Synthesis of Frontalin, the Aggregati~nPheromone of the Southern Pine Beetle A Multistep Organic Synthesis for Undergraduate Students Paul A. Bartlett, Charles K. Marlowe, Peter J. Connolly, Kevin M. Banks, David W.-H. Chui, Peter S. Dahlberg, Ann M. Haberman, John S. Kim, Kevin J. Klassen, Raymond W. Lee, Robert T. Lum, Eric W. Mebane, James A. Ng, Juei-Chang Ong, Nasser Sagheb, Brian Smith, and Pauline Yu University of California, Berkeley, CA 94720 As a group, the insect pheromones are ideal targets for multistep organic synthesis experiments for the undergraduate lahoratory: in most cases they are low-molecular-weight compounds of interesting structure hut modest complexity, and they are of current scientific and economic importance outside organic chemistry ( I ) . Indeed, a number of recent experiments focus on this topic (2-4).
There are a numher of pheromones with the 6,s-dioxahicyclo[3.2.l]octane skeleton, among them frontalin (I), the aggregation pheromone of the southern pine beetle, Dendroctonus frontalis, (V); hrevicomin (II), the sex attractant of the western pine beetle, Dendroctonus breuicomis, (6); and multistriatin (1111, the sex attractmt of the European elm bark beetle, Scolytus multistriatus (7). These all can he synthesized by isomerization of the appropriate 6,~-epoxyketones, either with Lewis acid or via the ketodiol(8). Frontalin and hrevicomin are attractive targets for an undergraduate experiment since the desired epoxy ketones can he obtained by a straightforward sequence involving an acetoacetic ester synthesis and epoxidation, as illustrated for frontalin in the reaction scheme given below.
are told that modifications may well he necessary. Far from discouraging the students, this approach provides a challenge, removes the fixation on "yield" that often occurs in synthesis experiments, and gives some flavor of research to their experience. Coping with reactions that "should" work but do not is in many ways more instructive than simply trying to reproduce a well-worn sequence that is known to afford a certain amount of the vroduct. It is certainly more realistic in portraying chemistry as it is actually pr&tired and morr rffrcri\,ein instilling an inquisitive, analytical apuroach to the .. experiments. Initially, the procedure given to the students for converting 3-methyl-3-buten-1-01 (IV) into an alkylating agent is a standard method using PBr3 and pyridine in ether a t O°C, followed by distillation of the product. They soon discover that this sequence, which is so effective for other primary alcohols, is thwarted in the homoallylic system by ready elimination t o give isoprene as the major product. At this point an alternative method of activating the alcohol is suggested, namely by formation of the tosylate, V.' This reaction proceeds in high yield, and since the product does not have to he distilled, avoids the problem of elimination. The next pitfall encountered is the sluggishness with which tosylate V is alkylated by the acetoacetate anion in ethanol. This problem is remedied easily by inclusion of a catalytic amount of potassium iodide in the reaction mixture and affords an opportunity to discuss the mechanism by which this general method accelerates displacement reactions. The crude alkylation product VI is not purified hut is carried on directly through the hydrolysisldecarboxylationsequence to give the unsaturated ketone VII. At this stage, care must he taken to isolate the product since it is quite volatile and can be lost easily if the student becomes overly zealous when removing the solvent on the rotary evaporator (with a hot water bath instead of one a t room temnerature.~,for example). Even the best stud~mtsobtaina rehtivclg poor yield for the rhrer stevs leading" to rhr ketone (alkvlution.. hvdrolysis, and decarboxylation). However, barring the inevitable accidents, ample material is isolated for completion of the sequence. The modest yield on a classic reaction such as the acetoacetate ester svnthesis allows one to sveculate concernine the reasons ( t ~ i m i ~ a t i of o nthe humoallyiic dkglating ayen;; loas oi thr vro(1uct during thc ~soiatimdue to its \,ulatilitv. ., etc.) and t o propose alternatives. Formation of the epoxy ketone VIII can potentially be complicated or thwarted by Baeyer-Villiger oxidation of the ketone during the epoxidation reaction. Indeed, the model
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The sequence of reactions depicted in this scheme has been carried out as a laboratory experiment by honors students at the end of the first-year organic chemistry sequence a t Berkeley. In contrast to the usual format for undergraduate laboratory experiments, i t is not presented to the students as an optimized procedure. Instead, they are provided with a model experimental procedure for each of the steps, and they 816
Journal of Chemical Education
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Although the students have to start over at this point, the starting material is relatively inexpensive. The cost can be further minimized by performingthe unsuccessful bromination experiment on a relatively small scale. Of course, if time is a limitation, the unsuccessful bromination can be avoided altogether hy starting with the tosylation.
~ r o c e d u r egiven t o t h e students a t the outset includes protection of t h e ketone moiety a s t h e ethylene ketal duringthe epoxidation. However, they are also urged first t o attempt to epoxidize a small amount of t h e enone itself, to find o u t whether t h e Baeyer-Villiger reaction will, in fact, interfere. T h e first few students soon discover t h a t this side reaction is not a problem, and everyone can then proceed with the epoxidation directly. T h e final step of t h e synthesis is a straichtforward one which proceedsin high yield. I n fact, epoxy ketone VIII has already undergone partial isomerization to frontalin under t h e mildly acidic conditions of the preceding epoxidation reaction, a s can he ascertained readily by 'H-NMR analysis of t h e crude ~ r o d u c t .T h e formation of the ketal moietv of frontalin in aqueous acid provides a n opportunity to discuss t h e influence on eauilibrium and rate t h a t the intramolecular nature of a reaction can exert. I n summary, t h e multistep synthesis of frontalin outlined here exposes the students t o a range of practical laboratory problems a s well a s important synthetic reactions, and it requires them t o work on a medium-size, a s well a s a relatively small, scale. Perhaps most importantly, i t generates a n atmosphere of "experimentation" in t h e literal sense of t h e word, and a real sense of accomplishment when t h e sample of frontalin is placed in the vial.
Experimental Sectlon
mixture is filtered, the salts are washed with ether, and the combined organic layers are concentrated on the rotary evaporator to give the crude ketoester VI. To this crude ketoester VI is added 140mL of 10%NaOH and the mixture is stirred for 20 h. The resulting aqueous solution is washed with two 50-mL portions of CHzC12 and carefully acidified with 60 mL of 6N HzS04. After evolution of COzsubsides,the reaction mixture is heated on the steam bath for 30 min. After cooling,the reaction mixture is extracted with two 50-mL portions of CH2C12,and the combined oraanic phase is washed twice with saturated NaHCO-. ". dried (M~so;), andconcentrated on the rotary evaporator to give the crude ketone VII. During this concentration, it is important to keep the bath at rwm temperature or below, since the ketone is quite volatile and can he lost. The ketone VII is purified by distillation under aspirator vacuum, to give 7.9 g (23%yield; range of yields obtained by students: 15-3090) of material; bp 69-72"C/20 torr. 67-Epoxy-6-methyl-2-heptanone( VIII)
To a solution of 7.7 g (61 mmol) of ketone VII in 100mL of CHzC12 stirred at O°C is added 13.3 g (67 mmol) of 85%m-chloroperoxybenzoic acid over a 30-min period. The mixture is stirred at room temperature for 2 h, washed once with 40 mL of saturated aqueous Na2S03 and twice with 75 mL of I N NaOH. After drying (MgSO4) and concentrating on the rotary evaporator (keep bath cool!), 6.1 g (64%crude yield; range obtained by students: 50-7570) of a mixture consistingof epoxy ketone VIII and frontalin 1ina ratioof approximately 3:l (ratio varies, readily determined by NMR) is obtained.
Frontalin ( I ) A 5.9-e s u n d e (41 mmol) of this enoaide-frontalin mixture and 43 . ~ mL of 01: N ~ ~ 1 is0stirred 4 at room temperature for 2.5 h. The product is extracted with two 90-mL portions of ether, the organic layer is dried (MgSOa) and concentrated on a rotary evaporator at room temperature, and the crude product is purified by distillation to give 4.1 g (70%yield) of frontalin; bp 58-60°C/23 torr. ~
3-Methyl-%butenyl Tosylate ( V) A solution of 68.4 g (0.36 moll ofp-toluenesulfonyl chloride in 29 mL (0.36mol) of pyridine and 100mL of CHzCb is stirred at 0°C while 26.0 g (0.31 moll of 3-methyl-3-huten-1-01is added dropwise. After stirring for an additional 20 h a t room temperature, 100mL of water is added and the mixture is stirred vigorously for 30 min to hydrolyze the excess acid chloride. After separating the layers, the organic phase is washed with two 50-mL portions of 2N H2S01 and dried (MgS03, and the CHzClz is removed on the rotary evaporatorto give 66.8 g (90% yield; range of yields obtained by students: 75-9390) of the tosylate I1 as an oil. This material should not be distilled, to avoid elimination, but it can be characterized adequately by NMR. 6-Methyl-6-heptenone ( VII) ~
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Literature Cited ~
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(11 ~eonhardt.~.~..and~arms,~.."~nsect~h~,omoae~eehno~ogy:~hemis~y~d~p. pliestions." ACS Symposium Seriea No. 190,Washington, DC. 1982; Birch, M. C. (Editor). "Pheromonaa,"American Elsevier, New York, 1974, (2) silver stein,^. M..J. C~~~.E~~~..45,794(1966). (3) cormier. R. A,, ~ h a nM. , D.. ~raddis, T.. and singer, R.. J. C-. EDUC.. 56, 345
(19791.
Einterz, R.M.,Ponder, J. W., and Lenm, R. S.,J. CHEM. Eouc.,54,382 (19771. (51 Kinzer, G. W..Fentiman,A.F.,Jr.,Psge.T. F., Jr.,Folte,R.L.,Vit(.J.P.,andPitman, (4)
G. B..Noture.221.477 11969).
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dissolving 6.3 g (0.27 mol) of sodium spheres in 190 mL of ahsolu& ethanol (alternatively, commercial sodium ethoxide can he used to avoid the hazard of sodium After all of the sodium has dissolved, 37.2 g (0.28 mol) of ethyl acetoacetate and 4.6 g (28 mmol) of potassiumicdide are added. The mixture is heated to reflux, and 66.4 g (0.27 mol) of the tosylate V is added dropwise. The mixture is stirred and heated at reflux for another 7-10 h, during which time a thick precipitate of sodium tosylate appears. After cooling, the
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(71 Peare. G. T.. Gore. W.E.,Shratein, R. M.,~eacoek, J. w.. cuthbert,R.A,. ~ ~ G. N.,and Simeone,J.B.,J Chem. E d . I, 115 (1975): Gore, W. E.,Pearee,G.T., and Si1vcrstein.R. M., J Ow. Chem., 40,1705 (19751. (8) Frontalin: Man, K.. Kobayashi,S..ahd Msteui, M., Bid Chem., 39,1889 (1975): ~mvicomin:B ~ I ,IT~ E.. . ~ro-iee .R.G.. and si~vrrstcin. R.M.. ~ h~d r o n ZL . ~~~~~.~~ ~~~~~~~~,~~ ~ -p,.t m . ~ 5149 (1969); Wassennan, H. H., and Barber, E. H., J. ~ m e r Chem. . Soe.. 91,3674 (1969): ~oeienski,P. J., and Ostrow, R. w.,J. erg. chem.. 41,398 (1976); ~ u l t i atriatian: Pemce, G. T.,Gore, W. E., and Silverstein. R.M., J Org. Chem, dl. 2797 ~
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(1976);Cemigliaro,G. Land Koeienaki, P. J.,J Org. Chem.,42,3622 (1977); Bartiott, P. A., and Myeman, J.. J Org. Chem., 44.1625 (1979).
Volume 61
Number 9
Se~tember1984
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