. Some MEG funds were also used to purchase chemicals and other consumable supplies.
This mentoring environment has been productive and fruitful. We have achieved milestones, published papers, and presented posters. We have learned much from the research funded by this MEG, and the future results are likely to have strong impacts on the fields of organic synthesis, medicinal chemistry, and peptide science. Importantly, each of the six undergraduates who participated in this environment has experienced personal growth and development as a scientist. I am grateful for the MEG program and the opportunities it has provided for me to work with outstanding undergraduates who are dedicated to the pursuit of knowledge.