Undergraduate Research As Chemical Education A S~moosium
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An Undergraduate Laboratory Experiment The Total Synthesis of Maytansine Thomas E. Goodwin Hendrix College, Conway. AR 72032 For the last four years we havebeen engaged in a prolonged experiment at Hendrix College. The experiment assesses the feasibility of establishing a viable undergraduate research program in natural product synthesis a t a small liberal arts college. One of our long-range goals is to prepare the potent antileukemic natural product maytansine (I) and its conge-
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ners. Although we are still far from attaining that goal, a number of our initial obiectives are beine realized. These objectives are enumerated and discussed h o w and are followed hv some euidelines which have been useful in the establishment of our research program. Finally, a few of our accomplishments en route to maytansinoids are summarized. Objectives 1) Undergraduate Research as Chemical Education. The first objective was a pedagogical one. We believe that participation in basic research is a valuable complement to traditional lecture and laboratory learning experiences. We wanted our students to have this opportunity. 2) Personal and Professional Deuelonment of the Principal Inuestigator. Fackty involvement &I an undergraduate research oroeram nrovides a mechanism for keenine abreast & chemistry, serves as an outlet fdr creativity, of allows the research director to be a better professional role model, and enriches, refreshes and informs lectures in regularly scheduled courses. 3) Development of New Methodology for Organic Synthesis. Our research program is designed so that new, practical methodology can be developed which will he of use to other organic chemists. Thanas E. Ooodwln was barn in Nashville. Arkansas In 1947. He did unaergraduateresearch in atomc absorpt!on ana ysts wlth Joe Ntx a1 Ouachm Baptist Un versoty whcn rer~lted n a p m catton Alter compiet ng h s PnD in organ c synthesis m 1974 w tn Waiter Meyer at the University of Arkansas and a postdoc with Emest Wenkerl at Rice, he was a research scientist at Continental Oil Company anda iechlrer at Texas A 8 M. He was appointsdto the faculty at Hendrix College in 1978 where he is now Awciate Rolessa. Therecipient d seven grams lor research in synthetic organic chemistry w i b undergraduates since 1979. Gaodwin has authored 15 research papers including two with undergraduates.
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4) Preparation of Medicinally Useful Compounds. For altruistic and motivational reasons, we seek the preparation of compounds which are potentially valuable as medicinal agents. Guldellnes We wish to offer some useful euidelines oertainine to the de now establishment of an und&graduate iesearch provam in a small colleae. We do not suezest that these ~uidelinrsare novel, nor thatthey are universzly applicable, only that they are useful products of our experience. 1) Choose problems which interest you. We quickly decided that it was fruitless to search for research oroiects which were "appropriate for" (i.e., "simple enough f o p ) undergraduates to carry out, for these often seemed to be somewhat mundane. ~ e n c ewe , chose problems which excited us, no matter how difficult or "inappropriate" they might seem, since the advantages of enthusiasm on the part of the research director in motivation of the students cannot be gainsaid. 2) Keen euervone informed. When a new research nroeram is initiatld in situation where research has not bLenUemohasized traditionallv. ..one verv serious nroblem mav be encountered, uiz. the overt (or covert) opposition of abministrators and colleaeues. Fortunatelv. we have been stronelv encouraged by hoti groups. While c i s true that our was initiated fortuitously a t a propitious time in the development of the College, one factor in our success has been a conscious effort to establish a continuing didome with schwl officials and colleagues during all phases of this undertaking. 3) Keep in touch with the "biggies." Invariably, a research project builds upon prior knowledge. We have found it very advantageous to establish contact with the acknowledged experts in the area of our research. These contacts serve many purposes, for example
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a) Practical information and advice can be obtained which may not be evident in published accounts. Tips on leading and perham obscure references (e.e. "nost-doc" reoorts) . - unoublished . . . may be forthcoming. b) These scientists are the obvious choices as referees for your manuscripts and reviewers for your research proposals; their insights and concerns are helpful. 4) Get by with a little help from your friends. The importance of participation in scientific meetings (ACS meetings, Gordon Research Conferences, etc.) cannot be overstated. One of the many benefits is the establishment of contacts a t larger universities. Since small colleges usually are not blessed with an abundance of research-grade instrumentation, the generous offers of assistance from these friends to obtain hieh struc" resolution NMR snectra. X-rav .crvstalloeraohic . tures, etc. are indispensable. NSF Regional Instrumentation Facilities also ~ r o v i d ethese services at a reasonable cost. 5) Be thaniful for P R F and Research Corporation. Research orooosals from small colleees must meet at least two criteriaheiore being funded. onecriterion is common for all proposals-the scientific significance of the work; the other v
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involves the ability of the principal investigator to do the research. One can easilv - imaeine - the reviewers thinkina that the proposed project was a good one, but questioning the feasibility of bringing i t to fruition a t a small college with only undergraduate researchers. Fortunately, some grants programs are designed for that context. The Petroleum Research Fund (PRF) of the ACS and Research Corporation both operate special funding programs for scientists at small colleges (Type B Grants and Cottrell College Science Grants, respectively). Research funds from these agencies can serve as "seed" money which allows the Principal Investigator to establish the viability of his or her research program before seeking larger grants. Progress Toward Maytansinoid Synthesis Maytansine, I, is an antileukemic ( I ) natural product (2) which has been prepared by total synthesis (3).A number of biologically active congeners have been recently discovered (4).
Our retrosynthetic analysis of the maytansine problem led to the designation of synthons for the vinyl anion, 11, and the electrophile 111 as initial synthesis targets. The former ohY-R
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Acknowledgment The success of our Droeram is directlv attributable to the excellent student rollahor~torswho have-participated. A total of 16 students have worked full-time over at least one of the last four summers and others have worked part-time during the academic years. Their enthusiasm and diligence have been inspirational. Critical financial assistance has been provided by P R F and Research Corporation. In addition we have been generously supported hy a grant from NSF-EPSCOR (Experimental Program to Stimulate Competitive Research). Literature Cited I11 Komoda, Y.,and Ki8hi.T.h "Anticancer AgentsBasedon NsturalProduct Models? (Editors: C-dy. J. M., and Douroa, J. D.1, Academic Press.New Yurk, 1980, p.
jedive has heen realized with model compounds via alkylation of an allylic sulfide and a subsequent [2,3]-sigmatropic rearrangement (5). The latter objective has centered about development of the model compound IV from D-glucal(6). Our current objective is the maytansinoid model compound VI. Toward that end we have recently prepared enone V from iodide IV. The details of this synthesis will be presented in subsequent publications.
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Journal of Chemical Education
353. (21 Kupehan. S. M., Komods, Y., B1aufman.A. R.,Sneden,A. T.,Co"rt, W.A.,Thomar, G. J., Hint%,H. P. J.. Srnith,R.M.,Karim, A., Howie. G. A.,Verma,A. K.,Nsgao. Y.. Daily, R,G.,Jr., Zimmarly, V. A,, and Summer, W. C.,Jr., J. O n . Cllem., 42, 2349
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131 (a) Corey,E J.. Wekel. L. 0.. C h h b e b e I i n , A . R . , Chem. Soc., IO2,6613(19801.(bl Meye7s.A.l.,Reider,P.J..sndCampbeII,A.L., J. Amer. Cham. Soc.. lO2.6S97119801. . . lel. imbe.M.. . . Kitamura.M..andGuto.T..J.Amsr. . . . . Chrm. Soc., 104,4997'(19821. 14) e t PowelLR. G.,Weisleder, D.,andSmith.C.R.,Jr.. J. O m Chem.,46,4398119811. Is) Goodwin, T. E.. Ratcliff, 0. G.,Crowder, C. M..and Seitzinper, N. K., J Org. Chsm.. 47.815 (19821.
I61 Par tho d~seriptionofa portion of thiswork see Gmdwin, T. E..Crowder,C.M..White. R. B.,Swanson, J.S.,Evans,P. E.,andMoyer, W . 1 . L Org. Chem.,48,376(1983l.
