Molecular rearrangements of (-)-modhephene and (-)-isocomene to a (-)-triquinane

Article abstract of DOI:10.1021/jo060258t

The preparation and further rearrangement of (-)-modhephene (1) to a (-)-triquinane 5 has been assessed through acid catalysis. The rearrangement involved protonation, 1,2 σ-bond and methyl shifts, and deprotonation. Monitored experiments by ¹H NMR spectroscopy suggested the intermediate (-)-isocomene (3), which was further evidenced when a sample of natural (-)-3 undergoes acid-catalyzed conversion to the (-)-triquinane 5. In addition, deuterated (-)-modhephene (1-d) labeled stereospecifically at the 14β geminal methyl group at C4 was synthesized, through the corresponding chiral deuterated primary alcohol, in 5 steps, starting from natural (-)-14-hydroxymodhephene (8), and rearranged under acid catalysis to elucidate the stereochemical factors that control the methyl shift at this position. The final deuterium-labeled (-)-triquinane, 5-d, obtained from [14- ²H₁]-1-d was established to have deuterium in the methyl group at C5 by ¹³C NMR spectroscopy. This stereoselective methyl migration is in accordance with the molecular orbital demand formulated by the quantum chemical calculations performed in the present study.

Full text of DOI:10.1021/jo060258t

Molecular Rearrangements of (-)-Modhephene and (-)-Isocomene
to a (-)-Triquinane
Pedro Joseph-Nathan,† Benito Reyes-Trejo,‡ and Martha S. Morales-R´ıos*,†
Departamento de Qu´ımica, Centro de InVestigacio´n y de Estudios AVanzados del Instituto Polite´cnico
Nacional, Apartado 14-740, Me´xico, D. F., 07000 Me´xico, and Laboratorio de Productos Naturales, AÄ rea
de Qu´ımica, UniVersidad Auto´noma Chapingo, Apartado 74, Oficina de Correos Chapingo, Texcoco,
Me´xico, 56230 Me´xico
smorales@cinVestaV.mx
ReceiVed February 7, 2006
The preparation and further rearrangement of (-)-modhephene (1) to a (-)-triquinane 5 has been assessed
through acid catalysis. The rearrangement involved protonation, 1,2 σ-bond and methyl shifts, and
deprotonation. Monitored experiments by 1H NMR spectroscopy suggested the intermediate (-)-isocomene
(3), which was further evidenced when a sample of natural (-)-3 undergoes acid-catalyzed conversion
to the (-)-triquinane 5. In addition, deuterated (-)-modhephene (1-d) labeled stereospecifically at the
14â geminal methyl group at C4 was synthesized, through the corresponding chiral deuterated primary
alcohol, in 5 steps, starting from natural (-)-14-hydroxymodhephene (8), and rearranged under acid
catalysis to elucidate the stereochemical factors that control the methyl shift at this position. The final
deuterium-labeled (-)-triquinane, 5-d, obtained from [14-2H1]-1-d was established to have deuterium in
the methyl group at C5 by 13C NMR spectroscopy. This stereoselective methyl migration is in accordance
with the molecular orbital demand formulated by the quantum chemical calculations performed in the
present study.
Introduction
was determined by single-crystal X-ray analysis of a derived
diol,2a and the absolute stereochemistry was established through
the stereospecific rearrangement of (+)- and (-)-dispirounde-
canol 2.3 From Isocoma wrigthii was also isolated (-)-
isocomene (3),4 a triquinane possessing a cyclopenta[c]pentalene
framework.
(-)-Modhephene (1) has been the subject of a number of
total racemic, diasteroselective, and enantioselective syntheses.5
Within the strategies used, a new approach involves cationic
cascade rearrangements of (()-dispiroundecanol 2.6 Under
A small class of tricyclopentenoid compounds known as
triquinanes have received considerable attention in recent years
as a result of their unique architecture, which presents significant
synthetic challenges as well as a wide range of biological activity
exhibited by some of them.1 Although triquinanes are found in
relatively abundant plants, they are present in only minute
amounts as complex volatile mixtures of structurally similar
isomers, thus, isolation of the pure components represents a
major challenge. (-)-Modhephene (1), isolated from Isocoma
wrigthii,2 (Chart 1) was the first reported triquinane possessing
the [3.3.3]propellane nucleus. The relative structure of (-)-1
(2) (a) Zalkow, L. H.; Harris, R. N., III; Van Derveer, D. J. Chem. Soc.,
Chem. Commun. 1978, 420-421. (b) Bohlmann, F.; Zdero, C.; Bohlmann,
R.; King, R. M.; Robinson, H. Phytochemistry 1980, 19, 579-582.
(3) Fitjer, L.; Monzo´-Oltra, H.; Noltemeyer, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1492-1494.
(4) (a) Zalkow, L. H.; Harris, R. N., III; Van Derveer, D.; Bertrand, J.
A. J. Chem. Soc., Chem. Commun. 1977, 456-457. (b) Bohlmann, F.; Le
Van, N.; Pickardt, J. Chem. Ber. 1977, 110, 3777-3781.
† Centro de Investigacio´n y de Estudios Avanzados del IPN.
‡ Universidad Auto´noma Chapingo.
(1) (a) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671-719. (b)
Dobner, M. J.; Schwaiger, S.; Jenewein, I. H.; Stuppner, H. J. Ethnophar-
macol. 2003, 89, 301-303.
10.1021/jo060258t CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/16/2006
J. Org. Chem. 2006, 71, 4411-4417
4411

Joseph-Nathan et al.
CHART 1
SCHEME 1 a
a Reagents: (a) CrO3-Py2, CH2Cl2; (b) NaBD4, MeOD; (c) anhydrous
CuSO4, (CH2SH)2, benzene; (d) Raney-Ni, EtOH.
SCHEME 2 a
kinetic control, the Wagner-Meerwein cascade reactions of
(()-2 gave (()-modhephene (1) and a (()-triquinane 4 in a
ratio 2:1. Whereas, under thermodynamic control, (()-2 was
rearranged into (()-isocomene (3), (()-triquinanes 4-6, and
the (()-propellane 7 in a ratio 7:8:5:2:2, respectively. In
addition, it has been proposed that (()-1 may formally rearrange
to (()-3 by three consecutive 1,2 shifts and to triquinane (()-5
by seven 1,2 shifts, in which the last comprises a 1,2-methyl
migration.6
Recently, we reported the isolation and stereostructural
characterization of a new hydroxyl derivative of (-)-1, the (-)-
14-hydroxymodhephene 8 from Pluchea sericea roots.7a Our
interest in the latter compound arises from the fact that it could
be advantagely transformed into (-)-1. To get experimental
evidence concerning the acid-catalyzed conversion of (-)-1 to
(-)-triquinane 5, protio and deuterated isotopomers of (-)-1
were prepared. Herein, we provide an account of an efficient
method for the stereoselective labeling of the 14â geminal
methyl group at C4 of (-)-modhephene (1), using a previously
described protocol to insert deuterium at the neopentylic position
in cedrene derivatives,8 with the aim to elucidate the stereo-
chemical factors that control the 1,2-methyl migration. In
addition, we used a semiempirical PM3 method9 to obtain the
total energies of the cationic intermediates proposed to be
formed in the rearrangement of (-)-modhephene (1).
a Reagents: (a) CCl3CONCO; (b) phthalyc anhydride, toluene.
are shown in Scheme 1. Starting from natural (-)-14-hydroxy-
modhephene 8, (-)-1 was synthesized, employing a convenient
selective oxidation/sulfur acetalization/reductive desulfurization
sequence. The first step was the selective oxidation of neopen-
tylic alcohol (-)-8 with the complex CrO3-Py2. The oxidation
was performed with 93% isolated yield of (+)-9, which
underwent sulfur acetalization by treatment with 1,2-ethanedithi-
ol and anhydrous CuSO4 to give (-)-10 in 62% yield. Finally,
Raney-Ni-catalyzed reductive desulfurization of (-)-10 gave
(-)-1 in 80% yield.
Additionally, using the same methodology, [14-2H1]-(-)-1
was synthesized from aldehyde (+)-9 (Scheme 1). First, the
reduction of (+)-9 with NaBD4 to give (-)-8-d was ac-
complished in 79% yield. Compounds (+)-9-d, (-)-10-d, and
(-)-1-d were then prepared, analogously to protio isotopomers
(+)-9, (-)-10, and (-)-1, in 88, 64, and 75% yields, respec-
tively.
Results and Discussion
Preparation of Protio and Deuterated Isotopomers of (-)-
Modhephene (1). The syntheses of (-)-1 and [14-2H1]-(-)-1
(5) (a) Paquette, L. A. Top. Curr. Chem. 1984, 119, 1-163. (b) Hudlicky,
T.; Price, J. D. Chem. ReV. 1989, 89, 1467-1486. (c) Ramaiah, M. Synthesis
1984, 529-570. (d) Lee, H.-Y.; Moon, D. K.; Bahn, J. S. Tetrahedron Lett.
2005, 46, 1455-1458.
(6) Fitjer, L.; Majewski, M.; Monzo´-Oltra, H. Tetrahedron 1995, 51,
8835-8852.
(7) (a) Reyes-Trejo, B.; Joseph-Nathan, P. Phytochemistry 1999, 51, 75-
78. (b) Reyes-Trejo, B.; Morales-R´ıos, M. S.; Alvarez-Cisneros, C.; Joseph-
Nathan, P. Magn. Reson. Chem. 2003, 41, 1021-1025.
(8) Joseph-Nathan, P.; Santilla´n, R. L.; Gutie´rrez, A. J. Nat. Prod. 1984,
47, 924-933.
(9) Stewart, J. J. P.; Davis, L. P.; Burggraf, L. W. J. Comput. Chem.
1987, 8, 1117-1123.
The deuterium content of (-)-8-d, determined in the trichlo-
roacetyl isocyanate (TAI) derivative 11-d,10 after being treated
in situ by the addition of TAI (Scheme 2), was 91 ( 1%.
Whereas, for the oxidized product (-)-9-d, the isotope effect
leads to a deuteration degree greater than 78%, as determined
1
by H NMR peak areas.
(10) Samek, Z.; Budesinsky, M. Collect. Czech. Chem. Commun. 1979,
44, 558-588.
4412 J. Org. Chem., Vol. 71, No. 12, 2006

Rearrangements of (-)-Modhephene and (-)-Isocomene
FIGURE 1. Minimal energy conformations of syn ( C3-C4-C14-
O14 ) 11.21°) and anti ( C3-C4-C14-O14 ) 163.48°) rotamers
of (+)-9 (hydrogen atoms omitted for clarity) calculated at the PM3
level of theory. The values in parentheses are the total energies in kcal/
mol. Boltzmann populations correspond to a ratio of ca. 2:1 in favor
of the syn conformer.
The good diastereoselectivity (dr 9:1) in the reduction of
(+)-9 with NaBD4 to afford (-)-8-d was determined on the
basis of 1H NMR analysis of the corresponding TAI derivative
11-d (see Supporting Information, S17). This result suggests
that the reaction benefits from conformational control and
specific steric effects. Although the π-facial stereoselectivity
in nucleophilic additions to â,γ-unsaturated carbonyl compounds
may be also controlled by electrostatic effects,11 in this case,
evidence of the homoconjugation12 between the aldehyde
carbonyl group and the C2dC3 double bond of â,γ-unsaturated
aldehyde (+)-9 was obtained from the UV spectrum, which
exhibits a characteristic absorption band at 220 nm (ꢀmax 2300),
assigned to the π-π* transition, allowing significant stabiliza-
tion of the syn-oriented carbonyl conformer with respect to the
anti conformer. The initial Monte Carlo conformational search
of (+)-9 reveals the existence of four structures, two of which
are produced by a rotation at the C4-C14 bond, with relative
energies (∆G) of 0 (reference value) and +0.381 kcal/mol. The
remaining two higher-energy species, +3.626 and +4.466 kcal/
mol, result from a conformational change in the propellane C
ring.13 The PM3 geometry optimizations of the two lower-energy
conformations, produced by rotation of the C4-C14 bond,
corresponding to the syn and anti conformers, show C3-C4-
C14-O14 dihedral angles of 11.21° and 163.48°, respectively.
On the basis of the depicted geometries in Figure 1, it is clear
that for the lowest-energy syn conformer, the C-ring effectively
blockades the re face of the carbonyl group for deuteride attack,
which in consequence occurs from the less-stereohindered si
face to give (-)-8-d in the (14S)-configuration. In this regard,
controlled selectivity of metal deuteride reductions of aldehydes
to afford chiral deuterated primary alcohols has been induced
until now by the use of chiral reagents.14a-f
FIGURE 2. Minimal energy conformation of (+)-12, calculated at
the PM3 level of theory, and a two-dimensional NMR plot showing
NOESY correlations.
The absolute stereochemistry at C14 for the major diastere-
omer (-)-8-d, assigned as 14S, was established by the study of
the derived hemiphthalate (+)-12-d (Scheme 2). A detailed
evaluation of the NOESY correlations of the protio hemiph-
thalate derivative (+)-12 allowed a distinction between the
prochiral methylene protons. Thus, pro-S H14 gives a cross-
peak with the methyl group on C4, whereas pro-R H14 shows
a cross-peak with H6â. These results are diagnostic of a priority
conformation in solution, which is coincident with that obtained
by molecular modeling (Figure 2) and by X-ray diffraction
analysis.7b The NMR study of (+)-12-d clearly indicates the
(14S)-configuration of its precursor (-)-8-d.
Precise measurements of the 13C NMR spectra of (-)-1-d
demonstrate the presence of a mixture of isotopically labeled
(CH2D) and unlabeled (CH3) species. The triplet CH2D signal
(11) Fujita, M.; Akimoto, S.; Ogura, K. Tetrahedron Lett. 1993, 34,
5139-5142.
(12) (a) Baggiolini, E.; Hamlow, H. P.; Schaffner, K. J. Am. Chem. Soc.
1970, 92, 4906-4921. (b) Suzuki, K.; Katayama, E.; Tsuchihashi, G.
Tetrahedron Lett. 1984, 25, 2479-2482. (c) Sato, F.; Takeda, Y.; Uchiyama,
H.; Kobayashi, Y. J. Chem. Soc., Chem. Commun. 1984, 1132-1134.
(13) For a detailed description of [3.3.3]propellane conformers, see:
Krivdin, L. B. Magn. Reson. Chem. 2004, 42, 1-13.
1
of C14 showed a J(13C,D) of 19 Hz and was shifted to low
frequency by 0.307 ppm (307 ppb) with respect to the singlet
of the CH3 species, in accord with isotopic-induced shifts for
methyl groups15 (Figure 3). These data allowed to reassign the
geminal methyl resonances at C4 for (-)-1.7a
Acid-Catalized Conversion of (-)-Modhephene (1) to (-)-
Triquinane 5. The equilibration experiments were done by
refluxing solutions of (-)-1 (0.59 mmol) in benzene containing
(14) For the preparation of chiral deuterated primary alcohols by the
enantioselective deuteride reduction of aldehydes, see: (a) Miyazaki, D.;
Nomura, K.; Ichihara, H.; Ohtsuka, Y.; Ikeno, T.; Yamada, T. New J. Chem.
2003, 27, 1164-1166. (b) Xu, L.; Price, N. P. J. Carbohydr. Res. 2004,
339, 1173-1178. (c) Yamada, I.; Noyori, R. Org. Lett. 2000, 2, 3425-
3427. (d) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1989, 30, 6275-
6278. (e) Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638-
7639. (f) Dupre, M.; Gaudemer, A. Tetrahedron Lett. 1978, 31, 2783-
2786.
(15) Morales-R´ıos, M. S.; Cervantes-Cuevas, H.; Salgado-Escobar, I.;
Joseph-Nathan, P. Magn. Reson. Chem. 1999, 37, 243-245.
J. Org. Chem, Vol. 71, No. 12, 2006 4413

Joseph-Nathan et al.
that arises is which of the geminal methyl groups of (-)-1 are
being rearranged. For this purpose, computational and stereo-
chemical deuterium-labeling studies were conducted, which are
subsequently described.
Computational Studies. The stationary structures and prod-
ucts were obtained by geometry optimization, without symmetry
constraint at the semiempirical PM3 level of calculations, using
a SPARTAN 04 package. Harmonic frequency analysis was
used to confirm all structures as stationary points. The initial
conformational searches were performed with Monte Carlo
calculations.
The stepwise mechanism for the rearrangement of (-)-1 to
(-)-5 has been proposed by Fitjer et al.6 to account through
five 1,2 σ-bond shifts and an epimerization through a bridge-
headed olefin16 as the bifurcation point.17 To have further insight
into the molecular rearrangement of (-)-1, theoretical studies
were carried out on the stationary structures of the possible
carbenium ion intermediates 13-21 (Figure 5). Thus, relative
energies, geometrical features, and hyperconjugative stabilization
in the corresponding carbenium ions, not previously described,
have been examined and compared.
FIGURE 3. 13C NMR (75 MHz, CDCl3) spectra of (a) (-)-1 and (b)
(-)-1-d.
As shown in Figure 5, the first step of the rearrangement is
the protonation of (-)-1 at the C3, generating the stabilized
tertiary cation 13, which in turn undergoes a C1-C9 bond shift,
producing the less-stable bridgehead cation 14 (Table 1). At
this point, two energy paths are possible through the intermediate
cation 14 (paths I and II in Figure 5). In path I, the higher-
energy cation 15, formed by the epimerization of cation 14, is
rearranged into the more-stable cation 16 by a C2-C9 bond
shift. The cation 17 is formed by a C1-C8 bond migration from
cation 16 and is 10.50 kcal/mol less stable than cation 16. Then,
cation 17 gives rearranged cation 18 by C5-C6 bond shift, being
more stable than cation 17 by 7.45 kcal/mol. The specific 1,2
migration of C14â leads to the final cation intermediate 19,
which appears to be the most stable. The terminating proton
abstraction removes H3â from cation 19, in agreement with
calculations, as detailed below, forming (-)-triquinane 5. The
whole molecular rearrangement (-)-1 f (-)-5 has an enthalpy
of -1.95 kcal/mol. Alternatively,16 in path II (Figure 5), the
common cation 14 is rearranged into cation 20 by a C5-C11
bond shift that lies 6.83 kcal/mol lower in energy than 14. The
specific 1,2 migration of C13R leads to cation intermediate 21,
which appears to be energetically favorable by 3.47 kcal/mol.
This cation 21 leads to (-)-3 by an H3R elimination. The
reversibility of the process leads to the final product (-)-5,
which is the global minimum of this system (Table 1).
Stereospecific 1,2-Methyl Migration: Deuterium Experi-
ments. The elucidation between which of the geminal methyl
groups of cations 18 and 20 are being rearranged should be
possible by means of deuterium-labeled substrates in combina-
tion with the stereoelectronic requirement of the Wagner-
Meerwein-type rearrangements. The stereochemical deuterium-
labeling equilibration studies were performed by refluxing a
benzene solution of [14-2H1]-1-d, prepared following the
sequence depicted in Scheme 1, with 1 equiv of TsOH. The
1
FIGURE 4. Partial H NMR (300 MHz, CDCl3) spectral change of
(-)-1 (0.59 mmol) upon the addition of TsOH (0.58 mmol) in refluxing
benzene (a) before adding TsOH, (b) of the natural (-)-isocomene (3),
(c) after reacting for 30 min, (d) and after reacting for 90 min.
1 equiv of TsOH. Due to signal overlap, not all the regions of
the 1H NMR spectrum are convenient for monitoring the
Wagner-Meerwein-type rearrangements. However, the remote-
ness of the vinylic H3 and Me signals of (-)-1, (-)-3, and (-)-5
from other signals and their spread (1,2b 3,4b and 56) enables
their unequivocal identity.
When the equilibration reaction of (-)-1 was quenched with
saturated aqueous NaHCO3 (3 mL), after 30 min the resulting
(-)-isocomene 3 and (-)-triquinane 5 were observed in about
equal proportion and (-)-1 was completely consumed, as
1
inferred from the H NMR analysis of the reaction mixture.
The use of a longer reaction time (90 min), resulting in
thermodynamic reaction conditions, yielded (-)-triquinane 5
as the sole product. Figure 4 shows the 1H NMR spectral
changes with time observed for the vinylic proton and methyl
signals in (-)-1 upon addition of 1 equiv of TsOH. Control
experiments from natural (-)-3 showed that its total conversion
to (-)-5 occurs in about 90 min, demonstrating that the (-)-
triquinane 5 is produced from the rearrangement of both (-)-
modhephene (1) and (-)-isocomene (3). These results are in
agreement with the report of Fitjer et al.6 However, the question
(16) Although molecular modeling indicates that a direct 1,3-alkyl shift
for cation 13 is stereoelectronically favorable to give 20 in path II, the
postulated process through the higher-energy cation 14, mediated by two
consecutive 1,2-alkyl shifts, is required to account for the Me15R f Me15â
isomerization to afford cation 15 in path I.
(17) (a) Fitjer, L.; Kanschik, A.; Majewski, M. Tetrahedron Lett. 1988,
29, 5525-5528. (b) Fitjer, L.; Monzo´-Oltra, H. J. Org. Chem. 1993, 58,
6171-6173.
4414 J. Org. Chem., Vol. 71, No. 12, 2006

Rearrangements of (-)-Modhephene and (-)-Isocomene
FIGURE 5. Total energies (kcal/mol) for cations 13-21 proposed to be formed through 1,2 σ-migrations (paths I and II) in the equilibration
reactions of (-)-1 f (-)-5 calculated at the PM3 level of theory.
TABLE 1. Total and Relative Energiesa (kcal/mol) for the
Carbocations and Neutral Molecules (given in Figure 5) Involved in
Paths I and II
EPM3
G°
∆Gb
EPM3
G°
∆G
13 142.451 347.733
+0.428 19 141.762 347.304
0
14 153.769 359.333 +12.028 20 148.336 352.495 +5.191b
15 154.872 359.914 +12.610 21 144.039 349.028 +1.724b
16 143.450 349.034
17 154.203 359.536 +12.232
18 147.921 352.091 +4.786
+1.730
1
3
5
-32.931 168.202 +2.410c
-33.469 166.630 +0.838c
-34.256 165.792
0
a Optimized geometries at PM3. b Relative to cation 19. c Relative to 5.
deuterium-labeling studies clearly disclose that the acid-
catalyzed rearrangement of (-)-1-d gave the [14-2H1]-(-)-
triquinane 5-d after 90 min of reaction. The selected isotopically
shifted peak of the 14âCH2D group in the 13C NMR spectrum
of (-)-5-d provided evidence that this group is transferred
stereospecifically from C4 to the angular 5â-position of product
(-)-5-d, indicating that the fraction of the reaction that proceeds
through path I is relevant. The triplet signal of the 14âCH2D
FIGURE 6. Partial 13C NMR (75 MHz, CDCl3) spectra of (a) unlabeled
(-)-triquinane 5 and (b) [14-2H1]-(-)-triquinane 5-d, obtained by the
rearrangement of [14-2H1]-(-)-modhephene (1-d).
1
group showed a J(13C,D) of 19 Hz and was shifted to low
frequency by 0.303 ppm with respect to the singlet of the
unlabeled species (Figure 6).
A parallel finding shows that isocomene (-)-3 derived from
(-)-1-d does not show any noticeable deuterium content on
The observed stereospecific rearrangement of the 14âCH2D
group indicates the likelihood of a stereoelectronically favorable
antiperiplanar 1,2-migration step, that is, the migrating σ-bond
should be perpendicular to the plane of the sp2 cation carbon.
At this point, it would be important to stress that molecular
modeling indicates that, for cation structure 18, the dihedral
angle composed by the migrating σ-bond and the plane of the
sp2 cation carbon is within the range of 90 to 102° ( C14-
C4-C5-C1 and C14-C4-C5-C11, Table 2), in good
accordance with the molecular orbital demand and experimental
findings. In addition, in cation 19, a noticeable dihedral angle
difference was observed between H3â-C3-C4-C13 (73.81°)
and H3R-C3-C4-C13 (39.35°) or between H3â-C3-C4-
C5 (-107.80°) and H3R-C3-C4-C5 (139.04°), indicating that
proton elimination forming (-)-5 must occur on the â-face.
1
methyl carbons C13 or C14, as deduced from the H NMR
spectrum obtained after reacting for 30 min. Apparently, the
loss of deuterium occurs from the hyperconjugated stabilized
cation structure 21-d through a scrambling with the medium,
according to path II. Information about a possible isotope effect18
on the relative amounts of (-)-3 and (-)-5 was also obtained
when the equilibration reaction of (-)-1-d was quenched after
30 min. The increased proportion of (-)-5 was established by
the integration of the vinylic H3 signals in the 1H NMR
spectrum of the reaction mixture. Effectively, the (-)-3/(-)-5
ratio was 2:3 in contrast to the about equal proportion observed
(18) Vre`ek, V.; Saunders, M.; Kronja, O. J. Org. Chem. 2003, 68, 1859-
1866.
J. Org. Chem, Vol. 71, No. 12, 2006 4415

Joseph-Nathan et al.
TABLE 2. Comparison of Relevant Dihedral Angles ( ) for Cations 18-21 Calculated at the PM3 Level of Theory
18 (deg)
19 (deg)
20 (deg)
21 (deg)
C14-C4-C5-C1 ) 101.96
C14-C4-C5-C11 ) 89.68
C13-C4-C5-C1 ) -136.69
C13-C4-C5-C11 ) -31.67
H3â-C3-C4-C5 ) -107.80
H3â-C3-C4-C13 ) 73.81
H3R-C3-C4-C5 ) 139.04
H3R-C3-C4-C13 ) -39.35
C14-C4-C5-C1 ) -133.00
C14-C4-C5-C6 ) 37.11
C13-C4-C5-C1 ) 106.01
C13-C4-C5-C6 ) -83.87
H3â-C3-C4-C5 ) -132.76
H3â-C3-C4-C14 ) 44.98
H3R-C3-C4-C5 ) 114.20
H3R-C3-C4-C14 ) -68.06
TABLE 3. Relevant Bond Lengths (Å) and Bond Orders (in
Parentheses) for Carbocations 13, 16, 19, and 21
25 °C. After the addition of alcohol (-)-8 (0.5 g, 2.25 mmol) in
CH2Cl2 (5 mL), the mixture was stirred at the same temperature
for an additional 5 min. The mixture was filtered through a pad of
silica gel (20 g), and the pad was washed with CH2Cl2 (100 mL).
The filtrate and washings were combined, washed with 10% HCl
(2 × 25 mL), H2O (25 mL), saturated aqueous NaHCO3 (25 mL),
and H2O (25 mL), dried (Na2SO4), and evaporated under vacuum
to leave a yellow oily residue, which was purified by chromatog-
raphy on silica gel (hexane) to give (+)-9 (461 mg, 93%) as a
cation
C2-C12
C4-C13
C4-C14
C8-C15
13
1.445
1.520
1.528
1.509
(1.102756)
1.445
(1.104236)
1.523
(0.986825)
1.522
(0.985944)
1.529
(0.984167)
1.449
(0.984264)
1.523
(0.985716)
(0.995994)
1.515
(0.994287)
1.514
(0.993996)
1.520
16
19
21
(1.094106)
colorless oil: [R]20589 +130, (c 1.30, CHCl3), [R]20578 +136, [R]20
1.448
546
+164, [R]20 +391, [R]20 +1140; UV (EtOH, ꢀ) λmax 220
(0.986655)
(1.096004)
(0.992799)
436
365
(2300); IR (CHCl3) νmax 3030, 2948, 2866, 1712, 1628, 1468, 1378
cm-1; H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H, H14), 4.90 (q,
1
for the corresponding nondeuterated counterpart (see Figure 4).
This result implies that the less “kinetically acidic” deuterium
atom gave rise to an attenuation in the formation of (-)-
isocomene (3).
J ) 1.4 Hz, 1H, H3), 2.12 (m, 1H, H11), 1.84-0.98 (m, 10H, 5 ×
CH2), 1.73 (d, J ) 1.4 Hz, 3H, H12), 1.11 (m, 1H, H11′), 1.10 (s,
3H, H13), 1.02 (d, J ) 6.5 Hz, 3H, H15); 13C NMR (75 MHz,
CDCl3) δ 205.5 (C14), 148.3 (C2), 125.8 (C3), 73.7 (C1), 65.7
(C5), 62.0 (C4), 43.2 (C8), 38.0 (C11), 35.4 (C7), 35.1 (C6), 29.7
(C9), 26.9 (C10), 17.3 (C13), 15.4 (C15), 14.1 (C12). EIMS (20
eV) m/z: 218 (M+, 0.1), 189 (100), 187 (19.5).
Molecular modeling indicates the likelihood of a stereoelec-
tronically favorable alignment of the 13RMe group with the
sp2 carbon cation in the calculated cation structure 20 (Table
2), to generate the hyperconjugated stabilized intermediate cation
21 by vicinal 13RMe rearrangement from C4 to C5, in
agreement with experimental data. In the case of cation 21, H3R
shows a better geometrical disposition for elimination than H3â
to give (-)-3 (Table 2). The hyperconjugative stabilization of
cations 13, 16, 19, and 21 is corroborated by the fact that the
C+-Me bond lengths are shorter than in the neutral Csp3sMe
bonds (Table 3), reflecting the strength of the π interactions
between the methyl substituent and the empty p orbital on the
cation center (see bond orders in Table 3).
(-)-Modhephen-14-ethylenedithioacetal (10). To a stirred
solution of (+)-modhephen-14-al (9; 480 mg, 2.2 mmol) and 1,2-
ethanedithiol (0.85 mL, 1.0 g, 10.6 mmol) in anhydrous benzene
(20 mL) was added anhydrous CuSO4 (840 mg, 5.3 mmol). The
resulting mixture was refluxed for 2 h, quenched by the addition
of ice water (20 mL), and extracted with EtOAc (3 × 50 mL). The
combined organic layers were washed with cold 10% NaOH
solution (12 × 25 mL) and H2O (2 × 25 mL), dried (Na2SO4),
filtered, and evaporated under vacuum to leave a whitish oily
residue, which was purified by chromatography on silica gel
(hexane) to give (-)-10 (403 mg, 62%) as a colorless oil: [R]20
589
-45, (c 3.2, CHCl3), [R]20 -47, [R]20 -53, [R]20 -86,
578
546
436
Conclusions
[R]20365 -120; IR (CHCl3) νmax 3016, 2952, 2868, 1522, 1474, 1426
1
cm-1; H NMR (300 MHz, CDCl3) δ 4.94 (q, J ) 1.4 Hz, 1H,
Starting from natural (-)-14-hydroxymodhephene (8), we
synthesized and characterized modhephene (-)-1 and [14-2H1]-
(-)-1 by the application of a selective oxidation/sulfur acetal-
ization/reductive desulfurization sequence. The stereoselective
1,2-methyl migration in the rearrangement of (-)-1 to iso-
comene (-)-3 and triquinanne (-)-5 was assessed by stereospe-
cific labeling of the 14â geminal methyl group of (-)-1. The
NaBD4 reduction of (+)-modhephen-14-al (9) to the corre-
sponding deuterated primary alcohol (14S)-(-)-8-d provides the
first example of a high diastereoselective NaBD4 reduction
involving a â,γ-unsaturated aldehyde, without an added chiral
reagent. In this reduction, the resident stereogenic centers could
exhibit modest stereoinduction, leading to the stereohindered
re-face-controlled selectivity. Isotope effects demonstrated that
the major reaction route to triquinane (-)-5 is that presented
as path I, and the fraction of the reaction that proceeds through
path II can be rationalized if an epimerization step occurs at
the stage of cation 14. In addition, the stereospecific mechanisms
of the 1,2-methyl shifts and the terminating proton eliminations
were investigated using the PM3 semiempirical method.
H3), 4.77 (s, 1H, H-14), 3.15 (m, 4H, H16, H16′, H17, H17′), 2.12
(m, 1H, H11), 1.84-1.04 (m, 10H, 5 × CH2), 1.62 (d, J ) 1.4 Hz,
3H, H12), 1.22 (s, 3H, H13), 1.09 (m, 1H, H11′), 0.98 (d, J ) 6.5
Hz, 3H, H15); 13C NMR (75 MHz, CDCl3) δ 144.4 (C2), 132.3
(C3), 73.4 (C1), 67.5 (C5), 64.2 (C14), 55.2 (C4), 43.2 (C8), 39.2
(C16), 39.0 (C17), 38.7 (C11), 36.0 (C7), 35.3 (C6), 27.6 (C10),
30.6 (C9), 17.7 (C13), 15.4 (C15), 13.8 (C12). CIMS (20 eV) m/z:
295 (M+ + H, 100), 201 (39), 189 (10); HRCIMS calcd for
C17H27S2, 295.1554 (M+ + H); found, 295.1550.
(-)-Modhephene (1). To a solution of dithioacetal (-)-10 (90
mg, 0.31 mmol) in absolute ethanol (15 mL) was added Raney
nickel (1.0 g), and the solution was refluxed for 5 h. The mixture
was filtered through a pad of Celite (10 g), and the pad was washed
with ethanol (4 × 20 mL). The filtrate and washings were combined
and concentrated under reduced pressure to give an oily residue,
which was purified by chromatography on AgNO3-impregnated19
silica gel (20%, w/w), using hexane as the eluent to afford (-)-1
(50 mg, 80%) as a colorless oil. The spectral data of (-)-1 were
identical with those reported,2b,7a except the reassignment of the
13C NMR signals at δ 26.3 (C13) and 29.3 (C14).
[14-2H1]-(-)-14-Hydroxymodhephene (8-d). To a stirred solu-
tion of aldehyde (+)-9 (50 mg, 0.23 mmol) in MeOD (2 mL, 93%
D) at 0 °C was added NaBD4 (5 mg, 0.12 mmol, 98% D). The
reaction mixture was allowed to stir at the same temperature for 5
Experimental Section
(+)-Modhephen-14-al (9). To a stirred solution of CH2Cl2 (35
mL) and anhydrous pyridine (2.3 mL, 27 mmol) at 5 °C was added
CrO3 (1.4 g, 14 mmol), and the stirring was continued for 1 h at
(19) Jin, Q.; Williams, D. C.; Hezari, M.; Croteau, R.; Coates, R. M. J.
Org. Chem. 2005, 70, 4667-4675.
4416 J. Org. Chem., Vol. 71, No. 12, 2006

Rearrangements of (-)-Modhephene and (-)-Isocomene
min, quenched with ice water (2 mL), extracted with CH2Cl2 (3 ×
50 mL), dried (Na2SO4), filtered, and evaporated to dryness to give
an oily residue. The residue was purified by chromatography on
silica gel (hexane) to afford (-)-8-d as an inseparable epimeric
mixture with a 14S/14R selectivity of 9:1 (40 mg, 79%). The major
compound exhibited an identical 1H NMR spectrum to that of (-)-
14-hydroxymodhephene (8), except for the integrated peak area
corresponding to the primary alcohol methylene signals at δ 3.30
and δ 3.41.7b The deuterium content was determined to be 91 (
1% on the basis of the 1H NMR analysis of the corresponding TAI
derivative 11-d.
127b to give (+)-12-d (322 mg, 80%) as colorless needles that were
recrystallized from MeOH, mp 102-104 °C. The title compound
1
exhibited an identical H NMR spectrum to that of hemiphthalate
(+)-12, except for the integrated peak area corresponding to the
ester methylene signals at δ 4.22 and δ 4.08. The deuterium content
1
was determined to be 91 ( 1% by H NMR.
(-)-Triquinane 5. Method A. A solution containing (-)-1 (120
mg, 0.59 mmol) and p-TsOH (110 mg, 0.58 mmol) in anhydrous
benzene (5 mL) was refluxed for 30 min. The mixture was cooled
to room temperature and one aliquot of 1 mL was removed,
quenched with saturated aqueous NaHCO3 (3 mL), and extracted
with pentane (3 × 3 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give an oily
residue (20 mg). The product was an equimolar mixture of (-)-
isocomene 3 and (-)-triquinane 5, as evidenced by 1H NMR
analysis. The remaining reaction mixture was refluxed for an
additional 1 h and quenched with saturated aqueous NaHCO3 (3
mL). The same workup procedure gave a crude product, which
was purified by chromatography on AgNO3-impregnated silica gel
(20%, w/w), using hexane as the eluent to afford (-)-5 (60 mg,
63%) as a clear oil, whose spectral data were identical to those of
literature.6 Method B. A solution containing (-)-3 (24 mg, 0.12
mmol) and p-TsOH (27 mg, 0.14 mmol) in 5 mL of anhydrous
benzene was refluxed for 90 min. Following the same workup
procedure described in method A, the obtained crude product was
purified by chromatography on AgNO3-impregnated silica gel (20%,
w/w), using hexane as the eluent to afford (-)-5 (8 mg, 33%) as a
clear oil.
[14-2H1]-(+)-Modhephen-14-al (9-d). Compound (-)-8-d (250
mg, 1.13 mmol) was oxidized with the complex CrO3-Py2 (700
mg, 7 mmol) by the same procedure used in the preparation of
(+)-9 to give (+)-9-d (218 mg, 88%) as a clear oil. The title
compound exhibited an identical 1H NMR spectrum to the unlabeled
compound (+)-9, except for the integrated peak area corresponding
to the aldehyde signal at δ 9.55. The deuterium content was
1
determined to be 78 ( 1% by H NMR.
[14-2H1]-(-)-Modhephen-14-ethylenedithioacetal (10-d). Com-
pound (+)-9-d (210 mg, 0.96 mmol) was sulfur acetalized with
1,2-ethanedithiol (0.25 mL, 0.3 g, 3.19 mmol) and anhydrous CuSO4
(260 mg, 1.60 mmol) by the same procedure used in the preparation
of (-)-10 to give (-)-10-d (181 mg, 64%) as a clear oil. The title
compound showed an identical 1H NMR spectrum to the unlabeled
compound (-)-10, except for the integrated peak area corresponding
to the methine-14 signal at δ 4.77. The deuterium content was
1
determined to be 79 ( 1% by H NMR.
[14-2H1]-(-)-Modhephene (1-d). Compound (-)-10-d (355 mg,
1.2 mmol) was desulfurized with Raney nickel (4.3 g) by the same
procedure used in the preparation of (-)-1 to afford (-)-1-d (186
mg, 75%) as a clear oil. The title compound exhibited identical 1H
NMR spectrum to the unlabeled compound (-)-1, except for the
integrated peak area of the methyl-14 signal at which deuterium
was introduced. The deuterium content was estimated to be 76%
[14-2H1]-(-)-Triquinane 5-d. A solution containing (-)-1-d (75
mg, 0.37 mmol) and p-TsOH (81 mg, 0.42 mmol) in 3 mL of
anhydrous benzene was refluxed for 90 min. The mixture was
cooled to room temperature and then quenched with saturated
aqueous NaHCO3 (3 mL). Following the same workup procedure
described in method A, the obtained crude product was purified
by chromatography on AgNO3-impregnated silica gel (20%, w/w),
using hexane as the eluent to afford (-)-5-d (30 mg, 40%) as a
clear oil. The title compound exhibited identical 1H NMR spectrum
to the unlabeled compound (-)-5, except for the integrated peak
area corresponding to the singlet at δ 1.01 assigned to Me14. The
1
by H NMR.
(+)-Hemiphthalate (12).7b Recrystallized from MeOH, mp
102-104 °C; [R]589 +6, (c 1.13, CHCl3), [R]20578 +5, [R]20546 +7,
[R]20 +11, [R]20 +10; UV (EtOH, ꢀ) λmax 225 (7800), 275
436
365
(1000); IR νmax (CHCl3) 3508, 1720, 1701, 1600, 1580, 1492 cm-1
;
1
deuterium content was determined to be 50 ( 1% by H NMR.
1H NMR (300 MHz, CDCl3) δ 8.57 (br, 1H, COOH), 7.89 (dd,
1H, J ) 7.4, 1.5 Hz, H3′), 7.68 (dd, 1H, J ) 7.4, 1.4 Hz, H6′),
7.59 (td, 1H, J ) 7.3, 1.5 Hz, H5′), 7.56 (td, 1H, J ) 7.3, 1.5 Hz,
H4′), 4.78 (q, J ) 1.4 Hz, 1H, H3), 4.22 (d, J ) 10.8 Hz, 1H,
pro-R H14), 4.08 (d, J ) 10.8 Hz, 1H, pro-S H14), 2.02 (m, 1H,
H11), 2.02-1.00 (m, 10H, 5 × CH2), 1.59 (d, J ) 1.4 Hz, 3H,
H12), 1.04 (s, 3H, H13), 0.92 (d, J ) 6.5 Hz, 3H, H15); 13C NMR
(75 MHz, CDCl3) δ 172.2 (COOH), 168.1 (COOR), 144.9 (C2),
133.3 (C1′), 132.0 (C5′), 130.8 (C4′), 130.4 (C2′), 129.9 (C3′), 129.4
(C3), 128.8 (C6′), 73.4 (C1), 73.3 (C14), 65.3 (C5), 49.5 (C4), 43.3
(C8), 38.9 (C11), 35.0 (C6), 34.9 (C9), 34.1 (C7), 26.8 (C10), 21.1
(C13), 15.2 (C15), 13.9 (C12). EIMS (20 eV) m/z: 368 (M+, 0.1),
190 (19.4), 189 (100).
Acknowledgment. This research was supported by grants
from CONACYT (Me´xico). We are grateful to Dr. L. U. Roma´n,
Instituto de Investigaciones Qu´ımico Biolo´gicas, Universidad
Michoacana de San Nicola´s de Hidalgo, Morelia, Me´xico, who
kindly supplied an authentic sample of (-)-isocomene.
Supporting Information Available: Copies of 1H NMR spectra
of (-)-1, (-)-1-d, (-)-3, (-)-8-d, (+)-9, (+)-9-d, (-)-10, (-)-10-
d, 11, 11-d, (+)-12, and (+)-12-d; 13C NMR spectra of (+)-9, and
(-)-10; EIMS spectra of (-)-1 and (-)-1-d; and Cartesian
coordinates of calculated minimum energies of (-)-1, (-)-3, (-)-
5, (+)-9, (+)-12, and cations 13-21. This material is available
free of charge via the Internet at http://pubs.acs.org.
[14-2H1]-(+)-Hemiphthalate (12-d). Compound (-)-8-d (140
mg, 0.63 mmol) was esterified with phthalyc anhydride (240 mg,
1.60 mmol) by the same procedure used in the preparation of (+)-
JO060258T
J. Org. Chem, Vol. 71, No. 12, 2006 4417