Application of[5+2] cycloaddition toward the functionalized bicyclo[4.3.1]decane ring system: Synthetic study of phomoidride B (CP-263,114)

Article abstract of DOI:10.1039/b110607b

Oxidopyrylium-alkene [5+2] cycloaddition was utilized in combination with an intramolecular aldol reaction to construct the bicyclo[4.3.1]decane ring system of phomoidride B (CP-263,114).

Full text of DOI:10.1039/b110607b

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Application of [5؉2] cycloaddition toward the functionalized
bicyclo[4.3.1]decane ring system: synthetic study of phomoidride B
CP-263,114)†
(
1
Naoki Ohmori*‡
Department of Chemistry, Graduate School of Science, Hiroshima University,
1
-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan. E-mail: d1174001@hiroshima-u.ac.jp
Received (in Cambridge, UK) 19th November 2001, Accepted 25th January 2002
First published as an Advance Article on the web 19th February 2002
Oxidopyrylium–alkene [5ϩ2] cycloaddition was utilized in combination with an intramolecular aldol reaction to
construct the bicyclo[4.3.1]decane ring system of phomoidride B (CP-263,114).
Introduction
being derived from suitably functionalized oxabicyclic com-
pound 3. Compound 3 in turn could be viewed as the product
from the reaction between oxidopyrylium ylide and a fumarate
ester or its variant, thus providing an easy access to the maleic
anhydride moiety of 1.
On the basis of this retrosynthetic plan, we began the syn-
thesis with but-2-ene-1,4-diol. After tert-butyldimethylsilyl
Phomoidride B (CP-263,114 1) has attracted considerable inter-
est since the original report of its isolation by a Pfizer group.
Phomoidride B possesses potent inhibitory activity against
both farnesyl transferase and squalene synthase with IC -
values in the micromolar range. The structural features of this
compound lie in the anti-Bredt bridgehead double bond, a
maleic anhydride moiety, a quaternary carbon center adjacent
to the anti-Bredt bridgehead and most importantly this com-
pound bears two hydrophobic moieties attached to the highly
functionalized hydrophilic core. This ambiphilic structural
nature is believed to be the key to its biological activities.
Prompted by the promising biological activities as well as
the fascinating structural features, numerous chemists have
1
2
3
50
(
TBS) protection of the diol, the alkenic moiety was cleaved by
means of ozonolysis to give 2 equiv. of aldehyde 6. 2-Furyl-
lithium prepared from furan and n-BuLi was added to this
aldehyde to deliver furan adduct 7. Treatment of 7 with m-CPBA
followed by acetylation of the resultant lactol provided oxido-
pyrylium ylide precursor 8 (39% from but-2-enediol, dia-
stereomeric ratio dr ≈ 2 : 1). We were pleased to find that treating
8
with dimethyl fumarate in the presence of triethylamine at
4
embarked on the total synthesis of phomoidride B and so far
four groups have completed the total synthesis of compound 1.
the reflux temperature of acetonitrile delivered oxabicyclic
compounds 9a and 9b in 65–77 % yield in a high diastereo-
meric ratio (dr ≈ 13 : 1, Scheme 2). Surprisingly, with other
activated alkenes such as dimethyl maleate and maleic
anhydride, we observed no desired reaction and only recovery
or decomposition of the oxidopyrylium precursor, or, in the
case of dimethyl maleate, isomerization of the maleate to the
more stable fumarate ester. While the reason for this reactivity
is unclear, this demonstrates the very subtle reactivity associ-
ated with intermolecular oxidopyrylium cycloaddition com-
pared with the intramolecular one. The major product in this
reaction can be rationalized to arise from the transition state
in which the steric repulsion created by the sterically demand-
5
[
5ϩ2] Cycloaddition reaction between oxidopyrylium ylide
and an alkene offers a suitably functionalized seven-membered
ring in a relatively easy (heating of the reaction mixture or base-
6
assisted) way and has been applied to the synthesis of some
7,8
seven-membered ring containing natural products. Among
them, Wender successfully applied this approach to the syn-
8
a
8b
thesis of phorbol and resiniferatoxin in which the [5ϩ2]
reaction was employed in an intramolecular fashion. Although
there had been relatively few precedents of the utilization of
intermolecular oxidopyrylium [5ϩ2] cycloaddition to the
synthesis of natural products, we anticipated that the bicyclo-
[4.3.1]decane ring system, the core cyclic system of phomo-
ing TBSOCH - and one of the methoxycarbonyl groups on
2
idride B, could be constructed based on the [5ϩ2] cycloaddition
strategy followed by some further manipulations.
In this article we report our utilization of the [5ϩ2]
cycloaddition approach towards the highly substituted bicyclo-
10
dimethyl fumarate is avoided as shown in Fig. 1.
With the oxabicycles in hand we then decided on the con-
struction of the bicyclo[4.3.1]decane ring system lacking the
quaternary carbon center adjacent to a bridgehead as a model
study. To this end, the alkenic moiety of compound 9a was first
reduced by hydrogenation in the presence of Pd on carbon to
give compound 11. Removal of TBS was done with aqueous
HCl followed by iodination of the alcohol 12 to give iodide 13
in 64% yield (3 steps). Among several conditions we employed,
the use of Zn proved to be the most effective in the subsequent
reductive opening of the bridging ether of bicycle 13, yielding
exocyclic enone 14 in 96% yield.
Our initial focus was tuned to the introduction of the
additional carbon chain for the construction of the desired
bicyclo[4.3.1]decane ring system by the inverse-electron-demand
Diels–Alder (IEDDA) reaction. This was under the assump-
tion that product 16 from the IEDDA reaction with certain silyl
enol ethers would give rise to the bicyclo[4.3.1]decane ring
[4.3.1]decane ring system of 1.
Results and discussion
Arising from our interest in the evaluation of the hydrophobic
side chains of ambiphilic natural products, we decided on an
approach that would allow us to introduce the hydrophobic side
chains (and possibly some variants) at a late stage of the syn-
thesis. Thus, as illustrated in Scheme 1, our disconnection left us
with bicycle 2 as our primal target, which could be envisaged as
9
†
1
‡
Preliminary communication: N. Ohmori, Chem. Commun., 2001,
552.
For inquiries contact Prof. K. Ohkata. E-mail: ohkata@sci.hiroshima-
11
u.ac.jp
DOI: 10.1039/b110607b
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
This journal is © The Royal Society of Chemistry 2002
755

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Scheme 1 Strategy for the total synthesis of phomoidride B 1.
Scheme 2 Reagents and conditions (and yields): (a) TBSCl, Et N, DMAP, THF, rt; (b) O , MeOH, Ϫ78 ЊC; then NaHCO , Me S, Ϫ78 ЊC to rt;
3
3
3
2
(
c) 2-furyllithium, Et O, Ϫ78 ЊC to rt; (d) m-CPBA, CH Cl , 0 ЊC to rt; (e) Ac O, pyridine, rt (39% in 5 steps); (f ) dimethyl fumarate, Et N, CH CN,
2
2
2
2
3
3
reflux (77% 9a : 9b, 13 : 1).
Having failed with the above strategy, we then attempted to
install the two-carbon unit required for the construction of the
bicyclic system by allylation followed by oxidative cleavage of
the terminal alkene. To this end, the secondary hydroxy group
of 14 was protected with TBSOTf in the presence of 2,6-
dimethylpyridine (2,6-lutidine) to give ketal 20 (61%) along
with exocyclic enone 21 (21%) as a minor component. Ketal 20
was treated with allyltrimethylsilane in the presence of TiCl to
4
give allylated product 22 with concomitant loss of the TBS
group (82%). Compound 22 was obtained exclusively with no
presence of the isomer based on the C2 stereocenter. The direct
proton transfer from the hydroxy group in the intermediate silyl
enol ether 25 formed upon work-up seems to be operative, thus
leading to the observed selectivity since almost 1 : 1 selectivity
was obtained with exocyclic enone 21 in the same transform-
13
ation (Scheme 4). The liberated free hydroxy group in com-
pound 22 was once again protected with TBSOTf in the
presence of 2,6-lutidine to give compound 24 (42%) along with
the undesired ketal 23 (58%). Compound 23 could be recycled
by TBS deprotection (87%) followed by reprotection to
14
reproduce mixtures of 23 and 24. After three deprotection–
protection sequences, compound 24 was obtained in a total
yield of ≈ 60%, sufficient for further transformations.
By means of ozonolysis of 24, the terminal alkene was
cleaved to give a keto aldehyde (structure not shown; Scheme 5).
Intramolecular aldol reaction under basic conditions gave a
Fig. 1 Origin of stereoselectivity.
15
crude aldol adduct, which was used directly without puri-
fication. Pyridinium chlorochromate (PCC) oxidation of this
crude aldol adduct provided diones 26a (66%) and 26b (16%)
bearing the desired bicyclo[4.3.1]decane ring system. To install
the two hydrophobic side chains of phomoidride B, the major
product 26a needed to be converted to the corresponding
enone. For this purpose, the Saegusa reaction was employed,
system upon treatment with fluoride via a thermodynamically
12
driven ring-reconstruction. However, enone 15, protected with
an acetyl group, turned out to be totally unreactive towards the
IEDDA reaction with silyl enol ether even under sealed-tube
(
120 ЊC) conditions, resulting in only recovery of starting
material (Scheme 3).
7
56
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

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Scheme 3 IEDDA route to the bicyclo[4.3.1]decane core: Reagents and conditions (and yields): (a) H , Pd/C, MeOH, rt; (b) aq. HCl, rt; (c) I , PPh ,
2
2
3
imidazole, benzene, reflux, (64% in 3 steps); (d) Zn, MeOH, reflux (96%); (e) Ac O, pyridine, 0 ЊC to rt (86%).
2
16
yielding enone 27 in rather low yield (35%). An improved yield
was achieved by employing the recently developed Nicolaou
method using 2-iodosylbenzoic acid (IBX), providing enone
17
(
30%) along with starting material (42% recovery). The
recovered starting material was re-treated with IBX and this
process was repeated twice to give a sufficient amount of enone
2
7 (42%, 52% based on consumed starting material) for further
studies. 1,4-Addition of an allyl group under Lewis acidic con-
ditions gave compound 28, a product from convex-face attack
of the enone as the sole stereoisomer in 57% yield. The dia-
stereomeric identity of 28 was established upon carrying out
NOE measurements on the product of the ensuing reaction
(
29). Attempts to introduce substituents α to the carbonyl
group in a one-pot procedure met with failure and thus we
decided to look into a stepwise method. To incorporate an add-
itional allyl group at the α position of the ketone, compound 28
was treated with potassium hexamethyldisilazide (KHMDS)
followed by allyl bromide. To our surprise, this allylation proto-
col proved to be disappointing and the compound we obtained
was only the bridgehead-allylated material 29 (57%, 76% based
on consumed starting material). To obtain further knowledge
about this unique reactivity, a deuterium-exchange experiment
was performed on 28 and mono-deuterated material was
obtained upon treatment with 1.3 eq. of KHMDS at Ϫ78 ЊC
followed by the addition of deuterium chloride in deuterium
oxide at the same temperature (Scheme 6). This experiment
resulted in incorporation of deuterium (99% deuterium
incorporation) at C-6 and C-8 in the ratio 21 : 79. This result, in
conjunction with results from the allylation experiment, sug-
gested that an equilibration of anions between C-6 and C-8
takes place and that the allyl group can access only from the
supposedly less hindered bridgehead position. Also, the reac-
tivity of this anion seems to be highly dependent on the nature
of electrophile, and in the case of allyl chloroformate as the
electrophile the reaction proceeded preferencially via the C8
anion to provide the carbonate 31 as a 4 : 1 (63%) mixture with
a minor product that we believe to be 30. Palladium-mediated
18
allyl migration using this mixture provided diallyl species 32
19
and 29 in a 2 : 1 ratio (81%). Thus, we established a protocol to
obtain the fully functionalized bicyclo[4.3.1]decane ring system
minus the quaternary center (C5) adjacent to a bridgehead.
Since the introduction of the two hydrophobic side chains was
planned after functionalization of C5, we envisaged that steric
factors would make the C6 site less accessible and drive the
Scheme 4 Reagents and conditions (and yields): (a) TBSOTf, 2,6-
lutidine, CH Cl , Ϫ78 ЊC (82% 20 : 21, 3 : 1); (b) allyltrimethylsilane,
2
2
TiCl , CH Cl , Ϫ78 ЊC (82%); (c) TBSOTf, 2,6-lutidine, CH Cl , rt (23,
4
2
2
2
2
5
8%; 24, 42%); (d) TBAF, THF, rt (87%).
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
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Scheme 5 Reagents and conditions (and yields): (a) O , MeOH; then NaHCO , Me S, Ϫ78 ЊC to rt, (78%); (b) DBU, CH Cl ; (c) PCC, CH Cl ,
3
3
2
2
2
2
2
4
Å MS, rt (82% in 2 steps) (26a : 26b, 4 : 1); (d) IBX, DMSO–toluene (1 : 2), 80 ЊC (52%); (e) allyltrimethylsilane, TiCl , CH Cl , Ϫ78 ЊC (57%);
4 2 2
(
f ) KHMDS, allyl bromide, THF, Ϫ78 ЊC (57%); (g) KHMDS, allyl chloroformate, THF, Ϫ78 ЊC (63% 30 : 31, 1 : 4); (h) Pd (dba) ؒCHCl , PPh ,
2 3 3 3
THF, rt (81% 32 : 29, 2 : 1).
Scheme 6 Deuterium-exchange experiment and equilibration of the anion.
selectivities towards the desired diastereomers in the actual
total synthesis and make these processes more favourable.
Having succeeded in obtaining the bicyclo[4.3.1]decane core
in the model system, we then focused on the installation of
the quaternary carbon center adjacent to a bridgehead. Our
strategy to install the quaternary carbon center lay in cyclo-
propane formation followed by regioselective cleavage of the
cyclopropane ring (Scheme 7). We envisaged that if we could
cleave the cyclopropane ring in a regioselective fashion it would
be a simple procedure for incorporating a quaternary carbon in
the desired position. According to this strategy, compound
9a was dibrominated followed by elimination of HBr to give
7
58
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

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22
oxylation. To this end, compound 9a was treated with the
anion of dimethyl malonate to give bicycle 42 in 83% yield. TBS
deprotection by means of aqueous HCl followed by iodination
of the alcohol 43 gave iodide 44 in 82% yield (2 steps).
Subsequent zinc-mediated cleavage gave cyclic hemiketal 45 in
5
9% yield. Without protecting the lactol, allylation was carried
out with allyltrimethylsilane in the presence of TiCl to give
4
allylated hemiketal 46 in 46% yield as the sole isomer, which
was used for the next step without elucidating the stereo-
chemistry at C2. To expose the ketone carbonyl group masked
as a hemiketal, compound 46 was treated with sodium meth-
oxide to liberate the secondary alkoxide, which immediately
reacted further to give lactone 47. Attempts to perform ozono-
lytic cleavage of the terminal alkene turned out to be prob-
lematic due to the decomposition of the aldehyde 48 during
attempted purification. Since the subsequent base-promoted
aldol reaction using a crude mixture of the aldehyde (contain-
ing aldehyde, PPh , O = PPh ) didn’t give any signals indicating
3
3
the presence of the desired material, utilization of this com-
pound was abandoned (Scheme 9). Following the failure to
utilize 48 to gain access to 40, a modified approach was next
pursued (Scheme 10). Since the cause of the instability of alde-
hyde 48 seemed to lie in the lability of the lactone group due to
a possible β-elimination leading to the opening of the lactone,
we next focused upon compound 53, which lacks the lactone
moiety. By introducing a dimethyl malonate group into enone
50, we thought we could overcome the complications associated
with the instability of 48. To this end compound 24 was sub-
jected to the Saegusa oxidation protocol. Treatment of 24 with
KHMDS followed by trapping of the resulting enolate with
TMSCl gave a silyl enol ether and this silyl enol ether was used
Scheme 7 Reagents and conditions (and yields): (a) Br , CH Cl ,
2
2
2
Ϫ40 ЊC, then Et N, Ϫ40 ЊC to rt (99%); (b) NaCN, Bu NI, CH Cl –
3
4
2
2
H O, rt, then Et N, rt (97%); (c) Me S᎐CHCO Me, THF, 0 ЊC to rt
2
3
2
2
(
61%); (d) SmI , THF, Ϫ78 ЊC (79%); (e) aq. HCl 0 ЊC to rt; (f ) I , PPh ,
2
2
3
imidazole, benzene, reflux (65% in 2 steps); (g) Zn, Ac O, 50 ЊC (25%).
2
bromo enone 33. This was next treated with NaCN and sub-
sequent elimination of HBr gave a β-cyanized compound 34 in
20
9
6% yield (2 steps). With nitrile 34 in hand, cyclopropanation
was examined and a sulfonium ylide turned out to be most
effective for this transformation of electron-deficient enone 34,
providing the desired cyclopropane compound 35 (61%) as a
single isomer. This cyclopropanation occurred by way of the
less hindered exo-face of the oxabicycle. With the cyclopropane
in hand, the next critical regioselective cyclopropane opening
was performed. Among the reaction conditions we employed
in the next reaction with Pd(OAc) without purification. From
2
this reaction we obtained the desired enone 50 (35%) as well as
oxidatively cyclized compound 51 (<30%). The mechanism of
the reaction yielding 51 can be considered to be as in Scheme
23
23b
11. According to the proposal by Kende in a similar system,
compound 51 seemed to have formed by initial coordination of
Pd to exocyclic olefin (59) followed by the attack of the enol
ether upon the Pd-coordinated olefin. Oxidative cleavage of this
terminal alkene provided an additional access to 26a (14%, 2
steps). The malonate addition of 50 proceeded uneventfully in
refluxing THF to give 52 (61%) as the sole product, which was
next subjected to ozonolysis to give aldehyde 53. As expected,
this aldehyde bore sufficient stability against silica gel column
chromatography and could be easily purified. With 53 in hand,
we performed a base-promoted intramolecular aldol reaction
and obtained two products. The major constituent turned
out to be a tricyclic compound 54 (29% yield, 2 steps). The
structure of this material was unambiguously established by
means of DEPT, H–H COSY, NOE, etc. The minor one turned
out to be the desired bicyclo[4.3.1]decane compound 55 (7%
yield, 2 steps). This was oxidized with PCC to give dione 56
(77%), a suitable candidate for further studies. Thus, we could
secure a pathway to the bicyclic core functionalized at the C5
center.
21
(
Zn, Na–naphthalene), samarium diiodide most efficiently
met our requirement and provided compound 36 (79%) bearing
the stereochemically defined quaternary carbon center in the
desired position as the sole reductive cleavage product. This
completely regioselective reduction was rather surprising since
electron-stabilizing groups are appended on all three carbon
centers in the cyclopropane ring. To reductively cleave the
bridging ether in the oxabicycle, the TBS group was removed by
means of aqueous HCl, and subsequent iodination of the
alcohol 37 gave iodide 38 in 65% yield (2 steps). Zn reduc-
tion in Ac O was next performed to give compound 39 in 25%
2
yield (Scheme 7). Although the yield here was somewhat low,
we were able to establish a diastereoselective route to a fully
functionalized seven-membered-ring analog of 20.
As an alternative strategy for the construction of the fully
functionalized bicyclic system, we envisaged that radical reac-
tion would be useful for the installation of a quaternary carbon
center such as with compound 40 (Scheme 8). Previous liter-
Conclusions and outlook
The chemistry presented in this article includes the efficient
utilization of oxidopyrylium [5ϩ2] cycloaddition combined
with an intramolecular aldol reaction to construct the bicyclo-
[4.3.1]decane ring system of phomoidride B. During the course
of this study some less precedented observations were made,
such as the unique reactivity of the anions of 28 and the
completely selective cleavage of a cyclopropane ring bearing
electron-withdrawing groups on all three carbon atoms. Efforts
to utilize diester 39 for further studies, to improve the yield
of compound 55, and to develop a strategy for suitably intro-
ducing the actual side chains of phomoidride B are now
ongoing.
Scheme 8 Plausible strategy to install the quaternary carbon center by
a 5-exo-trig pathway.
ature precedence has shown that various γ-lactones were rel-
atively easily prepared by acyl radical 5-exo-trig cyclization and
that this cyclization is normally favoured over plausible decarb-
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
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Scheme 9 Reagents and conditions (and yields): (a) NaH, dimethyl malonate, THF, 0 ЊC to rt (83%); (b) aq. HCl rt; (c) I , PPh , imidazole, benzene,
2
3
reflux (82% in 2 steps); (d) Zn, MeOH, reflux (59%); (e) allyltrimethylsilane, TiCl , CH Cl , Ϫ78 ЊC (46%); (f ) NaOMe, THF, rt (66%);
4
2
2
(
g) O , MeOH; then NaHCO , Me S, Ϫ78 ЊC to rt.
3
3
2
Scheme 10 Reagents and conditions (and yields): (a) KHMDS, TMSCl, THF, Ϫ78 ЊC; then Pd(OAc) , CH CN, rt (50 35%, 51 ≈ 30%); (b) NaH,
2
3
dimethyl malonate, THF, rt to reflux (61%); (c) O , MeOH, then NaHCO , Me S, Ϫ78 ЊC to rt; (d) K CO , MeOH, rt (54 29% in 2 steps; 55 7% in
3
3
2
2
3
2
steps); (e) PCC, CH Cl , 4 Å MS, rt (77%); (f ) O , MeOH, then NaHCO , Me S, Ϫ78 ЊC to rt (14% from 24).
2
2
3
3
2
Experimental
All reactions were carried out under N unless otherwise noted.
Yanagimoto melting-point apparatus and are uncorrected.
Elemental analyses were performed on a Perkin-Elmer 2400-
CHN elemental analyzer.
2
THF and Et O were distilled after refluxing over Na–benzo-
2
phenone prior to use. CH Cl , Et N, CH CN, DMSO, HMPA,
2
2
3
3
(
1R*,5S*,6R*,7R*)-1-tert-Butyldimethylsilyloxymethyl-6,7-
benzene and toluene were distilled over CaH before use. Silica
2
bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]oct-3-en-2-one (9a)
and (1R*,5S*,6S*,7S*)-1-tert-butyldimethylsilyloxymethyl-6,7-
bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]oct-3-en-2-one (9b)
gel 60F254 was used for preparative thin-layer chromato-
graphy (PLC). NMR spectra were recorded on JNM-LA500
1
13
and JNM-ECP500 instruments. H and C NMR spectra were
observed in CDCl3 solutions with tetramethylsilane (TMS)
as the internal reference. J-values are given in Hz. IR spectra
were recorded on a JASCO IRA-1H instrument. MS spectra
were recorded on a JEOL JMS-SX102A instrument. FAB
spectra were obtained with glycerol as a matrix and EI data
were obtained at 70 eV. Melting points were recorded on a
24
To a solution of compound 8 (16 mg, 0.053 mmol) in CH CN
(0.5 ml) was added dimethyl fumarate (35 mg, 0.24 mmol)
followed by Et N (0.010 ml, 0.072 mmol). The mixture was
refluxed for 2 d and then treated with CH Cl and H O. The
separated aqueous layer was extracted with CH Cl . The
combined organic solutions were dried (MgSO ), filtered and
3
3
2
2
2
2
2
4
7
60
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

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ϩ
ϩ
(
EI) m/z 387 (M ϩ H), 355 (M Ϫ OCH ), 329, 297, 269;
3
HRMS (EI) Calc. for C H O Si (M Ϫ tBu): m/z, 329.1057.
14
21
7
Found: m/z, 329.1070.
(
1R*,5S*,6R*,7R*)-1-Hydroxymethyl-6,7-bis(methoxy-
carbonyl)-8-oxabicyclo[3.2.1]octan-2-one (12)
To a solution of silyl ether 11 (2.1 g, 5.4 mmol) in THF (40 ml)
were added H O (20 ml), AcOH (20 ml) and 12 M HCl (4 ml).
2
The mixture was stirred for 1 h at room temperature, then
neutralized with saturated aq. NaHCO . The aqueous solution
3
was extracted with EtOAc and the combined organic solutions
were dried (MgSO ), filtered and concentrated. Chromato-
4
graphy of the residue on silica gel (elution with EtOAc–hexane,
2
: 1) gave the alcohol 12 (1.2 g, 4.5 mmol, 83%) as a colourless
Ϫ1
oil; R = 0.13 (silica gel; EtOAc–hexane, 1 : 2); νmax(neat)/cm
f
3
4
3
515, 2955 and 1710; δ (500 MHz, CDCl ) 4.83 (d, J 4.3, 1 H),
.05 (d, J 13, 1 H), 4.00–3.89 (m, 2 H), 3.78 (s, 3 H), 3.71 (s,
H), 3.63 (dd, J 6.4, 1.5, 1 H), 2.60–2.48 (m, 2 H), 2.44–2.36
H
3
(
m, 1 H), 2.15–2.09 (m, 1 H) and 2.01 (br s, 1 H); δ (125 MHz,
C
CDCl ) 204.7, 172.5, 170.1, 90.4, 78.0, 61.4, 52.9, 52.8, 50.9,
3
ϩ
5
0.8, 33.4 and 31.0; MS (EI) m/z 272 (M ), 240, 226, 212, 194;
HRMS (EI) Calc. for C H O (M): 272.0896. Found: M ,
ϩ
12
16
7
2
72.0896.
(
1R*,5R*,6S*,7S*)-1-Iodomethyl-6,7-bis(methoxycarbonyl)-8-
oxabicyclo[3.2.1]octan-2-one (13)
To a solution of alcohol 12 (1.4 g, 5.1 mmol) in benzene
(
130 ml) were added PPh (3.7 g, 14 mmol), imidazole (0.93 g,
3
1
4 mmol) and I (2.9 g, 11 mmol). The mixture was refluxed
2
for 3 h and then quenched with saturated aq. Na S O . The
2
2
3
separated aqueous solution was extracted with CH Cl and
2
2
Scheme 11 Plausible mechanism of Pd-catalyzed oxidative cyclization.
the combined organic solutions were dried (MgSO ), filtered
4
and concentrated. Chromatography of the residue on silica gel
concentrated. Chromatography of the residue on silica gel
(
elution with EtOAc–hexane, 1 : 6) gave iodide 13 (1.63 g,
(
elution with EtOAc–hexane–CH Cl , 1 : 12 : 1) gave diastereo-
2 2
4
.3 mmol, 84%) as a yellow oil; R = 0.40 (silica gel; EtOAc–
f
mers 9a and 9b in 13 : 1 ratio (15.8 mg, 0.041 mmol, 77%) as
white solids.
Ϫ1
hexane, 1 : 2); νmax(neat)/cm 2955, 1745, 1740 and 1435; δH
(
500 MHz, CDCl ) 4.85 (d, J 4.9, 1 H), 3.89 (d, J 6.4, 1 H), 3.80
3
For compounds 9a, R = 0.40 (silica gel; EtOAc–hexane, 1 : 2);
f
(
d, J 11, 1 H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.67 (dd, J 6.4, 1.5,
Ϫ1
mp 92–94 ЊC (CH Cl ); νmax(neat)/cm 2955, 2930, 2855, 1740
2
2
1
1
5
H), 3.65 (d, J 11, 1 H), 2.60–2.40 (m, 3 H) and 2.13–2.07 (m,
H); δ (125 MHz, CDCl ) 202.4, 172.0, 169.5, 88.7, 77.8, 54.5,
and 1695; δ (500 MHz, CDCl ) 7.34 (dd, J 9.7, 4.6, 1 H), 6.02
H
3
C
3
(
d, J 9.7, 1 H), 5.20 (d, J 4.6, 1 H), 4.25 (d, J 12, 1 H), 4.22 (d,
ϩ
3.0, 52.9, 51.2, 33.3, 30.9 and 6.0; MS (EI) m/z 382 (M ), 351
J 4.3, 1 H), 4.01 (d, J 12, 1 H), 3.76 (s, 3 H), 3.66 (s, 3 H), 3.61
ϩ
(M Ϫ OCH ), 255, 223, 195; HRMS (EI) Calc. for C H lO
3 12 15 6
ϩ
(M): 381.9913. Found: M , 381.9906.
(
(
d, J 4.3, 1 H), 0.90 (s, 9 H), 0.11 (s, 3 H) and 0.07 (s, 3 H); δC
125 MHz, CDCl ) 193.6, 171.0, 170.3, 150.7, 127.0, 91.7, 75.9,
3
6
0.3, 52.6, 52.4, 50.6, 46.6, 25.6(× 3), 18.1, Ϫ5.5 and Ϫ5.7; MS
(
3R*,4R*,5S*)-5-Hydroxy-3,4-bis(methoxycarbonyl)-2-methyl-
ϩ
(
EI) m/z 384 (M ); HRMS (EI) Calc. for C H O Si (M):
1
8
28
7
enecycloheptanone (14)
ϩ
3
84.1604. Found: M , 384.1588; Calc. for C H O Si: C, 56.23,
18 28 7
To a solution of iodide 13 (1.2 g, 3.1 mmol) in MeOH (100 ml)
was added activated Zn (by means of successive washing with
saturated aq. NH Cl, H O, EtOH and Et O, 900 mg, 14 mmol).
The mixture was refluxed for 30 min, quenched with solid
NH Cl at room temperature, filtered and concentrated. Chrom-
atography of the residue on silica gel (elution with EtOAc–
hexane, 1 : 1) gave enone 14 (770 mg, 3.0 mmol, 96%) as a
H, 7.34. Found: C, 56.13; H, 7.43%.
For 9b, R = 0.39 (silica gel; EtOAc–hexane, 1 : 2); δH
f
(
500 MHz, CDCl ) 7.21 (dd, J 9.7, 4.3, 1 H), 6.03 (d, J 9.7, 1 H),
4
2
2
3
5
4
1
.10 (dd, J 7.3, 4.3, 1 H), 4.16 (d, J 7.3, 1 H), 4.14 (d, J 12, 1 H),
.04 (d, J 12, 1 H), 3.75 (s, 3 H), 3.70 (s, 3 H), 3.21 (d, J 7.3,
H), 0.86 (s, 9 H), 0.04 (s, 3 H) and 0.03 (s, 3 H).
4
(
1R*,5S*,6R*,7R*)-1-tert-Butyldimethylsilyloxymethyl-6,7-
colourless oil; R = 0.11 (silica gel; EtOAc–hexane, 1 : 2);
νmax(neat)/cm 3470, 2955, 2850, 1735, 1695, 1610 and 1435;
f
Ϫ1
bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octan-2-one (11)
δ (500 MHz, CDCl ) 6.16 (s, 1 H), 5.38 (s, 1 H), 4.21–4.15 (m,
H
3
To a solution of enone 9a (2.5 g, 6.5 mmol) in MeOH (70 ml)
was added 5% Pd/C (0.3 g). The mixture was stirred under a
hydrogen atmosphere for 3 h at room temperature, then filtered
and concentrated. Chromatography of the residue on silica gel
2
1
H), 3.78–3.70 (m, 7 H), 3.32–3.28 (m, 1 H), 3.00 (dd, J 15, 10,
H), 2.39 (dd, J 15, 9.1, 1 H), 2.22–2.15 (m, 1 H) and 1.91–1.84
(
m, 1 H); δC (125 MHz, CDCl ) 200.8, 173.4, 172.2, 143.4,
3
1
25.9, 68.7, 53.2, 52.7, 52.5, 45.5, 35.6 and 29.4; MS (EI)
ϩ
(
elution with EtOAc–hexane, 1 : 4) gave compound 11 (2.3 g,
m/z 256 (M ), 324, 329, 197, 179, 165; HRMS (EI) Calc. for
C H O (M): 256.0947. Found: M , 256.0940.
6
.0 mmol, 92%) as a colourless oil; R = 0.33 (silica gel; EtOAc–
f
ϩ
Ϫ1
12 16
6
hexane, 1 : 4); νmax(neat)/cm 2955, 2930, 2855 and 1740; δH
(
(
(
500 MHz, CDCl ) 4.84 (d, J 4.9, 1 H), 4.11 (d, J 5.8, 1 H), 4.09
d, J 12, 1 H), 3.93 (d, J 12, 1 H), 3.75 (s, 1 H), 3.70 (s, 3 H), 3.60
dd, J 5.8, 1.8, 3 H), 2.50–2.40 (m, 2 H), 2.43–2.35 (m, 1 H),
3
(
3
1R*,3S*,4S*,5R*)-1-tert-Butyldimethylsilyloxy-2-methylene-
,4-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octane (20) and
3R*,4R*,5S*)-5-tert-butyldimethylsilyloxy-2-methylene-3,4-
(
2
.10–2.04 (m, 1 H), 0.90 (s, 9 H), 0.09 (s, 3 H) and 0.06 (s, 3 H);
bis(methoxycarbonyl)cycloheptanone (21)
δ (125 MHz, CDCl ) 204.6, 172.4, 170.5, 91.1, 77.3, 60.5, 52.6,
C
3
5
2.5, 51.0, 49.5, 33.5, 31.0, 25.7(× 3), 18.2, Ϫ5.4 and Ϫ5.6; MS
To a solution of enone 14 (3.0 g, 12 mmol) in CH Cl (3 ml) at
2
2
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
761

View Article Online
Ϫ78 ЊC were added 2,6-lutidine (1.75 ml, 15 mmol) and
TBSOTf (3.0 ml, 13 mmol). The mixture was stirred at this
The bicycle 23 was treated with TBAF (1.2 eq.) in THF at
room temperature to afford compound 22 (550 mg, 87%).
Compound 22 was subjected to the above conditions to give
23 and 24 again. This procedure was repeated once again to
give a final total of 110 mg 23 (7%) and 860 mg of 24 (57%) as
colourless oils.
temperature for 1 h, then quenched with saturated aq. NH Cl.
4
The separated aqueous solution was extracted with CH Cl and
2
2
the combined organic extracts were dried (MgSO ), filtered
4
and concentrated. Chromatography of the residue on silica gel
(
(
elution with EtOAc–hexane, 1 : 8) gave silyl ether isomers 20
2.7 g, 7.3 mmol, 61%) and 21 (0.94 g, 2.5 mmol, 21%) as
For bicycle 23, R = 0.56 (silica gel; EtOAc–hexane, 1 : 3);
νmax(neat)/cm 2950, 1735, 1435 and 1195; δH (500 MHz,
f
Ϫ1
colourless oils.
CDCl ) 5.82 (m, 1 H), 5.03 (dq, J 17, 1.5, 1 H), 4.99–4.95 (m,
3
For isomer 20, R = 0.33 (silica gel; EtOAc–hexane, 1 : 5);
1 H), 4.78 (br s, 1 H), 3.75 (s, 3 H), 3.67 (s, 3 H), 3.52 (br d, 1 H),
2.88 (t, J 1.8 Hz, 1 H), 2.36–2.29 (m, 1 H), 2.22–2.09 (m, 3 H),
2.08–1.99 (m, 1 H), 1.91–1.83 (m, 1 H), 1.78–1.64 (m, 2 H), 1.49
(ddt, J 13, 4.9, 1.8, 1 H), 0.86 (s, 9 H), 0.08 (s, 3 H) and 0.07
(s, 3 H); δ (125 MHz, CDCl ) 174.0, 172.9, 138.8, 114.6, 107.4,
f
Ϫ1
νmax(neat)/cm 2925, 2855, 1735, 1465 and 1250; δ (500 MHz,
H
CDCl ) 5.50 (s, 1 H), 5.00 (s, 1 H), 4.89 (d, J 7.9, 1 H), 4.09 (s,
3
1
(
(
7
H), 3.72 (s, 6 H), 3.18 (s, 1 H), 2.20–2.10 (m, 1 H), 2.00–1.94
m, 1 H), 1.82–1.74 (m, 2 H), 0.89 (s, 9 H), 0.09 (s, 3 H) and 0.07
s, 3 H); δ (125 MHz, CDCl ) 173.4, 172.5, 143.6, 112.6, 104.7,
C
3
75.6, 52.4, 51.7, 48.0, 45.2, 40.0, 31.6, 31.3, 27.6, 26.5, 26.0(× 3),
C
3
ϩ ϩ
5.6, 52.6, 52.3, 48.5, 45.3, 36.1, 27.0, 25.9(× 3), 18.0, Ϫ3.0
18.0, Ϫ2.9 and Ϫ2.9; MS (EI) m/z 412 (M ), 355 (M Ϫ tBu),
ϩ
ϩ
and Ϫ3.2; MS (EI) m/z 370 (M ), 339 (M Ϫ OCH ), 313
272, 169; HRMS (EI) Calc. for C H O Si (M): 412.2281.
3
21 36
6
ϩ
ϩ
(
3
M
Ϫ tBu), 281, 253; HRMS (EI) Calc. for C H O Si (M):
70.1812. Found: M , 370.1797.
For isomer 21, R = 0.17 (silica gel; EtOAc–hexane, 1 : 5);
Found: M , 412.2276.
18
30
6
ϩ
For isomer 24, R = 0.41 (silica gel; EtOAc–hexane, 1 : 2);
f
Ϫ1
νmax(neat)/cm 2950, 2930, 1730, 1435 and 1165; δ (500 MHz,
f
H
Ϫ1
νmax(neat)/cm 2950, 1700, 1435 and 1160; δH (500 MHz,
CDCl ) 5.75–5.67 (m, 1 H), 5.02–4.95 (m, 2 H), 4.56 (dt, J 7.3,
3
CDCl ) 6.00 (s, 1 H), 5.39 (s, 1 H), 4.45–4.47 (m, 1 H), 3.99 (d,
J 10.4, 1 H), 3.69 (s, 3 H), 3.67 (s, 3 H), 3.09 (ddd, J 16, 12, 1.8,
2.3, 1 H), 3.70 (s, 3 H), 3.68 (s, 3 H), 3.31 (dd, J 9.9, 3.9, 1 H),
3.15 (dt, J 10, 3.9, 1 H), 3.09 (dd, J 9.9, 2.3, 1 H), 2.66 (ddd,
J 17, 10, 5.5, 1 H), 2.42 (dt, J 17, 5.5, 1 H), 2.18–2.10 (m, 1 H),
2.09–1.93 (m, 3 H), 1.88–1.80 (m, 1 H), 1.60–1.52 (m, 1 H), 0.86
(s, 9 H), 0.04 (s, 3 H) and Ϫ0.03 (s, 3 H); δ (125 MHz, CDCl )
3
1
2
3
1
2
H), 3.01 (dd, J 10, 2.7, 1 H), 2.30 (ddd, J 16, 7.9, 1.5, 1 H),
.09–2.02 (m, 1 H), 1.82–1.75 (m, 1 H), 0.87 (s, 9 H), 0.03 (s,
H) and Ϫ0.01 (s, 3 H); δ (125 MHz, CDCl ) 202.1, 172.9,
C
3
C
3
72.1, 144.7, 123.8, 69.1, 55.8, 52.2, 51.9, 43.8, 33.8, 30.2,
210.9, 173.8, 173.1, 137.4, 115.8, 70.2, 52.1, 52.0, 51.2, 51.0,
ϩ
5.6(× 3), 17.9, Ϫ4.5 and Ϫ5.5; MS (EI) m/z 370 (M ), 339
42.8, 37.7, 32.1, 29.8, 26.4, 25.7(× 3), 18.0, Ϫ4.6 and Ϫ5.5; MS
ϩ
ϩ
ϩ
ϩ
ϩ
(
M Ϫ OCH ), 313 (M Ϫ tBu), 281, 253; HRMS (EI) Calc. for
(EI) m/z 412 (M ), 381 (M Ϫ OCH ), 355 (M Ϫ tBu), 323,
3
3
ϩ
C H O Si (M): 370.1812. Found: M , 370.1815.
295; HRMS (EI) Calc. for C H O Si (M Ϫ tBu): 355.1577.
18
30
6
17 27
6
Found: m/z, 355.1570.
(
2R*,3S*,4R*,5S*)-2-(But-3-enyl)-5-hydroxy-3,4-bis(methoxy-
Ozonolysis of compound 24
carbonyl)cycloheptanone (22)
Compound 24 (72 mg, 0.18 mmol) in MeOH (3 ml) was
ozonolyzed at Ϫ78 ЊC for 12 h. After removal of excess of
ozone by bubbling oxygen through the solution for 10 min,
sodium bicarbonate (20 mg) was introduced followed by the
addition of dimethyl sulfide (0.1 ml). This mixture was allowed
to warm to room temperature, then was stirred overnight. The
reaction mixture was filtered and the filtrate was concen-
trated. Chromatography of the residue on silica gel (elution
with EtOAc–hexane, 1 : 2) gave the expected aldehyde (59 mg,
0.14 mmol, 78%) as a colourless oil.
To a solution of bicycle 20 (2.6 g, 7.0 mmol) in CH Cl (50 ml)
at Ϫ78 ЊC were added allyltrimethylsilane (1.8 ml, 11 mmol)
2
2
and TiCl (0.6 ml, 5.5 mmol). The mixture was stirred at this
4
temperature for 30 min, then quenched with saturated aq.
NaHCO . The separated aqueous solution was extracted with
3
CH Cl and the combined organic extracts were dried (MgSO ),
2
2
4
filtered and concentrated. Chromatography of the residue on
silica gel (elution with EtOAc–hexane, 1 : 1) gave compound 22
(
1.7 g, 5.8 mmol, 82%) as a colourless oil; R = 0.33 (silica gel;
f
Ϫ1
EtOAc–hexane, 1 : 1); νmax(neat)/cm 3450, 2950, 1735, 1435
and 1170; δ (500 MHz, CDCl ) 5.77–5.70 (m, 1 H), 5.04–4.96
(1R*,2S*,3R*,4S*,6R*)-4-tert-Butyldimethylsilyloxy-2,3-bis-
(methoxycarbonyl)bicyclo[4.3.1]decane-7,10-dione (26a) and
(1R*,2R*,3S*,4R*,6R*)-4-tert-butyldimethylsilyloxy-2,3-bis-
(methoxycarbonyl)bicyclo[4.3.1]decane-7,10-dione (26b)
H
3
(
m, 2 H), 4.18 (br s, 1 H), 3.78 (s, 3 H), 3.70 (s, 3 H), 3.47 (dd,
J 7.0, 2.7, 1 H), 3.32 (dd, J 7.0, 3.1, 1 H), 2.83 (br s, 1 H), 2.72
ddd, J 18, 9.1, 3.7, 1 H), 2.44 (ddd, J 18, 9.1, 3.1, 1 H), 2.30–
.21 (m, 1 H), 2.10–1.94 (m, 4 H) and 1.50–1.48 (m, 1 H), OH
not observed; δ (125 MHz, CDCl ) 210.9, 174.4, 173.8, 137.9,
(
2
To a solution of the foregoing aldehyde (10.2 mg, 24 µmol) in
CH Cl (1 ml) was added DBU (0.01 ml, 67 µmol) at room
C
3
2
2
1
15.5, 70.1, 52.8, 52.4, 52.1, 49.6, 43.7, 38.6, 32.7, 28.9 and 26.3;
temperature. This mixture was stirred overnight and then
ϩ
MS (EI) m/z 298 (M ), 280, 266, 212, 152; HRMS (EI) Calc. for
C H O (M): 298.1416. Found: M , 298.1408.
quenched with saturated aq. NH Cl. The separated aqueous
ϩ
4
15
22
6
solution was extracted with CH Cl and the combined organic
2
2
extracts were dried (MgSO ), filtered and concentrated.
4
To a solution of this material in CH Cl (1 ml) were added
2
2
(
1R*,2S*,3R*,4S*,5R*)-2-(But-3-enyl)-1-tert-butyldimethyl-
silyloxy-3,4-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octane
23) and (2R*,3S*,4R*,5S*)-2-(but-3-enyl)-5-tert-butyl-
PCC (8 mg, 37 µmol) and 4 Å MS (20 mg) at room temperature.
The mixture was stirred at room temperature for 3 h, then
filtered and concentrated. Chromatography of the residue on
silica gel (elution with EtOAc–hexane, 1 : 2) gave stereoisomers
26a and 26b in 4 : 1 ratio (8.3 mg, 20 µmol, 82%) as white solids.
(
dimethylsilyloxy-3,4-bis(methoxycarbonyl)cycloheptanone (24)
To a solution of hydroxy ketone 22 (1.1 g, 3.7 mmol) in CH Cl2
2
(
(
50 ml) were added 2,6-lutidine (0.9 ml, 7.7 mmol) and TBSOTf
1.4 ml, 6.1 mmol) at room temperature. The mixture was
For isomer 26a, R = 0.40 (silica gel; EtOAc–hexane, 1 : 1);
f
Ϫ1
mp 142–143 ЊC (CH Cl ); νmax(neat)/cm 2950, 1740, 1445 and
2
2
stirred at this temperature for 1 h, then quenched with saturated
1180; δH (500 MHz, CDCl ) 4.72 (d, J 6.7, 1 H), 3.74 (s, 3 H),
3
aq. NH Cl. The separated aqueous solution was extracted with
3.69 (s, 3 H), 3.52 (dd, J 12, 3.4, 1 H), 3.32 (dd, J 12, 7.9, 1 H),
3.27–3.21 (m, 2 H), 2.67 (dt, J 18, 3.0, 1 H), 2.58–2.51 (m,
1 H), 2.28–2.20 (m, 1 H), 2.13–2.03 (m, 1 H), 1.93 (dd, J 16, 7.9,
1 H), 1.91–1.83 (m, 1 H), 0.84 (s, 9 H), 0.05 (s, 3 H) and Ϫ0.06
(s, 3 H); δ (125 MHz, CDCl ) 206.2, 204.3, 173.5, 172.5, 70.6,
4
CH Cl and the combined organic extracts were dried (MgSO ),
2
2
4
filtered and concentrated. Chromatography of the residue on
silica gel (elution with EtOAc–hexane, 1 : 6) gave bicycle 23
(
880 mg, 2.1 mmol, 58%) along with its isomer 24 (640 mg,
C
3
1
.6 mmol, 42%) as colourless oils.
61.2, 52.6, 52.4, 51.0, 48.0, 42.1, 37.5, 33.1, 25.5(× 3), 18.0,
7
62 J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

View Article Online
ϩ
1
7.9, Ϫ4.7 and Ϫ5.7; MS (EI) m/z 355 (M Ϫ tBu), 211, 159,
(1R*,2S*,3R*,4S*,6R*,9R*)-6,9-Diallyl-4-tert-butyldimethyl-
1
38; HRMS (EI) Calc. for C H O Si (M Ϫ tBu): 355.1213.
silyloxy-2,3-bis(methoxycarbonyl)bicyclo[4.3.1]decane-7,10-
16
23
7
Found: m/z, 355.1214; Calc. for C H O Si: C, 58.23, H, 7.82.
dione (29)
20
32
7
Found: C, 57.63; H, 7.83%.
To a solution of compound 28 (14 mg, 32 µmol) in THF (1 ml)
at Ϫ78 ЊC, was added KHMDS (0.5 M in toluene, 40 µmol),
then the mixture was stirred for 10 min. To this solution was
added at this temperature, allyl bromide (0.01 ml, 120 µmol)
and the resulting solution was stirred for 30 min. Saturated aq.
NH Cl and Et O were added and the organic layer was separ-
For isomer 26b, R = 0.53 (silica gel; EtOAc–hexane, 1 : 1);
f
Ϫ1
mp 92–95 ЊC (CH Cl ); νmax(neat)/cm 2950, 2930, 1740, 1435
2
2
and 1160; δH (500 MHz, CDCl ) 4.47 (t, J 2.7, 1 H), 3.73 (s,
3
3 H), 3.66 (s, 3 H), 3.38 (dd, J 12, 5.5, 1 H), 3.28 (dd, J 14, 6.1,
1 H), 3.26–3.22 (m, 1 H), 2.94–2.90 (m, 1 H), 2.84 (d, J 12, 1 H),
2.54–2.47 (m, 2 H), 2.44–2.37 (m, 1 H), 2.05 (ddd, J 15, 6.1, 3.0,
1 H), 2.02–1.95 (m, 1 H), 0.87 (s, 9 H), 0.01 (s, 3 H) and Ϫ0.03
4
2
ated. The aqueous layer was extracted with Et O then the com-
2
bined organic layers were washed with brine, dried (MgSO ),
4
(
s, 3 H); δ (125 MHz, CDCl ) 209.1, 207.6, 174.9, 172.9, 71.3,
C
3
filtered and concentrated. Purification by means of chrom-
atography on silica gel (elution with EtOAc–hexane, 1 : 6) gave
compound 29 (9.0 mg, 18 µmol, 57%, 76% based on consumed
starting material) as a colourless oil along with recovered start-
6
1.8, 52.6, 52.3, 51.6, 49.0, 41.4, 38.7, 34.1, 25.8(× 3), 23.7, 18.1,
ϩ
Ϫ4.9 and Ϫ5.7; MS (EI) m/z 355 (M Ϫ tBu), 323, 159; HRMS
(
EI) Calc. for C H O Si (M Ϫ tBu): 355.1213. Found: m/z,
16 23 7
3
55.1216; Calc. for C H O Si: C, 58.23; H, 7.82. Found:
20 32 7
ing material (3.5 mg, 7.7 µmol); R = 0.43 (silica gel; EtOAc–
f
C 58.90: H, 8.12%.
Ϫ1
hexane, 1 : 4); νmax(neat)/cm 3455, 3415, 1735 and 1700;
δ (500 MHz, CDCl ) 5.74–5.57 (m, 2 H), 5.10 (d, J 9.5, 1 H),
H
3
(
1R*,2S*,3R*,4S*,6R*)-4-tert-Butyldimethylsilyloxy-2,3-
5
.05 (d, J 7.9, 1 H), 5.03–5.00 (m, 2 H), 4.39 (t, J 3.4, 1 H), 3.71
bis(methoxycarbonyl)bicyclo[4.3.1]dec-8-ene-7,10-dione (27)
(
s, 3 H), 3.66 (s, 3 H), 3.60 (dd, J 12, 4.6, 1 H), 3.10 (dd, J 6.4,
A solution of ketone 26a (160 mg, 0.39 mmol) in toluene (6 ml)
and DMSO (3 ml) was treated with IBX (430 mg, 1.5 mmol),
stirred at 80 ЊC for 3 h, then quenched with saturated aq.
4.6, 1 H), 2.98 (d, J 12, 1 H), 2.70 (dd, J 14, 5.2, 1 H), 2.65 (dd,
J 14, 3.7, 1 H), 2.43–2.37 (m, 2 H), 2.12–1.82 (m, 5 H), 0.88 (s,
9 H), 0.02 (s, 3 H) and Ϫ0.11 (s, 3 H); δ (125 MHz, CDCl )
C
3
NaHCO . The separated aqueous solution was extracted with
209.1, 205.0, 173.8, 173.1, 133.6, 133.3, 119.3, 119.0, 70.0, 63.0,
3
EtOAc and the combined organic extracts were dried (MgSO ),
53.9, 52.3(× 2), 49.7, 44.7, 43.0, 41.6, 40.7, 39.9, 30.1, 25.7(× 3),
17.9, Ϫ4.2 and Ϫ5.6; MS (EI) m/z 435 (M Ϫ tBu), 403, 375,
4
ϩ
filtered and concentrated. Chromatography of the residue on
silica gel (elution with EtOAc–hexane, 1 : 4) gave enone 27 (47
mg, 0.12 mmol, 30%) along with starting material (66 mg, 0.16
mmol, 41% recovery). This procedure was repeated once again
to provide a final total of 68 mg (43%) of 27 as a white solid
along with 30 mg (19%) recovery of starting material (52% yield
343; HRMS (EI) Calc. for C H O Si (M Ϫ tBu): 435.1839.
22
31
7
Found: m/z, 435.1834.
(1R*,2S*,3R*,4S*,6R*,9R*)-9-(Allyl)-7-allyloxycarbonyloxy-
4-tert-butyldimethylsilyloxy-2,3-bis(methoxycarbonyl)bicyclo-
[4.3.1]dec-7-en-10-one (31)
based on consumed starting material); R = 0.43 (silica gel;
f
Ϫ1
EtOAc–hexane, 1 : 1); mp 131–134 ЊC (CH Cl ); νmax(neat)/cm
2
2
To a solution of dione 28 (7.1 mg, 16 µmol) in THF (1 ml) at
Ϫ78 ЊC was added KHMDS (0.5 M in toluene; 50 µl, 25 µmol).
The mixture was stirred at this temperature for 30 min, then
allyl chloroformate (5 ml, 47 µmol) was to the mixture added at
Ϫ78 ЊC. The resulting material was further stirred for 3 h at
2
955, 2925, 2855, 1725 and 1685; δH (500 MHz, CDCl ) 6.81
3
(dd, J 10, 4.3, 1 H), 6.30 (d, J 10, 1 H), 4.54 (d, J 5.5, 1 H), 3.79
(s, 3 H), 3.72–3.65 (m, 5 H), 3.55 (dd, J 12, 4.6, 1 H), 3.0
(d, J 11, 1 H), 2.66–2.59 (m, 1 H), 1.88–1.83 (m, 1 H),
0
.86 (s, 9 H), 0.04 (s, 3 H) and Ϫ0.06 (s, 3 H); δ (125 MHz,
C
Ϫ78 ЊC and then quenched with saturated aq. NH Cl. The
4
CDCl ) 199.9, 196.9, 172.7, 172.6, 144.7, 129.9, 71.2, 60.7,
3
separated aqueous solution was extracted with EtOAc and the
5
2.8, 52.4, 51.5, 50.9, 43.2, 36.9, 25.5(× 3), 18.0, Ϫ4.8 and
ϩ
combined organic extracts were dried (MgSO
concentrated. Chromatography of the residue on silica gel
elution with EtOAc–hexane, 1 : 6) gave the mixed enol carb-
4
), filtered and
Ϫ5.6; MS (EI) m/z 396, 353 (M Ϫ tBu), 229, 209; HRMS
(
EI) Calc. for C H O Si (M Ϫ tBu): 353.1057, Found: m/z,
16 21 7
(
3
53.1047.
onates 30 and 31 in a 1 : 4 ratio (5.0 mg, 9.8 µmol, 63%) as
colourless oils.
(
1R*,2S*,3R*,4S*,6R*,9R*)-9-Allyl-4-tert-butyldimethylsilyl-
oxy-2,3-bis(methoxycarbonyl)bicyclo[4.3.1]decane-7,10-dione
28)
For isomer 31, R = 0.40 (silica gel; EtOAc–hexane, 1 : 4);
f
Ϫ1
νmax(neat)/cm 2950, 2855 and 1735; δH (500 MHz, CDCl3)
(
6
.00–5.90 (m, 1H), 5.72 (d, J 6.1, 1 H), 5.66–5.56 (m, 1 H), 5.40
To a solution of enone 27 (11.0 mg, 27 µmol) in CH Cl (1 ml)
at Ϫ78 ЊC were added allyltrimethylsilane (10 µl, 63 µmol) and
(d, J 17, 1 H), 5.32 (d, J 10, 1 H), 5.10–5.01 (m, 2 H), 4.67 (d,
J 5.5, 2 H), 4.39–4.37 (m, 1 H), 3.70 (s, 3 H), 3.65 (s, 3 H), 3.62
(dd, J 12, 5.5, 1 H), 3.53 (d, J 12, 1 H), 3.19 (d, J 9.7, 1 H), 3.08
(d, J 5.5, 1 H), 2.49 (dd, J 12, 6.1, 1 H), 2.23–2.17 (m, 1 H),
2.12–2.05 (m, 2 H), 2.00–1.92 (m, 1 H), 0.86 (s, 9 H), 0.00 (s,
3 H) and Ϫ0.09 (s, 3 H); δ (125 MHz, CDCl ) 204.5, 174.0,
2
2
TiCl (5 µl, 46 µmol). The mixture was stirred at this temper-
4
ature for 30 min, then quenched with saturated aq. NaHCO3.
The separated aqueous solution was extracted with CH Cl and
2
2
the combined organic extracts were dried (MgSO ), filtered
4
C
3
and concentrated. Chromatography of the residue on silica gel
173.8, 152.8, 146.9, 134.2, 131.0, 119.7, 118.6, 118.0, 70.8, 69.3,
(
1
elution with EtOAc–hexane, 1 : 6) gave compound 28 (6.9 mg,
52.2, 52.1, 51.2, 48.0, 47.3, 41.9, 40.3, 36.2, 35.4, 25.6(× 3), 17.9,
Ϫ4.7 and Ϫ5.5; MS (EI) m/z 480 (M ϩ H Ϫ tBu), 435, 390,
ϩ
5 µmol, 57%) as a colourless oil; R = 0.32 (silica gel; EtOAc–
f
Ϫ1
hexane, 1 : 4); νmax(neat)/cm 2925, 1740, 1710 and 1435;
386, 257; HRMS (EI) Calc. for C H O Si (M Ϫ tBu):
23
31
9
δH (500 MHz, CDCl ) 5.67–5.59 (m, 1 H), 5.16 (m, 1 H), 5.04
479.1737, Found: m/z, 479.1752.
3
(
d, J 17, 1 H), 4.62 (d, J 6.4, 1 H), 3.74 (s, 3 H), 3.69 (s,
H), 3.52 (dd, J 12, 3.4, 1 H), 3.28 (dd, J 11, 7.6, 1 H), 3.2
d, J 12, 1 H), 3.06–3.03 (m, 1 H), 2.70 (dd, J 17, 4.0, 1 H),
.50 (ddd, J 15, 11.3, 6.4, 1 H), 2.37–2.29 (m, 1 H), 2.10–2.03
m, 2 H), 1.96 (dd, J 15, 7.6, 1 H), 1.87–1.79 (m, 1 H), 0.84 (s, 9
H), 0.04 (s, 3 H) and Ϫ0.07 (s, 3 H); δC (125 MHz, CDCl3)
3
(
2
(
(1R*,2S*,3R*,4S*,6R*,8R*,9R*)-8,9-Diallyl-4-tert-butyl-
dimethylsilyloxy-2,3-bis(methoxycarbonyl)bicyclo[4.3.1]decane-
7,10-dione (32)
To a solution of double-bond isomers 30 and 31 (1 : 4, 5.0 mg,
9
.8 µmol) in THF were added Pd (dba) ؒCHCl § (0.5 mg) and
2 3 3
2
5
06.6, 205.6, 174.1, 172.7, 133.5, 119.2, 70.4, 60.3, 53.7, 52.4,
PPh (1.0 mg, 3.8 µmol). The mixture was stirred at room
3
2.4, 51.2, 43.5, 41.4, 39.1, 33.8, 30.0, 25.5(× 3), 17.9, Ϫ4.7 and
ϩ
ϩ
temperature for 2 h and then concentrated. Chromatography of
Ϫ5.7; MS (EI) m/z 452 (M ), 437 (M Ϫ CH ), 396, 362, 251;
HRMS (EI) Calc. for C H O Si (M): 452.2230. Found: M ,
3
ϩ
23
36
7
4
52.2218.
§ Pd (dba) is tris(dibenzylideneacetone)dipalladium.
2
3
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
763

View Article Online
the residue on silica gel (elution with EtOAc–hexane, 1 : 6) gave
isomers 32 and 29 in a 2 : 1 ratio (3.9 mg, 7.9 µmol, 81%) as
colourless oils.
(210 mg, 0.98 mmol) in HMPA (10 ml) at 0 ЊC. After stirring of
the mixture for 30 min at room temperature, a solution of
nitrile 34 (320 mg, 0.78 mmol) in THF (10 ml) was added to the
suspension at 0 ЊC. The mixture was stirred at room temper-
For isomer 32, R = 0.43 (silica gel; EtOAc–hexane, 1 : 4);
f
Ϫ1
νmax(neat)/cm 2925, 2855, 1735, 1700 and 1435; δ (500 MHz,
ature for 1 h, then quenched with saturated aq. NH Cl and
H
4
CDCl ) 5.73–5.49 (m, 2 H), 5.12–5.00 (m, 4 H), 4.58 (d, J 5.0,
Et O. The separated aqueous solution was extracted with Et O
3
2
2
1
H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.62 (dd, J 12, 4.4, 1 H), 3.41
and the combined organic extracts were washed with H O,
2
(
dd, J 13, 3.2, 1 H), 3.33 (d, J 12, 1 H), 3.26 (t, J 4.4, 1 H), 3.03–
dried (MgSO ), filtered and concentrated. Chromatography of
4
2
2
.98 (m, 1 H), 2.54 (ddd, J 16, 13, 5.0, 1 H), 2.36–2.29 (m, 1 H),
.26–2.19 (m, 1 H), 2.12–1.82 (m, 4 H), 0.85 (s, 9 H), 0.03 (s, 3
the residue on silica gel (elution with EtOAc–hexane, 1 : 6) gave
tricycle 35 (231 mg, 0.48 mmol, 61%) as a colourless oil; R =
f
Ϫ1
H) and Ϫ0.07 (s, 3 H); δC (125 MHz, CDCl ) 206.5, 203.1,
0.33 (silica gel; EtOAc–hexane, 1 : 2); νmax(neat)/cm 2955,
3
1
5
73.7, 173.5, 134.6, 134.2, 118.6, 117.6, 70.8, 61.6, 52.6, 52.4,
2930, 2250 and 1740; δ (500 MHz, CDCl ) 5.16 (s, 1 H), 4.00
H
3
2.3, 51.1, 47.9, 41.4, 35.4(× 2), 32.9, 29.7, 25.5(× 3), 17.9, Ϫ4.7
(dd, J 5.5, 0.9, 1 H), 3.96 (d, J 12, 1 H), 3.91 (d, J 12, 1 H), 3.84
(d, J 5.5, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 3.03 (d,
J 5.5, 1 H), 2.87 (dd, J 5.5, 0.60, 1 H), 0.86 (s, 9 H), 0.06 (s, 3 H)
ϩ
and Ϫ5.6; MS (EI) m/z 435 (M Ϫ tBu), 403, 374, 341; HRMS
(
EI) Calc. for C H O Si (M Ϫ tBu): 435.1839. Found: m/z,
22 31 7
4
35.1861.
and 0.03 (s, 3 H); δC (125 MHz, CDCl ) 194.9, 170.3, 169.2,
3
1
2
66.5, 114.4, 92.6, 75.7, 60.9, 53.3, 53.1(× 2), 51.0, 50.7, 34.7,
7.9, 25.6(× 3), 22.7, 18.1 and Ϫ5.6(× 2); MS (EI) m/z 466
(
1R*,5R*,6R*,7R*)-3-Bromo-1-tert-butyldimethylsilyloxy-
methyl-6,7-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]oct-3-en-
-one (33)
ϩ
ϩ
ϩ
(
M Ϫ CH ), 450 (M Ϫ OCH ), 424 (M Ϫ tBu), 392, 364;
3 3
ϩ
2
HRMS (EI) Calc. for C H NO Si (M Ϫ tBu): 424.1064.
18
22
9
Found: m/z, 424.1075.
To a solution of enone 9a (7.4 g, 19 mmol) in CH Cl (300 ml)
2
2
at Ϫ40 ЊC was added Br (2.4 ml, 45 mmol). The mixture was
stirred at this temperature for 30 min, followed by the addition
2
Methyl {(1R*,2R*,5R*,6R*,7R*)-5-tert-butyldimethylsilyloxy-
methyl-2-cyano-6,7-bis(methoxycarbonyl)-4-oxo-8-oxabicyclo-
of Et N (16 ml, 110 mmol). The resulting solution was allowed
3
[
3.2.1]octan-2-yl}acetate (36)
to warm to room temperature, then was stirred for 10 min. The
solvent was evaporated and chromatography of the residue on
silica gel (elution with EtOAc–hexane, 1 : 4) gave bromide 33
To a solution of tricycle 35 (1.2 g, 2.6 mmol) in THF (10 ml) at
Ϫ78 ЊC was added Sml (0.1 M in THF; 57 ml). The resulting
2
(
8.7 g, 19 mmol, 99%) as a yellow oil; R = 0.42 (silica gel;
f
Ϫ1
solution was stirred for 1 h prior to the addition of saturated
EtOAc–hexane, 1 : 2); νmax(neat)/cm 2955, 2930, 2855, 1740,
aq. NaHCO and EtOAc. The separated aqueous solution was
3
1
5
710, 1600 and 1435; δ (500 MHz, CDCl ) 7.66 (d, J 5.2, 1 H),
.20 (d, J 5.2, 1 H), 4.26 (d, J 12, 1 H), 4.21 (d, J 4.3, 1 H), 4.04
H
3
further extracted with EtOAc and the combined organic
extracts were washed with H O, dried (MgSO ), filtered and
2
4
(
0
d, J 12, 1 H), 3.76 (s, 3 H), 3.67 (s, 3 H), 3.62 (d, J 4.3, 1 H),
.90 (s, 9 H), 0.11 (s, 3 H) and 0.07 (s, 3 H); δC (125 MHz,
CDCl ) 186.9, 170.5, 169.8, 150.3, 122.4, 92.1, 77.6, 60.7, 52.8,
concentrated. Chromatography of the residue on silica gel
elution with EtOAc–hexane, 1 : 6) gave compound 36 (991 mg,
.1 mmol, 79%) as a colourless oil; R = 0.33 (silica gel; EtOAc–
(
3
2
f
5
4
2.7, 50.5, 47.0, 25.7(× 3), 18.2, Ϫ5.5 and Ϫ5.6; MS (EI) m/z
Ϫ1
hexane, 1 : 2); νmax(neat)/cm 2955, 2930, 2250, 1740 and 1440;
ϩ
ϩ
07 (M Ϫ tBu), 405 (M Ϫ tBu), 263, 261; HRMS (EI) Calc.
δH (500 MHz, CDCl ) 4.95 (s, 1 H), 4.18 (d, J 7.0, 1 H), 4.06
3
79
for C H BrO Si (M Ϫ tBu): 405.0005. Found: m/z, 405.0009;
14
18
7
(
(
d, J 12, 1 H), 4.05 (dd, J 7.0, 1.8, 1 H), 3.86 (d, J 12, 1 H), 3.82
s, 3 H), 3.75 (s, 3 H), 3.72 (s, 3 H), 3.04–2.84 (m, 4 H), 0.89 (s,
Calc. for C H BrO Si: C, 46.65; H, 5.87. Found: C, 46.72,
18
27
2
H, 5.70%.
9
1
4
H), 0.08 (s, 3 H) and 0.06 (s, 3 H); δ (125 MHz, CDCl ) 197.8,
70.9, 169.7, 168.9, 119.0, 91.5, 80.9, 59.7, 53.3, 53.1, 52.4, 49.4,
C
3
(
1R*,5R*,6R*,7R*)-1-tert-Butyldimethylsilyloxymethyl-4-
9.1, 42.8, 41.7, 40.0, 25.8(× 3), 18.3, Ϫ5.3 and Ϫ5.5; MS (EI)
cyano-6,7-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]oct-3-en-
-one (34)
ϩ
ϩ
m/z 452 (M Ϫ OCH ), 426 (M Ϫ tBu), 394, 366, 241; HRMS
3
2
ϩ
(
EI) Calc. for C H NO Si (M Ϫ tBu): 426.1220. Found: m/z,
18 24 9
To a solution of bromide 33 (8.7 g, 19 mmol) in CH Cl (300 ml)
426.1230.
2
2
and H O (100 ml) were added n-BuN I (100 mg) and NaCN
2
4
(
1.0 g, 20 mmol) at room temperature. The mixture was stirred
Methyl {(1R*,2R*,5R*,6R*,7R*)-2-cyano-5-hydroxymethyl-
6,7-bis(methoxycarbonyl)-4-oxo-8-oxabicyclo[3.2.1]octan-2-yl}-
acetate (37)
vigorously for 1 h, then the organic phase was separated. Et N
3
(
4.9 ml, 35 mmol) was added, and the resulting solution was
stirred for 30 min. The solvent was evaporated off and chrom-
atography of the residue on silica gel (elution with EtOAc–
hexane, 1 : 4) gave nitrile 34 (7.5 g, 18 mmol, 97%) as a yellow
With the procedure as described for the alcohol 12, silyl ether
3
6 (103 mg, 0.21 mmol) was desilylated to give alcohol 37
Ϫ1
(70 mg, 0.19 mmol, 89%) as a colourless oil; R = 0.10 (silica gel;
EtOAc–hexane, 1 : 2); νmax(neat)/cm 3505, 2925, 2855, 2245,
f
oil; R = 0.46 (silica gel; EtOAc–hexane, 1 : 2); νmax(neat)/cm
f
Ϫ1
2
6
1
955, 2930, 2230, 1740, 1705 and 1440; δH (500 MHz, CDCl3)
.51 (s, 1 H), 5.28 (s, 1 H), 4.23 (d, J 4.3, 1 H), 4.18 (d, J 12,
H), 4.00 (d, J 12, 1 H), 3.80 (s, 3 H), 3.71 (d, J 4.3, 1 H), 3.68
1
720 and 1435; δ (500 MHz, CDCl ) 5.00 (t, J 1.8, 1 H), 4.06
H
3
(
(
dd, J 7.0, 1.8, 1 H), 4.01–3.93 (m, 3 H), 3.84 (s, 3 H), 3.76
s, 3 H), 3.74 (s, 3 H), 3.07 (d, J 18, 1 H) and 2.96–2.86 (m,
(
s, 3 H), 0.89 (s, 9 H), 0.10 (s, 3 H) and 0.06 (s, 3 H);
3
1
H), OH not observed; δC (125 MHz, CDCl ) 198.1, 170.9,
3
δC (125 MHz, CDCl ) 190.8, 169.8(× 2), 136.4, 133.5, 113.6,
9
Ϫ5.6; MS (EI) m/z 394 (M Ϫ CH ), 378 (M Ϫ OCH ), 352
3
69.2, 168.8, 118.7, 90.9, 80.9, 60.5, 53.3, 53.2, 52.4, 50.4,
2.1, 77.3, 60.1, 53.1, 53.0, 51.5, 47.4, 25.7(× 3), 18.2, Ϫ5.5 and
ϩ
ϩ
ϩ ϩ
49.3, 42.7, 41.4 and 39.8; MS (FAB ) m/z 370 (M ϩ H), 338
(M Ϫ OCH ), 306, 185; HRMS (FAB ) Calc. for C H NO
3
3
ϩ
ϩ
ϩ
3
16 20
9
(
(
M Ϫ tBu), 294, 234, 208; HRMS (EI) Calc. for C H NO Si
15 18 7
(
M ϩ H): 370.1138. Found: m/z, 370.1129.
M Ϫ tBu): 352.0853. Found: m/z, 352.0869; Calc. for
C H NO Si: C, 55.73, H, 6.65, N, 3.42. Found: C, 55.67,
H, 6.86, N, 3.22%.
19
27
2
Methyl {(1R*,2R*,5S*,6R*,7R*)-2-cyano-5-iodomethyl-6,7-bis-
methoxycarbonyl)-4-oxo-oxabicyclo[3.2.1]octan-2-yl}acetate
(
(
1R*,2R*,3R*,4R*,6R*,7R*,8R*)-6-tert-Butyldimethylsilyloxy-
(38)
methyl-2-cyano-3,7,8-tris(methoxycarbonyl)-9-oxatricyclo-
Alcohol 37 (21.2 mg, 56 µmol) was iodinated with the
procedure as described previously for iodide 13 to give iodide
2,4
[
4.2.1.0 ]nonan-5-one (35)
To a suspension of NaH (60%, prewashed with hexane; 100 mg,
38 (20 mg, 42 µmol, 73%) as a pale yellow oil; R = 0.29 (silica
gel; EtOAc–hexane, 1 : 2); νmax(neat)/cm 2955, 2250, 1735 and
f
Ϫ1
2
.5 mmol) in THF (10 ml) was added the sulfonium salt
7
64 J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

View Article Online
1
1
440; δ (500 MHz, CDCl ) 4.99 (t, J 1.8, 1 H), 4.13 (dd, J 6.7,
.8, 1 H), 3.96 (d, J 6.7, 1 H), 3.86 (s, 3 H), 3.77 (s, 3 H), 3.74
1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.72 (s, 3 H), 3.69
H
3
(dd, J 6.7, 1.8, 1 H), 3.65 (d, J 7.6, 1 H), 2.99 (tdd, J 7.6, 3.0, 1.2,
1 H), 2.73 (dd, J 18, 7.6, 1 H), 2.53 (ddd, J 18, 3.1, 1.5, 1 H) and
1.91 (dd, J 9.1, 4.8, 1 H); δ (125 MHz, CDCl ) 203.8, 171.9,
(
s, 3 H), 3.71 (d, J 12, 1 H), 3.59 (d, J 12, 1 H) and 3.03–2.86 (m,
4
8
H); δ (125 MHz, CDCl ) 195.7, 170.6, 168.9, 168.6, 118.7,
C
3
C
3
9.4, 80.9, 54.0, 53.6, 53.6, 52.5, 49.7, 42.7, 41.6, 39.9 and 3.7;
169.9, 168.3, 168.1, 91.0, 79.9, 61.2, 54.6, 53.0, 52.9(×2), 52.7,
ϩ
ϩ
ϩ
MS (EI) m/z 448 (M Ϫ OCH ), 352 (M Ϫ I), 320, 292, 250;
51.7, 50.9, 40.8 and 37.2; HRMS (FAB ) Calc. for C H O
3
17 23 11
HRMS (EI) Calc. for C H NO (M Ϫ I): 352.1032. Found:
(M ϩ H): 403.1240. Found: m/z, 403.1255; Calc. for C17H22O11:
16
18
8
m/z, 352.1035.
C, 50.75; H, 5.51. Found: C, 51.10; H, 5.81%.
Methyl {(1S*,3R*,4R*,5R*,6R*)-1-acetoxy-6-cyano-2-methyl-
ene-3,4-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octan-6-yl}-
acetate (39)
Dimethyl {(1R*,2S*,5R*,6S*,7S*)-5-iodomethyl-6,7-bis(meth-
oxycarbonyl)-4-oxo-8-oxabicyclo[3.2.1]octan-2-yl}malonate (44)
Alcohol 43 (26 mg, 65 µmol) was iodinated with the procedure
as described previously for iodide 13 to give iodide 44 (28 mg,
To a solution of iodide 38 (20 mg, 42 µmol) in Ac O was added
2
activated Zn. The mixture was stirred at 50 ЊC for 3 h and then
5
5 µmol, 84%) as a colourless oil; R = 0.3 (silica gel; EtOAc–
f
Ϫ1
saturated aq. NaHCO and CH Cl were added. The separated
3
2
2
hexane, 1 : 2); νmax(neat)/cm 2955, 1730 and 1440; δH (500
aqueous solution was extracted with CH Cl and the combined
2
2
MHz, CDCl ) 4.79 (br s, 1 H), 3.79 (s, 3 H), 3.78–3.76 (m, 1 H),
3
organic solutions were dried (MgSO ), filtered and concen-
4
3.77 (s, 3 H), 3.75 (s, 3 H), 3.72 (s, 3 H), 3.73–3.69 (m, 2 H), 3.66
trated. Chromatography of the residue on silica gel (elution
with EtOAc–hexane, 1 : 4) gave compound 39 (4.1 mg, 10 µmol,
(
2
d, J 7.9, 1 H), 3.61 (d, J 12, 1 H), 2.96 (tdd, J 7.9, 4.0, 1.2, 1 H),
.67 (dd, J 17, 7.9, 1 H) and 2.53 (ddd, J 17, 4.0, 1.2, 1 H); δC
2
1
5%) as a colourless oil; R = 0.52 (silica gel; EtOAc–hexane,
: 1); νmax(neat)/cm 2955, 1740 and 1440; δH (500 MHz,
f
(125 MHz, CDCl ) 202.2, 171.5, 169.1, 168.2, 167.9, 89.1, 79.6,
3
Ϫ1
54.6, 54.4, 53.1, 52.9(×2), 52.8, 52.1, 40.8, 37.1 and 4.8; MS (EI)
ϩ
ϩ
CDCl ) 5.59 (br s, 1 H), 5.09 (s, 1 H), 4.99 (s, 1 H), 4.23 (d, J 7.0,
3
m/z 513 (M ϩ H), 385 (M Ϫ I); HRMS (EI) Calc. for
C H O (M Ϫ I): 385.1135. Found: m/z, 385.1146.
1
1
2
1
5
H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.66 (dd, J 7.0, 1.8,
H), 3.08 (d, J 17, 1 H), 3.00 (d, J 17, 1 H), 2.89 (d, J 14, 1 H),
17
21 10
.
6
2
(
d
,
J
1
4
,
1
H
)
a
n
d
2
.
1
1
(
s
,
3
H
)
;
δ
(
1
2
5
M
H
z
,
C
D
C
l
)
C
3
Dimethyl {(1R*,3R*,4R*,5S*,6R*)-1-hydroxy-2-methylene-3,4-
bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octan-6-yl}malonate
71.8, 171.5, 169.4, 167.6, 141.4, 119.8, 113.3, 104.9, 80.9, 53.1,
2.8, 52.3, 45.9, 45.5, 44.6, 43.1, 40.9 and 21.6; MS (EI) m/z 396
(
45)
ϩ
(
(
M ϩ H), 363, 353, 322, 275; HRMS (EI) Calc. for C H NO
M): 395.1216. Found: M , 395.1212.
18
21
9
ϩ
Iodide 44 (352 mg, 0.69 mmol) in MeOH (15 ml) was treated
with activated Zn as described for enone 14. Chromatography
on silica gel (elution with EtOAc–hexane, 1 : 1) gave hemiketal
Dimethyl {(1R*,2S*,5S*,6S*,7S*)-5-tert-butyldimethylsilyloxy-
methyl-6,7-bis(methoxycarbonyl)-4-oxo-8-oxabicyclo[3.2.1]-
octan-2-yl}malonate (42)
4
5 (158 mg, 0.41 mmol, 59%) as a colourless oil; R = 0.09 (silica
f
gel; EtOAc–hexane, 1 : 2); δH (500 MHz, CDCl ) 5.53 (br s, 1
3
H), 5.15 (d, J 1.2, 1 H), 4.75 (br s, 1 H), 4.20 (br s, 1 H), 3.78 (s, 3
H), 3.77 (s, 3 H), 3.75 (s, 6 H), 3.55 (d, J 9.1, 1 H), 3.37 (t, J 5.3,
To a solution of NaH (60%, prewashed with hexane; 100 mg,
2
.5 mmol) in THF (5 ml) at 0 ЊC was added dimethyl malonate
1
H), 3.10 (br s, 1 H), 2.90 (tdd, J 9.1, 5.8, 1.5, 1 H), 2.28 (dd,
(
0.25 ml, 2.2 mmol) in THF (10 ml). The resulting solution was
J 9.1, 1.3, 1 H) and 1.78 (dd, J 13, 5.8, 1 H); MS (EI) m/z 386
stirred for 20 min at room temperature. Then a solution of
compound 9a (700 mg, 1.8 mmol) in THF (15 ml) was added to
this solution at 0 ЊC, then the mixture was stirred at room
temperature for 30 min. The reaction mixture was diluted with
Et O, then saturated aq. NH Cl was added. The organic layer
ϩ
(
M ), 337, 250; HRMS (EI) Calc. for C H O (M): 386.1213.
17 22 10
ϩ
Found: M , 386.1216.
Dimethyl {(1R*,3S*,4R*,5S*,6R*)-2-(but-3-enyl)-1-hydroxy-
,4-bis(methoxycarbonyl)-8-oxabicyclo[3.2.1]octan-6-yl}-
2
4
3
was separated, the aqueous phase was extracted with ether and
the combined organic layers were washed with brine, dried
malonate (46)
(
MgSO ), filtered and concentrated. Purification with chrom-
2
To a solution of alkene 45 (158 mg, 0.41 mmol) in CH Cl2
4
(
0
5 ml) at Ϫ78 ЊC were added allyltrimethylsilane (0.12 ml,
.76 mmol) and TiCl (0.05 ml, 0.46 mmol). The mixture was
atography on silica gel (elution with EtOAc–hexane, 1 : 3) gave
compound 42 (780 mg, 1.5 mmol, 83%) as a white solid; R =
4
f
stirred at this temperature for 30 min, then quenched with satur-
ated aq. NaHCO . The separated aqueous solution was
0
.17 (silica gel; EtOAc–hexane, 1 : 2); mp 103–106 ЊC (CH Cl );
2 2
Ϫ1
νmax(neat)/cm 2950, 2860, 1735 and 1435; δH (500 MHz,
3
extracted with CH Cl and the combined organic extracts were
CDCl ) 4.76 (br s, 1 H), 4.04 (d, J 12, 1 H), 3.96 (d, J 6.7, 1 H),
2
2
3
dried (MgSO ), filtered and concentrated. Chromatography of
3
(
.90 (d, J 12, 1 H), 3.76 (s, 3 H), 3.75 (s, 3 H), 3.73 (s, 3 H), 3.70
s, 3 H), 3.65 (d, J 8.2, 1 H), 3.63 (dd, J 6.7, 1.8, 1 H), 2.94 (tdd,
J 8.2, 4.3, 1.2, 1 H), 2.62 (dd, J 17, 8.2, 1 H), 2.44 (dd, J 17, 4.3,
H), 0.89 (s, 9 H), 0.07 (s, 3 H) and 0.05 (s, 3 H); δ (125 MHz,
4
the residue on silica gel (elution with EtOAc–hexane, 1 : 2) gave
compound 46 (80 mg, 0.19 mmol, 46%) as a colourless oil; R =
f
Ϫ1
0
2
5
3
1
2
1
1
.31 (silica gel; EtOAc–hexane, 1 : 1); νmax(neat)/cm 3575,
1
C
954, 1725 and 1440; δ (500 MHz, CDCl ) 5.84–5.74 (m, 1 H),
CDCl ) 204.1, 171.8, 170.1, 168.2, 168.0, 91.8, 79.4, 60.6, 54.9,
H
3
3
.02 (d, J 17, 1 H), 4.95 (d, J 10, 1 H), 4.57 (br s, 1 H), 3.74 (s,
H), 3.73 (s, 3 H), 3.72 (s, 3 H), 3.69 (s, 3 H), 3.61 (d, J 7.6,
H), 3.50 (d, J 9.4, 1 H), 3.01 (s, 1 H), 2.82 (dt, J 9.4, 5.2, 1 H),
.69 (dd, J 13, 9.4, 1 H), 2.19–2.09 (m, 2 H), 2.09–1.99 (m, 1 H),
.86–1.77 (m, 1 H), 1.71–1.62 (m, 1 H) and 1.39 (dd, J 13, 5.2,
5
2.8, 52.7(×2), 52.6, 51.9, 49.7, 40.8, 37.2, 25.7(×3), 18.2, Ϫ5.5
ϩ ϩ
and Ϫ5.6; MS (FAB ) m/z 517 (M ϩ H), 485, 427, 385;
HRMS (FAB ) Calc. for C H O Si (M ϩ H): 517.2105.
ϩ
23
37 11
Found: m/z 517.2108; Calc. for C H O Si: C, 53.47; H, 7.02.
23
36 11
Found: C, 53.33; H, 7.07%.
H), OH not observed; δC (125 MHz, CDCl ) 173.5, 172.2,
3
Dimethyl {(1R*,2S*,5S*,6S*,7S*)-5-hydroxymethyl-6,7-bis-
168.9, 168.8, 138.2, 114.9, 106.5, 78.8, 56.0, 52.7(×2), 52.6, 51.9,
47.0, 42.9, 41.0, 40.2, 35.3, 31.5 and 26.4; MS (EI) m/z 385
(
methoxycarbonyl)-4-oxo-8-oxabicyclo[3.2.1]octan-2-yl}-
ϩ
malonate (43)
(M Ϫ allyl), 353, 288, 225; HRMS (EI) Calc. for C H O
20
28 10
ϩ
(
M): 428.1682. Found: M , 428.1697.
With the procedure as described for alcohol 12, the silyl ether 42
(
1
600 mg, 1.2 mmol) was desilylated to give alcohol 43 (450 mg,
.1 mmol, 97%) as a white solid; R = 0.27 (silica gel; EtOAc–
(
1R*,5S*,6R*,7S*)-4-(But-3-enyl)-5,6,10-tris(methoxy-
f
carbonyl)-8-oxabicyclo[5.3.0]decane-3,9-dione (47)
Ϫ1
hexane, 2 : 1); mp 105–110 ЊC (CH Cl ); νmax(neat)/cm 3520,
2
2
2
960, 1730 and 1440; δH (500 MHz, CDCl ) 4.80 (br s, 1 H),
To a solution of hemiketal 46 (59 mg, 0.14 mmol) in THF (5 ml)
3
3
.99 (dd, J 13, 4.9, 1 H), 3.93 (dd, J 13, 9.1, 1 H), 3.82 (d, J 6.7,
at room temperature was added NaOMe (45 mg, 0.83 mmol)
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767
765

View Article Online
during 2 h. Saturated aq. NaHCO was added and the organic
phase was extracted with EtOAc. The combined organic layers
concentrated. Purification with chromatography on silica gel
(elution with EtOAc–hexane, 1 : 4) gave compound 52 (56 mg,
3
were washed with brine, dried (MgSO ), filtered and concen-
trated. Chromatography on silica gel (elution with EtOAc–
hexane, 1 : 2) gave bicycle 47 (36 mg, 0.091 mmol, 66%) as a
0.10 mmol, 61%) as a colourless oil; R = 0.11 (silica gel;
EtOAc–hexane, 1 : 3); νmax(neat)/cm 2955, 2860, 1740 and
4
f
Ϫ1
1435; δH (500 MHz, CDCl ) 5.77–5.68 (m, 1 H), 4.99 (d, J 17,
3
colourless oil; R = 0.29 (silica gel; EtOAc–hexane, 1 : 1);
1 H), 4.96 (d, J 8.8, 1 H), 4.55 (br s, 1 H), 3.77 (s, 3 H), 3.75 (s, 3
H), 3.69 (s, 6 H), 3.73–3.68 (m, 1 H), 3.39–3.28 (m, 2 H), 3.22
(d, J 10, 1 H), 2.93–2.79 (br s, 1 H), 2.74–2.63 (m, 2 H), 2.04
(sept, J 7.6, 2 H), 1.86 (sept, J 6.7, 1 H), 1.50–1.41 (m, 1 H), 0.88
(s, 9 H), 0.11 (s, 3 H) and 0.03 (s, 3 H); δ (125 MHz, CDCl )
f
Ϫ1
νmax(neat)/cm 2950, 2925, 1785, 1735 and 1435; δ (500 MHz,
H
CDCl ) 5.71–5.62 (m, 1 H), 5.06 (d, J 17, 1 H), 5.01–4.96 (m, 2
3
H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.71 (s, 3 H), 3.66 (d, J 7.6, 1 H),
3
1
3
.58 (dd, J 6.4, 3.4, 1 H), 3.51 (dd, J 6.4, 5.8, 1 H), 3.47–3.39 (m,
H), 2.81–2.71 (m, 1 H), 2.57 (dt, J 7.6, 5.5, 1 H), 2.10–1.88 (m,
C
3
208.7, 172.7, 172.6, 168.5, 168.1, 137.8, 115.5, 73.4, 52.8(×2),
52.6(×2), 52.3, 52.0, 48.7, 47.1, 42.3, 41.1, 31.7, 27.1, 25.6(×3),
H) and 1.39–1.31 (m, 1 H), OH not observed; δ (125 MHz,
C
ϩ
ϩ
CDCl ) 205.3, 171.0, 170.8, 169.9, 167.5, 137.1, 115.9, 78.0,
17.9, Ϫ4.8 and Ϫ5.0; MS (EI) m/z 485 (M Ϫ tBu), 454 (M Ϫ
tBu Ϫ OMe); HRMS (EI) Calc. for C H O Si (M Ϫ tBu):
3
5
3.3, 53.0, 52.8, 52.5, 50.5, 46.4, 44.3, 44.1, 36.1, 31.2 and 26.7;
22
33 10
ϩ ϩ
MS (EI) m/z 397 (M ϩ H), 353 (M Ϫ allyl), 225; HRMS (EI)
Calc. for C H O (M): 396.1420. Found: M , 396.1412.
485.1843. Found: m/z, 485.1843.
ϩ
19
24
9
Dimethyl [(1R*,2R*,3S*,4R*,5S*)-2-tert-butyldimethylsilyl-
oxy-5-(2-formylethyl)-3,4-bis(methoxycarbonyl)-6-oxocyclo-
heptyl]malonate (53)
(
5
(
4R*,5S*,6R*,7S*)-7-(But-3-enyl)-4-tert-butyldimethylsilyloxy-
,6-bis(methoxycarbonyl)cyclohept-2-enone (50) and
1R*,2S*,3R*,4S*,6R*)-4-tert-butyldimethylsilyloxy-7-methyl-
The olefin 52 (36 mg, 66 µmol) in MeOH (3 ml) was ozonolyzed
at Ϫ78 ЊC for 30 min. After removal of excess of ozone by
bubbling oxygen through the solution for 10 min, sodium
bicarbonate (5 mg) was introduced followed by the addition of
dimethyl sulfide (0.3 ml). This mixture was allowed to warm to
room temperature, then was stirred overnight. The reaction
mixture was filtered and concentrated. Chromatography of the
residue on silica gel (elution with EtOAc–hexane, 1 : 1) gave the
aldehyde 53 as a colourless oil.
ene-2,3-bis(methoxycarbonyl)bicyclo[4.3.1]decan-10-one (51)
To a solution of the cycloheptanone 24 (200 mg, 0.46 mmol)
in THF (10 ml) at Ϫ78 ЊC was added KHMDS (0.5 M sol-
ution in toluene, 0.55 mmol) and then the resulting mixture
was stirred for 15 min. To this solution at Ϫ78 ЊC was added
TMSCl (0.08 ml, 0.63 mmol) and then the solution was
stirred for 30 min. Saturated aq. NaHCO was added and the
3
aqueous phase was extracted with Et O. The combined organic
2
layers were washed with brine, dried (MgSO ), filtered and
concentrated.
4
Dimethyl {(1R*,4R*,7S*,10S*,11S*,12S*)-11-tert-butyl-
dimethylsilyloxy-12-methoxycarbonyl-2,10-dioxo-3-oxatricyclo-
To the above material in CH CN (10 ml) at room temperature
3
4
,12
[
5.4.1.0 ]dodecan-10-yl}malonate (54) and dimethyl
(1R*,2S*,3S*,4R*,5S*,6R*)-3-tert-butyldimethylsilyloxy-9-
hydroxy-4,5-bis(methoxycarbonyl)-10-oxobicyclo[4.3.1]decan-
-yl}malonate (55)
was added Pd(OAc) (170 mg, 0.75 mmol). The resulting sol-
2
{
ution was stirred for 3 h at this temperature and the solvent was
evaporated. Purification with PLC (EtOAc–hexane, 1 : 7, twice)
gave enone 50 (70 mg, 0.17 mmol, 35%) and bicycle 51 along
with starting material (60 mg, 4 : 1), which could not be
separated.
2
To a solution of aldehyde 53 in MeOH (2 ml) was added solid
K CO at room temperature, then the resulting mixture was
2
3
For compound 50, R = 0.43 (silica gel; EtOAc–hexane, 1 : 3);
f
stirred for 1.5 h. Saturated aq. NH Cl and EtOAc were added,
4
Ϫ1
νmax(neat)/cm 2950, 2930, 1735 and 1685; δH (500 MHz,
then the organic layer was separated. The aqueous layer was
extracted with EtOAc and the combined organic layers were
CDCl ) 6.61 (dd, J 12, 7.0, 1 H), 6.06 (d, J 12, 1 H), 5.83–5.74
3
(
(
m, 1 H), 5.01 (dq, J 17, 1.8, 1 H), 4.97–4.93 (m, 2 H), 3.73
s, 3 H), 3.67 (d, J 4.26, 1 H), 3.67 (s, 3 H), 3.50 (dd, J 7.0, 4.3,
washed with brine, dried (MgSO ), filtered and concentrated.
4
Purification by means of chromatography on silica gel (elution
with EtOAc–hexane 1 : 4) gave tricycle 54 (9.9 mg, 19 µmol,
1
(
(
H), 3.45 (dd, J 7.0, 2.7, 1 H), 2.19–2.12 (m, 2 H), 2.10–2.02
m, 1 H), 1.59–1.50 (m, 1 H), 0.84 (s, 9 H), 0.04 (s, 3 H) and 0.04
s, 3 H); δ (125 MHz, CDCl ) 201.9, 173.3, 172.0, 142.4, 138.0,
2
9%, 2 steps) along with bicycle 55 (2.7 mg, 4.9 µmol, 7%,
C
3
2 steps) as colourless oils.
1
2
34.8, 115.3, 68.0, 52.3, 52.1, 51.1, 48.5, 43.7, 31.7, 28.0,
For compound 54, R = 0.37 (silica gel; EtOAc–hexane, 1 : 2);
f
ϩ
Ϫ1
5.5(×3), 17.8, Ϫ4.4 and Ϫ5.5; MS (EI) m/z 410 (M ), 353
νmax(neat)/cm 2955, 2930, 2855 and 1735; δH (500 MHz,
ϩ
ϩ
(
M Ϫ tBu); HRMS (FAB ) Calc. for C H O Si (M ϩ H Ϫ
17 26 6
CDCl ) 4.93 (d, J 5.5, 1 H), 4.49 (t, J 2.7, 1 H), 3.89 (s, 3 H),
3
tBu): 354.1499. Found: m/z, 354.1490.
3
.83 (d, J 2.7, 1 H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.62 (d, J 11,
For compound 51, R = 0.46 (silica gel; EtOAc–hexane, 1 : 3);
f
1 H), 3.42 (dd, J 11, 6.7, 1 H), 3.00 (q, J 10, 1 H), 2.55 (dd, J 12,
9.1, 1 H), 2.37–2.30 (m, 1 H), 2.29–2.15 (m, 3 H), 1.97–1.88 (m,
δ (500 MHz, CDCl ) 4.76 (s, 1 H), 4.75 (s, 1 H), 4.57 (d, J 6.1, 1
H
3
H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.48 (dd, J 12, 4.0, 1 H), 3.28–
.23 (m, 2 H), 3.08–3.03 (m, 1 H), 2.53–2.46 (m, 2 H), 2.22–2.17
1
H), 0.86 (s, 9 H), 0.17 (s, 3 H) and 0.09 (s, 3 H); δ (125 MHz,
C
3
CDCl ) 202.9, 175.5(×2), 167.9, 167.4, 88.3, 72.5, 62.1, 57.5,
3
(
(
m, 1 H), 2.00–1.93 (m, 1 H), 1.82 (d, J 15, 5.5, 1 H), 1.73–1.65
m, 1 H), 0.85 (s, 9 H), 0.05 (s, 3 H) and Ϫ0.07 (s, 3 H).
5
4.4, 54.1, 53.0, 52.9, 48.2, 40.9, 40.5, 32.2, 27.2, 25.9(×3), 18.3,
ϩ
Ϫ5.0 and Ϫ5.3; MS (EI) m/z 455 (M Ϫ tBu), 395, 303, 275;
HRMS (EI) calc. for C H O Si (M Ϫ tBu): 455.1374. Found:
20
27 10
Dimethyl [(1R*,2R*,3S*,4R*,5S*)-5-(but-3-enyl)-2-tert-butyl-
dimethylsilyloxy-3,4-bis(methoxycarbonyl)-6-oxocycloheptyl]
malonate (52)
m/z, 455.1364.
For compound 55 (major isomer), R = 0.22 (silica gel;
f
EtOAc–hexane, 1 : 2); δH (500 MHz, CDCl ) 4.43 (br s, 1 H),
3
4
(
2
.18 (s, 1 H), 3.79 (s, 3 H), 3.78–3.76 (m, 4 H), 3.68 (s, 3 H), 3.62
s, 3 H), 3.23 (dd, J 12, 5.2, 1 H), 2.94 (dt, J 12, 2.4, 1 H), 2.87–
.80 (m, 1 H), 2.74 (d, J 12, 1 H), 2.65 (br s, 1 H), 2.44 (br s, 1
H), 2.31–2.21 (m, 1 H), 2.07–2.01 (m, 1 H), 1.66–1.62 (m, 1 H),
.93 (s, 9 H), 0.16 (s, 3 H) and Ϫ0.04 (s, 3 H), OH not observed.
To a solution of NaH (60%, prewashed with hexane; 15 mg,
0
.38 mmol) in THF (1 ml) at 0 ЊC was added dimethyl malonate
0.05 ml, 0.44 mmol) in THF (2 ml). The resulting solution was
stirred for 20 min at room temperature. A solution of enone 50
70 mg, 0.17 mmol) in THF 15 min was added to this solution
at 0 ЊC, then the mixture was stirred at reflux temperature for
d. The reaction mixture was diluted with Et O, then saturated
(
0
(
Dimethyl {(1R*,2S*,3S*,4R*,5S*,6R*)-3-tert-butyldimethyl-
silyloxy-4,5-bis(methoxycarbonyl)-9,10-dioxobicyclo[4.3.1]-
decan-2-yl}malonate (56)
1
2
aq. NH Cl was added. The organic layer was separated and the
4
aqueous phase was extracted with ether. The combined organic
layers were washed with brine, dried (MgSO ), filtered and
To a solution of the alcohol 55 (2.6 mg, 4.8 µmol) in CH Cl2
4
2
7
66
J. Chem. Soc., Perkin Trans. 1, 2002, 755–767

View Article Online
(
1 ml) were added PCC (10 mg, 46 µmol) and 4 Å MS at room
temperature. The mixture was stirred at room temperature for
d, then filtered and concentrated. Chromatography of the
residue on silica gel (elution with EtOAc–hexane, 1 : 3) gave
dione 56 (2.0 mg, 3.7 µmol, 77%) as a colourless oil; R = 0.37
2001, 3, 2435; (s) D. L. J. Clive and S. Sun, Tetrahedron Lett., 2001,
2, 6267; (t) M. G. Banwell, K. J. McRae and A. C. Willis, J. Chem.
Soc., Perkin Trans. 1, 2001, 2194.
(a) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, H.-S. Choi, W. H.
Yoon, Y. He and K. C. Fong, Angew. Chem., Int. Ed., 1999, 38, 1669;
(b) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong, K. C. Fong, Y. He,
W. H. Yoon and H.-S. Choi, Angew. Chem., Int. Ed., 1999, 38, 1676;
(c) K. C. Nicolaou, J. K. Jung, W. H. Yoon, Y. He, Y.-L. Zhong and
P. S. Baran, Angew. Chem., Int. Ed., 2000, 39, 1829; (d ) C. Chen,
M. E. Layton, S. M. Sheehan and M. D. Shair, J. Am. Chem. Soc.,
4
2
5
f
Ϫ1
(
2
3
silica gel; EtOAc–hexane, 1 : 2); νmax(neat)/cm 2955, 2930,
855, 1735 and 1445; δ (500 MHz, CDCl ) 4.21 (d, J 2.7, 1 H),
H
3
.80 (s, 3 H), 3.78 (s, 3 H), 3.72 (s, 3 H), 3.65 (s, 3 H), 3.53 (d,
J 12, 1 H), 3.40 (dd, J 12, 5.8, 1 H), 3.34 (dt, J 12, 2.7, 1 H), 3.26
2
000, 122, 7424; (e) N. Waizumi, T. Itoh and T. Fukuyama, J. Am.
(
(
(
br s, 1 H), 3.19 (ddd, J 18, 12, 7.3, 1 H), 2.90 (br s, 1 H), 2.83
d, J 12, 1 H), 2.53 (d, J 18, 1 H), 2.41–2.35 (m, 1 H), 2.02–1.94
m, 1 H), 0.88 (s, 9 H), 0.12 (s, 3 H) and Ϫ0.06 (s, 3 H):
Chem. Soc., 2000, 122, 7825; ( f ) Q. Tan and S. J. Danishefsky,
Angew. Chem., Int. Ed., 2000, 39, 4509.
6 (a) J. B. Hendrickson and J. S. Farina, J. Org. Chem., 1980, 45, 3359;
(b) P. G. Sammes, Gazz. Chim. Ital., 1986, 116, 109.
δ (125 MHz, CDCl ) 206.9, 206.6, 174.6, 172.5, 168.1, 167.1,
C
3
7
(a) K. A. Marshall, A. K. Mapp and C. H. Heathcock, J. Org.
Chem., 1996, 61, 9135; (b) P. Magnus and L. Shen, Tetrahedron,
7
3
5
(
5
3.0, 62.1, 53.3, 53.0, 52.6, 52.4, 51.6, 49.1, 48.2, 47.5, 38.9,
ϩ
4.3, 25.9(×3), 23.5, 18.0, Ϫ4.9 and Ϫ6.0; MS (FAB ) m/z
1
999, 55, 3553.
ϩ
ϩ
43 (M ϩ H), 512 (M Ϫ OCH ), 475, 206, 185; HRMS
3
8
(a) P. A. Wender, K. D. Rice and M. E. Schnute, J. Am. Chem. Soc.,
1997, 119, 7897; (b) P. A. Wender, C. D. Jesudason, H. Nakahira,
N. Tamura, A. L. Tebbe and Y. Ueno, J. Am. Chem. Soc., 1997, 119,
ϩ
ϩ
FAB ) Calc. for C H O Si (M ϩ H): 543.2261. Found: m/z,
25 39 11
43.2278.
1
2976.
9
(a) R. Takagi, A. Sasaoka, S. Kojima and K. Ohkata, Chem.
Commun., 1997, 1887; (b) R. Takagi, A. Sasaoka, H. Nishitani,
S. Kojima, Y. Hiraga and K. Ohkata, J. Chem. Soc., Perkin Trans. 1,
1998, 925; (c) M. Tokumasu, H. Ando, Y. Hiraga, S. Kojima and
K. Ohkata, J. Chem. Soc., Perkin Trans. 1, 1999, 489; (d ) H.
Nishitani, A. Sasaoka, M. Tokumasu and K. Ohkata, Heterocycles,
Acknowledgements
The author is grateful to Prof K. Ohkata for his valuable advice
and to Dr S. Kojima for prereading the manuscript. He is also
grateful to Drs Y. Hiraga and R. Takagi for assistance in
NMR. He thanks Dr M. Sawada for support of elemental
analysis. The Instrument Center for Chemical Analysis of
Hiroshima University and the Hiroshima Prefectural Institute
of Industrial Science and Technology are heartily acknow-
ledged for providing machine time on NMR and MS.
1
999, 50, 35; (e) Y. Hiraga, M. Ago, M. Tokumasu, K. Kaku and
K. Ohkata, Aust. J. Chem., 2000, 53, 909.
0 N. Ohmori, T. Miyazaki, S. Kojima and K. Ohkata, Chem. Lett.,
001, 906.
1
2
11 (a) L. F. Tietze, G. Kettschau, J. A. Gewart and A. Schuffenhauer,
Curr. Org. Chem., 1998, 2, 19; (b) L. F. Tietze and G. Kettschau,
Top. Curr. Chem., 1997, 189, 1.
2 (a) C. Mukai, K. Kagayama and M. Hanaoka, J. Chem. Soc., Perkin
Trans. 1, 1998, 3517; (b) see also ref. 4d.
3 R. Hara, T. Furukawa, Y. Horiguchi and I. Kuwajima, J. Am. Chem.
Soc., 1996, 118, 9186 . H NMR data for C2α isomer of 24; δH
(500 MHz, CDCl ) 5.72–5.64 (m, 1 H), 4.97–4.92 (m, 2 H), 4.64 (d
1
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