Synthetic studies on the preparation of oxygenated spongiane diterpenes from carvone

Article abstract of DOI:10.1016/j.tet.2003.10.017

The paper describes a new diastereoselective approach to oxygenated spongiane diterpenes functionally related to natural dorisenones. The strategy followed for the preparation of the spongiane framework, a B→AB→ ABC→ABCD approach, is based on the preparation of epoxydecalone 11 (AB rings) from R-(-)-carvone, followed by an intramolecular Diels-Alder reaction for the construction of the C ring (compound 26). Further manipulation of the Diels-Alder adduct functionality allows the completion of the spongiane framework and the elaboration of several oxygenated spongiane-type compounds. The structures of two compounds 27 and 31, has been established by single-crystal X-ray crystallography.

Full text of DOI:10.1016/j.tet.2003.10.017

Tetrahedron 59 (2003) 9523–9536
Synthetic studies on the preparation of oxygenated spongiane
diterpenes from carvone
a
a
a
Antonio Abad,a Consuelo Agullo, Ana C. Cun˜at, Ana Belen Garcıa
,
*
´
and Carlos Gimenez-Saiz
´
´
†
,
b
´
a
´
´
Departamento de Quımica Organica, Universidad de Valencia, Dr. Moliner 50, 46100-Burjassot, Valencia, Spain
bInstituto de Ciencia Molecular, Universidad de Valencia, Dr. Moliner 50, 46100-Burjassot, Valencia, Spain
Received 20 May 2003; revised 2 October 2003; accepted 6 October 2003
Abstract—The paper describes a new diastereoselective approach to oxygenated spongiane diterpenes functionally related to natural
dorisenones. The strategy followed for the preparation of the spongiane framework, a B!AB!ABC!ABCD approach, is based on the
preparation of epoxydecalone 11 (AB rings) from R-(2)-carvone, followed by an intramolecular Diels–Alder reaction for the construction of
the C ring (compound 26). Further manipulation of the Diels–Alder adduct functionality allows the completion of the spongiane framework
and the elaboration of several oxygenated spongiane-type compounds. The structures of two compounds 27 and 31, has been established by
single-crystal X-ray crystallography.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
A wide variety of diterpenes with the spongiane tetracyclic
skeleton (1) has been isolated from various species of
sponges and sponge-eating marine nudibranchs.1 Many of
these metabolites show a wide spectrum of biological
properties,2 that may be associated in some cases with the
presence of an electrophilic g-butenolide moiety at the D
ring.3 Such is the case of dorisenones A (2), B (3), C (4) and
D (5), four spongiane diterpenoids recently isolated together
with other related saturated compounds (e.g. 6 and 7)
from the Japanese marine mollusc Chromodoris obsoleta
(Chromodorididae). These dorisenones showed strong
cytotoxicity against several cell lines.4 As has been
previously suggested for related systems,5 the enhanced
biological activity of these and other highly oxygenated
spongiane diterpenes may be due to the presence of polar
groups (i.e. OH, acetate, epoxide, etc.) in the region of the
Michael acceptor center.6
Although various strategies have been employed in the
construction of the spongiane framework,7,8 few of them are
non-racemic synthesis and allow the incorporation of
no synthetic approaches to oxygenated spongianes of the
type of those showed above have been reported. Thus, and
in connection with our previous work on the synthesis of
spongianes9 and the use of the readily available mono-
terpene carvone as the chiral building block for the synthesis
of polycyclic terpenes,10 we report here complete details of
our efforts directed towards the preparation of spongiane-
type diterpenoids structurally and functionally related to
dorisenones.11 Our interest was focused on the development
sufficient functionality for elaboration of the more oxygen-
ated natural products. In fact, to the best of our knowledge,
Keywords: terpene; spongiane; synthesis; carvone; Diels–Alder reaction;
X-ray; epoxide rearrangement; cytotoxic activity.
*
Corresponding author. Tel.: þ34-96-3544509; fax: þ34-96-3544328;
e-mail: antonio.abad@uv.es; saiz@uv.es
To whom correspondence should be addressed regarding the X-ray
diffraction studies.
†
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.017

9524
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
Scheme 1. The B!AB!ABC!ABCD approach to the spongiane tetracyclic framework from carvone.
of a simple procedure for enantiomerically preparing the
spongiane framework with a functionality that could permit
us to prepare not only the natural compounds but also some
non-natural analogues, which may be used to study the
biological profile of these kinds of spongiane diterpenes.
was the conversion of (R)-carvone (8) into the epoxy-
decalone 11 (Scheme 2). This transformation was based on
the methodology previously developed by Gesson for the
stereoselective transformation of carvone into a decalone
system.12 Thus, the (R)-carvone was stereoselectively
transformed into a chromatographically homogeneous 3:2
mixture of regioisomeric vinyl bromides 9 by double
alkylation of its kinetic enolate, first with MeI and then
with 2,3-dibromopropene, followed by trifluoroacetic acid
catalyzed cationic cyclisation. The conjugate double bond
of both vinyl bromides 9 was chemo- and stereoselectively
epoxidated by treatment with alkaline hydrogen peroxide to
provide a mixture of a,b-epoxy-enones 10a,b, only partially
separable by chromatography. Conversion of this mixture
to the a-epoxy decalone 11 was finally completed by
hydrogenation in EtOH, using 10% Pd–C as the catalyst
and Et3N to capture the HBr formed. The assigned
stereochemistry of the epoxide 11 was supported by its
NMR data. Particularly relevant was the signal due to C-6a‡
(d 39.0 ppm) in the 13C NMR spectra which is shifted
appreciably in this compound (ca. 8 ppm) with respect to the
saturated decalone resulting from complete hydrogenation
of 9,13 due to the shielding effect (g-effect) exerted by the
2. Results and discussion
The approach followed for the construction of the spongiane
framework was based (Scheme 1) on the initial conversion
of (R)-(2)-carvone (8) into a trans-decalin, the AB ring
system, having an oxygenated function at C-7 (spongiane
numbering) and a diene moiety suitably to be used in a
Diels–Alder reaction for the construction of the C-ring.
In principle, the C-ring formed in this manner has an
appropriate functionality for further elaboration of the
g-lactone D-ring and introduction of the oxygenated
functionality at the C-11 position of the spongiane skeleton.
2.1. Preparation of the AB ring system from carvone
The first stage of the synthesis of the required bicyclic diene
Scheme 2.
‡
All compounds have been named throughout the paper as required by IUPAC nomenclature rules, with the exception of tetracyclic compounds that have been
named as spongiane derivatives using the system numbering given in structure 1.

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9525
a-oriented epoxide moiety. The global yield for the
transformation of carvone into 11 via this five-step reaction
sequence was around 50%.
Diels–Alder adducts. In the former case most of the starting
material was recovered and the only adduct isolated (less
than 10% after 24 h of heating at 1408C) was identified as
the adduct formed by b-approach of the dienophile,
compound 17, that has at the newly created stereogenic
center the opposite configuration of the spongiane frame-
work. In the second case, the reaction was less stereo-
selective, affording after heating 20 with DMAD for 60 h at
1408C, workup and chromatography, the starting material
(80%), the 10aa-Me adduct 21 (6%) and the 10ab-Me
adduct 22 (6%). The stereochemistry at C-10a of the three
adducts (C-8 of the spongiane skeleton) was readily
deduced by comparison of the chemical shift of the
Me-10a with that of related compounds.14 This Me group
resonates at higher fields when anti to the Me group at C-4b
(1.25 and 1.32 ppm for 17 and 21, respectively) than when
syn to the same Me group (1.44 ppm for 22). The reaction
of 20 with the sterically less demanding dienophile
MeO2CCuCCHO was also non-stereoselective but
much less clean, affording only trace amounts of the
corresponding Diels–Alder adducts.
Addition of the lithium derivative of a-methoxymethyldi-
phenylphosphine oxide to the carbonyl group of 11 took
place stereoselectively in THF at low temperature to afford a
mixture of two diastereoisomeric b-hydroxyphosphine
oxides 12 in nearly quantitative yield after column
chromatography. Subjection of the mixture of epimeric
b-hydroxyphosphine oxides to syn elimination by treatment
with sodium hydride in DMF at room temperature gave a
mixture of isomeric vinyl ethers 13, which were very labile,
extensive hydrolysis occurring on attempted isolation and,
particularly, with column chromatography. For this reason,
they were not isolated but treated in situ with aqueous
formic acid to effect hydrolysis of the vinyl ether moiety and
subsequent opening of the initially formed b,g-epoxy
aldehyde 14, providing the desired unsaturated hydroxy
aldehyde 15 in 87% overall yield for the three-step reaction
sequence from epoxy ketone 11. Finally, the required diene
moiety was completed in high yield via Wittig methyl-
enation of the aldehyde group of 15 by reaction with
methylidenetriphenylphosphorane (Ph3PvCH2) under
standard conditions.
In view of the above results, we attempted to control the
stereochemistry of the Diels–Alder adduct through an
intramolecular process by linking an adequate acetylenic
dienophile to the hydroxyl group of bicyclic dienol 16.
Several temporary bridging groups were explored with
varying success.15 Attempts to establish an ester linkage
between the diene and the acetylenic dienophile moieties by
reaction of the hydroxyl group of 16 with propiolic acid or
propiolic acid derivatives were unsuccessful.16 However,
the silicon tethered diene-acetylenic ester 23 was easily
prepared in one-pot reaction by successive treatment
of 16 at 2788C with (CH3)2SiCl2 –Et3N and then
2.2. Construction of the C ring system
With compound 16 at hand, our next task focused on the
elaboration of the C-ring through a Diels–Alder reaction. In
a first approach we tried to construct the C-ring through an
intermolecular Diels–Alder reaction of both the diene-
alcohol 16 and its epimeric silylated alcohol 20, readily
obtained from 16 via an oxidation–reduction–trimethyl-
silylation procedure (Scheme 3), with dimethyl acetylene-
dicarboxylate (DMAD). However, in both cases the
cycloaddition reaction was very slow and did not reach
completion providing a very low yield of the corresponding
17
HOCH2CuCCO2CH3 and catalytic DMAP (Scheme 4)
(see Section 4).18 Heating of 23, however, failed to give
any cycloadduct even under forcing conditions (2208C in
toluene), with only starting material being recovered. The
inertia of 23 to undergo the IMDA reaction was somewhat
unexpected, but may be explained by noting that in the TS
leading to the cycloadduct, the diene methyl group and one
of the methyl groups attached to silicon are in very close
proximity. In the end, excellent results were obtained with
the use of the ether tethering system previously used by
Liu and co-workers in their synthetic approach towards
forskolin.19 Thus, propargylation of dienol 16 with
propargyl bromide under phase-transfer conditions provided
the propargyl ether derivative 24. In contrast to the results
obtained with related monocyclic dienols,20 propargylation
of 16 proceeded quite sluggishly giving only a 55–60%
conversion after 28 h. Nevertheless, the unreacted starting
material was efficiently recovered during purification by
flash chromatography and conveniently recycled, thereby
increasing the yield of propargyl ether 24 to 75–80%.
Carboxylation of the acetylene group of 24 by sequential
treatment with butyl lithium and methyl cyanoformate
provided 84% of acetylenic ester 25, which on heating at
1128C overnight in anhydrous toluene underwent a smooth
and clean IMDA cycloaddition to afford the tetracyclic
adduct 26 in 95% yield after column chromatography. The
structure and stereochemistry of compound 26 was
confirmed by 1D and 2D NMR spectroscopy, including
NOE difference experiments. Particularly relevant was the
Scheme 3.

9526
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
Scheme 4.
NOE enhancement of the signal due to the methyl group at
C-10c at d 1.10 ppm upon irradiation of either H-5ab or H-
2b at d 3.87 and 2.64 ppm, respectively, that provides
evidence not only of the b-orientation of the angular methyl
group at C-10c but also of the boat conformation adopted by
the C-ring as a consequence of the conformational
constraint imposed by the ether bridge.{
BH3·Me2S in THF at 08C or rt and then with aqueous H2O2–
NaOH) resulted only in the formation of alcohol 28 (see
Scheme 5). On the other hand, performing the hydrobora-
tion reaction at a higher temperature (50–608C) resulted in
the formation of complex reaction mixtures, from which the
desired 9(11)-double bond hydroboration product could not
be isolated. Similarly disappointing results were obtained
with the alcohol 28, obtained in high yield by controlled
hydrolysis of the acetate moiety of 27 with methanolic
KOH, and also with the ketone 29, obtained by oxidation of
alcohol 28 under Swern oxidation conditions. It should be
mentioned that in the latter case, the low temperature
hydroboration reaction afforded the equatorial alcohol 30
stereoselectively in nearly quantitative yield. The epimeric
relationship at C-7 between alcohols 28 and 30 was evident
by comparison of their 1H NMR data and in particular of the
coupling constant pattern observed for H-7. This proton
appeared in 28 at d 3.88 ppm as a broad singlet (two small
coupling constants) and in 30 at d 3.65 ppm with two
coupling constants (double doublets, J¼11.2, 4.9 Hz), the
major one clearly indicating that H-7 was in this alcohol in
an axial disposition. Thus, this two-step reaction sequence
constitutes an efficient way to establish stereoselectively at
C-7 the stereochemistry of the oxygenated function present
in natural dorisenones.
2.3. Construction and further functionalisation of the D
ring system
Once completed the C ring and the correct stereochemistry
of the methyl group at C-8, we centered our attention on
the elaboration of the g-lactone D-ring, thus completing the
natural spongiane framework, and the introduction of the
oxygen functionality at C-11. The first task was readily
accomplished in a single operation by treatment of the
Diels–Alder adduct 26 with acetic anhydride and zinc
iodide at room temperature.21 Under these conditions,
regioselective ring-opening of the dihydrofuran ring of 26
took place to give initially the corresponding 7-acetoxy-15-
iodo-derivative, which rapidly underwent lactonization to
cleanly afford the spongiane-type compound 27 in nearly
quantitative yield for the whole process. The structure of
the unsaturated g-lactone 27 was initially assigned on the
basis of a detailed spectroscopic study that included
bidimensional correlations and NOE difference experi-
ments. The final proof of the structure assignment was
obtained by single-crystal X-ray diffraction analysis.
We were also unable to conveniently functionalize the
9(11)-double bond of 27 via hydroxylation or bromohydrin
formation. Thus, no reaction was observed under standard
osmylation conditions, both catalytic and stoichiometric,22
whereas complex reaction mixtures were obtained on
treatment of 27 with N-bromosuccinimide in aqueous
acetone.23 However, epoxidation of diene 27 occurred
smoothly on treatment with m-CPBA in dichloromethane at
room temperature overnight, to provide regioselectively an
approximately 1:1 mixture (determined by analysis of the
A variety of methods were investigated to introduce an
oxygenated function at the C-11 position of the spongiane
skeleton. Unfortunately, repeated attempts to hydrate the
9(11)-double bond of 27, via the hydroboration–oxidation
protocol, were unsuccessful. Thus, hydroboration of 27
under standard conditions (first treatment with BH3·THF or
{
Although the Diels–Alder adduct 26 was relatively stable, it was partially but cleanly transformed into two more polar compounds when left at 2208C in the
fridge for several months. These compounds were easily separated by column chromatography (hexane–ethyl acetate 8:2). The major and less polar
compound was identified (HRMS, IR, 1H and 13C NMR, see Section 4) as the hydroperoxide ii (see below). The structure iii was tentatively assigned to the
minor product (only traces of this more polar product were isolated), based on the analysis of its 1H NMR spectrum (see Section 4). As shown below, the
formation of these compounds could be explained by the initial formation of a stabilized diallyl radical from 26, e.g. i, followed by its reaction with oxygen.

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9527
Scheme 5.
400 MHz 1H NMR spectrum) of the a- and b-oriented
epoxides, 31 and 32 respectively, in 86% combined yield.
Both diastereomeric epoxides were separated by careful
flash chromatography and their structures were initially
assigned on the basis of detailed spectroscopic analysis.
Particularly significant was the difference observed in the
chemical shifts due to C-1 and C-11 in both epoxides,
observed at d 31.4/50.8 and 35.6/58.4 ppm for compounds
31 and 32, respectively. The shielding of these carbon atoms
observed in 31 reflexes a stronger g-effect between them
with respect to the same carbon atoms of 32, which is
clearly inferred from the analysis of the optimized geometry
obtained for both compounds using MM2. Also in
agreement with the a-orientation of the epoxide moiety in
31 were the NOE enhancements observed for the Me group
at C-10 and H-1b at d 1.26 and 1.14 ppm, respectively, upon
irradiation of H-11 at d 3.36 ppm. The geometry of this
epoxide was confirmed when suitable crystals for X-ray
analysis were obtained that unambiguously established that
the epoxide moiety was on the a-face (Fig. 1).
It is interesting to note that the formation of 31 in the above
reaction requires the approach of the peracid from the
apparently more hindered concave face of 27 (see its X-ray
structure), and it seems reasonable to assume that the
epoxidation from this face occurs with the anchimeric
assistance of the homoallylic acetate group. In this way, and
in contrast to the stereochemical result obtained in the
epoxidation of acetate 27, epoxidation of alcohol 28 under
catalytic non-asymmetric Sharpless epoxidation conditions
afforded exclusively the a-epoxy alcohol 33 (Scheme 5),
which has, with the exception of the expected modifications
attributed to the acetate-hydroxyl group exchange produced
at C-7, spectroscopic properties identical to that of 31.
1
Interestingly, the hydroxyl hydrogen is observed in the H
NMR spectrum of 33 as a doublet at d 2.52 ppm, with a
coupling constant with H-7b of 10 Hz. This coupling
pattern suggests the existence of an intramolecular hydro-
gen bond between the 7a-OH and the 9a,11a-epoxide
groups. Obviously in this case, the exclusive a-attack of the
electrophilic epoxidation reagent is due to the directive
effect of the 7a-hydroxyl group.
With the aim of creating functionalisation at C-11 like that
of the natural spongiane systems we examined the acid-
catalyzed rearrangement of the 9,11-epoxide moiety of both
31 and 32 to the corresponding 11-carbonyl group. This ring
opening reaction of epoxides is a synthetically useful
reaction that has been successfully used many times in the
terpene field.24 However, all attempts to promote the
rearrangement of 31 and 32 to the corresponding carbonyl
compound failed. Both epoxides were stable under the
relatively milder conditions used in this kind of trans-
formation, e.g. LiClO4 diethyl ether at rt25 or LiClO4 in
benzene at reflux,26 but eventually reacted when treated
with the most commonly used reagent BF3–etherate to give
not the desired carbonyl compound, but products of skeletal
rearrangement instead. Thus, treatment of the more reactive
b-epoxide 32 with BF3–etherate in benzene at 08C gave a
fast and clean reaction to afford nearly exclusively a single
product, the alcohol 35, formed by a [1,2]-suprafacial
migration of the angular methyl group at C-10 (Scheme 6).
Figure 1. X-Ray structure of compound 31.

9528
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
products was obtained, apparently resulting from skeletal
rearrangements, and no definitive conclusions could be
drawn from this reaction.
It was supposed that the 7a-acetoxy group was responsible
for the different behaviour of the epoxide 31, since it could
interfere with the BF3 in its approach towards the similarly
a-oriented epoxide moiety. So it was decided to transform
the epoxide 31 into the epoxy ketone 34 in a last attempt to
promote the desired epoxide ring rearrangement. Successful
epoxide–ketone rearrangements have been described in
related tetracyclic systems.27 Epoxy ketone 34 was readily
prepared in a non-optimized 50% yield by oxidation of
epoxy alcohol 33 under Swern oxidation conditions. As a
alternative, 34 was also prepared by reaction of the
previously obtained ketone 29 with m-CPBA in CH2Cl2,
although in a rather low yield (ca. 45%). It is noticeable that
only the a-epoxide (e.g. 34) was isolated from this reaction,
with no significant amounts of the diastereomeric b-epoxide
being detected. This result is in contrast with the epoxida-
tion of other structurally related b-keto-9(11)-olefins (see
Ref. 27). Treatment of 34 with BF3–etherate in benzene at rt
resulted in a smooth reaction to give, after 8 h, a 7:3 mixture
of two chromatographically homogeneous products in 88%
yield. However, neither of these products was the desired
Scheme 6.
The structure and stereochemistry of 35 was established on
the basis of a combination of spectroscopic data, including
COSY, HSQC, and 2D NOESY experiments. Particularly
relevant was the information deduced from the analysis of
the coupling constants and NOESY spectrum that not only
confirms the proposed structure for 35 but also sheds light
on the preferred conformation adopted by this molecule.
Thus, the coupling constants between H-7 and both H-6 in
35 are 10.8 and 5.4 Hz and the coupling constants between
H-11 and both H-12 are 3.3 and 2.6 Hz, which fits well with
the expected values calculated by MMX for the conforma-
tion represented in Figure 2. In the NOESY spectrum, the
cross-peak patterns observed also strongly support the
structure-conformation depicted in Figure 2.
1
11-ketone. Analysis of the H and 13C NMR spectra of the
mixture and comparison of these data with those of 35
allowed the identification of the major product of this
mixture as the ketone 36, formed as 35 by a [1,2]-shift of the
methyl group at C-10 followed by elimination of a hydrogen
atom (Scheme 6). No definitive structure could be assigned
from these data to the minor component of the mixture, but
the presence of an olefinic CH and the relatively large
chemical shift changes experienced by some methyl groups
suggested that it was also likely to be a product of skeletal
rearrangement.
In clear contrast to 32, the a-epoxide 31 was fairly resistant
to similar reaction conditions, being recovered practically
unchanged after its treatment with BF3–etherate at low
temperature. Reaction of epoxide 31 required treatment
with BF3–etherate at rt over a long period of time.
However, the reaction was not clean and a mixture of
3. Conclusion
An efficient approach for preparing the spongiane frame-
work in enantiomerically pure form has been developed.
The synthetic sequence used follows a B!AB!ABC!
ABCD approach and makes use of the monoterpene carvone
as the starting chiral synthon. Since both (R)-(2)- and
(S)-(þ)-carvone are commercially available, this approach
allows the synthesis of the spongiane skeleton in both
enantiomeric forms. Although the adaptation of the
functionalisation of the C-11 position to that present in
natural dorisenones remains a problem, this study has
allowed the efficient preparation of several oxygenated,
non-natural, dorisinonone-type spongianes that can provide
complementary and valuable information about structure-
activity relationships for cytotoxicity in these kinds of
spongiane diterpenes.§
Figure 2. Cross-peaks observed in the 2D NOESY spectrum of 35.
§
A selection of the prepared compounds has been tested for their cytotoxic activity against several human cancer cell lines in the NCI 3-cell line, one dose
primary anticancer assay [NCI-H460 (Lung), MCF7 (Breast) and SF-268 (CNS) cell lines]. First preliminary results have shown a significant activity of some
of them that have been passed on for evaluation in the full panel of 60 cell lines over a 5-log dose range. Paradoxically, the more active compounds of all
tested so far do not have the natural spongiane framework. Thus, while compounds 27 and 31 have no significant activity at a 1024 M concentration, the
compound 26 reduces the growth of the above mentioned cell lines in comparison to the untreated control cells, to 3, 21 and 70%, respectively.

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9529
4. Experimental
4.1. General information
pound 31). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: 144-(0)1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
All melting points were determined using a Kofler hot-stage
apparatus and are uncorrected. Optical rotations were
determined using a 5 cm path length cell. [a]D values are
given in units of 1021 deg cm2 g21. IR spectra were
measured as KBr pellets or liquid films. Elemental analyses
4.3. Synthesis of the AB ring system from carvone
4.3.1. (4aS,8aR)-7-Bromo-2,5,5,8a-tetramethyl-4a,5,6,
8a-tetrahydro-4H-naphthalen-1-one and (4aS,8aS)-7-
bromo-2,5,5,8a-tetramethyl-4a,5,8,8a-tetrahydro-4H-
naphthalen-1-one (9). A mixture of regioisomeric vinyl
bromides 9 was prepared from (R)-(2)-carvone in three
steps and 55–60% overall yield as described by Gesson and
Seifert in Ref. 12.
´
were performed by Servicio de semimicroanalisis of
S.C.S.I.E. (Valencia); final purification of all products for
microanalysis was done by preparative HPLC on a mPorasil
column. Mass spectra were obtained by electron impact (EI)
at 70 eV. 1H NMR spectra were recorded in CDCl3 or C6D6
at 300 or 400 MHz, and NMR 13C spectra at 75 or 100 MHz.
1H spectra were referenced to residual CHCl3 (d 7.26) and
13C spectra to the central component of the CDCl3 triplet at
d 77.0. Carbon substitution degrees were established by
4.3.2. (1aR,2aR,6aS,7aR)-4-Bromo-1a,2a,6,6-tetramethyl-
2a,5,6,6a,7,7a-hexahydro-1aH-1-oxa-cyclopropa[b]naph-
thalen-2-one (10a) and (1aR,2aS,6aS,7aR)-4-bromo-1a,
2a,6,6-tetramethyl-2a,3,6,6a,7,7a-hexahydro-1aH-1-oxa-
cyclopropa[b]naphthalen-2-one (10b). 6 M NaOH
(0.1 mL, 0.6 mmol) and 35% H2O2 (0.64 mL, 7.44 mmol)
were added to a solution of the mixture of vinyl bromides 9
(615 mg, 2.17 mmol) in MeOH (5 mL) at 08C. The mixture
was stirred overnight at rt and then poured into a saturated
aq. solution of NH4Cl. The mixture was extracted with ether
and worked up as usual. The yellowish oily residue obtained
was purified by column chromatography, using hexane–
ether (95:5) as eluent, to afford a 3:2 mixture (1H NMR
analysis) of regioisomeric vinyl bromides 10a and 10b
(597.7 mg, 92%) as an oil. A small amount of each of
the regioisomers could be partially separated during the
chromatographic process and their spectroscopic data (1H
and 13C NMR) were determined independently.
DEPT pulse sequences. Complete assignment of 1H and 13
C
chemical shifts of selected compound in the synthetic
sequence, e.g. compounds 11, 15, 20, 27, 28, 31 and 35, was
made on the basis of a combination of COSY, HMQC, and
NOE experiments. Signals with the same superscript in the
1H or 13C NMR data may be interchanged. Column
chromatography refers to flash chromatography and was
performed on Merck silica gel 60, 230–400 mesh. All
operations involving air-sensitive reagents were performed
under an inert atmosphere of dry argon using syringe and
cannula techniques, oven-dried glassware, and freshly
distilled and dried solvents. The ampoules used for the
Diels–Alder reactions were previously treated during at
least 48 h with 5% solution of 1,1,1,3,3,3-hexamenthyl-
disilazane in ether, washed with dry acetone and THF, and
dried at 1208C overnight. Unless stated otherwise, reactions
mixtures were worked up by addition of water, and
extraction with the appropriated solvent, the organic layer
being washed with water and brine and dried using
anhydrous sodium sulfate. Evaporation was performed
under reduced pressure.
1
Compound 10a. H NMR (400 MHz) d 6.39 (1H, d, J¼
2.7 Hz, H-3), 3.38 (1H, dd, J¼1.9, 1.9 Hz, H-7a), 2.33 (1H,
ddd, J¼17.8, 13.1, 1.9 Hz, H-7b), 2.32 (1H, dd, J¼14.0,
2.7 Hz, H-5), 2.19 (1H, dd, J¼17.8, 1.9 Hz, H-7a), 1.90
(1H, dd, J¼14.0, 1.5 Hz, H-5), 1.433 (3H, s, Me-C1a), 1.81
(1H, dd, J¼13.1, 2.8 Hz, H-6a), 1.151 (3H, s, Me-C2a),
1.016 (3H, s, Meb-C6), 0.965 (3H, s, Mea-C6); 13C NMR
(100 MHz) d 203.6 (C2), 129.9 (C3), 121.9 (C4), 59.7 (C7a),
57.1 (C1a), 51.1 (C5), 50.7 (C2a), 36.1 (C6a), 35.3 (C6), 30.3
(Mea-C6), 23.6 (Meb-C6), 21.7 (C7), 17.7a (Me-C2a), 17.2a
(Me-C1a).
4.2. X-Ray structure determinations
Single crystals of compounds 27 and 31 were mounted on a
Nonius Kappa CCD diffractometer and using a graphite
˚
monochromated Mo Ka radiation source (l¼0.71073 A).
Data collection was performed at room temperature. No
absorption correction was performed and the structures were
solved by direct methods (SIR97)28 and refined against F 2
with a fullmatrix least-squares algorithm using SHELX-
9729 and the WinGX (1.64) software package.30 The
position of the hydrogen atoms were added in calculated
positions and refined riding on the corresponding C atoms.
The refined values of the Flack31 parameters (0.4 (13) and
21.5 (12) for 27 and 31, respectively) were inconclusive,32
hence the Friedel pairs were merged before the final
refinement. The absolute configurations were assigned to
correspond with that of the known chiral centres in the
precursor molecules, which remained unchanged during the
synthesis of the compounds. Crystallographic data (exclu-
ding structure factors) for the structures reported in this
paper have been deposited with the Cambridge Crystallo-
graphic Data Center as supplementary publication numbers
CCDC 199545 (compound 27) and CCDC 203130 (com-
Compound 10b. 1H NMR (400 MHz) d 5.73 (1H, dd, J¼2.1,
1.0 Hz, H-5), 3.43 (1H, d, J¼2.7 Hz, H-7a), 2.60 and 2.54
(2H, AB system, J¼16.0, 2.0, 16.0, 1.0 Hz, H-3), 2.28 (1H,
ddd, J¼21.0, 11.0, 2.6 Hz, H-7b), 2.04-1.94 (2H, m, H-7a
and H-6a), 1.427 (3H, s, Me-C1a), 1.102 (3H, s, Me-C2a),
1.016 (3H, s, Meb-C6), 1.040 (3H, s, Mea-C6); 13C NMR
(100 MHz) d 207.5 (C2), 137.7 (C5), 117.5 (C4), 59.7 (C7a),
56.8 (C1a), 47.3 (C2a), 42.9 (C3), 38.1 (C6), 36.3 (C6a), 31.1
(Mea-C6), 24.0 (Meb-C6), 21.9 (C7), 18.3a (Me-C1a), 16.2a
(Me-C2a).
4.3.3. (2R,3R,4aS,8aS)-1a,2a,6,6-Tetramethyl-octahydro-
1-oxa-cyclopropa[b]naphthalen-2-one (11). 153 mg of
palladium on charcoal (10% w/w) were added to a solution
of the above mixture (576 mg, 1.93 mmol) in absolute EtOH
(30 mL) and Et3N (0.54 mL). The mixture was shaken
under an atmosphere of hydrogen (using a balloon) for 24 h.

9530
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
The catalyst was removed by filtration through a short pad
of celite. The filtrate was concentrated and the residue was
purified by chromatography, using hexane–ether (95:5) as
eluent, to provide the epoxy-ketone 11 (393.4 mg, 92%)
as a white solid. Mp 72–748C (from cold pentane).
[a]2D3¼þ205.48 (0.7, CHCl3); IR nmax/cm21 (KBr) 2920,
of hexane and ethyl acetate as eluent, to give the hydroxy-
aldehyde 15 (627.4 mg, 87% from 11) as a white solid. Mp
1108C (with decomp) (from cold AcOEt–hexane). [a]2D3¼
þ61.08 (0.6, CHCl3); IR nmax/cm21 (KBr) 3374, 2957,
2925, 2896, 2866, 1662, 1458, 1366, 1248, 1211, 1127,
1064. 1H NMR (300 MHz) d 10.10 (1H, s, CHO), 4.02 (1H,
dd, J¼4.5, 1.2 Hz, H-3), 2.36 (1H, dddd, J¼13.2, 3.3, 3.2,
1.2 Hz, H-8b), 2.136 (3H, s, Me-C2), 1.84 (1H, ddd, J¼
14.4, 2.1, 1.2 Hz, H-4a), 1.76 (1H, ddd, J¼14.1, 12.9,
4.5 Hz, H-4b), 1.52 (1H, m, H-7), 1.46 (1H, m, H-6), 1.30
(1H, dd, J¼12.9, 2.7 Hz, H-4a), 1.20 (1H, dd, J¼13.9,
4.5 Hz, H-6), 1.165 (3H, s, Me-C8a), 1.16 (1H, dd, J¼9.0,
3.9 Hz, H-70), 1.02 (1H, ddd, J¼13.2, 13.2, 3.9 Hz, H-8a),
0.924 (3H, s, Mea-C5), 0.871 (3H, s, Meb-C5); 13C NMR
(75 MHz) d 194.2 (CHO), 145.1 (C2), 109.5 (C1), 70.2 (C3),
45.8 (C4a), 41.3 (C6), 38.4 (C8a), 35.8 (C8), 33.1 (Mea-C5),
32.8 (C5), 28.1 (C4), 21.6 (Meb-C5), 18.78 (Me-C8a), 18.75
(C7), 16.8 (Me-C2); MS (EI) m/z 236 (Mþ, 100), 221 (56),
207 (59), 119 (34); HRMS m/z calcd for C15H24O2
236.1776, found 236.1776. Anal. calcd for C15H24O2: C
76.23, H 10.24; found: C 76.08, H 10.30.
1
2860, 1695, 1430, 1370, 995. H NMR (400 MHz) d 3.34
(1H, dd, J¼3.2, 1.7 Hz, H-7a), 2.25 (1H, ddd, J¼15.1, 3.2,
3.0 Hz, H-7a), 1.92 (1H, ddd, J¼15.1, 12.8, 1.7 Hz H-7b),
1.84 (1H, ddd, J¼13.4, 4.9, 3.0 Hz, H-3b), 1.52 (1H, dd,
J¼12.8, 3.4 Hz, H-6a), 1.50 (2H, m, H-4), 1.42 (1H, m,
H-5), 1.32-1.22 (1H, m, H-3a), 1.417 (3H, s, Me-C1a), 1.14
(1H, ddd, J¼13.0, 13.0, 5.0 Hz, H-5), 1.022 (3H, s, Meb-
C6), 0.933 (3H, s, Me-C2a), 0.902 (3H, s, Mea-C6); 13C
NMR (100 MHz) d 208.3 (C2), 59.5 (C7a), 56.3 (C1a),
46.1 (C2a), 41.4 (C5), 39.0 (C6a), 33.2 (C6), 32.9 (C3), 32.8
(Mea-C6), 22.2 (Meb-C6), 22.0 (C7), 17.8 (C4), 16.9
(Me-C2a), 16.7 (Me-C1a); MS (EI) m/z 222 (Mþ, 42), 207
(13), 166 (100), 123 (69), 153 (53), 123 (69), 109 (41);
HRMS m/z calcd for C14H22O2 222.1619, found 222.1613.
Anal. calcd for C14H22O2: C 75.63, H 9.97; found: C 75.75,
H 9.80.
4.3.5. (2R,4aS,8aS)-3,4a,8,8-Tetramethyl-4-vinyl-1,2,4a,
5,6,7,8,8a-octahydro-naphthalen-2-ol (16). A suspension
of methyltriphenylphosphonium bromide (2.15 g, 6.01 mmol)
in THF (31 mL) at 2208C was treated with BuLi (3.78 mL
of a 1.56 M solution in hexanes, 5.90 mmol). The mixture
was stirred for 1 h while allowed to warm to room
temperature. The resulting deep yellow solution was cooled
to 2208C and a solution of the aldehyde 15 (590 mg,
2.50 mmol) in THF (4 mL) was added to give a pale yellow
mixture that was stirred for 30 min and then allowed to
warm to room temperature for 1 h. The reaction was
quenched with aq. NaHCO3, extracted with hexane and
worked up. The residue was purified by column chroma-
tography, using hexane–ethyl acetate (95:5) as eluent, to
furnish the dienol 16 (549.3 mg, 94%) as a white solid.
Mp 109–1108C (from cold pentane). [a]2D6¼þ83.18 (1.5,
CHCl3); IR nmax/cm21 (KBr) 3280, 2920, 1440, 1410, 1055,
1000, 910. 1H NMR (300 MHz) d 6.09 (1H, ddcd, J¼17.05,
11.2, 1.0, 1.0 Hz, H-10), 5.27 (1H, dd, J¼11.2, 2.5 Hz, H-2 ),
4.94 (1H, dd, J¼17.5, 2.6 Hz, H-20), 4.00 (1H, br s, H-2)
1.81 (1H, ddd, J¼14.1, 4.2, 1.5 Hz, H-1), 1.795 (3H, d,
J¼0.75 Hz, Me-C3), 1.72 (1H, ddd, J¼14.1, 12.3, 4.5 Hz,
H-1), 1.58 (1H, m, H-5), 1.50 (1H, m, H-6), 1.43 (1H, ddd,
J¼13.2, 3.4, 1.5 Hz, H-7), 1.34 (1H, dd, J¼12.2, 3.2 Hz,
H-8a), 1.21 (1H, dd, J¼13.0, 4.0 Hz, H-7), 1.11 (1H, ddd,
J¼12.6, 12.3, 3.8 Hz, H-5), 0.968 (3H, s, Me-C4a), 0.919
(3H, s, Meb-C8), 0.856 (3H, s, Mea-C8); 13C NMR
4.3.4. (4aS,8aS)-3-Hydroxy-2,5,5,8a-tetramethyl-3,4,4a,
5,6,7,8,8a-octahydro-naphthalene-1-carbaldehyde (15).
A solution of LDA in THF (12.5 mL, 0.5 M, 6.2 mmol)
was added dropwise to a solution of Ph2POCH2OCH3
(1.520 g, 6.2 mmol) in dry THF (15 mL) at 08C. After
stirring for 1 h at 08C and then 30 min at room temperature,
the mixture was cooled to 2788C and treated slowly with a
solution of the epoxy-ketone 11 (687 mg, 3.1 mmol) in THF
(11 mL). The reaction mixture was stirred for 4 h, during
which time the temperature raised to 2508C, then treated
with a saturated aq. solution of NH4Cl and extracted with
ether. Workup as usual afforded a solid residue, which was
purified by silica gel chromatography, using hexane–ethyl
acetate (8:2) as eluent, to afford a 3:2 mixture of two
epimeric b-hydroxyphosphine oxides 12 as a white solid
1
(1.43 g, 99% yield). H NMR (300 MHz) for the major
isomer: d 5.29 (1H, s, OH), 4.60 (1H, d, J¼4.7 Hz,
CHP(O)), 3.15 (1H, br s, H-7a), 2.96 (3H, s, MeO), 1.140
(3H, s, Me-1a), 0.860 (3H, s, Me-2a), 0.831 (3H, s, Me-6a),
0.795 (3H, s, Me-6b); for the minor isomer: d 5.88 (1H, s,
OH), 4.41 (1H, d, J¼8.2 Hz, CHP(O)), 3.02 (3H, s, MeO),
2.75 (1H, br s, H-7a), 1.244 (3H, s, Me-1a), 0.939 (3H, s,
Me-2a), 0.883 (3H, s, Me-6a), 0.808 (3H, s, Me-6b).
To a suspension of NaH (305 mg of a 60% suspension in
mineral oil, corresponding to 7.6 mmol), previously washed
with anhydrous pentane, in anhydrous DMF (4.4 mL)
maintained at 08C, was added dropwise during 1 h a
solution of the above mixture of b-hydroxyphosphine
oxides 12 (1.43 g, 3.05 mmol) in the same DMF (15 mL).
The resulting brownish suspension was stirred at the same
temperature for 2.5 h, then cooled to 2108C and cautiously
treated with water (4.9 mL) to decompose the excess NaH.
The homogeneous reaction mixture obtained was stirred at
the same temperature until the hydrogen evolution ceased
and then treated with HCOOH (14.7 mL). After stirring at
room temperature for 30 min the mixture was poured into
water and the product was extracted with hexane and
worked up. The crude product obtained was purified by
column chromatography in silica gel, using an 8:2 mixture
0
(75 MHz) d 146.3 (C4), 134.4 (C1 ), 127.2 (C3), 119.1
0
(C2 ), 70.2 (C2), 45.7 (C8a), 41.5 (C7), 38.5 (C4a), 37.6 (C5),
33.0 (Mea-C8), 32.9 (C8), 28.6 (C1), 21.6 (Meb-C8), 18.9
(C6), 18.8 (Me-C3)a, 18.4 (Me-C4a)a; MS (EI) m/z 234 (Mþ,
13), 219 (100), 110 (77); HRMS m/z calcd for C16H26O
234.1983, found 234.1989. Anal. calcd for C16H26O: C
81.99, H 11.18; found: C 82.01, H 11.14.
4.4. Construction of the C ring system
4.4.1. Intermolecular Diels–Alder reactions of bicyclic
dienes 16 and 20 with DMAD
4.4.1.1. Reaction of diene 16 with DMAD. A mixture
of diene 16 (5.7 mg, 0.024 mmol), dimethylacetylene

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9531
dicarboxylate (DMAD) (15 mg, 0.10 mmol), and toluene
(50 mL) contained in a sealed ampoule was heated at 1408C
for 24 h. The toluene and the excess of DMAD were
eliminated under reduced pressure. The resulting residue
was purified by chromatography, using hexane–ethyl
acetate from 8:2 to 1:1 as eluent, to give mainly the starting
material 16 mixed with DMAD, and the adduct 10aa-Me 17
(less than 1 mg) as an amorphous solid. 1H NMR (300 MHz,
CDCl3) of 17: d 5.71 (1H, dd, J¼6.6, 1.9 Hz, H-4), 4.41
(1H, t, J¼8.2 Hz, H-10), 3.81 and 3.73 (3H each, each s,
2£CO2Me), 3.11 (1H, dd, J¼21.9, 6.6 Hz, H-3), 2.83 (1H,
dd, J¼21.9, 1.9 Hz, H0-3), 2.2–1.9 (2H, m, H-5), 1.267 (3H,
s, Me-C10a), 0.999 (3H, s, Me-C4b), 0.923 (3H, s, Me-C8),
0.857 (3H, s, Me0-C8); MS (EI) m/z 377 (Mþþ1, 1.5), 13),
376 (Mþ, 0.2), 344 (8.7), 327 (7.1), 326 (14.4), 311 (5.5),
284 (11.2), 283 (40.5), 273 (12.6), 272 (100); HRMS m/z
calcd for C22H22O5 376.2249; found: 376.2207.
(3H, s, Me0-C8); 13C NMR (75 MHz, CDCl3) d 145.7 (C4),
0
0
134.5 (C1 ), 128.6 (C3), 119.4 (C2 ), 73.3 (C2), 49.6 (C8a),
41.4 (C7), 38.7 (C4a), 37.6 (C5), 32.99 (Mea-C8), 32.95 (C8),
29.6 (C1), 21.5 (Meb-C8), 20.1 (Me-C4a), 18.7 (C6), 16.6
(Me-C3); MS (EI) m/z 234 (Mþ, 1), 201 (5), 131 (24), 110
(100), 69 (60), 57 (80); HRMS m/z calcd for C16H26O
234.1984, found 234.1996. Anal. calcd for C16H26O: C
81.99, H 11.18; found: C 81.78, H 11.30.
A solution of the alcohol 19 (13.8 mg, 0.059 mmol) in
CH2C12 (0.8 mL) was treated at 788C with Et3N (25 mL,
0.18 mmol) and tert-butyldimethylsilyl trifluoromethane-
sulfonate (22 mL, 0.094 mmol) and stirred for 1 h at the
same temperature. The mixture was diluted with ether and
worked up. Chromatography, using hexane–ether 9:1 as
eluent, afforded tert-butyldimethyl silyl ether 20 (17.7 mg,
86%) as an oil. [a]1D9¼þ48.98 (0.5, CHCl3); IR nmax/cm21
1
4.4.1.2. Preparation of diene 20 from 16. A solution of
alcohol 16 (24 mg, 0.10 mmol) and pyridine (0.046 mmol,
37.8 mL) in anhydrous CH2Cl2 (0.5 mL) was added to a
solution of Dess-Martin periodinane (54.8 mg, 0.13 mmol)
in CH2Cl2 (0.8 mL). After stirring at 08C for 30 min, the
reaction mixture was stirred for a further 15 min period at rt.
The reaction mixture was diluted with ethyl ether, cooled to
08C and quenched with an aq. solution of NaHCO3 and
Na2S2O3. After 10 min of vigorous stirring the organic
phase was separated and worked up as usual. The residue
obtained after evaporation of the solvent was filtered
through a short pad of silica gel, using hexane–ether 9:1
as eluent, to give (4aS,8aS)-3,4a,8,8-tetramethyl-4-vinyl-
4a,5,6,7,8,8a-hexahydro-1H-naphthalen-2-one ketone (18)
(20.8 mg, 86%) as a semisolid. [a]2D8¼þ28.28 (0.6, CHCl3);
IR nmax/cm21 (film) 3084, 2995, 2949, 2933, 2902, 1661,
(KBr) 2928, 2856, 1473, 1256, 1027, 835, 772. H NMR
(300 MHz, CDCl3) d 6.10 (1H, ddcd, J¼17.6, 11.2, 1.9,
1 Hz, H-10), 5.26 (1H,0dd, J¼11.2, 2.6 Hz, H-20), 4.95 (1H,
dd, J¼17.6, 2.6 Hz, H -20), 4.12 (1H, br dd, J¼8.1, 8.1 Hz,
H-2), 1.92 (ddd, J¼12.3, 6.8, 1.1 Hz, H-1), 1.664 (3H, br s,
Me-C3), 1.052 (3H, s, Me-C4a), 0.921 (9H, s, Me3CSi),
0.879 (3H, s, Meb-C8), 0.857 (3H, s, Mea-C8), 0.102 (6H, s,
2£MeSi); 13C NMR (75 MHz, CDCl3) d 144.2 (C4), 134.8
0
0
(C1 ), 129.9 (C3), 119.0 (C2 ), 74.1 (C2), 49.7 (C8a), 41.4
(C7), 38.6 (C4a), 37.8 (C5), 33.0 (Mea-C8), 32.9 (C8), 29.8
(C1), 26.0 (Me3CSi), 21.6 (Meb-C8), 20.1 (Me-C4a), 18.8
(C6), 18.2 (Me3CSi), 17.1 (Me-C3), 24.0 and 24.6 (Me2Si);
HRMS m/z calcd for C22H40OSi 348.2848; found:
348.2855.
4.4.1.3. Reaction of diene 20 with DMAD. A mixture
of diene 20 (17.1 mg, 0.049 mmol), DMAD (30 mg,
0.20 mmol), and toluene (0.25 mL) contained in a sealed
ampoule was heated at 1408C for 60 h. The solvent and the
excess of DMAD were eliminated at reduced pressure and
the resulting residue was purified by chromatography, using
hexane–ether from 9:1 to 7:3 as eluent, to give unreacted
starting material 20 (13.6 mg, 80%), adduct 10aa-Me 21
(ca. 1 mg, 6%) and adduct 10ab-Me 22 (ca. 1 mg, 6%).
1
1599, 1458, 1319, 1007, 916. H NMR (300 MHz) d 6.29
(1H, dcd, J¼017.7, 11.8, 0.9 Hz, H-10), 5.47 (1H, dd, J¼11.8,
2.1 Hz, H-2 ), 5.11 (1H, dd, J¼17.7, 2.1 Hz, H0-20), 2.53
(1H, dd, J¼17.7, 4.0 Hz, H-1a), 2.39 (1H, dd, J¼17.7,
13.9 Hz, H-1b), 1.785 (3H, d, J¼0.9 Hz, Me-C3), 1.130
(3H, s, Me-C4a), 0.921 (3H, s, Meb-C8), 0.886 (3H, s,
Mea-C8); 13C NMR (75 MHz) d 200.9 (C2), 165.4 (C4),
0
0
133.2 (C1 ), 128.9 (C3), 120.7 (C2 ), 49.9 (C8a), 41.1 (C7),
39.7 (C4a), 35.3 (C5), 37.2 (C1), 33.1 (C8), 32.4 (Mea-C8),
21.2 (Meb-C8), 18.6 (C6), 18.2 (Me-C4a), 13.2 (Me-C3); MS
(EI) m/z 232 (Mþ, 15), 217 (6), 189 (6), 149 (31), 109 (42),
69 (100); HRMS m/z calcd for C16H24O 232.1827; found:
232.1831.
1H NMR (200 MHz, CDCl3) of the more polar adduct
10aa-Me (21): d 5.61 (1H, dd, J¼5.6, 2.5 Hz, H-4), 4.19
(1H, dd, J¼11.5, 5.1 Hz, H-10), 3.786 and 3.692 (3H each,
each s, 2£CO2Me), 3.06 (1H, dd, J¼22.4, 5.6 Hz, H-3), 2.78
(1H, dd, J¼22.4, 2.5 Hz, H0-3), 1.325 (3H, s, Me-C10a),
1.147 (3H, s, Me-C4b), 0.915 (9H, s, Me3CSi), 0.850 (3H, s,
Me-C8), 0.823 (3H, s, Me0-C8), 0.123 and 0.092 (3H each,
each s, 2£MeSi); MS (EI) m/z 490 (Mþ, 1.8), 475 (1.7), 444
(0.5), 435 (9.1), 434 (30.9), 433 (100), 418 (2.7), 417 (9.3),
366 (2.4), 328 (2.2), 327 (9.5), 326 (5.2), 331 (4.3); HRMS
m/z calcd for C28H46O5Si 490.3114; found: 490.3151.
The above obtained ketone (20.3 mg, 0.087 mmol) and
CeCl3·7H2O (33.2 mg, 0.089 mmol) were dissolved in
MeOH (0.21 mL). NaBH4 (3.3 mg, 0.087 mmol) was
added in one portion with stirring at room temperature.
The stirring was maintained for 30 min, the reaction mixture
was cooled to 08C and the pH was adjusted to neutrality with
diluted HCl. Work up as usual and chromatography, using
hexane–ether 8:2, gave alcohol 19 (17.4 mg, 85%) as a
solid. Mp 106–1098C (from cold hexane). [a]2D2¼þ133.88
(0.3, CHCl3); IR nmax/cm21 (KBr) 3500–3100, 2922, 2846,
1456, 1374, 1022, 916. 1H NMR (300 MHz, CDCl3): d 6.09
(1H, ddcd, J¼17.6, 011.2, 1.2, 1.2 Hz, H-10), 5.27 (1H0, d0d,
J¼11.2, 2.6 Hz, H-2 ), 4.94 (1H, dd, J¼17.6, 2.6 Hz, H -2 ),
4.10 (1H, br dd, J¼8.5, 7.8 Hz, H-2), 2.09 (ddd, J¼12.5,
7.4, 1.5 Hz, H-1a), 1.716 (3H, dd, J¼1.2, 1.2 Hz, H,
Me-C3), 1.03 (3H, s, Me-C4a), 0.87 (3H, s, Me-C8), 0.84
1H NMR (200 MHz, CDCl3) of the less polar adduct
10ab-Me (22): d 5.641 (1H, dd, J¼5.1, 2.5 Hz, H-4), 4.43
(1H, d, J¼7.9 Hz, H-10), 3.706 and 3.662 (3H each, each s,
2£CO2Me), 3.07 (1H, dd, J¼23.1, 5.1 Hz, H-3), 2.84 (1H,
dd, J¼23.1, 2.5 Hz, H0-3), 1.442 (3H, s, Me-C10a), 1.253
(3H, s, Me-C4b), 0.884 (3H, s, Me-C8), 0.822 (3H, s,
Me0-C8), 0.789 (9H, s, Me3CSi), 0.117 and 20.040 (3H
each, each s, 2£MeSi); MS (EI) m/z 490 (Mþ, 2.3), 475
(1.8), 474 (3.4), 444 (0.5), 443 (1.8), 435 (9.1), 434 (32), 433
(100), 431 (3.1), 418 (4.7), 418 (13.7), 417 (45.7), 366 (3.4),

9532
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
343 (4), 328 (4.4), 327 (13), 326 (9.9), 312 (3.9), 311 (16.2);
HRMS m/z calcd for C28H46O5Si 490.3114; found:
490.3035.
H-100a), 4.16 (1H, dd, J¼15.9, 2.4 Hz, H-100b),003.83 (1H, br
d, J¼3.1 Hz, H-6), 2.40 (1H, t, J¼2.4 Hz, H-3 ), 1.91 (1H,
dd, J¼12.4, 1.1 Hz, H-5), 1.775 (3H, d, J¼0.9 Hz, Me-C7),
1.20 (1H, dd, J¼13.6, 4.3 Hz, H-3), 1.11 (1H, ddd, J¼12.1,
12.1, 3.8 Hz, H-1), 0.965 (3H, s, Meb-C4), 0.902 (3H, s,
Mea-C4), 0.856 (3H, s, Me-C8a); 13C NMR (75 MHz) d
4.4.2. Construction of the C ring by intramolecular
Diels–Alder reaction.
0 0 00
147.2 (C8), 134.4 (C1 ), 125.7 (C7), 119.1 (C2 ), 80.6 (C2 ),
4.4.2.1. 4-[Dimethyl-(3,4a,8,8-tetramethyl-4-vinyl-
1,2,4a,5,6,7,8,8a-octahydro-naphthalen-2-yloxy)-silanyl-
oxy]-but-2-ynoic acid methyl ester (23). Et3N (33 mL,
0.236 mmol), a solution of dienol 16 (18.4 mg, 0.078 mmol)
in CH2Cl2 (0.3 mL) and a solution of DMAP (1.9 mg,
0.015 mmol) in CH2Cl2 (0.05 mL) were successively added
to a solution of Me2SiCl2 (14.3 mL, 0.118 mmol) in
anhydrous CH2Cl2 (0.1 mL) at 788C. The mixture was
stirred at the same temperature for 1 h and then was treated
00
00
76.8 (C6), 73.8 (C3 ), 55.9 (C1 ), 45.5 (C4a), 41.3 (C3), 38.4
(C8a), 37.3 (C1), 32.9 (C4), 32.8 (Mea-C4), 23.1 (C5), 21.6
(Meb-C4), 18.8 (C2), 18.6a (Me-C7), 18.4a (Me-C8a); MS
(EI) m/z 272 (Mþ, 10), 257 (100), 123 (65), 105 (41), 91
(33); HRMS m/z calcd for C19H28O 272.2140; found:
272.2133.
4.4.2.3. (2R,4aS,8aS)-4-(3,4a,8,8-Tetramethyl-4-vinyl-
1,2,4a,5,6,7,8,8a-octahydro-naphthalen-2-yloxy)-but-2-
ynoic acid methyl ester (25). A solution of propargyl ether
24 (200.1 mg, 0.735 mmol) in THF (5 mL) at 2788C was
treated dropwise with a solution of BuLi in hexanes
(563 mL, 1.6 M, 0.740 mmol). After a few minutes, the
reaction mixture was treated with methyl cyanoformate
(125 mL, 1.57 mmol) and stirred at the same temperature for
50 min. Saturated aq. NH4Cl and hexane were added, and
the aq. phase was extracted with hexane. Workup followed
by column chromatography, using hexane–ethyl acetate
(95:5) as eluent, afforded the acetylenic ester 25 (201.5 mg,
84.5%) as a colorless oil. [a]2D7¼þ34.08 (4.0, CHCl3); IR
with
a solution of HOCH2CuCCO2CH3 (17.9 mg,
0.156 mmol) in CH2Cl2 (0.1 mL). The mixture was stirred
at 788C for 1 h and then diluted with pentane. The white
precipitated was filtered off and the filtrated concentrated in
vacuum and rapidly chromatographed, using hexane–ethyl
acetate 9:1 (with a few drops of Et3N) as eluent, to afford the
silylacetal 23 (21.6 mg, 68%) as a colorless oil. The
compound was quite labile to the chromatographic process,
being partially hydrolyzed to the starting alcohol during the
1
purification. H NMR (200 MHz) d 6.12 (1H, dd, J¼17.7,
11.4 Hz, H-100), 5.27 (1H, dd, 0J0 ¼11.4, 2.7 Hz, H-200), 4.95
(1H, dd, J¼17.7, 2.7 Hz, H-2 ), 4.50 (2H, s, H2-4), 3.76
(3H, s, CO2CH3), 4.15 (1H, br s, H-20), 1.704 (3H, br s, Me-
n
max/cm21 (film) 2926, 2860, 2243, 1718, 1433, 1251, 1045.
1H NMR (300 MHz) d 6.11 (1H, ddcd, J¼17.6, 11.2, 1.0,
1.0 Hz, H-100), 5.29 (1H, dd, J¼17.6, 2.4 Hz, Htrans-200), 4.98
(1H, dd, J¼11.4, 2.4 Hz, Hcis-200), 4.38 and 4.30 (2H, AB
0
0
0
C3 ), 0.935 (3H, s, Me-C4 a), 0.882 (3H, s, Meb-C8 ), 0.823
0
(3H, s, Mea-C8 ), 0.222 (6H, s, Si(CH3)2); 13C NMR
0
00
(75 MHz, C6D6) d 153.2 (C1), 145.3 (C4 ), 134.8 (C1 ),
system, J¼17.0 Hz, H-4), 3.85 (1H, broad d, J¼4.2 Hz,
0
0
127.6 (C3 ), 118.7 (C2 ), 85.4 (C3), 76.9 (C2), 70.8 (C2 ), 51.6
00
0
0
H-2 ), 3.782 (3H, s, CH3O), 1.779 (3H, s, Me-C3 ), 1.50
(1H, dd, J¼13.7, 3.8 Hz, H-60), 1.40 (1H, dd, J¼12.9,
1.5 Hz, H-8a0), 1.20 (1H, dd, J¼13.7, 4.6 Hz, H-70), 1.13
(1H, ddd, J¼12.9, 12.9, 4.2 Hz, H-50), 0.964 (3H, s,
0
0
(CH3O), 50.1 (C4), 44.9 (C8 a), 41.4 (C7 ), 38.2 (C4 a), 37.4
0
0
(C5 ), 32.8 (C8 ), 32.6 (Mea-C8 ), 29.0 (C1 ), 21.35 (Meb-
0
0
0
a
a
0
0
0
0
C8 ), 18.8 (C6 ), 18.76 (Me-C3 ), 18.2 (Me-C4a ), 22.5 and
22.6 (both SiCH3); MS (EI) m/z 404 (Mþ, 22.8), 390 (19.4),
389 (65.9), 367 (3), 321 (5), 319 (7.5), 281 (6.8), 266 (9),
265 (43.9), 247 (12.6), 246 (21.6), 245 (100); HRMS m/z
calcd for C23H36O4Si 404.2383; found: 404.2389.
0
0
0
Me-C8 b), 0.900 (3H, s, Me-C8 a), 0.858 (3H, s, Me-C4a );
13
0
00
C NMR (75 MHz) d 153.6 (C1), 147.7 (C4 ), 134.3 (C1 ),
0
125.4 (C3 ), 119.2 (C2 ), 84.6 (C3), 77.7 (C2), 77.7 (C2 ), 55.8
00
0
0
(C4), 52.7 (CH3O), 45.6 (C8a ), 41.3 (C7 ), 38.4 (C4a ), 37.4
0
0
0
0
0
0
0
4.4.2.2. (4aS,6R,8aS)-4,4,7,8a-Tetramethyl-6-prop-2-
ynyloxy-8-vinyl-1,2,3,4,4a,5,6,8a-octahydro-naphthalene
(24). The dienol 16 (200 mg, 0.84 mmol) was dissolved in
the minimum amount of ethyl acetate in a cylindrical flask
equipped with an efficient magnetic stirrer. The solvent was
evaporated with the aid of a current of argon to leave an oily
residue, to which tetrabutylammonium iodide (TBAI)
(156 mg, 0.428 mmol) and propargyl bromide (1.6 mL,
14.5 mmol) were added successfully. The mixture was
stirred while an aq. solution of 60% NaOH (1 mL) was
added dropwise and the two phase reaction mixture
was vigorously stirred in a bath thermostated at 258C for
28 h. After this time, the brownish reaction mixture was
poured into water, extracted with a mixture 1:1 of hexane–
ether and worked up. The brown oily residue obtained was
purified by column chromatography, using a 95:5 mixture of
hexane–ethyl acetate as eluent, to afford in order of elution:
propargyl ether 24 (130.2, 56%), as a colorless oil, and
unreacted starting dienol 16 (72 mg, 36%). Data for 24.
[a]2D5¼þ30.68 (1.2, CHCl3); IR nmax/cm21 (film) 3308,
(C5 ), 32.9 (C8 ), 32.8 (Mea-C8 ), 23.2 (C1 ), 21.6 (Meb-C8 ),
a
a
0
0
0
18.8 (C6 ), 18.6 (Me-C3 ), 18.4 (Me-C4a ); MS (EI) m/z 330
(Mþ, 2), 315 (25), 232 (35), 201 (29), 123 (100), 69 (89);
HRMS m/z calcd for C21H30O3 330.2195; found: 330.2189.
4.4.2.4. (5aR,6aS,10aS,10cR)-7,7,10a,10c-Tetra-
methyl-2,5a,6,6a,7,8,9,10,10a,10c-decahydro-4H-5-oxa-
acephenanthrylene-3-carboxylic acid methyl ester (26).
A solution of diene 25 (224.0 mg, 0.678 mmol) in degassed
anhydrous toluene (2 mL) was heated in a vacuum sealed
ampoule at 1128C for 17 h. After evaporation of the solvent
under reduced pressure, the residue was chromatographed
on silica gel, using a 9:1 mixture of hexane–ethyl acetate as
eluent, to afford the Diels–Alder adduct 26 (212.8 mg,
95%) as a white solid. Mp 95–968C (from EtOH). [a]2D7¼
þ52.98 (1.6, CHCl3); IR nmax/cm21 (KBr) 2960, 2932,
2859, 2818, 1708, 1678, 1455, 1436, 1267, 1190, 1117. 1H
NMR (300 MHz) d 5.64 (1H, dd, J¼6.4, 1.5 Hz, H-1), 4.94
(1H, dd, J¼14.1, 2.4 Hz, H-4a), 4.30 (1H, ddd, J¼14.0, 3.9,
0.7 Hz, H-4b), 3.87 (1H, dd, J¼3.7, 2.9 Hz, H-5a), 3.719
(3H, s, CH3O), 3.32 (1H, dd, J¼20.5, 6.4 Hz, H-2a), 2.64
(1H, dddd, J¼20.6, 3.9, 2.4, 1.5 Hz, H-2b), 1.93 (2H, m,
H-6), 1.82 (1H, ddd, J¼12.6, 3.1, 1.6 Hz, H-10b), 1.59 (1H,
ddd, J¼12.6, 3.1, 3.0 Hz, H-9), 1.50 (1H, m, J¼12.6, 7.0,
4.0 Hz, H-9), 1.40 (1H, m, H-8), 1.33 (1H, dd, J¼12.6,
1
2924, 2862, 1459, 1440, 1370, 1070, 1059, 919. H NMR
(300 MHz) d 6.11 (1H, ddcd, J¼17.7, 11.4, 0.9, 0.9 Hz,
H-10), 5.28 (1H, dd, J¼11.4, 2.6 Hz, Hcis-20), 4.98 (1H, dd,
J¼17.7, 2.6 Hz, Htrans-20), 4.26 (1H, dd, J¼15.9, 2.4 Hz,

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9533
3.9 Hz, H-10a), 1.14 (1H, dd, J¼12.6, 4.0 Hz, H-8), 1.125
(3H, s, Me-C10a), 1.101 (3H, s, Me-C10c), 1.15 (1H, dd
partly overlapped with Me-C10a, H-6a), 0.873 (3H, s,
Me-C7b), 0.870 (3H, s, Me-C7a); 13C NMR (75 MHz) d
166.8 (CO2), 164.0 (C3a), 154.5 (C10b), 121.3 (C3), 117.4
(C1), 82.8 (C5a), 68.6 (C4), 51.6 (CH3O), 45.6 (C10c), 43.8
(C6a), 42.0 (C8), 38.5 (C10), 38.3 (C10a), 33.2 (C7),
32.8 (Mea-C7), 27.0 (C2), 24.8 (C6), 24.6 (Me-C10c), 21.7
(Meb-C7), 21.6 (Me-C10a), 18.6 (C9); MS (EI) m/z 330 (Mþ,
100), 315 (38), 177 (30), 163 (55); HRMS m/z calcd for
C21H30O3 330.2195, found 330.2198. Anal. calcd for
C21H30O3: C 76.33, H 9.15; found: C 76.5, H 9.01.
2.7 Hz, H-7), 4.82 (1H, ddd, J¼16.8, 3.3, 1.8 Hz, H-15),
4.47 (1H, ddd, J¼16.8, 2.4, 2.4 Hz, H-15), 2.96 (1H, dddd,
J¼22.5, 4.5, 3.0, 1.8 Hz, H-12b), 2.81 (1H, dddd, J¼22.5,
3.3, 2.7, 2.4 Hz, H-12a), 1.970 (3H, s, CH3CO), 1.92 (1H,
m, H-6), 1.81 (1H, m, H-6), 1.426 (3H, s, Me-C8), 1.198
(3H, d, J¼0.9 Hz, Me-C10), 0.835 (3H, s, Meb-C4), 0.763
(3H, s, Mea-C4); 13C NMR (75 MHz) d 173.4 (C16), 170.4
(COCH3), 164.6 (C14), 147.7 (C9), 123.4 (C13), 116.7 (C11),
75.5 (C7), 68.6 (C15), 45.6 (C5), 41.7 (C8), 41.6 (C3), 40.1
(C10), 39.0 (C1), 33.2 (C4), 32.8 (Mea-C4), 27.6 (Me-C8),
23.6 (Me-C10), 23.0 (C6), 22.3 (C12), 21.3 (CH3CO), 21.2
(Meb-C4), 18.8 (C2); MS (EI) m/z 358 (Mþ, 2), 316 (100),
298 (75), 175 (45); HRMS m/z calcd for C22H30O4
358.2144, found 358.2142. Anal. calcd for C22H30O4: C
73.71, H 8.44; found: C 73.60, H 8.56.
4.4.2.5. Spectroscopic data for compounds formed by
oxidation of adduct 26 on storage. 2R,5aR,6aS,10aS,
10cR)-2-Hydroperoxy-7,7,10a,10c-tetramethyl-2,5a,6,6a,7,
8,9,10,10a,10c-decahydro-4H-5-oxa-acephenanthrylene-3-
carboxylic acid methyl ester (Compound ii). IR nmax/cm21
(film) 3400, 3000, 2940, 2360, 1710, 1690, 1623, 1440,
4.5.2. 7a-Hydroxy-spongia-9(11),13-dien-16-one (28). A
solution of the acetate-lactone 27 (86.1 mg, 0.241 mmol) in
a 10% aq. solution of KOH in MeOH (3 mL) was stirred at
08C for 1 h. The reaction mixture was poured into cold water
and acidified with diluted HCl. Extraction with ether and
workup as usual afforded a solid residue that was purified by
chromatography, using hexane–ethyl acetate 7:3 as eluent,
to afford the hydroxy-lactone 28 (69.6 mg, 92%) as a white
solid. Mp 184–1868C (from EtOAc). [a]2D6¼232.88 (1.0,
CHCl3); IR nmax/cm21 (film) 3500–3100, 2924, 2854,
1741, 1696, 1460, 1696, 1377, 1038, 750. 1H NMR
(400 MHz) d 5.80 (1H, dd, J¼4.5, 2.8 Hz, H-11), 5.04
(1H, ddd, J¼16.2, 2.6, 2.4 Hz, H-15), 4.86 (1H, ddd, J¼
16.2, 3.2, 1.5 Hz, H-15), 3.88 (1H, br s, H-7), 2.95 (1H,
dddd, J¼22.3, 4.5, 2.6, 1.5 Hz, H-12b), 2.81 (1H, dddd,
J¼22.3, 3.2, 2.8, 2.4 Hz, H-12a), 1.99 (1H, ddd, J¼14.4,
13.2, 2.4 Hz, H-6b), 1.80 (1H, m, H-1), 1.75 (1H, ddd, J¼
14.4, 3.3, 3.3 Hz, H-6a), 1.66 (1H, ddd, J¼13.5, 3.3, 3.3 Hz,
H-2), 1.55 (1H, dddd, J¼13.5, 7.1, 3.6, 3.6 Hz, H-2), 1.42
(1H, m, H-3), 1.41 (1H, m partly overlapped with H-3, H-1),
1.35 (1H, dd, J¼13.2, 2.5 Hz, H-5), 1.24 (1H, m, H-3),
1.395 (3H, s, Me-C8), 1.193 (3H, d, J¼0.9 Hz, Me-C10),
0.873 (3H, s, Meb-C4), 0.852 (3H, s, Mea-C4); 13C NMR
(75 MHz) d 173.8 (C16), 166.3 (C14), 147.7 (C9), 123.1
(C13), 118.2 (C11), 72.8 (C7), 69.4 (C15), 45.1 (C5), 43.6
(C8), 41.7 (C3), 40.2 (C10), 39.0 (C1), 33.3 (Mea-C4), 32.9
(C4), 27.6 (Me-C8), 26.2 (C6), 23.4 (Me-C10), 22.6 (C12),
21.5 (Meb-C4), 18.8 (C2); MS (EI) m/z 316 (Mþ, 15), 301
(6), 298 (9), 283 (17), 164 (100); HRMS m/z calcd for
C20H28O3 316.2038, found 316.2028. Anal. calcd for
C20H28O3: C 75.91, H 8.92; found: C 75.80, H 9.01.
1
1280, 1065. H NMR (300 MHz, CDCl3) dH 8.2 (1H, br s,
OOH), 5.76 (1H, d, J¼5.8 Hz, H-1), 5.64 (1H, d, J¼5.8 Hz,
H-2), 4.880 (1H, d, J¼14.6 Hz, H-4), 4.38 (1H, d, J¼
14.6 Hz, H -4), 3.89 (1H, dd, J¼4.3, 2.9 Hz, H-5a), 3.767
(3H, s, CO2Me), 1.9 (1H, m, H-6), 1.82 (1H, m, H-10b),
1.573 (3H, s, Me-C10c), 1.128 (30H, s, Hz, Me-C10a), 0.870
(3H, s, Me-C7), 0.847 (3H, s, Me -C7); 13C NMR (75 MHz,
CDCl3) dC 172.9 (CO2), 165.5 (C3a), 120.5 (C3), 115.3 (C1),
82.6 (C5a), 78.1 (C2), 68.7 (C4), 51.9 (OMe), 44.3 (C6a),
47.5 (C10c), 42.0 (C8), 39.0 (C10a), 38.02 (C10), 34.4
(Me-C10c), 33.4 (C7), 32.7 (Mea-C7), 24.9 (C6), 21.7
(Meb-C7), 20.6 (Me-C10a), 18.5 (C9); MS (EI) m/z 362
(Mþ, 20), 346 (15), 345 (25), 344 (99), 331 (13), 329 (31),
315 (28), 314 (76), 313 (47), 299 (49), 297 (44), 281 (24),
243 (54), 203 (100); HRMS m/z calcd for C21H30O5
362.20932; found: 362.20986.
(3aS,5aR,6aS,10aS,10cS)-3a-Hydroperoxy-7,7,10a,10c-
tetramethyl-3a,5a,6,6a,7,8,9,10,10a,10c-decahydro-4H-5-
oxa-acephenanthrylene-3-carboxylicacidmethylester (Com-
pound iii). IR nmax/cm21 (film) 3350, 3000, 2930, 2855,
1
1680, 1580, 1445, 1460, 1310. H NMR dH (300 MHz,
CDCl3) 11.34 (1H, s, OOH), 7.10 (1H, d, J¼6.2 Hz, H-2),
5.78 (1H, d, J¼6.2 Hz, H-1), 4.65 (d, J¼9.5 Hz, H-4), 3.63
(1H, d J¼9.5 Hz, H0-4), 4.41 (1H, dd, J¼2.7, 2.7 Hz, H-5a),
3.797 (3H, s, CO2Me), 2.05 (1H, m, H-6), 1.76 (1H, m,
H-10b), 1.132 (3H, s, Me-C10c), 1.129 (3H, s, Me-C10a),
0.901 (3H, s, Me-C7b), 0.877 (3H, s, Me-C7a).
4.5. Construction and further functionalisation of the D
ring system
4.5.3. 7-Oxo-spongia-9(11),13-dien-16-one (29). A solu-
tion of DMSO (51 mL, 0.70 mmol) in CH2Cl2 (0.5 mL) was
added to a solution of oxalyl chloride (58 mL, 0.68 mmol)
in CH2Cl2 (0.5 mL) at 2608C, the mixture was stirred for
5 min and then a solution of alcohol 28 (13.8 mg,
0.041 mmol) in CH2Cl2 (0.3 mL) was added. The mixture
was stirred at 2608C for 30 min, Et3N (30 mL, 0.21 mmol)
was added and the stirring was maintained for 15 min.
The mixture was warmed to 08C and maintained at this
temperature for 30 min, diluted with water, extracted with
CH2Cl2 and worked up. Chromatography, using a mixture
of hexane–ethyl acetate 8:2 as eluent yielded ketone 29
(11.9 mg, 89%). Mp 143–1458C (from cold methanol).
[a]2D7¼28.88 (1.1, CHCl3); IR nmax/cm21 (KBr) 2930,
2869, 1758, 1708, 1190, 1027, 1003, 748. 1H NMR
4.5.1. 7a-Acetyl-spongia-9(11),13-dien-16-one (27). A
mixture of the Diels–Alder adduct 26 (100 mg,
0.303 mmol) and ZnI2 (120 mg, 0, 376 mmol) in acetic
anhydride (2 mL) was stirred at rt for 48 h. The reaction
mixture was poured into water and extracted with ether.
The organic extracts were washed with aq. NaHCO3, brine
and dried. Chromatography of the residue obtained after
evaporation of the solvent, using hexane–acetate (8:2) as
eluent, afforded the lactone 27 (107.5 mg, nearly quanti-
tative) as a white solid. Mp 183–1848C (from hexane).
[a]2D7¼247.78 (1.5, CHCl3); IR nmax/cm21 (KBr) 2990,
1
2940, 2868, 1757, 1728, 1246, 1021. H NMR (300 MHz)
d5.75 (1H, dd, J¼4.5, 2.7 Hz, H-11), 4.95 (1H, dd, J¼2.7,

9534
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
(400 MHz) d 5.82 (1H, dd, J¼5.4, 2.1 Hz, H-11), 5.14 (2H,
m, H-15), 2.99 (1H, dddd, J¼22.3, 5.4, 2.1, 1.9 Hz, H-12b),
2.82 (1H, ddd, J¼22.3, 3.0, 2.8, 2.1 Hz, H-12a), 2.69 (1H,
dd, J 16.8, 14.4 Hz, H-6b), 2.53 (1H, dd, J 16.8, 3.5 Hz, H-
6a), 1.96 (1H, m, H-1), 1.38 (1H, dd, J 14.4, 3.5 Hz, H-5),
1.516 (3H, s, Me-C8), 1.333 (3H, s, Me-C10), 1.19 (1H, ddd,
J¼13.5, 12.6, 4.2 Hz, H-3a), 0.907 (3H, s, Meb-C4)a, 0.872
(3H, s, Mea-C4)a; 13C NMR (75 MHz) d 210.6 (C7), 173.7
(C16), 162.9 (C14), 149.9 (C9), 125.0 (C13), 117.6 (C11), 71.5
(C15), 48.8 (C5), 52.4 (C8), 41.4 (C3), 39.5 (C10), 39.3 (C1),
36.4 (C6), 33.7 (C4), 32.4 (Mea-C4), 22.30a (Me-C8), 22.36a
(Me-C10), 30.5 (C12), 21.1 (Meb-C4), 18.6 (C2); MS (EI) m/
z 314 (Mþ, 15), 298 (7), 281 (10), 211 (17), 191 (100), 109
(68); HRMS m/z calcd for C20H26O3 314.1882; found:
314.1896.
(Me-C10), 21.20 (Meb-C4), 17.6 (C2); MS (EI) m/z 374
(Mþ, 15), 330 (23), 314 (83), 256 (100), 69 (98); HRMS m/z
calcd for C22H30O5 374.2093; found: 374.2099.
Less polar epoxide 32 (6.8 mg; 40%), a white solid. Mp
114–1168C (from EtOAc–hexane). [a]2D6¼21.08 (1.3,
CHCl3). 1H NMR (400 MHz) d 5.16 (1H, dd, J¼3.0,
2.8 Hz, H-7), 4.71 (1H, ddd, J¼16.8, 2.9, 2.4 Hz, H-15),
4.64 (1H, ddd, J¼16.8, 3.1, 1.5 Hz, H-15), 3.89 (1H, dd, J¼
2.1, 1.9 Hz, H-11), 2.84 (1H, dddd, J¼19.3, 2.4, 1.9, 1.5 Hz,
H-12), 2.54 (1H, dddd, J¼19.3, 3.1, 2.9, 2.1 Hz, H-12),
1.924 (3H, s, MeCO), 1.427 (3H, s, Me-C8), 1.198 (3H, s,
Me-C10), 0.872 (3H, s, Meb-C4), 0.842 (3H, s, Mea-C4);
13C NMR (75 MHz) d 173.4 (C16), 169.6 (COMe), 161.7
(C14), 122.0 (C13), 74.7 (C7), 69.5 (C15), 68.1 (C9), 58.1 (C11),
45.5 (C5), 44.0 (C8), 41.8 (C3), 39.5 (C10), 35.6 (C1), 33.4
(C4), 32.8 (Mea-C4), 23.1 (C6), 22.1 (C12), 21.8 (Meb-C4),
21.5 (COMe), 20.9 (Me-C8), 19.3 (Me-C10), 18.3 (C2);
HRMS m/z calcd for C22H30O5 374.2093; found: 374.2098.
4.5.4. 7b-Hydroxy-spongi-9(11),13-dien-16-one (30).
Borane–THF complex (1.0 M borane solution en THF,
50 mL, 0.050 mmol) was added to a stirred solution of
compound 29 (5.3 mg, 0.017 mmol) in dry THF (150 mL)
at 08C. After 30 min 10% aqueous NaOH (0.25 mL) was
added cautiously followed by addition of 35% H2O2
(0.25 mL) within 15 min. After the addition, the bath was
removed and the mixture stirred for an additional 30 min.
The reaction mixture was worked up and subjected to flash
chromatography (using hexane–ethyl acetate 7:3 as eluent)
4.5.6. Rearrangement of epoxide 32. Boron trifluoride-
diethyl ether (12.5 mL) was added to a stirred solution of the
epoxide 32 (4 mg, 0.01 mmol) in dry benzene (265 mL) at
58C. After stirring for 3 h at this temperature the mixture
was allowed to warm to room temperature and stirred for an
additional hour. The mixture was diluted with ether and
washed with 5% aq. solution of NaHCO3 and brine and
dried. Purification of the residue left after evaporation of
the solvent by chromatography, using hexane–ethyl acetate
7:3 as eluent, afforded the alcohol 35 (2.8 mg, 70%) as an
amorphous solid. 1H NMR (400 MHz) d 5.09 (1H, dd,
J¼10.8, 5.4 Hz, H-7), 5.03 (1H, ddd, J¼17.5, 3.5, 0.9 Hz,
H-15), 4.87 (1H, ddd, J¼17.5, 2.6, 2.6 Hz, H-15), 4.31 (1H,
ddd, J¼6.4, 3.3, 2.6 Hz, H-11), 2.42 (1H, dddd, J¼17.7, 3.5,
3.3, 2.6 Hz, H-12a), 2.33 (1H, dddd, J¼17.7, 2.6, 2.6,
0.9 Hz, H-12b), 2.126 (3H, s, MeCO), 2.28 (1H, ddd,
J¼14.8, 5.4, 2.1 Hz, H-6b), 2.15 (1H, m, H-1b), 1.76 (1H,
dd, J¼14.8, 10.8 Hz, H-6a), 1.75 (1H, m, H-1a), 1.64 (1H,
m, H-2), 1.48 (2H, m, H-3bH-20), 1.45 (1H, d, J¼6.4 Hz,
OH), 1.371 (3H, s, Me-C8), 1.334 (3H, s, Me-C9), 1.25 (1H,
m, H-3a), 0.982 (3H, s, Meb-C4), 0.822 (3H, s, Mea-C4);
13C NMR (100 MHz) d 176.2 (C16), 170.1 (COMe), 162.7
(C14), 134.9 (C10)a, 130.9 (C5)a, 124.5 (C13), 73.5 (C7), 71.5
(C11), 71.3 (C15), 47.7 (C9), 43.4 (C8), 39.2 (C3), 34.5 (C4),
28.7 (Mea-C4), 27.3 (Meb-C4), 29.0 (C6), 26.7 (C1þC12),
21.3 (COMe), 19.8 (C2), 19.5 (Me-C8), 18.6 (Me-C9); MS
(EI) m/z 374 (Mþ, 2), 332 (10), 314 (100), 299 (85); HRMS
m/z calcd for C22H30O5 374.2093; found: 374.2076.
1
to give alcohol 30 (5.2 mg, 99%). H NMR (250 MHz) d
5.70 (1H, dd, J¼4.6, 2.9 Hz), 4.98 (1H, ddd, J¼16.2, 2.6,
2.4 Hz), 4.88 (1H, ddd, J¼16.2, 3.2, 1.5 Hz,), 3.65 (1H, dd,
J¼11.2, 4.9 Hz), 2.92 (1H, dddd, J¼22.3, 4.5, 2.6, 1.5 Hz),
2.79 (1H, dddd, J¼22.3, 3.2, 2.8, 2.4 Hz), 1.306 (3H, s),
1.172 (3H, d, J¼0.9 Hz), 0.864 (3H, s), 0.855 (3H, s); MS
(EI) m/z 316 (Mþ, 20), 301 (8), 298 (6), 283 (15), 164 (100);
HRMS m/z calcd for C20H28O3 316.2038; found: 316.2034.
4.5.5. 7a-Acetyl-9a,11a-epoxy-spongi-13-en-16-one (31)
and 7a-acetyl-9b,11b-epoxy-spongi-13-en-16-one (32).
A solution of 27 (16.2 mg, 0.045 mmol) and m-CPBA,
free of m-chlorobenzoic acid,33 (23.3 mg, 0.136 mmol) in
CH2Cl2 (0.85 mL) was stirred at room temperature for 17 h.
The dichoromethane mixture was treated with sodium
metabisulphate and extracted with CH2Cl2. The combined
organic extracts were washed with water, aq. Na2CO3 and
brine and dried (Na2SO4). The solid residue obtained after
evaporation of the solvent was purified by flash chroma-
tography (hexane–ethyl acetate, 8:2) to afford the following
compounds.
More polar epoxide 31 (7.8 mg, 46%), a white solid. Mp
115–1168C (from EtOAc–hexane). [a]2D6¼16.78 (1.6,
CHCl3). 1H NMR (400 MHz) d 4.99 (1H, dd, J¼2.5,
2.3 Hz, H-7), 4.70 (1H, dd, J¼17.0, 2.8 Hz, H-15b), 4.47
(1H, ddd, J¼17.0, 2.8, 1.9 Hz, H-15a), 3.36 (1H, dd, J¼2.3,
1.1 Hz, H-11), 2.95 (1H, ddd, J¼18.6, 2.3, 1.9 Hz, H-12b),
2.47 (1H, dddd, J¼18.6, 2.8, 2.8, 1.1 Hz, H-12a), 2.098
(3H, s, MeCO), 1.86 (1H, ddd, J¼14.9, 12.8, 2.5 Hz, H-6b),
1.71 (1H, dd, J¼12.8, 2.3 Hz, H-6a), 1.385 (3H, s, Me-C8),
1.261 (3H, s, Me-C10), 1.14 (1H, m, H-1b), 0.832 (3H, s,
Meb-C4), 0.815 (3H, s, Mea-C4); 13C NMR (100 MHz) d
173.5 (C16), 170.6 (COMe), 165.0 (C14), 120.1 (C13), 74.6
(C7), 68.3 (C9), 67.9 (C15), 50.8 (C11), 43.3 (C5), 43.2 (C8),
41.0 (C3), 39.1 (C10), 32.9 (C4), 32.4 (Mea-C4), 31.4 (C1),
24.5 (Me-C8), 23.0 (C6), 22.0 (C12), 21.37 (COMe), 21.35
4.5.7. 7-Oxo-9a,11a-epoxy-spongi-13-en-16-one (34). A
solution of tert-butyl hydroperoxide in benzene (450 mL,
0.051 mmol; prepared from 50 mL of a 5.5 M solution of a
tert-BuOOH in nonane and 2.5 mL of benzene) was added
to a mixture of vanadyl acetoacetonate (2 mg, 2.5 mol%,
0.0008 mmol) and homoallylic alcohol 28 (15 mg,
0.048 mmol) at 08C. After 10 min, the solution was allowed
to warm to room temperature and stirred for a further 24 h.
The reaction mixture was filtered through a short pad of
silica gel, washing with a mixture of hexane–ethyl acetate
9:1, to give the hydroxy epoxide 33 (11.1 mg, 70%), as a
1
solid. Mp 263–2678C (from benzene–hexane). H NMR
(300 MHz) d 5.13 (1H, ddd, J¼16.9, 2.7, 2.5 Hz, H-15),
4.78 (1H, dd, J¼16.9, 3.6 Hz, H-15), 3.87 (1H, ddd, J¼10.0,

A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
9535
2.8, 1 Hz, H-7), 3.42 (1H, dd, J¼2.5, 1 Hz, H-11), 2.92 (1H,
References
ddd, J¼19.0, 2.7, 2.5 Hz, H-12), 2.52 (1H, d, J¼10.0 Hz,
OH), 2.49 (1H, dddd partly overlapped with OH, J¼19.0,
3.6, 2.5, 1 Hz, H-12), 1.358 (3H, s, Me-C8), 1.252 (3H, s,
Me-C10), 0.906 (3H, s, Meb-C4), 0.874 (3H, s, Mea-C4);
MS (EI) m/z 332 (Mþ, 10.1), 317 (5.8), 314 (13.3), 299
(24.3), 281 (36.4), 271 (19.4), 125 (17.5), 205 (13.8), 189
(40.8),123 (100); HRMS m/z calcd for C20H28O4 332.1987;
found: 332.1985.
1. (a) Connolly, J. D.; Hill, R. A.; 1st ed. Dictionary of
Terpenoids; Chapman & Hall: London, 1991; Vol. 2, p 895.
(b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48, and
previous reviews of this series.
2. (a) Walker, R. P.; Thompson, J. E.; Faulkner, D. J. J. Org.
Chem. 1980, 45, 4976. (b) Capelle, N.; Braeckman, J. C.;
Daloze, D.; Tursch, B. Bull. Soc. Chim. Belg. 1980, 89, 399.
´ ´
(c) Gonzalez, A. G.; Estrada, D. M.; Martın, J. D.; Martın,
´
´
A solution of DMSO (26 mL, 0.36 mmol) in CH2Cl2
(0.5 mL) was added to a solution of oxalyl chloride
(30 mL, 0.35 mmol) in CH2Cl2 (0.5 mL) at 2608C. The
mixture was stirred for 5 min, a solution of the above
alcohol (10.7 mg, 0.031 mmol) in CH2Cl2 (0.2 mL) was
added and the mixture was stirred at the same temperature
for 30 min. Et3N (15 mL, 0.108 mmol) was added to the
solution, which was stirred at 2608C for 15 min, then
warmed and maintained at 08C for 30 min. The reaction
mixture was diluted with water, extracted with CH2Cl2 and
worked up. Chromatography, using a mixture of hexane–
ethyl acetate 8:2 as eluent yielded epoxyketone 34 (5.4 mg,
V. S.; Perez, C.; Perez, R. Tetrahedron 1984, 40, 4109.
(d) Kohmoto, S.; McConnell, O. J.; Wrigth, A.; Cross, S.
Chem. Lett. 1987, 1687. (e) Cimino, G.; Crispino, A.;
Gavagnin, M.; Sodano, G. J. Nat. Prod. 1990, 53, 102.
(f) Gunasekera, S. P.; Schmitz, F. J. J. Org. Chem. 1991, 56,
1250. (g) Potts, B. C. M.; Faulkner, D. J.; Jacobs, R. S. J. Nat.
Prod. 1992, 55, 1701. (h) Betancur-Galvis, L.; Zuluaga, C.;
´ ´
Arno, M.; Gonzalez, M. A.; Zaragoza, R. J. J. Nat. Prod. 2002,
65, 189.
3. (a) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1985, 24, 94. (b) Spring, O.; Kupka, J.; Maier, B.; Hager, A.
Z. Naturforsch. 1982, C37, 1087.
1
50%). H NMR (300 MHz) d 5.26 (1H, ddd, J¼18.50, 3.2,
4. Miyamoto, T.; Sakamoto, K.; Arao, K.; Komori, T.; Higuchi,
R.; Sasaki, T. Tetrahedron 1996, 52, 8187.
2.3 Hz, H-15), 5.02 (1H, ddd, J¼18.5, 3.4, ,1 Hz, H -15),
3.53 (1H, dd, J¼2.8, 1.1 Hz, H-11), 2.98 (1H, dddd, J¼18.7,
2.8, 2.3, ,1 Hz, H-12), 2.70 (1H, dd, J¼15.8, 14.3 Hz,
H-6b), 2.55 (1H, dd, J¼15.8, 3.4 Hz, H-6a), 2.51
(1H, dddd, J¼18.7, 3.4, 3.2, 1.1 Hz, H-12), 1.76 (1H, dd,
J¼14.3, 3.4 Hz, H-5), 1.555a (3H, s, Me-C8), 1.423a (3H, s,
Me-C10), 0.902 (3H, s, Meb-C4), 0.896 (3H, s, Mea-C4);
MS (EI) m/z 330 (Mþ, 28), 315 (16), 123 (74), 109 (100), 69
(53); HRMS m/z calcd for C20H26O4 330.1831; found:
330.1823.
5. La Clair, J. J.; Lansbury, P. T.; Zhi, B.; Hoogsteen, K. J. Org.
Chem. 1995, 60, 4822, and references cited therein.
6. (a) Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med.
Chem. 1971, 14, 1147. (b) Sasaki, S.; Maruka, K.; Naito, H.;
Maemura, R.; Kawahara, E.; Maeda, M. Chem. Pharm. Bull.
1998, 46, 154.
7. For partial synthesis of spongianes, see: (a) Immanura, P. M.;
´
Gonzalez-Sierra, M.; Ruveda, E. A. J. Chem. Soc., Chem.
Commun. 1981, 734. (b) De Miranda, D. S.; Brendola, G.;
´
Inmamura, P. M.; Gonzalez-Sierra, M.; Marsaioli, A. J.;
4.5.8. Rearrangement of epoxide 34. A solution of the
epoxide 34 (4.4 mg, 0.13 mmol) in dry benzene (250 mL)
was treated with boron trifluoride-diethyl ether (12 mL,
0.094 mmol) at room temperature for 8 h. Work-up as for 35
afforded a residue which was purified by chromatography,
using hexane–ethyl acetate 8:2 as eluent, to give 3.8 mg of a
7:3 mixture of two compounds. The major compound was
identified as the alcohol 36 by analysis of its spectroscopic
data deduced from the spectra of the mixture. Data for 36.
1H NMR (400 MHz) d 4.87 (1H, ddd, J¼17.6, 2.8, 2.8 Hz,
H-15), 4.72 (1H, ddd, J¼17.6, 3.4, 1.8 Hz, H0-15), 4.11 (1H,
dd, J¼3, 1.7 Hz, H-11), 2.25 (01H, dt, J¼17, 1.9 Hz, H-6),
2.45 (1H, dt, J¼17, 1.6 Hz, H -6), 1.050 (3H, s, Me-C8)a,
1.046 (3H, s, Me-C9)a, 1.002 (3H, s, Meb-C4), 0.949 (3H,
s, Mea-C4); 13C NMR (75 MHz) d (only some signals
assigned), 82.3 (C11), 71.6 (C15), 162.2 (C14), 136.1, 128.3
and 130.5 (C10, C13 and C5), 38.7 (C3), 36.9 (C6), 28.0
(C1), 26.8 (C12), 28.6 and 27.4 (2£Me-C4), 19.7 (C2), 12.5
(Me-C9), 9.6 (Me-C8).
´
´
Ruveda, E. A. J. Org. Chem. 1981, 46, 4851. (c) Gonzalez-
´
Sierra, M.; Mischne, M. P.; Ruveda, E. A. Synth. Commun.
´
1985, 15, 727. (d) Nakano, T.; Hernandez, M. I. Tetrahedron
´
Lett. 1982, 23, 1423. (e) Nakano, T.; Hernandez, M. I. J. Chem.
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Soc., Perkin Trans. 1 1983, 135. (f) Nakano, T.; Hernandez,
´
M. I.; Gomez, M.; Medina, J. D. J. Chem. Res. Synop. 1989,
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54. (g) Arno, M.; Gonzalez, M. A.; Zaragoza, R. J.
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Tetrahedron 1999, 55, 12419. (h) Arno, M.; Gonzalez,
´
´
M. A.; Marın, M. L.; Zaragoza, R. J. Tetrahedron Lett.
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2001, 42, 1669. (i) Arno, M.; Gonzalez, M. A.; Zaragoza, R. J.
J. Org. Chem. 2003, 68, 1242.
8. For total synthesis of spongianes and spongiane-type com-
pounds, see: (a) Nishizawa, M.; Takenaka, H.; Hayashi, Y.
Chem. Lett. 1983, 1459. (b) Zoretic, P. A.; Shen, Z.; Wang,
M.; Ribeiro, A. A. Tetrahedron Lett. 1995, 36, 2925.
(c) Sakamoto, T.; Kanematsu, K. Tetrahedron 1995, 51,
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Ribeiro, A. A. J. Org. Chem. 1996, 61, 1806. (f) Zoretic, P. A.;
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Blake, A. J. J. Chem. Soc., Perkin Trans. 1 1998, 863.
(h) Goeller, F.; Heinemann, C.; Demuth, M. Synthesis 2001,
1114.
Acknowledgements
´
Financial support from the Direccion General de Ensen˜anza
´ ´
9. (a) Abad, A.; Arno, M.; Marın, M. L.; Zaragoza, R. J. J. Org.
´
´
´
Superior e Investigacion Cientıfica (Grants PB98-1421-
C02-01and BQU2002-00272) is gratefully acknowledged.
We are also grateful to the Ministerio Espan˜ol de Ciencia y
´ ´
Chem. 1992, 57, 6861. (b) Abad, A.; Arno, M.; Marın, M. L.;
´
Zaragoza, R. J. J. Chem. Soc., Perkin Trans. 1 1993, 1861.
´ ´ ´
(c) Abad, A.; Agullo, C.; Arno, M.; Cun˜at, A. C.; Marın, M. L.;
´
Zaragoza, R. J. J. Chem. Soc., Perkin Trans. 1 1996, 2193.
´
Tecnologıa for providing a research fellowship to A. B. G.

9536
A. Abad et al. / Tetrahedron 59 (2003) 9523–9536
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