The absolute configuration of cuauhtemone and related compounds

Article abstract of DOI:10.1016/S0957-4166(03)00042-9

The absolute configuration of cuauhtemone, a eudesmane-type sesquiterpene isolated from Pluchea species (Asteraceae), has been revised from 1 to 2 by chemical correlation with (R)-(+)-2-methyl-1,2-butanediol 3 through the naturally occurring 2,3-epoxy-2-methylbutanoate derivative 4. The relative stereochemistry of 4 was confirmed by X-ray diffraction analysis. The obtained data are also useful for reconsideration of the absolute configurations of a relevant group of natural products, which were elucidated according to the stereochemistry of cuauhtemone.

Full text of DOI:10.1016/S0957-4166(03)00042-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 543–548
The absolute configuration of cuauhtemone and related
compounds
J. Mart´ın Torres-Valencia,a,* Dora L. Quintero-Mogica,a Guadalupe I. Leo´n,a
Oscar R. Sua´rez-Castillo,a J. Roberto Villago´mez-Ibarra,a Emma Maldonado,b
Carlos M. Cerda-Garc´ıa-Rojasc and Pedro Joseph-Nathanc
aCentro de Investigaciones Qu´ımicas, Universidad Auto´noma del Estado de Hidalgo, Apartado 1-622, Pachuca,
Hidalgo 42001, Mexico
bInstituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico, Circuito Exterior, Cd. Universitaria, Coyoaca´n, Me´xico,
D.F. 04510, Mexico
cDepartamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado 14-740, Me´xico, D.F. 07000, Mexico
Received 10 October 2002; accepted 3 January 2003
Abstract—The absolute configuration of cuauhtemone, a eudesmane-type sesquiterpene isolated from Pluchea species (Aster-
aceae), has been revised from 1 to 2 by chemical correlation with (R)-(+)-2-methyl-1,2-butanediol 3 through the naturally
occurring 2,3-epoxy-2-methylbutanoate derivative 4. The relative stereochemistry of 4 was confirmed by X-ray diffraction analysis.
The obtained data are also useful for reconsideration of the absolute configurations of a relevant group of natural products, which
were elucidated according to the stereochemistry of cuauhtemone. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Herein, the absolute configuration of cuauhtemone is
revised from 1 to 2 by means of chemical correlation
with (R)-(+)-2-methyl-1,2-butanediol 326,27 through the
Cuauhtemone is a bicyclic eudesmane-type sesquiter-
pene isolated from the aerial parts of Pluchea species1–3
to which growth inhibition activity of corn and bean
seeds has been attributed.1,4 Since the flexibility of the
enone group precluded the application of various rules
for determining its chirality, the absolute configuration
of the molecule was proposed using CD measurements
in the absence and presence of a europium NMR shift
reagent.1 By doing so, it seems that the authors
neglected the severe steric effects to which the NMR
shift reagents are exposed,5,6 and therefore assumed
that the secondary and tertiary hydroxyl groups present
in the 1,2-diol moiety of the natural product should
behave as the model secondary diol compounds7 used
to develop the methodology for absolute configura-
tion determination. Since then, the stereochemistry
of various eudesmane derivatives has been described
based on the erroneous absolute configuration of
cuauhtemone,1–4,8–25 whose structure and relative stereo-
chemistry was secured by X-ray diffraction analysis.4
naturally
occurring
2,3-epoxy-2-methylbutanoate
derivative 4. The stereochemical relationship between
the ester residue and the sesquiterpenic moiety in com-
pound 4 is confirmed herein by X-ray diffraction analy-
sis. Compound 4 is a bioactive natural product23
isolated from Pluchea foetida (L.) D.C.,2 P. odorata
Cass.,8 P. symphytifolia (Miller) Gills,13 Laggera alata
(D. Don) Schultz-Bip. ex Oliver,19 and Epaltes mexi-
cana Less.20,23
2. Results and discussion
A methodology to determine the absolute configuration
of
2,3-epoxy-2-methylbutanoate
ester
residues
(epoxyangelate or epoxytiglate moieties) in natural
products, based on reduction of the ester functionality
to yield a 2-methyl-1,2-butanediol, esterification of the
obtained primary alcohol with either the (R)-(+)- or
(S)-(−)-Mosher acid to afford the corresponding
1
Mosher ester, and H NMR spectral comparison of the
* Corresponding author. Fax: (52-771) 717-2000 internal number
6502; e-mail: jmartin@uaeh.reduaeh.mx
final product with those of the Mosher esters prepared
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00042-9

544
J. M. Torres-Valencia et al. / Tetrahedron: Asymmetry 14 (2003) 543–548
methylbutyroyloxy) group. The two methyl groups on
the oxirane ring (at C17 and C18) are in a trans
disposition and the dihedral angle between the oxirane
ring and the carboxyl group (O2ꢀC16ꢁC17ꢁO3) is −8.4°.
The torsion angle for the O1ꢁC3ꢁC4ꢁO4 fragment is
+48.0°, which indicates significant twisting of the ester
group around C3 and the hydroxyl group at C4 from its
ideal arrangement (~=+60°). The conjugated system of
double bonds, C11ꢀC7ꢁC8ꢀO5, is not planar [torsion
angle +17.1°], but is less twisted than in cuauhtemone
(~=+46°). All CꢁC and CꢁO bond distances, as well as
intra-annular torsion angles, are similar to the corre-
sponding distances and torsion angles in cuauhtemone4
or in 5-O-acetylcuauhtemonyl 6-O-2%,3%-epoxy-2%-
methylbutyrate.24
from 2-methyl-1,2-butanediols of known stereochem-
istry, has been put forward from our laboratories
recently.28 In the work presented herein, we use this
methodology to determine the absolute configuration of
the epoxyangelic residue found in the naturally occur-
ring cuauhtemone derivative 4, which one of us isolated
from Epaltes mexicana Less in 1989.20
Following this procedure,28 reductive cleavage of 4 with
LiAlH4 generated a single stereoisomer of 2-methyl-1,2-
butanediol, which, after esterification with both (R)-(+
)-and (S)-(−)-Mosher acids, gave Mosher esters 5 and
6, respectively. The absolute configuration of the 2-
methyl-1,2-butanediol was assigned as R, as depicted
1
for compound 3, after H NMR spectral comparison of
the esters with authentic samples.28 Therefore, the
epoxyangelate moiety has the 2R,3R absolute configu-
ration, as depicted for compound 4. Correlation of the
epoxyangelate residue of 4 with the 2-methyl-1,2-
butanediol 3 is possible because in addition to reducing
the ester group, hydride attacks the epoxy group at
C-3%, while the C-2% absolute configuration remains
unchanged.29
On the other hand, 4 was treated with KOH/H2O in
MeOH to give a mixture of cuauhtemone 2 and 11-
methoxy-7,11-dihydrocuauhtemone 7 in a 17:3 ratio, in
87% overall yield. This mixture was separated by
column chromatography to give pure samples of 2 and
7. Compound 7 was characterized by 1D and 2D NMR
data, including 1H, 13C, gCOSY, gHMQC and
gHMBC, as well as mass spectrometry. The configura-
1
tion at C-7 was assigned on the basis of the H–1H
Once the absolute configuration of the epoxy ester
moiety of 4 was determined, we carried out an X-ray
diffraction analysis on this compound, which provided
the stereostructure shown in Fig. 1. From this it became
evident, on the basis of the absolute configuration of the
epoxyangelate moiety, that the absolute configuration
of cuauhtemone needed to be corrected from 1 to 2. The
X-ray diffraction structure of 4 showed that the two
cyclohexane rings are trans fused and are in the chair
conformation, with both methyl groups (at C4 and C10)
being axial. The hydroxyl group is equatorial and
located cis relative to the bulky axial (2,3-epoxy-2-
NMR coupling constants for H-5 (dd, J=12.7 and 2.9
Hz), H-6a (ddd, J=13.2, 12.7 and 12.2 Hz), H-6b (ddd,
J=13.2, 5.8 and 2.9 Hz) and H-7 (dd, J=12.2 and 5.8
Hz) (Table 1). This coupling constant pattern was
consistent with an axial orientation of H-7 in the
cyclohexanone ring and an equatorial orientation of the
methoxyisopropyl group. Additionally, a molecular
model using the ab initio (HF/3-21G*) method for
geometry optimization was carried out for 7 (Fig. 2).
The calculated coupling constants using the ab initio
dihedral angles in combination with an empirically
generalized Karplus-type equation30,31 were in very

J. M. Torres-Valencia et al. / Tetrahedron: Asymmetry 14 (2003) 543–548
545
Figure 1. (a) ORTEP drawing and (b) chemical structure of 3-O-[2,3-epoxy-2-methylbutyroyl]cuauhtemone 4.
good agreement with the observed coupling constants
found in the C5ꢁC6ꢁC7 fragment (Table 1). Finally,
the positive Cotton effect observed in the CD spec-
trum of 7, in combination with the octant rule for
cyclohexanones,32 confirmed the absolute configuration
of the cuauhtemone derivatives (Fig. 2).
Table 1. HꢁCꢁCꢁH dihedral angles (ƒ), observed (Jobsd),
1
and calculated vicinal H–1H coupling constants (Jcalcd
)
for the C5ꢁC6ꢁC7 fragment of 7
a
b
c
Protons
ƒ
Jobsd
Jcalcd
H5ꢁH6a
H5ꢁH6b
H6aꢁH7
H6bꢁH7
−177.7
+63.7
−171.4
−53.6
12.7
2.9
12.2
5.8
12.3
2.7
12.1
4.1
a In degrees from the ab initio (HF/3-21G*) molecular model.
b In Hz, measured at 300 MHz from CDCl3.
c In Hz, calculated by means of an empirically generalized Karplus-
type equation.
A quantitative conformational description for the six-
membered rings of cuauhtemone 2 and derivatives 4
and 7 was achieved by using the polar set of parame-
ters proposed by Cremer and Pople.33 These parame-
ters, listed in Table 2, were calculated with the
RICON program,34 using the HF/3-21G* ab initio
coordinates. For comparative purposes, we also
employed the X-ray coordinates of epoxyangelate
derivative 4.
A group of eudesmane derivatives with the same abso-
lute stereochemistry as that proposed herein for
cuauhtemone has been obtained from the taxonomi-
cally related species Laggera pterodonta (Asteraceae).35
Figure 2. (a) Ab initio HF/3-21G* minimum energy structure
of 11-methoxy-7,11-dihydrocuauhtemone 7 and (b) applica-
tion of the octant rule.

546
J. M. Torres-Valencia et al. / Tetrahedron: Asymmetry 14 (2003) 543–548
Table 2. Conformational parameters of compounds 2, 4
and 7
at rt for 2 h, filtered and extracted with EtOAc (10
mL). The organic layer was dried over Na2SO4 and
evaporated under vacuum. The residue was chro-
matographed on silica gel (mesh 230–400; 1.0 g) in a
column (0.6 cm i.d.) eluting with CH2Cl2 (10 mL)
followed by CH2Cl2:EtOAc (1:1, v/v; 15 mL) and col-
lecting fractions of 1 mL. The last fractions gave 2-
methyl-1,2-butanediol, which was treated with CH2Cl2
solutions of dicyclohexylcarbodiimide (8.5 mg, in 1.0
mL), 4-N,N-dimethylaminopyridine (0.5 mg, in 0.4 mL)
b
Compound
Qa
qb
ƒ
Ring conformation
2 (ring A)c,d
2 (ring B)e,d
0.559
0.543
5.1
16.5
8.8
18.5
Distorted chair
Between chair and
half-chair
Distorted chair
Between half-chair and
envelope
Distorted chair
Between chair and
half-chair
Distorted chair
Between chair and
envelope
4 (ring A)c,f
4 (ring B)e,f
0.546
0.529
6.1
36.7
11.1
15.0
4 (ring A)c,d
4 (ring B)e,d
0.550
0.545
5.8
16.6
27.0
17.4
and
(R)-(+)-3,3,3-trifluoro-2-methoxy-2-phenyl-
propanoic acid (Mosher acid, 6.5 mg, in 1.0 mL), at rt
for 48 h. The reaction mixture was diluted with CH2Cl2
(3 mL), filtered and evaporated. The residue was chro-
matographed on silica gel (mesh 230–400; 1.0 g) in a
column (0.6 cm i. d.) using hexane–EtOAc (5:1, v/v; 5
mL) followed by hexane–EtOAc (1:1, v/v; 5 mL) and
finally EtOAc (5 mL), collecting fractions of 1 mL. The
corresponding ester 5 was obtained in fractions 6–8 (4
7 (ring A)c,d
7 (ring B)e,d
0.559
0.591
4.9
7.2
15.2
0.7
a
,
Total puckering amplitude in A.
b In degrees.
c C1ꢁC2ꢁC3ꢁC4ꢁC5ꢁC10.
d From ab initio HF/3-21G* coordinates.
e C5ꢁC6ꢁC7ꢁC8ꢁC9ꢁC10.
f From X-ray coordinates.
1
mg, 44%). The H NMR spectrum was identical to that
of compound 1 in Ref. 28.
3.4. (2S,2%R)-2%-Hydroxy-2%-methylbutyl 3,3,3-trifluoro-
2-methoxy-2-phenylpropanoate, 6 from compound 4
3. Experimental
Prepared as ester 5, but using (S)-(−)-Mosher acid
1
(43%). The H NMR spectrum of this compound was
identical to that of compound 3 in Ref. 28.
3.1. General
3.5. (3S,4R,5S,10S)-Cuauhtemone 2 and
(3S,4R,5S,7S,10S)-11-methoxy-7,11-dihydrocuauhte-
mone, 7
Column chromatography was carried out using Merck
silica gel (230–400 mesh). Melting points were deter-
mined on a Fisher–Johns apparatus and are uncor-
rected. Optical rotations were measured on
Perkin–Elmer 241 or 341 polarimeters. The CD spec-
trum was measured on a JASCO J-720 spectropolar-
imeter. IR spectra were recorded on a Perkin–Elmer
2000 FT-IR spectrophotometer. 1D NMR spectra were
obtained on a JEOL Eclipse 400 spectrometer, using
CDCl3 as the solvent and TMS as the internal standard
while 2D NMR spectra, including COSY-45, NOESY,
gHSQC and gHMBC, were recorded on a Varian Mer-
cury 300 spectrometer. Mass spectra were measured on
a JEOL JMS-SX 102A spectrometer.
A solution of 4 (20 mg) in MeOH (1 mL) was treated
with KOH (5 mg) in H2O (50 mL). The reaction mixture
was refluxed for 6 h, the solvent was removed using a
nitrogen stream and acetone (5 mL) was added. The
suspension was filtered and the solvent evaporated
under reduced pressure. The residue was chro-
matographed over silica gel (2 g) with CH2Cl2:acetone
(7:3, v/v) as the eluent to yield 2 (9 mg, 62%) and 7 (5
mg, 30%). Spectroscopic data of 2 were identical to
literature data.1 Mp=138–140°C (lit. 140°C);1 [h]2D0 +60
(c 0.10, CHCl3) (lit. [h]D +59.2).1 Compound 7 showed
mp=112–115°C; [h]2D5 +62 (c 0.29, CHCl3); CD
(MeOH) [q]247=−572, [q]298=+5264; UV (MeOH) 254
nm (m 3240); IR (CHCl3) wmax=3422, 2942, 1708, 1456,
3.2. (3S,4R,5S,10S, 2%R,3%R)-3-O-[2,3-Epoxy-2-methyl-
butyroyl]cuauhtemone, 4
1
1387, 1363, 1076 cm−1; H NMR (CDCl3): l 3.66 (br s,
The natural compound was obtained from Epaltes
mexicana.20 [h]D20 +120 (c 0.10, CHCl3) (lit. [h]D +122).8
13C NMR (CDCl3): l 202.1 (C-8), 169.6 (C-1%), 145.5
(C-11), 130.7 (C-7), 78.5 (C-3), 72.2 (C-4), 60.3 (C-2%),
60.0 (C-9), 59.8 (C-3%), 47.2 (C-5), 36.2 (C-10), 33.6
(C-1), 25.6 (C-6), 23.8 (C-2), 23.6 (C-12), 23.0 (C-13),
21.2 (C-15), 19.5 (C-5%), 18.7 (C-14), 14.2 (C-4%).
1H, H-3), 3.16 (s, 3H, OMe), 2.58 (br dd, 1H, J=12.2,
5.8 Hz, H-7), 2.41 (ddd, 1H, J=13.2, 5.8, 2.9 Hz,
H-6b), 2.30 (br d, 1H, J=12.2 Hz, H-9b), 2.16 (dd, 1H,
J=12.7, 2.9 Hz, H-5), 2.02 (d, H-1, J=12.2 Hz, H-9a),
1.79 (m, 2H, H-2), 1.79 (m, 1H, H-1b), 1.50 (ddd, 1H,
J=13.2, 12.7, 12.2 Hz, H-6a), 1.16 (m, 1H, H-1a), 1.33
(s, 3H, Me-12), 1.25 (s, 3H, Me-13), 1.18 (s, 3H,
Me-15), 0.85 (s, 3H, Me-14); 13C NMR (CDCl3): l
209.5 (C-8), 75.0 (C-11), 74.0 (C-3), 73.1 (C-4), 60.2
(C-9), 58.1 (C-7), 48.3 (OMe), 46.9 (C-5), 39.5 (C-10),
33.1 (C-1), 25.7 (C-2), 23.5 (C-6), 23.5 (C-12), 22.0
(C-15), 21.1 (C-13), 18.4 (C-14); FABMS (positive) m/z
307 [M+Na]+ (24%), 285 [M+H]+ (32), 254 (7), 253 (40),
154 (100), 136 (68), 120 (10), 107 (21), 89 (20), 73 (54);
HRFABMS (positive) m/z 285.2061 [M+H]+(calcd for
C16H28O4+H, 285.2066).
3.3. (2R,2%R)-2%-Hydroxy-2%-methylbutyl 3,3,3-trifluoro-
2-methoxy-2-phenylpropanoate, 5 from compound 4
A solution of the naturally occurring cuauhtemone
derivative 4 (10 mg) in anhydrous THF (5 mL) was
treated at 0°C with LiAlH4 (5.5 mg). The mixture was
stirred under reflux for 4 h, cooled to 0°C, treated with
EtOAc (5 mL), MeOH (1 mL) and H2O (5 mL), stored

J. M. Torres-Valencia et al. / Tetrahedron: Asymmetry 14 (2003) 543–548
547
3.6. X-Ray diffraction analysis of 4
6. Joseph-Nathan, P.; Herz, J. E.; Rodr´ıguez, V. M. Can. J.
Chem. 1972, 50, 2788–2791.
Single crystals of 4 were grown by slow crystallization
from CHCl3–hexane. The size of the crystal was 0.31×
0.32×0.21 mm3. It was orthorhombic, space group
7. Nakanishi, K.; Dillon, J. J. Am. Chem. Soc. 1971, 93,
4058–4060.
8. Bohlmann, F.; Zdero, C. Chem. Ber. 1976, 109, 2653–
2656.
9. Bohlmann, F.; Ziesche, J.; King, R. M.; Robinson, H.
Phytochemistry 1980, 19, 969–970.
10. Dom´ınguez, X. A.; Franco, R.; Cano, G.; Villarreal, R.;
Bapuji, M.; Bohlmann, F. Phytochemistry 1981, 20,
2297–2298.
11. Arriaga-Giner, F. J.; Borges-del-Castillo, J.; Manresa-
Ferrero, M. T.; Va´zquez-Bueno, P.; Rodr´ıguez-Luis, F.;
Valde´s-Iraheta, S. Phytochemistry 1983, 22, 1767–1769.
12. Bohlmann, F.; Wallmeyer, M.; Jakupovic, J.; Gerke, T.;
King, R. M.; Robinson, H. Phytochemistry 1985, 24,
505–509.
13. Jakupovic, J.; Misra, L. N.; Chau, T. V.; Bohlmann, F.;
Castro, V. Phytochemistry 1985, 24, 3053–3055.
14. Ahmad, V. U.; Fizza, K. Phytochemistry 1986, 25, 949–
950.
15. Ahmad, V. U.; Fizza, K. Liebigs Ann. Chem. 1987,
643–644.
16. Rojatkar, S. R.; Puranik, V. G.; Tavale, S. S.; Guru, T.
N.; Nagasampagi, B. A. Phytochemistry 1987, 26, 569–
570.
P212121, with a=10.1318(5), b=12.8992(6), c=
3
14.3754(6) A, V=1878.8(2) A , zcalcd=1.24 mg/mm3
for Z=4, C20H30O5, MW=350.44, and F000=760. The
absorption coefficient was 0.088 mm−1. Reflections were
collected on a Bruker Smart 6000 CCD diffractometer.
A total of 1321 frames were collected at a scan width of
0.3° and an exposure time of 10 s/frame, using Mo
,
,
,
radiation (u=0.7073 A). The qrange for data collection
was 2.12 to 26.03° with limiting indices −75h512,
−155k515, −175l517. A total of 12585 reflections
were collected from which 3700 were considered as
unique. The frames were processed with the SAINT
software package, provided by the diffractometer man-
ufacturer, by using
a
narrow-frame integration
algorithm. The structure was solved by direct methods
using the SHELXS-9736 program included in the
WINGX VI.637 crystallographic software package. The
structural refinement was carried out by full-matrix
least squares on F2 (goodness-of-fit on F2=0.862) tak-
ing into account 2318 data and 353 parameters. The
non-hydrogen atoms were treated anisotropically, and
the hydrogen atoms, included in the structure factor
calculation, were refined isotropically. Final dis-
crepancy indices were R=4.2%, Rw=7.5%. The final
17. Ahmad, V. U.; Fizza, K. Planta Med. 1988, 54, 462–463.
18. Ahmad, V. U.; Fizza, K. Phytochemistry 1988, 27, 1861–
1862.
difference Fourier map was essentially featureless, the
highest residual peaks having densities of 0.197 e A .
Atomic coordinates, bond lengths, bond angles,
anisotropic thermal parameters, hydrogen coordinates,
calculated and observed structure factors and torsion
angles are deposited at the Cambridge Crystallographic
Data Center. The CCDC deposition number is 199960.
19. Zdero, C.; Bohlmann, F. Phytochemistry 1989, 28, 3097–
3100.
20. Maldonado, E. Phytochemistry 1989, 28, 1973–1974.
21. Ahmad, V. U.; Fizza, K.; Khan, M. A.; Farooqui, T. A.
Phytochemistry 1991, 30, 689–691.
22. Ahmad, V. U.; Farooqui, T. A.; Fizza, K.; Sultana, A.;
Khattonn, R. J. Nat. Prod. 1992, 55, 730–735.
23. Kato, T.; Frei, B.; Heinrich, M.; Sticher, O. Planta Med.
1996, 62, 66–67.
−3
,
24. Ahmed, A. A.; Ali, B. A.; Krawiec, M.; Watson, W. H.
Acknowledgements
Acta Crystallogr. 1996, C52, 235–237.
25. Ahmed, A. A.; El-Seedi, H. R.; Mahmoud, A. A.; El-
Douski, A. E.-A. A.; Zeid, I. F.; Bohlin, L. Phytochem-
istry 1998, 49, 2421–2424.
26. Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313–1324.
27. Torres-Valencia, J. M.; Cerda-Garc´ıa-Rojas, C. M.;
Joseph-Nathan, P. Phytochem. Anal. 1999, 10, 221–237.
28. Torres-Valencia, J. M.; Leo´n, G. I.; Villago´mez-Ibarra, J.
R.; Sua´rez-Castillo, O. R.; Cerda-Garc´ıa-Rojas, C. M.;
Joseph-Nathan, P. Phytochem. Anal. 2002, 13, 1147–
1152.
Partial financial support from CONACYT (Mexico) is
acknowledged. The authors wish to thank Luis Velasco
Ibarra and Mar´ıa del Roc´ıo Patin˜o Maya, Instituto de
Qu´ımica, Universidad Nacional Auto´noma de Me´xico,
for measuring the HRMS and the CD spectrum,
respectively.
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