Leverett R. Smith Dept. of Chemistry Oberlin College Oberlin. OH 44074 and Howard J. Williams' Dept. of Entomology Texas A & M University College Station. TX 77840
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Glutamic Acid in Pheromone A useful chiral synthon
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In recent years the field of "chemical ecology," the study of chemically-mediated interactions within and between species, has become an area of increasing scientific interest (i). within this potentially very broad subject, the study of pheromones, chemicals serving for communication between kernhers of a particular species, has assumed major proportions. Most extensivrly studied have heen insect pheromones (2),hut such interactions are under investigation in hoth lower ( 3 )and higher (1)organisms as well. This dev~lopmrnthas renernted a oroductive interface between behavioral biolocv . . and organic chemistry. An important development of the past several years has been a realization of theimportance ofparticular mixtures of isomers (for example, ratios of E to Z in olefins) in communication within somespecies (5).This subject bas generated a certain controversy a t times (6). A specific discovery has been the finding that insects usually find the naturally dominant enantiomer of a chiral pheromone to be more attractive than its antipode (7). Since the final step in reliahly establishing pheromonal structures has been synthesis and biological testing of presumed structures, the synthesis of pheromones in optically active form has become an often impor(8). tant ~rereouisitefor orooerbioassav . . For economic reasons, preparations of many of these compounds have begun with one of a small number of inexpensive optically active precursors. A study of the often ingeniousways chemists have manipulated these compounds in synthesizing diverse pheromonai structures gives organic che&try st< dents insight into the thought processes involved in modern synthesis design and reinforces their stereochemistry background. Discussions of the biological activity and possible economic importance of the products contribute added student interest to this study. Glutamic acid (compound 1, Fig. I), the single starting material which has had the most varied use in chiral pheromone synthesis, is a well-known substance, probably most familiar to the world a t large in the form of its monosodium
Figure 2. Formation of y-Butyrolactone-y-carbDxylic Acid trom Glutamic Acid. salt. In Fieure 1.. oheromones oreoared . . from this startine material are shown. These are y-caprolactone (3), component of the attractive substances of several dermestid beetles (9): . .. 2-ethyl-1,6-dioxaspir0[4,4]nonane(41, from Pityogenes chalcographus (L.), a beetle pest of Norway spruce (10); (2)-6-dodecen-4-olide (5), from the "social scent" of the black-tailed deer (11): (Z)-5-tetradecen-4-olide (6). sex pheromone of the female Japanese t~eetle(70), 6-methyl-5pheromone her~ten-2-t1l ("su1eau~l"J(7). from the accrecation . . . of'the ambrosia beetle Gnathotrichus sulcat& (12); 1methylhutyl (E)-2,4-dimethyl-2-pentenoate(8) and 1methylbutyl (E)-2-methyl-2-pentenoate (9), pheromonal components from the lesser grain borer beetle Rhyzopertha dominica (13); and finally (2)-7,s-epoxy-2-methyloctadecane ("disparlure") (lo), from the gypsy moth, Porthetria disoar (14). . . Glutamic acid provides a relatively inexpensive starting material, both of whose enantiomers are available commercially in pure form. More importantly, the conversion of glutamic acid (by nitrous acid diazotization) to the central inacid (2), termediate of Figure 1, y-butyrolactone-y-carboxylic proceeds with complete retention of confiauration (15). The mechanism for 2's formation is presumed to include anchimeric assistance by the carboxyl group adjacent to the departing nitrogen molecule (Fig. 2). The resulting labile a-lactone reopens on nucleophilic attack by the molecule's other carboxyl group. (Anchimeric assistance by the carboxylate anion group appears in Figure 2. Involvement of the anion's conjugate acid, proceeding on through a protonated a-lactone, also seems plausible.) As is immediately apparent from Figure 1, the small synthon (2) has been amenable to a variety of alterations. The carboxylic acid group of 2 provides a convenient "handle" where all of the indicated syntheses begin. It can conveniently he reduced to the corresponding alcohol (11) by horane reduction, converted to the acid chloride (12), or (via Rosenmund reduction of 12) reduced to an aldehyde (13) (Figure
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2) -,.
Figure 1. C h i d Pheromones Synthesized trom Glutamic Acid 696 / Journal of Chemical Education
The aldehyde (13) was converted into the Japanese beetle pheromone (6) by a straightforward Wittig reaction (eqn. 1, Fig. 4) (7a). The synthesis of disparlure (10) began with the acid chloride (12), which was first alkylated by di-n-decyl cadmium (eqn. 2, Fig. 4). Several steps further, another alkyl fragment was added a t the other "end" of the original lactone fragment, and a few more conversions completed the synthesis (14). This article approved as TA-14572 by the Director of the Texas Agricultural Experiment Station in cooperation with the USDAFR-SEA.
c1 12 Figure 3. Synthetic Intermediates from y-Butyrolactone-yarboxyllc Acid. Unquestionably the most useful intermediate to date has been the alcohol (11). . .. in the form of itso-toIuenesulfonate ester (tusylate), as eqn. 3 of Figure 4 illustrates. Treatment with the a~nrooriate .. . dialkvlcou~erlithiumrearents formed optically active caprolactone (3); and "deer lac&ne2' (5) (9). Reductive removal of the tosylate group, followed hy diisohutyl aluminum hydride (DIBAH) reduction of the lactone to a hemiacetal, allowed completion of the sulcatol (7) synthesis by a Wittig reaction (12). The chiral alcohol moiety of the R. dominica esters 8 and 9 was formed by a sequence involving lithium aluminum hydride reduction, selective formation of the primary monotosylate of the resulting diol, and further reduction with lithium aluminum hydride (13).Finally (eqn. 4, Fig. 41, the unusual spirocyclic compound (4) from P. chalcographus began with caprolactone (31, and thus i t also came from the tosylate of 11. Alkylation by the lithium salt of the tetrahvdroavranvl ether of ~rouarevlalcohol was followed by catalytic hydrogenation andacgtreatment to give 4. Because the ketal center in 4 is chiral. the ~ r o d u cexists t as a mixture of diastereomers (as does the natural material); these can, however, be separated gas chromatographically (~l o b.) . As the foregoing discussion has pointed out, the lactone-acid (2) from glutamic acid has been a useful intermediate in pheromone synthesis both hecause of its availability in optically pure form and because its functional groups lend themselves to a wide variety of chemical transformations. It seems very likely that these characteristics will lead to further use of the "glutamic acid route" in the future. In addition to research interest, though, this topic lends itself well to inclusion in the introductory organic lecture c o u r ~ e In . ~ that the pheromones 3-10 represent a variety of common compound types, they can be brought in as functional mouD and chiral structural examules fairlv earlv in the come. Eomkents on their origins, a t times salted with-remarks about such characteristics as odor? definitely enhance presentation. The topic's chemical diversity provides examples of diazotization, acyl chloride formation, nucleophilic displacements, catalytic and complex hydride reductions, esterification, ketalization, the Wittig reaction, andthe use ofradmium, lith~
While probably too demanding for a n introductor.~or,gaaic lahi ~optically n active 7 -capndartonc (3). via the oratory, the p r ~ p ~ r a tof 1-ll-torylav-rR,mighr hesuited tmnnadvanwd sequence 1-2-1 undergraduate synthesis lab. Experimental details of this sequence appear in reference 9; a short procedure can also he obtained by writing to L. R. S. Those purifying the diazotization product (2) hv vacuum distillation are ureed to heat eraduallv under vacu u m and not to carry out this distillation un a large scale. bem u s e violcnt eruptions haveoccasionally occurred betoredistillation commenced. Uqe oia ,odn-lme trap t o prmm the pump is also recommended for this distillation. "he mildly fruity smell of ladone (3) and the almost minty aroma of ketal (4) generally strike people as agreeable. The remarkably penetrating, lingering scent of the "deer lactone" (61,however, generates mixed commentaries. TheR. dominica esters 18) and (9) have been variously described as evocative of "honey"or of''hor& urine" (16) (we tend to favor the former school, but samples may well vary).
Figure 4. Outlines of Synthetic Routes. ium, and dialkylcopperlithium reagents. From a more general point of view (best held for the second semester) come selectivity (e.g. in borane reduction and tosylate formation), tetrahydropyranyl ether protection of alcohols, and, of course, questions of overall synthetic strategy. Literature Cited (1) (a1Schildknecht, H., Angeu. Chom., 88,235 11976): (bl Whittsker, R. H., and Feeny, P. P..Science 171.757 119711: lcl Sondheimer. E.. and Simeone. J. B..1EdiforrI.
'"~h&id E ~ I O E ~ . '~. e a d ~ r nPress. j c New york, 1970. (2) (a) Shorey, H.H.,andMcKalvey, Jr.. J.J.. (Editorsl,"Chemical Controlofinsect Behavior," Wiley.NewYork, 1971; lbl Birch, M. C., (Editorl,"Pheromma,"Ameriesn Elsevier, New York, 1974.
(31 Jaanieke, L.,Ndurwissennehofrpn.64.69 (10771. (4) (a1 MBller-bhwane. D..and Maell, M., iEditora1:'ChemiedSignalsin Vertebrates," Plenum Press, New York, 1971; lbl Albone, E..Chem, in Britain, 13.92 119771. (5) (s) Silverstein,R. M. and Young, J. C., in &roza. M., (Editor), '"Pest Management
~ i t ln&SexAttrsetants," h Amencan Chemical Saeiety. Waehingfoq D.C., 1976; (b) Chapman, O.L.,Mattes,K.C.,Sheridan,R. S.,snd Kiun, 3. A,. J Amar Chsm. Sor.. 100.4878 (19781. ( 6 ) Eiter. K., Pure Appl. Chem., 41.201 (19751. (7) (a) Tumlinson, J. H.,Klein,M.S.,Dmiittle,R. E.,Ladd,T.C.,andProueaur,A.T., Science, 191,789 (19771: lbl Mori,K.,T~fmhedmn,30,4223 (1974): (el Riley. R. G.,Si1verstein.R. M.,end Maser, J.C.,Seience,183,760i1974):ldl Bordon,J.G., Chong, L., M e k n . J. A,. Slessor, K. N.. and Mori. K..S&nee, 192,894 (19761. (8) (a) Roasi, R., Synthesis, 413 119781: lbl Henrick, C. A , T@frah@dron, 33, 1845 ,tm,,> \.".,,.
(9) Rsvid, U., Silverstein. R.
M., and Smith. L. R, Tetrahedron, 34.1449 (19781.
Volume 56, Nwnber 10. October 1979 / 897
(101 la1 Pranekc, W.,Heeman.Y., O o r k k k , B . , R e n w i ~ aenachoflen. 6C 590 11977h ibl Smith. L. R.. Willisma. H. J..and Silvemtoin. R. M..
4,217 (1978). (I21 Mori,K.. Trfrohedron. 31.3011 (1975). (131 Willisma.H.J..Siluemtein.R. M.,Burkholder, W. E.,sndKhnmamshahi,A..orrscntaiim at the 8th N. E.Regional Meeting of the Ameri-chemicai Saiety, kmfon. June 1978;to hesuhrnittod, J. Cham E d
698 / Journal of Chemical Education
(141 k a k i , S., Marumo, S.,Saifo,T.,Yamada, M., and Ketapiri, K.. J. A m r . Chem. Soc,
P.A. D,S., Nature, 166, 179 (19501. (el Capon, 8.. Quart. Reu. (Londonl, 18.45 ,19641 , ~
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their Control"pubiished in Iran in 1966. 116) Sepangouuian.H.,'~Sfotoag~Ppj~soflranand Exscl details of this reforone unfortunately elude ua under present circumstances.
