Tctmbdon.

1965, Vol. 21, pp. IS01

, to 1507. Pa-gatlml Pm6 Ltd. PrInted In Northern h-eland

THE ABSOLUTE CONFIGURAT1ON JASMONATE

OF METHYL

R. K. HILLY and A. G. EDWARDS Frick Chemical Laboratory, Princeton University, Princeton, NJ.
(RecefWj 15 &Xambt?r 1964) Abstract-The absolute configuration of the jasmine oil constituent methyl jasmonate has determined. Methyl dihydrojasmonate was synthesized from (-) 3-oxocyclopentaneacetic whose configuration was established by three independent methods: (a) ORD comparison 3-methylcyclopentanone, (b) synthesis from optically active norcamphor, and (c) synthesis (-) cyclopent-2-eneacetic acid. been acid, with from

THE essential oil of the jasmine (Jasminium gmnd~orum L.) has been the object of

numerous investigations, and from it nearly thirty distinct components have been isolated and characterized. Among the most striking of these are the three cyclopentanones, jasmone (I), methyl jasmonate (II), and the ketolactone (III), substances closely allied in structure to the pyrethrolone portion (IV) of the natural pyrethrins.

"0.. I

,W \

% 0 lx

Methyl jasmonate (II), one of the last constituents to be isolated, was reported in 1962 to be essential for the characteristic odour of jasmine? Its structure, assigned from degradative and spectroscopic evidence, was contied by synthesis of the dihydro derivative4 (V) and subsequently of D&-methyl jasmonate itselK The synthetic methods employed established the relative stereochemistry of the molecule :
l Presented at the 147th Meeting of the Am&cm Chemicai Society. Philadelphia, Pa., April 7 (1964).
This work was generously supported by a resear& grant (GM-568) from the Public Health Service, to whom the authon express their appreciation. g Alfred P. Sloan Research Fellow, 1%3-1965. a E. Demole, E. Lederer and D. Mercier, Ileltl. Clccm. Actu #, 675 (1962). E. Demole, E. Lederer and D. Mercier, Heb. Ckm. Rcta 4S, 685 (1962). 6 E. Demole and M. Stall, He/u. Chem. Actu 45, 692 (1962). IS01

1502

R. K. HILL and A. G. EDWARDS

the olefinic bond, created by partial hydrogenation of an acetylenic link, is c~s,~while the two ring substituents have the thermodynamically more stable tram orientation4 These assignments leave only the absolute configuration to be established, and it is that subject to which this paper is addressed. Determination of the absolute configuration at either asymmetric centre would suffice to establish the molecular stereochemistry. The approach chosen was to synthesize methyl dihydrojasmonate (V)from the keto acid (VI), which could then be related to substances of known configuration.
CH,CO&H,

CHaCOzR /

VI

VII
VIII

R=H R= CH,
R = n-CIH1,

Optically active 3-oxocyclopentaneSynthesis of (-) methyl dihydrojasmonate. acetic acid (VI), [a]: -246, was obtained by resolution of the racemic acid6 with brucine. The levorotatory methyl ester (VII), [a]: -27, was then alkylated by the enamine procedure of Stork ef al. 6 Treatment of the pyrrolidine enamine of (-) VII with n-amyl bromide and sodium iodide in refluxing toluene gave a mixture of two products, carefully separated by fractional distillation and chromatography. The highest-boiling fraction was identified as{ -) methyldihydrojasmonate (V), [a]n, -6.8, shown to be identical with the hydrogenation product of the natural material by comparison of IR and NMR spectra and of v.p.c. retention times,7 and by hydrolysis to dihydrojasmonic acid, identified as its crystalline dinitrophenylhydrazone. No attempt was made to isolate the keto-ester isomeric with methyl dihydrojasmonate, resulting from alkylation at the other alpha carbon. An unexpected product of the alkylation, however, was the n-amyI ester (VIII) of the starting acid, identified by hydrolysis to VI and n-amyl alcohol, and by synthesis from its components. Its origin is obscure; although it might conceivably result from dispIacement by the ester carbonyl on a quaternary ammonium salt (IX), evidence is available on this point. no

I G. Stork, A. Brizzolara, H. Landesman, J. Szmuszkovicz and R. Terrell, J. Amer. Chem.Sot. 85, (1963). 207 7 We are indebted to Dr. E. Demole, of Firmenich and Cie, for kindly furnishing us with a sample of I%-methyl dihydrojasmonate for comparison.

The absolute configurationof methyl jasmonate

1503

The synthesis of (-) methyl dihydrojasmonate from the levorotatory acid (VI) reduces the stereochemical problem to the determination of absolute configuration at the single asymmetric eentre of VI. This was accomplished by three independent methods. A. ~~t~ca~~utat~~y dj~~r~~~~~t~i~~. The ORD curves of the (-) methyl ester (VII) and of R-(+) 3-methylcyclopentanone8 are enantiomorphic, as shown in Fig. I. The close similarity in structure suggests that on the basis of this comparison, (-) VI may be assigned the S-configuration.

-200

- 400 I

FIG. ORD qwztra of R-(+)-3-methykyclopentanone(upper curve) 1. and S-(- ))-methyl-3-oxocyclopentaneacetate (VII).

B. ~y~~~e~~~ (+) VI bud t-C_)~u$ca~~~~~. Baeyer-Villiger oxida~~u of noruf camphor has been reportede to yield the single lactone (X). It appeared that this reaction could be used to provide a chemical correlation of the configuration of VI. Accordingly, (+) norcamphor, obtained by asymmetric hydroborationlo of norbornene followed by chromic acid Oberon, was oxidized with ~r~~uoroa~~~ acid to the (+) lactone (X). Hydrolysis of the l&one with dilute alkali gave the corresponding hydroxyacid, which was immediately oxidized by the chromic acid-pyridine reagent to (-+-) VI. Since (+) norcamphor is known to have the (1s; 4R) configuration shown,ll f+) VI must have the R #nfi~~tion.
* C. Djerassi, L. M&her and B. J. Mitscher,J. Amer. C&m. Sot. 81,947 (1959); E. J. Eisenbraun and S. M. McElvain, Ibid. 77, 3383 (1955). @ G. Ourisson and A. Rassat, &II. Sm. Chim. Fr. o 1133 (1959); b J. Meinwald and E. Frauenglass, .I. Amer. Ckm. Sue. 82,5235 (1960). lo H. C. Brown, N. R. Awns, and G. Zweifel, J. Amer. Calm. Sm. Ss, 397 (1964). l1 J. A. Bcrson, J. S. Walia, A. Remanick, S. Suzuki, P. Reynolds-War&off and D. Willner, J. Amer. Chern.Sot. 83,3986 (1961).
18

1504

R. K.

HILL and A. G. EDWARDS

H - b. - &:2c027
(+I (+I x

C. Synthesis of (-) VI from (-) cyclopenf-2-eneacetic acid. The absolute configuration of R-(-) cyclopent-2-eneacetic acid (XI) was established by Mislow and Steinbe@ during their work on the stereochemistry of chaulmoogric acid. Consequently, this acid was another standard with which the configuration of VI could be compared. Selective attack on the 3-position of the double bond was possible by taking advantage of participation of the carboxyl in electrophilic additions. Thus, when (-) XI was oxidized with perbenzoic acid or with iodine and bicarbonate, the lactones XII and XIII were formed. Both XII and XIII showed IR absorption at 574 p characteristic of y-lactones. Hydrolysis of XIII with concentrated alkali, followed by acidification, gave XII. Oxidation of XII with a variety of reagents proceeded with unexpected difficulty, but aqueous chromic acid in 7 N H,SOI led to a low yield of the crystalline ketolacetone (XIV). Reduction of XIV with zinc in acetic acid led smoothly to (-) VI. The absolute configuration assigned to VI by this route is in agreement with the other methods.

xu
XIII

RaOH
R=I

(+I

xm

In passing, it may be noted that the NMR spectra of the rigid lactones XII, XIII and XIV allow an unambiguous assignment of stereochemistry. Proton Ha in XIV is easily discernible as a doublet centred at 545 tau; the coupling constant J of 7 c/s is consistent with a cis relationship of Ha and Hb, with a dihedral angle of about 20. The coupling constants measured from the spectra of XII and XIII are Jab = 7 c/s and Jex = 2 c/s, from which it may be concluded that H, and Hb are again cis, while H, is tram to H=. The same relative configuration has been assigned to iodolactones from related unsaturated acids of the cyclohexene series? l8 K. MisIow and I. V. Steinberg, J. Amer. C&I. Sot. 77.3807 (1955).
fi Q Y. A. Arbuzov, M. N. Kolosov, Y. A. Ovchinnulcov and M. M. Shemyakin, kvest. &ad. Mwk S.S.S.R., Otuid. K/&I. Nuuk 377 (1961); b H. 0. House, R. G. Carlson, and H. &bad, J. Org. Chew. 28, 3359 (1963); c H. 0. House, R. G. Carlson, H. Miiller, A. W. Noltes, and C. D. Slater, J. Amer. Chtm. Sot. 84,2614 (1962).

The absolute con6guration of methyl jasmonate CONCLUSIONS

1505

The straightforward correlation of (-) VI with three different standards of known configuration, and the synthesis of (-) methyl dihydrojasmonate from (-) VI without affecting the asymmetric carbon of VI, provide unambiguous evidence for the absolute configuration of methyl jasmonate shown below. Since the ketolactone III has been directly converted to methyl jasmonate by the elegant work of Demole ef aI.J4 its configuration also follows from these results.

Ii

EXPERIMENTAL Resolution of3-0xocyclopentaneacet ucti (VI). A mixture of 3dxocyclopentaneacetic acid (5.68 g) and brucine (20 g) was dissolved in 100 ml aoetone heated under reflux. The solution deposited crystals of the salt, m.p. f 2%136, on cooling and standing forseveral Two crystallizations hr. from acetone yielded colourless crystals (68 g), m.p. 169-170, [ag -57-6 (c = 5 in CHClJ. A totalof 217-8 g of the recrystallized brucine salt was dissolved in 1200 ml hot water and made alkaline to litmus with 1: 1 NH,OH. The brucine was filtered off and the filtrate acidilkd with 1: 1 HClaq, then extracted exhaustively with ether. The ether solution was washed with brine, dried over MgSO, and concentrated, leaving 31-5 g of acid VI, [a%* -x6 (c = 5 in CHCl& (-) Methyl 3-oxocyclopen~~uce~~k (VII). A mixture of 31.5 g of (-) VI, 300 ml MeOH, and 16 ml cont. H,SO, was refluxed 3-5 hr, diluted with ice water, saturated with NaCl and extracted with ether. The ether solution was washed with NaHCQaq, dried, and distilled, affording 23-4 g of ester VII, b.p. 85-95 (0.1 mm), [a]: -27-O (c = 397in CHCla. The ORD curve was measured in CHClt on a Rudolph photoelectric polarimeter. The IR spectrum was identical with that of authentic racemic ester. Syntkssis of rtzcemic met@1 diQ&c+~rrate (V). A mixture of 23.7 g of DL-methyl-3-oxocyclopentaneacetate, 17.6 g dry pyrrolidine, 20 mg p-toluenesulphonic acid, and 400 ml dry benzene was heated under reflux for about 8 hr with a Dean-Stark trap; 2.4 ml water was collected (theor. 2-74 ml). The solvent was removed and the residue (30 g) heated under reflux for 20 hr with 45 g n-amyl bromide, 1 g NaX, and 200 ml toluene. Heating under reflux was continued for another 30 min following the addition of 30 ml water. After 30 ml of 10% H&J, was added, the layers were sepa rated and the aqueous layer extracted 7 times with ether. The combined organic layers were washed with NaHCQaq, Na&O,aq, dried over MgSO,, and concentrated. Distillation through a spinning band column (25 theoretical plates) gave the following fractions: Fraction 1 8.55 g Fraction 2 1.36 g Fraction 3 6-38 g Fraction 4 2.44 g Residue 4027g Fraction 1, asevidenced from the IR spectrum, b.p. 73-88 (1 mm) b.p. 92-127 (2 mm) b.p. 128-134 (2 mm) b.p. 134-137 (2 mm)

consisted largely of recovered ester VII. Fraction 3 was chromatographed on a 2-5 cm diameter column of 130 g alumina, and eluted . wth CC&; 3knl fractions were collected. The first 13 fractions containing ester absorption had similar IR spectra and were combined (total wt l-66 g) and rechromatographed on 75 g of alumina.

Elution with CCl, gave O-71g of colourkss oil, 92 1*4582(reported* l-4572), identitled as DbmChyl &ydiu$wmute. The IR spectrum, both in CC& and Cs, solution, was identical with that of an
authentic sample,T as was the NMR spectrum in Ccl. Identity was confkned by preparation of l E. Demole, B. Willhalm and M. Stoll, Helu. Cclim. Acta 47, 1152 (1964).

1506

R. IL I&u and A. G. EDwm

the Z&DNPH of the #~pon~ng acid: 0.43 g of the pure ester was hy~ol~ in a mixture of 8 ml A&H and 5 ml cow HCI at 60 for 6 hr, the acid isolated by extraction with ether, and converted to the 2,4-DNPH in AcOHaq. The precipitate was collected after 3 days and recrystallized 3 times from benzene-pet, ether, giving yellow crystals, m.p. 173-177 (reported 17~177~). The IR spectrum was identical with that of authentic material. n-Arnyl3~~~~c~~~~~~~~~~~ (WI), Fractions 14-22 from the above c~~to~phy had similar IR spectra and were #rnbin~ (3.06 g). The material was heated at 60 with 35 ml A&H and 17 ml cone WCl for 5 hr and the product separated into neutral and acidic fractions. The neutral fraction distilled at 12%MO, and had an IR spectrum identical with that of n-amyl acetate. The acidic fraction was converted to the semicarbne, m-p. 203~204, identical with the scmicarbazone of VI. Es~ifi~tion of VI with nbmyl alcohol gave ester VIII with an IR scorn identical with that of the material isolated from the c~omato~aph, ( -) Merhyl dfi~&~j~m~~& (V). Repetition of the enamine alkyiation with 11.85 g of (-) VI gave 10.17 g of crude product, which was separated on a spinning-band column into 4.42 g of recovered starting material and 2-72 g of impure V, b.p. 110-l 15 (O-6mm). Three successive chromatographic purifications, eluting with CC& on alumina columns, gave pure methyl dihydrojasmonate @34g, [Q61 -6.8 (c = 5 in CC&). Its IR and NMR spectra ore identical with those of racemic material, as was its mention time (40 min) on a VFC column (10% XE-60 on 80-100 Diatoport S, column temp 200). (Found: C, 68*96; H, 9.84. C&I& requires C, 69.03; H, 9.73x.) (+) ~~reu~~~. To 282 ml of a l-40 N solution of NaBH, in diglyme was added 143*1g of ac-pinenc, [c& 2+37. The solution was cooled to 0 while 74.7 g of mistier BF,- ether&e was added, followed by 494 g of norbomene. The mixture was kept at 0 for 4 hr, then o~i~t at room temp. While the solution was stirred and maintained at 25-303 1300 ml of a solution containing 345 g of Na&r&ZH,O and 258 ml of cant. H&0, was added over 1 hr. After stirring for another 2 hr, 400 ml of water was added and the mixture extracted exhausti~ly with ether. The ether extracts (25 1) were washed with NaHCOBaq, water, and brine, dried over MgSO,, and concentrated by careful distillation through a 12 in VigRux column. The residual oil was fmtionated through an 18 in spin~ng-end column. Fractions d~til~ng up to 49 (5 mm) showed a single arbonyl peak at 5.75 p in the IR, and were combined as crude norcamphor; later fractions, b.p. S&6@ (5 mm) showed an additional carbonyl band at 585 $, due to isopinocampbone. The crude no~mphor fractions were converted to the semicarbazone by heating with an aqueous solution of 60 g of ~~~~de hy~~~o~de and 105 g of NaOAc at 100 for 30 min. After seeding, 3&l g of semicarbazone, m.p. 183-186, was obtained. A mixture of the semicarbazone and an squal weight of oxalic acid dihydrate was steam-distilled. The distillate was saturated with salt and extracted with ether. After drying and careful distillation of the ether, the sticky residue was further dried by distilling CH&lL from it. The crystalline norcamphor thus obtained (15-S g, 26.8%) melted at g&92 and had [cx]~ +4*6 (c = 5 in Et0H). The IR spectrum was idcnti~l with that of authentic racemic no~~hor. (+) 2-Oxabi;cyc~[3,2,1]-ocr~-3-one (X). To a solution of 2S*4ml (0*18mol) of trifluoroacetic anhydride in 200 ml of CHoClo, cooled to O, was added 4.3 ml @*lSmol) of 90 % H& After stirring for an additional 10 min, a so&ion of 11.0 g of (+) norcamphor (O*lO mol) in 200 mI of was kept for 21 hr and ~~ with CH,C& was added dropwise over 45 min. The ~ture ~tum~d NaHCO,. The layers were separated and the aqueous layer extracted with CH&l*. IBe combined organic solutions were washed with brine, dried over MgSQ, and the solvent removed through a 6 in Vigrwx column. The residual oil (11.87 g, 94*4x), m.p. about 0, [I]~ +2*7 (c = 13.3 in CH&&) showed the characteristicMactone peak in the IR at 5.78 p. A portion of the lactone was puriGedby chromatography on a silicic acid column, eluting with 2: 1 60-70 pet. et&-acetone. C~stalline material was obtained from centre fractions, which was dried over paraffin wax in a vacuum desiccator and then subli~d at red. pms. Lactone p&led in this manner melted at M-56; the race& lactone is reported* to melt at 64. (Found: C, 66.0; H, 8*0f. C,H& re+ires C, 66=6; H, 7*97x.1 C~~~r~~~~ of (+) X tt, (+~3-0x~cy(ckrpen~~e~c~rjc acid fvr). Lactone X (650 mg1 was hydrc+ lyzed by heating with 4-Oml of 212 N NaOH in a ~i~ng watwbath for 15 min. The solution was cooled in ice, exactly neutralized with 17-Oml of i-old 0.5 N HCI, and quickly extracted with twelve 29ml portions of cold ether. The extracts were washed with brine, dried over N@Q, concentrated at red. press., and the residual hydroxy-acid taken up at once in 10 ml of pyridine.