1978 1267 Absolute Configuration of the (+)-Calamenenes : t Crystal Structure of 7-Hydroxycalamenene * By Kevin D. Croft, Emilio L. Ghisalberti, Charles H. Hocart, Phillip R. Jefferies,' Colin L. Raston, and Allan H. White, School of Chemistry, University of Western Australia, Nedlands 6009, Western Australia The sesquiterpenes 7-hydroxycalamenene and (+) -calamenene isolated from Eremophila drummondii have been interrelated. The crystal structure and absolute configuration of the p-bromobenzoate of 7-hydroxycalamenene, C,,H,5Br0,, has been determined ; crystals are orthorhombic, space group P2,2,2,. unit cell dimensions a = 9.471 (5). b = 11.469(5), c = 18.253(7) A, for Z = 4. These results show that both sesquiterpenes have the (1R.4R) -configurations and resolve the present confusion on this point.INan investigation of the sesquiterpenes of Eremophila drummondii we isolated calamenene and 7-hydroxy- calamenene. The structure of these sesquiterpenes was identified by spectroscopic methods and by comparison of their physical properties with those reported in the literature (see later). In attempting to define the relative and absolute stereochemistry of these sesquiter- penes it became evident that contradictory claims had been made regarding the configuration of the common naturally occurring (-)-calamenene. Rowe and Toda established the absolute configuration at C-4 of (-)-calamenene ( a= -47") and 7-hydroxycalamenene as (4s)- by interrelation of the latter with the compound derived from (-)-copaene and tentatively suggested that the C-1 methyl was cis (1s)to the isopropyl group.Andersen et aL2 assigned the trans-configuration to the common naturally occurring calamenene and reported the identification of the 1RJ4R-isomer in Alaska cedar oil. These authors also calculated values for the optical rotation of (1RJ4R)-calamenene( aID-22") and (1R,4S)- calamenene (a, -96"). However these results were based on studies with inseparable mixtures of cis-and trans-calamenenes. In view of these contradictory t Also known as cadina-1,3,5-trienes (see Chemical Abstracts Index Guide) ; the cadinane numbering system is different from that used here. # The Chemistry of Eremophila spp. Part IX. For Part VIII see P. Coates, E.L. Ghisalberti, and P. R. Jefferies, Austral. J. Chem., 1977, 30, 2717. results we decided to obtain unequivocal evidence for the absolute stereochemistry of the calamenenes from E. drummondii. This was achieved by carrying out an X-ray diffraction study of the p-bromobenzoate deriv- ative of 7-hydroxycalamenene which showed it to have 0 20 19 Br 16 17 (2) R=OH (3) R =OCOC,H,(N02),-3,5 (4) R=H the absolute configuration depicted in (1). 7-Hydroxy-calamenene (2) was then converted into calamenene which was identical with a sample of calamenene isolated from E. drummondii. In this report we present evidence which shows that the calamenenes isolated from this plant are enantiomeric with the common naturally 1 J.W. Rowe and J. K. Toda, Chem. and Ind., 1969, 922; and references therein. N. H. Andersen, D. D. Syrdal, and C. Graham, Tetrahedron Letters, 1972, 905. 1268 occurring (-)-calamenene which must now be considered to have the (lS,4S)-configuration. Alumina chromatography of the defatted neutral fraction from E. drummondii afforded 7-hydroxycalame- nene (2) as the major component. The mass spectrum showed a molecular ion peak at m/e 218 and a base peak at m/e 175. The n.m.r. and U.V. spectra were essentially similar to those reported1s3 for this compound. The identity of the compound was supported by preparation of the 3,lj-dinitrobenzoate derivative (3)which had m.p. 133-135 "C (uncorr.) (1it.l 136-137 "C, corr.).A comparison of the optical rotation values of (2) and of its benzoate derivative (3) (27 and 12" respectively) with those reported for 7-hydroxycalamenene isolated from Ulmus thomasii and its benzoate derivative (-30" and -10" respectively) indicated an enantiomeric relationship. Careful inspection of the 90 MHz n.m.r. spectra of (2) and (3)showed that these compounds were essentially homogeneous with respect to the stereo-J.C.S. Perkin I chemical outcome of two syntheses of calamenenes. The first involves a sequence starting from dihydro- khusinol, in which the stereochemistry of the l-methyl substituent does not appear to have been unambiguously assigned. The (+)-calamenene thus obtained showed a, +37.5" and must have the (lfi,4R)-configuration.The second,7 starting from (-)-menthone, leads to calamenene with a,+43.7" which was later claimed (see ref. 5) to be an 80 :20 mixture of diastereoisomers. It appears that in fact this synthesis involves equilibration of the isopropyl group largely favouring the (4R)-configuration. EXPERIMENTAL General experimental details have been described .@ Analytical g.1.c. was carried out with a Perkin-Elmer 880 gas chromatograph equipped with a copper column (10 ft,6 in 0.d.) packed with 5 Carbowax 20M on Chromosorb W (85/ 100 mesh). Temperature was programmed between 100-210chemistry of the 1-methyl and 4-isopropyl gro~p.~~~?~ For the X-ray crystallographic analysis the p-bromo- benzoate derivative (1) provided suitable crystals.As described later the absolute stereochemistry of 7-hydroxycalamenene was found to be that shown in (l), (1R,4R), enantiomeric to that of the compound isolated from U. thomasii.l The 7-hydroxycalamenene from E. drummondii was converted into the phenyltetrazoyl ether 396 which on hydrogenation at 2 000 p.s.i. was converted to calamenene (4) (a,+43.0"). Separation of the less-polar neutral components of the essential oil from E. drummondii by column chromatography afforded a sample of calamenene (a, +41.3"). The similarity in the optical rotation values indicates little or no epimerisation of the labile benzylic centres during hydrogenation. Samples of calamenene isolated follow- ing steam distillation of the neutral extract or preparative g.1.c.showed similar rotations (43.7" and 41.9" respect- ively) to those of the samples already described, again indicating that under these conditions no detectable epimerization had taken place. In general, calamenene occurs in nature as a mixture of diastereoisomers which can however be distinguished by n.m.r.2,4*5 In all the samples of (lR,4R)-calamenene (cis) obtained by us there was no indication from their high-resolution n.m.r. for the presence of the trans-diastereoisomer. Allowing that the limit of detection for the n.m.r. method is ca. lo, then using the known rotation of 82" or 80" re-ported for the (+)-(lS,4R)-calamenene (trans) 798 (assum-ing that this is the likely diastereomeric contaminant) one can calculate the likely range for the rotation values of the (lR,4R)-isomers as 37-41.3".These results also allow us to clarify the stereo-M. Fracheboud, J. W. Rowe, R. W. Scott, S. M. Fanega, A. J. Buhl, and J. K. Toda, Forest Product J., 1968, 18, 37. N. H. Andersen and D. D. Syrdal, Phytochemistry, 1970, 9, 1325. 6 S. V. Bhatwadekar, K. G. Gore, K. K. Chakravarti, andS. K. Paknikar, Indian J. Chem., 1972, 10,1111. W. J. Musliner and J. W. Gates, J. Amer. Chem. Soc., 1966,88, 4271. "C at 8" min-l. Preparative g.1.c. was carried out with a Varian Aerograph Series 1800 gas chromatograph using an aluminium column (10 ft, Q in 0.d.) packed with 10 Carbowax 20M on Chromosorb W (60-80 mesh). Temperature was programmed between 135-200" at 4" min-l.Optical rotations were determined with a Perkin-Elmer 141 polarimeter operating at 589 nm for CHC1, solutions. All identities were confirmed by a com- parison of t.l.c., g.l.c., behaviour, n.m.r., and mass spectra. Isolation of (lR,4R)-7-Hydroxycalamenene(2).-Fresh leaves and twigs of E. drummondii (1.8 kg) collected near Pithara in Western Australia were washed with ether and the ethereal solution was extracted sequentially with aqueous NaHCO, (8) and Na,CO, (5) solutions. The remaining neutral material (ca. 20 g) was recovered by evaporation of the solvent. Part of the neutral extract (10 g)was partitioned between methanol-water (95 : 5) and light petroleum. The material recovered (5 g) from the methanol-water fraction was chromatographed on neutral alumina (Act.11) and elution with light petroleum and light petroleum-5yo chloroform gave factions containing inter alia (+)-( lR,4R) -calamenene (see later). Further elution with light petroleum-lOyo chloroform gave fractions con- taining (lR,4R)-7-hydroxycalamenene(2; 2.8 g) as an oil a, 27" (c 9.0) (lit.,I a, -30' for the lS,4S-enantiomer); Lax.(nm) 280 (E 2 500) lit1 280 (c 2 480)l; mass spectro- nietry (m/e) 218 (AT+, lo), 175 (loo), 160 (8), and 145 (8); 6 (90 MHz, CDCl,) 0.75, 1.00 (d, J 7 Hz, isopropyl methyls), 1.16 (d, J 7 Hz, C-1 methyl), 1.62 (m, 2-and 3-H,), 2.18 (s, C-6 methyl), 2.56 (m, 1-and 4-H), 6.15 (brs, 0-H),6.53 (s,8-H), and 6.91 (brs, 5-H) (essentially similar to that reported l9,) (Found: C, 82.75; H, 10.05.C,,H,,O requires: C, 82.50; H, 10.16). Derivatives of (lR,4R)-7-HydroxycaZamenene(2).-The phenol in pyridine was treated with 3,5-dinitrobenzoyl chloride to give the 3,5-dinitrobenzoate (3) which was recrystallized from n-hexane as needles, m.p. 133-135 "C, a:.,12" (c, 2.5) (1it.l 136-137" (corr), aID-10" (c, 1)for the enantiomer); 6 (90 HMz, CDCl,), 0.81, 1.06 (d, J 7 Hz, P. H. Ladwa, G. D. Joshi, and S. N. Kulkarni, Chem. and Ind., 1968, 1601 ; and references therein. G. K. Trivedi, A. D. Wagh, S. K. Paknikar, K. K. Chakra-varti, and S. C. Bhattacharyya, Tetrahedron, 1966, 22, 1641. 0 E. L. Ghisalberti, P. R. Jefferies, T. G. Payne, and G. K. Worth, Tetrahedron, 1973, 29, 403. 1978 1269 isopropyl methyls), 1.27 (d, J 7 Hz, C-1 methyl), 2.19 (s, portion was adsorbed on a cQlumn of alumina impregnated C-6 methyl), 2.97, 2.61 (m, 1-and 4-H), 6.94 (s, 8-H), with 10 silver nitrate (60 g).Elution with light petroleum 7.14 (brs, 5-H), and 9.31 (m, 3 aromatic H) (essentially yielded fractions of calamenene which were purified by similar to that reported 15,). filtration through a column of neutral alumina (Act. I) to Thep-bromobenzoate(1) was recrystallized from n-hexane as give (+)-(lR,4R)-calamenene as an oil, a, 41.3" (c, 1.2), prisms, m.p. 140 "C, a, +23.7" (c, 5.2); vmax. (CCl,) 1 740 Rt 10 f 0.5 min; Lax.(nm) 224 (E, 1300), 270 (E, 620), and (GO); mass spectrometry (m/e, ) 402, 400 (M+, 8), 279 (E, 680) (similar to those reported 4, ; mass spectrometry 359, 357 (66), 185, and 183 (100); 6 (60 MHz, CDCl,) 0.78, (m/e, ), 202 (M+,19), 159 (loo), and 145 (19); 6 (90 MHz, 1.02 (d, J 7 Hz, isopropyl methyls), 1.25 (d, J 7 Hz, C-1 CDCl,) 0.76, 1.02 (d, J, 6.5 Hz, isopropyl methyls), 1.23 (d, methyl), 2.14 (s, C-6 methyl), 6.84, 7.02 (s, 5- and 8-H), J 7.1 Hz, C-1 methyl), 2.28 (s, C-6 methyl), 2.53 2.82 (m, 1-7.55, and 8.0 (AA'BB' system, aromatic H) (Found: C, and 4-H), and 6.98 (m, 5- and 8-H) (essentially similar to that reported ,y5) (Found: C, 89 45; H, 11.25.Calc. for TABLE1 C15H22: C, 89.03; H, 10.96). (b) Steam distillation. A portion (4.8 g) of the light Atomic fractional cell co-ordinates (x 103 for hydrogen, petroleum soluble fraction of the neutral extract from E.x lo4for others) drummondii was steam distilled yielding 3.5 ml of oil, which x Y 2 contained 30 calamenene as determined by g.1.c.The oil 2 046(21) 7 997(17) 1977(12) was adsorbed on neutral alumina (Act. I, 80 g) and eluted 268(20) 748 (14) 181(10)0 668(31) 7 942(19) 1506(12) with light petroleum and light petroleum-chloroform 055(25) 722(14) 154(11) (gradient up to 5 chloroform). The fractions enriched in 074(18) 856(13) 012(7) calamenene were adsorbed on a column of alumina im- -0 534(26) 8 307(19) 1972(12) pregnated with 10 silver nitrate (33 g) and eluted with -155(16) 819(14) 162(8) -049( 21) 907( 13) 204 (9) -0 871(20) 7 623(14) 2 682(9) TABLE 2 -124( 14) 665 (1 2) 261(7)0 514(17) 7 170(13) 3 002(8) Molecular geometry (non-hydrogen atoms only) 0 427(16) 6 517(16) 3 631(8) -059(14) 664(13) 392(7)1523(16) 5 981( 12) 3 990(7) 1.56(3) c(s)-c(w 1.41(2) 2 837(16) 6 156(12) 3 673(8) 1.52(3) c(10)-c (11) 1.54( 2) 2 985(17) 6 802(16) 3 030(9) 1.51(3) c(10)-C( 12) 1.52 (3) 398(15) 692(12) 278(7) 1.48(4) 0(7)-C(14) 1.30(2) 1814(17) 7 310(13) 2 676(8) 1.55(3) C(14)-O(14) * 1.21 (2) 2 568(21) 9 215(15) 2 136(10) 1.53( 2) C( 14) (15) 1.52(3) 192(-) 967(-) 247(-) 1.48(3) C(15)-C (16) 1.40(3) 354(-) 920(-) 240(-) 1.32 (2) C(16)-C (17) 1.42 (3) 273(-) 968(-) 168(-) 1.37( 2) C(17)-C(18) 1.37(3) -1745(19) 8 266(18) 3 216(9) 1.37 (2) C(18)-Br 1.87(2) -172(16) 807(13) 376(7) 1.39(2) C( 18)-C( 19) 1.34(4) -3 208(17) 8 610(18) 2 910(10) 1.49(2) C(19)-C (20) 1.37( 3) -305(-) 918(-) 241(-) 1.46( 2) C(15)-C (20) 1.39(3) -377(-) 797(-) 269(-) 1.40( 2) -384(-) 914(-) 320(-) -1 123(21) 9 400( 16) 3 503(9) -024(-) 917(-) 378(-) 109(2) C( 8)-C( 8a)-C( 1) 119(1) -088(-) 994(-) 310(-) 112(2) C(1)-C (8a)-C (4a) 124(1) -172(-) 986(-) 387(-) 115(2) C (4)--C (lo)+ (11) 113(1)116(2) 1449( 17) 5 269(15) 4 670(9) 108(2) c(4)-c (10)-c (12) 179(-) 441(-) 465(-) 120(2) c(1l)-c(1O)-C (12) 105(2) 202(-) 566(-) 506(-) 108(2) C (7)-0 (7)-C (14) 119(1) 043(-) 523(-) 483(-) 114(2) 0(7)-C(14)-0 (14) 124(2) 4 094(12) 5 606(9) 3 976(6) 114(1) O(7)-C( 14)-C (15) 123(2) 4 909(22) 6 218(18) 4 399(11) 117(1) 0(14)-C(14)-C (15) 113(2) 4 867(15) 7 269(12) 4 440(8) 124(1) C( 14)-C(15)-C(16) 121(2) 6 018(21) 5 489(21) 4 786(9) 119(1) C(14)-C(15)-C(20) 116(2) 5 936(24) 4 272(22) 4 796(11) 127(1) C(16)-C ( 15)-C (20) 123(2) 5 12 (16) 387(13) 455(8) 127(1) C( 1Q-C (16)-C( 17) 114(2) 6 985(29) 3 720(17) 5 233(15) 118(1) C( 16)-C( 17)-C( 18) 123(2) 681 (18) 287(12) 518(9) 114(1) C(17)-C (18)-C (19) 119(2) 7 993(21) 4 328(24) 5 617(10) 121(1) C(17)-C(18)-Br 114(2) 9 220(3) 3 392(2) 6 162(1) 121(1) C( 19)-C( 18)-Br 127(2) 7 954(26) 5 495(19) 5 608(13) 118(1) C(18)-C (19)-C (20) 122(2)119(2) 881(16) 594(13) 583(7) 122(1) c(15)-c(20)-c (19) 7 027(27) 6 105(19) 5 179(13) 117(1) 7 19 (18) 707(12) 522(8) * O(l4) has a close contact of 2.3(1) A to H(19) at x-1/2, 3/29. * Methyl hydrogen atoms constrained during refinement (see 1-2.text) light petroleum to give fractions of (+)-( 1R,4R)-calamenene 65.60; H, 6.35. C,,H,,O,Br requires: C, 65.82; H, (4), oilD +43.7" (c, 1.0).The n.m.r. spectrum, and g.1.c. 6.28). and t.1.c. retention time were identical with those of the Isolation of (+)-( lR,4R)-Calamenene (4).-(a) Column sample obtained in (a). chromatography. The fractions obtained before elution (c) Prefiarative g.1.c. A portion of the fractions from the of 7-hydroxycalamenene (see earlier) were combined and a first column chromatography described in (u)was separated by preparative g.1.c. The sample of calamenene thus obtained showed a,41.9" (c, 6.9) and was identical with that obtained in (a). Synthesis of ( + ) -( 1R,4R) -CaZamenene (4) .-7-Hydroxy- calamenene (2) (495 mg) in dimethylformamide (18 ml) and K2C03 (2 g) was treated with l-phenyl-5-chlorotetr- azole (1.0 g).The solution was stirred and heated (80 "C) under nitrogen for 1.5 h. The filtered solution was diluted with H20and extracted with ether. The product recovered contained unchanged l-phenyl-5-chlorotetrazolewhich was found difficult to remove. One quarter of this mixture was taken and the oily tetrazole ether isolated by preparative t.1.c. had the following properties: a, 4.6 (c, 1.3); mass spectrometry (m/e, ) 362 (M+, 29), 319 (loo), 291 (67), 249 (96), 175 (62), 159 (37), and 117 (100); 6 (60 MHz, CC1,) 0.78, 1.01 (d, J 7 Hz, isopropyl methyls), 1.22 (d, J 7 Hz, C-1 methyl), 2.15 (s, C-6 methyl), 2.6 (m, 1-and 4-H), 6.95 (s,5-H), 7.10 (s, 8-H),and 7.6 (brm, phenyl hydrogens).Without further purification the remaining mixture contain- ing the tetrazole ether was dissolved in EtOH and hydrogen- ated over 10 Pd-C at 200 "C and 2 000 p.s.i. for 2 h. The catalyst was removed by filtration and the solvent evapo- rated. The residue was taken up in CHC1, and filtered through neutral alumina (Act. I, 10 g), to give fractions of (f)-(lR,4R)-calamenene (4; 275 mg) a, 43.0 (c, 1.0) identical in all respects with that isolated from E. drum-mondii. CrystaZZogr~phy.-C~~H~~O~Br,M 40 1.4. Orthorhombic, u = 9.471(5), b = 11.469(5),c = 18.253(7)A; U 1983(2) A3, D, = 1.34(1), 2 = 4, D, = 1.34 g ~m-~,F(000) 832, specimen size 0.40 x 0.14 x 0.17 mm. Mo-K, radiation, h = 0.710 7 A; ~(Mo-K,)= 20.5 cm-l.Space group P2,2,2, (Dt,No. 19). Data Collection.-A Syntex PI four-circle diffractometer was used, the 20-0 mode (20 40") yielding 1081 inde- pendent reflections of which 667 were considered observed, having I 2a(I), and used in the structure solution and refinement after absorption correction. Friedel pairs (not reported) were also collected to 20 20" to confirm the absolute configuration. Structure solution was by vector methods. Refinement by block-diagonal least-squares, one block for the parameters of the p-bromobenzoate group, one block for each of the other atoms, including associated hydrogen parameters. Thermal parameters were aniso-tropic for non-hydrogen atoms and isotropic for hydrogen constrained at ( Uii(C)+ 0.01)A3.Hydrogen atoms of non- methyl groups were refined in (x,y, z) only; those of methyl groups were constrained in (x, y, z, U). Residuals (on F) were R 0.056, R' 0.053 (other parity: 0.069, 0.069), S 1.22. Reflection weights were w =1 a2(Fo)+ 0.000 6 (F,)7-1. Scattering factors for neutral non-hydrogen atoms, that for bromine corrected for anomalous dispersion (Af, Af"), were taken from refs. 10 and 11, those for hydro- #gen from ref. 12. The X-Ray '76' program system was used,l3 on a CYBER 73 computer. Structure factor * For details see J.C.S. Perkin 1, 1977, Index issue. 10 D. T. Cromer and J. B. Mann, Acta Cryst., 1968, A24, 321. 11 D. T. Cromer and D. Liberman, J. Chem. Phys., 1970, 53, 1891. J.C.S. Perkin I amplitudes, thermal parameters, hydrogen geometries are listed in Supplementary Publication No.SUP 22273 (8 pp.).* Carbon atom numbering follows that given for (l), the sequence C(14)-(20) being carried through the carboxy-carbon C(14) and then around the phenyl group. Hydrogen and oxygen atoms follow the labelling of the parent carbon, methyl hydrogens being suffixed a,p,y, Final atom co-ordinates are listed in Table 1. The b FIGUREUnit-cell contents projected down b; hydrogen atoms are only shown where they assist in defining critical stereo- chemical features. The axes are right-handed molecular geometry is depicted in the Figure and given in detail in Table 2; deviations from the plane through the calamenene skeleton are shown in Table 3. Because of TABLE3 Deviations (A) of atoms from the least-squares plane through the calamenene skeleton Atoms defining plane: C(1), C(4)-(81, C(4a), C(8a), C(13), O(7) Deviations: C(l) -0.01, C(4) -0.04, C(4a) 0.03, C(5) 0.02, C(6)0.00, C(7) 0.02. C(8) 0.02, C(8a) 0.00, C(13) -0.01, O(7) -0.04, C(9) 1.37, C(2) -0.70, C(3) -0.05, C(10) 0.99, C(11) 0.82, C(12)2.43 the bromine content, the skeletal dimensions are relatively imprecise and does not warrant further discussion; in the solid the conformation adopted by the cyclohexane ring is as expected from consideration of the interactions be- tween the ring alkyl substituents and the aromatic peri-hydrogen atoms. Likewise, the disposition of the isopropyl group is also consistent with minimum interaction energy requirements. We thank the Australian Research Grants Committee for a grant supporting this work. 7/2182 Received, 14th December, 19771 12 R. F. Stewart, E. R. Davidson, and W. T. Simpson, J. Chem. Phys., 1965, 42, 3175. 13 X-Ray program system, version of March, 1976, Technical Report, TK 446, Computer Science Centre, University of Mary- land, U.S.A.
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