In the Classroom
Teaching Organic Synthesis: A Comparative Case Study Approach David A. Vosburg Department of Chemistry, Harvey Mudd College, Claremont, CA 91711;
[email protected] There are myriad possible approaches (1) to an advanced organic course for undergraduate or graduate students. Formats could include traditional lectures, group problem sets, class discussions, or student presentations. Course content could focus on a catalog of reaction types, detailed analysis of reaction mechanisms, a selection of literature syntheses, or the development of student-proposed syntheses. I construct my upper-division synthesis course around group presentations (2) on several literature syntheses of complex, bioactive molecules. The course culminates in individual synthesis proposals of student-selected compounds. To develop students’ understanding of synthetic strategy, I contextualize the literature syntheses by juxtaposing different approaches to related or identical molecules. I then challenge the students to articulate the strengths and weaknesses of the synthetic strategies in preparation for their critical analysis of their own synthetic plans at the end of the semester (3). In this model, the chalk and laser pointer are not in my hands but in the hands of the students. I serve as a guide and resource (4), particularly between class meetings.
• Develop students’ understanding of synthetic strategies and reaction mechanisms
• Stimulate written and oral critical analysis of synthetic strategies and tactics
• Expose students to the challenges and excitement of modern organic synthesis
• Focus on molecules of particular historical, medical, or commercial significance
• Establish students’ proficiency in reading original research papers and using electronic resources
• Promote collaborative and individual presentation skills
Course Structure This course was offered in the fall semester of 2006 as a two-credit course, with one 75-minute meeting each week for 13 weeks. The course enrollment was eight students and all had previously completed a year of organic chemistry. I selected five pairs of literature syntheses (ten total) to illustrate diverse strategic approaches to related molecules. In this case, I chose β -lactams, steroids, hexoses, tetracyclines, and oseltamivir phosphate (Tamiflu) as representative structural classes (Figure 1). Many of the molecules were chosen in part because their names would be recognizable to the students even before the course began, thus piquing students’ interest. The syntheses also represented a variety of strategies and reaction types. I intentionally provided examples from both academic and industrial laboratories and crafted a smooth transition mid-course from an excellent textbook (5) to the primary literature.
Course Objectives The course objectives are to
C-lactams H H N
O O
steroids OH
H
H
NH3
H
H
S
O
CO2H
H
O
H
H
S
N
N
O
O
CO2
H
H
H
O
HO
penicillin V
thienamycin
estrone
progesterone
Sheehan (1957) antibiotic
Merck (1980) antibiotic
Vollhardt (1977) contraceptive
Johnson (1971) contraceptive
hexoses
tetracyclines HO
OH
OH
H
OH
H
Tamiflu EtO
N
NH2
OH OH
Masamune and Sharpless (1983) MacMillan (2004) sugars
H2PO4
OH
CHO OH
O
OH
OH
O
O
Stork (1996) Myers (2005) antibiotics
O
O
NH3 NHAc
Roche (2004) Corey (2006) antiviral (bird flu)
Figure 1. Paired literature syntheses for student presentations; the year and lab associated with the synthesis are also given.
© Division of Chemical Education • www.JCE.DivCHED.org • Vol. 85 No. 11 November 2008 • Journal of Chemical Education
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In the Classroom Table 1. Course Schedule with Alternating Group Presentations on Pairs of Syntheses Week
Presenting Group
Topic
Reading
1
Course introduction/resources
—
Classics,† pp 1–19
2
β-Lactams: penicillin (Sheehan)
A
Classics, pp 41–53
3
β-Lactams: thienamycin (Merck)
B
Classics, pp 249–263
4
Steroids: progesterone (Johnson)
A
Classics, pp 83–94
5
Steroids: estrone (Vollhardt)
B
Classics, pp 153–166
6
Hexoses (Sharpless/Masamune)
A
Classics, pp 293–315
7
Hexoses (MacMillan)
B
Science 2004, 305, 1752–1755, 1725–1726
8
Tetracyclines (Stork); synthesis abstract due
A
J. Am. Chem. Soc. 1996, 118, 5304–5305
9
Tetracyclines (Myers)
B
Science 2005, 308, 395–398, 367–368
10
Tamiflu (Roche)
A
Org. Process Res. Dev. 2004, 8, 86–91
11
Tamiflu (Corey); retrosynthesis due
B
J. Am. Chem. Soc. 2006, 128, 6310–6311
12
Synthesis presentations
13
Synthesis presentations; first draft of synthesis paper due
14
Final draft of synthesis paper due
†Nicolaou,
K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods; VCH: Weinheim, Germany, 1996.
The course schedule for the 2006 offering is listed in Table 1. On the first day I explain the course goals and structure, describe the library resources available, give a general overview of organic synthesis (including a brief review of retrosynthesis) and the molecules under discussion, and have the students divide themselves into two groups whose schedules allow for out-ofclass weekly group meetings. In addition to their textbook for the course (5), I place a variety of books on reserve for their use in the library or in my office (6). Students draw chemical structures and search the chemical literature with ease using institutional site licenses for ChemDraw, SciFinder Scholar, and Web of Science. Before the second class meeting, student group A meets both as a group and also with me to prepare the first β-lactam presentation: the Sheehan synthesis of penicillin V (7). I give the students considerable freedom in organizing their 60-minute presentations and dividing the labor, as long as certain key elements are included: (a) the historical, commercial, medicinal, and biological significance of the molecule, (b) a thorough retrosynthetic analysis, (c) a detailed walk through the forward synthesis with explanations ready for any of the mechanisms if requested, and (d) a summary of the highlights and “take-home messages” from the synthesis. Students frequently use mixed media for presentations: PowerPoint, overhead transparencies, chalkboards, handouts, worksheets, molecular models, and group activities for the other students. Meanwhile, the students from group B and I interact freely with the presenters, questioning and challenging them as necessary. These non-presenting students complete peer evaluation forms at the end of the class meeting and post questions and comments (which are graded based on quality) for the presenters on the course Web site within the next 36 hours. I then post my own questions and comments online. Time-stamped discussions between class meetings are possible using a dynamic course Web site.1 1520
For the first 10–15 minutes of the following class period, the students from group A respond to the questions and comments that were posted online, hopefully correcting any errors or omissions, perhaps speculating about the rationale for specific strategies or tactics, and often providing extra information about other synthetic approaches to the target molecule or other applications of a key reaction. Group B then gives the second β-lactam presentation, a Merck synthesis of thienamycin (8), and the cycle continues as indicated in Table 1. Comparative Writing Assignments Following each pair of group presentations, students have the opportunity to submit a short written assignment that compares the two related syntheses (9). Students are required to turn in at least two of these papers during the semester. Among the issues I suggest for consideration are elegance, ingenuity, convergency, divergency, flexibility, number of steps, average or overall yield, stereocontrol, cost or availability of materials, scalability, practical considerations (e.g., safety, toxicity, challenging procedure), new or interesting reactions, biosynthetic insights, and value of the final product. Students combine careful presentation and creativity, often taking one of the following forms:
• Imagine that you are an industrial process chemist and need to make kilograms (or tons) of product. Which route would you choose? Perhaps a hybrid route? Defend your decision in a report to your supervisor.
• Write a dialogue or mini-play in which two chemists with different opinions argue about the merits of each approach.
• Summarize each approach and describe the relative strengths and weaknesses of each.
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom
O
O
HO2C
O H
O H H H O
H HO
dehydrocholic acid
H
O O H
salvinorin A
N
HO
HO
O
R NH
OMe H
NMe
N
O
H
dextromethorphan
pyrethrin I
OMe
N
O
grandisine D
O O
MeO
H
O
MeO 2C
ouabagenin
H
H
H
MeO N
H
OH
OH
MeO
O
O AcO
H H
O
H
H
HO HO HO
RbO
O-methylpsychotrine
N O
rifaximin subunit
Figure 2. Student-selected targets for synthesis proposals in 2006.
Novel Synthesis Proposals
Course Assessment
These comparative assignments are intended to prepare the students for the culmination of the course: novel synthesis proposals of student-selected targets. Deadlines for this project are indicated in Table 1. I direct each student to select a reasonable target from any source (e.g., the Journal of Natural Products, Natural Product Updates, The Merck Index) for my approval and to provide a brief abstract describing their interest in the molecule. Three weeks later, the students submit a retrosynthetic plan for their proposal both to me and to another student. The student pairs meet to share advice about each other’s retrosynthesis, then I provide my own feedback. The final two class periods are extended to two hours to accommodate the student presentations of their proposals. The other students and I provide critical feedback for the presenter to consider in preparing his or her written proposal. The final draft of the written proposal, written in the form of a research proposal (10), must include two different retrosynthetic approaches to the target molecule and one detailed proposed forward synthesis. The molecules students selected in the fall term of 2006 are shown in Figure 2.
In addition to the standard course evaluations at the end of the term, I distributed an anonymous student survey to assess the success of the course in meeting the learning objectives. The students responded to each question on a scale of 1–5 (scale: 1 = strongly disagree, 2 = disagree, 3 = neutral, 4 = agree, 5 = strongly agree). The results of the survey are given in Table 2. The students were also invited to give anonymous comments about the course, some of which are excerpted here:
Grading Structure and Workload Half of each student’s grade is based on the five group presentations (including individual and group grades, class participation, and online posts) with the remainder divided between two comparative assignments (20%) and the final project (30%). I concluded that more typical graded work such as problem sets, midterms, and a final were unnecessary and did not contribute significantly to the course goals. As student feedback confirmed, the difficulty and intellectual challenge of this course would have merited three credits instead of two. The faculty workload is primarily course planning, coaching students, and grading written work.
Excellent layout. Don’t change it. I really, really liked this class! Fantastic course. I liked the comparisons of the syntheses. I liked … how they were grouped in 2-week sets. Having students teach the class was a great idea, it gave us the chance to critically analyze complex and relevant syntheses by ourselves and not be lectured on it; so much more exciting to do it this way, both an intellectual challenge and personal challenge for each presenter to show their mastery of the material! Don’t change it too much! This was by far the coolest course I’ve taken. Less work maybe.
As a result of witnessing students planning a group presentation, a faculty colleague commented, “I would love to see my students engaged so deeply.” Indeed, I was greatly encouraged by the motivation and performance of the students. No student dropped the course and several spread their enthusiasm about the course to other students and faculty. Faculty seeking to adapt this model to their situations may wish to also consider the 2008 offering for a class size of 15–16 students (see the online material). At some schools it may be
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In the Classroom Table 2. Student Course Survey Response ± σ (n = 8)
Survey Statement I can now critically analyze synthetic strategies and tactics.
4.5 ± 0.5
This course strengthened my understanding of synthetic reaction mechanisms.
4.6 ± 0.7
The comparative case study approach was more helpful than isolated cases would have been.
4.6 ± 0.5
The comparative writing assignments were a useful exercise.
3.9 ± 0.6
I can read and understand original research papers in the field better as a result of this course.
4.6 ± 0.5
I am now more able to research reactions and use electronic or paper resources.
4.6 ± 0.5
This course was challenging and made me grow.
4.8 ± 0.4
I am more comfortable working in a group to prepare a scientific presentation than I was before this course.
4.3 ± 0.7
The group presentation format was an effective way for me to learn.
4.1 ± 0.6
The molecules we studied were interesting.
4.8 ± 0.4
The Sakai [Web site] posts and 15-min rebuttal times extended student engagement and made the presentations more complete.
4.0 ± 1.2
The final project made me apply concepts I learned earlier in the course.
4.3 ± 1.0
suitable to extend the introductory material or to add a laboratory component in which students attempt different routes to the same molecule and report on the relative merits of each approach. This course is not intended to be a comprehensive treatment of synthetic strategy or of organic reactions, but an introduction that engages students and gives them the confidence and ability to comprehend and analyze other syntheses and reactions on their own. Conclusions I have described a challenging but extremely rewarding course in organic synthesis for advanced undergraduate or graduate students. The comparative case study approach provides sufficient context to illuminate the relative merits of literature syntheses and enhance student learning. Students are eased into the primary literature and develop remarkable synthesis proposals. Individual and group presentations enhance students’ learning experiences and develop their oral and written communication skills far beyond what a traditional lecture course can provide. The obvious flexibility in selecting pairs of literature syntheses and target molecules for proposals makes this course format easily adaptable over time and from one instructor to another. Acknowledgments This article is dedicated to the memory of J. Hodge Markgraf, who was an inspiration in teaching, in undergraduate research, and in noble character for generations of students at Williams College. Many of the learning goals for my course were met admirably in his heterocyclic chemistry tutorial course. I acknowledge support from a Camille and Henry Dreyfus Foundation Faculty Start-up Award and a Research Corporation Cottrell College Scholar Award (CC6510). 1522
Note 1. The Web site is open to members of the course only and is located with all of the other Claremont College course Web sites at http://sakai.claremont.edu (accessed June 2008). For more information about Sakai software, see http://www.sakaiproject.org (accessed June 2008).
Literature Cited 1. For example, see: (a) Fikes, L. E. J. Chem. Educ. 1989, 66, 920– 921. (b) French, L. G. J. Chem. Educ. 1992, 69, 287–289. (c) Cannon, K. C.; Krow, G. R. J. Chem. Educ. 1998, 75, 1259–1260. 2. (a) Light, R. J. Making the Most of College: Students Speak Their Minds; Harvard University Press: Cambridge, 2001; Chapter 4. (b) Bean, J. C. Engaging Ideas: The Professor’s Guide to Integrating Writing, Critical Thinking, and Active Learning in the Classroom; Jossey–Bass: San Francisco, 2001; Chapter 9. 3. Bain, K. What the Best College Teachers Do; Harvard University Press: Cambridge, 2004; Chapter 5. 4. (a) Black, K. A. J. Chem. Educ. 1993, 70, 140–144. (b) Katz, M. J. Chem. Educ. 1996, 73, 440–445. (c) Shiland, T. W. J. Chem. Educ. 1999, 76, 107–109. (d) Duncan, A. P.; Johnson, A. R. J. Chem. Educ. 2007, 84, 443–446. 5. Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods; VCH: Weinheim, Germany, 1996. 6. (a) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995. (b) Stereoselective Synthesis (Houben–Weyl); Helmchen, G., Ed.; Thieme: New York, 1996. (c) Boger, D. L. Modern Organic Synthesis Lecture Notes; TSRI Press: La Jolla, CA, 1999. (d) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part A and B, 3rd ed.; Plenum: New York, 1990. (e) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1999. (f ) Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations; VCH: New York, 1999. (g) Smith, M.; March,
Journal of Chemical Education • Vol. 85 No. 11 November 2008 • www.JCE.DivCHED.org • © Division of Chemical Education
In the Classroom J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure; Wiley: New York, 2001. (h) Warren, S. G. Organic Synthesis, The Disconnection Approach; Wiley: New York, 1982. (i) Zweifel, G. S.; Nantz, M. H. Modern Organic Synthesis: An Introduction; W. H. Freeman: New York, 2007. 7. (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods; VCH: Weinheim, Germany, 1996; Chapter 3. (b) Sheehan, J. C.; Henery–Logan, K. R. J. Am. Chem. Soc. 1957, 79, 1262–1263. 8. (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis: Targets, Strategies, Methods; VCH: Weinheim, Germany, 1996; Chapter 16. (b) Salzmann, T. N.; Ratcliffe, R. W.; Christensen, B. G.; Bouffard, F. A. J. Am. Chem. Soc. 1980, 102, 6161–6163. 9. For a discussion of creative writing assignments, see Bean, J. C. Engaging Ideas: The Professor’s Guide to Integrating Writing, Critical Thinking, and Active Learning in the Classroom; Jossey–Bass: San Francisco, 2001; Chapter 5.
10. For an example of a course focused on writing creative scientific research proposals, see Miller, L. L. J. Chem. Educ. 1996, 73, 332–336.
Supporting JCE Online Material
http://www.jce.divched.org/Journal/Issues/2008/Nov/abs1519.html Abstract and keywords Full text (PDF) with links to cited URLs and JCE articles Supplement Syllabuses from fall 2006 and spring 2008 Peer evaluation forms JCE Featured Molecules for November 2008 (see p 1584 for details) Structures of some of the molecules discussed in this article are available in fully manipulable Jmol format in the JCE Digital Library at http://www.JCE.DivCHED.org/JCEWWW/Features/ MonthlyMolecules/2008/Nov/.
JCE Concept Connections: Novel Organic Courses JCE offers a wealth of materials for teaching and learning chemistry that you can explore at our Web site, JCE Online (http://www.jce.divched.org). Below are some additional resources for teaching organic chemistry suggested by Arrietta Clauss of the Editorial Staff that are available through JCE.
JCE Print
www.jce.divched.org/Journal
Web edition of the Journal of Chemical Education
Vosburg developed a novel organic course utilizing a student-centered approach that fostered independent critical evaluation of organic synthesis. The Journal has published other articles focused on course development to provide the student with an independent self-directed component. Four additional articles are given below. A New Model for Transitioning Students from the Undergraduate Teaching Laboratory to the Research Laboratory. The Evolution of an Intermediate Organic Synthesis Laboratory Course. Jessica J. Hollenbeck, Emily N. Wixson, Grant D. Geske, Matthew W. Dodge, T. Andrew Tseng, Allen D. Clauss, and Helen E. Blackwell. J. Chem. Educ. 2006, 83, 1835; http://www.jce.divched.org/Journal/Issues/2006/Dec/abs1835.html. Two-Cycle Organic Chemistry and the Student-Designed Research Lab. Dennis J. Gravert. J. Chem. Educ. 2006, 83, 898; http://www.jce.divched.org/Journal/Issues/2006/Jun/abs898.html. Instrumental Proficiency Program for Undergraduates. Duane E. Weisshaar, Gary W. Earl, Milton P. Hanson, Arlen E. Viste, R. Roy Kintner, and Jetty L. Duffy-Matzner. J. Chem. Educ. 2005, 82, 898; http://www.jce.divched.org/ Journal/Issues/2005/Jun/abs898.html. Organic Chemistry Lab as a Research Experience. Thomas R. Ruttledge. J. Chem. Educ. 1998, 75, 1575; http:// www.jce.divched.org/Journal/Issues/1998/Dec/abs1575.html.
For a useful review paper on the art and science of organic and natural products synthesis and the impact of this discipline on biology and medicine, see the Viewpoints article: The Art and Science of Organic and Natural Products Synthesis. K. C. Nicolaou, E. J. Sorensen, and N. Winssinger. J. Chem. Educ. 1998, 75, 1225; http://www.jce.divched.org/Journal/Issues/1998/Oct/abs1225.html.
All articles from Volume 1 to the current issue are available in full-text PDF at JCE Online. For browsing by year, month, and page, go to http://www.jce.divched.org/Journal/Issues/index.html. For title and author searching of all issues of JCE, go to http://www.jce.divched.org/Journal/Search/index.html.
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