Synthesis of terpenoid unsaturated 1,4-dialdehydes. π-Facial selectivity in the Diels-Alder reaction of the 1-vinyl-2-methylcyclohexene moiety of polycyclic systems with DMAD

Full text of DOI:10.1021/jo9919097

J . Org. Chem. 2000, 65, 4189-4192
4189
Sch em e 1. Rep r esen ta tive Ter p en oid
Un sa tu r a ted 1,4-d ia ld eh yd es w ith Dr im a n e (1),
Sp on gia n e (2), a n d Sca la r a n e (3) Sk eleton s
Syn th esis of Ter p en oid Un sa tu r a ted
1,4-Dia ld eh yd es. π-F a cia l Selectivity in th e
Diels-Ald er Rea ction of th e
1-Vin yl-2-m eth ylcycloh exen e Moiety of
P olycyclic System s w ith DMAD
Antonio Abad,* Consuelo Agullo´,
Lourdes Castelblanque, Ana C. Cun˜at,
Ismael Navarro, and M. Carmen Ram´ırez de Arellano
Departamento de Quı´mica Orga´nica, Facultad de Quı´micas,
Universidad de Valencia, C/ Dr. Moliner 50,
E-46100 Burjassot, Valencia, Spain
Sch em e 2
Received December 14, 1999
In tr od u ction
An increasing number of polycyclic terpenoids contain-
ing the unsaturated 1,4-dialdehyde moiety, either as
actual aldehyde groups or latent as γ-butenolide or furan
rings, have been isolated from different terrestrial and
marine sources.1 The more representative compounds of
this type show structures based on the drimane, spon-
giane, and scalarane skeletons (Scheme 1). Many of these
compounds exhibit a variety of potent biological activities,
including antibacterial, antifungal, antifeedant, antiin-
flammatory, antitumor-promoting, cytotoxic, enzyme-
inhibiting, and plant growth regulatory properties,1,2 that
have greatly stimulated the synthetic work in this area
of natural products.
Sch em e 3
Although a number of different synthetic approaches
to natural products within this class have been reported,3
the use of the intermolecular Diels-Alder reaction of an
appropriately substituted 1,3-diene with dimethyl acety-
lenedicarboxylate (DMAD) to construct the B, C, or D ring
of drimane, spongiane, and scalarane terpenoids, respec-
tively, in a concise manner is particularly attractive
(Scheme 2).
This strategy has been successfully used to prepare the
simplest member of this group of natural products,
polygodial (1), as well as many other drimane sesquit-
erpenes.4 In connection with our synthetic studies on
scalarane and spongiane terpenoids,5 we have investi-
gated the potential application of this Diels-Alder reac-
tion to the synthesis of these polycyclic compounds. We
report here the results of this study.
Resu lts a n d Discu ssion
The Diels-Alder reaction of the diene 6 with DMAD
as a potential route to the spongiane system was first
studied. The synthesis of the diene 66 is summarized in
Scheme 3. The known decalone 4, prepared in four steps
from commercial (R)-(-)-carvone,7 was treated with vi-
nylmagnesium bromide in THF at low temperature to
afford stereoselectively the axial alcohol 5 in 80% yield
after chromatographic purification.8 Finally, treatment
of 5 with thionyl chloride-pyridine at low temperature
cleanly furnished the diene 6.
(1) (a) J onassohn, M.; Sterner, O. Trends Org. Chem. 1997, 6, 23
and references therein. (b) Connolly, J . D.; Hill, R. A. In Dictionary of
Terpenoids, 1st ed.; Chapman and Hall: London, 1991; Vol. 1, p 453;
Vol. 2, pp 895 and 1110. (c) Fraga, B. M. Nat. Prod. Rep. 1999, 16, 21
and previous reviews on sesquiterpenes of this series. (b) Hanson, J .
R. Nat. Prod. Rep. 1999, 16, 209 and previous reviews on diterpenes
of this series. (c) Faulkner, D. J . Nat. Prod. Rep. 1997, 14, 259 and
previous reviews on sesterterpenes of this series.
(2) J ansen, B. J . M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 309.
(3) (a) J ansen, B. J . M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 319.
(b) Zoretic, P. A.; Zhang, Y.; Fang, H. J .; Ribeiro, A.; Dubay, G. J . Org.
Chem. 1998, 63, 1162. (c) Pattenden, G.; Roberts, L.; Blake, A. J . J .
Chem. Soc., Perkin Trans. 1 1998, 863 and references therein. (d)
Corey, E. J .; Luo, G.; Lin, S. J . Am. Chem. Soc. 1997, 119, 9927 and
references therein.
When a neat mixture of DMAD and the bicyclic diene
6 was heated at 110 °C for 24 h, a smooth and clean
(4) For a review of the application of this strategy to the synthesis
of drimane sesquiterpenes, see: (a) de Groot, A.; van Beek, T. A. Recl.
Trav. Chim. Pays-Bas 1987, 106, 1. See also: (b) Hollinshead, D. M.;
Howell, S. C.; Ley, S. V.; Mahon, M.; Ratcliffe, N. M.; Worthington, P.
A. J . Chem. Soc., Perkin Trans. 1 1983, 1579.
(5) (a) Abad, A.; Agullo´, C.; Arno´, M.; Marin, M. L.; Zaragoza´, R. J .
J . Chem. Soc., Perkin Trans. 1 1996, 2193 and references therein. (b)
Abad, A.; Agullo´, C.; Cun˜at, A. C.; Llosa´, M. C. J . Chem. Soc., Chem.
Commun. 1999, 427.
(6) Racemic diene 6 has been previously prepared in nine synthetic
steps from cyclohexane-1,3-dione: Daniewski, W. M.; Kubak, E.;
J urczak, J . J . Org. Chem. 1985, 50, 3963.
(7) Gesson, J . P.; J acquesy, J . C.; Renoux, B. Tetrahedron 1989, 45,
5853.
(8) A 5-6% amount of the more polar epimeric equatorial alcohol
was also obtained in this reaction (see Experimental Section). The
equatorial disposition of the vinyl group in
5 was assigned by
intramolecular NOE studies. In particular, irradiation of the vinylic
10.1021/jo9919097 CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/31/2000

4190 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
between the methyl groups at C-8a and C-5, there does
not seem to exist an evident steric bulk on the R-face that
will direct the approach of the dienophile from the
opposite face and much less to predict the high level of
observed syn-selectivity. In fact, it has been previously
observed that the Diels-Alder reaction of the same diene
with a carbonyl heterodienophile6 gave a 65:35 mixture
of anti and syn Diels-Alder adducts, respectively. The
same pattern has also been observed in the thermal
cycloaddition reaction of a related diene (2-desmethyl)
with 2,6-dimethylbenzoquinone,10 in which the anti- and
syn-adducts are obtained in a ratio that varies from 100:0
to 70:30 depending upon the reaction conditions used.
Theoretical calculations, using the GAUSSIAN98 pro-
gram, have been carried out in order to understand the
stereochemical outcome of the Diels-Alder reaction of 6
with DMAD. The geometry of the two transition struc-
tures, corresponding to the epimeric syn- and anti-
adducts, was searched using the AM1 method, and it was
not possible to find a concerted mechanism for the
reaction. This could be due to the very well-known
tendency of the semiempirical methods to give stepwise
mechanisms in the Diels-Alder reactions. The transition
structures were also optimized using low-level ab initio
(HF/STO-3G) methods, due to the size of the system, and
in this case two concerted and slightly asynchronous
transition structures were found (see Figure 3 of the
Supporting Information). However, the transition struc-
ture corresponding to the formation of the anti-adduct
is favored by 0.9 kcal/mol, which is in contradiction with
the facial selectivity experimentally observed. It is con-
cluded from these preliminary calculations that semiem-
pirical methods are not adequate to study this reaction
and, if it takes place through a concerted mechanism,
the theoretical study should be carried out using a high-
level ab initio method.14
To determine if the observed selectivity in the above
Diels-Alder reaction was related with the acetylenic
nature of the dienophile used, the reaction of 6 with other
dienophiles was examined. Although longer reaction
times than with DMAD were required, the Diels-Alder
reaction of diene 6 with other differently functionalized
acetylenic compounds (e.g. Me3SiCtCCHO, PhSO2Ct
CH) took place with similar syn:anti stereoselectivity. No
appreciable reaction of 6 with sterically more demanding
dienophiles such as methyl fumarate, methyl maleate,
or maleic anhydride was observed under the same
reaction conditions used with DMAD. Higher tempera-
tures or the use of Lewis acid conditions promoted
extensive isomerization of the diene double bonds.15 As
an exception, the Diels-Alder reaction of 6 with tetra-
F igu r e 1. Molecular structure of 7 determined by X-ray
crystallography.
reaction took place giving a chromatographically homo-
geneous approximately 95:5 mixture (1H NMR analysis)9
of Diels-Alder adducts in nearly quantitative yield. From
this mixture, the major adduct could be obtained in
analytically pure form by crystallization from hexane-
dichloromethane. The structure 7 was initially assigned
to this Diels-Alder adduct on the basis of intramolecular
NOE studies and analysis of the 13C NMR data. In
particular, no NOE was observed upon irradiation of
either the Me-7 (δ 1.31 ppm) or the Me-1 (δ 1.05 ppm)
on each other, which strongly suggested the anti disposi-
tion of both methyl groups. Comparison of the chemical
shift of the A/B rings carbon atoms with those of related
epimeric compounds at C-710,11 revealed that C-10 (δ
43.98 ppm) is appreciably shifted upfield (between 8 and
9 ppm) in 7 with respect to those tricyclic compounds with
a syn arrangement of the methyl groups at C-7 and C-1.
This shielding of C-10 could not be explained by assuming
a â orientation of the Me group at C-7 but should be in
agreement with an R disposition of this group which
forces the B ring to adopt a boatlike conformation.10,12
This hypothesis was confirmed when suitable crystals for
X-ray analysis could be obtained that unambiguously
established the structure of 7 (Figure 1).
The formation of compound 7 as the major adduct in
the Diels-Alder reaction of 6 with DMAD was unex-
pected and contrary to our initial assumption that the
Diels-Alder condensation would take place by approach
of the dienophile anti (below plane) to the angular methyl
group at C-8a of the diene. It has been pointed out that
steric effects are the main factor that control the face
selectivity in Diels-Alder reaction of semicyclic dienes.13
Examination of the lowest energy conformation of diene
6 suggests that, despite the slightly curved geometry
adopted by the molecule to relieve the diaxial interaction
CH at δ 5.82 ppm gave a NOE enhancement for the Me-8aâ at 0.95
ppm and the H-2â at 1.9 ppm. A similar stereochemical result has
been recently observed in the addition of other Grignard reagents to
the ketone 4; see: Drew, M. G. B.; Harwood, L. M.; J ahans, A.;
Robertson, J .; Swallow, S. Synlett 1999, 185.
(9) By integration of the dCH signals for both adducts which are
clearly resolved in the 1H NMR spectrum of the mixture (δ 5.64 ppm
for the major isomer and δ 5.50 ppm for the minor one).
(10) Arse´niyadis, S.; Rodriguez, R.; Spanevello, R.; Camara, J .;
Thompson, A.; Guittet, E.; Ourisson, G. Tetrahedron 1992, 48, 1255.
(11) Abad, A.; Agullo´, C.; Arno´, M.; Marin, M. L.; Zaragoza´, R. J . J .
Chem. Soc., Perkin Trans. 1 1996, 2193.
(12) Weibel, J . M.; Heissler, D. Tetrahedron Lett. 1994, 35, 473.
(13) Fallis, A. G.; Yee-Fung, L. π-Facial Diastereoselection in Diels-
Alder Cycloadditions and Related Reactions: Understanding Planar
Interactions and Establishing Synthetic Potential. In Advances in
Cycloaddition; Curran, D. P., Ed.; J AI Press Inc.: Greenwich, CT, 1993;
Vol. 3, p 1.
(14) The geometry of the two [4 + 2]-cycloadducts was also optimized
using molecular mechanics (MM2 force field) and semiempirical (AM1
and PM3 Hamiltonians) methods. The result of these calculations
indicates that the anti-adduct is the most stable one (between 0.6 and
1.3 kcal/mol; see Figure 2 of the Supporting Information for the
optimized structures of the adducts). On the basis of these data, a
possible thermodynamic control of this Diels-Alder reaction seems
unlikely.
(15) This circumstance has also been observed in the Diels-Alder
reaction of related monocyclic dienes with ethylenic dienophiles; see:
J alali-Naini, M.; Guillerm, D.; Lallemand, J . Y. Tetrahedron 1983, 39,
749. For these conformationally more mobile monocyclic systems a
combination of high-pressure and Lewis acid-catalyzed conditions has
been used to promote the cycloaddition reaction; see: (a) Engler, T.
A., Sampath, U.; Naganathan, S.; Vander Velde, D.; Takusagawa, F.;
Yohannes, D. J . Org. Chem. 1989, 54, 5712. (b) Mayelvaganan, T.;
Hadimani, S. B.; Shreeshailkumar, B.; Bhat, S. V. Tetrahedron, 1997,
53, 2185 and references therein.

Notes
J . Org. Chem., Vol. 65, No. 13, 2000 4191
route previously followed by us and others18 for the
preparation of related polycyclic systems.
Sch em e 4
Chemoselective Wittig reaction of the aldehyde group
of 8 with (R-formylethylidene)triphenylphosphorane gave
the chain-extended aldehyde 9, which by Wittig meth-
ylenation under the usual conditions gave the triene 10
in 81% overall yield for the two steps. Heating a solution
of 10 in toluene and a small amount of propylene oxide
in a sealed tube at 185 °C for 6 days stereoselectively
afforded the trans-anti-trans tricyclic ketone 11 in 86%
yield. The reduction of the enone moiety of 11 with
sodium tellurium hydride gave a mixture of epimeric
ketones, which were equilibrated to the thermodynami-
cally more stable equatorial methyl ketone 12 by sodium
methoxide treatment. This ketone, obtained in 80%
overall yield from the enone 11, was then stereoselec-
tively cyclopropanated under standard Simmons-Smith
cyclopropanation conditions in very high yield. This was
an indirect way of introducing the characteristic geminal
dimethyl group that exists at the A ring of many natural
scalaranes.
Completion of the synthesis of the diene 15 from 13
was finally effected by following the same protocol used
for the previously described conversion of 4 into 6. Thus,
treatment of the ketone 13 with vinylmagnesium bromide
and subsequent exposure to thionyl chloride-pyridine
afforded the expected diene 15 in 73% overall yield.
With the diene 15 readily at hand, we tried its Diels-
Alder reaction with DMAD. Heating a mixture of this
diene and DMAD at 120 °C overnight cleanly afforded
an approximately 95:5 mixture of Diels-Alder adducts
in 92% yield after chromatographic purification of the
crude product. Crystallization of this mixture from MeOH
furnished the major adduct practically free of the minor
one. Not unexpectedly, with knowledge of the previous
result obtained in the Diels-Alder reaction of 6, the
structure 16 was assigned, on the basis of its spectro-
scopic data, to the major adduct obtained. Both Diels-
Alder adducts 7 and 16 showed 1H and 13C NMR
spectroscopic data that were superimposable on all the
signals associated with their common structural fea-
tures.19
cyanoethylene as dienophile took place under very smooth
conditions (e.g.: THF, room temperature, 48 h) to give a
roughly 1:1 mixture of anti- and syn-adducts in nearly
quantitative yield. However it has been shown that this
highly reactive dienophile reacts by an aziridinium imide
(1,4-zwitterion) mechanism, and thus, to draw conclu-
sions from this reaction about the influence of the
ethylenic nature of the dienophile in the stereochemical
course of the Diels-Alder reaction of 6 does not seem
reasonable.
In conclusion, the direction of the attack observed in
the thermal Diels-Alder reaction of polycyclic 1,3-dienes
6 and 15 with DMAD is contrary to the expected
R-approach of the dienophile, anti to the angular methyl
groups. Consequently, the strategy outlined in Scheme
2, successfully used previously for the synthesis of bicyclic
drimane sesquiterpenes, is not useful for the preparation
of higher terpenes possessing spongiane (2) or scalarane
(3) structures.20
Concurrently with the transformation described above
we also studied the Diels-Alder reaction of the diene 15
with DMAD as a possible approach to the construction
of the scalarane skeleton (Scheme 4).16 The synthesis of
the diene 15 commences with the preparation of the
tricyclic ketone 12, which is effected from (S)-(+)-carvone
through the known keto aldehyde 8,17 following a similar
Exp er im en ta l Section 21
(4a S,8a S,1R,2R)-2,5,5,8a -Tetr a m eth yl-1-vin ylp er h yd r o-
1-n a p h th ta len ol (5). A solution of the ketone 4 (510 mg, 2.45
mmol) (prepared as described in ref 7; see also Supporting
Information) in THF (13 mL) was treated at -78 °C with a 1 M
solution of vinylmagnesium bromide in THF (4.9 mL, 4.9 mmol).
(16) The Diels-Alder reaction of a related diene with DMAD has
been previously described; see: Nakano, T.; Herna´ndez, M. I.; Mart´ın,
A.; Medina, J . D. J . Chem. Soc., Perkin Trans. 1 1988, 1349. It follows
from our work described here that the stereochemistry assigned by
these authors to the Diels-Alder adduct prepared by them is incorrect
and must be inverted at C-13 (terpene numbering; see ref 1b), thus
making the work described in that paper the synthesis of a 13-
episcalarane system.
(17) Abad, A.; Agullo´, C.; Arno´, M.; Cun˜at, A. C.; Meseguer, B.;
Zaragoza´, R. J . J . Org. Chem. 1998, 63, 5100.
(18) (a) Rawal, V. H.; Iwasa, S. Abstracts of Papers; 204th National
Meeting of the American Chemistry Society, Washington, DC; Ameri-
can Chemical Society: Washington, DC, 1992; ORGN 35. (b) Shing,
T. K. M.; J iang, Q.; Mak, T. C. W. J . Org. Chem. 1998, 63, 2056 and
literature cited therein.

4192 J . Org. Chem., Vol. 65, No. 13, 2000
Notes
The reaction mixture was allowed to warm to room temperature,
and the stirring was continued for 30 min. The mixture was
diluted with saturated aqueous NH4Cl solution and extracted
with hexane. The combined organic phases were washed with
brine, dried, and concentrated. The residue was purified by
chromatography, using 95:5 hexanes-ether as eluent, to afford
the alcohol 5 (463 mg, 80%): mp 35-36 °C (from cold pentane);
enylation of ketone 13 (136 mg, 0.50 mmol) (prepared as
described in the Supporting Information) by treatment with
vinylmagnesium bromide (1 mL of a 1 M solution in THF, 1
mmol) in THF (4 mL) in the same way described for 4 afforded,
after chromatographic purification using 9:1 hexanes-ether as
eluent, the alcohol 14 (124 mg, 89%) as a white solid: mp 106.5-
107 °C (from MeOH); [R]25D +38.4 (c 1.3, CHCl3); IR (KBr) 3635,
1454, 1363, 996, 936 cm-1; 1H NMR (299.95 MHz, CDCl3) δ 5.83
(1H, dd, J 16.7, 11.5), 5.16 (1H, dd, J 16.7, 1.7), 5.15 (1H, dd, J
11.5, 1.7), 1.9 (2H, m), 1.01 (3H, s), 0.94 (3 H, s), 0.79 (3H, s),
0.70 (3H, d J 6.6), 0.5 (1H, m), 0.4 (1H, dd, J 9.0, 3.6), -0.09
(1H, dd, J 6.0, 3.6); HRMS calcd for C21H34O 302.2609, found
302.2604.
[R]22 -14.3 (c 10.2, CHCl3); IR (KBr) 3600 cm-1 1H NMR
;
D
(199.95 MHz, CDCl3) δ 5.82 (1H, dd, J 17.2, 10.8), 5.13 (1H, dd,
J 10.8, 1.6), 5.04 (1H, dd, J 17.2, 1.6), 0.95 (3H, s), 0.86 (3H, s),
0.81 (3H, s), 0.70 (3H, d, J 6.7); HRMS calcd for C16H28
O
236.2140, found 236.2147. This was followed by the (1S)-epimer
of 5 (28 mg, 5%): [R]22D -10.7 (c 9.9, CHCl3); IR (film) 3511 cm-1
1H NMR (299.95 MHz, CDCl3) δ 6.20 (1H, dd, J 16.8, 11.5), 5.24
(1H, dd, J 11.5, 1.9), 5.23 (1H, dd, J 16.8, 1.9), 1.05 (3H, s), 0.84
;
(1S,10S,13S,2R,7R,11R)-1,5,7,11-Tetr am eth yl-6-vin yltetr a-
cyclo[8.5.0.02,7.011,13]p en ta d ec-5-en e (15). This compound was
prepared by treatment of 14 (124 mg, 0.42 mmol) with pyridine
(1.6 mL) and thionyl chloride (40 µL, 0.42 mmol), as described
above for the synthesis of 6. Extraction with hexane and workup
of the extract afforded a residue, which was purified by chro-
matography, using 9:1 hexanes-ether as eluent, to give diene
(3H, s), 0.83 (3H, s), 0.70 (3H, d, J 6.6); HRMS calcd for C16H28
236.2140, found 236.2135.
O
(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octah ydr o-2,5,5,8a-tetr am eth yl-
1-vin yln a p h th a len e (6). To a solution of the alcohol 5 (450 mg,
1.9 mmol) in anhydrous pyridine (4 mL) was added dropwise
thionyl chloride (0.18 mL, 2.09 mmol) at -30 °C. The reaction
mixture was allowed to warm to -10 °C during 1 h and then
diluted with hexane. The organic layer was washed with diluted
hydrochloric acid, aqueous NaHCO3, and brine. Drying and
evaporation of the solvent gave an oily residue. This was purified
by chromatography, using 95:5 hexanes-ether as eluent, to give
the diene 6 (374 mg, 90%) as a relatively volatile colorless oil:
[R]22D +85 (c 6, CHCl3); IR (film) 3091, 1621, 915 cm-1; 1H NMR
(200.13 MHz, CDCl3) δ 6.10 (1H, dd, J 17.5, 11.1), 5.21 (1H, dd,
J 11.1, 2.9), 4.87 (1H, dd, J 17.5, 2.9), 1.62 (3H, s), 0.97 (3H, s),
0.87 (3H, s), 0.82 (3H, s); HRMS calcd for C16H26 218.2034, found
218.2033.
15 (96 mg, 82%) as a colorless oil: [R]25 -10.6 (c 1.7, CHCl3);
D
IR (KBr) 3073, 3047, 1619, 915, 846 cm-1; 1H NMR (299.95 MHz,
CDCl3) δ 6.10 (1H, ddd, J 17.6, 11.2, 1), 5.22 (1 H, ddd, J 11.2,
2.9, 1), 4.90 (1H, dd, J 17.6, 11.2), 1.61 (3H, s), 1.02 (3H, s), 0.94
(3H, s), 0.81 (3H, s), 0.5 (1H, m), 0.42 (1H, dd, J 9.3, 3.6), -0.05
(1H, dd, J 6.0, 3.6); HRMS calcd for C21H32 284.2504, found
284.2501.
Dim eth yl (2S,5S,8S,1R,7R,11R,17R)-2,7,11,17-tetr am eth yl-
p en ta cyclo[9.8.0.02,8.05,7.012,17]n on a d eca -12,15-d ien e-15,16-
d ica r boxyla te (16). In the same manner as described above
for the conversion of 6 into 7, a mixture of 15 (36.8 mg, 0.13
mmol) and DMAD (32 µL, 0.26 mmol) was heated at 120 °C for
15 h. Chromatography of the crude product, using 8:2 hexanes-
ether as eluent, yielded the adduct 16 (50.7 mg, 92%) as a solid,
which was contaminated, as shown by its 1H NMR spectrum,
by approximately 5% of the epimeric adduct at C-13. Pure 16
was obtained by crystallization from MeOH: mp 117.5-118 °C;
Dim eth yl
(1S,7S,10S)-1,7,11,11-Tetr a m eth yltr icyclo-
[8.4.0.02,7]tetr a d eca -2,5-d ien e-5,6-d ica r boxyla te (7). A mix-
ture of diene 6 (68.4 mg, 0.316 mmol) and recently distilled
DMAD (100 µL, 0.632 mmol) was sealed in a tube under argon
and heated at 110 °C for 24 h. After cooling, the tube was opened
and the excess of DMAD was eliminated at reduced pressure.
The residue obtained was purified by chromatography eluting
with 95:5 hexanes-ether to give an approximately 95:5 mixture
of the Diels-Alder adducts (105 mg, 95%), as determined by
[R]25 +30 (c 9.4, CHCl3); IR (KBr) 1723 cm-1; 1H NMR (299.95
D
MHz, CDCl3) δ 5.62 (1H, dd, J 6.3, 1.7), 3.79 (3H, s), 3.71 (3 H,
s), 3.14 (1H, dd, J 21.7, 1.7), 2.76 (1H, dd, J 21.7, 6.6), 2.09 (1H,
ddd, J 12.8, 3.8, 3.8),1.9 (1H, m),1.57 (1H, m), 1.25 (3H, s), 0.97
(3H, s), 0.89 (3 H, s), 1.10 (3 H, s), 0.54 (1H, m), 0.5 (1H, m),
0.41 (1H, dd; J 10.0, 3.6), -0.04 (1H, dd, J 6.4, 3.6); HRMS calcd
for C27H38O4 426.2770, found 426.2774.
1
integration of the dCH signals for both adducts in the H NMR
spectrum of the mixture. Recrystallization from hexane-dichlo-
romethane gave pure 7: mp 154-156 °C; [R]22 +16 (c 2.4,
D
CHCl3); IR (KBr) 1720, 1660, 1630 cm-1; 1H NMR (299.95 MHz,
CDCl3) δ 5.64 (1H, dd, J 6.5, 1.9), 3.81 (3H, s), 3.73 (3H, s), 3.14
(1H, dd, J 21.8, 6.5), 2.77 (1H, dd, J 21.8, 1.9), 1.31 (3H, s), 1.05
(3H, s), 0.91 (3H, s), 0.85 (3H, s); HRMS calcd for C22H32O4
360.2301, found 360.2311.
Ack n ow led gm en t. Financial support from the Di-
reccio´n General de Ensen˜anza Superior e Investigacio´n
Cient´ıfica (Grant 1FD-97-0705) and the Generalitat
Valenciana (Grant GVDOC99-022) is gratefully acknowl-
edged.
(1bS,4S,5S,7bS,9aS,1aR,3aR,7aR)-1a,3a,5,7b-Tetr am eth yl-
4-vin ylp er h yd r ocyclop r op a [a ]p h en a n th r en -4-ol (14). Eth-
(19) It is noteworthy that the Diels-Alder reaction of the 1,3-diene
containing the double bond in the A ring (prepared from 12 following
the same procedure previously described for the conversion of 4 into
6) took place with identical efficacy and stereoselectivity, but in this
case and previously to the Diels-Alder reactions as showed control
experiments, the ene reaction of the A ring olefin moiety with DMAD
as enophile also occurred. Interesting, initial biological evaluation
revealed that this compound possesses promising antifungal and
â-glucuronidase inhibition activities. These results should be published
elsewhere.
(20) However, the results obtained in this work are of interest since
they could allow the preparation of tricyclic terpenoid systems with
the uncommon trans-anti-cis arrangement. For a relevant compound
of this type, see: Manes, L. V.; Crews, P.; Kernan, M. R.; Faulkner,
D. J .; Fronczek, F. R.; Gandour, R. D. J . Org. Chem. 1988, 53, 570.
This possibility is being studied in our laboratory.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 4-16, tables of 13C NMR data of compounds 4-7
(Table I), 8-10 (Table II), and 11-16 (Table III), X-ray
structural analysis of compound 7 containing crystal data,
tables of atomic coordinates, thermal parameters, and bond
lengths and angles, and the labeled structure (Figure 1 and
Tables IV-IX), optimized geometries and HF/STO-3G transi-
tion structures for syn- and anti-adducts of the reaction of 6
with DMAD (Figures 2 and 3), and spectroscopic data and
detailed experimental procedures for the preparation of com-
pounds 4 and 9-13. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) For general experimental information, please see ref 17.
J O9919097