[2.2.1]-Bicyclic systems relevant to synthetic studies on CP-225,917 - Use of a new silylated cyclopentadiene

Article abstract of DOI:10.1016/j.tet.2004.03.042

The [2.2.1]-bicyclic ketone 6, a potential synthetic precursor to CP-225,917, was prepared by a sequence beginning with Diels-Alder reaction between dimethyl fumarate and the silylated cyclopentadiene 38. The adduct 40 was subjected to Tamao-Fleming oxidation, which converted it into alcohol 21. During the oxidation BF₃·Et₂O-AcOH was used instead of the more expensive BF₃·2AcOH complex. Alcohol 21 was elaborated into 6, which carries one of the sidechains of CP-225,917, as well as other substituents that are appropriate for further elaboration.

Full text of DOI:10.1016/j.tet.2004.03.042

Tetrahedron 60 (2004) 4205–4221
[
2.2.1]-Bicyclic systems relevant to synthetic studies on
CP-225,917—use of a new silylated cyclopentadiene
*
Derrick L. J. Clive, Hua Cheng, Pulak Gangopadhyay, Xiaojun Huang and Bodhuri Prabhudas
Department of Chemistry, University of Alberta, Edmonton, Alberta., Canada T6G 2G2
Received 26 January 2004; revised 16 March 2004; accepted 16 March 2004
Abstract—The [2.2.1]-bicyclic ketone 6, a potential synthetic precursor to CP-225,917, was prepared by a sequence beginning with Diels–
Alder reaction between dimethyl fumarate and the silylated cyclopentadiene 38. The adduct 40 was subjected to Tamao–Fleming oxidation,
which converted it into alcohol 21. During the oxidation BF ·Et O–AcOH was used instead of the more expensive BF ·2AcOH complex.
3 2 3
Alcohol 21 was elaborated into 6, which carries one of the sidechains of CP-225,917, as well as other substituents that are appropriate for
further elaboration.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction and discussion
1
,2
Publications from this laboratory have described two
routes leading to the crystalline compound 1, which
represents the core structure of CP-225,917 (2), a fungal
3
,4
metabolite that has attracted considerable attention from
5
synthetic chemists because of the challenge it poses, and
the fact that it has potentially important biochemical
properties related to the design of drugs for treatment of
3
1
cancer and hypercholersterolemia. One of our routes
involves the strain-assisted oxy-Cope rearrangement 4!5,
as summarized in Scheme 1. In order to explore further the
use of this approach to CP-225,917 we needed to prepare a
[
2.2.1]-bicyclic system analogous to 3, but with suitable
4
substituents at C(8) and C(9). In this paper we deal with the
construction of 6, a [2.2.1]-bicycle with the required
substituent at C(8), a truncated substituent at C(9), and
functional groups that should allow further elaboration
Scheme 1.
1
along lines we have studied with model compounds.
2. First route
Our initial approaches to 6 were based on two Diels–Alder
6
sequences: (i) the known cycloaddition of 7 and 8 to
generate 9, followed by conversion into 11 (Scheme 2), and
(ii) the sequence of Scheme 3. Esters 11 and 14 were
then elaborated into several compounds of type 15.
However, attempts to displace the TsO group using I2 or
Keywords: Diels–Alder reaction; Silylated cyclopentadiene; Modified
Tamao–Fleming oxidation; [2.2.1]-Bicyclic ketone; Boron trifluoride
etherate-acetic acid.
6
,7
6
8
*
Corresponding author. Tel.: þ1-780-492-3251; fax: þ1-780-492-8231;
e-mail address: derrick.clive@ualberta.ca
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.042

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D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
0
arise if the C(2) oxygen function were anti to C(1 ) and, in
the event, this was indeed the case. Attempts to invert the
C(2) stereochemistry (see 15 for numbering) of several of
our [2.2.1]-bicycles were unsuccessful, and so we decided to
modify the synthesis in such a way that the desired anti
stereochemistry would be an intrinsic outcome of the route.
In this regard, we were guided by the method we had used to
make 11. The structure of the precursor 9 suggested that an
appropriate choice of silyl group would allow use of the
1
5
Tamao–Fleming oxidation to replace the silyl group by an
hydroxyl with retention of stereochemistry. For this
1
5
purpose, the silicon atom must carry certain substituents,
and the corresponding silylated cyclopentadiene (cf. 7)
1
6
should be available. A suitable cyclopentadiene (18) had
indeed been subjected to sequential Diels–Alder reaction
Scheme 2.
1
7
and Tamao–Fleming oxidation, and so we examined the
1
6
Diels–Alder reaction between 18 and dimethyl fumarate
Scheme 5). A stoichiometric amount of Me AlCl was
(
2
required at 278 8C and, under these conditions, the desired
product (20) was obtained in ca. 53% yield, as well as the
corresponding desilylated material (19). We assume that
the latter is formed by desilylation of 18 before it undergoes
the cycloaddition. Tamao–Fleming oxidation then afforded
the desired alcohol 21 in 43% yield from 20. X-ray
Scheme 3.
9
18
Bu CuLi—the latter serving as a simple model cuprate —
2
analysis of the 3,5-dinitrobenzoate derivative of 21
were unsuccessful or gave poor yields.
confirmed the indicated stereochemistry. Although the
Diels–Alder-oxidation sequence in its present form was
not satisfactory (23% overall from 18), we used our supply
of 21 to develop a method for introducing the C(8)
sidechain, as described below. Later, however, we found a
better silylated diene, and we also modified our approach for
elaborating the C(8) sidechain.
In one series of experiments, aldehyde 16 (stereochemistry
at starred atom not established) was treated with the
Grignard reagent derived from (E)-7-bromo-2-heptene
to generate the expected alcohols 17 (Scheme 4). The yield
in this process was high (96%) when Rieke magnesium was
used to generate the reagent. Unfortunately, deoxygenation
of the resulting alcohols proved troublesome. Tosylation
was unsuccessful, and sequential treatment with MsCl and
1
0,14
LiAlH gave a complex mixture, as did attempts to convert
4
the alcohols into the corresponding bromides. The derived
methyl xanthate and p-fluorophenylthionocarbonate could
be formed (ca. 90% yield), but deoxygenation with Bu SnH
3
caused some (ca. 30% in the case of the thionocarbonate)
E!Z isomerization of the sidechain double bond.
Scheme 5.
Alcohol 21 was protected as its MOM ether and subjected to
bromolactonization (Scheme 6, 21!22!23). Debromina-
tion with Bu SnH (23!24), and selective reduction of the
3
lactone carbonyl to the corresponding lactols (24!25),
followed by treatment with t-BuMe SiCl, took the route as
2
far as the lactol ether 26 [a single isomer of unestablished
stereochemistry at the starred carbon (Scheme 6)]. The
remaining ester carbonyl was converted by reduction and
oxidation into an aldehyde (26!27!28). Reaction of 28
with (E)-5-heptenylmagnesium bromide (generated using
1
9
Rieke magnesium ) gave a complex mixture, and we
suspected that the silyl-protected lactol unit was unstable in
the presence of the Grignard reagent. Accordingly, we
modified our selection of protecting groups, as summarized
in Scheme 7, choosing a lactol methyl ether because our
earlier experiments (see Scheme 4, 16!17) had shown that
Scheme 4.
By this stage, our observations had made it clear that steric
factors were responsible for the problems met in the
0
for numbering). We assumed these problems would not
reactions at C(1 ) of the [2.2.1]-bicyclic substrates (see 15

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4207
a
Scheme 6. Single stereoisomer at starred atom.
this mode of protection was compatible with the Grignard
reagent.
Following standard procedures, alcohol 21 was silylated
(
21!29), subjected to bromolactonization (29!30), and
then to tin hydride reduction (30!31). The dehalogenation
was done with a stoichiometric amount of stannane, but
could also be accomplished with a catalytic amount of
Bu SnCl and a stoichiometric amount of NaCNBH in
refluxing t-BuOH. The catalytic procedure allowed us to
generate lactone 31 in 76% yield from 30; in the
stoichiometric reaction the yield was 95%. The lactone
carbonyl was then reduced selectively (76%) with
DIBAL-H at 278 8C, and treatment of the resulting lactols
a
b
3
3
Scheme 7. 76% by catalytic method. The ‘a’ series refers to exo OMe, ‘b’
c
series refers to endo OMe. Single isomer at C(1 ) if no TMEDA is used.
0
corresponds to the single product obtained in the absence of
TMEDA), and reduction with Et
pleted elaboration of the C(8) sidechain (59% from 36a).
BHLi (36a!37a) com-
3
3
2 with HC(OMe) in the presence of TsOH·pyridine gave
3
0
the desired lactol methyl ethers 33 (77%) as a mixture of
two isomers. The ester group was then reduced with
DIBAL-H at 278 8C to room temperature; the two isomeric
products (34a and 34b) were separable and could be isolated
in 79 and 14% yield (from a small scale experiment),
Similar treatment of the minor C(1 ) isomer of 36a
(mesylation, 96%; reduction 52%) also gave 37a, as
expected. We did not subject 35b to the same sequence of
reactions but, as described below, we later elaborated both
the major (35a) and minor (35b) isomers in a different way.
1
8
respectively. X-ray analysis of the minor isomer (34b)
showed that the methoxy group was endo, a conclusion also
reached by NOE measurements on 34a and 34b. Dess–
Martin oxidation of the major (exo) isomer (34a), afforded
the required aldehyde (35a, 80%), but Swern oxidation gave
a higher yield (94%), and the Swern method was applied to
the minor isomer 34b (92%). Aldehyde 35a reacted with
3. Second route
While the above work was in progress, we considered
2
0
alternatives to the silylated cyclopentadiene 18; this was
not a stable compound, and appeared to be subject to
extensive desilylation under conditions of the Diels–Alder
reaction. Among the silicon groups that permit Tamao–
(
Rieke magnesium, to give a single alcohol (36a) in 60%
E)-5-heptenylmagnesium bromide, again generated with
0
When reaction of aldehyde 35a with (E)-5-heptenyl-
yield. The stereochemistry at C(1 ) was not established.
Fleming oxidation, we decided to examine an ArMe Si
2
group, in which the aromatic unit carries an electron-
donating substituent, whose presence was expected to
magnesium bromide (from Rieke Mg) was done in the
presence of 35 equiv. TMEDA per equiv aldehyde, alcohol
2
1
facilitate the Si!O exchange. We prepared the two
compounds 38 and 39, in each case by treatment of
lithium cyclopentadienide with the appropriate silane,
0
3
8
6a was obtained as a 1:1.64 mixture of C(1 ) isomers in
2% yield. Mesylation of the major isomer of 36a (which

4208
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
2
2
chlorodimethyltolylsilane or chloro(4-methoxyphenyl)-
2
3
dimethylsilane. Diene 38 gave a cleaner product in its
reaction with dimethyl fumarate, and was therefore used in
subsequent work. The material, which was used crude,
1
could be stored at room temperature without change ( H
NMR) for at least two weeks; in contrast, 18 has to be kept at
a low temperature (i.e. below 10 8C), and even then did not
2
4
survive for more than a few days. Attempts to purify 38
did not effect much improvement, but the crude material
was suitable for direct use in the next step (Scheme 8).
Scheme 8.
Reaction of an excess of 38 with dimethyl fumarate (8) at
0
for 24 h gave 40 in ca. 94% yield (Scheme 9), but
8C in the presence of a stoichiometric amount of Et AlCl
2
1
contaminated by ca. 7% ( H NMR) of another substance
which we speculate may be the syn isomer or the result of
Diels–Alder reaction of a double bond isomer of the
original cyclopentadiene. The impurity was not separable by
chromatography. Replacement of the silyl unit by hydroxyl
required some optimization, but we eventually found that
this could be achieved by modification of a published
a
Scheme 10. ‘a’ series refers to exo OMe, ‘b’ series refers to endo OMe.
Both isomers at C(2 ).
b
0
2
5
26
procedure. Treatment with 2 equiv. AcOH and 1 equiv.
BF ·Et O served to generate the fluorosilane 41. The
by treatment with Hg(OAc)2 in aqueous THF (94%).
Reaction with the appropriate Grignard reagent—in this
3
2
2
7
AcOH–BF ·Et O mixture is less expensive than the BF ·
3
case (E)-4-hexenylmagnesium bromide, generated using
0
3
2
2
5
2AcOH complex originally used, and appears to work just
as well. The crude fluorosilane was then treated with
Rieke magnesium—gave alcohols 45a as a mixture of C(2 )
isomers in 86% yield. We initially used TMEDA as an
additive in the Grignard reaction, but later found that the
yield was the same in its absence. The hydroxyl group of
45a is less sterically hindered than that of 36a, and
anhydrous MeOH in the presence of NaHCO , to afford the
3
methoxysilane 42. Finally, treatment of 42 in situ with 30%
H O , KF, and KHCO in 1:1 THF–MeOH gave the desired
2
2
3
alcohol 21 in 77% overall yield from 40 (starting with 10 g
of 40). On a smaller scale (500 mg of 40) the yield was 95%.
Alcohol 21 was obtained pure, but its immediate precursors
mesylation (45a!46a) and reduction with LiAlH gave
4
37a (71% for the two steps). Aldehyde 35b was converted in
the same way and in comparable yield into 37b. In both
cases the reduction with LiAlH went to completion, unlike
4
1 and 42 were not characterized.
4
the previous experiments with Et BHLi (see Scheme 7), and
3
we regard the longer route of Scheme 10 as experimentally
more convenient. In repeating this route we used a mixture
of 35a and 35b for Wittig homologation, and obtained the
desired enol ethers in 90% yield on a scale that affords 5 g of
a mixture of 43a and 43b. On a similar scale, with this
isomer mixture, the yield for the hydrolysis (43a,b!44a,b)
was 94%, for the Grignard reaction 95%, and for the
mesylation–reduction sequence (46a,b!47a,b) 90%
(Scheme 11).
Demethylation of both 37a and 37b was initially trouble-
some, but we eventually found that treatment of 37a with
BCl ·SMe in Et O gave the expected lactol (as a single
3
2
2
isomer) in 74% yield; the minor isomer 37b gave the same
product in 73% yield. However, the lactol was too sensitive
for further work and behaved in uncharacteristic ways.
Fortunately, a way around these difficulties was quickly
Scheme 9.
2
8
Although we had already generated the C -sidechain (see
8
Scheme 7), we decided to examine a modified route, which
is shown in Scheme 10.
found. Treatment of 37a with propanedithiol in the presence
of TiCl at 278 8C gave the desired dithioketal 47 in 94%
4
Aldehyde 35a reacted smoothly with (methoxymethyl)-
triphenylphosphorane, giving the enol ethers 43a (81%),
which were converted into the corresponding aldehyde 44a
yield. Likewise, the minor isomer 37b gave the same
compound in 81% yield. When using a mixture of 37a and
37b, the yield was 84–98%. The secondary hydroxyl was

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4209
hexanes, 9.80 mL, 9.80 mmol) was added dropwise by
syringe over 5 min to a stirred and cooled (278 8C) solution
of dimethyl fumarate (1.452 g, 9.780 mmol). Stirring was
continued for 10 min, and a solution of 5-dimethylsilyl-
1
6
cyclopentadiene (ca. 26.52 g, ca. 27.4 mmol) in hexanes
37 mL) was added dropwise by cannula. Stirring was
continued for 5 h at 278 8C and the mixture was quenched
(
by addition of 10% aqueous NaHCO3 (100 mL). The
mixture was extracted with Et O (100 mL), and the organic
2
extract was washed with brine (2£100 mL), dried (MgSO )
4
and evaporated. Flash chromatography of the residue over
silica gel (3.5£20 cm), using 1:10 EtOAc–hexanes, gave a
mixture (2.11 g) of 19 and 20 (ca. 1:1.7, yield of 20 by
calculation is ca. 53%). The material was used directly
without characterization.
5.1.2. (2-endo,3-exo,7-anti)-7-Hydroxybicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxylic acid dimethyl ester (21)
and (2-endo,3-exo)-bicyclo[2.2.1]hept-5-ene-2,3-dicar-
boxylic acid dimethyl ester (19). Bu NF (1 M in THF,
4
3.60 mL, 3.60 mmol), KHCO (128 mg, 1.28 mmol) and
H O (30 w/w%, 1.0 mL, 9.7 mmol) were added in that
3
2
2
order to a stirred solution of a mixture of 19 (ca. 80.3 mg, ca.
.382 mmol) and 20 (ca. 163 mg, 0.598 mmol) in MeOH
1.5 mL) and THF (1.5 mL). Stirring was continued over-
0
(
night. The mixture was diluted with brine (10 mL) and
extracted with Et O (3£25 mL). The aqueous phase was
Scheme 11.
2
readily benzoylated (47!48, 96%), and then the silyl group
saved for acidification at a later stage, and the combined
organic extracts were washed with saturated aqueous
was removed in the standard way (Bu NF, 98%) and the
4
liberated hydroxyl was oxidized with TPAP to form the
target ketone 6 (87%).
Na
brine (25 mL), dried (MgSO
chromatography of the residue over silica gel
2
S
2
O
3
(25 mL), 10% aqueous NaHCO
3
(25 mL) and
) and evaporated. Flash
4
(
3.5£20 cm), using 1:10 EtOAc–hexanes, gave 19
4. Conclusion
(80.3 mg) and 21 (47.1 mg) as oils.
The silylated diene 38 has proven to be a convenient
component in Diels–Alder reaction with dimethyl fumarate,
and the silicon unit can be replaced by an hydroxyl in good
yield and with retention of configuration. BF ·OEt in the
The aqueous phase that had been saved was acidified to pH
2 with 2 N hydrochloric acid, and extracted with Et
(3£25 mL). The combined organic extracts were washed
with brine (2£30 mL) and dried (MgSO ). Evaporation of
the solvent gave an oil (160 mg). This material (160 mg)
was dissolved in acetone (3.0 mL), and K CO (447 mg,
3.24 mmol) and Me SO (0.30 mL, 3.2 mmol) were added.
The mixture was stirred overnight, diluted with EtOAc
) and
O
2
3
2
4
presence of AcOH, instead of the conventional reagent
BF ·2AcOH, can be used for conversion of 40 to 41, and is a
3
2
3
considerably cheaper alternative. The sequence
3
2
4
8!40!21!44!6 constitutes a practical route to bicyclic
ketones which have the functionality appropriate for further
elaboration along lines already studied with model com-
pounds in this laboratory.
(25 mL), washed with brine (2£20 mL), dried (MgSO
4
evaporated. Flash chromatography of the residue over silica
gel (1.5£10 cm), using 1:3 to 3:1 EtOAc–hexanes, gave 21
(11.0 mg), bringing the total yield of 21 to 43%. The above
procedure was used because some ester hydrolysis occurred
in the oxidation step.
5
. Experimental
cast) 1731 cm2 ; H NMR
1
1
5
.1. General
Compound 19. FTIR (CH Cl
2 2
(
C D , 500 MHz) d 1.27 (d, J¼8.5 Hz, 1H), 1.58 (d,
6
6
2
9
The general procedures used previously in this laboratory
J¼8.5 Hz, 1H), 2.84–2.89 (m, 1H), 2.96–2.99 (m, 1H),
1
3
were followed. The symbols s, d, t, and q used for C NMR
signals indicate zero, one, two, or three attached hydrogens,
respectively. Unless indicated to the contrary, all new
compounds were pure as judged by thin layer chromato-
3.09–3.13 (m, 1H), 3.26 (s, 3H), 3.33 (s, 3H), 3.46–3.51
(m, 1H), 5.96–6.02 (m, 2H); C NMR (C D , 125 MHz) d
6 6
1
3
46.0 (d), 47.5 (t), 47.6 (d), 48.1 (d), 48.4 (d), 51.4 (q), 51.7
(q), 135.4 (d), 137.6 (d), 173.0 (s), 174.4 (s); exact mass m/z
calcd for C11
1
13
graphy, and H NMR and C NMR spectra.
H14NaO
4
233.0790, found 233.0788.
Compound 21. FTIR (CH
NMR (C D , 300 MHz) d 2.58–2.77 (broad peak, –OH),
6 6
Cl
2 2
cast) 3436, 1731 cm2 ; H
1
1
5
.1.1. (2-endo,3-exo,7-anti)-7-(Dimethylsilanyl)bicyclo-
2.2.1]hept-5-ene-2,3-dicarboxylic acid dimethyl ester
[
(
20) and (2-endo,3-exo)-bicyclo[2.2.1]hept-5-ene-2,3-
2.75 (d, J¼5.2 Hz, 1H), 2.89–2.96 (m, 1H), 2.97–3.04 (m,
dicarboxylic acid dimethyl ester (19). Me AlCl (1 M in
2
1H), 3.21 (s, 3H), 3.27 (s, 3H), 4.12–4.17 (m, 1H),

4210
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
1
3
5
4
8
.73–5.83 (m, 3H); C NMR (CDCl , 50 MHz) d 44.6 (d),
3
methyl ester (23). Br (0.15 mL, 2.9 mmol) was added to
2
5.4 (d), 50.5 (d), 52.1 (d or q), 52.2 (d or q), 52.3 (d or q),
4.9 (d), 131.9 (d), 133.9 (d), 172.6 (s), 173.6 (s); exact
a stirred and cooled (0 8C) solution of 22 (706 mg,
2.61 mmol) in CH Cl (20 mL). The cold bath was left in
2
2
mass m/z calcd for C H NaO 249.0739, found 249.0735.
1
place, but not recharged, and stirring was continued
overnight. The mixture was quenched by addition of
saturated aqueous Na S O (15 mL), and the organic
1
14
5
5
.1.3. (2-endo,3-exo,7-anti)-7-(3,5-Dinitrobenzoyloxy)bi-
2
2 3
cyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid dimethyl
ester. A solution of pyridine (0.8 mL, 10 mmol) in
CH Cl (10 mL) was prepared. An aliquot of this solution
phase was washed with brine (2£30 mL), dried (MgSO )
4
and evaporated. Flash chromatography of the residue over
silica gel (4£13 cm), using 1:10 to 1:3 EtOAc–hexanes,
gave 23 (578 mg, 66%). FTIR (CH Cl cast) 1796,
2
2
(
dinitrobenzoyl chloride (143 mg, 0.600 mmol) in CH Cl
1 mL, 0.9 mmol) was added to a stirred solution of 3,5-
2
2
1734 cm2 ; H NMR (C D , 500 MHz) d 2.07–2.09 (m,
1
1
2
2
6 6
(
0
2 mL). After 10 min a solution of alcohol 21 (70 mg,
.30 mmol) in CH Cl (2 mL) was added dropwise, and
2 2
1H), 2.40–2.43 (m, 1H), 2.70–2.77 (m, 2H), 3.04 (s, 3H),
3.16 (s, 3H), 3.31 (s, 1H), 4.06–4.09 (m, 1H), 4.26 (d,
J¼9.4 Hz, 1H), 4.33 (d, J¼9.4 Hz, 1H), 4.88–4.93 (m 1H);
stirring was continued overnight. The mixture was poured
into dilute hydrochloric acid (2 N, 10 mL) and the aqueous
phase was extracted with CH Cl (2£5 mL). The combined
1
3
C NMR (C D , 125 MHz) d 39.2 (d), 47.7 (d), 48.8
6
6
(d), 49.0 (d), 49.1 (d), 52.3 (q), 55.8 (q), 82.2 (d), 88.6 (d),
95.9 (t), 170.1 (s), 175.4 (s); exact mass m/z calcd for
2
2
organic extracts were washed with saturated aqueous
NaHCO (5 mL), dried (MgSO ) and evaporated. Crystal-
lization of the residue from premixed 1:9 MeOH–hexane
7
9
C H
12 15
BrNaO 356.9950, found 356.9944.
6
3
4
p
5.1.6. (8R ,9R )-8-(Methoxymethoxy)-5-oxo-4-oxatri-
p
gave the derived dinitrobenzoate (60 mg, 46%). FTIR (Et O
2
cast) 1732 cm2 ; H NMR (CDCl , 400 MHz) d 2.80 (d,
1
1
6,7
cyclo[4.2.1.0 ]nonane-9-carboxylic acid methyl ester
(24). A solution of 23 (578 mg, 1.73 mmol), AIBN
3
J¼4.8 Hz, 1H), 3.43–3.44 (m, 1H), 3.51 (dd, J¼4.8, 4.0 Hz,
1
5
2
H), 3.61–3.62 (m, 1H), 3.68 (s, 3H), 3.76 (s, 3H), 5.11–
.12 (m, 1H), 6.08 (dd, J¼5.6, 2.8 Hz, 1H), 6.31 (dd, J¼5.6,
.8 Hz, 1H), 9.02 (d, J¼2.4 Hz, 2H), 9.18 (t, J¼2.1 Hz, 1H);
(42.9 mg, 0.262 mmol) and Bu SnH (0.52 mL, 1.9 mmol)
3
in PhH (10 mL) was refluxed for 3.5 h. Evaporation of the
solvent and flash chromatography of the residue over silica
gel (3.5£15 cm), using 1:10 to 1:2 EtOAc–hexanes, gave
;
1
3
C NMR (CDCl , 100 MHz) d 44.3 (d), 44.8 (d), 47.6 (d),
3
2
1
4
1
(
9.3 (d), 52.3 (q), 52.6 (q), 87.4 (d), 122.4 (d), 129.4 (d),
31.2 (d), 133.59 (s), 133.64 (d), 148.6 (s), 162.3 (s), 171.9
24 (365 mg, 83%). FTIR (CH Cl cast) 1783, 1733 cm
2
2
1
H NMR (C D , 500 MHz) d 1.08 (d, J¼14.0 Hz, 1H),
6
6
s), 173.4 (s); exact mass m/z calcd for C H N NaO
10
1.93–1.98 (m, 1H), 2.35–2.39 (m, 2H), 2.43–2.47 (m, 1H),
2.85–2.87 (m, 1H), 2.91 (s, 3H), 3.17 (s, 3H), 3.98 (s, 1H),
1
8
16
2
1
8
433.0697, found 443.0699. Single crystal X-ray analysis
confirmed the stereochemistry shown.
1
3
4.14 (s, 2H), 4.49–4.52 (m, 1H); C NMR (C D ,
6 6
125 MHz) d 34.7 (t), 40.7 (d), 43.2 (d), 47.6 (d), 48.2 (d),
52.0 (q), 55.4 (q), 79.9 (d), 83.3 (d), 96.2 (t), 171.9 (s), 177.0
5.1.4. (2-endo,3-exo,7-anti)-7-(Methoxymethoxy)bi-
cyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid dimethyl
(s); exact mass m/z calcd for C H NaO 279.0845, found
1
2
16
6
ester (22). MeOCH Cl (1.73 mL, 22.8 mmol) was added
2
279.0849.
to a stirred and cooled (0 8C) solution of 21 (1.51 g,
.53 mmol) and i-Pr NEt (4.60 mL, 26.5 mmol) in CH Cl
2 2 2
p
p
6
5.1.7. (8R ,9R )-5-Hydroxy-8-(methoxymethoxy)-4-
6
,7
(
22 mL). The cold bath was left in place, but not recharged,
oxatricyclo[4.2.1.0 ]nonane-9-carboxylic acid methyl
ester (25). DIBAL-H (1 M in THF, 1.40 mL, 1.40 mmol)
was added to a stirred and cooled (278 8C) solution of 24
(145 mg, 0.566 mmol) in THF (5.0 mL). Stirring at 278 8C
was continued for 4 h, and the mixture was quenched by
addition of MeOH (3 mL). The mixture was taken up in
EtOAc (75 mL), washed with 5% hydrochloric acid (5 mL),
and stirring was continued overnight. At this point,
examination by TLC (silica, 1:3 EtOAc–hexane) suggested
that ca. 50% conversion had occurred. i-Pr NEt (4.80 mL,
2
2
2.6 mmol), DMAP (16 mg, 0.13 mmol) and MeOCH Cl
2
(
1.50 mL, 19.7 mmol) were added to the solution at 0 8C.
The cold bath was left in place, but not recharged, and
stirring was continued overnight. The reaction was
quenched with 5% hydrochloric acid (25 mL), and the
organic phase was washed with brine (2£40 mL), dried
10% aqueous NaHCO (10 mL) and brine (2£10 mL), dried
3
(MgSO ) and evaporated. Flash chromatography of the
4
residue over silica gel (3.5£10 cm), using 1:2 to 1:1
EtOAc–hexanes, gave 25 (82 mg, 56%) as an oily mixture
of two isomers (ca. 10:1). FTIR (CH Cl cast) 3412,
(
MgSO ) and evaporated. Flash chromatography of the
4
residue over silica gel (4£15 cm), using 1:3 to 3:1 EtOAc–
2
2
1732 cm2 ; H NMR (C D , 500 MHz) (major isomer) d
1
1
hexanes, gave 21 (272 mg) and 22 (731 mg, 49% based on
conversion). Compound 22. FTIR (CH Cl2 cast)
6
6
1.18 (d, J¼12.5 Hz, 1H), 2.01–2.06 (m, 1H), 2.11–2.16 (m,
1H), 2.37–2.42 (m, 1H), 2.40–2.48 (m, 1H), 2.69–2.75 (m,
1H), 2.97–3.02 (m, 4H), 3.26 (s, 3H), 4.27–4.33 (m, 3H),
2
1
1
1
733 cm2
;
H NMR (C D , 300 MHz) d 2.86 (d,
6 6
J¼5.1 Hz, 1H), 3.04 (s, 3H), 3.18–3.25 (m, 4H), 3.27 (s,
1
3
3
1
1
H), 3.33–3.37 (m, 1H), 3.39–3.44 (m, 1H), 4.03–4.07 (m,
H), 4.33 (s, 2H), 5.94–6.01 (m, 2H); C NMR (CDCl3,
00 MHz) d 44.4 (d), 44.9 (d), 48.5 (d), 50.2 (d or q), 51.9 (d
4.70–4.72 (m, 1H), 4.99–5.04 (m, 1H); C NMR (C D ,
6 6
1
3
125 MHz) (major isomer) d 37.1 (t), 42.0 (d), 47.2 (d), 47.35
(d), 47.39 (d), 51.6 (q), 55.3 (q), 80.1 (d), 84.0 (d), 96.3 (t),
102.5 (d), 173.5 (s); exact mass m/z calcd for C H NaO
6
or q), 52.2 (d or q), 55.4 (d or q), 90.3 (d), 95.9 (t), 130.8 (d),
33.6 (d), 172.6 (s), 173.8 (s) [seven d and three q in all];
exact mass m/z calcd for C H NaO 293.1001, found
1
2
18
1
281.1001, found 281.1004.
1
3
18
6
p
p
2
93.1005.
5.1.8. (8R ,9R )-5-(tert-Butyldimethylsilanyloxy)-8-
,7
6
(methoxymethoxy)-4-oxatricyclo[4.2.1.0 ]nonane-9-
carboxylic acid methyl ester (26). Et N (0.36 mL,
p
.1.5. (2R ,8R ,9R )-2-Bromo-8-(methoxymethoxy)-5-
p
p
5
oxo-4-oxatricyclo[4.2.1.0 ]nonane-9-carboxylic acid
3
6
,7
2.6 mmol), DMAP (one grain) and t-BuMe SiCl (250 mg,
2

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4211
1
.66 mmol) were added to a stirred solution of 25 (200 mg,
2.23 (s, 1H), 2.63–2.65 (m, 1H), 2.94–2.96 (m, 1H), 3.00
(s, 3H), 3.75 (s, 1H), 4.25 (s, 2H), 4.64–4.67 (m, 1H), 5.05
(s, 1H), 9.07 (s, 1H); C NMR (C D , 125 MHz) d 24.7
6 6
0
for 13 h, and then additional portions of Et N (0.40 mL,
.776 mmol) in CH Cl (5.5 mL). Stirring was continued
2
2
1
3
3
2
.9 mmol), DMAP (26.1 mg, 0.214 mmol) and t-BuMe2-
(q), 23.9 (q), 18.2 (s), 26.1 (q), 37.0 (q), 39.1 (d), 44.7 (d),
47.4 (d), 54.6 (d or q), 55.2 (d or q), 80.1 (d), 83.1 (d), 96.1
(t), 102.9 (d), 199.2 (d); exact mass m/z calcd for C H -
SiCl (240 mg, 1.59 mmol) were added. Stirring was
continued for another 20 h. The mixture was diluted with
EtOAc (20 mL), washed with brine (2£20 mL), dried
1
7 30
NaO Si 365.1760, found 365.1765.
5
(
MgSO ) and evaporated. Flash chromatography of the
4
residue over silica gel (3£10 cm), using 1:20 to 7:10
EtOAc–hexanes, gave 26 (253.2 mg, 88%) as a single
isomer (of unestablished stereochemistry), which was an oil.
5.1.11. (2-endo,3-exo,7-anti)-7-(tert-Butyldimethyl-
silanyloxy)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic
acid dimethyl ester (29). Imidazole (10.1 g, 148 mmol) and
DMAP (1.04 g, 8.50 mmol) were tipped into a stirred and
cooled (ice-bath) solution of 21 (19.1 g, 84.5 mmol) in dry
DMF (170 mL). t-BuMe SiCl (19.11 g, 126.8 mmol) was
2
then tipped in. The cold bath was removed and stirring was
continued for 24 h. The mixture was poured into ice-cold
2
1 1
FTIR (CHCl cast) 1737 cm ; H NMR (C D , 500 MHz)
3
6 6
d 0.15 (s, 3H), 0.17 (s, 3H), 0.97 (s, 9H), 1.20 (d, J¼12.5 Hz,
1
1
4
H), 2.08–2.09 (m, 1H), 2.11–2.16 (m, 1H), 2.49–2.53 (m,
H), 2.72–2.77 (m, 1H), 3.02–3.08 (m, 4H), 3.25 (s, 3H),
1
3
.30–4.38 (m, 3H), 4.66–4.72 (m, 1H), 5.22 (s, 1H);
C
NMR (C D , 125 MHz) d 24.6 (q), 24.0 (q), 18.2 (s), 26.1
6
water (500 mL) and extracted with Et O (4£100 mL). The
6
2
(
5
q), 37.1 (t), 42.0 (d), 47.0 (d), 47.3 (d), 48.7 (d), 51.5 (q),
5.2 (q), 80.0 (d), 83.9 (d), 96.2 (t), 103.0 (d), 173.7 (s);
exact mass m/z calcd for C H NaO Si 395.1866, found
combined organic extracts were dried (MgSO ) and
4
evaporated (water pump). Flash chromatography of the
residue over silica gel (6.5£30 cm), using 3:7 EtOAc–
hexane, gave 29 (27.0 g, 94%) as a viscous oil. FTIR
1
8
32
6
3
95.1869.
2
1 1
(
CHCl cast) 1735 cm ; H NMR (C D , 400 MHz) d 0.00
3 6 6
p
p
.1.9. [(8R ,9R )-5-(tert-Butyldimethylsilanyloxy)-8-
5
(
(s, 6H), 0.89 (s, 9H), 2.86 (d, J¼5.1 Hz, 1H), 3.01–3.06 (m,
6
,7
methoxymethoxy)-4-oxatricyclo[4.2.1.0 ]non-9-
yl]methanol (27). DIBAL-H (1 M in THF, 2.0 mL,
.0 mmol) was added dropwise to a stirred and cooled
278 8C) solution of 26 (251 mg, 0.674 mmol) in CH Cl
1H), 3.15–3.18 (m, 1H), 3.24 (s, 3H), 3.30 (s, 3H), 3.38–
3.41 (m, 1H), 4.32–4.35 (m, 1H), 5.93–5.97 (m, 2H); C
NMR (C D , 100 MHz) d 24.79 (q), 24.77 (q), 18.3 (s),
1
3
2
(
(
6
6
25.9 (q), 45.1 (d), 45.4 (d), 51.0 (d or q), 51.4 (d or q), 51.6
(d or q), 52.7 (d or q), 86.1 (d), 131.0 (d), 133.4 (d), 172.4
(s), 174.2 (s); exact mass m/z calcd for C H NaO Si
2
2
8.0 mL). Stirring at 278 8C was continued for 7 h and then
overnight at room temperature. The mixture was quenched
by addition of MeOH (2.0 mL) and diluted with EtOAc
1
7
28
5
363.1604, found 363.1607.
(
(
25 mL). Saturated aqueous potassium sodium tartrate
25 mL) was added and the mixture was stirred for 1 h.
p
5.1.12. (2R ,8R ,9R )-2-Bromo-8-(tert-butyldimethyl-
p
p
6
,7
The organic phase was separated and washed with brine
25 mL), dried (MgSO ) and evaporated. Flash chromato-
silanyloxy)-5-oxo-4-oxatricyclo[4.2.1.0 ]nonane-9-car-
boxylic acid methyl ester (30). Br (0.78 mL, 15 mmol)
(
4
2
graphy of the residue over silica gel (3.5£9.5 cm), using
was added dropwise by syringe to a stirred and cooled (0 8C)
solution of 29 (4.110 g, 12.07 mmol) in CH Cl (60 mL).
1:10 to 1:1 EtOAc–hexanes, gave 27 (203.2 mg, 87%) as a
solid: mp 85–87 8C. FTIR (CHCl cast) 3445 cm ; H
2
2
2
1
1
The cold bath was removed and stirring was continued
overnight and the mixture was quenched by addition of
saturated aqueous NaHCO . The organic phase was washed
3
NMR (C D , 500 MHz) d 0.19 (s, 6H), 1.00 (s, 9H), 1.34 (d,
6
6
J¼12.5 Hz, 1H), 1.38–1.42 (m, 1H), 1.64–1.69 (m, 1H),
3
1
3
4
1
.87–1.93 (m, 1H), 2.09 (s, 1H), 2.13–2.22 (m, 1H), 2.98–
.02 (m, 1H), 3.07–3.17 (m, 5H), 4.06 (s, 1H), 4.37 (s, 2H),
with brine (50 mL), dried (MgSO ) and evaporated. Flash
4
chromatography of the residue over silica gel (3.5£20 cm),
using 1:10 EtOAc–hexanes, gave 30 as solid (3.9112 g,
80%): mp 110–111 8C. FTIR (CHCl3 cast) 1800,
1
3
.72–4.77 (m, 1H), 5.24 (s, 1H); C NMR (C D ,
6
6
25 MHz) d 24.6 (q), 23.9 (q), 18.2 (s), 26.1 (q), 37.9
1738 cm2 ; H NMR (C D , 500 MHz) d 20.03 (s, 3H),
1
1
(
8
t), 40.2 (d), 46.0 (d), 47.5 (d), 48.2 (d), 55.1 (q), 64.5 (t),
0.3 (d), 83.5 (d), 96.0 (t), 103.4 (d); exact mass m/z calcd
for C H NaO Si 367.1917, found 367.1914.
6 6
0.01 (s, 3H), 0.90 (s, 9H), 2.06 (s, 1H), 2.23–2.26 (m, 1H),
2.54 (s, 1H), 2.63–2.66 (m, 1H), 3.19 (s, 3H), 3.35 (s, 1H),
17
32
5
1
3
4
.28 (s, 1H), 4.89–4.91 (m, 1H); C NMR (C D ,
6 6
p
p
5
(
.1.10. (8R ,9R )-5-(tert-Butyldimethylsilanyloxy)-8-
125 MHz) d 25.1 (q), 24.9 (q), 18.3 (s), 26.0 (q), 39.3
(d), 47.4 (d), 48.9 (d), 50.8 (d or q), 51.0 (d or q), 52.1 (d or
q), 79.1 (d), 89.0 (d), 170.6 (s), 175.7 (s); exact mass m/z
6
,7
methoxymethoxy)-4-oxatricyclo[4.2.1.0 ]nonane-9-
carbaldehyde (28). Dess–Martin periodinane (218 mg,
.514 mmol) was added to a stirred solution of 27
80.0 mg, 0.232 mmol) and pyridine (0.40 mL, 4.9 mmol)
in CH Cl (10 mL). Stirring was continued overnight,
7
9
0
(
calcd for C H
1
BrNaO Si 427.0552, found 427.0553. In
6
25 5
some experiments run on a larger scale (e.g. 27 g of 29),
some desilylation occurs, but the resulting alcohol can be
resilylated to afford 30 in the same overall yield.
2
2
CH Cl (10 mL) was added, and the mixture was washed
2
2
with saturated aqueous Na S O (5 mL) and saturated
2 3
aqueous NaHCO (5 mL). The aqueous phase was extracted
3
2
p
5.1.13. (8R ,9R )-8-(tert-Butyldimethylsilanyloxy)-5-
p
6
,7
with CH Cl (20 mL), and the combined organic extracts
2
oxo-4-oxatricyclo[4.2.1.0 ]nonane-9-carboxylic acid
methyl ester (31). A solution of Bu SnH (3.10 mL,
2
were washed with brine (2£20 mL), dried (MgSO ) and
4
3
evaporated. Flash chromatography of the residue over silica
gel (2.5£13 cm), using 1:10 EtOAc–hexanes, gave 28
11.5 mmol) and AIBN (234 mg, 1.43 mmol) was added to
a solution of 30 (3.89 g, 9.59 mmol) in PhH (80 mL). The
mixture was refluxed for 4 h, and the solvent was then
concentrated to ca. 30 mL. Flash chromatography of the
residue (the solution was applied directly to the column)
2
1 1
(
NMR (C D , 500 MHz) d 0.17 (s, 6H), 0.99 (s, 9H), 1.13 (d,
60.1 mg, 76%) as an oil. FTIR (CHCl cast) 1726 cm ; H
3
6
6
J¼12.5 Hz, 1H), 1.56–1.59 (m, 1H), 2.07–2.12 (m, 1H),

4212
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
1
3
over silica gel (3.5£20 cm), using 1:5 EtOAc–hexanes,
gave 31 as a solid (2.967 g, 95%): mp 79–80 8C. FTIR
1H), 4.59–4.62 (m, 1H), 4.86–4.87 (m, 1H); C NMR
(C D , 100 MHz) (major isomer signals) d 24.98 (q),
6
6
2
1 1
(
CHCl cast) 1785, 1736 cm ; H NMR (C D , 500 MHz)
3
24.95 (q), 18.1 (s), 25.9 (q), 36.8 (t), 43.7 (d), 46.4 (d), 47.2
(d), 49.5 (d), 51.4 (q), 54.3 (q), 79.1 (d), 80.4 (d), 108.9 (d),
173.9 (s); C NMR (C D , 100 MHz) (minor isomer
6 6
6 6
d 20.11 (s, 6H), 0.82 (s, 9H), 1.05–1.10 (m, 1H), 1.99–2.06
m, 1H), 2.14–2.22 (m, 1H), 2.18–2.27 (m, 1H), 2.37 (s,
1
3
(
1
H), 2.780 (d, J¼5.2 Hz, 1H), 3.20 (s, 3H), 4.22 (s, 1H),
signals) d 24.96 (q), 24.94 (q), 18.1 (s), 25.9 (q), 35.9 (t),
42.8 (d), 43.1 (d), 43.4 (d), 51.3 (d or q), 51.8 (d or q), 56.3
(q), 78.8 (d), 80.1 (d), 106.5 (d), 174.8 (s); exact mass
(mixture of the isomers) m/z calcd for C H NaO Si
1
3
4
2
.51 (t, J¼6.2 Hz, 1H); C NMR (C D , 125 MHz) d
6
6
5.10 (q), 25.07 (q), 18.1 (s), 25.8 (q), 34.3 (t), 40.8 (d),
4
(
4.8 (d), 46.9 (d), 50.0 (d), 51.8 (q), 78.6 (d), 80.3 (d), 172.3
s), 177.3 (s); exact mass m/z calcd for C H NaO Si
1
7
30
5
365.1760, found 365.1759.
1
6
26
5
3
49.1447, found 349.1447.
p
p
p
5.1.16. [(5R ,8S ,9S )-8-(tert-Butyldimethylsilanyloxy)-
5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]methanol
p
.1.14. (8R ,9R )-8-(tert-Butyldimethylsilanyloxy)-5-
p
6,7
5
hydroxy-4-oxatricyclo[4.2.1.0 ]nonane-9-carboxylic
6
,7
p
p
p
(34a) and (5R ,8R ,9R )-[8-(tert-butyldimethylsilanyl-
6
,7
acid methyl ester (32). DIBAL-H (1 M in CH Cl , 3.0 mL,
2
oxy)-5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]metha-
nol (34b). The ‘a’ series refers to major isomer at acetal
carbon, ‘b’ series is minor isomer at acetal carbon.
2
3
.0 mmol) was added dropwise over 5 min to a stirred and
cooled (278 8C) solution of 31 (456 mg, 1.39 mmol) in
THF (15 mL). Stirring at 278 8C was continued for 5.75 h
and then MeOH (2 mL) was added dropwise. The cooling
bath was removed and, after 15 min, the mixture was diluted
with EtOAc (15 mL). Saturated sodium potassium tartrate
DIBAL-H (1 M in CH Cl , 53 mL, 53 mmol) was added
2
2
dropwise over 20 min to a stirred and cooled (278 8C)
solution of 33 (5.65 g, 16.6 mmol) in THF (80 mL). The
cooling bath was removed and stirring was continued
overnight. The mixture was cooled (278 8C) and precooled
(278 8C) MeOH (50 mL) was added dropwise by cannula.
Stirring was continued for 15 min, and saturated aqueous
sodium potassium tartrate (50 mL) was added. The cooling
bath was removed, the mixture was diluted with EtOAc
(50 mL), and stirring was continued for 1 h. The mixture
was filtered through a pad of Celite (0.5£8 cm) using EtOAc
(3£100 mL) as a rinse. The organic phase was dried
(
1 mL) was added and stirring was continued for 15 min.
The solution was dried (MgSO ) and filtered through a
4
sintered disk. The solid was washed with EtOAc
(3£10 mL). The combined organic extracts were evaporated
and flash chromatography of the residue over silica gel
(1.5£22 cm), using first 1:19 EtOAc–hexane (50 mL), and
then 3:7 EtOAc–hexane gave 32 (350 mg, 76%) as a
colorless oil which solidified after standing overnight: mp
2
1 1
6
(
(
2
2
1
(
(
0–65 8C. FTIR (CHCl cast) 3400, 1736 cm ; H NMR
3
C D , 500 MHz) (major isomer signals) d 0.04 (s, 6H), 0.88
6
(MgSO ) and evaporated. Flash chromatography of the
6
4
s, 9H), 1.17 (d, J¼13.0 Hz, 1H), 2.04–2.09 (m, 1H),
residue over silica gel (5£28.5 cm), using 1:1 EtOAc–
hexane, gave three fractions: minor isomer 34b (0.63 g),
major isomer 34a (2.48 g), and a mixed fraction of both
isomers (1.69 g), the total yield being 4.8 g (92%). The
minor isomer (34b) had: mp 67–69 8C. FTIR (CH Cl cast)
.18–2.26 (m, 1H), 2.27–2.32 (m, 1H), 2.72–2.76 (m, 1H),
.87–2.93 (m, 1H), 3.29 (s, 3H), 3.33–3.38 (m,
H), 4.48–4.56 (m, 1H), 4.70–4.78 (m, 1H), 5.12–5.18
1
3
m, 1H); C NMR (C D , 125 MHz) d 24.92 (q), 24.88
6 6
2
2
1
1
q), 18.2 (s), 25.9 (q), 36.6 (t), 43.7 (d), 47.2 (d), 47.3 (d),
9.1 (d), 51.5 (q), 79.2 (d), 80.5 (d), 102.8 (d), 174.0 (s);
exact mass m/z calcd for C H NaO Si 351.1604, found
3435 cm2 ; H NMR (C D , 300 MHz) d 0.00 (s, 3H), 0.01
6 6
4
(s, 3H), 0.89 (s, 9H), 1.44 (d, J¼12.4 Hz, 1H), 1.77–1.91
(m, 2H), 1.98 (s, 1H), 2.30 (ddd, J¼12.6, 7.5, 3.9 Hz, 1H),
2.35–2.48 (m, 2H), 3.23–3.41 (m, 5H), 4.28 (s, 1H), 4.63
1
6
28
5
3
51.1604.
1
3
(
dd, J¼7.5, 5.1 Hz, 1H), 4.86 (d, J¼4.2 Hz, 1H); C NMR
p
.1.15. (8R ,9R )-8-(tert-Butyldimethylsilanyloxy)-5-
p
5
(C D , 100 MHz) d 24.6 (q), 18.3 (s), 26.1 (q), 37.4 (t),
6
6
6
,7
methoxy-4-oxatricyclo[4.2.1.0 ]nonane-9-carboxylic
acid methyl ester (33). Lactols 32 (1.93 g, 5.87 mmol) and
pyridinium p-toluenesulfonate (23.0 mg, 0.0915 mmol)
41.7 (d), 41.8 (d), 43.3 (d), 52.0 (d), 56.6 (q), 65.1 (t), 78.5
(d), 80.3 (d), 107.3 (d); exact mass m/z calcd for C H -
1
6 30
NaO Si 337.1811, found 337.1813. A TROESY experiment
4
were dissolved in HC(OMe) (10 mL). The solution was
3
showed an NOE effect between C(5)H and C(7)H.
stirred overnight, diluted with EtOAc (60 mL), washed with
saturated aqueous NaHCO (50 mL) and brine (60 mL),
dried (MgSO ) and evaporated. Flash chromatography of
4
The major isomer (34a) was an oil. FTIR (CHCl cast)
3
3
3440 cm2 ; H NMR (C D , 300 MHz) d 20.02 (s, 3H),
1
1
6 6
the residue over silica gel (4.5£18.5 cm), using 1:5 to 1:3
EtOAc–hexanes, gave 33 (1.551 g, 77%) as two oily
fractions, one being largely the major isomer and the
other being largely the minor isomer: FTIR on mixture of
20.01 (s, 3H), 0.88 (s, 9H), 0.90–0.99 (m, 1H), 1.30 (d,
J¼12.3 Hz, 1H), 1.39 (td, J¼7.5, 2.7 Hz, 1H), 1.90 (s, 1H),
1.98–2.05 (m, 1H), 2.30 (ddd, J¼12.6, 7.2, 3.9 Hz, 1H),
2.90–2.95 (m, 1H), 3.00–3.20 (m, 2H), 3.26 (s, 3H), 4.26
2
1
1
13
isomers (CHCl3 cast) 1736 cm
4
;
00 MHz) (major isomer signals) d 20.02 (s, 3H), 20.01
H NMR (C D ,
(s, 1H), 4.65 (s, 1H), 4.71–4.80 (m, 1H); C NMR (C D ,
6 6
6
6
100 MHz) d 24.7 (q), 24.6 (q), 18.3 (s), 26.1 (q), 38.0
(t), 42.7 (d), 46.0 (d), 46.5 (d), 50.0 (d), 54.4 (q), 64.8 (t),
78.9 (d), 80.8 (d), 109.5 (d); exact mass m/z calcd for
C H NaO Si 337.1811, found 337.1811. A TROESY
(
(
(
s, 3H), 0.86 (s, 9H), 1.24 (d, J¼12.8 Hz, 1H), 2.08–2.13
m, 1H), 2.22–2.30 (m, 1H), 2.31–2.36 (m, 1H), 2.77–2.82
m, 1H), 2.86–2.89 (m, 1H), 3.19 (s, 3H), 3.28 (s, 3H),
1
6
30
4
1
4
NMR (C D , 400 MHz) (minor isomer signals) d 20.01 (s,
.52–4.56 (m, 1H), 4.59 (s, 1H), 4.68–4.74 (m, 1H); H
experiment showed an NOE effect between C(1)H and
C(5)H.
6
6
6H), 0.86 (s, 9H), 1.43 (d, J¼13.6 Hz, 1H), 2.22–2.28 (m,
1H), 2.38–2.39 (m, 1H), 2.41–2.44 (m, 1H), 2.83–2.86 (m,
1H), 3.27 (s, 3H), 3.30 (s, 3H), 3.33–3.34 (m, 1H), 4.42 (s,
The structure of the minor isomer was established by single
8
crystal X-ray analysis.
1

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4213
p
p
p
5
5
.1.17. (5R ,8S ,9S )-8-(tert-Butyldimethylsilanyloxy)-
,7
chromatography of the residue over silica gel (4£20 cm),
using 1:4 EtOAc–hexane, gave 35b (346.1 mg, 92%). FTIR
(Et O cast) 1726 cm ; H NMR (CDCl , 300 MHz) d
2 3
6
-methoxy-4-oxatricyclo[4.2.1.0 ]nonane-9-carbalde-
2
1
1
hyde (35a). Use of the Dess–Martin reagent. Dess–Martin
periodinane (1.80 g, 4.20 mmol) was added to a stirred
solution of 34a (548 mg, 1.75 mmol) and pyridine (4.0 mL,
50 mmol) in CH Cl (23 mL), and stirring was continued
2 2
overnight. The mixture was diluted with CH Cl (20 mL)
20.01 (s, 6H), 0.82 (s, 9H), 1.36 (d, J¼13.2 Hz, 1H), 2.27
(ddd, J¼13.2, 8.0, 4.4 Hz, 1H), 2.37 (br s, 1H), 2.56 (t,
J¼4.6 Hz, 1H), 2.6 (dd, J¼7.2, 4.4 Hz, 1H), 3.04 (d,
J¼2.4 Hz, 1H), 3.38 (s, 3H), 3.89 (br s, 1H), 4.49 (dd,
J¼7.6, 5.2 Hz, 1H), 5.01 (d, J¼4.4 Hz, 1H), 9.67 (s, 1H);
2
2
and then washed with a mixture of saturated aqueous
NaHCO (25 mL) and saturated aqueous Na S O (25 mL).
1
3
C NMR (CDCl , 100 MHz) d 25.0 (q), 17.8 (s), 25.6 (q),
3
2
2
3
3
The organic phase was washed with brine (40 mL), dried
MgSO ) and evaporated. Flash chromatography (it is
important to remove all Et N under oil pump vacuum
35.5 (t), 39.2 (d), 39.7 (d), 50.8 (d), 51.3 (d), 56.4 (q), 77.7
(d), 80.1 (d), 106.2 (d), 201.7 (d); exact mass m/z calcd for
C H NaO Si 335.1649, found 335.1652.
(
4
3
16 28
4
before loading the material onto a flash chromatography
column) of the residue over silica gel (4£19 cm), using 1:20
to 1:10 EtOAc–hexanes, gave 35a (434.5 mg, 80%) as a
p
p
p
5.1.19. 1-[(5R ,8S ,9S )-8-(tert-Butyldimethylsilanyl-
6
,7
oxy)-5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]-(E)-
oct-6-en-1-ol (36a). Procedure in absence of TMEDA. K
(118.7 mg, 3.035 mmol) cut into two pieces under hexane
contained in a mortar was added to a suspension of MgCl2
(159 mg, 1.63 mmol) in THF (10 mL) and the mixture was
stirred and refluxed for 2 h (the metal pieces were removed
with tweezers from the hexane, shaken free of solvent and
added to the reaction mixture). The resulting dark gray
suspension was cooled to room temperature (this took ca.
2
1
1
solid: mp 32–34 8C. FTIR (CHCl cast) 1723 cm ; H
3
NMR (C D , 500 MHz) d 20.10 (s, 3H), 20.09 (s, 3H),
6
6
0
1
1
1
1
.84 (s, 9H), 1.17 (d, J¼13.0 Hz, 1H), 1.64 (d, J¼3.0 Hz,
H), 2.06–2.12 (m, 1H), 2.18–2.26 (m, 1H), 2.70–2.74 (m,
H), 2.78–2.84 (m, 1H), 3.21 (s, 3H), 3.98 (s, 1H), 4.41 (s,
1
3
H), 4.66–4.69 (m, 1H), 9.12 (s, 1H); C NMR (C D ,
6
6
00 MHz) d 25.09 (q), 25.04 (q), 18.0 (s), 25.8 (q), 36.7
(
7
t), 40.9 (d), 42.3 (d), 49.6 (d), 54.3 (d or q), 54.9 (d or q),
8.3 (d), 80.5 (d), 108.8 (d), 199.3 (d); exact mass m/z calcd
for C H NaO Si 335.1655, found 335.1658.
1
0
0.5 h), and
a
solution of (E)-7-bromo-2-heptene
(142.6 mg, 0.805 mmol) in THF (5 mL) was added drop-
wise over 3 min with stirring at 0 8C. Stirring at 0 8C was
continued for 1 h, and a portion (10 mL, ca. 0.55 mmol) was
transferred by syringe to a 50 mL flask cooled to 278 8C. A
solution of 35a (50.1 mg, 0.160 mmol) in THF (5.0 mL)
was added dropwise with stirring to the above solution.
Stirring at 278 8C was continued for 5 h, and then saturated
16
28
4
Use of Swern oxidation. Dry DMSO (1.23 mL, 17.5 mmol)
was added dropwise from a syringe over 15 min to a stirred
and cooled (278 8C) solution of (COCl)2 (0.76 mL,
8.7 mmol) in CH Cl (25 mL). The mixture was stirred
2 2
for 20 min and then 34a (i.e. major isomer) (1.80 g,
5
1
.81 mmol) in CH Cl (15 mL) was added dropwise over
2
5 min, and stirring was continued for 30 min at 278 8C.
aqueous NH Cl was added until pH¼5 (pH paper). The
2
4
mixture was filtered through a pad of Celite (5£1 cm) and
Dry Et N (3.04 mL, 21.8 mmol) was added dropwise over
3
5
the pad was washed with EtOAc (40 mL). The organic
filtrate was washed with brine (45 mL), dried (MgSO ) and
min. The cold bath was left in place, but not recharged,
4
and stirring was continued for 2 h, by which time the
temperature was ca. 250 8C. The cold bath was removed,
and stirring was continued for 40 min, by which time the
mixture had attained room temperature. Cold water (50 mL)
was added and the aqueous phase was extracted with
CH Cl (3£50 mL). The combined organic extracts were
evaporated. Flash chromatography of the residue over silica
gel (4£19 cm), using 1:20 to 1:10 EtOAc–hexanes, gave
36a as a single isomer (39.4 mg, 60%) as an oil. FTIR
2
1 1
(CHCl cast) 3454 cm ; H NMR (C D , 500 MHz) d 0.02
3
6 6
(s, 6H), 0.88 (s, 9H), 1.02–1.38 (m, 9H), 1.58–1.67 (m,
3H), 1.83–1.89 (m, 1H), 1.93–2.04 (m, 2H), 2.31–2.39 (m,
1H), 2.47–2.53 (m, 1H), 2.90–2.97 (m, 1H), 3.13–3.23 (m,
1H), 3.31 (s, 3H), 4.50 (s, 1H), 4.74 (s, 1H), 4.79–4.75 (m,
2
2
dried (MgSO ) and evaporated. Flash chromatography of
4
the residue over silica gel (4£23 cm), using 1:4 EtOAc–
hexane, gave 35a (1.77 g, 98%). On a 2-g scale the yield
was 98%.
1
3
1H), 5.40–5.48 (m, 2H); C NMR (C D , 125 MHz) d
6
6
24.9 (q), 24.7 (q), 18.1 (s), 18.2 (t), 25.3 (t), 26.0 (q), 29.8
t), 32.9 (t), 36.3 (t), 38.1 (t), 44.1 (d), 45.4 (d), 50.0 (d), 52.2
(d), 54.3 (q), 73.1 (d), 79.0 (d), 80.7 (d), 109.8 (d), 125.1 (d),
(
p
p
p
5
.1.18. (5R ,8R ,9R )-8-(tert-Butyldimethylsilanyloxy)-
,7
5
hyde (35b). A solution of DMSO (0.25 mL, 3.6 mmol) in
-methoxy-4-oxatricyclo[4.2.1.06 ]nonane-9-carbalde-
131.6 (d); exact mass m/z calcd for C H NaO Si
2
3
42
4
433.2750, found 433.2751.
CH Cl (5 mL) was added dropwise from a syringe to a
2
2
stirred and cooled (278 8C) solution of (COCl) (0.15 mL,
2
Procedure in presence of TMEDA. K (1.278 g, 32.69 mmol)
cut into small cubes (ca. 2£2£2 mm) under hexane in a
mortar was added to a stirred suspension of anhydrous
1
.8 mmol) in CH Cl (20 mL). The mixture was stirred for
2 2
2
plus 2 mL as a rinse) was added dropwise, and stirring was
0 min and then 34b (377 mg, 1.21 mmol) in CH Cl (5 mL
2
2
MgCl (1.674 g, 17.40 mmol) in THF (30 mL) (the metal
2
continued for 40 min at 278 8C. Dry Et N (0.63 mL,
3
pieces were removed with tweezers from the hexane, shaken
free of solvent and added to the reaction mixture). The
mixture was refluxed for 2 h, cooled first to room
temperature, and then to 0 8C. A solution of (E)-7-bromo-
4
.6 mmol) was added dropwise. The cold bath was left in
place, but not recharged, and stirring was continued for 3 h,
by which time the temperature was ca. 250 8C. The cold
bath was removed, and stirring was continued for 40 min, by
which time the mixture had attained room temperature. Cold
water (20 mL) was added and the aqueous phase was
extracted with CH Cl (3£25 mL). The combined organic
1
0
2-heptene (1.038 g, 5.862 mmol) and BrCH CH Br (2
2
2
drops) in THF (10 mL) was added dropwise from a syringe
over ca. 10 min. The mixture was stirred at 0 8C for 1 h. At
this stage no bromide was detected by TLC (silica, 1:19
EtOAc–hexane). The ice-bath was removed and replaced
2
2
extracts were dried (MgSO ) and evaporated. Flash
4

4214
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
by a dry ice-acetone bath. Dry TMEDA (7.5 mL, 50 mmol)
was added to the stirred and cooled (278 8C) Grignard
solution, and a solution of 35a (450 mg, 1.44 mmol) in THF
temperature and water (0.5 mL) was added, followed by 3 N
NaOH (0.8 mL) and 30% H O (1.0 mL). The solution was
2
2
stirred for 5 min and then diluted with EtOAc (25 mL). The
organic phase was washed with brine (20 mL), dried MgSO4
and evaporated. Flash chromatography of the residue over
silica gel (2.5£17 cm), using 1:20 to 1:4 EtOAc–hexanes,
(
10 mL plus 2 mL as a rinse) was added dropwise by
syringe. Stirring at 278 8C was continued for 1 h, and the
reaction flask was transferred to a cooling bath (Haake
immersion cooler, model EK 51-1) set at 0 8C, and stirring
was continued for 20 h. MeOH (5 mL) was added at 0 8C,
and the mixture was stirred for 15 min. Saturated aqueous
1
gave 37a (12.9 mg, 59%) as an oil. Compound 37a: H
NMR (C D , 400 MHz) d 20.02 (s, 6H), 0.87 (s, 9H), 1.03–
6
6
1.39 (m, 10H), 1.58–1.64 (m, 3H), 1.75–1.79 (m, 1H),
1.92–2.02 (m, 3H), 2.26–2.33 (m, 1H), 2.83–2.92 (m, 1H),
3.27 (s, 3H), 4.29 (s, 1H), 4.67 (s, 1H), 4.75–4.81 (m, 1H),
NH Cl (20 mL) was added. The flask was removed from the
4
cold bath and stirring was continued for 30 min, by which
time the mixture had attained room temperature. The
mixture was diluted with EtOAc (50 mL) and filtered
through a pad of Celite (6.5£2 cm) supported on a sintered
disc. The pad was washed with EtOAc (3£25 mL). The
filtrate separated into two layers, and the aqueous phase was
1
3
5.36–5.45 (m, 2H); C NMR (C D , 100 MHz) d 24.9 (q),
6
6
24.8 (q), 18.1 (q), 18.2 (s), 25.9 (q), 27.9 (t), 29.5 (t), 29.8
(t), 33.0 (t), 35.2 (t), 38.1 (t), 44.0 (d), 45.4 (d), 49.5 (d), 50.1
(d), 54.2 (q), 79.1 (d), 80.6 (d), 109.5 (d), 125.0 (d), 131.8
(d); exact mass m/z calcd for C H NaO Si 417.2801,
2
3
42
3
extracted with Et O (3£10 mL). The combined organic
found 417.2800.
2
extracts were dried (MgSO ) and evaporated. Flash
4
p
p
p
5.1.21. tert-Butyl[(5R ,8S ,9S )-5-methoxy-9-[(E)-oct-
chromatography of the residue over silica gel
(3.5£25.5 cm), using 7:13 EtOAc–hexane, gave a major
isomer (300 mg) and a mixed fraction. The latter was
6
,7
6-enyl]-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]dimethyl-
silane (37a). Et N (0.2 mL) was added to CH Cl (9.8 mL).
3
2
2
rechromatographed over silica gel (3.5£25.5 cm), using first
An aliquot (1.0 mL, 0.14 mmol) was added to a stirred
solution of 36a (minor isomer at CHOH) (48 mg,
0.12 mmol) in CH Cl (2 mL). The solution was cooled to
1
:9 EtOAc–hexane (200 mL), then 1:4 EtOAc–hexane
200 mL) and then 1:3 EtOAc–hexane (200 mL), to obtain
(
2
2
the minor isomer (36a minor isomer at CHOH) (186.1 mg)
and the major isomer (36a major isomer at CHOH; this
corresponds to the single product obtained in the absence of
TMEDA) (305.3 mg), total yield 491.4 mg (82%). The
0 8C and an aliquot (1.0 mL, 0.14 mmol) of a solution of
MsCl (0.1 mL) in CH Cl (9.9 mL) was injected. The cold
bath was removed and stirring was continued for 5 h.
Examination by TLC (silica, 1:4 EtOAc–hexane) showed
the presence of some 36a (minor isomer at CHOH). More
2
2
2
1
1
minor isomer of 36a: FTIR (Et O cast) 3463 cm ; H
2
NMR (CDCl , 400 MHz) d 20.01 (s, 3H), 0.00 (s, 3H), 0.81
3
Et N (0.2 mL stock solution) was added, followed by MsCl
3
(
(
s, 9H), 1.11 (d, J¼12.8 Hz, 1H), 1.21–1.60 (m, 11H), 1.86
(0.1 mL stock solution) and stirring was continued over-
night. Evaporation of the solvent and flash chromatography
of the residue over silica gel (1£10 cm), using 35% EtOAc–
t, J¼3.6 Hz, 1H), 1.92–1.95 (m, 2H), 2.14–2.22 (m, 2H),
2
.64 (t, J¼4.6 Hz, 1H), 3.24 (s, 3H), 3.27–3.35 (m, 1H),
.31 (br s, 1H), 4.55–4.58 (m, 2H), 5.35–5.38 (m, 2H); C
NMR (CDCl , 100 MHz) d 25.0 (q), 24.9 (q), 17.86 (s),
1
3
4
hexane containing Et N (1%), gave the mesylate (55 mg,
3
96%) as an oil, which was used without characterization.
3
1
4
7.93 (t), 25.3 (t), 25.7 (q), 29.5 (t), 32.5 (t), 35.0 (t), 37.3 (t),
1.0 (d), 45.9 (d), 49.5 (d), 50.2 (d), 54.4 (q), 72.9 (d), 78.0
Et BHLi (1 M, THF, 1.12 mL) was added dropwise to a
3
(d), 80.7 (d), 109.0 (d), 124.9 (d), 131.1 (d); exact mass m/z
calcd for C H NaO Si 433.2745, found 433.2747.
stirred solution of the mesylate (minor isomer at CHOMs)
(55.0 mg, 0.112 mmol) in THF (5 mL), and stirring was
continued for 23 h. More Et BHLi (1 M, THF, 1.12 mL)
2
3
42
4
3
p
p
p
5
6
.1.20. tert-Butyl[(5R ,8S ,9S )-5-methoxy-9-[(E)-oct-
,7
was added dropwise and the mixture was refluxed for 4 h.
Another portion of Et BHLi (1 M, THF, 1.12 mL) was
6
-enyl]-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]dimethyl-
3
silane (37a). A solution of MsCl (0.101 mmol) in CH Cl
2
added dropwise and the mixture was refluxed for 5 h. No
further change was observed by TLC (silica, 3:7 EtOAc–
hexane). The mixture was cooled to 0 8C and water (1 mL),
followed by aqueous NaOH (4 N, 2 mL) and H O (30%,
2
(
0.7 mL) was added to a stirred and cooled (0 8C) solution of
3
0
6a (the single isomer obtained without TMEDA) (22.9 mg,
.0559 mmol) and Et N (0.10 mL, 0.72 mmol) in CH Cl
3
2
2
2 2
(
3.0 mL). The cold bath was left in place, but not recharged,
1 mL) were added. The mixture was stirred for 15 min and
then diluted with EtOAc (10 mL) and filtered. The solid was
washed with EtOAc (3£5 mL). Evaporation of the filtrate
and flash chromatography over silica gel (1£20 cm), using
1:3 EtOAc–hexane, gave 37a (24 mg, 52%).
and stirring was continued overnight. The mixture was
diluted with EtOAc (30 mL), washed with water (30 mL)
and brine (30 mL), dried (MgSO ) and evaporated. Flash
chromatography of the residue over silica gel
(
4
2.5£13.5 cm), using 1:20 to 1:4 EtOAc–hexanes, gave
the desired mesylate as an oil, which was used without
characterization.
5.1.22. Cyclopenta-2,4-dienyl(4-methoxyphenyl)di-
methylsilane (38). Cyclopentadiene dimer was cracked by
heating (oil bath at 180 8C) in a simple distillation unit with
a receiver cooled to 278 8C and protected from moisture.
BuLi (1.6 M in hexanes, 78.0 mL, 125 mmol) was added
dropwise over 45 min to a stirred and cooled (278 8C)
solution of freshly generated cyclopentadiene [9.9 mL
(taken up into a syringe), 125 mmol] in dry THF
(250 mL). After the addition the cold bath was replaced
by an ice-water bath and stirring was continued for 30 min.
The lithiated cyclopentadiene was added via cannula at
The mesylate was dissolved in THF (4 mL) and Et BHLi
3
(
The resulting solution was refluxed for 1.5 h. Examination
by TLC (silica, 1:3 EtOAc–hexane) suggested that ca. 50%
conversion had occurred. Refluxing was continued for
1 M in THF, 0.60 mL, 0.60 mmol) was added with stirring.
another 8 h and Et BHLi (1 M in THF, ca. 0.30 mL, ca.
3
0.30 mmol) was added at the beginning of this period and
after 2, 4, and 6 h. The mixture was then cooled to room

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4215
2
nyl)dimethylsilane
(
containing flask, and N was admitted to the flask containing
the lithiated cyclopentadiene]. The cooling bath was
removed and the mixture was stirred overnight. Most (ca.
78 8C over 90 min to a solution of chloro(4-methoxyphe-
2
5.1.24. (2-endo,3-exo,7-anti)-7-(Fluorodimethylsilanyl)-
bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid dimethyl
ester (41). AcOH (13.6 mL, 238 mmol) was added drop-
wise to a stirred and cooled (ice bath) solution of 40 (16.8 g,
44.9 mmol) in CH Cl (170 mL) over 10 min. BF ·OEt
2
3a
(25.02 g, 125.1 mmol) in THF
250 mL) [a slight vacuum was applied to the silane-
2
2
2
3
(13.6 mL, 107 mmol) was added dropwise over 10 min with
stirring. The cooling bath was removed and stirring was
continued for 1 h. The mixture was poured into ice-water
(100 mL) with swirling, and extracted with CH Cl
2
90%) of the THF was removed (rotary evaporator, water
pump) and cold water (ca. 200 mL) was added to the
residue, which was extracted with Et O (4£200 mL). The
2
2
combined organic extracts were dried (MgSO ) and
4
(3£100 mL). The combined organic extracts were washed
evaporated to give a brownish, oily liquid (26 g, 90%),
which is suitable for the next step. FTIR (CDCl cast) 1593,
with saturated aqueous NaHCO and dried (MgSO ).
3
4
Evaporation of the solvent (rotary evaporator) at room
temperature gave the crude product (which contains
anisole). The material was used immediately for the next
step.
3
2
1 1
1
502, 1278, 1247, 1112 cm ; H NMR (CDCl , 300 MHz)
3
1
(The integration of the H NMR spectrum is poor, the main
signals being) d 0.20 (s, 6H), 3.56–3.64 (m, 1H), 3.84 (s,
3
2
5
1
2
H), 6.40–6.70 (m, 4H), 6.90–7.00 (m, 2H), 7.44–7.60 (m,
H); C NMR (CDCl , 100 MHz) d 24.1 (q), 54.9 (d or q),
13
5.1.25. (2-endo,3-exo,7-anti)-7-(Methoxydimethyl-
silanyl)bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid
dimethyl ester (42). NaHCO (8.4 g. 100 mmol) was tipped
3
3
5.0 (d or q), 113.52 (d), 113.54 (d), 129.0 (s), 134.9 (d),
35.0 (d), 160.6 (s); exact mass m/z calcd for C H OSi
30.1127, found 230.1126.
1
4
18
into a stirred and cooled (ice bath) solution of the above
crude product (18.32 g) in dry THF (84 mL). Dry MeOH
(84 mL) was then added dropwise over 10 min from a
syringe. The cold bath was removed and stirring was
continued for 24 h. Evaporation of the solvents (rotary
evaporator) at room temperature gave a semisolid. This was
diluted with CH Cl (200 mL) and the mixture was filtered
5.1.23. (2-endo,3-exo,7-anti)-7-[(4-Methoxyphenyl)di-
methylsilanyl]bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic
acid dimethyl ester (40). Et AlCl (90.3 mL, 1 M in
2
hexanes, 90.3 mmol) was added dropwise over 45 min to
a stirred and cooled (278 8C; dry ice-acetone) suspension of
dimethyl fumarate (13.0 g, 90.3 mmol) in dry CH Cl
2
2
through a sintered disc, the solids being washed with
CH Cl . The solvent was evaporated (rotary evaporator) at
2
2
(
(
90 mL). After 10 min, the cyclopentadienylsilane 38
26.0 g, 113 mmol) was added dropwise by syringe over
2
2
room temperature to afford the crude product as an oil,
which was used directly in the next step.
6
0 min to the stirred mixture. The nitrogen inlet was
removed and the reaction vessel was transferred to a
preprepared bath set at 220 8C. Stirring at 220 8C was
continued for 24 h (TLC control, silica, 1:9 EtOAc–
hexane), by which time no dimethyl fumarate was present.
The mixture was poured into saturated aqueous potassium
sodium tartrate (200 mL) and the resulting thin emulsion
was filtered through a pad of Celite (1£10 cm), using
CH Cl as a rinse. The aqueous phase of the filtrate was
5.1.26. (2-endo,3-exo,7-anti)-7-Hydroxybicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxylic acid dimethyl ester (21).
Powdered KF (14 g, 0.24 mol) and KHCO (already in
3
powder form, 24 g, 0.24 mol) were tipped into a stirred and
cooled (ice bath) solution of the above methoxysilane
(theoretical amount would be 13.34 g, 44.92 mmol) in 1:1
THF–MeOH (150 mL). Then H O (30%, 134 mL,
2
2
2 2
extracted with CH Cl (4£200 mL) and the combined
1.18 mol) was added over 30 min from a syringe. The
cooling bath was removed and stirring was continued
overnight. The mixture was concentrated using a rotary
evaporator at room temperature until 200 mL of solvent had
been collected (the evaporator was equipped with a dry ice
cold finger condenser). The residual mixture was filtered
through a sintered disc and the solid was washed with
CH Cl . The filtrate separated into two layers and the
2
2
organic extracts were dried (MgSO ). The solvent was
4
evaporated and a portion of the residue was purified by flash
chromatography over silica gel (250 g silica gel for 10 g of
the crude product, 5.5£22 cm), using first 1:9 EtOAc–
hexane. After the excess of cyclopentadienylsilane had been
eluted, the solvent was changed to 3:17 EtOAc–hexane.
Another three batches of the crude Diels–Alder adduct
were chromatographed on the same column, the 3:17
EtOAc–hexane solvent being expelled from the column
before adding 1:9 EtOAc–hexane and applying the next
batch. The Diels–Alder adduct was obtained as a colorless
liquid (31.7 g, 94% based dimethyl fumarate as the
2
2
aqueous phase was extracted with CH Cl (4£100 mL).
2
2
CAUTION. The discarded aqueous phase should then be
diluted with an equal volume of water, otherwise it becomes
warm. The combined organic extracts were washed with
saturated aqueous Na S O (1£100 mL) and dried
2
2 3
2
1
1
limiting reagent). FTIR (CHCl3 cast) 1731 cm
NMR (CDCl , 300 MHz) d 0.16 (s, 6H), 0.36–0.44 (m,
;
H
(MgSO ). Evaporation of the solvent and flash chromato-
4
graphy of the residue over silica gel (5£21 cm), using 1:1
EtOAc–hexane, gave pure 21 (6.46 g, 64% over three
steps).
3
1
H), 2.73 (d, J¼4.5 Hz, 1H), 3.16–3.20 (m, 1H), 3.28–3.33
(
m, 1H), 3.35–3.38 (m, 1H), 3.61 (s, 3H), 3.70 (s, 3H), 3.80
s, 3H), 5.95 (dd, J¼5.4, 2.7 Hz, 1H), 6.16 (dd, J¼5.7,
(
1
3
3
NMR (CDCl , 100 MHz) d 21.4 (q), 21.3 (q), 14.0 (d),
.0 Hz, 1H), 6.87–6.90 (m, 1H), 7.33–7.37 (m, 1H);
C
On a larger scale (15.7 g of the methoxysilane) the yield was
53%.
3
2
2.6 (t), 31.5 (t), 48.6 (d), 48.8 (d), 49.1 (d), 50.1 (d), 50.7
(
(
d), 51.5 (d), 51.8 (d), 54.7 (q), 113.4 (d), 129.7 (s), 134.7
d), 134.9 (d), 137.1 (d), 160.3 (s), 173.1 (s), 174.6 (s); exact
5.1.27. (2-endo,3-exo,7-anti)-7-Hydroxybicyclo[2.2.1]-
hept-5-ene-2,3-dicarboxylic acid dimethyl ester (21).
Preparation without isolation of the methoxysilane inter-
mediate AcOH (8.23 mL, 144 mmol) was added dropwise
mass m/z calcd for C H NaO Si 397.1447, found
0
3
2
26
5
97.1442.

4216
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
over 10 min to a stirred and cooled (ice bath) solution of 40
0.01 (s, 0.9H, minor isomer) 0.02 (s, 2.1H, major isomer),
0.03 (s, 0.9H, minor isomer), 0.04 (s, 2.1H, major isomer),
0.83 (s, 9H), 1.18–1.22 (m, 1H), 1.77–1.83 (m, 1H), 1.88–
1.91 (m, 1H), 1.96–1.97 (m, 1H), 2.13–2.18 (m, 1H), 2.67–
2.69 (m, 1H), 3.27 (s, 3H), 3.49 (s, 2.1H for major isomer),
3.56 (s, 0.9H for minor isomer), 4.29–4.33 (m, 1H), 4.57–
4.60 (m, 1H), 4.65 (s, 1H), 4.70–4.75 (m, 1H), 5.78 (d,
J¼8.0 Hz, 0.3H, minor isomer), 6.26 (d, J¼12.0 Hz, 0.7H,
(
(
1
10.15 g, 27.13 mmol) in CH Cl2 (150 mL). BF ·OEt
2 3 2
8.25 mL, 65.1 mmol) was then added dropwise over
0 min. The cooling bath was removed and stirring was
continued for 1 h. The mixture was poured into ice-water
(
(
100 mL) with swirling, and extracted with CH Cl
2 2
3£100 mL). The combined organic extracts were washed
with saturated aqueous NaHCO and dried (Na SO ). Evapor-
3
2
4
1
3
ation of the solvent (rotary evaporator) at room temperature
gave the crude fluorosilane 41 (which contains anisole)
major isomer); C NMR (CDCl , 100 MHz) d 24.98 (q),
3
24.90 (q), 17.9 (s), 25.7 (q), 36.9 (t), 37.1 (t), 38.3 (d), 41.9
(d), 46.2 (d), 46.7 (d), 49.3 (d), 49.5 (d), 50.1 (d or q), 50.6
(10.0 g). This material was used immediately for the next step.
(d or q), 54.48 (d or q), 54.51 (d or q), 56.19 (d or q), 56.22
KHCO (16.31 g, 162.8 mmol) was added over 15 min in
3
(d or q), 59.60 (d or q), 59.62 (d or q), 78.3 (d), 78.7 (d),
80.39 (d), 80.45 (d), 106.35 (d), 106.38 (d), 109.0 (d), 109.3
(d), 110.1 (d), 145.6 (d), 147.1 (d); exact mass m/z calcd for
C H NaO Si 363.1962, found 363.1961.
three equal portions to a stirred and cooled (ice bath)
solution of the above crude product (41) (10.0 g) in a
mixture of dry THF (75 mL) and dry MeOH (75 mL). The
cold bath was removed and stirring continued for 8 h. [A
very small amount of 41 was still present, as judged by TLC
1
8
32
4
Later experiments were done using a mixture of 35a and
35b; these experiments gave a mixture of 43a and 43b in
90% yield (starting with 4.5 g of aldehyde).
(
silica, 1:9 EtOAc–hexane)]. The mixture was cooled in an
ice bath and KF (7.88 g, 136 mmol) was tipped in, and then
H O (30%, 77.0 mL, 678 mmol) was added over 20 min.
2
2
p
p
p
5.1.29. tert-Butyl[(5R ,8R ,9R )-5-methoxy-9-(2-
The ice bath was removed and stirring was continued for
h. The mixture was concentrated on a rotary evaporator at
6
,7
8
methoxyvinyl)-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]di-
methylsilane (43b). A solution of t-BuOK (321 mg,
2.85 mmol) in THF (10 mL) was added at a fast dropwise
rate to a stirred and cooled (0 8C) suspension of Ph PCH -
room temperature until 100 mL of solvent had been
collected, the evaporator being equipped with a solid CO2
cold finger condenser. The residual mixture was cooled to
3
2
2
15 8C (ice-salt bath) and ice-cold water (100 mL) and then
OMeCl (dried for 2 h at 80 8C under oil pump vacuum,
1.0747 g, 3.1351 mmol) in THF (15 mL). Stirring was
continued for 10 min and then a solution of the 35b
(322.4 mg, 1.045 mmol) in THF (5 mL plus 5 mL as a rinse)
was added by syringe to the ruby-red solution. Stirring at
0 8C was continued for 4 h, and the mixture was quenched at
EtOAc (100 mL) were added slowly. Saturated aqueous
Na S O (100 mL) was then added over 30 min with
vigorous stirring. CAUTION. If the Na S O solution is
2
2 3
2
2 3
added at a faster rate, an exothermic reaction occurs and the
contents of the flask are ejected. The mixture was allowed to
come to room temperature over a period of 1 h by
maintaining the mixture in an ice bath for 30 min and then
in a cold water bath (25 8C) for 30 min. Stirring was then
continued for 4 h. The mixture was filtered through a sintered
disc and the solids were washed with EtOAc (100 mL). The
aqueous phase was extracted with EtOAc (4£100 mL) and the
combined organic extracts were dried (Na SO ). Evaporation
0 8C with saturated aqueous NaHCO solution (25 mL) and
3
stirred for 10 min. The aqueous phase was extracted with
Et O (3£25 mL). The combined organic extracts were dried
2
(MgSO ) and evaporated. Flash chromatography of the
4
residue over silica gel (4£20 cm), using first 1:19 EtOAc–
hexane (500 mL) to elute nonpolar material, and then 1:9
EtOAc–hexane, gave 43b (266.7 mg, 75%) as a 2:1 mixture
2
4
1
of the solvent and flash chromatography of the residue over
silica gel (4£20 cm), using 1:1 EtOAc–hexane, gave pure
alcohol 21 (4.74 g, 77% overall from 40).
of Z,E isomers. FTIR (Et O cast) unexceptional; H NMR
2
(CDCl , 400 MHz) d 0.00 (s, 0.9H), 0.01 (s, 2.1H), 0.02 (s,
3
0.9H), 0.03 (s, 2.1H), 0.80 (s, 9H), 1.23–1.32 (m, 1H), 1.78
(br s, 0.7H), 1.88 (br s, 0.3H for minor isomer), 2.06–2.18
p
p
p
5.1.28. tert-Butyl[(5R ,8S ,9S )-5-Methoxy-9-(2-
6
methoxyvinyl)-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]di-
methylsilane (43a). A solution of t-BuOK (1.1734 g,
10.456 mmol) in THF (20 mL) was added dropwise to a
stirred and cooled (0 8C) suspension of Ph PCH OMeCl
(m, 2H), 2.51–2.55 (m, 1H), 2.69 (d, J¼8.0 Hz, 0.7H), 3.07
(d, J¼8.4 Hz, 0.3H), 3.36 (s, 3H), 3.50 (s, 2.1H), 3.56 (s,
0.9H), 4.24–4.30 (m, 1H), 4.44 (dd, J¼7.2, 5.2 Hz, 1H),
4.73 (dd, J¼12.4, 8.8 Hz, 1H), 4.94 (dd, J¼4.0, 1.2 Hz, 1H),
,7
1
3
5.76 (d, J¼8.0 Hz, 0.3H), 6.30 (d, J¼12.0 Hz, 0.7H);
C
3
2
(
dried for 2 h at 80 8C under oil pump vacuum, 3.9430 g,
1.502 mmol) in THF (30 mL plus 5 mL as a rinse). Stirring
was continued for 5 min and then a solution of the 35a
1.1828 g, 3.834 mmol) in THF (20 mL plus 5 mL as a
NMR (CDCl , 100 MHz), d 25.0 (q), 24.9 (q), 18.0 (s),
3
1
25.7 (q), 33.2 (d), 36.1 (t), 36.3 (d), 36.4 (t), 45.6 (d), 45.8
(d), 47.4 (d), 51.83 (d or q), 51.9 (d or q), 56.2 (d or q), 56.4
(d or q), 56.5 (d or q), 59.7 (d or q), 78.0 (d), 78.5 (d), 79.97
(d), 80.02 (d), 106.8 (d), 107.29 (d), 107.32 (d), 110.2 (d),
145.5 (d), 147.4 (d); exact mass m/z calcd for C H NaO Si
(
rinse) was added over 10 min by syringe to the ruby-red
solution. Stirring at 0 8C was continued for 4 h, and the
mixture was quenched at 0 8C with saturated aqueous
1
8
32
4
363.1962, found 363.1963.
NaHCO solution (20 mL). The cold bath was removed and
3
stirring was continued for 30 min. The mixture was filtered
through a sintered disc and the solids were washed with
Later experiments were done using a mixture of 35a and
35b; these experiments gave a mixture of 43a and 43b in
90% yield (starting with 4.5 g of aldehyde).
hexane (3£25 mL). The organic filtrate was dried (MgSO )
4
and evaporated. Flash chromatography over silica gel
p
p
p
(
(
(
3.5£29 cm), using 1:9 EtOAc–hexane, gave 43a
5.1.30. [(5R ,8S ,9S )-8-(tert-Butyldimethylsilanyloxy)-
6
,7
1.0607 g, 81%) as a 2.6:1 mixture of Z,E isomers. FTIR
Et O cast) unexceptional; H NMR (CDCl , 400 MHz) d
5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]acetalde-
hyde (44a). Hg(OAc) (2.60 g, 8.13 mmol) was added in
1
2
3
2

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4217
one portion to a stirred and cooled (0 8C) solution of enol
ethers 43a (921 mg, 2.70 mmol) in THF (70 mL) and water
oct-6-en-2-ol (45a). Use of TMEDA.
K
(2.235 g,
57.33 mmol) cut into small cubes (ca. 2£2£2 mm) under
(7 mL). The cooling bath was removed and stirring was
continued for 3 h. The mixture was recooled to 0 8C, diluted
hexane in a mortar was added to a stirred suspension of
anhydrous MgCl (2.898 g, 30.51 mmol) in THF (60 mL)
2
with Et O (100 mL) and quenched by dropwise addition
2
(the metal pieces were removed with tweezers from the
hexane, shaken free of solvent and added to the reaction
mixture). The mixture was refluxed for 2 h, cooled first to
room temperature, and then to 0 8C. A solution of (E)-6-
(
over 10 min) of freshly prepared saturated aqueous KI
solution (50 mL). The ice bath was removed and stirring
was continued for 15 min. The organic phase was separated
2
7
and the aqueous phase was extracted with Et O (3£50 mL).
bromo-2-hexene (1.38 mL, 10.2 mmol) and BrCH CH Br
2 2
2
The combined organic extracts were washed with saturated
aqueous KI (50 mL), dried (MgSO ) and evaporated. Flash
(2 drops) in THF (15 mL) was added dropwise from a
syringe. The mixture was stirred at 0 8C for 4 h. At this stage
no bromide was detected by TLC (silica, 1:19 EtOAc–
hexane). The ice-bath was removed and replaced by a dry
ice-acetone bath. Dry TMEDA (15.0 mL, 99.4 mmol) was
added to the stirred and cooled (278 8C) Grignard solution,
and a solution of 44a (829 mg, 2.54 mmol) in THF (15 mL
plus 5 mL as a rinse) was added dropwise by syringe. The
reaction flask was transferred to a cooling bath (Haake
immersion cooler, model EK 51-1) set at 0 8C, and stirring
was continued overnight. MeOH (10 mL) was added at
0 8C, and the mixture was stirred for 15 min and diluted with
4
chromatography of the residue over silica gel (3.5£29 cm),
using 7:13 EtOAc–hexane, gave 44a (829.3 mg, 94%).
FTIR (CDCl3 cast): 1725 cm
2
1
1
;
H NMR (CDCl3,
4
1
1
00 MHz) d 20.04 (s, 3H), 20.02 (s, 3H), 0.78 (s, 9H),
.19 (d, J¼12.0 Hz, 1H), 1.71 (br s, 1H), 1.78 (br s, 1H),
.83 (t, J¼7.4 Hz, 1H), 2.09–2.14 (m, 1H), 2.47 (d,
J¼8.0 Hz, 2H), 2.63 (br s, 1H), 3.21 (s, 3H), 4.21 (br s,
1
H), 4.52 (t, J¼6.0 Hz, 1H), 4.69 (br s, 1H), 9.67 (br s, 1H);
1
3
C NMR (CDCl , 100 MHz) d 25.1 (q), 25.0 (q), 17.9 (s),
3
2
5.6 (q), 36.5 (d), 37.3 (t), 44.5 (d), 48.9 (d), 49.1 (t), 49.6
d), 54.4 (q), 78.1 (d), 80.0 (d), 108.8 (d), 200.4 (d); exact
(
mass m/z calcd for C H O Si 327.1986, found 327.1989.
Et O. The mixture was filtered through a sintered disk, and
2
the residue was washed with Et O. Saturated aqueous
2
1
7
31
4
NH Cl (20 mL) was added to the filtrate, and the mixture
4
Later experiments were done using a mixture of 43a and
4
9
was filtered, using Et O to wash the solid. The organic
2
filtrate was dried (MgSO ) and evaporated. Flash chroma-
4
3b; these experiments gave a mixture of 44a and 44b in
4% yield (starting with 7.9 g of enol ethers).
tography of the residue over silica gel (3.5£29 cm), using
3:17 EtOAc–hexane (500 mL) and then 1:3 EtOAc–hexane
p
.1.31. [(5R ,8R ,9R )-8-(tert-Butyldimethylsilanyl-
p
p
5
oxy)-5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]acetal-
(200 mL), and then 7:13 EtOAc–hexane (200 mL), gave
(45a, major isomer at CHOH) (374.5 mg) and a mixed
fraction of major and minor isomers (45a, major isomer at
CHOH and minor isomer at CHOH) (519.6 mg), total yield
894.1 mg (86%). Compound 45a (major isomer at CHOH).
6
,7
dehyde (44b). Hg(OAc) (674 mg, 2.11 mmol) was added
2
in one portion to a stirred and cooled (0 8C) solution of enol
ethers 43b (238.7 mg, 0.7009 mmol) in THF (18 mL) and
water (1.8 mL). The cooling bath was removed and stirring
was continued for 3 h. The mixture was cooled (0 8C) and
quenched by slow addition (over 10 min) of freshly prepared
saturated aqueous KI solution (20 mL). Stirring was
continued for 10 min, the cold bath was removed, and the
FTIR (CDCl3 cast): 3461 cm2
1
;
1
H NMR (CDCl3,
400 MHz) d 20.01 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H),
1.17 (d, J¼12.4 Hz, 1H), 1.26–1.60 (m, 11H), 1.70–1.75
(m, 1H), 1.80–1.90 (m, 1H), 1.90–2.00 (m, 2H), 2.10–2.15
(m, 1H), 2.60–2.65 (m, 1H), 3.25 (s, 3H), 3.55–3.65 (m,
1H), 4.26 (br s, 1H), 4.53 (t, J¼6.8 Hz, 1H), 4.62 (br s, 1H),
aqueous phase was extracted with Et O (3£25 mL). The
2
1
3
combined organic extracts were washed with saturated
aqueous KI (50 mL), dried (MgSO ) and evaporated. Flash
5.36–5.40 (m, 2H); C NMR (CDCl , 100 MHz) d 24.99
3
(q), 24.90 (q), 17.8 (q), 17.9 (s), 25.4 (t), 25.7 (q), 32.4 (t),
37.4 (t), 37.6 (t), 39.6 (d), 42.4 (t), 45.4 (d), 48.5 (d), 49.6
(d), 54.4 (q), 69.4 (d), 78.5 (d), 80.5 (d), 109.1 (d), 125.2 (d),
130.9 (d); exact mass m/z calcd for C H NaO Si
4
chromatography of the residue over silica gel (2.5£27 cm),
using first 1:9 EtOAc–hexane (500 mL) and then 7:13
EtOAc–hexane, gave 44b (210.8 mg, 92%). FTIR (Et O
2
23 42
4
cast): 1725 cm2 ; H NMR (CDCl , 400 MHz) d 20.00 (s,
1
1
433.2745, found 433.2748.
3
3
1
H), 0.01 (s, 3H), 0.84 (s, 9H), 1.31 (d, J¼12.8 Hz, 1H),
.80 (br s, 1H), 1.97 (dd, J¼6.4, 4.4 Hz, 1H), 2.19 (ddd,
The minor sidechain alcohol isomer (which was obtained
pure from another experiment done in the same way, but on
a smaller scale): FTIR (CDCl cast): 3434 cm ; H NMR
3
J¼13.2, 7.6, 4.0 Hz, 1H), 2.30 (ddd, J¼15.6, 8.0, 2.4 Hz,
2
1 1
1
1
1
H), 2.42 (ddd, J¼15.6, 8.0, 2.4 Hz, 1H), 2.54–2.58 (m,
H), 2.67 (dt, J¼8.0, 2.0 Hz, 1H), 3.38 (s, 3H), 4.24 (br s,
H), 4.44 (dd, J¼12.4, 4.8 Hz, 1H), 4.91 (d, J¼4.0 Hz), 9.64
(CDCl , 400 MHz) d 0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H),
3
1.18 (d, J¼12.8 Hz, 1H), 1.30–1.60 (m, 8H), 1.61–1.65 (m,
3H), 1.78–1.84 (m, 1H), 1.90–2.02 (m, 3H), 2.10–2.20 (m,
1H), 2.62–2.70 (m, 1H), 3.28 (s, 3H), 3.56–3.65 (m, 1H),
4.276 (br s, 1H), 4.58 (dd, J¼7.2, 5.2 Hz, 1H), 4.64 (br s,
1
3
(
(
t, J¼2.4 Hz, 1H); C NMR (CDCl , 100 MHz), d 24.99
3
q), 4.95 (q), 17.9 (s), 25.6 (q), 32.0 (d), 36.7 (t), 43.6 (d),
4
(
5.9 (d), 48.5 (t), 51.8 (d or q), 56.7 (d or q), 77.7 (d), 79.7
d), 106.9 (d), 202.0 (d); exact mass m/z calcd for
C H NaO Si 349.1806, found 349.1808.
1
3
1H), 5.36–5.42 (m, 2H); C NMR (CDCl , 100 MHz) d
3
24.99 (q), 24.89 (q), 17.8 (q), 17.9 (s), 25.4 (t), 25.7 (q),
32.4 (t), 37.3 (t), 37.4 (t), 39.9 (d), 42.7 (d), 44.4 (d), 49.42
(d), 49.44 (d), 54.5 (q), 70.4 (d), 78.4 (d), 80.4 (d), 109.2 (d),
1
7
30
4
Later experiments were done using a mixture of 43a and
4
9
3b; these experiments gave a mixture of 44a and 44b in
4% yield (starting with 7.9 g of enol ethers).
125.2 (d), 130.9 (d); exact mass m/z calcd for C H NaO Si
2
3
42
4
433.2745, found 433.2745.
p
.1.32. 1-[(5R ,8S ,9S )-8-(tert-Butyldimethylsilanyl-
p
p
5
oxy)-5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]-(E)-
Experiment in absence of TMEDA. K (3.81 g, 97.4 mmol)
cut into small cubes (ca. 2£2£2 mm) under hexane in a
6
,7

4218
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
mortar was added to a stirred suspension of anhydrous
MgCl (4.88 g, 51.4 mmol) in THF (100 mL). (The metal
which was used as such for the mesylation step. FTIR (Et O
2
cast): 3508 cm2 ; H NMR (CDCl , 400 MHz) d 0.01 (s,
1 1
2
3
pieces were removed with tweezers from the hexane, shaken
free of solvent and added to the reaction mixture.) The
mixture was refluxed for 2 h, and then cooled first to room
temperature, and then to 0 8C. A solution of (E)-6-bromo-2-
6H), 0.82 (s, 9H), 1.20–1.52 (m, 7H), 1.60–1.65 (m, 3H),
1.70–1.75 (m, 1H), 1.90–2.25 (m, 5H), 2.50–2.55 (m, 1H),
2.76 (br s, 0.5H), 3.03 (br s, 0.5H), 3.45 (s, 3H), 3.55–3.70
(m, 1H), 4.25 (d, J¼10.4 Hz, 1H), 4.43 (ddd, J¼11.6, 7.2,
5.2 Hz, 71H), 4.91 (dd, J¼7.6, 3.6 Hz, 1H), 5.38–5.41 (m,
2
7
hexene (3.49 mL, 4.29 g, 25.7 mmol) and BrCH CH Br
2
2
1
3
(
4 drops) in THF (25 mL) was added dropwise from a
2H); C NMR (CDCl , 100 MHz) d 24.95 (q), 24.93 (q),
3
syringe. The mixture was stirred at 0 8C for 4 h. At this stage
no bromide was detected by TLC (silica, 1:19 EtOAc–
hexane). The ice-bath was removed and replaced by a dry
ice-acetone bath. A solution of 44a (2.10 g, 6.43 mmol) in
THF (20 mL plus 5 mL as a rinse) was added dropwise by
syringe. The reaction flask was transferred to a cooling bath
17.87 (q), 17.96 (s), 25.62 (t), 25.68 (d), 25.89 (t), 32.51 (t),
32.60 (t), 34.4 (d), 36.4 (t), 36.55 (d), 36.64 (t), 37.2 (t), 37.5
(t), 40.8 (t), 43.1 (t), 43.9 (d), 44.3 (d), 45.7 (d), 47.7 (d),
51.5 (d), 51.7 (d), 56.97 (q), 56.99 (q), 67.6 (d), 72.8 (d),
78.07 (d), 78.15 (d), 79.9 (d), 80.2 (d), 106.9 (d), 107.1 (d),
124.83 (d), 124.85 (d), 131.26 (d), 131.29 (d); exact mass
m/z calcd for C H NaO Si 433.2745, found 433.2740.
(Haake immersion cooler, model EK 51-1) set at 0 8C, and
stirring was continued overnight. MeOH (25 mL) was added
2
3
42
4
at 0 8C, and the mixture was stirred for 15 min and diluted
with Et O (50 mL). The mixture was filtered through a
sintered disk, and the residue was washed with Et O
2
Later experiments were done using a mixture of 44a and
44b; these experiments gave a mixture of 45a and 45b in
95% yield (starting with 5.1 g of aldehydes).
2
(
to the filtrate, and the mixture was filtered, using Et O
3£25 mL). Saturated aqueous NH Cl (25 mL) was added
4
p
p
p
5.1.34. Methanesulfonic acid 1-[(5R ,8S ,9S )-8-(tert-
butyldimethylsilanyloxy)-5-methoxy-4-oxatricyclo-
2
(
(
3£25 mL) to wash the solid. The organic filtrate was dried
6
,7
MgSO ) and evaporated. Flash chromatography of the
4
[4.2.1.0 ]non-9-ylmethyl]-(E)-hept-5-en-yl ester (46a).
MeSO Cl (0.25 mL, 3.2 mmol) was added dropwise to a
stirred and cooled (0 8C) solution of 45a (mixture of both
alcohol isomers) (865 mg, 2.11 mmol) and Et N (0.58 mL,
residue over silica gel (4.5£26 cm), using 1:4 EtOAc–
2
hexane, gave 45a (2.33 g, 89%) as a mixture of isomers
(
isomeric at CHOH).
3
4.2 mmol) in dry CH Cl (10 mL). The cold bath was
removed and stirring was continued for 5 h. The mixture
was diluted with Et O (25 mL) and quenched with water
2
2 2
Later experiments were done using a mixture of 44a and
4
9
4b; these experiments gave a mixture of 45a and 45b in
5% yield (starting with 5.1 g of aldehydes).
(25 mL). The organic phase was separated and the aqueous
phase was extracted with Et O (3£25 mL). The combined
2
p
.1.33. 1-[(5R ,8R ,9R )-8-(tert-Butyldimethylsilanyl-
p
p
5
organic extracts were dried (MgSO ) and evaporated to give
4
6
,7
oxy)-5-methoxy-4-oxatricyclo[4.2.1.0 ]non-9-yl]-(E)-
oct-6-en-2-ol (45b). K (539 mg, 13.8 mmol) cut into small
cubes (ca. 2£2£2 mm) under hexane in a mortar was added
to a stirred suspension of anhydrous MgCl2 (698 mg,
crude mesylates 46a (1.032 g, ca. 100%), which were used
directly in the next step without characterization.
Later experiments were done using a mixture of 45a and
45b; these experiments also appeared to be quantitative
(starting with 6.1 g of the alcohols).
7
.34 mmol) in THF (15 mL). (The metal pieces were
removed with tweezers from the hexane, shaken free of
solvent and added to the reaction mixture.) The mixture was
refluxed for 2 h, and then cooled first to room temperature,
p
p
p
5.1.35. Methanesulfonic acid 1-[(5R ,8R ,9R )-8-(tert-
butyldimethylsilanyloxy)-5-methoxy-4-oxatricyclo-
2
7
and then to 0 8C. A solution of (E)-6-bromo-2-hexene
0.33 mL, 2.5 mmol) and BrCH CH Br (2 drops) in THF
6
,7
(
[4.2.1.0 ]non-9-ylmethyl]-(E)-hept-5-en-yl ester (46b).
A stock solution of MeSO Cl (0.6 mL) in CH Cl (9.4 mL)
2
2
(5 mL) was added dropwise from a syringe over 5 min,
using THF (5 mL) as a rinse. The mixture was stirred at 0 8C
for 3.5 h. At this stage no bromide was detected by TLC
(silica, 1:19 EtOAc–hexane). The ice-bath was removed
and replaced by a dry ice-acetone bath. Dry TMEDA
2
2
2
was prepared. An aliquot (1.0 mL, 0.78 mmol) of the stock
solution was added dropwise to a stirred and cooled (0 8C)
solution of 45b (mixture of both isomers at CHOH)
(200 mg, 0.487 mmol) and Et N (0.13 mL, 0.93 mmol) in
3
(
(
0
5.0 mL, 33 mmol) was added to the stirred and cooled
278 8C) Grignard solution, and a solution of 44b (186 mg,
.569 mmol) in THF (5 mL plus 2 mL as a rinse) was added
dry CH Cl (5 mL). The cold bath was left in place, but was
2
2
not recharged, and stirring was continued overnight. The
mixture was quenched with water (10 mL) and diluted with
CH Cl (25 mL). The organic phase was dried (MgSO ) and
dropwise by syringe. The reaction flask was transferred to a
cooling bath (Haake immersion cooler, model EK 51-1) set
at 0 8C, and stirring was continued for 20 h. MeOH (10 mL)
was added over 10 min at 0 8C, and the mixture was stirred
2
2
4
evaporated to give crude mesylates 46b (238 mg, 100%),
which were used directly in the next step without
characterization.
for 15 min. Et O (25 mL) was added, and the mixture was
2
filtered through a sintered disc. The filtrate was quenched
with saturated aqueous NH Cl (8 mL), and the mixture was
Later experiments were done using a mixture of 45a and
45b; these experiments also appeared to be quantitative
(starting with 6.1 g of the alcohols).
4
filtered through a sintered disc, and the filtrate was dried
(
MgSO ) and evaporated. The residue was kept overnight
4
p
p
p
under good oil pump vacuum (0.001 mm Hg) to remove the
hexenol formed in the reaction. Flash chromatography of
the residue over silica gel (2£24 cm), using 1:3 EtOAc–
hexane, gave 45b (206.6 mg, 88%) as a mixture of isomers,
5.1.36. tert-Butyl[(5R ,8S ,9S )-5-methoxy-9-[(E)-oct-
6
,7
6-enyl]-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]dimethyl-
silane (37a). A solution of 46a (mixture of isomers at
CHOMs) (1.03 g, 2.11 mmol) in THF (10 mL) was injected

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4219
dropwise over 10 min to a stirred slurry of LiAlH (240 mg,
4
(627 mg, 94%) as a colorless oil. FTIR (Et O cast)
2
3471 cm2 ; H NMR (CDCl , 500 MHz) d 0.025 (s, 3H),
1 1
6
.33 mmol) in THF (10 mL). An additional portion of THF
10 mL) was used as a rinse. The mixture was refluxed for
h, and then cooled to 0 8C. MeOH (5 mL) was added
dropwise with stirring, and stirring was continued for
5 min. Saturated aqueous Na SO (10 mL) was added, the
3
(
8
0.03 (s, 3H), 0.86 (s, 9H), 1.06–2.40 (m, 21H), 2.44 (ddd,
J¼12.6, 10.2, 5.1 Hz, 1H), 2.72–2.92 (m, 4H), 3.99 (s, 1H),
4.70 (d, J¼11.8 Hz, 1H), 4.71–4.77 (m, 1H), 5.35–5.46 (m,
1
3
1
2H); C NMR (CDCl , 125 MHz) d 25.03 (q), 24.99 (q),
2
4
3
ice bath was removed, and stirring was continued for
0 min, by which time the mixture had attained room
temperature. The mixture was diluted with Et O (25 mL)
17.89 (q), 17.94 (s), 25.7 (q), 26.0 (t), 28.6 (t), 29.2 (t), 29.5
(t), 30.2 (t), 30.3 (t), 32.5 (t), 37.3 (t), 37.4 (t), 45.1 (d), 47.9
(d), 48.3 (d), 49.2 (d), 52.7 (d), 73.6 (d), 79.8 (d), 124.6 (d),
131.6 (d); exact mass (electrospray) m/z calcd for C H -
3
2
and filtered through a sintered funnel. The solids were
washed with Et O (3£25 mL) and the organic filtrate was
2
5 46
NaO S Si 493.2601, found 493.2606.
2 2
2
dried (MgSO ) and evaporated. Flash chromatography of
4
the residue over silica gel (1.5£29 cm), using 1:9 EtOAc–
From 37b. TiCl (1.0 M in CH Cl , 0.36 mL, 0.36 mmol)
4 2 2
hexane, gave 37a (593.4 mg, 71% over two steps).
was added dropwise to a stirred and cooled (278 8C)
solution of 37b (47.4 mg, 0.120 mmol) and 1,3-propane-
dithiol (36.2 mL, 0.36 mmol) in CH Cl (2 mL). The
Later experiments were done using a mixture of 46a and
2
2
4
9
4
6b; these experiments gave a mixture of 37a and 37b in
0% yield from the parent alcohols (starting with 6.1 g of
5a and 45b).
mixture was stirred for 30 min at 278 8C. Saturated aqueous
NaHCO (2 drops) was added and stirring was continued for
3
5 min. The cooling bath was removed, the mixture was
diluted with Et O (5 mL), and stirring was continued for
2
p
p
p
5
6
.1.37. tert-Butyl[(5R ,8R ,9R )-5-methoxy-9-[(E)-oct-
6
15 min, by which time the mixture had attained room
temperature. The solution was dried (Mg SO ) and
,7
-enyl]-4-oxatricyclo[4.2.1.0 ]non-8-yloxy]dimethyl-
2
4
silane (37b). A solution of 46b (mixture of isomers at
CHOMs) (238 mg, 0.49 mmol) in THF (5 mL) was injected
dropwise over 5 min to a stirred slurry of LiAlH (55.8 mg,
evaporated. Flash chromatography of the residue over silica
gel (1£18 cm), using 3:17 EtOAc–hexane, gave 47
(45.6 mg, 81%) as a colorless oil, spectroscopically
identical with material made from 37a.
4
1
(
6
.46 mmol) in THF (8 mL). An additional portion of THF
2 mL) was used as a rinse. The mixture was refluxed for
h, and then cooled to 0 8C. EtOAc (2 mL) was added with
5.1.39. Benzoic acid (2-endo,5-exo,6-endo,7-syn)-7-(tert-
butyldimethylsilanyloxy)-6-[1,3]dithian-2-yl-5-[(E)-oct-
6-enyl]bicyclo[2.2.1]hept-2-yl ester (48). PhCOCl
(0.90 mL, 7.8 mmol) was added dropwise to a stirred and
cooled (0 8C) solution of 47 (612 mg, 1.30 mmol) in
pyridine (20.0 mL, 247 mmol). The ice bath was removed
and stirring was continued for 3 h. The mixture was diluted
stirring and stirring was continued for 10 min. The mixture
was diluted with Et O (10 mL), and aqueous saturated
2
Na SO (3 mL) was added. The ice bath was removed, and
4
2
stirring was continued for 15 min. The mixture was filtered
through a sintered funnel, and the solids were washed with
Et O (2£5 mL). The organic filtrate was dried (MgSO ) and
2
4
evaporated. Flash chromatography of the residue over silica
with Et O (150 mL), and washed successively with water,
2
gel (2.5£22 cm), using 1:9 EtOAc–hexane, gave 37b
saturated aqueous CuSO (twice) and brine, dried (Na SO )
2
4
4
(141.5 mg, 73% over two steps). FTIR (Et O cast):
unexceptional; H NMR (CDCl , 400 MHz) d 0.01 (s,
and evaporated. Flash chromatography of the residue over
silica gel (1.6£28 cm), using 1:20 EtOAc–hexane, gave 48
(716 mg, 96%) as a white solid: mp 60–62 8C. FTIR
2
1
3
6
1
7
1
5
H), 0.82 (s, 9H), 1.15–1.35 (m, 9H), 1.60–1.65 (m, 3H),
.75–1.80 (m, 1H), 1.87–2.02 (m, 4H), 2.14 (ddd, J¼12.8,
.6, 4.0 Hz, 1H), 2.45–2.55 (m, 1H), 3.37 (s, 3H), 4.25 (br s,
H), 4.41 (dd, J¼7.2, 4.4 Hz, 1H), 4.90 (d, J¼4.4 Hz, 1H),
2
1 1
(CH Cl cast) 1724 cm ; H NMR (CDCl , 400 MHz) d
2
2
3
0.08 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.14–2.08 (m, 20H),
2.26–2.38 (m, 1H), 2.54–2.76 (m, 4H), 4.08 (s, 1H), 4.44
(d, J¼12.2 Hz, 1H), 5.35–5.49 (m, 2H), 5.78 (dt, J¼10.6,
1
3
.35–5.42 (m, 2H); C NMR (CDCl , 100 MHz) d 24.9
3
1
3
(
3
(
q), 17.8 (q), 17.9 (s), 25.7 (q), 27.4 (t), 29.5 (t), 32.5 (t),
4.8 (t), 36.8 (t), 38.1 (d), 43.5 (d), 46.4 (d), 51.6 (d), 56.6
q), 78.1 (d), 79.8 (d), 107.5 (d), 124.5 (d), 131.5 (d); exact
mass m/z calcd for C H NaO Si 417.2795, found
3.9 Hz, 1H), 7.43–7.59 (m, 3H), 8.06–8.12 (m, 2H);
C
NMR (CDCl , 100 MHz) d 25.0 (q), 24.9 (q), 17.9 (q),
3
18.0 (s), 25.72 (q), 25.74 (t), 28.6 (t), 29.1 (t), 29.2 (t), 29.5
(t), 29.9 (t), 32.5 (t), 35.0 (t), 37.3 (t), 44.9 (d), 46.3 (d), 47.1
(d), 49.2 (d), 50.9 (d), 76.5 (d), 79.3 (d), 124.6 (d), 128.3 (d),
2
3
42
3
4
17.2801.
129.5 (d), 131.1 (s), 131.6 (d), 132.6 (d), 166.4 (s); exact
mass (electrospray) m/z calcd for C H O NaS Si
597.2863, found 597.2860.
5
.1.38. (2-endo,5-exo,6-endo,7-syn)-7-(tert-Butyl-
3
2
50
3
2
dimethylsilanyloxy)-6-[1,3]dithian-2-yl-5-[(E)-oct-6-
enyl]bicyclo[2.2.1]heptan-2-ol (47). From 37a. TiCl4
(
1.0 M in CH Cl , 4.2 mL, 4.2 mmol) was added dropwise
2
5.1.40. Benzoic acid (2-endo,5-exo,6-endo,7-syn)-6-
[1,3]dithian-2-yl-7-hydroxy-5-[(E)-oct-6-enyl]bicyclo-
[2.2.1]hept-2-yl ester (49). Bu NF (1.0 M in THF,
1.05 mL, 1.05 mmol) was added dropwise to a stirred and
cooled (0 8C) solution of 48 (202 mg, 0.351 mmol) in THF
(20 mL). Stirring was continued for 45 min at 0 8C, and
2
to a stirred and cooled (278 8C) solution of 37a (562.0 mg,
.424 mmol) and 1,3-propanedithiol (0.56 mL, 5.6 mmol)
in CH Cl (40 mL). The mixture was stirred for 30 min at
1
4
2
2
2
and the cooling bath was removed. The mixture was diluted
78 8C. Saturated aqueous NaHCO (20 mL) was added,
3
with Et O (50 mL) and filtered through a pad of Celite
2
saturated aqueous NH Cl (10 mL) was added. The mixture
4
(
saturated aqueous NaHCO and brine, dried (Na SO ) and
4£3 cm), using Et O (50 mL). The filtrate was washed with
was diluted with Et O (120 mL), washed with saturated
2
2
aqueous NH Cl and brine, dried (Na SO ) and evaporated.
4
3
2
4
2
4
evaporated. Flash chromatography of the residue over silica
gel (1.6£30 cm), using 1:12 EtOAc–hexane, gave 47
Flash chromatography of the residue over silica gel
(1.2£35 cm), using 1:3 EtOAc–hexane, gave 49 (158 mg,

4220
D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
9
3
8%) as a white solid: mp 100–101 8C. FTIR (CH Cl cast)
2
Baran, P. S.; Zhong, Y.-L.; Fong, K. C.; He, Y.; Yoon, W. H.;
Choi, H.-S. Angew. Chem., Int. Ed. Engl. 1999, 38,
1676–1678. (c) Nicolaou, K. C.; Jung, J.-K.; Yoon, W. H.;
He, Y.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed.
Engl. 2000, 39, 1829–1832. (d) Nicolaou, K. C.; Zhong,
Y.-L.; Baran, P. S.; Jung, J.; Choi, H.-S.; Yoon, W. H. J. Am.
Chem. Soc. 2002, 124, 2202–2211. (e) Tan, Q.; Danishefsky,
S. J. Angew. Chem., Int. Ed. Engl. 2000, 39, 4509–4511.
(f) Synthesis of the related CP-263,114: Parts a–e and g of this
reference. (g) Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am.
Chem. Soc. 2000, 122, 7825–7826. (h) Chen, C.; Layton,
M. E.; Sheehan, S. M.; Shair, M. D. J. Am. Chem. Soc. 2000,
122, 7424–7425. (i) Synthesis of naturally occurring isomers
of CP-molecules: Meng, D.; Tan, Q.; Danishefsky, S. J.
Angew. Chem., Int. Ed. Engl. 1999, 38, 3197–3201. (j) For
references to model studies, see Ref. 2, and (k) Bio, M. M.;
Leighton, J. L. J. Org. Chem. 2003, 68, 1693–1700.
(l) Spiegel, D. A.; Njardarson, J. T.; Wood, J. L. Tetrahedron
2002, 58, 6545–6554. (m) Review: Spiegel, D. A.;
Njardarson, J. T.; McDonald, I. M.; Wood, J. L. Chem. Rev.
2003, 103, 2691–2727.
2
429, 1721 cm2 ; H NMR (CDCl , 400 MHz) d 1.17–2.89
1 1
3
(
(
8
m, 26H), 4.24 (s, 1H), 4.46 (d, J¼12.2 Hz, 1H), 5.35–5.48
m, 2H), 5.84 (dt, J¼10.6, 4.0 Hz, 1H), 7.44–7.61 (m, 3H),
1
3
.09–8.14 (m, 2H); C NMR (CDCl , 100 MHz) d 17.9
3
(
(
q), 25.7 (t), 28.7 (t), 29.15 (t), 29.2 (t), 29.6 (t), 29.9 (t), 32.5
t), 34.7 (t), 37.2 (t), 44.0 (d), 46.2 (d), 47.7 (d), 49.5 (d),
5
1
0.8 (d), 76.0 (d), 79.1 (d), 124.6 (d), 128.4 (d), 129.5 (d),
31.0 (s), 131.6 (d), 132.7 (d), 166.5 (s); exact mass
(
electrospray) m/z calcd for C H O S 461.2179, found
26 37 3 2
4
61.2182.
.1.41. Benzoic acid (2-endo,5-exo,6-endo)-6-
1,3]dithian-2-yl-5-[(E)-oct-6-enyl]-7-oxobicyclo[2.2.1]-
5
[
hept-2-yl ester (6). NMO (62.0 mg, 0.529 mmol) and
TPAP (9.5 mg, 0.027 mmol) were added successively to a
˚
stirred solution of 49 (121.0 mg, 0.2626 mmol) and 4 A
molecular sieves (350 mg) in CH Cl (4.0 mL). Stirring was
2
continued for 10 min. The mixture was diluted with Et O
2
2
(10 mL), filtered through a pad of silica gel (1.5£1.2 cm),
using Et O (30 mL) as a rinse, and evaporated. Flash
2
chromatography of the residue over silica gel (1.1£30 cm),
6. Fleming, I.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 1981,
1549–1556.
using 1:6 EtOAc–hexane, gave 6 (105 mg, 87%) as a
colorless oil. FTIR (CDCl , cast) 1777, 1724 cm ; H
2
1
1
7. Cf. (a) Allred, E. L.; Anderson, C. J. Org. Chem. 1967, 32,
1874–1877. (b) Eaton, P. E.; Hudson, R. A. J. Am. Chem. Soc.
1965, 87, 2769–2771. (c) Birney, D. M.; Berson, J. A.
Tetrahedron 1986, 42, 1561–1570.
3
NMR (CDCl , 100 MHz) d 1.10–2.11 (m, 19H), 2.21 (d,
3
J¼5.1 Hz, 1H), 2.36–2.45 (m, 1H), 2.59–2.83 (m, 3H),
2
.91 (t, J¼4.0 Hz, 1H), 4.48 (d, J¼12.2 Hz, 1H), 5.34–5.47
(
m, 2H), 5.57 (dt, J¼10.8, 4.4 Hz, 1H), 7.46–7.54 (m, 2H),
8. Cf. Saha, G.; Karpha, A.; Roy, S. S.; Ghosh, S. J. Chem. Soc.,
Perkin Trans. 1 1992, 1587–1591.
1
3
7
.56–7.63 (m, 1H), 8.05–8.13 (m, 2H); C NMR (CDCl ,
3
1
00 MHz) d 17.9 (q), 25.5 (t), 27.8 (t), 28.6 (t), 28.9 (t), 29.2
9. Bis[(E)-5-heptenyl)copper lithium would be required for
constructing the sidechain of CP-225,917.
(
(
(
t), 29.4 (t), 32.5 (t), 34.0 (t), 36.7 (t), 45.5 (d), 45.6 (d), 46.3
d), 47.8 (d), 50.5 (d), 69.3 (d), 124.7 (d), 128.5 (d), 129.5
d), 130.2 (s), 131.4 (d), 133.2 (d), 165.9 (s), 208.3 (s); exact
10. For preparation of (E)-5-heptenoic acid, see: (a) Hudrlik, P. F.;
Hudrlik, A. M.; Nagendrappa, G.; Yimenu, T.; Zeller, E. T.;
Chin, E. J. Am. Chem. Soc. 1980, 102, 6894–6896. (b) Hudrlik,
P. F.; Hudrlik, A. M.; Yimenu, T.; Waugh, M. A.;
Nagendrappa, G. Tetrahedron 1988, 44, 3791–3803, The
mass (electrospray) m/z calcd for C H NaO S 481.1842,
2
found 481.1843.
6
34
3 2
acid was reduced (LiAlH
Ref. 12) was converted into the mesylate (Ref. 13), and then
into the bromide (Ref. 12).
4
) (Ref. 11) and the resulting alcohol
(
Acknowledgements
1
1
1. Julia, M.; Maumy, M. Bull. Soc. Chim. Fr. 1969, 2415–2427.
2. Cf. Knight, J. A.; Diamond, J. H. J. Org. Chem. 1959, 24,
We thank NSERC for financial support, Dr. S. Sun for
considerable assistance, and Dr. R. McDonald and Dr. M. J.
Ferguson for the X-ray analysis. We thank Professor
M. Hirama (Tohoku University) and Dr. S. Yokoshima
(Mitsubishi Pharma Corporation) for advice on the
preparation of 18.
4
00–403.
1
3. Tsai, Y.-M.; Chang, F.-C.; Huang, J.; Shiu, C.-L.; Kao, C.-L.;
Liu, J.-S. Tetrahedron 1997, 53, 4291–4308.
1
4. (a) It was expected that the Grignard reagent would be stable,
and would not undergo cyclization: (a) Bailey, W. F.; Patricia,
J. J.; DelGobbo, V. C.; Jarret, R. M.; Okarma, P. J. J. Org.
Chem. 1985, 50, 1999–2000, and references cited therein.
(b) Cf. Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002,
References and notes
67, 4337–4345. (c) Bartoli, G.; Bosco, M.; Pozzo, R. D.;
Ciminale, F. J. Org. Chem. 1982, 47, 5227–5229.
1
. Clive, D. L. J.; Sun, S. Tetrahedron Lett. 2001, 42,
267–6270.
6
15. Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599–7662.
16. Toyama, K.; Iguchi, S.; Sakazaki, H.; Oishi, T.; Hirama, M.
Bull. Chem. Soc. Jpn 2001, 74, 997–1008.
2
. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559–4563.
. (a) Dabrah, T. T.; Kaneko, T.; Massefski, W., Jr.; Whipple,
E. B. J. Am. Chem. Soc. 1997, 119, 1594–1598. (b) Dabrah,
T. T.; Harwood, H. J., Jr.; Huang, L. H.; Jankovich, N. D.;
Kaneko, T.; Li, J.-C.; Lindsey, S.; Moshier, P. M.; Subashi,
T. A.; Therrien, M.; Watts, P. C. J. Antibiot. 1997, 50, 1–7.
. Systematic numbering is used in the compound names given in
Section 5, non-systematic numbering is used in Section 1.
. Synthesis of 2: (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.;
Choi, H.-S.; Yoon, W. H.; He, Y.; Fong, K. C. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 1669–1675. (b) Nicolaou, K. C.;
3
17. Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem.,
Int. Ed. 2000, 39, 4073–4075.
18. The atomic coordinates have been submitted to the Cambridge
Crystallographic Data Centre.
4
5
19. Rieke, R. D.; Bales, S. E. J. Am. Chem. Soc. 1974, 96,
1775–1781.
20. For preparation of several 5-silylated cyclopentadienes, see:
Landais, Y.; Parrra-Rapado, Eur. J. Org. Chem. 2000,
401–418.

D. L. J. Clive et al. / Tetrahedron 60 (2004) 4205–4221
4221
2
1. (a) Fleming, I.; Ghosh, S. K. J. Chem. Soc., Chem. Commun.
1
Z-isomer by flash chromatography over silica gel impregnated
with AgNO –MeOH (800 mL) was added with swirling to a
solution of AgNO (20.7 g) in water (150 mL). Flash
992, 1775–1777. (b) Lee, T. W.; Corey, E. J. Org. Lett. 2001,
, 3337–3339.
3
3
3
2
2. Fleming, I.; Ghosh, S. K. J. Chem. Soc. 1998, 2711–2720.
3. (a) Rahman, Abd. N.; Fleming, I.; Zwicky, A. B. J. Chem. Soc.
Miniprint 1992, 2401–2408. (b) Kolodyazhnyi, Yu. V.;
Gruntfest, M. G.; Dmitrieva, V. K.; Osipov, O. A. J. Gen.
Chem. USSR 1982, 52, 554–558. (c) Our chlorosilane was
contaminated by a small amount of the corresponding
bromosilane, as previously reported (this reference, part a).
4. For discussion of the fluxional behavior of 5-silylated
cyclopentadienes, see: (a) Ashe, A. J., III. J. Am. Chem. Soc.
chromatography silica gel (400 g) was poured in with vigorous
swirling. Swirling was continued for 15 min after the addition
and the solvents were removed under waterpump vacuum
(rotary evaporator, bath temperature 40 8C), the flask being
protected from light with aluminum foil. The residual powder
was kept under oil pump vacuum (protection from light) at
50 8C for 12 h. The mixture was cooled and stored in a closed
flask (protection from light). A sample of 4-hexen-1-ol (6.8 g)
was chromatographed over this silica gel (5.5£29 cm), using
1:1 EtOAc–hexane (protection of the column from light), to
obtain isomerically pure E-4-hexen-1-ol (5.9283 g) as a
colorless oil. Two additional fractions (250 mg, mainly
E-isomer) and (300 mg, mainly Z-isomer) were obtained.
TLC plates for monitoring the chromatography were made by
dipping a silica TLC plate into a sample of the above silver
nitrate solution, and letting the plate air dry overnight in a
cupboard.
2
2
2
1
970, 92, 1233–1235. (b) Colvin, E. Silicon in organic
synthesis; Butterworths: London, 1981; Chapter 9, p 100.
c) Jutzi, P. Chem. Rev. 1986, 86, 983–996. (d) Grimmond,
(
B. J.; Corey, J. Y. Organometallics 1999, 18, 4646–4653.
5. (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29–31. (b) Fleming, I.; Winter, S. B. D.
Tetrahedron Lett. 1993, 34, 7287–7290. (c) Rahman, Abd. N.;
Fleming, I. Synth. Commun. 1993, 23, 1583–1594.
(
d) Kn o¨ lker, H.-J.; Wanzl, G. Synlett 1995, 378–382. (e) For
use of BF ·Et O alone, see: Krohn, K.; Khanbabaee, K.
4
28. For example, treatment with NaBH resulted in replacement of
3
2
the OH by H, rather than in formation of a diol. The lactol
decomposed on removal of solvent from its solutions. Also,
Liebigs Ann. Chem. 1994, 1109–1112.
6. Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron
2
2
reaction with MeOCH¼PPh proceeded in poor yield
3
2
002, 58, 1817–1834.
7. Clive, D. L. J.; Hisaindee, S. J. Org. Chem. 2000, 65,
923–4929, The intermediate 4-hexen-1-ol was freed from
(ca. 45%).
29. Clive, D. L. J.; Wickens, P. L.; Sgarbi, P. W. M. J. Org. Chem.
1996, 61, 7426–7437.
4