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Incorporation of Medicinal Chemistry into the Organic Chemistry Curriculum David C. Forbes Department of Chemistry, University of South Alabama, Mobile, AL 36688;
[email protected] be approximately 4–6 hours of work. The handout includes three areas that must be considered prior to selecting a compound: plan of procedure, getting started, and resources. A checklist is used to monitor the students’ progress and to ensure that the projects submitted do not follow existing literature protocols. The students schedule a one-on-one discussion with the instructor to validate and ensure that the plan of action is simply not a reproduction of existing literature preps. Furthermore, this initial discussion is followed by two additional meetings where the instructor can proof and advise on the direction of the exercise. The handout given to the students in the spring 2002 semester as well as a representative completed exercise by a former student are available in the Supplemental Material.W
When asked by students, colleagues, and friends about what makes an effective lecturer, I always refer back to a comment made to me while I was a postdoctoral research associate emphasizing the importance of reaching each student: Provide an experience that presents the objectives of the course while effectively communicating to a diverse audience. That is, when considering new and dynamic lecture styles to instill the topics presented in organic chemistry, nothing will substitute having a customized environment where each student can build the confidence necessary to excel. Accordingly, what better format than a capstone assignment of a two-semester organic chemistry sequence customized to every student? To this end I have introduced an optional exercise to the students enrolled in my second-semester organic chemistry lecture section that asks the students to synthesize, on paper, a compound of biological importance. The purpose of this optional exercise is to provide a unique level of awareness in the area of medicinal chemistry while applying the concepts presented in lecture (1). Starting with a retrosynthetic analysis, the students follow a checklist designed to instruct and guide them. The exercise concludes with a detailed multistep synthesis in which each commercial reagent or starting material is itemized and priced.
Results A total of 71 students, 36 in the spring 2001 semester and 35 in the spring 2002 semester, participated in this optional exercise. As shown in Figure 1 and in the Supplemental Material,W a host of medicinally important compounds were selected. Each exercise consists of a retrosynthetic analysis, forward synthesis, and a list of all commercial material used. Overall, the cost of making each drug on a per mole basis was less than $10,000. Either the Aldrich Chemical Catalog or a Web-based pricing mechanism was used as a reference. On average, the costs ranged from approximately $1,500 to $5,000 per mole of the drug. For example a student who examined Diflucan (C13H12N6F2O, FW = 306.26 g兾mol) calculated a cost of $8.83兾mol, which translates to just under $0.029兾g. Interestingly this calculation suggests that one 20 mg tablet costs $0.00058! Several issues evolve from this exercise such as cost effectiveness, strategy, and matters related to cost of heath care.
Method Each student is given the handout for this optional exercise the first class of a 15-week semester. The exercise is optional on two levels. First, this exercise is not a mandatory component of the course. Second, for those students who opt to complete this exercise, compound selection is optional as well. Selections ideally must challenge but not overwhelm the students since this extracurricular exercise is only equivalent to two take-home quizzes. The exercise is designed to
F HCl HCl
HO
O O
OH
Cl
H3C HN
N O OH H3C
Cl
O
CH3
N H
Paxil (paroxetine HCl)
Allegra (fexofenadine HCl)
Zoloft (sertraline)
Figure 1. Examples of drugs synthesized by undergraduate students while enrolled in the two semester organic chemistry course.
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Discussion The primary objective of this exercise is to apply the concepts presented in organic chemistry lecture using a virtual project involving the synthesis of medicinally important compounds. Because most two-semester sequences in organic chemistry begin with the foundation of organic transformations and highlight basic functional group manipulations such as oxidation and reduction, the students benefit the greatest when a significant quantity of organic chemistry has been presented. Most second-semester organic lecture courses introduce multistep processes that build upon the functional group manipulations presented during the first semester. Aside from the detailed discussions involving carbonyl derivatives, examples such as aromatic substitution or condensation processes are presented during the latter portions of the second-semester sequence and thus this project truly requires time to develop. When asked how to get started, I direct the students to prior or current ailments with which they, or someone they know, have had personal experience. Regardless of compound selection, the goal is to design on paper the total synthesis of a medicinal compound of biological importance starting with commercially available starting materials. Success with this project relies heavily on the application of the concepts presented in both the first and second semesters of organic chemistry. Pedagogically, understanding firsthand the details and pitfalls associated with total syntheses, an appreciation of drug design and drugs currently on the market will be realized. Interestingly, an overwhelming choice of drugs has been anti-depression agents. An extension of this optional exercise may involve the combination of a laboratory experience using a particular class of drugs. After performing a quick search online of this Journal, two recent articles highlight the feasibility of preparing several compounds in the laboratory curriculum (2, 3). It is important to recognize the potential in combining the efforts of both lecture and lab using this tuned organic exercise. Reinforcing the concepts from lecture in lab provides a powerful instructional means. Instructional laboratories are an essential teaching tool in the progression of a student’s career. The introduction of instructional research provides a unique and valuable experience rarely available outside the walls of the university.
A final observation is the significance of the organic chemistry course material applied to current applications in the pharmaceutical community; from the standpoint of a sophomore undergraduate student, this exercise in part dispels the myth of magical courses in post-undergraduate study on how drugs are manufactured. While issues related to chirality, costs associated with the manufacturing and marketing the commercial products, and the implementation of an efficient and environmentally-sound synthesis are of paramount importance when considering how to manufacture drugs on an industrial scale, every product on the market, interestingly, can be culled down to a central group of bondbreaking and bond-forming processes. That is, regardless of the protocol, all organic transformations can all be distilled down to the four reactions : 1. substitution (σ-to-σ bond conversion), 2. addition or elimination (π-to-σ bond conversion), 3. cycloaddition or cycloelimination (π systems transformed to σ systems) 4. rearrangement (a skeletal restructuring of organic template).
These processes are the core concepts of organic chemistry and interestingly, are first presented at the undergraduate level. Thus, the knowledge required to synthesize all the drugs on the market is instilled in the undergraduate setting. W
Supplemental Materials
A student handout, representative student proposal, and a composite of drugs selected by students are available in this issue of JCE Online. Literature Cited 1. Nicolaou, K. C.; Sorensen, E. J.; Winssinger, N. J. Chem. Educ. 1998, 75, 1225. 2. Perrine, D. M.; Sabanayagam, N. R.; Reynolds, K. J. J. Chem. Educ. 1998, 75, 1266. 3. Perrine, D. M.; Ross, J. T.; Nervi, S. J.; Zimmerman, R. H. J. Chem. Educ. 2000, 77, 1479.
The structures of a number of the molecules discussed in this article are available in fully manipulable Chime format as JCE Featured Molecules in JCE Online (see page 981).
Featured Molecules
an interactive modeling feature, Only@JCE Online
http://www.JCE.DivCHED.org/JCEWWW/Features/MonthlyMolecules
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