Total synthesis of (±)-dysidiolide

Article abstract of DOI:10.1016/S0040-4020(02)00663-4

The total synthesis of (±)-dysidiolide was accomplished with a high level of intramolecular stereo-induction. Methylation of 6-carboethoxy-3-chloro-5-methyl-cyclohex-2-enone provided 33 bearing the 6,7-trans-dimethyl substitution of the C6-C11 B-ring. Diastereoselective conjugate addition upon enone 34 installed the C11 stereogenic center. Annulation then provided an A-ring enone (23), a substrate for a challenging conjugate addition of the branched pentenyl side chain. The combination of tri-n-butylphosphine, boron trifluoride etherate, and a dialkylcuprate uniquely effected conjugate addition to yield 58. Incorporation of the hydroxybutenolide-containing side chain completed the total synthesis and established the viability of a general approach for the preparation of the isolabdanoid terpene system.

Full text of DOI:10.1016/S0040-4020(02)00663-4

Tetrahedron 58 (2002) 6531–6544
Total synthesis of (6)-dysidiolide
*
Damtew Demeke and Craig J. Forsyth
Department of Chemistry, University of Minnesota, 139 Smith Hall, 207 Pleasant Street, SE, Minneapolis, MN 55455, USA
Received 16 May 2002; accepted 10 June 2002
Abstract—The total synthesis of (^)-dysidiolide was accomplished with a high level of intramolecular stereo-induction. Methylation of
6-carboethoxy-3-chloro-5-methyl-cyclohex-2-enone provided 33 bearing the 6,7-trans-dimethyl substitution of the C6–C11 B-ring.
Diastereoselective conjugate addition upon enone 34 installed the C11 stereogenic center. Annulation then provided an A-ring enone (23), a
substrate for a challenging conjugate addition of the branched pentenyl side chain. The combination of tri-n-butylphosphine, boron trifluoride
etherate, and a dialkylcuprate uniquely effected conjugate addition to yield 58. Incorporation of the hydroxybutenolide-containing side chain
completed the total synthesis and established the viability of a general approach for the preparation of the isolabdanoid terpene
system. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2–50 mM.4 In the MCF 7 breast cancer cell line, dysidiolide
caused the loss of G2/M peak and the accumulation of
cells in G1 consistent with the inhibition of cdc25A.
Consequently, dysidiolide has emerged a promising new
anti-mitotic lead compound.
Dysdiolide (Fig. 1) is a structurally unique neo-isolabdanoid
sesterterpene isolated from the marine sponge Dysidea
etheria de Laubenfels that was collected off the Bahamian
islands.1 The structure of dysidiolide was shown by
Gunasekera et al. to possess a bicyclic dehydrodecalin
core adorned with four stereogenic centers including two
quaternary carbons and two unusual axially disposed
appendages. The latter project from the bicyclic framework
in a parallel fashion and in close spatial proximity to each
Due to the combination of structural novelty and biological
activity, dysidiolide has become the focus of several total
synthesis efforts. The groups of Corey,5 Boukouvalas6 and
Danishefsky4 succeeded in developing the first total
syntheses of dysidiolide. The enantioselective syntheses
by Corey and Boukouvalas established the absolute
configuration of the natural product (2)-1 as depicted in
Fig. 1. Subsequently, total syntheses have been reported
from our own laboratories,7 as well as by Shirai et al.,8 and
Yamada and co-workers.9 Additional synthetic efforts have
also been reported,10 including formal total syntheses by
Piers11 and Jung.12
˚
other (ca. 4 A). One extending arm is hydrophobic
terminating in an isoprenyl group and the other is
hydrophilic culminating with a g-hydroxybutenolide
moiety. The latter may mimic a phosphate ester.
The architectural novelty of dysidiolide is complemented by
its distinction as the first known natural inhibitor of the dual
specificity phosphatase enzyme cdc25A (IC50 9.4 mM),
causing stage specific arrest of the cell cycle at the G1/S
transition and loss of the G2/M peak.1 Although, Blanchard
et al. suggested that the inhibition was probably caused by
an unidentified component in the crude extract,2 Shirai and
co-workers subsequently confirmed that dysidiolide not
only inhibits cdc25A (IC50 35 mM) but also cdc25B (IC50
87 mM).3 In addition, Gunasekera et al. reported that
dysidiolide inhibited the growth of A-549 human lung
carcinoma and P388 murine leukemia cell lines with IC50
values of 4.7 and 1.5 mM, respectively.1 Furthermore,
Danishefsky has reported that racemic synthetic dysidiolide
inhibited PC3, TSU-Pr1, DU145 prostate cancer cells and
an MCF7 breast cancer cell line with IC50 values of
The initial syntheses fall into two of the three categories of
general approaches for bicyclic terpenoids outlined by
Tokoroyama.13 Corey used the Wieland–Miescher ketone
as a decalin template, and Boukouvalas and Danishefsky
Keywords: total synthesis; (^)-dysidiolide; intramolecular stereo-
induction.
*
Corresponding author. Tel.: þ1-612-624-0218; fax: þ1-612-626-7541;
e-mail: forsyth@chem.umn.edu
Figure 1. Structure and conformation of (2)-dysidiolide.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00663-4

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D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
used Diels–Alder cycloadditions to construct the core
bicyclic ring system. The earliest syntheses applied
synthetic methods developed for the preparation of
clerodane and isolabdane terpenoids with vicinal cis-
dimethyl substitution. We sought to complement these
approaches by devising a general entry into the isolabdane
class, which could be modified for the synthesis of labdane
and clerodane terpenoids. This approach could be placed in
Tokoroyama’s third and most flexible category of strategies
for the synthesis of labdane, isolabdane and clerodane
terpenoids.13 Specifically, dysidiolide’s bicyclic nucleus
would be constructed from an initial cyclohexenone
template for the B-ring (C6–C11) that bears the vicinal
trans-dimethyl substitutents at C6 and C7.14 The remaining
stereogenic centers could be relayed from the B-ring
precursor by a sequence of diastereoselective reactions.
The use of independently installed stereogenic centers in the
B-ring to control the creation of subsequent chirality would
enable the synthesis of dysidiolide and analogues in all
possible stereoisomeric combinations, as desired for
thorough SAR studies. Described here are the full details
of this versatile synthetic approach, culminating in the total
synthesis of (^)-dysidiolide.7
Scheme 2. Labdanyl cation partitioning.
2. Results and discussion
addition, dysidiolide’s trans-vicinal dimethyl substitution
pattern at C6, C7 represents a paused cyclization of a
labdanyl cation (3). Other natural products with similar
bicyclic systems include the aldose reductase inhibitor
dysideapalaunic acid (4, Scheme 1)15,16 and the cladocorans
A and B.17 Comparing the skeleta of these natural products,
dysideapalaunic acid has an unrearranged labdane skeleton
with a pentenyl appendage that has the more common
trisubstituted internal alkene. Cladocoran B (6, Scheme 2) is
isomeric with dysidiolide differing only in the position of its
core alkene and the cis-orientation of the vicinal methyl
groups. The unusual pentenyl appendage of dysdiolide and
the cladocorans may be formed in the initial stages of
isoprene elongation, during the synthesis of their linear
precursors.
2.1. Structure and biosynthesis
Several structural features make dysidiolide an unusual
sesterterpene. First, its biosynthetic cyclization appears to
occur exclusively with the central alkenes producing a
stereogenic quaternary carbon at C15 with methyl and
branched pentenyl substituents (cf. 2!3, Scheme 1) instead
of the more common dimethyl substituted quaternary
carbon. Second, this pentenyl appendage has a terminal
alkene rather than a trisubstituted internal alkene. In
Cationic cyclization could proceed in a concerted manner
via 5 with the migration of the ring junction methyl group,
producing the cis-dimethyl substitution pattern of clado-
corans (Scheme 2). Alternatively, cyclization may pause at
a labdanyl alkene (7) formed by the elimination of H1 from
3, giving rise to a structure similar to dysideapalaunic acid.
Protonation of this paused alkene 7 from the b-face would
reactivate the rearrangement cascade via 8 producing
dysidiolide’s C6,7-trans-dimethyl substitution and proceed-
ing until the elimination of H3.
The structural relationships among dysidiolide and its
biogenetic cogeners suggested that in the course of targeting
the former for total synthesis, a general entry to the
synthesis of labdanes, isolabdanes and clerodanes could be
developed. The dehydrodecalin cores of dysidiolide, the
cladocorans, and the cacospongionolide18 – 20 natural
products share a common 6,7-trans-vicinal dimethyl
substitution pattern (Fig. 2).14 The core structures of
dysidiolide and cacospongionolide F (10) belong to the
isolabdane terpenoid class, while that of cacospongionolide
E (9) belongs to the clerodane group. The core structures of
Scheme 1. Putative biosynthetic cyclizations.

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6533
2.2. Synthetic design
2.2.1. Core strategy. It was envisioned that the vicinal
trans- and cis-disubstituted cyclohexenones 13 and 14,
respectively, could serve as general B-ring (C6–C11)
templates (Scheme 3).22 A conjugate addition–annulation
sequence would install the A-ring (C10–C15), in principle
with either relative configuration at the C11 ring junction
(15 and 17 vs. 16 and 18). The quaternary center at C15
could be installed by another conjugate addition of a
substituent R2 on the b-face of the decalin system. By
alternating the order of introducing R1 and R2, either C15
epimer would be available.
Figure 2. Structures of related sesterterpenes.
Although this design may permit access to a variety of
stereoisomers of the dysidiolide core (19–22), further
functionalization of both rings would be required to access
the labdanes, isolabdanes and clerodanes. For ring B,
remaining functionalization would occur in the presence of
the ketone. For ring A, bicyclic enone 23 would be
converted into diketone 24, which may permit the addition
the parent cacospongionolide (11) and dysidotronic acid
(12),21 however, have not been assigned to specific skeletal
classes. Cacospongionolide has an additional cyclopropane
ring fused to its decalin core, and dysidotronic acid’s core
appears to be biosynthetically singular.
Aside from their core terpenoid skeleta, the natural products
dysidiolide, cladocorans, and cacospongionolides share
additional structural motifs. The most conspicuous is the
presence of a hydrophilic butenolide derivative attached
either directly to a hydrophobic core, or by an intervening
pyranyl or geranyl spacer. These butenolide moieties
display a range of oxidation states. The incorporation of
these variable side chain motifs upon the decalin cores could
be accomplished late in their total syntheses.
Scheme 4. Generality of enone 23.22
Scheme 3. Generality of the B-ring templates.
Scheme 5. Synthetic design for dysidiolide.22

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D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
of a ring junction methyl group at C10, as in cacospongio-
nolide E (Scheme 4).
and vinylogous ester functionalities. Subsequent to alkyl-
ation, reductive carbonyl transposition would take
advantage of the facile reduction of the ester functionality
of 30 to an alcohol, whereas reduction of the vinylogous
ester would stop at the stage of the vinylogous hemiacetal.
Net enone transposition would then be completed upon
acidic treatment to yield 13.
Application of this design to the total synthesis of
dysidiolide would utilize the 6,7-trans-dimethyl cyclo-
hexenone 13 (Scheme 5). The C11 ring junction would be
set by an axial conjugate addition of an A-ring annulation
precursor, using the equatorial disposition of the vicinal
methyl groups to enforce the conformation of the enone and
enhance the facial selectivity. Following the transformation
of the adduct to the enone 23, the quaternary center at C15
would be installed by the introduction of a branched
pentenyl nucleophile on the rigid bicyclic system to provide
25. Hydroxymethyl side chain elongation would then lead to
the addition of a furan moiety to obtain 26, as a masked form
of the natural product’s g-hydroxybutenolide. Final photo-
oxidation of the furan would complete the total synthesis of
dysidiolide.
A useful synthetic equivalent to b-ketoester 29 was found to
be the vinylogous acyl chloride 32, an intermediate reported
by Mukherjee (Scheme 8).25
Condensation of ethyl acetoacetate with ethyl crotonate
provided the tricarbonyl compound 31, which was
dehydrated with phosphorus trichloride to 32. Given the
susceptibility of the vinyl chloride to conjugate addition–
elimination, the alkylation required a non-nucleophilic base.
Reaction of 32 with sodium hydride and methyl iodide
provided a good yield of the alkylation product 33
(Scheme 8). Upon treatment of 33 with sodium ethoxide
in ethanol, the vinyl chloride was quantitatively converted
into the enol ether 30.
2.3. Synthesis of the decalin core
2.3.1. Synthesis of B-ring (C6–C11) enone 13. The key
enone 13 with the 6,7-trans-vicinal dimethyl substituents
was prepared by a variation of the Stork–Danheiser
alkylation.23 To establish that the requisite vicinal trans-
dimethyl substitution could be secured by alkylation, model
ester 27 was prepared using the Diels–Alder reaction of
Danishefsky’s diene with ethyl (E )-but-2-enoate (Scheme
6).24 When the deprotected cycloadduct 27 was treated with
potassium carbonate and excess methyl iodide, trans-
dimethyl substituted ester 28 was produced as the exclusive
diastereomer. The trans orientation of the methyl groups
was established by the observed NOE enhancement of the
C7 methine proton resonance upon irradiation of the C6
quaternary methyl group.
Intermediate 30 was surprisingly stable to reduction,
requiring excess lithium aluminum hydride and ambient
temperatures. Reduction at 08C mainly produced an over-
reduced, saturated compound. However, controlled
reduction occurred when 30 was added slowly to an excess
of lithium aluminum hydride at room temperature. Upon
hydrolysis with 2 M HCl, the reduction product gave the
expected enone 13, which was silylated to give 34.
This type of trans selective alkylation was extended to the
b-dicarbonyl compound 29 (Scheme 7), containing ester
Scheme 8. Synthesis of enone 34.
Scheme 6. Preparation of trans-dimethyl substitution by alkylation.
Scheme 7. Stork–Danheiser alkylation–enone transposition variation.
Scheme 9. Synthetic plan for bicyclic enone 36.

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6535
2.3.2. Synthesis of bicyclic enone 23. The B-ring
intermediate 34 would serve as a substrate for a conjugate
addition–annulation sequence to install the A-ring. Several
nucleophiles were considered as annulation precursors for
the A-ring. The required features were that the nucleophiles
were five carbons long and after conjugate addition they
should be easily converted into the methyl ketone 35, which
would be cyclized to the generic bicyclic enone 36
(Scheme 9).
In the first case, the cuprate reagent derived from
5-bromopent-1-ene, tert-butyllithium, and CuI was added
to enone 34 in the presence of trimethylsilyl chloride to give
the conjugate adduct 37 in 94% yield (Scheme 10). The silyl
ether was cleaved and the resulting alcohol was submitted to
standard Wacker oxidation26 conditions to afford diketone
38 in 58% yield.
Surprisingly, diketone 38 could not be cyclized under a
variety of conditions examined. In an attempt to rationalize
these observations, the infrared and carbon spectra of the
related keto-diol 39 suggest that this compound exists
largely as a hemiketal (40) with the primary alcohol
engaged with the cyclohexanone carbonyl group
(Scheme 11). There is neither an IR absorption, nor a 13C
resonance in the carbonyl regions of the corresponding
spectra of 40 (39). Instead, the 13C NMR spectrum displays
a hemiketal carbon resonance at 98 ppm. By analogy,
diketone 38 may also exist primarily as the cyclic hemiketal
41.
Scheme 12. Preparation of bicyclic enone 23.
As an alternative side chain annulation precursor, 1-bromo-
4-tert-butydimethylsilyloxypentane (43) was prepared from
levulinic acid (Scheme 12).27 Following literature
precedent, ethyl levulinate was reduced with sodium
borohydride and the resulting alcohol protected as its tert-
butyldimethylsilylether 42.28 The ethyl ester was then
reduced to the primary alcohol with lithium aluminum
hydride. After toluenesulfonate formation, treatment with
lithium bromide in the presence of sodium bicarbonate
provided bromide 43. Conjugate additions upon enone 34 of
both the higher order cyanocuprate and the lower order
Gilman reagent prepared from copper iodide and 43 were
successful, although the use of the cyanocuprate was
favored due to its more convenient preparation and
handling.
Both silyl ethers of 44 were cleaved under acidic conditions
and the resulting diol 45 was oxidized to the keto-acid with
Jones reagent. Treatment of the keto-acid with ethyl iodide
and potassium bicarbonate provided the ethyl ester 46
bearing the methyl ketone required for annulation, but
without the primary alcohol of 38.
Scheme 10. Diketo-alcohol preparation.
Cyclization of the 1,7-diketone 46 to afford the correspond-
ing bicyclic enone 23 required considerable optimization.
Initially, the annulation was conducted under standard
conditions with 10% potassium hydroxide, but the enone
was produced in less than 20% yield. Using 2–3 equiv. of
potassium tert-butoxide, the annulation proceeded with
70–80% conversion.
2.3.3. Completion of the dysidiolide core.
2.3.3.1. Installation of the alkenyl side chain at C15.
The first approach towards installing the branched pentenyl
appendage was to simultaneously incorporate the D9,10
alkene of dysidiolide via an SN20 displacement of an allylic
methanesulfonate (47) with an organocopper nucleophile to
Scheme 11. Diketone 38 as a hemiketal (41).

6536
D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
conjugated diene 51 formed by the in situ elimination of
the methanesulfonate could be isolated.
The corresponding allyic acetates were examined briefly as
an alternative to the allylic mesylates. Allylic alcohols 49
and 50 were acetylated to produce acetates 52 and 53,
respectively. Although these allylic acetates also had a
tendency for elimination, they could be handled under
neutral conditions. Yamamoto’s reagent was prepared by
treatment of 5-bromo-2-methyl-1-pentene with tert-butyl-
lithium followed by 1 equiv. each of copper cyanide, or
copper iodide, and BF3·OEt2. However, attempts to react the
organocopper species with the allylic acetates 52 or 53 were
unproductive. The starting materials remained unchanged
throughout the temperature range of 278 to 08C.
Scheme 13. Proposed Yamamoto-type SN20 addition.
On the theme of simultaneous installation of the C15
stereogenic quaternary center with the formation of the
D9,10 alkene, an Ireland–Claisen rearrangement was also
probed.32 It was envisioned that the allylic acetate 53 could
be converted into the corresponding silyl ketene acetal 54 en
route to the allylically transposed silyl ester 55 (Scheme 16).
The alkenyl side chain could then be elaborated from the
latter.
Scheme 14. Preparation of 5-bromo-2-methyl-1-pentene.
Following standard procedures, a solution of 53 was treated
with lithium diisopropylamide and trimethylsilyl chloride
then warmed to ambient temperature. Upon isolation of the
products only the diene 51, produced by elimination of the
acetate, and the C-silylated ester were found. However,
when allylic acetate 53 was treated with potassium
hexamethyldisilazane in toluene followed by tert-butyl-
dimethylsilyl chloride and warming to room temperature,
the rearranged silyl ester 55 was isolated in 27% yield.
Extensive attempts to optimize the reaction sequence led to
no overall improvements in yield, however. Therefore, a
stepwise sequence to introduce the side chain and D9,10
alkene was ultimately adopted.
provide 48 (Scheme 13). Yamamoto has reported that the
alkylcopper–boron trifluoride0 complex can displace allylic
methanesulfonates in an SN2 fashion to form quaternary
centers.29,30
To attempt implementation of this approach, ethyl
levulinate was converted into 5-bromo-2-methyl-1-pentene,
which would serve as a precursor to the organocopper
nucleophile (Scheme 14).
The targeted coupling partner of the organocopper nucleo-
phile was the allylic methanesulfonate 47. For this, the
bicyclic enone 23 was reduced to the a-allylic alcohol 49
(Scheme 15). This was accomplished under Luche con-
ditions,31 which gave a 3:1 ratio of 49 to the corresponding
b-allylic alcohol 50. Alternatively, 50 could be obtained as
the exclusive reduction product upon treatment of 23 with
lithium tri-sec-butylborohydride. However, the derived
methanesulfonate could not be isolated. When either the
a- or b-allylic alcohols 49 or 50 were treated with
methanesulfonyl chloride and triethylamine, only the
Returning to enone 23, the alkenyl side chain would be
installed in its entirety via conjugate addition. Thereafter,
Scheme 15. Attempted SN20 reactions.
Scheme 16. Ireland–Claisen rearrangement.

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6537
may depend upon both the electrophilicity of the enone
system and the reducing potential of the alkylcuprate
species, an attempt to increase the electron density of the
latter was also made by the addition of tri-n-butylphosphine
as a ligand for copper. Oppolzer had reported that addition
of tri-n-butylphosphine to Yamamoto’s alkylcopper reagent
enhanced its reactivity, but this finding had apparently not
been extended to alkylcuprates.34
Scheme 17. Sih’s conjugate addition.33
In the event, lithiation of 5-bromo-2-methyl-1-pentene
(4.2 equiv.) with tert-butyllithium in diethyl ether was
followed by the addition of CuI (2.1 equiv.) and tri-n-
butylphosphine (2.5 equiv.) in THF. To the cuprate mixture
was added enone 23 (1.0 equiv.) followed by BF3·OEt2
(4.2 equiv.). Normal quench and work up provided the
anticipated adduct 58 in 86% yield (Scheme 19). This
conjugate addition was reproducible, providing 80 to 90%
yields of the conjugate adduct on a variety of scales.
the resulting ketone would be serve to introduce the D9,10
alkene of 48. This approach was reserved as a late
alternative because b-disubstituted enone 23 is both
sterically hindered and, as detailed previously, bent out of
planarity by ,468.7
With a somewhat similar bicyclic system, Sih and
co-workers had reported the conjugate addition of a methyl
group to the enone 56 (Scheme 17).33 Whereas 56 was
unreactive towards conventional organocopper reagents
(Me2CuLi or Me2Cu(CN)Li2), when treated with
Yamamoto’s methyl copper reagent or trimethylsilyl
chloride augmented methylcuprate, high yields of the
conjugate adduct were obtained.
2.3.3.2. Formation of the core D9,10 alkene. With the
successful stereoselective addition of the alkenyl side chain
appendage, only formation of the D9,10 trisubstituted
alkene remained to complete the assembly of dysidiolide’s
core structure. Initially, it seemed that chemoselective
reduction of the C9 ketone of 58 to the alcohol 59, followed
by dehydration would produce the D9,10 alkene 48 (Scheme
20). But, the ketone was quite resistant to reduction with
sodium borohydride at ambient temperature and when the
reduction was conducted at elevated temperatures, the
Similarly, attempted conjugate additions upon bicyclic
enone 23 of conventional organocopper species prepared
from 4-methyl-4-pentenyllithium and various copper
sources were unsuccessful. Attempted conjugate addition
with the Yamamoto organocopper reagent, prepared from
equimolar amounts of copper iodide, 4-methyl-4-pentyl-
lithium (derived from of 5-bromo-2-methyl-1-pentene with
tert-butyllithium) and boron trifluroide etherate, also failed
to provide the anticipated product 58 (Scheme 18). Attempts
to effect 1,4-addition upon 23 with a 4-methyl-4-pentenyl
cuprate in the presence of trimethylsilyl chloride were
similarly unproductive. However, n-butylcuprate, prepared
from salt-free n-butyllithium, added to enone 23 in the
presence of trimethylsilyl chloride to provide adduct 59 in
41% yield.
Scheme 19. Successful conjugate addition upon enone 23.
To enhance the success of the conjugate addition, it was
reasoned that the addition of a Lewis acid such as BF3·OEt2
might planarize the bent enone by withdrawing electron
density from the carbonyl group and force allylic partici-
pation, and as a result may increase the electrophilicity of
the b-carbon. Further, because the rate of conjugate addition
Scheme 18. Attempted conjugate additions upon enone 23.
Scheme 20. Chemoselective reduction—lactonization.

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D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
Scheme 21. Global carbonyl reduction—dehydration.
resulting alcohol readily lactonized to generate 60. Exten-
sive attempts to use the carboxyl moiety of the lactone 60 as
a leaving group to prepare the D9,10 alkene of 48 were
unsuccessful.
Thus, 58 was reduced with an excess of lithium aluminum
hydride and the resulting diol 61 was mono-silylated at the
primary alcohol to provide 62 (Scheme 21). Dehydration of
62 could be accomplished with either phosphorus oxychlor-
ide or thionyl chloride,35 the latter being much faster.
Finally, cleavage of the trimethylsilyl ether provided
primary alcohol 25 bearing the core structure of dysidiolide.
Attention could then be turned to the installation of the
g-hydroxybutenolide moiety and the completion of the total
synthesis.
Scheme 22. Side chain elaboration.
Hydrolysis of the vinyl ethers with 2N hydrochloric acid in
dioxane cleanly provided the pivotal C4 aldehyde 66, which
has been a common advanced intermediate in each of the
total syntheses of dysidiolide reported to date.4–7,9,10
2.4.2. Furan addition. Mirroring the end-game strategy of
Corey5 and Danishefsky,4 the masked butenolide could be
installed via 3-lithiofuran, which is available by lithiation of
3-bromofuran. Because 3-lithiofuran is prone to isomeriza-
tion to the thermodynamically favored 2-lithiofuran above
2408C,37 3-bromofuran was lithiated and the aldehyde 66
was added at 2788C. This reaction provided a ca. 1:1 ratio
of epimeric alcohols 26 and 67.5 At this stage, diastereomer
67 bearing the unnatural relative configuration at C4 could
be epimerized via either Mitsunobu inversion,4 or an
oxidation–diastereoselective reduction process.5 Only
photooxidation of the furan moiety of 26 to reveal the
g-hydroxybutenolide remained to complete the total
synthesis (Scheme 23).
2.4. Side chain elaboration
2.4.1. Synthesis of sec-dysidiolide. Two key tasks
remained to complete the synthesis of dysidiolide, extension
of the hydroxymethyl substituent of 25 into a one-carbon
homologated aldehyde (66, Scheme 22), and installation of
the g-hydroxybutenolide moiety. As stated at the outset, the
butenolide moiety would be incorporated via the addition of
3-lithiofuran upon a C4 aldehyde, which would provide both
a photooxidation substrate for hydroxybutenolide formation
and the secondary hydroxyl group resident at C4 of 1.
2.5. Furan oxidation: total synthesis of dysidiolide
The neopentyl nature of the C6 carbon of 25 precluded the
use of substitution reactions for chain homologation.
Instead, a Wittig homologation was initiated via oxidation
of the hydroxyl group to the corresponding aldehyde 64 with
pyridinium chlorochromate. Exposure of 64 to methoxy-
methyltriphenylphosphorane, generated from methoxy-
methyltriphenylphosphonium chloride and potassium
hexamethyldisilazane, provided the isomeric (E,Z)-vinyl
methyl ethers 65.36
Faulkner and Kernan simplified the synthesis of hydroxy
Scheme 23. Regioselective endoperoxide fragmentation.38

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6539
regioselective photooxidation–fragmentation of an
incorporated furan moiety completed the total synthesis of
(^)-1.
This synthesis of dysidiolide establishes the viability of a
general approach for the preparation of the isolabdanoid
terpene system. On a final note, the key B-ring intermediate
enone (^)-13 could be resolved by treatment with vinyl
acetate and lipase AK Amano 20 in hexanes to provide
(6S,7S)-13 in 93% ee, which formally allows an enantio-
selective entry to 1 and congeners via the general route
established here.
Scheme 24. Furan oxidation to dysidiolide.22
4. Experimental
4.1. General
butenolides when they reported the regioselective oxidation
of 3-alkylfurans with singlet oxygen in the presence of
Hu¨nig’s base.38 Furan precursors to hydroxy butenolides
substituted at C1 with carboxylic acid, trimethylsilyl or
trialkylsilyloxy groups were known to undergo directed
fragmentation of the endoperoxide intermediates. Faulkner
reported that the activation at C1 provided by these
substituents could be replicated, in effect, by a regio-
selective deprotonation of a C1-unsubstituted endoperoxide
with a hindered base that would discriminate between C1
and C4 endoperoxide sites. Such discrimination can be
induced by substitution at C3, which leads to the 3-alkyl-5-
hydroxy-butenolide isomer (Scheme 24). This process has
been exploited in previous syntheses of 1.4,5
Unless noted otherwise, all oxygen and moisture-sensitive
reactions were executed in oven-dried glassware sealed
under a positive pressure of dry argon or nitrogen. Moisture-
sensitive solutions and anhydrous solvents were transferred
via standard syringe and cannula techniques. All com-
mercial reagents were used as received. Organic solvents
were dried under nitrogen: tetrahydrofuran (THF) and
diethyl ether were distilled over Na-benzophenone;
CH2Cl2, HMPA, triethylamine, and pyridine were distilled
from CaH2. Flash chromatography was performed using
Baker Flash silica gel 60 (40 mM); analytical TLC was
performed using 0.25 mm EM silica gel 60 F254 plates that
were visualized under UV light (254 nm) or by staining with
anisaldehyde reagent (450 mL of 95% ethanol, 25 mL conc.
H2SO4, 15 mL acetic acid, and 25 mL anisaldehyde) and
heating. Optical rotations were obtained using a JASCO
DIP-370 digital polarimeter. IR spectra were recorded using
a Perkin–Elmer 683 infrared spectrophotometer. NMR
spectra were obtained using INOVA 500 and 300 MHz
Varian instruments. High resolution mass spectrometric
data were obtained using a VG Analytical Sector-Field mass
spectrometer.
Optimal conditions for the photooxidation–fragmentation
were found to involve irradiation with a 28 W fluorescent
bulb of a 2788C solution of 26 and diisopropylethylamine
saturated with oxygen and containing Rose Bengal
sensitizer. After warming the solution to ambient tempera-
ture, (^)-dysidiolide was produced and isolated in 73%
1
yield. The synthetic dysidiolide obtained had identical H,
13C NMR, IR spectra and HPLC retention time as a sample
of the natural product kindly provided by Dr Gunasekera.
3. Conclusions
4.1.1. (6)-(5S p,6S p)-6-Carboethoxy-3-chloro-5,6-
dimethyl-cyclohex-2-enone (33). Dry NaH (95%, 3.39 g,
134 mmol) was added to a stirred solution of 6-carboethoxy-
The total synthesis of dysidiolide was accomplished via a
flexible synthetic route that is characterized by a high level
of intramolecular stereo-induction. This began with
6-carboethoxy-3-chloro-5-methyl-cyclohex-2-enone25 (32)
representing the B-ring and containing the priming methyl
bearing stereogenic center corresponding to C7 of dysidio-
lide. Diastereoselecitve methylation of 32 installed the 6,7-
trans-dimethyl substitution characteristic of dysidiolide and
the cacospongionolides. Unmasking of the transposed enone
system 34 led to a diastereoselective conjugate addition to
install the A-ring annulation precursor. Cyclization then
provided another enone system (23) that served as a
substrate for a challenging conjugate addition to incorporate
the branched pentenyl side chain at C15. The combination
of tri-n-butylphosphine and BF3·OEt2 in conjunction with a
dialkylcuprate uniquely effected conjugate addition upon
the sterically hindered and non-planar enone system of 23.
Thereafter, elaboration of the hydroxymethyl side chain
intercepted the common C4 aldehyde (66) used in each of
the total syntheses of 1 reported to date. A final
3-chloro-5-methyl-cyclohex-2-enone25
(32,
24.12 g,
111.6 mmol) in THF (372 mL) at 08C. When the evolution
of gas ceased, HMPA (38 mL, 0.22 mol) followed by
iodomethane (8.35 mL, 134 mmol) were added and the
mixture allowed to warm to rt and stir for 6 h. The solvent
was removed in vacuo and the residue was suspended in
diethyl ether (1 L) and washed with saturated aqueous
NH4Cl (100 mL) then brine (100 mL). The organic extract
was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was chromatographed with silica gel (hexanes–
ethyl acetate, 8:1, v/v) to give 33 (21.9 g, 94.9 mmol, 85%)
as a colorless oil: Rf (hexanes–ethyl acetate, 3:1, v/v) 0.70;
IR (film) nmax 2983, 2939, 1736, 1676, 1623, 1454, 1375,
1357, 1307, 1277, 1247, 1231, 1193, 1133, 1108 cm21; 1H
NMR (CDCl3, 500 MHz) d 6.27 (d, J¼2.4 Hz, 1H), 4.14 (m,
2H), 2.80 (ddd, J¼2.4, 11.1, 18.6 Hz, 1H), 2.56 (dd, J¼4.8,
18.6 Hz, 1H), 2.23 (m, 1H), 1.41 (s, 3H), 1.23 (t, J¼7.2 Hz,
3H), 1.13 (d, J¼6.9 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 194.5, 169.9, 157.5, 127.1, 61.2, 56.0, 40.1, 38.6, 18.3,

6540
D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
16.0, 14.1; HRMS (CI, NH3) m/z calcd for [C11H15ClO3þ
of 1-bromo-4-(tert-butydimethylsilyl)oxy-pentane (43,39
8.95 g, 32 mmol) in diethyl ether (70 mL), tert-butyllithium
(37.5 mL of 1.7 M solution in pentane, 64 mmol) was added
dropwise and the solution allowed to stir for 20 min before
CuCN (1.40 g, 16 mmol) was added via a solid addition
funnel. After gradual warming to 2108C, the solution was
re-cooled to 2788C and a solution of enone 34 (2.97 g,
13 mmol) in diethyl ether (10 mL) was added dropwise.
After stirring for 2 h, the solution was gradually warmed to
2308C. A 10% NH4OH/saturated aqueous NH4Cl solution
(10 mL) was added and the resulting mixture was warmed to
rt. Diethyl ether (400 mL) was added and the mixture was
washed with H2O (100 mL) and brine (100 mL), dried over
Na2SO4, and filtered. The filtrate was concentrated in vacuo
and the residue was chromatographed on silica gel
(hexanes–ethyl acetate–triethylamine 20:1:0.005, v/v/v)
to give 44 (4.6 g, 11 mmol, 82%) as a colorless oil: Rf 0.61
(hexanes–ethyl acetate, 5:1, v/v); IR (film) nmax 2958, 2929,
NH4]þ, 248.1052; found, 248.1066.
4.1.2. (6)-(4S p,5S p)-4-Hydroxymethyl-4,5-dimethyl-
cyclohex-2-enone (13). Dry NaH (95%, 2.88 g,
114 mmol) was added in small portions to a solution of 33
(21.89 g, 94.89 mmol) in absolute ethanol (500 mL) at 08C.
After 30 min the solvent was evaporated in vacuo and
replaced with diethyl ether (500 mL) and triethylamine
(30 mL). Vacuum filtration through a thin layer of silica gel
and concentration in vacuo gave a residue (30, 22.84 g).
This was dissolved in dry diethyl ether (250 mL) and the
resulting solution was added dropwise to a suspension of
LiAlH4 (3.6 g, 95 mmol) in diethyl ether (750 mL) at rt.
After stirring for 1 h, the mixture was cooled to 08C and
H2O (5 mL) and 2 M aqueous HCl (250 mL) were
sequentially added. The resulting mixture was warmed to
rt and stirred for 30 min. The aqueous layer was removed
and the organic phase was washed with saturated aqueous
NaHCO3 (100 mL), H2O (100 mL), and brine (100 mL).
The oranic phase was dried over Na2SO4 and filtered. The
filtrate was concentrated in vacuo and the residual oil was
chromatographed on silica gel (hexanes–ethyl acetate, 1:1,
v/v) to give 13 (13.20 g, 86 mmol, 90%) as a colorless oil:
Rf 0.25 (hexanes–ethyl acetate, 1:1, v/v); IR (film) nmax
3444, 2964, 2879, 1669, 1457, 1377, 1285, 1257,
2857, 1716, 1462, 1376, 1251, 1091 cm21 1H NMR
;
(CDCl3, 500 MHz) d 3.74 (sext, J¼6.0 Hz, 1H), 3.56 (d,
J¼9.5 Hz, 1H), 3.43 (d, J¼9.5 Hz, 1H), 2.46–2.41 (m, 2H),
2.20–2.14 (m, 1H), 2.12–2.03 (m, 2H), 1.96–1.90 (m, 1H),
1.44–0.83 (m, 6H), 1.09 (d, J¼6.5 Hz, 3H), 1.00 (d,
J¼3.0 Hz, 3H), 0.91 (dd, J¼2.0, 7.0 Hz, 3H), 0.87 (s, 9H),
0.10 (s, 9H), 0.05 (s, 6H); 13C NMR (CDCl3, 125 MHz) d
213.0, 68.5, 42.2, 39.9, 39.2, 38.5, 37.5, 29.9, 25.9, 23.9,
18.7, 18.1, 15.5, 20.7, 24.4, 24.7; HRMS (FAB) m/z calcd
for [C23H48O3Si2þH]þ, 429.3220; found, 429.3191.
4.1.5. (6)-(3S p,4S p,5S p)-3-(4-Hydroxy-1-n-pentyl)-4-
hydroxymethyl-4,5-dimethyl-cyclohex-2-enone (45). To
a stirred rt solution of 44 (3.77 g, 8.8 mmol) in methanol
(50 mL) and CH2Cl2 (50 mL) was added p-toluenesulfonic
acid monohydrate (0.17 g, 0.9 mmol). After stirring for 2 h,
NaHCO3 (70 mg) was added and the mixture was
concentrated in vacuo. The residue was chromatographed
over silica gel with ethyl acetate to give 45 (2.0 g, 8.3 mmol,
94%) as a colorless oil: Rf 0.32 (hexanes–ethyl acetate, 1:1,
v/v); IR (film) nmax 3432, 2959, 2932, 2860, 1456, 1373,
1348, 1328, 1177, 1110 cm21; 1H NMR (CDCl3, 500 MHz)
d 3.91 (d, J¼15 Hz, 1H), 3.73 (q, J¼7.5 Hz, 1H), 3.34 (dd,
J¼3.0, 15.0 Hz, 1H), 3.25 (s (br), 2H), 2.17–2.02 (m, 1H),
2.02 (brs, 1H), 1.91–1.74 (m, 2H), 1.63–1.57 (m, 1H),
1.49–0.98 (m, 7H), 1.22 (d, J¼10.5 Hz, 3H), 0.91 (d,
J¼11.5 Hz, 3H), 0.62 (s, 3H); 13C NMR (CDCl3, 75 MHz) d
98.6, 72.4, 67.9, 49.2, 42.3, 39.4, 36.9, 33.8, 30.7, 28.2,
23.6, 23.3, 17.6, 16.7; HRMS (CI, NH3) m/z calcd for
[C14H26O3þNH4]þ, 260.2226; found, 260.2215.
4.1.6. (6)-(3S p,4S p,5S p)-3-(4-Oxo-1-n-pentyl)-4-carbox-
ethoxy-4,5-dimethyl-cyclohex-2-enone (46). To a stirred
08C solution of 45 (2.20 g, 9.1 mmol) in acetone (50 mL)
was added Jones reagent until a red solution persisted. The
solution was allowed to stir for 30 min before 2-propanol
was added until the solution was decolorized. After removal
of the solvent in vacuo and addition of H2O (20 mL), the
mixture was extracted with diethyl ether (4£50 mL). The
combined diethyl ether extract was washed with brine
(20 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was dissolved in acetone (50 mL) and K2CO3
(6.27 g, 45.4 mmol) and iodoethane (2.18 mL, 27.2 mmol)
were added. The mixture was heated at reflux for 1 h, cooled
to rt, filtered through celite and concentrated in vacuo. The
1049 cm21
;
1H NMR (CDCl3, 500 MHz) d 6.60 (d,
J¼10.2 Hz, 1H), 5.91 (d, J¼10.2 Hz, 1H), 3.67 (d,
J¼10.8 Hz, 1H), 3.44 (d, J¼11.1 Hz, 1H), 3.29 (s, 1H),
2.50 (dd, J¼11.7, 17.4 Hz, 1H), 2.26 (dd, J¼4.8, 17.1 Hz,
1H), 2.01 (sept, J¼6.9 Hz, 1H), 1.04 (s, 3H), 0.98 (d,
J¼6.9 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 201.3, 157.4,
128.8, 66.2, 42.9, 40.9, 37.1, 22.7, 15.6; HRMS (CI, NH3)
m/z calcd for [C9H14O2þNH4]þ, 172.1338; found,
172.1327.
4.1.3. (6)-(4S p,5S p)-4-(Trimethylsilyl)oxymethyl-4,5-
dimethyl-cyclohex-2-enone (34). Trimethylsilyl chloride
(1.31 mL, 10.3 mmol) was added dropwise to a stirred
solution of 13 (1.06 g, 6.9 mmol), imidazole (2.34 g,
35.0 mmol) and 4-N,N-dimethylaminopyridine (0.12 g,
1.0 mmol) in CH2Cl2 (35 mL) at 08C. The solution was
allowed to warm to rt and stir for 1 h. Ethyl acetate
(150 mL) was added and the solution was washed with H2O
(25 mL) and brine (25 mL), then dried over Na2SO4 and
filtered. The filtrate was concentrated in vacuo and the
residue chromatographed over silica gel (hexanes–ethyl
acetate, 8:1, v/v, 0.5% triethylamine) to give 34 (1.45 g,
6.4 mmol, 93%) as a colorless oil: Rf 0.52 (hexanes–ethyl
acetate, 5:1, v/v); IR (film) nmax 2961, 2878, 1681, 1454,
1378, 1252, 1092 cm21; 1H NMR (CDCl3, 500 MHz) d 6.58
(d, J¼10.2 Hz, 1H), 6.00 (d, J¼10.2 Hz, 1H), 3.69 (d,
J¼9.6 Hz, 1H), 3.41 (d, J¼10.5 Hz, 1H), 2.58 (dd, J¼11.7,
16.8 Hz, 1H), 2.33 (dd, J¼5.1, 17.1 Hz, 1H), 2.6 (sept,
J¼4.8 Hz, 1H), 1.08 (s, 3H), 1.04 (d, J¼6.9 Hz, 3H), 0.07
(s, 9H); 13C NMR (CDCl3, 125 MHz) d 200.6, 156.7, 128.7,
66.3, 43.0, 40.6, 37.1, 22.8, 15.5, 20.73; HRMS (CI, NH3)
m/z calcd for [C12H22O2SiþNH4]þ, 244.1733; found,
244.1715.
4.1.4. (6)-(3S p,4S p,5S p)-3-(4-(tert-Butyldimethylsilyl)-
oxy-1-n-pentyl)-4-(trimethylsilyl)oxymethyl-4,5-di-
methyl-cyclohex-2-enone (44). To a stirred 2788C solution

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6541
residue was suspended in ethyl acetate (200 mL), washed
with H2O (40 mL) and brine (40 mL), dried over Na2SO4,
and filtered. After concentration in vacuo the remaining oil
was chromatographed on silica gel (hexanes–ethyl acetate,
3:1, v/v) to provide 46 (2.08 g, 7.4 mmol, 81%) as a
colorless oil: Rf 0.54 (hexanes–ethyl acetate, 1:1, v/v); IR
(film) nmax 2961, 1716, 1457, 1419, 1364, 1273, 1212, 1163,
2936, 2870, 1712, 1648, 1463, 1388, 1375, 1268, 1246,
1215, 1179, 1148, 1110 cm21; 1H NMR (CDCl3, 500 MHz)
d 4.65, (m, 2H), 4.14 (q, J¼6 Hz, 2H), 2.65–2.60 (m, 2H),
2.10–2.04 (m, 2H), 1.97–0.82 (m, 13H), 1.71 (s, 3H), 1.37
(s, 3H), 1.25 (t, J¼11.0 Hz, 3H), 1.10 (s, 3H), 0.83, (d,
J¼12 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d 210.4, 175.6,
146.3, 109.4, 60.3, 58.7, 48.5, 45.6, 40.7, 38.7, 37.6, 35.7,
29.9, 27.4, 22.3, 21.4, 18.9, 16.5, 14.1; HRMS (FAB) m/z
calcd for [C22H36O3þH]þ, 349.2743; found, 349.2721.
1118 cm21
;
1H NMR (CDCl3, 500 MHz) d 4.14 (t,
J¼7.5 Hz, 2H), 2.52 (dd, J¼5.1, 14.7 Hz, 1H), 2.45–2.36
(m, 4H), 2.27 (ddd, J¼1.5, 5.5, 14.5 Hz, 1H), 2.14–2.01 (m,
2H), 2.10 (s, 3H), 1.68–1.59 (m, 1H), 1.48–1.36 (m, 2H),
1.29 (s, 3H), 1.25 (t, J¼6.5 Hz, 3H), 1.08–1.00 (m, 1H),
0.88 (d, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d
210.6, 208.5, 175.6, 60.5, 48.4, 44.4, 43.3, 42.2, 39.3, 38.1,
31.3, 29.9, 21.5, 18.1, 16.7, 14.2; HRMS (CI, NH3) m/z
calcd for [C16H26O4þNH4]þ, 300.2149; found, 300.2175.
4.1.9. (6)-(1R p,3R p,4S p,4aS p,8R p8aR p)-4-Hydroxy-
methyl-3,4,8-trimethyl-8-(4-methyl-pent-4-enyl)-deca-
hydro-naphthalen-1-ol (61). A solution of 58 (0.10 g,
0.28 mmol) in diethyl ether (1 mL) was added dropwise to a
suspension of LiAlH4 (0.01 g, 0.3 mmol) in diethyl ether
(3 mL) at 08C. The mixture was allowed to warm to rt and
stir for 1 h. The mixture was cooled to 08C and H2O (1 mL)
and saturated aqueous sodium potassium tartrate (1 mL)
were added sequentially. The resulting mixture was
extracted with diethyl ether (3£10 mL) and the combined
extract was washed with brine (5 mL). The organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was chromatographed with silica gel (hexanes–
ethyl acetate, 4:1, v/v) to give 61 (80 mg, 0.25 mmol, 91%)
as a colorless oil: Rf 0.15 (hexanes–ethyl acetate, 5:1, v/v);
4.1.7. (6)-(1S p,2S p,8aS p)-1,2-Dimethyl-4-oxo-1,2,3,4,
6,7,8,8a-octahydro-naphthalene-1-carboxylic acid ethyl
ester (23). Potassium tert-butoxide (0.67 g, 5.5 mmol) was
added to a stirred solution of 46 (1.52 g, 5.38 mmol) in
absolute ethanol (100 mL). The mixture was heated at reflux
for 30 min, the heating source was removed, and NH4Cl
(0.3 g, 6 mmol) was added. After removing the ethanol in
vacuo, ethyl acetate (300 mL) was added and the mixture
was washed with H2O (50 mL) and brine (50 mL), dried
over Na2SO4, and filtered. The filtrate was concentrated in
vacuo and the residue was chromatographed on silica gel
(hexanes–ethyl acetate, 10:1, v/v) to give 23 (1.03 g,
3.89 mmol, 72%) as a colorless oil: Rf 0.49 (hexanes–ethyl
acetate, 5:1, v/v); IR (film) nmax 2936, 1725, 1683, 1608,
1456, 1423, 1377, 1252, 1220, 1174, 1134, 1100 cm21; 1H
NMR (CDCl3, 500 MHz) d 4.65 (t, J¼7.5 Hz, 2H), 3.12–
3.11 (m, 1H), 2.67 (dd, J¼5.0, 15.5 Hz, 1H), 2.31 (dd,
J¼4.0, 15.5 Hz, 1H), 2.16–2.13 (m, 3H), 1.95 (d, J¼2.5 Hz,
3H), 1.90–1.87 (m, 1H), 1.75–1.73 (m, 1H), 1.56–1.52 (m,
1H), 1.33–1.27 (m, 4H), 1.28 (t, J¼2.5 Hz, 3H), 0.96 (d,
J¼7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 202.5, 175.7,
148.5, 130.7, 60.4, 48.6, 45.0, 38.7, 38.5, 34.2, 24.7, 22.7,
21.4, 19.6, 19.8, 14.2; HRMS (CI, NH3) m/z calcd for
[C16H24O3þNH4]þ, 282.2069; found, 282.2069.
4.1.8. (6)-(1S p,2S p,4aR p,5R p8aS p)-1,2,5-Trimethyl-5-
(4-methyl-pent-4-enyl)-4-oxo-decahydro-naphthalene-1-
carboxylic acid ethyl ester (58). A solution of tert-
butyllithium (9.4 mL, 1.7 M in pentane, 16 mmol) was
added dropwise to a stirred solution of 5-bromo-2-methyl-
pent-1-ene (1.30 g, 8.0 mmol) in diethyl ether (53 mL) at
2788C. After 30 min, a mixture of CuI (0.73 g, 4.0 mmol)
and tri-n-butylphosphine (2.5 mL, 10 mmol) in THF
(21 mL) was added. The mixture was stirred for 20 min
before a solution of enone 23 (0.51 g, 1.9 mmol) in THF
(6 mL) was added dropwise. Boron trifluoride etherate
(1.0 mL, 8.0 mmol) was then added. After 4 h, saturated
aqueous NH4Cl (10 mL) was added and the mixture was
warmed to rt. Diethyl ether (100 mL) was added and the
separated organic solution was washed with H2O (20 mL)
then stirred with aqueous 30% H2O2 (2 mL) for 15 min. The
resulting brown mixture was filtered through silica gel and
concentrated in vacuo. The residue was chromatographed
with silica gel (hexanes–ethyl acetate, 15:1, v/v) to give 58
(0.58 g, 1.7 mmol, 86%) as a colorless oil: Rf 0.56
(hexanes–ethyl acetate, 5:1, v/v); IR (film) nmax 3072,
IR (film) nmax 3446, 2931, 1647, 1458, 1375, 1018 cm21
;
1H NMR (CDCl3, 500 MHz) d 4.67 (d, J¼7.5 Hz, 2H), 4.28
(d, J¼3.0 Hz, 1H), 3.54 (d, J¼3.5 Hz, 2H), 1.99–0.80 (m,
19H), 1.71 (s, 3H), 1.20 (d, J¼7.0 Hz, 3H), 0.98 (s, 3H),
0.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) d 146.6, 109.4,
70.0, 68.1, 50.3, 40.7, 39.0, 37.7, 37.4, 36.4, 34.4, 33.4, 29.7,
27.5, 26.6, 22.6, 21.9, 20.9, 18.7, 18.3; HRMS (CI, NH3) m/z
calcd for [C20H36O2þH]þ, 309.2794; found, 309.2791.
4.1.10. (6)-(1R p,3R p,4S p,4aS p,8R p8aR p)-4-(Trimethyl-
silanyloxymethyl)-3,4,8-trimethyl-8-(4-methyl-pent-4-
enyl)-decahydro-naphthalen-1-ol (62). Trimethylsilyl
chloride (0.11 mL, 0.86 mmol) and triethylamine
(4.3 mmol) were added to a stirred 08C solution of 61
(0.25 g, 0.81 mmol) and 4-N,N-dimethylaminopyridine
(0.01 g, 0.09 mmol) in CH2Cl2 (5 mL). The solution was
warmed to rt and stirred for 1 h. Ethyl acetate (20 mL) was
added and the solution was washed with H2O (5 mL) and
brine (5 mL), dried over Na2SO4, and filtered. The filtrate
was concentrated in vacuo and the residue was chromato-
graphed over silica gel (hexanes–ethyl acetate–triethyl-
amine, 10:1:0.005, v/v/v) to give 62 (0.27 g, 0.70 mmol,
86%) as a colorless oil: Rf 0.68 (hexanes–ethyl acetate, 5:1,
v/v); IR (film) nmax 2931, 1652, 1458, 1375, 1250, 1088,
1
1072 cm21; H NMR (CDCl3, 500 MHz) d 4.68 (d, J¼
6.0 Hz, 2H), 4.25 (s, 1H), 3.42 (s, 1H), 1.99 (t, J¼7.5 Hz,
2H), 1.95–1.86 (m, 2H), 1.76–1.67 (m, 2H), 1.72 (s, 3H),
1.63–1.57 (m, 2H), 1.50 (dt, J¼2.5, 14.4 Hz, 1H), 1.46–1.41
(m, 1H), 1.34–1.28 (m, 4H), 1.14 (d, J¼8 Hz, 3H), 1.13–
1.06 (m, 3H), 0.98 (s, 3H), 0.92 (s, 3H), 0.87–0.83 (m, 1H),
0.08 (s, 9H); 13C NMR (CDCl3, 125 MHz) d 146.7, 109.4,
69.2, 68.3, 50.5, 40.5, 39.1, 37.7, 37.5, 36.4, 34.0, 33.6, 29.8,
27.5, 26.7, 22.6, 21.9, 21.0, 18.8, 17.9, 20.5; HRMS (CI) m/z
calcd for [C23H44O2SiþH]þ, 381.3189; found, 381.3176.
4.1.11. (6)-Trimethyl-[(1R p,2R p,5S p,8aS p)-1,2,5-tri-
methyl-5-(4-methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-octa-
hydro-naphthalene-1-ylmethoxy]-silane (63). SOCl2

6542
D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
(0.12 mL, 1.6 mmol) was added dropwise to a stirred 08C
solution of 62 (0.12 g, 0.32 mmol) in pyridine (5 mL). The
solution was stirred for 30 min. Wet diethyl ether (200 mL)
was added and the resulting solution was washed with 1N
HCl (70 mL), saturated NaHCO3 (20 mL), H2O (20 mL),
and brine (20 mL). Drying over Na2SO4, filtration and
concentration in vacuo gave a residue that was chromato-
graphed over silica gel (hexanes–ethyl acetate–triethyl-
amine, 20:1:0.005, v/v/v) to give 63 (0.10 g, 0.28 mmol,
89%) as a colorless oil: Rf 0.74 (streaky, hexanes–ethyl
acetate, 15:1, v/v); IR (film) nmax 2953, 1652, 1456, 1374,
1250, 1093, 881, 839 cm21; 1H NMR (CDCl3, 500 MHz) d
5.29 (t, J¼2.8 Hz, 1H), 4.69 (s, 1H), 4.66 (s, 1H), 3.46 (d,
J¼9.5 Hz, 1H), 3.34 (d, J¼9.5 Hz, 1H), 2.00–1.95 (m, 4H),
1.77–1.62 (m, 4H), 1.71 (s, 3H), 1.59–1.55 (m, 1H),
1.52–1.49 (br, 1H), 1.30–1.26 (m, 1H), 1.20–1.00 (m,
5H), 0.98 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.07 (s, 9H);
13C NMR (CDCl3, 125 MHz) d 146.2, 116.7, 109.6,
66.0, 41.9, 40.0, 39.8, 38.7, 38.3, 37.1, 31.7, 31.6, 29.3,
26.2, 22.5, 22.4, 22.0, 20.9, 15.4, 20.54; HRMS (CI,
NH3) m/z calcd for [C23H42OSiþH]þ, 363.3083; found,
363.3058.
125 MHz) d 207.2, 146.1, 144.3, 116.9, 109.8, 49.9, 41.3,
39.7, 38.58, 37.2, 31.7, 31.1, 29.1, 26.1, 22.4, 22.3, 21.9,
17.7, 15.5; HRMS (CI, NH3) m/z calcd for
[C20H32OþNH4]þ, 306.2797; found, 306.2785.
4.1.14. (1S p,5R p,6R p,4aS p)-5-[(E,Z)-2-Methoxy-vinyl]-
1,5,6-trimethyl-1-(4-methyl-pent-4-enyl)-1,2,3,4,4a,
5,6,7-octahydro-naphthalene (65). A 15% solution of
KHMDS in toluene (1.10 mL, 0.73 mmol) was added
dropwise to a suspension of methoxymethyltriphenyl-
phosphonium chloride (0.25 g, 0.73 mmol) in THF (1 mL)
at 2788C. The mixture stirred for 30 min. A solution of 64
(88.1 mg, 0.31 mmol) in THF (1 mL) was added dropwise
and the resulting mixture was stirred for 1 h then gradually
warmed to rt. After re-cooling to 08C, wet diethyl ether
(20 mL) was added and the mixture was washed with H2O
(5 mL) and brine (5 mL), dried over Na2SO4, and filtered.
After concentration in vacuo, the residue was chromato-
graphed over silica gel (hexanes) to give 65 (71.1 mg,
0.22 mmol, 71%) as a colorless oil: Rf 0.73 (hexanes–ethyl
1
acetate, 10:1, v/v); H NMR (CDCl3, 500 MHz) d 6.26 (d,
J¼13.0 Hz, 1H), 5.32 (dd, J¼1.0, 5.0 Hz, 1H), 4.89 (d,
J¼13.0 Hz, 1H), 4.66 (s, 1H), 4.64 (s, 1H), 3.44 (s, 3H),
2.03–2.00 (m, 1H), 1.95 (t, J¼7.5 Hz, 2H), 1.83–1.50 (m,
8H), 1.69 (s, 3H), 1.33–0.95 (m, 5H), 0.99 (s, 3H), 0.95 (s,
3H), 0.76 (d, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 146.6, 146.3, 117.1, 109.6, 55.6, 42.3, 39.9, 39.5, 38.6,
37.6, 37.0, 34.8, 26.1, 22.5, 22.4, 22.2, 20.0, 15.5, 15.0;
HRMS (CI, NH3) m/z calcd for [C22H36OþH]þ, 317.2844;
found, 317.2857.
4.1.12. (6)-[(1R p,2R p,5S p,8aS p)-1,2,5-Trimethyl-5-(4-
methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-octahydro-naphtha-
lene-1-yl]-methanol (25). A solution of TBAF (0.2 mL of
1.0 M solution in THF, 0.20 mmol) was added to a stirred
08C solution of 63 (61.5 mg, 0.17 mmol) in THF (2 mL).
After stirring for 30 min, diethyl ether (10 mL) was added
and the resulting solution was washed with water (2 mL)
and brine (2 mL), dried over Na2SO4 and filtered. The
filtrate was removed in vacuo and the residue was
chromatographed over silica gel (hexanes–ethyl acetate,
8:1, v/v) to give 25 (43.3 mg, 0.15 mmol, 88%) as a
colorless oil: Rf 0.48 (hexanes–ethyl acetate, 5:1, v/v); IR
4.1.15. (6)-[(1R p,2R p,5S p,8aS p)-1,2,5-Trimethyl-5-(4-
methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-octahydro-naphtha-
lene-1-yl]-acetaldehyde (66). A 2N aqueous solution of
HCl (120 mL) was added to a stirred solution 65 (71.1 mg,
0.22 mmol) in 1,4-dioxane (12 mL) at rt. After 20 min
diethyl ether (50 mL) was added and the mixture was
washed with H2O (10 mL) and brine (10 mL), dried over
Na2SO4, and filtered. The solvent was removed in vacuo and
the residue was chromatographed over silica gel (hexanes–
ethyl acetate, 30:1, v/v) to give 66 (61.4 mg, 0.20 mmol,
91%) as a colorless oil: Rf 0.56 (hexanes–ethyl acetate,
10:1, v/v); IR (film) nmax 2936, 2724, 1719, 1649, 1445,
(film) nmax 3412, 2937, 1648, 1456, 1374, 1020, 887 cm21
;
1H NMR (CDCl3, 500 MHz) d 5.31 (s, 1H), 4.68 (s, 1H),
4.66 (s, 1H), 3.51 (m, 2H), 2.04 (br, 1H), 2.02 (br, 1H), 1.97
(t, J¼7.5 Hz, 2H), 1.76–1.50 (m, 7H), 1.70 (s, 3H), 1.30 (m,
1H), 1.20–1.05 (m, 5H), 0.98 (s, 3H), 0.94 (s, 3H), 0.88 (d,
J¼6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) d 146.6,
116.9, 109.6, 66.5, 41.9, 40.0, 39.9, 38.7, 38.6, 38.4, 37.1,
31.7, 31.6, 29.3, 26.14, 22.40, 22.36, 20.5, 15.3; HRMS (CI,
NH3) m/z calcd for [C20H34OþH]þ, 291.2688; found,
291.2699.
1
1374, 885, 812 cm21; H NMR (CDCl3, 500 MHz) d 9.90
(t, J¼3.0 Hz, 1H), 5.33 (t, J¼3.0 Hz, 1H), 4.67 (s, 1H), 4.64
(s, 1H), 2.33 (dd, J¼2.5, 15.0 Hz, 1H), 2.24 (dd, 3.0,
14.5 Hz, 1H), 2.08–1.93 (m, 4H), 1.80 (m, 1H), 1.73–1.51
(m, 6H), 1.68 (s, 3H), 1.31–1.28 (m, 1H), 1.20–1.09 (m,
4H), 1.07 (s, 3H), 0.99 (s, 3H), 0.84 (d, J¼6.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) d 204.6, 146.3, 117.12, 109.7,
42.0, 40.0, 38.6, 37.6, 37.0, 33.0, 31.6, 29.4, 26.0, 23.0,
22.5, 22.4, 22.3, 15.0; HRMS (CI, NH3) m/z calcd for
[C21H34OþH]þ, 303.2688; found 303.2685.
4.1.16. (6)-(R p)-1-Furan-3-yl-2-[(1R p,2R p,5S p,8aS p)-1,
2,5-trimethyl-5-(4-methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-
octahydro-naphthalene-1-yl]-ethanol (26), and (6)-(S p)-
1-furan-3-yl-2-[(1R p,2R p,5S p,8aS p)-1,2,5-trimethyl-5-
(4-methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-octahydro-
naphthalene-1-yl]-ethanol (67). A solution of n-BuLi
(0.14 mL of 2.5 M in hexane, 0.34 mmol) was added to a
solution of 3-bromofuran (31 mL, 0.34 mmol) in THF
(5 mL) at 2788C. The resulting solution was stirred for
4.1.13. (6)-(1R p,2R p,5S p,8aS p)-1,2,5-Trimethyl-5-(4-
methyl-pent-4-enyl)-1,2,3,5,6,7,8,8a-octahydro-naphtha-
lene-1-carbaldehyde (64). Silica gel (0.16 g) and pyri-
dinium chlorochromate (0.15 g, 0.71 mmol) were added to a
stirred solution of 25 (0.16 g, 0.54 mmol) in CH2Cl2 (5 mL)
at rt. After 1 h, the mixture was filtered through silica gel
and the solvent was removed in vacuo. The residue was
chromatographed over silica gel (hexanes–ethyl acetate,
10:1, v/v) to give 64 (0.14 g, 0.49 mmol, 91%) as a colorless
oil: Rf 0.70 (hexanes–ethyl acetate, 5:1, v/v); IR (film) nmax
1
2937, 2706, 1721, 1649, 1453, 1376, 886, 812 cm21; H
NMR (CDCl3, 500 MHz) d 9.57 (s, 1H), 5.36 (s, 1H), 4.67
(s, 1H), 4.64 (s, 1H), 2.35 (d, J¼11.5 Hz, 1H), 2.26 (d,
J¼18.0 Hz, 1H), 1.95 (t, J¼7.5 Hz, 2H), 1.89–1.85 (m,
1H), 1.82 (sext, J¼6.0 Hz, 1H), 1.71–1.66 (m, 3H), 1.68 (s,
3H), 1.60–1.53 (m, 2H), 1.31–1.06 (m, 5H), 1.00 (s, 3H),
0.99 (s, 3H), 0.90 (d, J¼6.5 Hz, 3H); 13C NMR (CDCl3,

D. Demeke, C. J. Forsyth / Tetrahedron 58 (2002) 6531–6544
6543
30 min before a solution of 66 (34.6 mg, 114 mmol) in THF
Acknowledgments
(2 mL) was added dropwise. After 30 min saturated aqueous
NH4Cl (1 mL) was added and the mixture allowed to warm
to rt. Diethyl ether (50 mL) was added and the resulting
mixture was washed with H2O (10 mL) and brine (10 mL).
The organic phase was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was chromatographed
on silica gel (hexanes–ethyl acetate, 10:1, v/v) to yield 26
(15.7 mg, 42 mmol, 37%) and 67 (19.1 mg, 51 mmol, 45%).
Characterization data for 26: Rf 0.30 (hexanes–ethyl
acetate, 8:1, v/v); IR (film) nmax 3388, 2937, 1650, 1503,
1445, 1374, 1161, 1025, 874; 1H NMR (CDCl3, 500 MHz) d
7.33 (d, J¼8.5 Hz, 2H), 6.38 (s, 1H), 5.32 (s, 1H), 4.85 (t,
J¼6.0 Hz, 1H), 4.66 (s, 1H), 4.59 (s, 1H), 1.90–1.03 (m,
21H), 1.65 (s, 3H), 0.97 (s, 3H), 0.88 (d, J¼6.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) d 145.9, 143.2, 142.0, 138.4,
131.1, 117.2, 113.9, 109.7, 108.7, 64.0, 41.5, 39.8, 38.5,
36.9, 36.2, 33.4, 31.8, 31.6, 29.7, 26.1, 22.5, 22.4, 22.1,
This work was supported by a generous unrestricted
Bristol–Myers Squibb Grant in Synthetic Organic
Chemistry (C. J. F.). We thank Dr Gunasekera for kindly
providing an authentic sample of dysidiolide for
comparison.
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21.9, 15.0 cm21
;
HRMS (FAB) m/z calcd for
[C21H34OþNa]þ, 393.2769; found, 393.2786. Characteriz-
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˚
(hexanes/ethyl acetate 1:1, v/v); HPLC (C-18, 5 mm, 100 A,
250 mm£4.6 mm ID column): tR¼17.01 min (85% MeOH–
15% H2O, flow rate¼0.75 mL/min); co-eluted with a
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