Synthesis of highly functionalised enantiopure bicyclo[3.2.1]-octane systems from carvone

Article abstract of DOI:10.3390/90500287

The commercially available monoterpene carvone has been efficiently converted into the tricyclo[3.2.1.0^2.7]octane and bicyclo[3.2.1]octane systems characteristic of some biologically active compounds. The sequence used for this transformation involves as key features an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a cyclopropane ring opening.

Full text of DOI:10.3390/90500287

Molecules 2004, 9, 287-299
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Highly Functionalised Enantiopure Bicyclo[3.2.1]-
octane Systems from Carvone
Antonio Abad *, Consuelo Agulló, Ana C. Cuñat *, Ignacio de Alfonso, Ismael Navarro and
Noelia Vera.
Departamento de Química Orgánica. Facultad de Ciencias Químicas. Dr. Moliner, 50, 46100-Burjasot,
(Valencia), Spain. Tel. (+34) 96 3544509/3543038. Fax: (+34) 96 3544328.
*Authors to whom correspondence should be addressed; e-mail: antonio.abad@uv.es;
ana.cunat@uv.es
Received: 2 February 2004 / Accepted: 8 March 2004 / Published: 30 April 2004
Abstract: The commercially available monoterpene carvone has been efficiently converted
into the tricyclo[3.2.1.02.7]octane and bicyclo[3.2.1]octane systems characteristic of some
biologically active compounds. The sequence used for this transformation involves as key
features an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a
cyclopropane ring opening.
Keywords: Carvone, Diels-Alder reaction, cyclopropane cleavage, 5-vinyl-1,3-
cyclohexadiene, samarium diiodide, bicyclo[3.2.1]octane, tricyclo[3.2.1.02.7]octane
Introduction
The bicyclo[3.2.1]octane ring system is the basic framework of many important biologically active
natural compounds, particularly tri- and tetracyclic sesqui- and diterpenes [1]. The widespread
occurrence of this common structural motif in so many biologically active natural products has
stimulated the preparation of simple non-natural structures containing the carbo-bicyclic system with
variable functional diversity, many of which have also shown relevant biological activity. A logical
consequence of the interest in this type of compounds has been the development of a plethora of
synthetic methods for making bicyclo[3.2.1]octanes [2], in many cases appropriately functionalised to
be useful intermediates in the synthesis of the more complex natural products containing this bicyclic

Molecules 2004, 9
288
subunit. Some of the more efficient methodologies developed for the preparation of the
bicyclo[3.2.1]octane system are based in the selective fragmentation of different types of
functionalised tricyclo[3.2.1.02.7]octane derivatives, whose tricyclic cores have been constructed
basically using two methods, an intramolecular cyclopropanation of a double bond [2,3], or a
bicycloannulation of cyclic dienolates with various Michael acceptors [2,4].
In this report we describe the preparation of several enantiopure bicyclo[3.2.1]octane systems 3
using an alternative approach for the construction of the bicyclic skeleton, one based on an
intramolecular Diels-Alder (IMDA) reaction of a 5-vinyl-1,3-cyclohexadiene 1 and the regioselective
cleavage of the obtained tricyclo-[3.2.1.02.7]octan-3-one intermediate 2 (Scheme 1) [5].
Scheme 1
6
6
7
7
5
6
8
1
3
5
4
4
2
5
1
1
8
4
O
2
2
3
3
OR
O
Tricyclo[3.2.1.02,7]octane (2)
Bicyclo[3.2.1]octane (3)
5-Vinyl-cyclohexa-1,3-diene (1)
It must be mentioned that although several intramolecular cycloadditions involving 5-vinyl-1,3-
cyclo-hexanedienes have been described in the literature [6], these types of Diels-Alder reactions have
not been previously evaluated for their synthetic utility. Only recently, and while this work was in
progress, Trauner described the preparation of several substituted tricyclo[3.2.1.02.7]oct-3-enes via
IMDA reactions of 5-vinyl-1,3-cyclohexadienes. He has also called attention to the synthetic potential
of this reaction in the synthesis of several polycyclic natural products and suggested the possible
implication of such a reaction in their biosynthesis [7].
Results and Discussion
Carvone (4) was used as the starting chiral material with the objective of preparing the
bicyclo[3.2.1]octane framework in enantiomerically pure form. This is a monoterpene, commercially
available in both enantiomerically pure forms, (R)-(-)- and (S)-(+)-carvone, that has been widely used
by us [8] and others [9] as a chiral starting material in the synthesis of numerous natural products.
The synthesis starts with the conversion of carvone (4) into the β-keto ester 5 using Mander´s
methoxycarbonylation procedure [10]. Thus, reaction of methyl cyanoformate with the kinetic lithium
enolate of 4, generated by treatment with LDA in THF at low temperature, afforded the β-keto ester 5
in very high yield (Scheme 2). Although irrelevant from the synthetic point of view, compound 5
seems to exist basically in only one tautomeric form in which the methoxycarbonyl groups occupies

Molecules 2004, 9
289
1
the equatorial position, as suggested by the coupling constant pattern observed in the H-NMR
spectrum for H-1 (a singlet with J = 13 Hz).
It should be pointed out that the methoxycarbonyl group was introduced at the C-2 position of
carvone with the dual purpose of installing a versatile functional group for further functionalization of
the target bicyclic systems as well as to avoid diene isomerisation during the subsequent Diels-Alder
step. In fact, attempts to directly elaborate the diene moiety from 4, e.g. compound 6, always afforded
a mixture of isomeric cyclohexadienes under different experimental conditions. With the
methoxycarbonyl group in place, the regioselective formation of the silyloxy diene moiety was readily
accomplished by enolization of 5 by treatment with lithium bis(trimethyl)silylamide and capture of the
enolate with tert-butyldimethylsilyl triflate. Conversion of (R)-carvone into the tert-butyldimethylsilyl
enol ether 7 was thus accomplished in ca. 82% overall yield.
The 5-vinyl-1,3-cyclohexadiene moiety of 7 underwent an intramolecular Diels-Alder reaction
smoothly and efficiently upon heating a degassed anhydrous toluene solution of this compound and a
small amount of propylene oxide in a sealed ampoule at 190 ºC for 48 h. Compound 8, containing the
tricyclo[3.2.1.02.7]oct-3-ene system, was thus obtained in 80% of yield after purification by column
chromatography. It must be mentioned that in the absence of propylene oxide as acid scavenger, both
the starting tert-butyldimethylsilyl enol ether 7 and the Diels-Alder adduct 8 were partially hydrolyzed
to the β-keto ester 5 and a mixture of epimeric tricyclo-ketones 9, respectively. The structure and
1
stereochemistry of the adduct 8 were confirmed by its spectroscopic data, particularly the H- and
13C-NMR signals which were unambiguously assigned using HMQC and NOESY experiments [11].
Scheme 2
CO2Me
H
O
9
R
R2
R2
1
8
c
b
2
5
6
7
CO2Me
R1
R1
OTBDMS
H
3
4
O
OTBDMS
4: R1 = R2 = H
5: R1 = CO2Me; R2 = H
a
7: R1 = CO2Me; R2 = H
6: R1 = R2 = H
8: R = H
10: R1 = H; R2 = OH
11: R1 = H; R2 = OSiPh2CH=CH2
13: R1 = CO2Me; R2 = OSiPh2CH=CH2
14: R = OSiPh2CH=CH2
12: R1 = CO2Me; R2 = OSiPh2CH=CH2
Reagents and conditions: (a) LDA, THF, -78ºC then CNCO2CH3-HMPA. (b)
LiN[Si(CH3)2]2, THF, -78ºC then TBDMSOTf. (c) Toluene, 190 ºC, 48h.

Molecules 2004, 9
290
It is interesting to note that the intramolecular Diels-Alder reaction of the 5-vinyl-1,3-cyclohexa-
diene moiety is strongly preferred to other alternative intramolecular cycloadditions that were also
attempted, in spite of the highly strained transition state presumably involved. Thus, when compound
13 (and also the corresponding dimethyl(vinyl)silyl analogue, 13 with R2 = OSiMe2CH=CH2), readily
prepared from hydroxycarvone 10 as described in the Experimental section, was heated in toluene
under the same conditions described above for 7, only the Diels-Alder adduct 14 was formed, without
any appreciable amounts of the adduct resulting from the alternative intramolecular cycloaddition of
the 1,3,10-undecatriene moiety being observed [12].
Having completed the construction of the tricyclo[3.2.1.02.7]octane framework, and prior to the
opening of the cyclopropane ring, we decided to use the existing tert-butyldimethylsilyl enol ether
moiety to incorporate an additional oxygenated function that could provide sites for further
functionalization of the final bicyclo[3.2.1]octane system. In this regard, it was decided to transform
the adduct 8 into the ketone 15 (Scheme 3).
Scheme 3
8: R = H
a
TBDMSO
H
R2
H
6
1
8
CO2Me
7
5
O
c
R1 O
H
1
8
2
H
5
17
6
H
7
CO2Me
4
H
3
2
3
CO2Me
H
4
TBDMSO
b
O
6
O
H
7
5
18: R1 = TBDMS; R2 = OMe
TBDMSO
1
H
4
8
15
H
19: R1 = TBDMS; R2 = OCH2Ph
20: R1 = TBDMS; R2 = OH
21: R1 = TBDMS; R2 = Cl
3
2
CO2Me
O
H
16
Reagents and conditions: (a) m-CPBA, CH2Cl2, -30ºC. (b) SmI2, THF-tBuOH, -40ºC. (c)
MeOH, HCl, rt for 18; PhCH2OH, PTSA, rt for 19; H2O-THF, HCl, rt for 20;.THF-HCl,
rt for 21.
This transformation was accomplished in a single step by treatment of 8 with m-CPBA in
methylene dichloride at -30 ºC. Under these conditions, epoxidation of the double bond took place
from the less hindered β-face initially giving the corresponding β-epoxide, which directly rearranged

Molecules 2004, 9
291
with concomitant migration of the tert-butyldimethylsilyl group to give the ketone 15. The structure
and relative stereochemistry of this compound were established by a detailed analysis of its NMR data.
In particular, protons H-8β and H-6α gave strong correlation signals with the tert-butyl protons and the
methyl protons at C-4, respectively, unequivocally stabilising the spatial orientation of both groups at
C-4.
With the tricyclic system 15 at hand, we investigated the opening of the cyclopropane ring in order
to elaborate the bicyclo[3.2.1]octane framework. In the literature, dissolving metal reductions with
metal-ammonia systems has been the most frequently used method for the cleavage of cyclopropyl
ketones [2]. The electron transfer homogenous reagent samarium(II) iodide has been less often used
for this purpose, although some examples of samarium(II)-mediated cyclopropane cleavage of rigid
cyclopropyl ketones have been described [2,13]. When applied to the opening of 15, a regioselective
cleavage of the C1-C2 bond of the cyclopropane ring took place to cleanly afford the
bicyclo[3.2.1]octane ring system (Scheme 3). It was found that the best results were obtained by
treatment of a cooled (-40 ºC) solution of 15 in a 9:1 mixture of THF and tert-butanol with a stock
solution of samarium(II) diiodide in THF. An 80% yield of the β-keto ester 16 was obtained under
these conditions, which both as a solid and in solution, basically exists in the enol tautomeric form. It
is noticeable that elimination of the 4-silyloxy moiety was never observed, even when an excess of the
reducing reagent was used. It is also interesting to note that when the samarium(II)-mediated
cyclopropane cleavage was effected in the absence of a protic solvent, the reaction was not so clean
and the compound 17 was the major product obtained. The formation of this compound is easily
explained by formation of a radical intermediate at C-7 and subsequent hydrogen abstraction from the
adjacent methyl group. The stereochemistry of 16 was unambiguously assigned on the basis of
coupling constant and NOESY data. Particularly relevant was the presence of a strong NOESY
correlation of methyl protons at C-7 to methyl protons of the ester moiety at C-2, which provided
evidence of the (R)-configuration at C-7.
The carbobicyclic ring system formed in the above cyclopropane cleavage reaction not only
constitutes the characteristic substructural fragment of some natural compounds that have been found
to display important biological activity [14], but is also the basic core structure of carbo-tropanes, a
group of synthetic compounds that are potent inhibitors of the dopamine transporter [15]. Thus, the
readily prepared enantiomerically pure compound 16 may be potentially used as an adequate scaffold
from which to append "side chain" groups, thereby generating small libraries with functional and
structural diversity that may be evaluated for biological activity.
In addition to the above radical opening of the cyclopropane ring of 15, we also evaluated the acid
catalysed nucleophilic addition reaction to the cyclopropyl ketone moiety as an alternative procedure
for the tricyclo[3.2.1.02.7]octane-to-bicyclo[3.2.1]octane interconversion. It was found that a rapid and
efficient opening of the cyclopropane ring of 15 took place upon treatment with different nucleophilic
reagents in the presence of an acid catalyst. Thus, treatment of 15 with methanol and catalytic
p-toluenesulphonic acid (PTSA) or HCl at room temperature afforded a high yield of methyl ether 18,
formed by acid initiated homoconjugate addition of methanol to the cyclopropyl ketone moiety. The

Molecules 2004, 9
292
addition of methanol takes place regio- and stereoselectively from the back of C-1, affording the
bicyclo[3.2.1]oct-1-ene system stereoselectively functionalized at C-7. The stereochemistry of 18 was
determined by comparison of its spectroscopic data with those of 16 and confirmed by a NOESY
experiment. Thus, the H-8β proton gives a strong correlation signal with the protons of the methoxy
group while the protons of the methyl group at C-7 give strong correlation signals with both the
protons of the methoxycarbonyl group and the H-6β proton.
Similar results were obtained with other nucleophiles. Thus, benzyl ether 19, alcohol 20 and
chloride 21 were readily formed by treatment of 15 with benzyl alcohol and catalytic PTSA in CH2Cl2
(80% yield), water and catalytic HCl in THF (80% yield), and concentrated HCl in THF (86% yield),
respectively. It should be mentioned that in the latter two cases, ie., compounds 20 and 21, partial
reversion to the starting tricyclic compound 15 occurs on attempted chromatographic purification on
silica gel. It is likely that this particularly easy interconversion is facilitated by the homoaromatic
character of the carbocationic intermediate generated.
Conclusions
In brief, the results obtained show the viability of the synthetic approach based on the combination
of an intramolecular Diels-Alder reaction of a 5-vinyl-1,3-cyclohexadiene and a cyclopropane ring
opening for the preparation of the bicyclo[3.2.1]octane framework. The application of this strategy,
starting from carvone, has allowed us to prepare several enantiopure, highly functionalised,
bicyclo[3.2.1]oct-1-ene derivatives.
Acknowledgments
Financial support from the Ministerio de Ciencia y Tecnología (BQU2002-00272) is gratefully
acknowledged. We are also grateful to the Generalitat Valenciana and the MCYT for providing
research fellowships to I. N and I. de A., respectively.
Experimental
General
Melting points were determined using a Buchi hot-stage apparatus. Optical rotations were
determined using a 5 cm path length cell. [α]D values are given in units of 10-1 deg cm2 g-1. All NMR
spectra were recorded on a Bruker AVANCE 300 DRX spectrophotometer in CDCl3 solutions (at 300
MHz for 1H and 75 MHz for 13C). Complete assignment of the NMR data for most of the compounds
described in the experimental section was done on the basis of a combination of HMQC, HMBC and
NOESY 2D experiments. Mass spectra were obtained by electron impact (EI) at 70 eV. IR spectra
were measured as KBr pellets or liquid films. All reactions were carried out under an inert atmosphere

Molecules 2004, 9
293
of dry argon, using oven-dried glassware and freshly distilled and dried solvents. Column
chromatography refers to flash chromatography and was performed on Merck silica gel 60, 230-400
mesh.
(5R,6R)-2-(tert-Butyldimethylsilanyloxy)-6-isopropenyl-3-methylcyclohexa-1,3-dienecarboxylic acid
methyl ester (7). A solution of commercial (R)-(-)-carvone (3.98 g, 25.9 mmol) in THF (20 mL) was
added dropwise to a solution of LDA in THF (44.3 mL of a 0.7 M solution, 31.1 mmol) at -78 ºC. The
reaction mixture was allowed to warm to -10 ºC and stirred at this temperature for 1 h, then cooled to -
78 ºC and HMPA (4.5 mL) was added, followed by methyl cyanoformate (3.2 mL, 38.9 mmol). After
30 min the reaction mixture was poured into saturated NH4Cl solution and extracted with ether. The
combined organic layers were washed with brine and dried over Na2SO4. The residue obtained after
evaporation of the solvent was purified by column chromatography, using 9:1 hexane-ethyl acetate as
eluent, to give β-keto ester 5 (5.4 g, 98%) as an oil, bp 103 ºC (2 mmHg) [lit. 142 (15 mmHg)] [10];
18
1
[
α
]
-30 (c 2.8, CHCl3); IR (film) 3040-2800, 1743, 1672, 1360, 1260, 900 cm_1; H-NMR δ 6.72 (1
D
H, m, H-4), 4.80 (2 H, m, H-2´), 3.69 (3 H, s, OMe), 3.46 (1 H, d, J 13 , H-1), 3.1 (1 H, ddd, J =13,
10.5 and 5 Hz, H-6), 2.5-2.2 (2 H, m, H-5), 1.76 (3 H, m, Me-3) and 1.72 ppm (3 H, s, Me-1´); C-
13
NMR δ 15.71 (C3-Me), 19.66 (Me-C1´), 30.36 (C5), 45.65 (C6), 51.97 (CO2CH3), 58.23 (C1), 112.80
(C2´), 134.8 (C3), 144.48 (C4), 144.55 (C1´), 170.32 (CO2) and 194.74 ppm (C2); MS m/z (CI) 210
(M++2, 10), 209 (M++1, 100), 178 (10), 177 (90), 167 (75), 149 (46), 135 (15), 123 (15) and 51 (3).
A solution of β-ketoester 5 (500 mg, 2.4 mmol) in THF (6 mL) was added dropwise to a 1M
solution of lithium bis(trimethyl)silylamide in hexane (3.2 mL, 3.2 mmol) cooled at –78 ºC. After 30
min of stirring, tert-butyldimethylsilyloxy trifluoromethanesulfonate (0.65 mL, 2.88 mmol) was added
and the mixture was stirred for an additional 1 h. Then, the mixture was poured into pentane, the
combined organic layers washed with water and brine and finally dried over Na2SO4. The residue
obtained after evaporating the solvent was purified by column chromatography, using 8:2 hexane-ethyl
acetate containing a small amount of Et3N (2%), to afford 641 mg of the enol silyl ether 7 (83%) as a
colourless oil.
α
[ ]
28 -0.61º (6.56, CHCl3); IR (film) 2949, 2859, 1704, 1580, 1249, 887 cm-1; 1H-NMR
D
(300 MHz) δ 5.72 (1H, ddq, J 5; 3; 1.5 Hz, H-4), 4.72 (2H, s, H-2’), 3.69 (3H, s, CO2Me), 3.41 (1H, d
br, J 8.8 Hz H-6), 2.44 (1H, dddd, J 17.3, 9.2, 2.8, 2.8 Hz, H-5α), 2.28 (1H, ddd, J 17.3, 6.6, 0.7 Hz, H-
5β), 1.79 (3H, br s, Me-C3) 1.72 (3H, s, Me-C1’), 0.99 (9H, s, t-Bu), 0.10 (3H, s, MeSi) and 0.08 (3H,
s, MeSi) ppm; 13C-NMR δ 168.5 (CO2Me), 157.2 (C1), 144.4 (C1’), 132.9 (C3), 127.6 (C4), 110.9 (C2),
110.9 (C2’), 51.0 (CO2Me), 40.2 (C6), 27.2 (C5), 25.6 (Me3C), 21.3 (Me-C3), 18.4 (Me3C), 17.5 (Me-
C1’) -4.35 and -4.5 (Me2Si) ppm; MS (EI) m/z 322 (M+, 0.1), 307 (4), 281 (1), 265 (100), 235 (2), 223
(5), 233 (9). HRMS calculated for C18H30O3Si 322.1964, found 322.1967.
(1S,2S,5S,7S)-13-(tert-Butyldimethylsilanyloxy)-1,4-dimethyltricyclo[3.2.1.02,7]oct-3-ene-2-carboxylic
acid methyl ester (8). A solution of diene 7 (641 mg, 1.99 mmol) in anhydrous toluene (10 mL) was
transferred to a previously silylated ampoule and rigorously degassed by the freeze-thaw-cycle. The
ampoule was cooled down under argon, a drop of propylene oxide was added and it was then sealed

Molecules 2004, 9
294
under vacuum. After heating at 190 ºC for 48 h, the solvent was eliminated on a rotary evaporator and
the residue was chromatographed, using 9:1 hexanes-ethyl acetate as eluent, to give 508 mg (80 %) of
the Diels-Alder adduct 8 as a yellowish oil.
[ ]
28 +26.2º (0.305, CHCl3); IR (film) 2929, 2856, 1727,
α
D
1669 cm-1; H-NMR δ 3.73 (3H, s, CO2Me), 2.27 (1H, dd, J 3.6, 3.6 Hz, H-5), 1.94 (1H, s br, H-7),
1.68 (1H, ddd, J 8.7, 3.5, 1.9 Hz, H-6β), 1.65 (3H, s br, Me-C4), 1.41 (1H, dd, J 8.8, 3.6 Hz, H-8α),
1.24 (3H, s, Me-C1) 1.08 (1H, d, J 8.7 Hz, H-8β), 0.92 (1H, d br, J 8.7 Hz, H-6α), 0.98 (9H, s, t-Bu),
0.05 (3H, s, MeSi), 0.00 (3H, s, MeSi) ppm; 13C-NMR δ 170.5 (CO2Me), 136.6 (C4), 114.8 (C3), 51.8
(CO2Me), 37.3 (C2), 37.0 (C5), 35.5 (C6), 31.3 (C1), 30.1 (C8), 26.9 (C7), 25.7 (Me3C), 18.05 (Me3C),
15.5 (Me-C1), 14.55 (Me-C4), -4.05 y -4.28 (Me2Si) ppm; MS (EI) m/z 322 (M+, 0.4), 307 (3), 291 (3),
266 (25, 265 (100), 210 (2). HRMS calculated for C18H30O3Si 322.1964, found 322.1953.
1
(6S)-2-[(tert-Butyldimethylsilanyl)methoxy]-6-[1-(diphenylvinylsilanyloxymethyl)vinyl]-3-
methylcyclo- hexa-1,3-dienecarboxylic acid methyl ester (13). 10-Hydroxycarvone (10) was prepared
from carvone as described in reference [16];
[ ]
22 -155º (c 3.4, CHCl3); IR (NaCl) 3424, 2922, 2887,
α
D
1668, 1451, 1414, 1143, 902, 903 cm-1; 1H-NMR δ 6.75 (1H, ddq, J 5.8, 2.6, 1.3, H-3), 5.15 (1H, s, H-
2’), 4.95 (1H, s, H´-2’), 4.15 (2H, s, CH2OH), 2.82 (1H, dddd, J 18.3, 5.8, 4.3, 1.4, H-5 ), 2.61 ( H,
ddd, J 16.0, 3.7, 1.5, H-6α), 2.48 (1H, dddd, J 18.3, 5.8, 4.3, 1.4, H-4α), 2.39 (1H, dd, J 16.0, 13, H-
6β), 2.32 (1-H, dddd, J 18.1, 10.6, 2.5, 2.6, H-4β), 1.78 (3H, s, CH3-C2) ppm. MS (EI) m/z, 166 (M+,
13), 148 (67), 135 (17), 106 (63), 91 (42), 82 (100); HRMS calculated for C10H14O2166.0994, found
166.1075.
Et3N (0.72 mL, 5.16 mmol) and chloro(diphenyl)vinylsilane (0.7 mL, 3.17 mmol) were
sequentially added to a solution of 10-hydroxycarvone (10, 360 mg, 2.16 mmol) in dry THF (8 mL) at
-20ºC. After 1h the reaction mixture was treated with aqueous saturated solution of NH4Cl and
extracted with hexane. The combined organic extracts were washed with dilute HCl, 10% aqueous
NaHCO3 solution and brine and dried over Na2SO4. Evaporation of the solvent afforded an oily residue
that was purified by column chromatography, using 8:2 hexane-ethyl acetate as eluent, to give 647 mg
(80%) of silyl ether 11 as an oil;
[ ]
22 -25º (c 0.65, CHCl3); IR (NaCl) 3068, 2922, 1675, 1428, 1117,
α
D
711 cm-1; H-NMR δ 7.6 (5 H, m, H-Ar), 7.6 (5 H, m, H-Ar), 6.72 (1H, dddq, J 5.7, 2.6, 1.32 H-3),
6.60 (1H, dd, J 14.9, 20.16 H-1’’), 6.28 (1H, dd, J 14.9, 3.9 H-2’’), 5.91 (1H, dd, J 20.16, 3.9 H-2’’),
5.2 (1H, s, H-2’), 4.90 (1H, s, H´-2’), 4.27 (2H, br s, H-3’), 2.76 ( 1H, dddd, J 17.71, 14.34, 3.5, 3.5
H-5), 2.60 (1H, ddd, J 16.2, 3.84, 1.51 H-6α ), 2.36 ( 1H, dd, J 16.2, 13.68 H-6β), 2.43 (1H, m, H-4),
1
13
2.25 (1H, m, H-4’), 1.78 (3H, s, CH3-C2) ppm; C-NMR δ 199.53 (C1), 149.22 (C1’), 144.49 (C3),
135.41 (C2), 134.94 (CAr), 137.30 (C2’’), 133.78 (CAr), 133.09 (C1’’), 130.13 (CAr), 127.90 (CAr),
110.12 (C2’), 65.30 (C3’), 43.62 (C6), 37.96 (C5), 32.00 (C4), 15.68 (Me-C2); MS (EI) m/z, 374 (M+, 6),
347 (15), 297 (43), 283 (30), 209 (100); HRMS calculated for C24H26O2Si 374.1702, found 374.1708.
A solution of compound 11 (200 mg, 0.56 mmol) in THF (2 mL) was added dropwise to a solution
of LDA in THF (1.2 mL of a 0.5M solution, 0.60 mmol) at -78 ºC. The reaction mixture was allowed
to warm to 0 ºC (ca. 2 h) and stirred at this temperature for 30 min, cooled to -78 ºC, and treated with
methyl cyanoformate (57 µL, 0.71 mmol). After 30 min the reaction mixture was allowed to warm to

Molecules 2004, 9
295
room temperature, poured into saturated NH4Cl solution and extracted with ether. The combined
organic layers were washed with brine and dried over Na2SO4. The residue obtained after evaporation
of the solvent was purified by column chromatography, using 9:1 hexane-ethyl acetate as eluent, to
give 200 mg (82%) of β-keto ester 12 as an oil;
[ ]
22 -47º (c 0.3, CHCl3); IR (NaCl) 3180, 2923, 1745,
α
D
1674, 1155, 1117, 711cm-1; H-NMR δ 7.6 (5 H, m, H-Ar), 7.6 (5 H, m, H-Ar), 6.73 (1H, m, H-4),
6.45 (1H, dd, J 14.9, 19.2 H-1’’), 6.30 (1H, dd, J 14.9, 4.0 H-2’’), 5.91 (1H, dd, J 19.2, 4.0 H-2’’),
5.29 (1H, s, H-2’), 5.05 (1H, s, H´-2’), 4.27 (1H, s, H3’), 3.67 (3H, s, CO2Me), 3.55 (1H, d, J 6.97 Hz,
H-1), 3.10 ( 1H, ddd, J 10.74, 12.81, 4.71 H-6), 2.50 ( 1H, dddd, J 18.9, 10.74, 4.71, 1.32 H-5α), 2.30 (
1
13
1H, dddd, J 18.9, 10.7, 2,5, 2,5 H-5β), 1.79 (3H, s, CH3-C3) ppm; C-NMR δ 194.73 (C2), 170.08
(CO2Me), 147.90 (C1’), 144.43 (C4), 135.68 (C3), 134.92 (CAr), 137.28 (C2’’), 133.72 (CAr), 133.01
(C1’’), 130.12 (CAr), 127.90 (CAr), 111.52 (C2’), 65.51 (C3’), 58.82 (C1), 51.98 (CO2Me), 40.97 (C6),
32.14 (C5), 15.71 (Me-C3); MS (EI) m/z, 432 (M+, 6), 405 (23), 355 (100), 323 (15), 208 (79), 183
(71); HRMS calculated for C26H28O4Si 432,1756, found 432,1729.
A solution of enone 12 (70 mg, 0.18 mmol) in dry CH2Cl2 (0.7 mL) was cooled to -78 ºC and
treated sequentially with 0.5M solution of lithium bis(trimethyl)silylamide in hexane (0.5 mL, 0.25
mmol) and tert-butyldimethylsilyl triflate (0.07 mL, 0.23 mmol). After 1 h at -78 ºC, the reaction
mixture was poured into pentane and washed with cool water and brine, before being dried over
Na2SO4. Evaporation of the solvent under vacuum furnished an oily residue which was purified by
column chromatography on silica gel, using hexane-ethyl acetate 8:2 with a 1% of Et3N as eluent, to
give 75 mg of the enol silyl ether 13 as a colourless oil (83%);
[ ]
28 -46.6º (0.3, CHCl3); IR (NaCl)
α
1
D
3120, 2949, 1704, 1578, 1430, 1360, 1173, 1118, 886, 841 cm-1; H-NMR (C6D6) δ 7.6 (5 H, m, H-
Ar), 7.6 (5 H, m, H-Ar), 6.42 (1H, dd, J =15.0, 20.16, H-1’’), 6.15 (1H, dd, J= 15.0, 3.9, H-2’’), 5.85
(1H, dd, J =20.16, 3.9, H-2’’), 5.28 (1H, br s, H-4), 5.28 (1H, br s, H-2’), 5.10 (1H, br s, H-2’), 4.2
(2H, br s, -CH2O-), 3.62 (1H, br d, J= 8.0 Hz, H-6), 3.32 (3H, s, CO2Me), 2.20 (1H, dddd, J 17.3, 9.2,
2.8, 2.8 Hz, H-5α), 1.19 (1H, ddd, J =17.3, 6.6, 0.7 Hz, H-5β), 1.65 (3H, br s, Me-C3) 1.04 (9H, s, t-
Bu), 0.15 (3H, s, MeSi) and -0.03 (3H, s, MeSi) ppm; 13C-NMR δ 167.23 (CO2Me), 157.7 (C1), 147.1
(C1’), 136.9 (C2’’), 135.5 (CAr), 134.0 (CAr), 133.26 (C3), 130.2 (C1’’), 128.4 (CAr), 128.2 (CAr), 127.9
(C4), 110.9 (C2), 110.6 (C2’), 65.7 (CH2O), 50.1 (CO2Me), 36.6 (C6), 27.9 (C5), 25.9 (Me3C), 18.7 (Me-
C3), 17.8 (Me3C), -3.4 and –3.1 (Me2Si) ppm; MS (EI) m/z 546 (M+, 3), 531 (10), 489 (83), 461 (14),
231 (100); HRMS calculated for C32H42O4Si2 546.2622, found 546.2636.
(1S,2S,5R,7S)-3-(tert-Butyldimethylsilanyloxy)-1-(diphenylvinylsilanyloxymethyl)-4-methyltricyclo-
[3.2.1.02,7]oct-3-ene-2-carboxylic acid methyl ester (14). A solution of diene 13 (20 mg, 0.04 mmol) in
anhydrous toluene (2 mL) was transferred to a previously silylated ampoule and degassed by the
freeze-thaw-cycle. The ampoule was cooled down under argon, a drop of propylene oxide was added
and it was then sealed. After heating at 190 ºC for 48 h, the solvent was eliminated under vacuum and
the residue was chromatographed, using 9:1 hexane-ethyl acetate as eluent, to give 18.5 mg (92 %) of
the Diels-Alder adduct 14 as an oil; 1H-NMR δ 7.6 (5 H, m, H-Ar), 7.6 (5 H, m, H-Ar), 6.45 (1H, dd, J
15.0, 20.16 H-1’’), 6.25 (1H, dd, J 15.0, 3.9 H-2’’), 5.84 (1H, dd, J 20.16, 3.9 H-2’’), 3.58 (3H, s,

Molecules 2004, 9
296
CO2Me), 2.30 (1H, dd, J 4.5, 4.5 Hz, H-5), 2.4 (1H, br s, H-7), 1.68 (1H, ddd, J 12, 4.5, 2.4 Hz, H-8β),
1.65 (3H, br s, Me-C4), 1.72 (1H, dd, J 11, 6 Hz, H-6α), 1.05 (1H, d, J 11 Hz, H-6β), 0.91 (1H, H-8α),
13
0.93 (9H, s, t-Bu), -0.05 (3H, s, MeSi), -0.06 (3H, s, MeSi) ppm. C-NMR δ 170.1 (CO2Me), 137.9
(C2’), 136.8 (C4), 135.8 (CAr), 134.1 (C1’), 134.0 (CAr), 130.6 (CAr), 128.7 (CAr), 115.4 (C3), 63.8
(CH2O), 52.6 (OMe), 37.5 (C5), 37.2 (C2), 36.4 (C1), 32.0 (C6), 30.5 (C8), 26.6 (Me3C), 26.2 (C7), 18.1
(Me3C), 16.5 (Me-C3), -4.0 and 4.1 (Me2Si).
(1S,2R,4S,5R)-4-(tert-Butyldimethylsilanyloxy)-1,4-dimethyl-3-oxo-tricyclo[3.2.1.02,7]octane-2-
carboxylic acid methyl ester (15). m-Chloroperbenzoic acid (1.71 g, 9.92 mmol) was added to a
solution of silyl enol ether 8 (800 mg, 2.48 mmol) in dichloromethane (30 mL) at –30 ºC. The reaction
mixture was stirred for 2 ½ h and then poured into ethyl acetate, washed with water and brine and
dried over Na2SO4. The residue left after vacuum evaporation of the solvent was purified by
chromatography, using 9:1 hexanes-ethyl acetate as eluent, to afford the silyl ether-ketone 15 (770 mg,
28
D
92 %) as a solid; mp 118.5-120.0 ºC (from methanol);
[
α
]
+31.06º (0.515, CHCl3); IR (KBr) 2953,
1734, 1704, 1252, 833 cm-1; 1H-NMR (300 MHz) δ 3.75 (3H, s, CO2Me), 2.34 (1H, d br, J 2.8 Hz, H-
7), 2.39 (1H, d, J 12.6 Hz, H-8β), 2.05 (1H, dd, J 4.9, 4.7 Hz, H-5), 1.98 (1H, ddd, J 13,5.5, 3.2 Hz, H-
6β), 1.85 (1H, d, J 12.8 Hz, H-6α), 1.66 (1H, dd, J 12.8, 5.1 Hz, H-8α), 1.29 (3H, s, Me-C1) 1.19 (3H, s
13
br, Me-C4), 0.85 (9H, s, t-Bu), 0.19 (3H, s, MeSi), 0.04 (3H, s, MeSi) ppm; C-NMR δ 203.3 (C3),
168.2 (CO2Me), 75.2 (C4), 52.3 (CO2Me), 47.0 (C2), 42.5 (C5), 38.45 (C1), 35.8 (C7), 33.2 (C8), 29.1
(C6), 25.7 (Me3C), 22.6 (Me-C4),18.3 (Me3C), 16.4 (Me-C1), -2.8 y -3.7 (Me2Si) ppm; MS (EI) m/z 338
(M+, 0.1), 281 (67), 249 (36), 175 (10), 155 (95), 138 (100); HRMS calculated for C18H30O4Si
338.1913, found 338.1926.
(1S,4S,5S,7R)-4-(tert-Butyldimethylsilanyloxy)-3-hydroxy-4,7-dimethylbicyclo[3.2.1]oct-2-ene-2-
carboxylic acid methyl ester (16). Silyl ether 15 (100 mg, 0.29 mmol) was dissolved under argon in a
9:1 mixture of THF/tert-butanol (1.2 mL). The mixture was cooled to –40 ºC and a 0.5 M solution of
SmI2 in THF was added dropwise until persistence of the blue colour. The reaction mixture was poured
into hexane and the organic layer was washed with water, 5% aqueous Na2S2O4 solution and brine and
dried over Na2SO4. The residue obtained after evaporation of the solvent was chromatographed, using
9:1 hexane-ethyl acetate as eluent, to give the cyclopropane cleavage product 16 (80 mg, 80 %) as an
1
oil; IR (film) 2954, 2828, 1726, 1650, 1608, 1262, 836 cm-1; H-NMR (400 MHz) δ 3.74 (3H, s,
CO2Me), 2.75 (1H, dd, J 4.8, 4.4 Hz, H-1), 2.11 (1H, dd, J 6.8, 5.6 Hz, H-5), 1.78 (1H, dd, J 14, 10.4,
7.6 Hz, H-6α), 1.73 (1H, d, J 9.2 Hz, H-8α), 1.62-1.55 (2H, m, H-8β and H-6β), 1.46 (3H, br s, Me-
C4), 0.84 (3H, d, J 6.8 Hz, Me-C7), 0.86 (9H, s, t-Bu), 0.16 (3H, s, MeSi), 0.08 (3H, s, MeSi) ppm;13C-
NMR (75 MHz) δ 173.3 (CO2Me), 173.1 (C3), 100.1 (C2), 78.4 (C4), 51.4 (CO2Me), 48.3 (C5), 39.2
(C7), 38.2 (C1), 36.7 (C6), 31.3 (C8), 27.05 (Me-C4), 25.9 (Me3C), 18.6 (Me3C),16.7 (Me-C7), -2.54 y -
2.88 (Me2Si) ppm; MS (EI) m/z 340 (M+, 0.0), 339 (0.1), 281 (45), 251 (100), 175 (3), 75 (22); HRMS
calculated for C18H32O4Si 340.2070, found 340.2071.

Molecules 2004, 9
297
(1R,4S,5R,7S)-4-(tert-Butyldimethylsilanyloxy)-3-hydroxy-7-methoxy-4,7-dimethyl-bicyclo[3.2.1]oct-
2-ene-2-carboxylic acid methyl ester (18). Concentrated HCl (0.15 mL) was added to a solution of
compound 15 (50 mg, 0.15 mmol) in CH3OH (4 mL). After stirring for 6 h, the mixture was diluted
with water and extracted with ethyl acetate. The combined organic layers were successively washed
with a saturated aqueous solution of NaHCO3, water and brine and dried over Na2SO4. The solvent
was evaporated under vacuum and the residue was chromatographed on silica gel, using 9:1 hexane-
ethyl acetate as eluent, to give 42 mg of methyl ether 17 (76%) as an oil;
[ ]
28 +18.96º (1.16, CHCl3);
α
D
IR (film) 3429, 2924, 1649, 1600, 1219, 829 cm-1; H-NMR (300 MHz) δ 3.77 (3H, s, CO2Me), 3.19
(3H, s, OMe), 2.88 (1H, d J 4.1 Hz, H-1), 2.18 (1H, dd, J 6.2, 6.6 Hz, H-5), 2.11-2.04 (2H, m, H-8β
and H-6β), 1.76 (1H, dd, J 14.9, 7.5 Hz, H-6α), 1.59 (1H, d, J 11.01 Hz, H-8α), 1.47 (3H, br. s, Me-
C4), 1.16 (3H, s, Me-C7), 0.86 (9H, s, t-Bu), 0.19 (3H, s, MeSi), 0.07 (3H, s, MeSi) ppm; 13C-NMR δ
173.1 (CO2Me), 172.8 (C3), 101.3 (C2), 87.4 (C7), 77.00 (C4), 51.65 (CO2Me), 49.8 (OMe), 47.7 (C5),
40.9 (C1), 37.6 (C6), 33.65 (C8), 26.7 (Me-C4), 25.9 (Me3C), 18.9 (Me-C7), 18.6 (Me3C), -2.5 and -3.3
(Me2Si) ppm.
1
(1R,4S,5R,7S)-7-Benzyloxy-4-(tert-butyldimethylsilanyloxy)-3-hydroxy-4,7-dimethylbicyclo
[3.2.1]-
oct- 2-ene-2-carboxylic acid methyl ester (19). A mixture of 15 (60 mg, 0.18 mmol), benzyl alcohol
(0.092 mL, 0.88 mmol) and PTSA (3 mg, 5%) in CH2Cl2 (1 mL) was stirred at room temperature for
6h. The reaction mixture was poured into an aqueous saturated solution of NaHCO3 and extracted with
CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. Evaporation of
the solvent and purification by column chromatography, using 8:2 hexane-ethyl acetate, afforded 61.0
28
1
mg (80%) of compound 19 as an oil;
[
α
]
D +20º (1.3, CHCl3); H-NMR (300 MHz) δ 12.18 (1H, s,
HO), 7.36-7.29 (5H, m, Ph), 3.79 (3H, s, CO2Me), 4.46 (1H, d AB system, J 11.7 Hz, CH2O), 4.42
(1H, d AB system, J 11.5 Hz, CH2O), 3.00 (1H, dd J 2.5, 2.5 Hz, H-1), 2.24-2.16 (3H, m, H-5, H-6β
and H-8β), 1.90 (1H, dd, J 14.8, 7.2 Hz, H-6α), 1.64 (1H, d, J 11.6 Hz, H-8α), 1.48 (3H, br s, Me-C4),
13
1.30 (3H, s, Me-C7), 0.86 (9H, s, t-Bu), 0.165 (3H, s, MeSi), 0.08 (3H, s, MeSi) ppm; C-NMR (75
MHz) δ 173.2 (CO2Me), 172.85 (C3), 139.7 (C1’), 128.3 and 127.2 (C2’-C6’ and C3’-C5’), 127.1
(C4’)101.2 (C2), 87.9 (C7), 77.2 (C4), 64.6 (CH2O) 51.7 (CO2Me), 47.8 (C5), 41.4 (C1), 38.2 (C6), 33.8
(C8), 26.7 (Me-C4), 25.7 (Me3C), 19.8 (Me-C1), 18.6 (Me3C), -2.5 and -2.8 (Me2Si) ppm; MS (EI) m/z
432 (M+, 0.2), 389 (60), 357 (100), 223 (47), 191 (39); HRMS C25H38O5Si requires 446.2488, found
446.2485.
(1R,4S,5R,7S)-4-(tert-Butyldimethylsilanyloxy)-3,7-dihydroxy-4,7-dimethyl-bicyclo[3.2.1]oct-2-ene-2-
carboxylic acid methyl ester (20). Concentrated HCl (0.1 mL) was added to a solution of 15 (35 mg,
0.1036 mmol) in a 1:1 mixture of THF-H2O (2 mL). The mixture was stirred at room temperature
overnight, then diluted with ethyl acetate and washed successively with 10% aqueous solution of
NaHCO3, water and brine. Drying over Na2SO4 and evaporation of the solvent afforded 29 mg (80%)
1
of crude alcohol 20, which by H-NMR appeared to be quite pure. The alcohol 20 was an amorphous
solid that could not be induced to crystallize, nor could it be purified by column chromatography due

Molecules 2004, 9
298
1
to its propensity to give 15. H-NMR δ 3.72 (3H, s, CO2Me), 3.05 (1H, dd J 3.7, 3.7 Hz, H-1), 1.53
(3H, s, Me-C7), 1.41 (3H, br s, Me-C4) 0.82 (9H, s, t-Bu), 0.10 (3H, s, MeSi), 0.02 (3H, s, MeSi) ppm;
13C-NMR δ 173.42 (CO2Me), 171.24 (C3), 101.45 (C2), 84.50 (C7), 77.52 (C4), 51.82 (CO2Me), 48.07
(C5), 47.55 (C1), 42.95 (C6), 33.93 (C8), 28.05 (Me-C4), 26.84 (Me-C7) 25.83 (Me3C), 18.43 (Me3C), -
2.55 and -2.39 (Me2Si) ppm.
(1R,4S,5R,7S)-4-(tert-Butyldimethylsilanyloxy)-7-chloro-3-hydroxy-4,7-dimethylbicyclo[3.2.1]oct-2-
ene- 2-carboxylic acid methyl ester (21). Concentrated HCl (0.7 mL) was added to a solution of
compound 15 (20 mg, 0.06 mmol) in THF (2 mL). The reaction mixture was stirred at room
temperature for 2h, diluted with ethyl acetate and successively washed with 10% aqueous solution of
NaHCO3, water and brine. Drying over Na2SO4 and evaporation of the solvent afforded 19 mg (86%)
1
of crude chloride 21 as an oil; H-NMR (300 MHz) δ 12.06 (1H, s, OH), 3.77 (3H, s, CO2Me), 2.67
(1H, dd J 3.8, 3.8 Hz, H-1), 1.47 (3H, br s, Me-C4), 1.27 (3H, s, Me-C7), 0.86 (9H, s, t-Bu), 0.15 (3H,
s, MeSi), 0.06 (3H, s, MeSi) ppm; 13C-NMR (75 MHz) δ 172.81 (CO2Me), 171.24 (C3), 101.39 (C2),
53.3 (C7), 77.52 (C4), 51.64 (CO2Me), 47.96 (C5), 45.57 (C1), 42.95 (C8), 34.6 (C6), 26.77 (Me-C4),
25.22 (Me-C7) 25.83 (Me3C), 18.56 (Me3C), -2.52 y -2.87 (Me2Si) ppm.
References and Notes
1. (a) Connolly, J. D.; Hill R. A. In Dictionary of Terpenoids, 1st Ed; Chapman and Hall: London,
1991; Vol. 2, pp. 906-970. (b) Hanson, J. R. Nat. Prod. Rep. 2002, 19, 650. (c) Fraga, B. M. Nat.
Prod. Rep. 2002, 19, 125, and previous reviews in this series.
2. Filippini, M. H.; Rodriguez, J. Chem. Rev. 1999, 99, 27-76.
3. For recent examples, see: Magnus, P.; Rainey, T.; Lynch, V. Tetrahedron Lett. 2003, 44, 2459-
2461.
4. For recent examples, see: Meijere, A.; Hadjirapoglou, L.; Noltemeyer, M.; Gutke, H-J.; Klein, I.;
Spitzner, D. Eur. J. Org. Chem. 1998, 441-451 and references cited therein.
5. This work forms part of our research program directed towards the synthesis of trachylobane-
beyerane- and atisane-type terpenoids, see: Abad, A.; Agulló, C.; Cuñat, A. C.; Navarro, I.; M.
Carmen Ramírez de Arellano, Synlett, 2001, 3, 349-352.
6. Ciganek, E.: The intramolecular Diels-Alder reaction; Organic Reactions; John Wiley: New
York, 1984; Vol 32, p. 165.
7. Stephanie, M. Ng.; Beaudry, C. M.; Trauner, D. Org. Lett. 5, 2003, 1701-1704.
8. Abad, A.; Agulló, C.; Cuñat, A. C.; García, A. B. Tetrahedron, 2003, 59, 9523-9536.
9. Ho, T.L. Ed.; Enantioselective Synthesis: Natural Products from Chiral Terpenes; John Wiley &
Sons: New York, 1992.
10. Llera, J, M.; Fraser-Reid, B. J. Org. Chem.1989, 54, 5544-5548.
11. The carbobicyclic ring system formed in this Diels-Alder reaction constitutes the characteristic
substructural fragment of some natural compounds endowed with significant biological activity.

Molecules 2004, 9
299
See, for example: (a) Fraga, B. M. Phytochem. Analysis, 1994, 5, 49-56; (b) Block, S.; Stevigny,
C.; De Pauw-Gillet, M. C.; de Hoffmann, E.; Llabres, G.; Adjakidje, V.; Quetin-Leclercq, J.
Planta Med. 2002, 68, 647-964.
12. For examples of Diels-Alder reactions of 1,3,10-undecatrienes, see: Brocksom, T. J.; Maria, J.;
Ferreira, L.; Brocksom, U. J. Braz. Chem. Soc. 2001, 12, 597-622.
13. Molander, G., Alonso-Alija C., Tetrahedron, 1997, 53, 8067-8084.
14. (a) Miller, J. A.; Ullah, G. M.; Welsh, G. M.; Mallon, P. Tetrahedron Lett. 2001, 42, 2729-2731.
(b) Snider, B.; Buckman, B. O. J. Org. Chem. 1992, 57, 4883-4888, and referenced cited therein.
15. (a) Meltzer, P. C. ; Zhengming, P. B,; Yong, C. Y. F.; Madras, B. K. Bioorg. Med. Chem. Lett.
1999, 9, 857-862. (b) Meltzer, P. C.; Blundell, P.; Huang, H.; Liu, S.; Yong, Y. F.; Madras, B.
K. Bioorg. Med. Chem., 2000, 8, 581-590. (c) Meltzer, P. C.; Blundell, P.; Yong, Y. F.; Chen, Z.;
George, C.; Gonzalez, M. D.; Madras, B K. J. Med. Chem. 2000, 43, 2982-2991. (d) Madras, B.
K.; Meltzer, P. C. Brit. UK Pat., Application: GB 2002-4596 (2003).
16. Weinges, K.; Schwarz, G. Liebigs Ann. Chem. 1993, 7, 811-814.
Sample Availability: The following compounds and amounts are available from the authors: compound
4, 15 mg; compound 8, 20 mg; compound 15, 15 mg; compound 16, 10 mg; compound 17, 10 mg;
compound 18, 30 mg.
© 2004 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.