H. W. Orf Harvard University Combr~dge,Massachusetts 02138
Computer-Assisted Instruction in Organic Synthesis
The use of computers as a teaching tool has increased dramatically in recent years ( I ) . With rising college enrollments forcing larger class sizes. computer assistance will soon become the most reasonable way of assuring individual student attention. In recent years, several programs designed to assist in various aspects of chemical education have appeared (2). The most notable of these is perhaps the PLATO system (3). which was developed a t the University of Illinois and which is now in use by several universities in the United States via telephone communication lines. This paper describes the use of a different computer program, one designed specifically to assist in the instruction of organic synthesis. The Program
During the past seven years, a research project has been in process a t Haward University aimed a t developing a computer program to assist chemists in the planning of organic syntheses (4, 5). This program is called LHASA, a mnenomic for Logic and Heuristics Applied to Synthetic Analysis. The LHASA program differs from instmctional programs such as PLATO in two significant areas. First, because LHASA was initially designed for use by organic chemists and not by chemistry students, it is designed to be more sophisticated and to address a more sophisticated user. Also, again because it was designed specifically for avnthptir chemists. more limited in that it is . ~ ~ . ~ -it~is~-much - -~~- ,~ designed to address only the problem of organic synthesis. The user-computer interaction in LHASA differs significantly from the conventional teletype communication of most interactive programs, in that all user-computer communication is graphical. Figure 1 shows the graphical input display of LHASA, where the student, using a Rand drawing tablet (ti), communicates to the computer via a simple pen and paper type ot i n t ~ r a c t i ~ m(See . reference (5, lor tunher details c ~ ~ n r e r n i nt he ~ graphical s unit r Thi.; highly interact~veniode of rorr~tnunicatimrliminates the nied for error-prone command languages and allows the student to concentrate more on the lesson a t hand. ~~
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Figure 1 . L H A S A graphical mput display. A ing tablet to communicate with t h e program.
student uses t h e
Rand
draw-
ply, its goal was to give the students a feeling for how a good synthetic organic chemist thinks. Factors Affecting the Choice of a Synthetic Strategy
A summation of those points emphasized in the course are listed in the table. Each will he briefly explained to facilitate an understanding of how the computer has been used to reinforce these concepts.
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The Course Organization
Since the LHASA program has now developed to a point where it is reasonably proficient in assisting synthetic design (7, a), it was decided to see whether this program could be used a s a teaching tool as well. Therefore, this past semester an experiment was undertaken using 15 volunteer students from a second semester course in organic chemistry. They were put in an additional, special section devoted to the teaching of organic synthesis. The students were given 1-hour lectures every other week which were coupled with computer assignments designed to exemplify the material stressed in lecture. Unlike the regular second semester organic lectures, which concentrate heavily on specific reactions and their mechanisms, the synthesis section emphasized general factors affecting the course of synthetic design. Put simPresented at the Biochemical-Biophysics Joint Symposium, Minneapolis, June. 1974. 464 / Journal of Chemical Education
Factors Affecting the Choice of a Synthetic Strategy . .-
1. A ~ a n p e m e n tof functionality 2. presence of ,-strategic bonds" 3. presence of special substrvctvres 4. Stereochemistry G. (Potential) symmetry 6. S c o ~ and e limitations of the reactions involved
Arrangement of Functionality The arrangement of functionality in the molecule being analyzed is of primary importance to the synthetic chemist, for this is what he must use to mentally key important retrosynthetic disconnections. For instance, the presence of the ketone and the olefin separated by one bond in jasmone (Fig. 2) is what suggests to the chemist (and also to the LHASA program) the fact that an aldol reaction on structure I could he used to synthetically construct this enone unit. Strategic Bonds An important factor to he considered when a molecule contains a complex cyclic network is the identification of "strategic" bonds (9). Strategic bonds are identified by
JASMONE Figure 2. A retrosynthetic disconnection of jasrnone.
I
Figure 3. Longifolene, showing strategic bonds (dashed) SHIKIMIC ACID
LHASA as those honds which, if hroken in the retrosynthetic direction, would most simplify the cyclic network. For example, in longifolene (Fig. 3) the computer has chosen the dashed bonds as strategic. Each of these honds, if broken, would leave a simple 5, 7 or 6, 7 fused system. Note that the thickened hond, which would give a 5, 8 fused system if broken, is not chosen as strategic by LHASA because of relative scarcity of readily available X, 8 fused systems. Special Substructures The need to recognize special substructures and the retrosynthetic strategies they key is also emphasized. A 10-membered ring, for example, is a substructure which is often derived from a strategy involving the opening of a more easily synthesized 6, 6 fused system (Fig. 4). Similarly, a 7-oxanorhornane substructure almost invariably sueeests a Diels-Alder strategy using furan as the diene component. uu
Figure 6.Symmetry-directed syntheses of shikimic acid.
Scope and Limitations of Important Synthetic Reactions In a synthesis course such as this, where great emphasis is placed on retmsynthetic analysis, it is most important to understand the scope and limitations of the chemical reactions selected to perform the synthetic conversions. For instance, the alcohol and the ketone moieties separated by two honds in structure I1 (Fig. 7) retmsynthetically suggests that an aldol condensation on 111 could yield II. Considering the reversibility of the aldol reaction, however, one finds that an alternate cyclization, leading instead to a 6-membered ring, would be preferred in this case. Student-Computer Interaction Figure 8 shows LHASA's "menu" display. Listed here are the processing options available to the student once he has drawn in the molecule he wishes to analyze. The primary classification of options is based on the arrangement of functionality, either single functional groups as in One Group Chemistry, or functional group pairs as in Two Gmup Chemistry. Several strategic hond processing options are available and special substructure processing, presently just directed at the use of powerful 6-membered
Figure 4. Special substructure strategies.
Stereochemistry Stereo-relationships in a molecule often dominate the synthetic strategies leading to it. In the case of isonootkatone (Fig. 5), the cis stereo-relationship of the dimethyl moiety was established by use of the Robinson annulation reaction (10). Had the stereochemistry of this initial reaction not left the methyl and ester moieties cis, then the Robinson annulation directed strategy might not have been used at all.
II
Ill
Figure 7. An impractical retrosynthetic disconnection.
iSONOOTKAlONf Figure 5. Marshall's synthesis of isonootkatone
Because symmetrical intermediates can greatly reduce the number of omducts to he expected from subsequent reactions, retroiynthetic strategies are often directed toward the symmetrization of intermediates. Shikimic acid, as shown in Figure 6, has been synthesized by two completely different Diels-Alder strategies (11, 12). Both of these strategies, however, were directed toward symmetrization of the initial diene component.
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TREE
CUTOFF
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I 0 r SUBGOAL CUTOPP r
Figure 8. LHASA's "menu" display.
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/ 465
this case, the aldol condensation. Here the students are asked to process the "target" molecule and to observe the rating value (in this case 45) that LHASA gives the retroaldol disconnection shown. (The rating value is a number generally between -50 and 200 telling how well LHASA thinks the reaction will go in the synthetic direction.) They then are asked first to modify the structure in a variety of ways, note the new rating of the same aldol disconnection, and then to explain why the computer either raised or lowered the rating. Take, for example, modification F., nlacine a ketone a t carhon 6. This stabilizes the desired enolate anion required for the condensation so LHASA now rates the reaction a t 135. Modification D. however, placing a halide on carhon 6, has so detrimental an effect that LHASA does not allow the aldol disconnection to he shown. It realizes that, in this case, HX elimination to give an a,p unsaturated ketone would occur instead. A strategic bond problem is shown in Figure 11. In this problem the students are asked not only to choose which honds they would term as strategic, but also to use the computer to learn how these can he retrosynthetically disconnected. The thickened bonds were chosen hy LHASA as strategic. Sample strategic disconnections, representative of those typically generated by LHASA, are also shown in Figure 11.
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Figure 9. An "arrangement of functionality" problem
ring forming reactions, is also possible. I t is important to note, however, that a t each "step backwards'' in his synthesis, the student must go to the menu and actively decide which are the most important factors in the molecule he is presently processing. If his selections are not well thought out, he usually ends u p with only long and/or impractical syntheses. The compounds shown in Figure 9 were taken from an assignment stressing the arrangement of functionality. Here, the student must process molecules IV through VII back several levels to simpler molecules, noting which routes he likes best and identifying those features that retrosynthetically key each disconnection to the computer. For example, in a typical sequence found for compound VI, the first disconnection was keyed to the computer by the presence of the delta lactone. The second disconnection, which synthetically corresponds to an aldol-type condensation, was keyed by the alcohol and the "vinylogous withdrawing" ester group separated by two bonds. The third and fourth disconnections, which correspond synthetically to an amine Michael addition and a Mannich reaction, respectively, were both keyed by the amine and the ketone groups separated by paths of two honds. Figure 10 shows a problem taken from a set dealing with the scope and limitations of important reactions, in
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I-GROUP
Figure 11. A "strategic bond" problem.
. . TA~GET PTOECII t h e a b o v e m o l e c u l e urinp t h e " F u l l Search" Two g r o u ~C h e m i s t r y hution and r e c o r d t h e RtTING o f the a b o v e dirconnectlon. Then alter t h e r t r u c t v r e o f t h e t a r g e t m o l e c u l e i n t h e rays d e ~ c r l h c dhelox nnd record t h e RATIST a { t h e d i r c o n n e c r i o n rysin. J u s t i f y ,he c h a n g e i n w ~ r h l :o f each altered rtiucrure.
E.
Place a carbon atom P l a c e n carhon ifam Placc an a d d i t i o n a l c n r h o n r J and 4 Attach a halide (XI Attach n halide 1x1
5.
.Aftail% a k r o n e
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B. C. D.
hetwen r t m s 1 ind 2 hetheen a t o m s 4 e n d I m e t h y l group (-1 on to
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cnrhon 6
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t o carbon 7
I = O l to carhon
LHASA RATINGS
6
D. KlLLED
F. F
Figure 10. A problem used to study the aldol condensatm reactton.
466 / Journal of ChemicalEducatbn
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A problem taken from a set dealing with general strategies applied to 6-membered ring substructures is shown in Figure 12. Here the student processes several structures using the Diels-Alder and Robinson annulation modes and observes LHASA as it attempts to modify each 6-membered ring and set it up for the direct retrosynthetic application of these powerful reactions. After processing several molecules using these modes, the student begins to realize the fruitfulness of taking an exhaustive and systematic approach to synthetic analysis. Summation
The computer-assisted synthesis section was well received by the students, getting high commendation in their course evaluation papers. It became apparent during
Figure 13. A student-derived Diels-Alder strategy
Acknowledgment Figure 12. Examplesaf special substructure strategies.
the latter assignments that the students were gaining confidence in their ability to work with non-trivial synthetic problems. This was best exemplified by the fact that, although none could find a reasonable synthetic route to structure WI a t the beginning of the course, 9 out of 15 found the sequence shown in Figure 13 without computer assistance when the problem was presented a second time during the last lecture. In summation, this experimental section appears t o have successfully demonstrated the potential of LHASA as an interactive and productive teaching tool in organic synthesis. This coming school year, senior undergraduate and graduate chemistry students will also make use of the program in order to determine a t what level of proficiency the student should he to benefit most from its use.
The author wishes to thank Professors E. J. Corey and Eric Block for their help and advice in planning the w m puter-synthesis section. Dr. W. Jeffrey Howe's assistance throughout the course is also gratefully acknowledged. Literature Cited
iai corey.'~.j.,BwmR ~ U X. ~
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X V , (1971). ~ ( 5 ) Corey,E,J., and Wipke, W, T., Slianee, 166,178i1969). ( 6 ) Sutherland,I.E.,S c i . Amer. 215(3), 86 (19%). (7) Corey, E. J., Cramer, R. D.. and Horn. W. J., J Amer Chom. Sac.. 91. 440
(1972). (81 C0rey.E. J..andPetonon.G.A.,J.Amar Chem.Soe.. 94,460 (1912). (91 Corev. E. J.. Hawe. W. J.. 0 6 H.W..Penaak. D. A,. and Peterson. G.. J Amer. ckem Soc, avbmiffdforpublication. (1975). (10) Manhall, J.A., Faubl, H., andWarne,T.M., Chom. Comrnun., 753l1967). (11) Grew%R..and Hinrieb. I.. Chem. Be,., 91,443 (IS+#.
(12) Smiasmsn. E. E.,Suh. J. T., Oxmsn. M., and Daniels, R., J Amer Chem. Sot.. 81. lMO(1962).
Vohune 52, Number 7, JuW 1975 / 467
