Teaching Organic Synthesis An Advanced Organic Chemistry Course That Uses the Primary Literature Larry G. French St. Lawrence University, Canton, NY 13617
The advanced o r e a ~ chemistrv c classroom resents a chemical educator with an ideal &lieu for both teaching and learniw. Tvpicallv, a small m o u ~ of prepared, ambitious, and ik&sted students popuiate c6urse unburdened by an oppressive roster of prescribed topical content. Recently, Fikes has described a literature-based approach for a mechanistically oriented advanced organic course ( 1I . In this paper, I present an overview of a n advanced organic synthesis course developed over the past several rears that uses primary literature sources in fieu of a text. I will also give advice in facilitating a n undergraduate's initial forays into the chemical literature,
tion of tareets from the realms of natural and nornatural products &d in the presentation of both classical and cont e m ~ o r a r vsvnthetic achievements. Care is exercised in cho6singthg papers studied so that the course allows broad exposure to the repertoire of synthetic methodology, but also allows for the insertion of topical features. The table provides a sample of the syntheses wvered in the course and the topical discussions which derive naturally from them (4).
Course Content and Structure The hub of our study wnsists of critical analvsis of noteworthy achievementsin the total synthesis of natural and nornatural products. Students are provided with copies of the originai journal articles to riad in for classroom lecture and discussion. All important facets of the synthetic process are explored with a focus on control and selectivity elements, rationales for target-molecule selection, strategic considerations in complex synthetic routes, and execution of synthetic plans (tactics and methodology). Much of the chemistry encountered is not fundamentally new to the students, but it is being applied in much more complex situations. Students enter the advanced course eauio~edwith some knowledee of most of the maior reaction types and with a fairly lGge arsenal of specifk chemical transformations. Unfortunatelv. most of this understanding has been developed in ihe setting of simple substrates that incorporate a lone reactive site. The real world of organic synthesis is populated by complex, polyfnnctionalized molecules with multifaceted reactivitv. Thus, the discovery and application of highly selective methodologies serve as a major unifying theme in the course. The method of case study adopted in this course has been supplanted by target independent problem-solving stratagems to instruct students in how to desim svnthetic routes @). However, the primary goal of an unJeGaduate wurse is clearly not to train an a m y of svnthetic chemists. Persmal cl&aroom experiences have jndicnted that the case study "synthesis appreciation" mode of presenting-olwanic . synthesis imore stirnulatingleaming environment than a semester devoted to systematic inculcation of the regimens of retrosynthetic analysis. However, retrosynthetic analysis is included, and can be the focus of discussion when coverim the svnthetic olannine staee. Furthermore, students may gain experience in its application while desienine routes to startine materials used in the synthetic endeavors under study. The svnthetic achievements that are selected for studv convey a n appreciation for the range of rationales tha"t have justified the pursuit of total synthesis. The current focus on the construction of supramolecular structures and molecules with carefullv wnceived forms and functions is given ample attention (3). Balance is sought in the selec-
Selected Syntheses
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chemo-,regio-, and stereowntrol in the manipulation of oxidation state; medicinal leads from folk medicine formation of smal and meolJm wed caryophyllene (6) (Corey, I 964) rmgs: enolate formation ana reactions: terpene biochemistry sterofdbiochemistry: fJseo ring systems cholesterol (7) (Woodward,1952) vta Rob nson type anne at ons: Stereowntro on rg~opo ycyc ic sdeletons preparation of cage wmpo~nds cubane (8) (Eaton, 1964) emp oying mtramolecLlar pnoto 2-2 cyc~oaddilons; mechan st c rat ona es for tne Favorsk react on heptelidic acid (91 organoseleniLm and organos icon (Danishefsky,1988) reagents; organocuprates and hlgn order cuprates: lactonization reagents: contro of relal ve stereochemlstry n a suost I L ~ Wcyclonexane system phorbol (IO) mu llslage chemlca carc nogenes s; 1.3-dpolar cycloadait~ons;lalent (Wender, 1989) tdncttonal ly,furansas 14-a;carbonyl eqJlvalents, isoxazol nes as alao eq.ivalents: wntro of relatwe stereocnemlstry on a brdged rng system with concave and convex faces [l.l .l]propeilane(11) formal on, slrJnure ana reactions of (Wiberg,1982) carbenes: react v ty of cyclopropy o bonds alkaloid biochemistw: -. - .-.reserpine (13 ,. use --- o -f conformalona ly restricted r gid ring (Woodward,1958) systems ana remote stte f u n d ona IW to contro rela1 ve stereocnem stry: B smerNapieralski isoquinoline synthesis; quinone DiebAlder cycloadditions soluble carceplex (13) host-guest chemistry (Cram. 1988) synthetic ATPase (14) host guest chemistry; synthetic enzymes (Lehn, 1988) showdomycin (15) radical based carbon-carbon bond (Banon, 1990) formation (+)-bourgeanicacid (16) alkylation of chiral amide enolates; (White. 1990) carbonyl addition of chiral crotyl boronates, chiral enolate eauivalents bilobalide (5) (Corey, 1987)
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Objectives and Strategies Get Everyone on the Same Playing Field Although students will enter the course with a wide range of abilities and previous accomplishment, even the beseprepared student will profit from some review and reexamination of introductory material. I believe that an initial investment of 4 to 5 hours of lecture time for review in a 40-hour course is worthwhile. First, a review of major patterns of reactivity with generalized and soecific examples is oresented. This is followed by a detsled examination and illustration of control and seiectivitv issues. Students must be caoable of identifymg the chemc-, regic-, and stereomntr~i~roblems that will be encountered, and they must understand the fundamental approaches that canbe used to solve them. The discussion of chemoselectivitv focuses more comorehensively on issues that were intldduced in the introductow course: chemical differentiation of muitiole functional g i i p s with similar reactivities, and control &I reactions of functional groups that may read more than once under a given set of reaction conditions. Similarly, regiocontrol is examined in the familiar contexts of controlling the orientation of addition and elimination processes. Finally, methods for achieving absolute control of stereochemical outcome are detailed. Strategies of chiral substrate, chiral auxiliary, chiral reagent, and chiral catalyst control are covered in depth and illustrated with specific examples. Of singular importance is the clarification of some concepts that are almost uniformly misunderstood by undereraduates: the difference between the control of relative and absolute stereochemistry, and how such selectivities can be effected. Before attemotine . to scrutinize the svnthesis of a natural product that incorporates eight tetrahedral stereocenters, attention must be &en to the fundamental means of achieving d i a s t e r e o s k e ~ t i v i and t ~ enantioselectivity in chemical transformations. ARer this review and intro-duction, the class is conducted in the format of a discussion or seminar, punctuated by periodical topical lectures.
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Encourage Class Parficipation and Critical Reading
I "institutionalize" class participation and ensure that students peruse the assigned reading in some detail before class. Students are given the assignment of formulating one nontrivial and unresolved question pertaining to the chemistry in the paper during consideration of the synthesis. These questions are submitted along with accounts of the students'state of understanding of the problem. How and where does their insight fall short? What must be learned in order to completely resolve the issue? Can the problem be related in any way to one with which they are familiar? Ideally, some backtracking through references will have been undertaken in completing this assignment. The instructor and students then collaborate to answer these questions. In many instances, further literature research is required. These assignments are graded in a progressive fashion, primarily by their degree of difficulty and by the effort exoended to eet a solution. I look for various s i m that the students are progressing during the semestecthe level of and soohistication and insight in their posing - of queries, . thkir progress toward tGe solutions.Prepare Students To Read the Primary Literature on Synthesis.
This is undeniably a supreme challenge even for the most capable undergraduate. Some would argue that it is unrealistic to expect a n undergraduate to comprehend
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Journal of Chemical Education
enough of these papers to make the educational endeavor worthwhile. There are problems with the literature itself. Accounts of synthetic studies published in the 1950's and early 1960's often incorporate extended digressions and descriptions of tangential studies. They often lack clear and complete schematic presentations of the final synthetic pathway. Conversely, contemporary manuscripts typically supply lucid and carefully presented schematic outlines of the synthesis. However, they are oRen unsupported by substantial textual commentary, and they often rely on extensive referencing. Furthermore, it is not uncommon to find 3-4 "trivial" steps consolidated over a single synthetic arrow. Synthesis of a Phorbol Precursor Wender, J. Am. Chem. Sac. 1989.111. 8954. Major Themes: lntramolec~lar1.3-d polar cycloaddttion reacloons; Latent functional~ly; soxazohnes as aldol equivalents and furansas 1A-dicarbonylprecursors Reacllon Summary: Step Reaction Reference 1
primary alcohol protected as silyl ether S. 385 ketone synthesis via aryllithium addition S. 744-745 to carboxylic acid controlled cross-aldolcondensation esterification of semndary alcohol ketone (R) with NaBH4 oxidative unveiling of 1,4-dicarbonyl moiety from a furan hemi-ketal acyiation (esterification) formation and intramolecular 1,3-dipolar cycioaddition of an oxidopyrylium mesionic heterocycle catalytic hydrogenation Wittlg reaction allylic hydroxylation with selenium dioxide allylic alcohol (0)via ~ n * conjugate addition of an organocuprate C and S. 408-410 S. 7612-762 formation of protected cyanohydrin K (R) of nitrile and ester with DlBAH S. 740 oxime formation S. 75€-659 formation and intramolecular 19-dipolar Accounts cycloaddition of a nitrile oxide 1984,410 N-0 hydrogenoiysls C. 257258 esterification of primary alcohol 5.838 E2 elimination 5.229 Luche H- (R) of spunsaturated ketone C. 462463 desilylation with F S. 812814 acetonide formation (ketalization) S. 749755 -Key: S. = Solomons (4th ed.) (18);C. = Carruthers (3rd ed.) (19);C and S. =Carey and Sundberg (Pan B, 3rd ed.) ( 2 ~ ) . Sample Reaction Summary
Two types ofsupplementary material are supplied to the students to reduce their burden. Adetailed, stepwise schematic presentation of the synthesis in its final form is supplied when i t is lacking in the original report. In addition, a reaction summary is prepared. (See the f ~ r e . This 1 provides short descriptions of each step in the synthesis with accompanying references of three types: appropriate review sections in a n introductory text, material in an advanced text on reserve in the library, or supporting material in the primary literature. I also give the students a compilation of acronyms to avoid confusion (17). Stress Learning by Analogy and Extrapolation
Students of omanic chemistm must be convinced of two things: that thefcan reach a plkeau in the factual content that must he assimilated. and that makineincremental increases in their understanding of organic chemistry bevend the introducmrv level will not reauire a -proponionate increase in memory work. Somewhat prophetically, Barton (21)noted in 1973
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Most of the synthetic work is done with organic reactions of the type which have been known for a long time. If you know 20 organic reactions you probably know most of the steps used in synthetic work, particularly in industry, but I am quite sure there must be hundreds of other organic reactions to be discovered. After 18 years and 12 additional volumes of Fieser a n d Fieser (22),this predicted expansion of the synthetic arsenal has indeed been forthcoming: Organic chemists have explored most of the vistas of the penudic table searching for reagents capable of effecting selective, high-yielding transfo&ations under mild conditions. As new functional groups, reagents, and reactions are presented to students, analogies should be emphasized with reactivity patterns and mechanisms of familiar reactions. When exotic new reagents and fundamentally novel reactions are used, it is also critical to highlight the synthetic advantages offered by these methodologies visa vis alternate, perhaps simpler, classical approaches. Students should begin to develop the capacity to assess the relative merits of complementary, and possibly redundant, synthetic methodology Challenge Them To Develop Communication Skills
The emphasis placed on class participation augments the students' abilities to speak the language of organic chemistry. Students are encouraged to clearly and concisely describe chemical transformations verbally, and to articulate relevant conceptual information. They also gained experience working a t the blackboard. These skills often are not well-developed after only the introductory course. Students are required to use these talents in endof-semester oral presentations that detail and critique a published total synthesis of their choice. Provide Individual Guidance and Challenge
Guiding students to appropriate papers is a n important part of the process. My personal preference is not to ensure a d o r m degree of dimculty. I match the students with the syntheses according to their ability, to provide substantial challenge, ~tis notdifficult to both the degree of difficulty and execution in judging their performances. Initially, I instruct my students to locate one or two syntheses that meet the following criterion.
The target molecule is of real practical or theoretical interest. Novel and interesting methodology is applied. Some of the reactions are familiar to them. I then meet with them individually to assess the suitability of the projects. Recent student presentations have included Lycodine (Heathcock, 19821, the trityrosine tripeptide K-13 (Boger, 19891, and (-1-denopamine (Corey, 1991). Student Assessment of the Course Student appraisal of course content and style has been uniformly favorable. No complaints pertaining to the lack of a text have been reeistered. This stands in marked contrast to the displeas&e often expressed with the textbooks used in the course in previous years. Regarding the reading assignments in the primary literature, no one complained that it was an unmanageable task. However, scveral students indicated that thc complementary study aids were essential in penetrating the papers under study. A constructive suggestion for improving course content was offered that a paper authored by a woman chemist be included. Conclusion This course helped students achieve various academic goals. Students reviewed and consolidated their previous foundations in the fundamentals of organic chemistry. They viewed the application of chemistry encountered in the introductory course in complex settings of target molecules of ~ r a c t i c a lor theoretical interest. Thev became aware of ;he limitations of this methodology,andthey witnessed the exoansion of the svnthetic re~ertoireto meet synthetic chalienges. In the process of accomplishing these ends, they gained experience and coddence in examining the primary literature of organic chemistry. Thus, they prepared themselves to comprehend and critique complex, multistep synthetic endeavors. Students also develoued various skills in sciencecommunication, both in writing descriptions and in oral presentation. Literature Cited 1. Flkes, h E. J. Chem Edue 1WD,66,920-921. . Sclo- 1886,228,408418. 2. &rw,E. J.; lang,A. K; Rubenstein, S. D 3. Seebach. DAngalwndfa Chemlol E lWD,29.1320-1367. 4. Many ofthe topics inmrporated have been identified aa appmpriate for anintmductorysyntheais muae.SeeThe k~hingofOr@n&Syntheak,Paperafmma Workshop held st the University ofLeeds September 1981, The Royal Smiety of Chemisby, Educstion D i i k i i . 5. C o w , E. J.: Su, W J . A m Chem. Sm. lsB?,109,753P7536. 6. Cores E. J.: Mitra. R. B.: Uda, H. J.Am. C k m Soc. lsBP.66.485-492. 7. Woodward, R. B.; Sondheimer, C.; Taub, D.; Heualer, K; McLamore, W M. J h . Chem. Soc 195& 74,42234251. 8. Eaton, P; Cole, T. W J A m Chem. Soe 18M.86.962-964,31574158. 9. Dmishefsky, S. J . ; M d o , N. J . A m C h w . Soc 1988,110,812%3133. 10. Wendcr, P. A ; Lee, H. Y.;Wllhelm, R. S.; Williams, P D .J . h Chem. 50%1989,111, , D.:WiLhclrn,R.S.;WiU 89568957. Wender, PA.: Kwn,H.:lae,H.Y.;M ~ g e rJ. iams,P D. J . h . Chem. Sos. 1989,111,89678958. 11. Wiberg, K.B.; Walker, F H. J . h . Chem Soc 1982,104,523~24rl bratead, R. W . 'ntmludd" 12. woodward,R B.; Bader, F E.: Biekcl, H.:Fres A. 19542, 1-57. 13. Cram, D. J.; Karbaek, S.; Kim,Y.H.: Knobler, C. B.;Maveriek, E. F.;Eticaon, J. L.; Hdgezan, R. C. J . Am. Ckem. Soc 1988,110,22%2217. 14. Lehn, J. M.; Hosseine, M. W: B1acker.A. J. J. Ckm. Sm. Ckm. Commvn 19% 596-598. 15. B.*, D. H. R.; ~ ~M. J . A~ ~ them. . ~ SX. i ~s m , 112,891-892. h , 16. White, J. D.; J o h o n , A. T. J. O w chem. 1980,55,59306940. 17. Daub. C.H.; Lean.A. A; Silverman. I. R.; Daub, 0. W.; Walker. S B.Aldrichimlm h t o ISM, 17,113-23. 18. Solomonr, T W . G. OrgMie Ckmism, 44~1ed.; wilw N ~ W Y O ~ L1988. . 19. C-there, W . S o w M o d m Methods of Owan* S~nfkkis,3rd ed.; Cam&dge Urivemiy Ress: New York, 1986. 20. k e y , F A,, sundbeq, R. J. .4dvaneod olgonie ckmistw, P ~ B3rd, ~d.; menRess: New York, 1990. B-n.o, H, R, Chem Br lWS 9. 14s153. ,~ 22. Fieseg M.;Fieaeg L.FRe"gpnI~fffOr@goiiSynUI~~Ir; Wilq: N N N Y Y Y ~ ; V Y ~ S . ~ ~ S .
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