Synthetic approach to analogues of betulinic acid

Article abstract of DOI:10.1016/j.tet.2006.07.023

2-Methylcyclohexane-1,3-dione 14 was converted via the Wieland-Miescher analogue 15 into the 6-silyloxy-2,5,5,8a-tetramethyldecalin-1-one 21 by an efficient process. Several routes were examined to transform this compound into the pentacyclic triterpene s

Full text of DOI:10.1016/j.tet.2006.07.023

Tetrahedron 62 (2006) 9321–9334
Synthetic approach to analogues of betulinic acid
*
Michael E. Jung and Brian A. Duclos
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA
Received 28 April 2006; revised 3 July 2006; accepted 7 July 2006
Available online 14 August 2006
Abstract—2-Methylcyclohexane-1,3-dione 14 was converted via the Wieland–Miescher analogue 15 into the 6-silyloxy-2,5,5,8a-tetra-
methyldecalin-1-one 21 by an efficient process. Several routes were examined to transform this compound into the pentacyclic triterpene
skeleton of betulinic acid and its structural analogues. For example, the iodide 39, easily prepared from 21, was converted via a
Sonogashira-hydroboration–Suzuki process into the E-triene 45. Photolysis of 45 using a benzanthrone sensitizer afforded the Z-triene 43.
However, all attempts at effecting the cyclization of this triene 43 to the cyclohexadiene 47 (electrocyclic via photochemical or thermal means,
metal-catalyzed processes, oxidative and radical cyclizations) failed to produce the key pentacyclic material.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
1.5 mM, TI 12,000). The most current data suggest that the
compounds are inhibitors of virion formation, disrupting
a late step in Gag processing involving conversion of the
capsid precursor (p25) to the mature capsid protein (p24).10
Betulinic acid (1, Fig. 1) was first isolated in 1948 from the
bark of the London plane tree (Platanus acerifolia) by
Bruckner.1 However, betulinic acid was a known derivative
2
€
of betulin (2, Fig. 1), which was isolated by Lowitz in
In addition to the anti-HIV activity of betulinic acid and its
derivatives, these compounds also exhibit anti-cancer activ-
ity in a wide variety of cell lines via selective cytotoxicity of
tumor cells. Various C16 amino acid derivatives exhibit anti-
melanoma/carcinoma activity with ED50’s ranging from 1.5
to >20 mg/mL.11
1788 from the bark of the white birch (Betula alba). The first
structural assignment of betulin and its derivatives was made
by Ruzicka in 1941.3 Betulin is one of the most plentiful
triterpenes, comprising up to 24% of the outer bark of the
white birch and as much as 35% of the outer bark of the
Manchurian white birch (Betula platyphylla).4
Since all known derivatives have been made starting from
natural materials, we chose to focus on the construction of
the pentacyclic core with the two anti-quaternary methyl
groups in the C ring. Due to the high steric demand of the
b-face of the core structure in the environment around these
methyl groups, their installation was seen to be quite chal-
lenging. Also, we wanted to develop a convergent synthesis
where two highly functionalized portions of the ultimate
core system could be joined late in the synthesis, with C
ring formation as the key step. Such a strategy would allow
for the facile synthesis of analogues by simply altering the
construction of either of the components.
Derivatives of betulinic acid 1 and betulin 2 have shown
promise as HIV therapeutics by inhibiting viral growth in
a manner different from that of current HIV drugs.5–9
Although betulinic acid and betulin themselves exhibited
only weak activity against HIV replication in H9 lympho-
cytes (1, EC50 1.4 mM, TI 9.3 and 2, EC50 23 mM, TI 1.9),
their corresponding mono and diester derivatives 3 and 4,
respectively, have been shown to be very potent inhibitors
(3, EC50<3.5ꢀ10ꢁ4 mM, TI>20,000 and 4, EC50<6.6ꢀ
10ꢁ4 mM, TI>21,515, Fig. 2).7,8 Thus, 3 and 4 are more
potent and less toxic than the well-known drug AZT (EC50
We envisioned the 11a-hydroxy betulinic acid derivative 5
to arise from dissolving metal reduction of the enone 6,
OH
Me
H
Me
19CO2H
H
H
Me
Me
Me
Me
Me
Me
5
16
HO
2
HO
8
14
Me
H
OR
Me
H
1
Me
H
Me
H
CO2H
Me
H
Me
H
H
Me
H
Me
H
Me
Me
Me
Me
1 Betulinic acid
2 Betulin
RO
RO
H
Me
Me
Me
H
Me
Figure 1.
H
H
3 R = COCH2C(Me)2CO2H
Figure 2.
4 R = COCH2C(Me)2CO2H
* Corresponding author. Tel.: +1 310 825 7954; fax: +1 310 206 3722;
e-mail: jung@chem.ucla.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.023

9322
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
Me
CO2H
Me
CO2H
Me
O
H
Me
Me
HO
Me
Me
Me
TBSO
HO 11
Me
H
H
Me
H
Me
Me
H
H
H
5
6
Me
CO2Me
CO2Me
OTMS
Me
Me
Me
O
Me
CH
Me
O
Me
Me
Me
O
TBSO
TBSO
H
H
NC
Me
Me
Me
H
Me
H
H
7
8
Me
CO2Me
CHO
Me
OTMS
Me
CO2Me
Me
HO
OTMS
Me
Me
Me
Me
TBSO
TBSO
NC
Me
NC
Me
H
H
Me
H
Me
H
9
10
11
Me
CO2Me
O
O
O
12
13
Scheme 1.
which in turn would be the product of an intramolecular
aldol condensation of the diketone 7 (Scheme 1). The dike-
tone 7 would be prepared from conversion of the aldehyde to
the corresponding methyl ketone, dihydroxylation, and sub-
sequent glycolytic cleavage of the silyl cyanohydrin of the
aldehyde 8. The aldehyde 8 would be formed via an anionic
oxy-Cope rearrangement of the diene 9, which would arise
from nucleophilic addition of the acyl anion equivalent 10
to the a,b-unsaturated aldehyde 11. The acyl anion equiva-
lent 10 would be easily prepared from the known optically
active enone ester 12.12 The a,b-unsaturated aldehyde 11
would be derived from the known Wieland–Miescher ketone
13.13 We report herein the full details of this approach,
namely the facile synthesis of several advanced intermedi-
ates and our attempts to convert them into betulinic acid
analogues.
acetone/H2O) to the ketone 18 and the alcohol protected
(TBSOTf, pyridine, dichloromethane) as the TBS ether 19
in 83% yield. The TBS ether 19 was then treated with
LDA followed by methyl iodide to furnish in 97% yield
the methylated ketone 20, as a mixture of diastereomers at
the methyl stereocenter. The mixture of a-keto diastereo-
mers was subjected to sodium methoxide in methanol to epi-
merize the mixture to give only the ketone 21 with the
methyl group in the equatorial position in quantitative yield.
A method was then pursued that allowed direct conversion of
the ketone 21 to the desired aldehyde 11.14 The procedure
utilized dichloromethyllithium generated in situ from
dichloromethane and LDA at ꢁ95 ꢂC followed by warming
to 23 ꢂC and eventual reflux in THF. The solvents were
removed and the newly generated a-chloro epoxide was
then subjected to treatment with HMPA, lithium perchlorate,
and calcium carbonate while being warmed to 130 ꢂC,
effecting conversion to the aldehyde 11 in 45% yield.
2. Results and discussion
The synthesis of the DE ring system 12 was readily accom-
plished according to the literature method of Cossy.12 We
began synthesis of the AB ring system by converting
2-methyl-1,3-cyclohexanedione 14 into the 1-methyl ana-
logue of the Wieland–Miescher ketone by treatment with
ethyl vinyl ketone (EVK) in the presence of potassium
hydroxide in methanol (Scheme 2). Subsequent reflux in
benzene in the presence of catalytic pyrrolidine afforded
the enone 15 in 61% yield. Selective protection of the ketone
over the enone with ethylene glycol and p-toluenesulfonic
It was decided to work out the chemistry of the silyl cyano-
hydrin formation and the nucleophilic addition to the alde-
hyde 11 in a dimeric manner due the relative abundance of
the aldehyde 11 over the enone 12, which had not been con-
verted to the corresponding aldehyde requisite for the syn-
thesis. With the aldehyde 11 in hand, the trimethylsilyl
cyanohydrin 22 of the aldehyde was prepared in 96% yield
(TMSCN, ZnI2, CH2Cl2) (Scheme 3) and the tert-butyl-di-
methylsilyl (TBS) analogue 23 in 48% yield (TBSCN,
ZnI2, dichloromethane). In both cases, addition of the lithi-
ate of the silyl cyanohydrin to the aldehyde 11 gave no reac-
tion. A variety of temperatures ranging from ꢁ78 ꢂC to
reflux was used but no addition was ever seen. The addition
of HMPA to the reaction mixture also had no effect on the
reaction. Due to the stabilizing effect of the neighboring
nitrile group as well as the sheer size of the nucleophile gen-
erated, it was believed that we would need a smaller and
˚
acid in the presence of 4 A molecular sieves provided the
enone 16 in 98% yield. Reductive alkylation (Li/NH3;
MeI, THF) of the enone proceeded smoothly. The ketone
was reduced in situ with additional lithium wire after the re-
ductive alkylation was complete and then quenched with
methanol to produce only the equatorial alcohol 17 in 54%
yield. The ketal group of 17 was then hydrolyzed (TsOH,

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9323
O
O
O
O
Me
Me
Me
Me
O
c
b
a
O
O
Me
14
15
16
O
O
O
O
Me
Me
Me
d
e
f
TBSO
h
HO
HO
H
H
H
Me Me
Me Me
17
Me Me
18
19
O
CH
O
O
Me
Me
Me
Me
Me
Me
g
TBSO
TBSO
TBSO
H
H
H
Me Me
Me Me
Me Me
20
21
11
˚
Scheme 2. Reagents and conditions: (a) KOH, MeOH, EVK; pyrrol., PhH, reflux, 61%; (b) HO(CH2)2OH, TsOH, 4 A MS, 98%; (c) Li/NH3; MeI, THF;
Li0/NH3; MeOH, 54%; (d) TsOH, acetone/H2O, quant.; (e) TBSOTf, pyr., CH2Cl2, 0–23 ꢂC, 83%; (f) LDA, THF, ꢁ78 ꢂC; MeI, ꢁ78 to 23 ꢂC, 97%; (g) NaOMe,
MeOH, 23 ꢂC, quant.; (h) LDA, ꢁ95 ꢂC; CH2Cl2, 21, ꢁ95 to ꢁ20 ꢂC to reflux; HMPA, LiClO4, CaCO3, 130 ꢂC, 45%.
OH
Me
much more reactive nucleophile to be able to add to the very
sterically hindered aldehyde 11.
CHO
Me
Me
H
Me
a
b
TBSO
TBSO
RO CN
H
Me Me
CHO
Me Me
11
Me
Me
Me
Me
26
a
b
OTBS
Me
OH
Me
TBSO
TBSO
H
Br
H
Me Me
Me Me
Me
Me
Me
H
H
Me
Me
c
22, R = TMS
23, R = TBS
11
Me
TBSO
TBSO
OTBS
Me
Me
HO
H
Me
NC
RO
Me
Me Me
Me Me
27
28
Me
H
Scheme 4. Reagents and conditions: (a) NaBH4, EtOH, 23 ꢂC, 70%; (b)
CBr4, PPh3, CH2Cl2, 0–23 ꢂC, 48%; (c) Mg, Et2O, reflux; 11, 23 ꢂC to reflux.
Me
TBSO
H
Me Me
24, R = TMS
25, R = TBS
Since nucleophilic additions to the aldehyde 11 were unsuc-
cessful, we concluded that using an anionic oxy-Cope as the
key step to set the anti-quaternary methyl groups and
ultimately close the C ring as originally designed was not
viable. Starting from the aldehyde 11, we devised a new syn-
thetic strategy that would assemble the C ring with the anti-
quaternary methyl groups through the use of a Diels–Alder
reaction. The synthesis of the AB ring component began
with methylation of the aldehyde 11 (MeLi, Et2O) to give
in 95% yield the allylic alcohol 29, which was subsequently
oxidized to the corresponding enone 30 in 80% yield (Dess–
Martin periodinane, DMP, dichloromethane) (Scheme 5).
The enone 30 was then converted into the kinetic silyl enol
ether 31 in 99% yield (TBSOTf, TEA, dichloromethane).
A possible dienophile 34 was synthesized by a three-step
procedure starting from the ketone 19 by first forming the
b-keto ester 32 with potassium hydride and dimethyl carbon-
ate (Scheme 6). The ketone of 32 was then reduced to the
alcohol 33 (NaBH4, MeOH), and the alcohol eliminated
(POCl3, pyr., 80 ꢂC) to form the a,b-unsaturated ester 34 in
an overall unoptimized yield of 22%. The diene 31 and the
dienophile 34 were reacted with a catalytic amount of a
5:1 mixture of aluminum tribromide and trimethylaluminum
(Scheme 7), conditions proven to work in our laboratories15
for highly hindered Diels–Alder reactions. However, these
Scheme 3. Reagents and conditions: (a) TMSCN/TBSCN, ZnI2, CH2Cl2, 0–
23 ꢂC, 96%/48% (22/23); (b) LDA, THF, ꢁ78 ꢂC; 11, ꢁ78 ꢂC to reflux, 0%.
Despite reaching the requisite acyl anion equivalent of the
silyl cyanohydrin and synthesizing the AB ring system as
planned, the lack of reactivity of our nucleophile toward
the aldehyde 11 would not allow us to prepare the substrate
required to demonstrate our anionic oxy-Cope methodology
for the construction of the anti-quaternary methyl groups in
the C ring of betulinic acid 1. Therefore, a smaller, stronger
nucleophile was required to add to our very sterically
hindered aldehyde in order to be able to test the validity of
our anionic oxy-Cope methodology. Thus, we moved to
other nucleophile sources for addition to the aldehyde 11
and the eventual construction of the ring system.
The aldehyde 11 was reduced in 98% yield to the correspond-
ing alcohol 26 (NaBH4, EtOH), which was readily converted
into the bromide 27 in 48% yield (CBr4, PPh3, DCM)
(Scheme 4). However, upon treatment of the bromide 27
with magnesium metal, even in the presence of iodine to ac-
tivate the surface of the metal, and addition of the aldehyde
11, there was no evidence of Grignard addition to form 28.

9324
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
conditions failed to give the desired Diels–Alder adduct 35.
Despite the strength of the Lewis acid, only starting material
was obtained. This outcome was undoubtedly due to the
severe steric demand of both 31 and 34.
steric demand of the AB ring system in the environment of
the silyl enol ether with its large TBS group could very easily
twist the silyl enol ether out of planarity with the olefin in the
B ring. Although we lacked evidence for this hypothesis
other than a lack of reactivity of the diene and dienophile,
we decided to test the hypothesis by eliminating the A ring
and working with a smaller model system. Without the A
ring present there would be no reason for the silyl enol ether
to twist out of planarity.
HO
Me
Me
Me
CHO
Me
Me
a
b
TBSO
TBSO
H
H
Me Me
Me Me
With this hypothesis in mind, the known compound 2-
methyl-1-acetyl-1-cyclohexene16 36 was converted into the
corresponding TBS enol ether 37 (TBSOTf, TEA, dichloro-
methane, 0 ꢂC) and reacted with the ester 34 using the same
set of Lewis acids previously screened (Scheme 8). Once
again only starting material or hydrolysis of the silyl enol
ether was observed. Therefore, a rotation out of planarity
was probably not the key issue since a substrate that could
not even undergo this rotation also failed to produce a Diels–
Alder adduct. Since the diene 37 has been successfully used
in other hindered Diels–Alder reactions,15a the most likely
explanation is that the ester 34 is just too poor a dienophile
to participate. It is well known that esters are quite poor
activators of alkenes as dienophiles.15b
11
29
TBSO
Me
O
Me
Me
Me
Me
c
TBSO
TBSO
H
H
Me Me
Me Me
31
30
Scheme 5. Reagents and conditions: (a) MeLi, Et2O, 0–23 ꢂC, 95%; (b)
DMP, CH2Cl2, 23 ꢂC, 80%; (c) TBSOTf, TEA, CH2Cl2, 0–23 ꢂC, 99%.
O
O
Me
Me
CO2Me
a
b
TBSO
TBSO
H
H
Me Me
OTBS
Me
Me Me
H
19
32
O
Me
Me
TBSO
TBSO
Me
Me
OH
Me
Me
H
Me
H
Me
CO2Me
Lewis Acids
CO2Me
a
c
CO2Me
38
34
TBSO
TBSO
H
Me Me
33
36
37
Me Me
Scheme 8. Reagents and conditions: (a) TBSOTf, TEA, CH2Cl2, 0–23 ꢂC,
quant.
34
Scheme 6. Reagents and conditions: (a) KH/NaH, THF, Me2CO3, reflux; (b)
NaBH4, MeOH, 23 ꢂC; (c) POCl3, pyr., 80 ꢂC, 22% (three steps).
Once again seeking a convergent strategy that would enable
the mild coupling of two fully elaborated pieces followed by
a key cyclization, we developed an organometallic coupling
approach, namely a double Sonogashira sequence. Utilizing
the advanced ketone 21, we sought to install a vinyl iodide
via the Barton vinyl iodide procedure (Scheme 9).17 Follow-
ing formation of the hydrazone of the ketone 21 in 75%
yield (H2NNH2, AcOH, EtOH, reflux), nitrogen gas was
eliminated by treatment with iodine and 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) in diethyl ether followed
by refluxing with DBU in benzene to afford the vinyl iodide
39 in 76% yield. Treatment of the vinyl iodide 39 with tri-
methylsilyl acetylene in the presence of palladium(II)
[PdCl2(PPh3)2], copper(I) iodide, and triethylamine at
23 ꢂC effected a Sonogashira reaction to afford the silyl
enyne 40.18 The first attempts at deprotection of the enyne
under basic conditions (K2CO3 or KOH in MeOH) were un-
successful. However, when fluoride ion (TBAF) was used,
the enyne 41 was obtained. A second Sonogashira reaction
mixture was then conducted using another equivalent of
the vinyl iodide 39, furnishing the dienyne 42 in 14% overall
yield from 39 over three steps. With the dienyne in hand,
several attempts were made at reduction of the alkyne to
the Z-alkene 43, including hydrogenation using Lindlar’s
catalyst as well as hydroboration (BH3$DMS; BH3$THF).
Each of the reagents provided only starting material, even
at extended reaction times of up to one week. We realized
that if a molecule as small as borane was not reacting with
TBSO
Me
Me
H
Me
CO2Me
a
TBSO
TBSO
TBSO
H
Me Me
Me Me
31
34
OTBS
Me
H
Me
Me
Me Me
H
CO2Me
35
TBSO
H
Me Me
Scheme 7. Reagents and conditions: (a) 5:1 AlBr3/AlMe3, PhMe/CH2Cl2,
ꢁ9 to 23 ꢂC.
A variety of other Lewis acids were then screened in this
system in hopes of finding a viable catalyst to furnish the
Diels–Alder adduct 35, but were ultimately unsuccessful.
The reaction time and the variety and strength of Lewis
acid catalysts should have been sufficient to see at least
some formation of the Diels–Alder adduct 35. At this point,
we believed the diene was probably not cis-coplanar due to
steric interaction between the silyloxy group and the adja-
cent quaternary center, thereby rendering the Diels–Alder
reaction impossible due to poor orbital overlap. The high

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9325
TMS
O
I
Me
Me
H
Me
Me
Me
Me
a-b
c
d
TBSO
TBSO
Me
TBSO
H
H
Me Me
Me Me
Me Me
21
39
40
Me
H
TBSO
Me
OTBS
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
e
f
Me
TBSO
TBSO
TBSO
H
H
H
Me Me
41
Me Me
Me Me
42
43
Scheme 9. Reagents and conditions: (a) NH2NH2, EtOH, AcOH, reflux, 75%; (b) I2, DBU, Et2O, 23 ꢂC, then DBU, PhH, reflux, 76%; (c) TMS–acetylene,
PdCl2(PPh3)2, CuI, TEA, 23 ꢂC; (d) TBAF, THF, 23 ꢂC; (e) 39, PdCl2(PPh3)2, CuI, TEA, 23 ꢂC, 14% (three steps); (f) H2, Lindlar’s cat. or BH3.
the dienyne, it was not likely that anything else would either.
Although the molecule seems not very sterically hindered,
the lack of these reactions indicated that the steric environ-
ment surrounding the alkyne was heavily congested.
First, superior conditions for performing the Sonogashira
reaction (Pd(dba)2, CuI, PPh3, triethylamine, 70 ꢂC)19 were
discovered, resulting in a much better crude yield of the silyl
enyne. A global desilylation was effected with excess TBAF.
The resulting alcohol could then be reprotected with TBSOTf
in the presence of triethylamine in dichloromethane at 0 ꢂC
to arrive at the enyne 41 in a much improved 75% yield for
the three-step sequence. Treatment of the enyne 41 with bis-
(cyclopentadienyl)-zirconium chloride hydride (Schwartz’s
reagent) to effect hydrozirconation followed by addition of
catecholborane to transmetallate to the desired vinyl boronate
44 proceeded smoothly and in excellent yield. Suzuki
coupling of the vinyl boronate 44 to the vinyl iodide 39
(PdCl2(dppf), 2 M NaOH, THF, 60 ꢂC)20 was carried out to
afford the E-triene 45 in 68% yield.
Even though we were unable to effect reduction to the requi-
site Z-alkene 43 for the cyclization to occur, we viewed this
problem as a minor setback. All that was required to over-
come this problem was a change in the type of coupling
utilized. Therefore, we decided to investigate a new method
of joining the two halves of the ring system that would avoid
the sterically challenging alkyne reduction. By converting
the enyne into a vinyl boron species, which could undergo
a Suzuki reaction with another equivalent of the vinyl iodide,
such as 39, we would arrive at an E-triene intermediate suit-
able for cyclization.
With the E-triene 45 in hand, photoisomerization with a
mercury lamp in the presence of a photosensitizer (benz-
anthrone) in a quartz tube was performed (Scheme 11).
The Z-triene 43 was obtained in quantitative yield. Even
though we ultimately wanted the Z-triene 43 to undergo a
Before we subjected the enyne 41 to catecholborane, we de-
cided to first optimize the synthesis of the enyne (Scheme 10).
TMS
I
Me
H
Me
Me
H
Me
H
Me
Me
Me
Me
a
b-c
TBSO
TBSO
OTBS
Me
Me
Me
TBSO
TBSO
H
Me
Me Me
Me Me
Me Me
Me
Me
Me
H
Me
H
a
39
40
41
Me
Me
H
Me
Me
TBSO
TBSO
Me Me
TBSO
O
H
O
43
Me
B
Me Me
45
Me
Me
OTBS
Me
Me
Me
Me
Me
d
e
Me
Me Me
Me
b
H
TBSO
TBSO
H
H
Me Me
45
Me Me
44
TBSO
H
Me Me
Scheme 10. Reagents and conditions: (a) TMS–acetylene, Pd(dba)2, CuI,
PPh3, TEA, 70 ꢂC; (b) excess TBAF, THF, 23 ꢂC; (c) TBSOTf, TEA,
CH2Cl2, 0–23 ꢂC, 75% (three steps); (d) Cp2Zr(H)Cl, catecholborane,
CH2Cl2, 96%; (e) 39, PdCl2(dppf), 2 M NaOH, THF, 60 ꢂC, 68%.
46
Scheme 11. Reagents and conditions: (a) hn (quartz), THF, benzanthrone,
84%; (b) DMF/1,2-C6H4Cl2, sealed tube, 250 ꢂC.

9326
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
conrotatory six electron cyclization to achieve the desired
anti-quaternary methyl groups in the C ring, we first tried
thermal methods of disrotatory ring closure due to the rea-
sonably similar precedent of Trost.21 In his case, a less ste-
rically hindered triene was able to cyclize under high heat.
However, the initial attempt at heating 43 in ortho-dichloro-
benzene and DMF (250 ꢂC, sealed tube) gave a mixture of
starting material and decomposition products arising from
the HCl liberated in the breakdown of ortho-dichlorobenz-
ene under the extreme heat instead of the desired diene 46.
nitrobenzoate) 49 (p-NO2–C6H4COCl, pyr., DMAP, di-
chloromethane, 23 ꢂC) was then prepared in good yield
(Scheme 12). After much experimentation, very thin plate
crystals of 49 were finally obtained from a 9:1 acetonitrile/
hexanes solution. X-ray crystallographic analysis of the
bis-(p-nitrobenzoate) 49 unambiguously showed that the tri-
ene 43 had cleaved by an unknown mechanism to give the
simple olefin 50 (X-ray analysis performed on 51) (Fig. 3).
OH
Me
Me
OTBS
Me
Me
Me Me
Me
Me Me
After this initial failure, a variety of other thermal experi-
ments were conducted in an effort to prepare the diene 46
(Table 1). Microwave heating (entries 2–5) was investigated
with solvents that had stable heating profiles, good solubility
with the triene, and that facilitated monitoring the reaction
by NMR. However, none of the runs furnished the diene
46. Flash vacuum pyrolysis (FVP) was then utilized to try
and effect triene cyclization (entries 6–10). Various vacuum
strengths were explored at extreme temperatures to try to
create as much intimate contact between the substrate and
the hot tube as possible after injection of a solution of the tri-
ene 43 in diethyl ether. However, once again no cyclization
was seen.
Me
a
H
H
Me
Me
HO
TBSO
H
H
Me Me
Me Me
48
47
O
O
Me
NO2
Me
b
Me
Me Me
Me
H
O
O
H
Me Me
49
O2N
Since the thermal methods did not afford any of the cyclized
substrate, we decided to switch to photochemical methods.
A conrotatory photochemical cyclization was ultimately
necessary to arrive at the anti-quaternary methyl groups,
and it was thought that perhaps the excitation of the triene
chromophore would more easily facilitate our sterically
challenging cyclization where the thermal methods failed.
Upon excitation of the triene 43, a compound that appeared
to be the desired C2-symmetric pentacycle 47 by NMR and
HRMS was isolated in 47% yield. However, the UV–vis
spectrum of the isolated compound did not show absorbance
typical of a s-cis diene in a ring, absorbing only up to about
245 nm. Therefore, it was necessary to obtain a crystal
structure of the compound for structural verification. Depro-
tection of the TBS groups was effected with p-toluenesul-
fonic acid in 1:1 acetone/water, to afford what appeared to
be the C2-symmetric diol 48. The corresponding bis-(para-
Scheme 12. Reagents and conditions: (a) TsOH, 1:1 H2O/acetone, 23 ꢂC,
64%; (b) p-NO2–C6H4COCl, pyr., DMAP, CH2Cl2, 23 ꢂC, 93%.
At this point it was likely that enough energy was available
to initiate photochemical transformations, but we wanted to
temper the amount of energy to which the triene 43 was be-
ing exposed. Thus, a borosilicate NMR tube was used as the
photolysis vessel as a thin filter against shorter wave UVand
deuterobenzene (C6D6) was used as an internal filter as well
(Table 2, entry 2). The consequence of this reaction was
evidence of [1,5]-hydrogen shifts in a complex mixture of
products. The identification of [1,5]-hydrogen shifts was
confirmed by the similar findings of Parra22 in his photo-
chemical work toward the synthesis of oleanolic and mas-
linic acids. Looking more closely at the UV–vis spectrum
of the triene, we decided to use filters to try and block out
all wavelengths of light below the tail end of the absorbance
Table 1
OTBS
OTBS
Me
Me
Me
Me
Me
conditions
Me
H
Me
Me Me
Me
Me
H
H
Me
TBSO
TBSO
H
Me Me
Me Me
43
46
Entry
Method
Conditions
Result
1
2
3
4
5
6
7
8
9
10
Sealed tube
m-Wave
m-Wave
m-Wave
m-Wave
FVP (Et2O carrier)
FVP (Et2O carrier)
FVP (Et2O carrier)
FVP (Et2O carrier)
FVP (Et2O carrier)
DMF/1,2-C6H4Cl2, 250 ꢂC
Hexanes, w250 ꢂC
CDCl3, w250 ꢂC
CDCl3, w200 ꢂC
C7D8, w250 ꢂC
SM+decomp.
SM+decomp.
Complex mixture
SM+decomp.
SM
SM
SM
SM
SM
SM
600 ꢂC, <0.1 Torr
600 ꢂC, 30 Torr
600 ꢂC, 50 Torr
600 ꢂC, 100 Torr
600 ꢂC, 100 Torr, 600 path of glass beads

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9327
Me
H
Me
Me
TBSO
Me Me
50
Me
O
O
H
Me Me
O2N
51
Figure 3.
Table 2
OTBS
OTBS
Me
Me
Me
Me Me
Me
Me
Me
conditions
Me
H
Me
H
H
Me
Me
TBSO
TBSO
H
Me Me
Me Me
43
47
Entry
Method
Conditions
THF, quartz tube
C6D6, NMR tube, 3 h
C6D6, NMR tube, <330 nm filter, 4 h
C6D6, NMR tube, <330 nm filter, 12 h
CD3OD, NMR tube, <330 nm filter, 4 h
CD3OD, NMR tube, <330 nm filter, 12 h
C6D6, 9,10-dicyanoanthracene, NMR tube, 12 h
PhSSPh, AIBN, PhH
Result
1
2
3
4
5
6
7
8
Photolysis
Photolysis
Photolysis
Photolysis
Photolysis
Photolysis
Photolysis
Reflux
47% Cleavage product
[1,5]-Hydrogen shifts
SM
[1,5]-Hydrogen shifts
SM
SM
SM
SM
9
Reflux
70 ꢂC
DDQ, CH2Cl2
Complex mixture
10
11
12
13
Pd2(dba)3, PPh3, AcOH, PhH
Pd(OAc)2, PhMe
Cp2ZrCl2, nBuLi, THF
SM
SM
SM
SM
110 ꢂC
ꢁ78 to 23 ꢂC
60 ꢂC
Ni(COD)2, PPh3, PhMe
(entries 3–6). With the filters in place, no reaction was ob-
served, except in the case of prolonged photolysis in C6D6,
in which some [1,5]-hydrogen shifts had begun to take place.
In hopes of activating the triene with a photooxidant, 9,10-
dicyanoanthracene was employed (entry 7), but once again
only starting material was obtained. Attempts were made
to induce a radical cyclization through the use of diphenyl
disulfide (entry 8) and a oxidative cyclization with DDQ
(entry 9); however, both reactions failed. Several organo-
metallic reagents were also employed that have been known
NH2
O
N
I
Me
Me
Me
Me
Me
Me
Me
Me
a
b
c
Me
52
53
54
Me
Me
Me
Me
Me Me
Me
Me
H
Me Me
Me
Me
d
e
Me
Me
Me
TBSO
TBSO
H
Me Me
TBSO
Me Me
H
Me Me
57
56
55
Scheme 13. Reagents and conditions: (a) H2NNH2, TEA, EtOH, reflux; (b) DBU, I2, Et2O, 23 ꢂC; DBU, PhH, reflux, 76% (two steps); (c) 44, PdCl2(dppf), 2 M
NaOH, THF, 60 ꢂC, 72%; (d) hn, benzanthrone, THF, 82%; (e) hn, C6D6, 0%.

9328
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
to promote metal-mediated oxidative cyclizations but all
were unsuccessful.23–26
the designation ‘b’ is placed before the multiplicity. FT-IR
spectra were obtained using either a Nicolet 510p or Nicolet
Avatar 370 FT-IR spectrometer using liquid films (neat) on
NaCl plates. High-resolution mass spectra (HRMS) and
low-resolution mass spectra (LRMS) were recorded on a
VG Analytical Autospec double focusing instrument using
electron impact (EI) or chemical ionization (CI) techniques.
The X-ray crystal structure was elucidated by Dr. Saeed
Although conditions to induce the desired cyclization were
exhaustively attempted, we decided to perform the cycliza-
tion on a smaller analogue of the triene 43 to completely
rule out steric complications from the larger analogue as
the reason for the failure of the cyclization (Scheme 13). Re-
peating the same synthetic scheme as before, commercially
available 2,2,6-trimethylcyclohexanone 52 was treated with
hydrazine and triethylamine in refluxing ethanol to give the
hydrazone 53, which was then converted into the vinyl
iodide 54 with DBU and iodine in 76% yield over the two
steps. The vinyl iodide 54 was then coupled to the vinyl bor-
onate 44 via a Suzuki reaction (PdCl2(dppf), 2 M NaOH,
THF, 60 ꢂC) to give the E-triene 55 in 72% yield. This triene
was then photolyzed in the presence of benzanthrone to
effect isomerization to the Z-triene 56. However, using the
same photochemical conditions employed in Table 2 (entries
3–7), no cyclization of 56 to the diene 57 was observed. Con-
sequently, we decided to abandon all work in this area, one
step away from completing the synthesis of the pentacyclic
core.
€
Khan on a Bruker Smart 1000 CCD diffractometer equipped
with a low temperature device from Oxford Cryosystems
Model 600.
4.1.1. 3,4,8,8a-Tetrahydro-5,8a-dimethylnaphthalen-
1(2H),6(7H)-dione (15). To a stirring solution of commer-
cially available 2-methyl-1,3-cyclohexanedione 14 (5 g,
39.6 mmol), methanol (18 mL), and two pellets of KOH
was added commercially available ethyl vinyl ketone
(6.3 mL, 63.4 mmol) and the mixture heated to 40 ꢂC. After
5 h, the solvent was removed in vacuo and excess water was
removed azeotropically with three washings of benzene. To
the crude residue was added benzene (21 mL) and pyrroli-
dine (0.37 mL, 4.4 mmol), and the mixture was heated to
reflux overnight with a Dean–Stark trap. The solvent was
removed in vacuo and the residue diluted with ether. The
organic extract was washed once with a solution of 5% aque-
ous HCl, once with brine, and dried (MgSO4). The solvents
were removed in vacuo and the residue vacuum distilled
(154–157 ꢂC, <1 mmHg) to yield the diketone 15 as a
pale yellow oil (4.6 g, 61%). The spectral data matched
that of the compound reported in the literature.13 IR (neat)
2953, 2872, 1711, 1686, 1611, 1455, 1421, 1356, 1308,
3. Conclusion
In conclusion, we have shown that the advanced bicyclic al-
dehyde 11, the iodide 39, and the silyl diene 31 can all be
readily prepared in good overall yield and have proven to
be very amenable to transformation into key compounds
for a variety of synthetic pathways. Although Suzuki cou-
pling of the advanced intermediates could be accomplished
as well as photoisomerization to the potentially reactive
Z-triene, final cyclization could not be achieved, despite ex-
tensive use of thermal, photochemical, and chemical means.
The heavy steric interactions in the vicinity of the methyl
groups on the olefins as well as the number of 1,3-diaxial in-
teractions in the ring system all worked against the cycliza-
tion and formation of the anti-quaternary methyl groups.
1009 cmꢁ1 1H NMR (400 MHz, CDCl3) d 2.80 (ddd,
;
J¼15.9, 4.9, 4.9 Hz, 1H), 2.61 (m, 1H), 1.91–2.52 (m,
8H), 1.73 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 212.1, 197.7, 158.3, 130.7, 50.6, 33.7, 33.3,
29.4, 27.3, 23.4, 21.5, 11.3.
4.1.2. ( )-30,40,80,80a-Tetrahydro-50,80a-dimethylspiro-
[1,3-dioxolane-2,10-naphthalen]-60(70H)-one (16). A solu-
tion of the diketone 15 (1.67 g, 8.7 mmol), p-toluenesulfonic
˚
acid (1.7 g, 9 mmol), ethylene glycol (51 mL), and 4 A MS
was stirred at 23 ꢂC overnight. The reaction mixture was
poured into a solution of ice and saturated NaHCO3 and ex-
tracted three times with ethyl acetate. The combined organic
extracts were washed with brine and dried (MgSO4). The
solvent was removed in vacuo to afford the ketal 16 as
a pale yellow oil (2.01 g, 98%). The spectral data matched
that of the compound reported in the literature.27 IR (neat)
2950, 2878, 1734, 1665, 1181, 1092, 1036 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 3.87–3.98 (m, 4H), 2.70 (br d,
J¼19.6 Hz, 1H), 1.53–2.65 (m, 9H), 1.75 (s, 3H), 1.30 (s,
3H); 13C NMR (100 MHz, CDCl3) d 198.8, 160.3, 130.1,
112.8, 65.3, 65.1, 45.3, 33.7, 29.7, 26.5, 26.4, 21.4, 20.9,
11.4; HRMS (EI) m/e (M+) calcd for C14H20O3 236.1412,
found 236.1420.
4. Experimental
4.1. General
Tetrahydrofuran (THF) and diethyl ether were both distilled
from sodium benzophenone-ketyl. Dichloromethane, benz-
ene, and toluene were all distilled from calcium hydride.
Methanol was distilled from magnesium. Pyridine and tri-
ethylamine were both distilled from calcium hydride and
diisopropylamine from NaOH. All reactions were carried
out in flame-dried glassware under an argon atmosphere un-
less otherwise stated. Flash chromatography was performed
using ACS certified solvents and Merck silica gel 60, mesh
230–400. Proton and carbon NMR spectra were obtained us-
4.1.3. ( )-(40aS,60S,80aS)-30,40,40a,50,60,70,80,80a-Octahydro-
50,50,800-trimethylspiro[1,3-dioxolane-2,10-naphthalen]-60-
ol (17). A solution of the ketal 16 (7.6 g, 32.2 mmol) in THF
(140 mL) was slowly added to a stirring solution of lithium
metal (1.47 g, 209 mmol) in NH3 (500 mL), and the resulting
anion allowed to stir for 45 min. A solution of methyl iodide
(30.1 mL, 483 mmol) in THF (60 mL) was added via syringe
€
ing a Bruker Avance 500 MHz, a Bruker ARX 400 MHz, or
a Bruker ARX 500 MHz spectrometer. The signals are re-
€
€
ported in parts per million relative to CDCl3. The chemical
shifts are reported in parts per million (ppm, d). The coupling
constants are reported in Hertz (Hz) using the following
abbreviations: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼
quartet, and m ¼ multiplet. When the signals are broad,

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9329
to the reaction, and the resulting mixture allowed to stir for
45 min. To the white slurry was added lithium metal (6.3 g,
900 mmol) and the solution allowed to stir for 30 min. Meth-
anol (50 mL) was added followed by 200 mL of ether, and the
system was opened to the atmosphere overnight. A solution of
10% aqueous HCl was slowly added to the slurry before
extracting three times with ether. The combined organic
extracts were washed with brine and dried (MgSO4). Solvents
were removed in vacuo and the resulting residue purified by
flash chromatography on silica gel (70% hexanes/ethyl ace-
tate) to yield the alcohol 17 as a clear, colorless oil (4.43 g,
54%). The spectral data matched that of the compound
reported in the literature.27 IR (neat) 3428 (br s), 2943,
37.5, 31.1, 28.4, 27.3, 26.4, 25.9, 21.0, 18.7, 18.1, 16.3,
ꢁ3.8, ꢁ5.0; HRMS (EI) m/e (M+) calcd for C19H36O2Si
324.2485, found 324.2493.
4.1.6. ( )-(2R,4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methylnaphthalen-1(2H)-one (21). To a stirring solution of
diisopropylamine (3.7 mL, 26.2 mmol) in THF (40 mL)
cooled to 0 ꢂC was added n-butyllithium (11.2 mL,
14.4 mmol, 1.28 M in hexanes). The solution was allowed
to warm to 23 ꢂC and stirred for 30 min before being cooled
to ꢁ78 ꢂC. A solution of the TBS ether 19 (4.25 g,
13.1 mmol) in THF (5 mL) was then added dropwise at
ꢁ78 ꢂC and the resulting solution allowed to warm to
23 ꢂC and stirred for 45 min. The solution was then cooled
to ꢁ78 ꢂC and methyl iodide (8.2 mL, 131 mmol) was added
and the solution allowed to warm to 23 ꢂC and stirred for 3 h.
The reaction was quenched with a saturated solution of
Na2S2O3 and extracted three times with ether. The combined
organic extracts were washed once with a solution of 10%
aqueous CuSO4, once with brine, and dried (MgSO4). The
solvents were removed in vacuo to yield both diastereomers
of the ketone 20 as a crude, orange-brown oil (4.43 g, 100%).
1
2872, 1451, 1175, 1105, 1042 cmꢁ1; H NMR (400 MHz,
CDCl3) d 3.79–3.94 (m, 4H), 3.24 (bdd, J¼11.1, 4.3 Hz,
1H), 1.25–1.72 (m, 11H), 1.05 (s, 3H), 0.98 (s, 3H), 0.79 (s,
3H); 13C NMR (100 MHz, CDCl3) d 113.3, 78.7, 65.3,
64.8, 48.2, 43.1, 38.8, 30.4, 28.7, 28.0, 27.1, 23.1, 20.6,
16.5, 15.4; HRMS (EI) m/e (M+) calcd for C15H26O3
254.1882, found 254.1867.
4.1.4. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-
6-hydroxy-5,5,8a-trimethylnaphthalen-1(2H)-one (18).
A solution of the alcohol 17 (697 mg, 2.74 mmol), p-tolue-
nesulfonic acid (521 mg, 2.74 mmol), and 1:1 acetone/water
(14 mL) was stirred together at 23 ꢂC overnight. The solu-
tion was poured into a solution of ice and saturated NaHCO3
and extracted three times with ether. The combined organic
extracts were washed with brine and dried (MgSO4). Sol-
vents were removed invacuo to yield the ketone 18 as a clear,
colorless oil (576 mg, 100%). The spectral data matched that
of the compound reported in the literature.27 IR (neat) 3447
(br s), 2940, 2869, 1701, 1458, 1113, 1042 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 3.17 (m, 1H), 2.54 (ddd, J¼14.0, 14.0,
7.0 Hz, 1H), 2.17 (br d, J¼14.0 Hz, 1H), 2.02–2.10 (m, 1H),
1.42–1.79 (m, 8H), 1.12 (s, 3H), 0.99 (s, 3H), 0.87 (s, 3H);
13C NMR (100 MHz, CDCl3) d 215.4, 78.1, 52.6, 48.6, 37.4,
31.2, 30.9, 27.8, 26.9, 26.2, 20.7, 18.6, 15.8; HRMS (EI) m/e
(M+) calcd for C13H22O2 210.1612, found 210.1613.
To a stirring solution of methanol (225 mL) and sodium
metal (3 g, 131 mmol) at 23 ꢂC was added a solution of
the ketone 20 (4.43 g, 13.1 mmol) in methanol (25 mL)
and the resulting mixture was allowed to stir overnight.
The solvent was removed in vacuo and the crude residue di-
luted with ether and water and extracted three times with
ether. The combined organic extracts were washed with
brine and dried (MgSO4). The solvent was removed in vacuo
and the crude residue purified by flash chromatography on
silica gel (70% hexanes/ethyl acetate) to yield the ketone
21 as an oily, white solid (4.3 g, 97%). IR (neat) 2851,
1
1703, 1674, 1470, 1388, 1250, 1070, 1026, 671 cmꢁ1; H
NMR (500 MHz, CDCl3) d 3.07 (dd, J¼10.0, 5.1 Hz, 1H),
2.57 (ddq, J¼13.0, 6.5, 6.5 Hz, 1H), 2.02 (m, 1H), 1.40–
1.70 (m, 8H), 1.04 (s, 3H), 0.92 (d, J¼6.5 Hz, 3H), 0.83
(s, 3H), 0.81 (s, 9H), 0.80 (s, 3H), ꢁ0.03 (s, 3H), ꢁ0.06 (s,
3H); 13C NMR (125 MHz, CDCl3) d 215.8, 78.6, 53.2,
48.1, 40.1, 39.6, 35.6, 31.1, 28.1, 27.2, 25.7, 21.1, 18.6,
17.9, 16.1, 14.8, ꢁ4.0, ꢁ5.2; HRMS (EI) m/e (M+) calcd
for C20H38O2Si 338.2641, found 338.2647.
4.1.5. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-
6-[(1,1-dimethylethyl)dimethylsilyloxy]-5,5,8a-tri-
methylnaphthalen-1(2H)-one (19). To a stirring solution
of the ketone 18 (3.3 g, 15.7 mmol), pyridine (5.08 mL,
62.8 mmol), and dichloromethane (27 mL) at 0 ꢂC was added
tert-butyldimethylsilyl trifluoromethanesulfonate (3.61 mL,
15.7 mmol). The solution was allowed to warm to 23 ꢂC
and stirred overnight. The solvent was removed in vacuo
and the residue taken up in ether and a saturated solution
of NaHCO3 and extracted three times with ether. The com-
bined organic extracts were washed once with a solution of
10% aqueous CuSO4, once with brine, and dried (MgSO4).
The solvent was removed in vacuo and the crude residue
purified by flash chromatography on silica gel (70%
hexanes/ethyl acetate) to afford the TBS ether 19 as an oily,
white solid (4.2 g, 83%). The spectral data matched that of
the compound reported in the literature.28 IR (neat) 2934,
4.1.7. ( )-(6S,4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methylnaphthalene-1-carboxaldehyde (11). To a stirring
solution of diisopropylamine (2.5 mL, 17.9 mmol) and THF
(9 mL) cooled to 0 ꢂC was added n-butyllithium (5.6 mL,
8.9 mmol, 1.6 M in hexanes). The solution was allowed to
stir for 30 min before being cooled to ꢁ95 ꢂC. A solution
of the ketone 21 in dichloromethane (9 mL) was added drop-
wise to the mixture and it was allowed to gradually warm to
ꢁ20 ꢂC over 2 h. The reaction mixture was then refluxed for
1 h, cooled to 0 ꢂC, and the solvents removed in vacuo. To
the crude residue was added hexamethylphosphoramide
(17 mL), lithium perchlorate (951 mg, 8.9 mmol), calcium
carbonate (1.12 g, 11.2 mmol), and the mixture was heated
with stirring to 130 ꢂC for 1.5 h. After the reaction mixture
cooled, it was diluted with water and extracted three times
with ether. The combined organic extracts were washed
once with brine and dried (MgSO4). The solvent was
1
2855, 1703, 1462, 1250, 1100, 1076, 833 cmꢁ1; H NMR
(400 MHz, CDCl3) d 3.15 (m, 1H), 2.56 (ddd, J¼14.0,
14.0, 7.0 Hz, 1H), 2.18 (br d, J¼14.0 Hz, 1H), 2.03–2.09
(m, 1H), 1.47–1.80 (m, 8H), 1.14 (s, 3H), 0.92 (s, 3H),
0.89 (s, 9H), 0.86 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 215.5, 78.7, 52.7, 48.6, 40.3,

9330
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
removed in vacuo and the crude residue purified by flash
chromatography on silica gel (90% hexanes/ethyl acetate)
to yield the aldehyde 11 as a brownish yellow oil (634 mg,
45%). IR (neat) 2945, 2856, 1676, 1472, 1389, 1253,
the crude residue purified by flash chromatography on silica
gel (90% hexanes/ethyl acetate) to afford the alcohol 26 as
a colorless oil (80 mg, 70%). H NMR (400 MHz, CDCl3)
1
d 4.17 (d, J¼11.4 Hz, 1H), 4.01 (d, J¼11.4 Hz, 1H), 3.20
(dd, J¼10.9, 5.1 Hz, 1H), 2.05 (m, 2H), 1.85 (dt, J¼12.9,
3.3 Hz, 1H), 1.70 (s, 3H), 1.35–1.67 (m, 6H), 0.95 (s, 3H),
0.91 (s, 3H), 0.88 (s, 9H), 0.76 (s, 3H), 0.02 (s, 3H), 0.01
(s, 3H); 13C NMR (100 MHz, CDCl3) d 140.5, 132.5, 79.3,
58.2, 50.9, 39.3, 37.7, 34.9, 34.0, 28.5, 28.0, 25.9, 20.7,
19.2, 18.8, 18.1, 15.9, ꢁ3.8, ꢁ5.0. HRMS (EI) m/e
(M+Na) calcd for C21H42O2SiNa 375.2690, found 375.2685.
1
1105, 836, 773 cmꢁ1; H NMR (400 MHz, CDCl3) d 10.2
(s, 1H), 3.19 (dd, J¼11.4, 4.7 Hz, 1H), 2.57 (ddd, J¼13.4,
3.6, 3.6 Hz, 1H), 2.26 (m, 1H), 2.02 (s, 3H), 0.74–1.73 (m,
7H), 1.14 (s, 3H), 0.94 (s, 3H), 0.88 (s, 9H), 0.78 (s, 3H),
0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 192.3, 154.2, 143.4, 79.1, 51.0, 39.5, 37.3, 36.8, 34.2,
28.6, 28.0, 25.9, 20.1, 19.0, 18.3, 18.1, 16.0, ꢁ3.7, ꢁ5.0;
HRMS (EI) m/e (MꢁH) calcd for C21H37O2Si 349.2563,
found 349.2568.
4.1.11. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-1-Bromo-
methyl-octahydro-6-[(1,1-dimethylethyl)dimethylsilyl-
oxy]-2,5,5,8a-tetramethylnaphthalene (27). To a stirring
solution of the allylic alcohol 26 (193 mg, 0.55 mmol) and
carbon tetrabromide (202 mg, 0.61 mmol) in dichloro-
methane (5.5 mL) cooled to 0 ꢂC was added triphenylphos-
phine (160 mg, 0.61 mmol). The reaction was allowed to
warm to 23 ꢂC and stirred for 2.5 h. Celite was added to
the reaction mixture and the solvent was removed in vacuo.
The solid mixture was purified by flash chromatography on
a very short column of silica gel (90% hexanes/ethyl acetate)
to afford the bromide 27 as a colorless oil (109 mg, 48%). 1H
NMR (400 MHz, CDCl3) d 4.13 (1H, d, J¼10.0 Hz), 3.97
(1H, d, J¼10.0 Hz), 3.20 (1H, m), 2.12 (2H, m), 1.39–1.90
(7H, m), 1.72 (3H, s), 1.00 (3H, s), 0.97 (3H, s), 0.90 (9H,
s), 0.78 (3H, s), 0.06 (3H, s), 0.04 (3H, s); 13C NMR
(100 MHz, CDCl3) d 136.8, 126.7, 79.3, 50.7, 48.1, 39.8,
37.5, 36.9, 35.8, 28.1, 25.9, 24.1, 21.2, 20.8, 18.1, 15.9,
ꢁ3.7, ꢁ4.9.
4.1.8. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-a-(trimethylsilyl-
oxy)-2,5,5,8a-tetramethylnaphthalene-1-acetonitrile
(22). To a stirring solution of the aldehyde 11 (95.8 mg,
0.27 mmol), zinc iodide (4 mg, 0.016 mmol), and dichloro-
methane (0.5 mL) at 23 ꢂC was added trimethylsilyl cyanide
(43 mL, 0.32 mmol). The mixture was allowed to stir for
24 h. The reaction was quenched with pH 7 buffer and
extracted three times with dichloromethane. The combined
organic extracts were washed once with brine and dried
(MgSO4). The solvents were removed in vacuo to yield the
TMS cyanohydrin 22 as a light brown oil (118 mg, 96%).
IR (neat) 2956, 2857, 2231, 1641, 1472, 1362, 1254, 1106,
842, 774 cmꢁ1 1H NMR (400 MHz, CDCl3) d 5.07 (s,
;
1H), 3.21 (m, 1H), 2.10 (m, 1H), 1.85 (s, 3H), 1.49–1.80
(m, 8H), 1.01 (s, 3H), 0.92 (s, 3H), 0.89 (s, 9H), 0.76 (s,
3H), 0.26 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H).
4.1.9. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-a-[(1,1-dimethyl-
ethyl)dimethylsilyloxy]-2,5,5,8a-tetramethylnaphtha-
lene-1-acetonitrile (23). To a stirring solution of the
aldehyde 11 (125 mg, 0.35 mmol), zinc iodide (4 mg,
0.016 mmol), and dichloromethane (0.6 mL) at 23 ꢂC was
added tert-butyldimethylsilyl cyanide (59 mg, 0.42 mmol).
The mixture was allowed to stir for 24 h. The reaction was
quenched with pH 7 buffer and extracted three times with
dichloromethane. The combined organic extracts were
washed once with brine and dried (MgSO4). The solvents
were removed in vacuo and the crude residue purified by
flash chromatography on silica gel (90% hexanes/ethyl ace-
tate) to yield the TBS cyanohydrin 23 as a colorless oil
(84 mg, 48%). 1H NMR (400 MHz, CDCl3) d 5.12 (s, 1H),
3.22 (m, 1H), 2.10 (m, 1H), 1.83 (s, 3H), 1.22–1.71 (m,
8H), 1.03 (s, 3H), 0.92 (s, 9H), 0.91 (s, 3H), 0.90 (s, 9H),
0.89 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 136.3, 120.6, 79.0, 58.5, 50.9,
50.8, 39.4, 38.6, 34.8, 34.1, 32.4, 28.5, 27.9, 25.9, 22.5,
20.1, 19.2, 18.6, 18.1, 16.0, ꢁ2.9, ꢁ3.5, ꢁ5.0, ꢁ5.2.
4.1.12. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-a,2,5,5,8a-penta-
methylnaphthalene-1-methanol (29). To a stirring solution
of the aldehyde 11 (141 mg, 0.40 mmol) in ether (1.4 mL)
cooled to 0 ꢂC was added methyllithium (0.57 mL,
0.80 mmol, 1.4 M in ether). The solution was allowed to
warm to 23 ꢂC and stirred for 1 h. The reaction was
quenched with a solution of 15% aqueous NH4Cl and
extracted three times with ether. The combined organic
extracts were washed once with brine and dried (MgSO4).
The solvent was removed in vacuo to yield a diastereomeric
mixture of the two alcohols 29 as a colorless oil (139 mg,
1
95%). H NMR (500 MHz, CDCl3) d 4.90 (q, J¼6.7 Hz,
1H), 4.60 (q, J¼6.8 Hz, 1H), 3.24 (m, 2H), 2.06 (m, 4H),
1.87 (s, 3H), 1.85 (s, 3H), 1.52–1.76 (m, 9H), 1.45 (d,
J¼6.8 Hz, 3H), 1.43 (d, J¼6.7 Hz, 3H), 1.05–1.38 (m,
5H), 0.98 (s, 3H), 0.96 (s, 3H), 0.93 (s, 9H), 0.80 (s, 3H),
0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 144.5, 143.5, 130.7, 129.3, 79.1, 79.0, 66.1, 65.7, 51.5,
50.9, 39.3, 38.6, 35.4, 34.9, 28.6, 28.1, 25.8, 23.8, 20.5,
20.1, 18.7, 18.0, 16.0, ꢁ3.9, ꢁ5.1. HRMS (EI) m/e (M+Na)
calcd for C22H42O2SiNa 389.2846, found 389.2840.
4.1.10. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methylnaphthalene-1-methanol (26). A mixture of the
aldehyde 11 (117 mg, 0.33 mmol), sodium borohydride
(6.5 mg, 0.17 mmol), and ethanol (3.3 mL) was stirred to-
gether at 23 ꢂC overnight. The reaction mixture was poured
into water and extracted three times with ether. The com-
bined organic extracts were washed once with brine and
dried (MgSO4). The solvents were removed in vacuo and
4.1.13. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methylnaphthalene-1-ethanone (30). To a stirring solution
of Dess–Martin periodinane (208 mg, 0.49 mmol) in di-
chloromethane (3 mL) at 23 ꢂC was added the alcohol 29
(139 mg, 0.38 mmol) in dichloromethane (1 mL). The mix-
ture was allowed to stir for 1 h, poured into a 1:1 mixture
of a saturated solution of NaHCO3 and a solution of 10%

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9331
aqueous NaHSO3, and extracted three times with dichloro-
methane. The combined organic extracts were washed
once with brine and dried (MgSO4). The solvent was re-
moved in vacuo and the crude residue purified by flash chro-
matography on silica gel (90% hexanes/ethyl acetate) to
(78 mL) and stirred at 23 ꢂC before phosphorus oxychloride
(2.2 mL, 23.3 mmol) was added and the mixture heated to
80 ꢂC for 4 h. The solvent was then removed in vacuo and
the crude residue dissolved in ether and a saturated solution
of sodium bicarbonate and extracted three times with ether.
The combined organic extracts were washed once with a so-
lution of 10% aqueous CuSO4, once with brine, and dried
(MgSO4). The solvents were removed in vacuo and the crude
residue purified by flash chromatography on silica gel (95%
hexanes/ethyl acetate) to afford the a,b-unsaturated ester 34
as a clear, colorless oil (610.7 mg, 22%, three steps). IR
(neat) 2951, 2855, 1747, 1717, 1472, 1389, 1250, 1106,
1
afford the enone 30 as a colorless oil (110 mg, 80%). H
NMR (500 MHz, CDCl3) d 3.21 (dd, J¼11.3, 4.7 Hz, 1H),
2.23 (s, 3H), 2.04 (m, 2H), 1.52 (s, 3H), 1.50–1.74 (m,
5H), 1.45 (dd, J¼13.0, 3.6, 3.6 Hz, 1H), 1.36 (dd, J¼13.0,
13.0, 3.6 Hz, 1H), 1.20 (s, 3H), 0.91 (s, 3H), 0.86 (s, 9H),
0.76 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 209.4, 146.4, 127.4, 79.1, 49.8, 39.4,
36.8, 35.2, 33.7, 32.1, 28.3, 27.7, 25.8, 20.5, 20.1, 18.4,
18.0, 15.7, ꢁ3.9, ꢁ5.1. HRMS (EI) m/e (M+H) calcd for
C22H41O2Si 365.2870, found 365.2879.
1
1058 cmꢁ1; H NMR (400 MHz, CDCl3) d 6.58 (s, 1H),
3.70 (s, 3H), 3.20 (dd, J¼11.3, 6.6 Hz, 1H), 1.25–1.78 (m,
9H), 0.98 (s, 3H), 0.93 (s, 3H), 0.87 (s, 9H), 0.76 (s, 3H),
0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 168.5, 150.7, 126.6, 79.3, 51.5, 49.2, 39.2, 36.5, 35.6,
28.2, 27.9, 26.1, 25.9, 20.5, 18.3, 18.1, 15.9, ꢁ3.8, ꢁ5.0;
HRMS (EI) m/e (M+) calcd for C21H38O3Si 366.2590, found
366.2593.
4.1.14. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-1-
(1-[(1,1-dimethylethyl)dimethylsilyloxy]ethenyl)-6-[(1,1-
dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetramethyl-
naphthalene (31). To a stirring solution of the enone 30
(94 mg, 0.26 mmol), triethylamine (0.11 mL, 0.78 mmol),
and dichloromethane (2.6 mL) cooled to 0 ꢂC was added
dropwise tert-butyldimethylsilyl trifluoromethanesulfonate
(0.09 mL, 0.39 mmol). The solution was allowed to warm
to 23 ꢂC and stirred for 2.5 h. The solvents were removed
in vacuo and the residue taken up in ether and extracted three
times from a saturated solution of NaHCO3. The combined
organic extracts were washed once with brine and dried
(MgSO4). The solvent was removed in vacuo and the crude
residue purified by flash chromatography on silica gel (90%
hexanes/ethyl acetate with 2% triethylamine buffer) to af-
ford the silyl enol ether 31 as a colorless oil (122 mg,
4.1.16. 1-(1-[(1,1-Dimethylethyl)dimethylsilyloxy]-
ethenyl)-2-methylcyclohexene (37). To a stirring solution
of the enone 36 (424 mg, 3.07 mmol), prepared according
to the literature,16 and triethylamine (1.3 mL, 9.2 mmol) in
dichloromethane (15 mL) at 0 ꢂC was added tert-butyldi-
methylsilyl trifluoromethanesulfonate (1.06 mL, 4.6 mmol).
The solution was allowed to warm to 23 ꢂC and stirred for
2 h. The reaction mixture was diluted with ether and
quenched with a saturated solution of sodium bicarbonate
and extracted three times with ether. The combined organic
extracts were washed once with brine and dried (MgSO4).
The solvents were removed in vacuo to afford the silyl
enol ether 37 as a crude, pale yellow oil (774 mg, 100%).
1H NMR (400 MHz, CDCl3) d 4.36 (d, J¼2.9 Hz, 1H),
4.10 (d, J¼2.9 Hz, 1H), 2.11 (m, 2H), 1.98 (m, 2H), 1.76
(s, 3H), 1.58–1.65 (m, 4H), 0.92 (s, 9H), 0.13 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 157.6, 136.1, 128.5, 94.1, 31.8,
28.0, 25.7, 22.9, 21.4, 18.2, 18.1, ꢁ3.0. HRMS (EI) m/e
(M+H) calcd for C15H29OSi 253.1982, found 253.1982.
1
99%). H NMR (500 MHz, CDCl3) d 4.31 (s, 1H), 3.91 (s,
1H), 3.26 (dd, J¼11.2, 4.6 Hz, 1H), 2.10 (m, 2H), 1.70 (s,
3H), 1.32–1.74 (m, 5H), 1.10–1.15 (m, 2H), 0.98 (s, 3H),
0.97 (s, 9H), 0.95 (s, 3H), 0.93 (s, 9H), 0.84 (s, 3H), 0.25
(s, 3H), 0.23 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 156.0, 141.7, 128.5, 125.0, 79.7,
50.3, 39.4, 35.5, 32.4, 31.5, 28.5, 28.2, 25.6 (2 C’s), 22.5,
20.9, 18.6, 17.9, 15.8, 14.0, ꢁ3.1, ꢁ3.9, ꢁ4.7, ꢁ5.1.
4.1.15. Methyl ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-octa-
hydro-6-[(1,1-dimethylethyl)dimethylsilyloxy]-5,5,8a-
trimethylnaphthalene-2-carboxylate (34). To a freshly
washed slurry of NaH (1.4 g, 31.12 mmol, 55% w/w) and
KH (five drops, 35% w/w) in THF (97 mL) was added
dimethyl carbonate (2 mL, 23.3 mmol). A solution of the
ketone 19 (2.5 g, 7.78 mmol) in THF (5 mL) was then added
and the combined solution heated to reflux overnight. The
solution was cooled to 0 ꢂC and quenched with a solution
of 15% aqueous ammonium chloride and extracted three
times with ether. The combined organic extracts were
washed once with brine and dried (MgSO4). The solvents
were removed in vacuo to afford the b-keto ester 32 as
a crude, brown oil. The crude b-keto ester 32 was dissolved
in methanol (78 mL), cooled to 0 ꢂC, and sodium borohy-
dride (194 mg, 5.13 mmol) was added. The reaction mixture
was stirred at 0 ꢂC for 6 h and quenched with a saturated so-
lution of ammonium chloride and extracted three times with
ether. The combined organic extracts were washed with
brine and dried (MgSO4). The solvents were removed
in vacuo to furnish the b-hydroxy ester 33 as a crude, brown
oil. The crude b-hydroxy ester 33 was dissolved in pyridine
4.1.17. ( )-(2S,4aS,8aS)-1,2,3,4,4a,7,8,8a-Octahydro-5-
iodo-2-[(1,1-dimethylethyl)dimethylsilyloxy]-1,1,4a,6-
tetramethylnaphthalene (39). A stirring solution of the
ketone 21 (474 mg, 1.4 mmol), hydrazine (2.2 mL,
70 mmol), acetic acid (0.4 mL, 7 mmol), and ethanol (5 mL)
was refluxed overnight. The mixture was cooled to 23 ꢂC,
diluted with ether and water, and extracted three times
with ether. The combined organic extracts were washed with
brine and dried (MgSO4). The solvents were removed
in vacuo and the crude residue purified by flash chromato-
graphy on silica gel (70% hexanes/ethyl acetate) to afford
1
the hydrazone as an oily, white solid (377 mg, 75%). H
NMR (400 MHz, CDCl3) d 4.90 (br s, 2H), 3.16 (dd,
J¼10.0, 5.5 Hz, 1H), 3.00 (m, 1H), 1.85 (ddd, J¼13.5, 3.3,
3.3 Hz, 1H), 1.37–1.69 (m, 8H), 1.16 (d, J¼5.5 Hz, 3H),
1.12 (s, 3H), 0.91 (s, 3H), 0.89 (s, 9H), 0.80 (s, 3H), 0.04
(s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 164.5, 79.2, 52.4, 42.1, 39.8, 34.8, 32.6, 28.5, 27.7, 25.9,
21.7, 18.4, 18.1, 17.6, 16.1, 14.1, ꢁ3.8, ꢁ4.9. To a stirring
solution of the hydrazone (79.4 mg, 0.22 mmol) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU, 0.66 mL, 4.4 mmol)
in ether (3 mL) at 23 ꢂC was added iodine (122 mg,

9332
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
0.48 mmol). The solution was allowed to stir for 30 min
before being quenched with a saturated solution of NaHCO3
and extracted three times with ether. The combined organic
extracts were washed with brine and dried (MgSO4). Sol-
vents were removed in vacuo and the crude residue dissolved
in toluene (3 mL) and DBU (0.16 mL, 1.1 mmol). The solu-
tion was then heated at 85–90 ꢂC for 5 h before the solvent
was removed in vacuo. The residue was dissolved in ether
and washed once with a saturated solution of Na2S2O3,
once with brine, and dried (MgSO4). The solvents were
removed in vacuo and the crude residue purified by flash
chromatography on silica gel (90% hexanes/ethyl acetate)
to afford the iodide 39 as an oily, white solid (76.3 mg,
76%). IR (neat): 2950, 2855, 2708, 2646, 1709, 1631,
d 141.4, 126.2, 81.7, 80.3, 79.2, 49.8, 39.3, 36.5, 36.1,
33.1, 28.3, 28.1, 25.8, 21.9, 20.4, 18.3, 18.0, 15.7, ꢁ3.9,
ꢁ5.1; HRMS (EI) m/e (M+) calcd for C22H38OSi
346.2692, found 346.2702.
4.1.19. Bis-( )-[(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-octahydro-
6-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methylnaphthalen-1-yl]ethyne (42). To a stirring solution
of the enyne 41 (61.5 mg, 0.14 mmol), copper(I) iodide
(8 mg, 0.04 mmol), bis(triphenylphosphine)palladium(II)
chloride (14 mg, 0.02 mmol), and triethylamine (4 mL) at
23 ꢂC was added a solution of the vinyl iodide 39 (46 mg,
0.20 mmol) in triethylamine (1 mL). The resulting solution
was allowed to stir overnight. The reaction mixture was fil-
tered through a plug of silica gel with ethyl acetate and the
solvents removed in vacuo. The crude residue was purified
by flash chromatography on silica gel (100% hexanes) to
afford the dienyne 42 as an oily, white solid (11 mg, 14%).
1H NMR (400 MHz, CDCl3) d 3.20 (m, 2H), 2.14 (m, 4H),
1.98 (ddd, J¼13.4, 3.1, 3.1 Hz, 2H), 1.86 (s, 3H), 1.85 (s,
3H), 1.19–1.75 (m, 12H), 1.06 (s, 6H), 0.92 (s, 6H), 0.89
(s, 18H), 0.76 (s, 6H), 0.04 (s, 6H), 0.03 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 143.8, 126.9, 79.9, 79.4, 77.6, 50.0,
39.4, 37.3, 36.4, 28.4, 28.2, 25.9, 22.4, 21.0, 18.1, 15.9,
ꢁ3.8, ꢁ4.9; HRMS (EI) m/e (M+) calcd for C42H74O2Si2
666.5227, found 666.5231.
1472, 1252, 1105, 836, 774 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 3.21 (m, 1H), 2.17–2.26 (m, 1H), 1.85 (s, 3H),
1.45–1.86 (m, 5H), 1.30 (dd, J¼12.4, 1.8 Hz, 1H), 1.14–
1.27 (m, 2H), 1.01 (s, 3H), 0.94 (s, 3H), 0.90 (s, 9H), 0.77
(s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 136.6, 120.7, 79.3, 51.3, 42.7, 42.1, 39.5, 35.1,
30.6, 28.6, 28.4, 26.0, 19.9, 18.9, 18.1, 15.9, ꢁ3.7, ꢁ4.9;
HRMS (EI) m/e (M+) calcd for C20H37OISi 448.1658, found
448.1641.
4.1.18. ( )-(4aS,6S,8aS)-1-Ethynyl-3,4,4a,5,6,7,8,8a-octa-
hydro-6-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-
tetramethylnaphthalene (41). To a stirring solution of the
vinyl iodide 39 (1.96 g, 4.36 mmol), bis(dibenzylidene-
acetone)palladium(II) (50 mg, 0.087 mmol), copper(I)
iodide (33 mg, 0.17 mmol), triphenylphosphine (114 mg,
0.44 mmol), and triethylamine (87 mL) was added (tri-
methylsilyl)acetylene (0.62 mL, 4.36 mmol). After the mix-
ture was heated to 70 ꢂC overnight, it was filtered through
Celite with ether and the solvents removed in vacuo to afford
the TMS enyne 40 as a crude, black oil. The crude TMS
enyne 40 was dissolved in THF (44 mL) and tetrabutyl-
ammonium fluoride (5.2 mL, 5.2 mmol, 1 M in THF) was
added with stirring at 23 ꢂC. The reaction mixture was
stirred overnight and the mixture was poured into a saturated
solution of NaHCO3 and extracted three times with ether.
The combined organic extracts were washed once with brine
and dried (MgSO4). The solvents were removed in vacuo and
the crude residue purified by flash chromatography on silica
gel (99% hexanes/ethyl acetate) to afford a crude, brown oil.
The crude oil was dissolved in dichloromethane (15 mL) and
triethylamine (1.8 mL, 13 mmol) and cooled to 0 ꢂC before
tert-butyldimethylsilyl trifluoromethanesulfonate (0.99 mL,
4.33 mmol) was added. The reaction was allowed to warm to
23 ꢂC and stirred for 3 h, diluted with ether and a saturated
solution of sodium bicarbonate, and extracted three times
with ether. The combined organic extracts were washed
once with brine and dried (MgSO4). The solvents were re-
moved in vacuo and the crude residue purified by flash chro-
matography on silica gel (99% hexanes/ethyl acetate) to
afford the enyne 41 as an oily, white solid (1.12 g, 75%, three
steps). IR (neat) 3311, 2950, 2856, 2087, 1472, 1361, 1255,
4.1.20. ( )-E-(4aS,6S,8aS)-1-[2-(1,3-Benzodioxaborolyl)-
ethenyl]-3,4,4a,5,6,7,8,8a-octahydro-6-[(1,1-dimethyl-
ethyl)dimethylsilyloxy]-2,5,5,8a-tetramethylnaphthalene
(44). To a stirring solution of the enyne 41 (268 mg,
0.77 mmol), Schwartz’s reagent (119 mg, 0.46 mmol), and
dichloromethane (8 mL) at 23 ꢂC in the dark was added cat-
echolborane (0.13 mL, 1.2 mmol) dropwise. The solution
was allowed to stir overnight in the dark. The reaction mix-
ture was diluted with ether and a saturated solution of so-
dium bicarbonate and extracted three times with ether. The
combined organic extracts were washed once with brine
and dried (MgSO4). The solvents were removed in vacuo
and the crude residue purified by flash chromatography on
silica gel (70% hexanes/ethyl acetate) to furnish the boro-
1
nate 44 as a clear, colorless oil (345 mg, 96%). H NMR
(400 MHz, CDCl3) d 7.32 (d, J¼18.6 Hz, 1H), 7.22 (dd,
J¼5.9, 3.3 Hz, 2H), 7.07 (dd, J¼5.9, 3.3 Hz, 2H), 5.71 (d,
J¼18.6 Hz, 1H), 3.22 (dd, J¼11.2, 4.8 Hz, 1H), 2.14 (m,
2H), 1.77 (ddd, J¼13.1, 3.4, 3.4 Hz, 1H), 1.72 (s, 3H),
1.20–1.65 (m, 5H), 1.15 (dd, J¼12.5, 1.9 Hz, 1H), 1.10 (s,
3H), 0.94 (s, 3H), 0.89 (s, 9H), 0.80 (s, 3H), 0.04 (s, 3H),
0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) d 152.5, 148.3,
122.5, 121.2, 115.5, 112.2, 79.3, 50.4, 39.6, 37.6, 36.4,
34.0, 28.4, 28.1, 25.9, 21.2, 20.4, 18.7, 18.1, 15.9, ꢁ3.8,
ꢁ4.9 (one downfield carbon not observed).
4.1.21. ( )-E-Bis-1,2-[(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-octa-
hydro-6-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-
tetramethylnaphthalen-1-yl]ethylene (45). A solution of
the vinyl boronate 44 (247 mg, 0.53 mmol), the vinyl iodide
39 (260 mg, 0.58 mmol), dichloro[1,10-bis(diphenylphos-
phino)ferrocene]palladium(II) (22 mg, 0.027 mmol), 2 M
NaOH (0.27 mL, 0.53 mmol), and THF (6 mL) was stirred
together at 23 ꢂC for 1 h before being heated to 60 ꢂC over-
night. The solution was diluted with a saturated solution of
NaHCO3 and extracted three times with ether. The combined
1105, 1070, 883, 836, 773 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d 3.26 (dd, J¼10.8, 5.3 Hz, 1H), 3.07 (s, 1H),
2.09–2.22 (m, 2H), 2.05 (ddd, J¼13.4, 3.5, 3.5 Hz, 1H),
1.89 (s, 3H), 1.59–1.79 (m, 4H), 1.51 (dddd, J¼12.5, 11.4,
11.4, 6.7 Hz, 1H), 1.32 (ddd, J¼13.4, 13.4, 4.6 Hz, 1H),
1.11 (s, 3H), 0.97 (s, 3H), 0.94 (s, 9H), 0.82 (s, 3H), 0.10
(s, 3H), 0.08 (s, 3H); 13C NMR (125 MHz, CDCl3)

M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
9333
organic extracts were washed once with brine and dried
(MgSO4). The solvents were removed in vacuo and the crude
residue purified by flash chromatography on silica gel (99%
hexanes/ethyl acetate) to afford the E-triene 45 as an oily,
white solid (282 mg, 80%, two steps, tiny amount of Z-43
4-nitrobenzoyl chloride (56 mg, 0.3 mmol) and stirring was
continued for 24 h. The reaction mixture was diluted with
ether, quenched with a saturated solution of sodium
bicarbonate, and extracted three times with ether. The com-
bined organic extracts were washed once with brine and
dried (MgSO4). The solvents were removed in vacuo and
the crude residue purified by flash chromatography on silica
gel (90% hexanes/ethyl acetate) to furnish the ester 51 as
colorless plates (71.4 mg, 93%). Crystals were obtained by
slow evaporation of a solution in 9:1 acetonitrile/hexanes,
which led to the determination of the X-ray crystal structure
shown in Figure 3. IR (neat) 3405 (br s), 2961, 2912, 1711,
1
present). H NMR (400 MHz, CDCl3) d 5.66 (s, 1H) (E),
5.05 (s, 1H) (Z), 3.21 (m, 2H), 1.84 (s, 6H), 1.27–2.25 (m,
18H), 1.01 (s, 6H), 0.94 (s, 3H), 0.93 (s, 3H), 0.89 (s,
18H), 0.77 (s, 6H), 0.04 (s, 6H), 0.02 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 136.6 (2 C’s), 135.2 (2 C’s), 126.6
(E), 120.7 (Z), 79.4, 79.3, 51.3 (2 C’s), 42.7 (2 C’s), 39.5,
35.1 (2 C’s), 31.6 (2 C’s), 30.6 (2 C’s), 28.4 (2 C’s), 25.9
(2 C’s), 22.7 (2 C’s), 21.8, 19.8 (2 C’s), 18.1 (2 C’s), 15.9
(2 C’s), 14.1 (2 C’s), ꢁ3.8 (2 C’s), ꢁ4.9 (2 C’s).
1
1609, 1531, 1351, 1291, 1124 cmꢁ1; H NMR (400 MHz,
CDCl3) d 8.28 (d, J¼10.8 Hz, 2H), 8.21 (d, J¼10.8 Hz,
2H), 5.08 (s, 1H), 4.81 (dd, J¼11.5, 5.0 Hz, 1H), 1.60 (s,
3H), 1.40–2.02 (m, 9H), 1.03 (s, 3H), 1.00 (s, 3H), 0.96 (s,
3H); 13C NMR (100 MHz, CDCl3) d 164.3, 150.5, 136.3,
134.4, 130.6, 130.5, 123.5, 83.2, 50.2, 38.0, 37.4, 34.8,
31.7, 28.1, 24.3, 23.2, 23.1, 18.7, 16.7.
4.1.22. ( )-Z-Bis-1,2-[(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-octa-
hydro-6-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-
tetramethylnaphthalen-1-yl]ethylene (43).
A stirring
solution of the E-triene 45 (282 mg, 0.42 mmol), benz-
anthrone (145 mg, 0.63 mmol), and THF (42 mL) was
photolyzed with a medium pressure Hanovia mercury arc
lamp in a Pyrex immersion well at ꢃ290 nm for 24 h. The
solvent was removed in vacuo and the crude residue purified
by flash chromatography on silica gel (99% hexanes/ethyl
acetate) to furnish the Z-triene 43 as an oily, white solid
(236 mg, 84%). IR (neat) 2936, 2855, 1472, 1462, 1389,
4.1.24. 1-Iodo-2,6,6-trimethylcyclohexene (54). A stirring
solution of commercially available 2,2,6-trimethylcyclo-
hexanone 52 (60 mg, 0.43 mmol), hydrazine (0.28 mL,
9.03 mmol), triethylamine (0.94 mL, 6.7 mmol), and ethyl
alcohol (0.72 mL) was refluxed for 3 h. The solution was
then diluted with water and extracted three times with ether.
The combined organic extracts were washed once with brine
and dried (MgSO4). The solvents were removed in vacuo to
furnish the hydrazone 53 as a white solid (66 mg, 100%).
To a stirring solution of the hydrazone 53 (102.4 mg,
0.66 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU,
2 mL, 13.2 mmol) in ether (6 mL) at 23 ꢂC was added iodine
(381 mg, 1.5 mmol). The viscous orange-brown mixture
was stirred for 30 min. The reaction was quenched with a
saturated solution of sodium bicarbonate and extracted three
times with ether. The combined organic extracts were
washed twice with brine and dried (K2CO3). The solvents
were removed in vacuo to afford a thick brown oil. The
oil was then dissolved in benzene (8.3 mL) and DBU
(0.49 mL, 3.3 mmol) was added before heating to reflux
for 3 h. The solvents were removed in vacuo and the crude
residue dissolved in ether and washed once with a saturated
solution of sodium sulfite, twice with brine, and dried
(K2CO3). The solvents were removed in vacuo and the crude
residue purified by flash chromatography on silica gel (80%
hexanes/ethyl acetate) to afford the known vinyl iodide 54 as
an oily, white solid (126.7 mg, 76%).29 1H NMR (400 MHz,
CDCl3) d 2.12 (t, J¼6.0 Hz, 2H), 1.87 (s, 3H), 1.61–1.70 (m,
4H), 1.09 (s, 6H); 13C NMR (100 MHz, CDCl3) d 137.8,
117.4, 39.6, 37.9, 33.7, 31.6, 31.1, 19.4.
1253, 1105, 1071, 883, 885, 773 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 5.05 (s, 2H), 3.21 (m, 2H), 1.94–2.23
(m, 3H), 1.84 (s, 6H), 1.21–1.72 (m, 15H), 1.06 (s, 6H),
0.94 (s, 6H), 0.89 (s, 18H), 0.78 (s, 6H), 0.05 (s, 6H), 0.02
(s, 6H); 13C NMR (100 MHz, CDCl3) d (all 2 C’s) 136.6,
135.2, 120.7, 79.3, 51.3, 42.7, 42.1, 39.5, 35.1, 30.6, 28.6,
25.9, 21.6, 19.8, 18.9, 18.1, 15.9, ꢁ3.8, ꢁ4.9; HRMS (EI)
m/e (M+) calcd for C42H76O2Si2 668.5384, found 668.5379.
4.1.23. ( )-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-
2,5,5,8a-tetramethyl-6-(4-nitrobenzoyloxy)-naphthalene
(51). A solution of the Z-triene 43 (42.8 mg, 0.064 mmol) in
THF (6.4 mL) was degassed with Ar for 20 min and photo-
lyzed in a quartz tube with a medium pressure Hanovia mer-
cury arc lamp in a quartz immersion well at ꢃ200 nm for
24 h. The solvent was removed in vacuo and the crude resi-
due purified by flash chromatography on silica gel (99%
hexanes/ethyl acetate) to afford the silyl ether as an oily,
white solid (20.1 mg, 47%). IR (neat) 2930, 2855, 1472,
1
1389, 1252, 1103, 1070, 882, 836, 773 cmꢁ1; H NMR
(400 MHz, CDCl3) d 5.05 (m, 1H), 3.21 (dd, J¼11.3,
4.8 Hz, 1H), 1.95 (m, 2H), 1.58 (s, 3H), 1.37–1.71 (m,
5H), 1.18–1.26 (m, 2H), 0.91 (s, 6H), 0.89 (s, 9H), 0.76 (s,
3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 135.2, 130.1, 79.8, 50.1, 39.1, 37.9, 34.8, 31.9,
28.4 (2 C’s), 25.9, 23.1, 21.6, 19.0, 18.1, 15.8, ꢁ3.7, ꢁ4.9.
To a stirring solution of the silyl ether (85 mg, 0.13 mmol)
in 1:1 acetone/water (1.5 mL) at 23 ꢂC was added p-toluene-
sulfonic acid (72 mg, 0.38 mmol). The solution was stirred
overnight, quenched with a saturated solution of sodium
bicarbonate, and extracted three times with ether. The
combined organic extracts were washed with brine and
dried (MgSO4). The solvents were removed in vacuo to
afford a colorless residue. The residue (45.9 mg, 0.1 mmol)
was dissolved in dichloromethane (1 mL) with 4-(N,N-
dimethylamino)pyridine (6 mg, 0.05 mmol) and pyridine
(40 mL, 0.5 mmol) at 23 ꢂC. To the mixture was added
4.1.25. ( )-E-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-
6-[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methyl-1-[2-(2,6,6-trimethylcyclohexen-1-yl)ethenyl]-
naphthalene (55). A stirring solution of the vinyl boronate
44 (829 mg, 1.78 mmol), the vinyl iodide 54 (423 mg,
1.69 mmol),
dichloro[1,10-bis(diphenylphosphino)ferro-
cene]palladium(II) (73 mg, 0.09 mmol), and 2 M NaOH
(1.1 mL, 2.1 mmol) in THF (18 mL) was heated to 60 ꢂC
overnight. The reaction was quenched with a saturated solu-
tion of sodium bicarbonate and extracted three times with
ether. The combined organic extracts were washed once
with brine and dried (MgSO4). The solvents were removed

9334
M. E. Jung, B. A. Duclos / Tetrahedron 62 (2006) 9321–9334
5. Lee, K.-H.; Morris-Natschke, S. L. Pure Appl. Chem. 1999, 71,
1045–1051.
in vacuo and the crude residue purified by flash chromato-
graphy on silica gel (99% hexanes/ethyl acetate) to yield
the E-triene 55 as an oily, white solid (601.6 mg, 72%).
IR (neat) 2933, 2856, 1667, 1472, 1361, 1253, 1106,
6. Kashiwada, Y.; Hashimoto, F.; Cosentino, L. M.; Chen, C.-H.;
Garrett, P. E.; Lee, K.-H. J. Med. Chem. 1996, 39, 1016–1017.
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Cosentino, L. M.; Chen, C.-H.; Yang, L.-M.; Lee, K.-H.
J. Med. Chem. 1998, 41, 4648–4657.
8. Kanamoto, T.; Kashiwada, Y.; Kanbara, K.; Gotoh, K.;
Yoshimori, M.; Goto, T.; Sano, K.; Nakashima, H. Antimicrob.
Agents Chemother. 2001, 45, 1225–1230.
9. Hashimoto, F.; Kashiwada, Y.; Cosentino, L. M.; Chen, C.-H.;
Garrett, P. E.; Lee, K.-H. Bioorg. Med. Chem. 1997, 5, 2133–
2143.
10. Li, F.; Wild, C. Curr. Opin. Investig. Drugs (Thomson Sci.)
2005, 6, 148–154.
1
1070 cmꢁ1; H NMR (400 MHz, CDCl3) d 5.76 (d, J¼
17.1 Hz, 1H), 5.70 (d, J¼17.1 Hz, 1H), 3.21 (dd, J¼11.0,
4.8 Hz, 1H), 2.14 (m, 3H), 1.99 (m, 2H), 1.74 (s, 3H), 1.73
(s, 3H), 1.47–1.71 (m, 7H), 1.28 (m, 3H), 1.09 (s, 3H),
1.02 (s, 6H), 0.93 (s, 3H), 0.89 (s, 9H), 0.78 (s, 3H), 0.04
(s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 141.7, 138.4, 132.3, 130.9, 127.8, 126.5, 79.4, 50.6,
39.6, 39.5, 38.0, 37.9, 34.1, 34.0, 33.0, 32.8, 31.6, 28.9,
28.5, 25.9, 22.0, 21.5, 20.2, 19.4, 18.5, 18.1, 15.9, ꢁ4.3,
ꢁ4.9; HRMS (EI) m/e (M+) calcd for C31H54OSi
470.3944, found 470.3937.
11. (a) Pisha, E.; Chai, H.; Lee, I. S.; Chagwedera, T. E.;
Farnsworth, N. R.; Cordell, G. A.; Beecher, C. W.; Fong,
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M. E.; Das Gupta, T. K.; Pezzuto, J. M. Nat. Med. 1995, 1,
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L.; Marchesi, E.; Gambacorti-Passerini, C.; Formelli, F.
Cancer Lett. 2002, 175, 17–25; (c) Jeong, H.-J.; Chai, H.-B.;
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12. Cossy, J.; Ibhi, S.; Kahn, P. H.; Tacchini, L. Tetrahedron Lett.
1995, 36, 7877–7880.
13. (a) Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215–
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14. Hagiwara, H.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1990,
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5458.
4.1.26. ( )-Z-(4aS,6S,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-6-
[(1,1-dimethylethyl)dimethylsilyloxy]-2,5,5,8a-tetra-
methyl-1-[2-(2,6,6-trimethylcyclohexen-1-yl)ethenyl]-
naphthalene (56). A stirring solution of the E-triene 55
(305.2 mg, 0.65 mmol), benzanthrone (255 mg, 0.98 mmol),
and THF (65 mL) was photolyzed with a mercury lamp at
290 nm for 24 h. The solvent was removed in vacuo and the
crude residue purified by flash chromatography on silica gel
(99% hexanes/ethyl acetate) to furnish the Z-triene 56 as an
oily, white solid (250.5 mg, 82%). 1H NMR (400 MHz,
CDCl3) d 5.90 (d, J¼11.0 Hz, 1H), 5.84 (d, J¼11.0 Hz,
1H), 3.15 (dd, J¼9.1, 3.6 Hz, 1H), 1.95–2.12 (m, 4H),
1.44–1.72 (m, 11H), 1.41 (s, 3H), 1.35 (s, 3H), 1.09 (s, 3H),
1.02 (s, 6H), 0.93 (s, 3H), 0.89 (s, 9H), 0.78 (s, 3H), 0.04 (s,
3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3) d 139.8,
137.5, 132.1, 131.2, 130.1, 127.8, 79.3, 50.6, 40.0, 39.5,
37.5, 36.0, 35.7, 33.4, 33.3, 31.5, 29.3, 28.5, 28.0, 25.8,
23.0, 22.2, 20.9, 19.2, 18.7, 18.0, 15.8, ꢁ3.9, ꢁ5.0.
17. Barton, D. H. R.; Bashiardes, G.; Fourrey, J. Tetrahedron Lett.
1983, 24, 1605–1608.
Acknowledgements
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We thank Professor Miguel Garcia-Garibay of the Univer-
sity of California, Los Angeles for the use of his photochem-
ical equipment and expertise. Support of this work from the
National Science Foundation (CHE 0314591) is gratefully
acknowledged.
21. Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J. J. Am. Chem.
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´
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Supplementary data
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Proton and carbon NMR data for all new compounds. Sup-
plementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.07.023.
References and notes
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