Anodic oxidations of electron-rich olefins: Radical cation based approaches to the synthesis of bridged bicyclic ring skeletons

Article abstract of DOI:10.1016/S0040-4020(01)00358-1

The use of intramolecular anodic olefin coupling reactions for building bicyclo[3.2.1]octane ring skeletons has been examined. While simple model systems using bis enol ether substrates readily led to the formation of bicyclic products, application of the reactions to total synthesis efforts were hindered by reactions forming dimethoxy acetal groups at both the terminating and initiating ends of the cyclization reactions. In an effort to solve this problem, ketene acetal based initiating groups have been studied. The use of a ketene dithioacetal group proved especially useful for this purpose.

Full text of DOI:10.1016/S0040-4020(01)00358-1

TETRAHEDRON
Pergamon
Tetrahedron 57 :2001) 5183±5197
Anodic oxidations of electron-rich ole®ns: radical cation based
approaches to the synthesis of bridged bicyclic ring skeletons
²
S. Hari Krishna Reddy, Kazuhiro Chiba, Yongmao Sun and Kevin D. Moellerp
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Dedicated to Professor Barry M. Trost on the occasion of his 60th birthday
Received 7 February 2001; revised 23 February 2001; accepted 26 February 2001
AbstractÐThe use ofintramolecular anodic ole®n coupling reactions for building bicyclo[3.2.1]octane ring skeletons has been examined.
While simple model systems using bis enol ether substrates readily led to the formation of bicyclic products, application of the reactions to
total synthesis efforts were hindered by reactions forming dimethoxy acetal groups at both the terminating and initiating ends of the
cyclization reactions. In an effort to solve this problem, ketene acetal based initiating groups have been studied. The use of a ketene
dithioacetal group proved especially useful for this purpose. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
reactions might prove useful as tools for constructing the
bicyclo[3.2.1]octane ring skeletons found in many natural
products.9,10 For example, consider the retrosynthetic analy-
sis of: 1)-scopadulcic acid B11,12 outlined in Scheme 2. In
this proposed synthesis, an anodic cyclization reaction
would appear useful for generating the bridged bicyclic
ring skeleton, as well as one ofthe critical quaternary
carbons found in the natural product. This transformation
looked particularly ideal because it would convert the enol
ether used to initiate the reaction into an acetal group that
could then be used to further elaborate the product. Similar
cyclization reactions had been used to construct quaternary
carbons with control ofrelative stereochemistry, and the
resulting acetals had been used in the synthesis ofangularly
fused tricyclic ring skeletons.8 However, these reactions had
struggled to make six-membered rings and quaternary
carbons at the same time. While enol ether±enol ether
based cyclization reactions had been successful, the corre-
sponding reactions using less reactive radical trapping
The anodic oxidation ofelectron-rich ole®ns can provide a
powerful means for triggering oxidative cyclization reac-
tions and building new ring systems.1 These reactions are
intriguing because they reverse the polarity ofenolate
equivalents and lead to the formation of new bonds without
giving up the functionality used to initiate the reaction, and
generate highly reactive radical cation intermediates
:Scheme 1). To date, the reactions have been terminated
2
with the use ofsimple alkyl ole®ns, styrenes, allylsilanes,
vinylsilanes,3 electron-rich aromatic rings,4 enol ethers,5
and alcohols.6 The reactions have proven to be compatible
3,7
with the use ofvery acid sensitive substrates
formation of quaternary carbons.5,7,8
and the
Having established the potential for the reactions in model
systems, efforts were begun to examine the utility of the
reactions for building natural products. As part of these
efforts, we became curious as to whether anodic cyclization
Scheme 1.
Keywords: ole®ns; anodic oxidation; cyclization.
Corresponding author. Tel.: 11-314-935-4270; fax: 11-314-935-4481;
p
e-mail: moeller@wuchem.wustl.edu
Visiting Professor from the Tokyo University of Agriculture and Tech-
nology.
²
Scheme 2.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020:01)00358-1

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S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
groups like allylsilanes had not been.8 These observations
raised questions about how the extra strain associated with
building a bicyclic ring skeleton would in¯uence the
reactions and ifa terminating group could be ofund that
would both allow for an effective cyclization and provide
a convenient handle in the product for completing the
synthesis. With these questions in mind, a study aimed at
determining the utility ofintramolecular anodic ole®n
coupling reactions for the synthesis of bridged bicyclic
ring skeletons was undertaken.
2. Initial studies
Work in this area began by examining the oxidation ofthree
bis enol ether substrates.13 The bis enol ether substrates were
selected as starting points because enol ether trapping
groups have been among the best radical cation trapping
groups studied to date. In this way, it was hoped that the
cyclization reactions would have the best possible chance
for success. The ®rst two substrates 10 and 11 were synthe-
sized from 3-allylcyclopentanone 8 :Scheme 3). The allyl-
cyclopentanone was synthesized by the cuprate-mediated
Scheme 4.
The addition ofthe independent reagents without premixing
was not successful. Following formation of 9, the alcohol
was oxidized with the use ofDMSO and oxalyl chloride and
the resulting keto aldehyde treated under Wittig conditions
in order to introduce the enol ethers needed for the electro-
chemical coupling reaction. For the synthesis of 11, the
ole®n in 8 was cleaved by ozonolysis and then the Wittig
reaction used to introduce the enol ethers.
14
addition ofallylmagnesium bromide to cyclopentenone.
For the synthesis of 10, compound 8 was converted into
keto alcohol 9. Attempts to effect this conversion in a single
step were not successful. Hence, the transformation was
completed by ®rst protecting the carbonyl as a dimethoxy
ketal, then converting the double bond into an alcohol with a
hydroboration reaction, and ®nally deprotecting the ketone.
This three-step sequence could be run without purifying the
intermediates. As a sidenote, formation of the dimethoxy
ketal bene®ted greatly from premixing the trimethyl-
orthoformate and montmorillonite clay and then allowing
the mixture to stir for at least 30 min prior to the addition of
the ketone. Without this premixing step, the yield ofthe
reaction was greatly reduced. In cases where the reaction
did not go to completion :as monitored by TLC), the equi-
librium was pushed toward product by adding more ofthe
premixed trimethylorthoformate and montmorillonite clay.
The third substrate 14 was synthesized by ®rst adding
dimethylmalonate to cyclopentene :Scheme 4). The ketone
was protected as a dimethoxy acetal, the malonate moiety
alkylated with isoprenyl bromide, and the ketone depro-
tected to form 13. Ozonolysis ofthe ole®n ofllowed by a
Wittig reaction to introduce the desired enol ethers then
completed the synthesis.
15
Each ofthe substrates was oxidized
at a reticulated
vitreous carbon :RVC) anode16 using a platinum wire
cathode, an undivided cell :a three neck round bottom
¯ask), a 0.1 M lithium perchlorate in 50% MeOH/THF
electrolyte solution, 2,6-lutidine as a proton scavenger,
and a constant current of28.6 mA :Scheme 5). All three
reactions were run until a total of2.2 F/mol ofelectricity
had been passed. The electrolyses were typically run with a
substrate concentration of0.03 M and a scale ranging from
100 to 400 mg.
In the case of 10, an 82% isolated yield ofthe
bicyclo[3.2.1]octane product 15 was obtained as a 1:1
Scheme 3. Reagents: :a) CuBr/Me2S, LiCl, allylMgBr, TMSCl, THF,
2788C, 80%; :b) :MeO)3CH, montmorillonite K-10, room temp.; :c) :i)
disiamylborane, THF, 08C to room temp, :ii) NaOH, H2O2; :d) H2O,
acetone, montmorillonite K-10, 60% over three steps; :e) :i) :COCl)2,
DMSO, THF, 278 to 2508C, :ii) Et3N, 2788C to room temp.;
:f) Ph3PyCHOMe, THF, room temp., 50% over two steps; :g) :i) O3,
MeOH/CH2Cl2 :1:1), :ii) Me2S, :iii) H2O, acetone, montmorillonite K-10,
60%; :h) Ph3PyCHOMe, THF, room temp., 60%.
Scheme 5.

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5185
mixture ofisomers. As with earlier anodic cyclization reac-
tions, it was found that this cyclization reaction could be
initiated with the use ofa 6-volt lantern battery as a power
supply.17 In this case, a 70% isolated yield ofproduct 15 was
obtained. All ofthe other conditions ofr the oxidation
remained the same as described above. While the yield of
the cyclization was not quite as high as the yield obtained
when the current passed through the reaction was more care-
fully controlled, the reaction did indicate that the viability of
such an electrolysis reaction can be readily tested without
the need for specialized equipment.
observed. The Ep/2 values18 :vs. Ag/AgCl) obtained for 10
and 11 were 11.13 and 11.10 V. The Ep/2 value measured
for the parent enol ether :21b) was 11.14 V. Evidently,
none ofthe cyclizations to form bridged bicyclic reactions
occurred at a rate equivalent to that observed for the earlier
cyclization to form a quaternary carbon. Presumably, this
was due to the formation of a six-membered ring in the case
of 10 and 14 and the formation of a strained ring system in
the case of 11. Finally, the very small difference in Ep/2
measured for 10 and 11 indicated that the cyclization reac-
tions resulting from these two substrates were not substan-
tially different in rate. Therefore, the lower yield obtained
for the oxidation of 11 could not be attributed to a rate
difference and was most likely a result of product instability.
Substrate 11 was studied in order to determine what effect
the additional strain offorming a bicyclo[2.2.1]heptane ring
skeleton would have on the cyclization reaction. In this case,
the anodic oxidation afforded a 65% isolated yield of
product 16 as a 1:1 mixture ofstereoisomers. Interestingly,
this reaction did not fare very well when a 6-volt lantern
battery was used as the power supply. Using the battery only
a 33% yield ofproduct 16 could be obtained. Clearly, either
the reaction or the product was sensitive to the much harsher
reaction conditions associated with the use ofthe battery.
Substrate 14 was studied in order to determine ifplacing
substituents on the chain connecting the ole®ns :as required
for an approach to scopadulcic acid B) would allow for
control over product stereochemistry. It was hoped that
the presence ofan axial ester group in the transition state
ofthe cyclization would ofrce the disubstituted enol ether
into an equatorial position :Fig. 2). From an electrochemical
standpoint the presence ofthe methyl esters had little
in¯uence on the reaction. The Ep/2 value measured for 14
was 11.15 V vs. Ag/AgCl while the value measured for the
parent enol ether in a substrate that did not cyclize :22,
Fig. 1) was 11.17 V. Once again the rate ofthe cyclization
reaction was not as rapid as earlier cyclizations generating
fused bicyclic ring skeletons. With respect to the preparative
electrolysis of 14, a 65% isolated yield ofthe desired
bicyclo[3.2.1]octane product 17 was formed :Scheme 5).
Because ofthe problems encountered using such products
for the synthesis of scopadulcic acid B :see below), the yield
ofthis reaction was not optimized. However, the cyclization
reaction did indicate that the presence ofthe gem sub-
stituents dramatically in¯uenced the stereochemistry of
the cyclization. In this experiment, a 19:1 ratio ofstereo-
isomers about the newly formed carbon±carbon bond was
obtained. The major isomer had the C2-dimethoxyacetal
substituent in an equatorial position. This assignment was
made by examining the NMR coupling pattern observed for
the C2-methine proton. This proton gave rise to a doublet of
triplets with Jdˆ12.7 Hz and Jtˆ4.0 Hz. The 12.7 Hz
coupling constant was indicative ofa trans diaxial coupling
indicating that the methine proton was in the axial position.
It was tempting to suggest that the lower yield obtained for
the oxidation of 11 relative to 10 was the result ofa slower
cyclization reaction. Ifthe strain associated with ofrming
the bicyclo[2.2.1]heptane ring skeleton slowed the cycliza-
tion, then the very reactive radical cation intermediate
would have more time to decompose prior to intramolecular
trapping by the second enol ether. However, cyclic volt-
ammetry data did not support such a conclusion. For a reac-
tion that involves an electrochemical oxidation followed by
a very fast chemical reaction, the potential measured for the
substrate depends on the rate ofthe chemical reaction. The
faster the chemical reaction, the lower the potential
measured. Intramolecular anodic ole®n coupling reactions
between enol ethers have typically shown this behavior.5
For example, the oxidation potential measured for 18a
:Fig. 1) was 200 mV lower than that measured for the parent
enol ether 19. The potential measured for 18b was 100 mV
lower than that measured for 19. These data indicated that
the formation of the six-membered ring from 18b was
slower that the formation of the ®ve-membered ring from
18a as would be expected. Even the formation of a quatern-
ary carbon showed this shift in potential.5 The Ep/2 value for
20 was 150 mV lower than that measured for its parent enol
ether 21a. In the current study, no such potential drops were
3. Working toward scopadulcic acid B; differentiating
the ends of the cyclization
While studying these initial substrates taught us a great deal
about the anodic cyclization reactions, they did not afford a
useful approach to building scopadulcic acid B. Because an
enol ether group was used as the trapping group for the enol
ether radical cation reactions, the products generated had a
pair ofdimethoxy acetal groups. Initial plans called ofr
Figure 1.
Figure 2.

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S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
deprotecting the acetals and then capitalizing on the steric
hindrance associated with the neopentyl aldehyde in order to
differentiate between these two groups. Unfortunately, such
efforts were never successful. While the acetals in15 could
be readily cleaved, the subsequent reactions studied either
failed to differentiate between the aldehydes or led to the
formation of tetrahydrofuran type products. Typically, the
reactions led to a bad mixture ofproducts.
Struggling to differentiate the ends of the cyclization reac-
tion was particularly bothersome because it pointed to a
limitation associated with the anodic reactions themselves.
Instead ofsearching to ®nd ways to manipulate the products,
would it not be better ifthe coupling reactions could be used
to generate products with the ends already differentiated?
While potentially ideal, such a suggestion was worrisome.
As mentioned earlier, the bis enol ether substrates were
selected because enol ethers had proven to be among the
most reactive groups found for trapping the radical cation
intermediates generated at the anode. It was clear from the
CV data discussed above that the cyclization reactions were
not fast. Would the use of a less reactive radical cation
trapping group still allow for the cyclization reaction to
occur?
Scheme 7.
ofthe silyl group with a methoxy substituent. 21 A hydrolysis
reaction then led to the formation of methyl ester 29.
With this in mind, three substrates :31a±c) were built in
order to determine ifthe oxidation ofa silylated enol
ether would also trigger the formation of new carbon±
carbon bonds. In each ofthese examples, the substrate
was built starting from an unsaturated alcohol22 using a
two-step TPAP oxidation±Peterson ole®nation strategy
:Scheme 9).23
Attempts to address this question were not promising. For
example, two cyclization substrates having an allylsilane
terminating group :23a and 23b) were synthesized19 and
oxidized :Scheme 6). In neither case was a cyclized product
obtained. Only products resulting from the elimination of a
proton from the initially formed radical cation were
observed. In all ofthe products obtained, the allylsilane
group remained unchanged. In a similar fashion, the anodic
oxidation ofa substrate having a trisubstituted ole®n
trapping group :22, Fig. 1)20 generated a similar mixture
ofproducts. Hence, it appeared that the reactive enol ether
trapping group was required for the cyclization.
The substrates were then oxidized using conditions similar
What was needed was a change in strategy. Ifthe ends ofthe
cyclization could not be differentiated by altering the termi-
nating group for the cyclization, then maybe they could be
differentiated by making a change in the initiating group.
For instance, ifan anodic ole®n coupling reaction could be
initiated by oxidizing an even more electron-rich ketene
acetal group, then the reaction would lead to the formation
ofa product having an ortho ester equivalent and an acetal
:Scheme 7).
A related oxidative cyclization reaction had proven useful
for the synthesis of a tetrahydrofuran ring :Scheme 8).6 In
this example, a trimethylsilyl substituted enol ether was
oxidized in order to generate a cyclic product having a
silyl substituted acetal. Further oxidation led to replacement
Scheme 8.
Scheme 6.
Scheme 9.

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5187
Scheme 10.
Substrate 31b was oxidized in order to determine ifthe
reactions were compatible with six-membered ring forma-
tion. In this example, a 65% yield ofthe cyclized products
was obtained. A 35% yield ofthe methyl ester products was
obtained as a 1.5:1 ratio of cis to trans isomers. A 30% yield
ofthe ortho ester product was obtained as a 1.7:1 ratio of cis
to trans isomers. For both molecules, the stereochemistry of
the isomer could be readily assigned by the coupling pattern
ofthe methine proton alpha to either the ester or the ortho
ester. For the trans compound, this proton gave rise to a
clean triplet ofdoublets in the proton NMR spectrum with
two large trans-diaxial couplings :11.8 Hz) and one smaller
axial±equatorial coupling :3.7 Hz). The same methine
proton in the cis product led to an apparent quartet with a
coupling constant ofapproximately 4.5 Hz.
Scheme 11.
The success ofthe two previous cyclizations caused us to
wonder ifthe ketene acetal groups could be coupled to
directly generate bis-ester products. To this end, substrate
31c was electrolyzed to form a 60% isolated yield of
cyclized product :Scheme 11). In this case, the major
product obtained was the trans-isomer which was initially
obtained as the ortho ester. The cis-isomer hydrolyzed upon
workup and was isolated as the ester.
to those described above. Two main changes were made.
First, the reactions were run in pure methanol solvent.
Second, the reactions were allowed to proceed until at
least 4.0 F/mol ofcharge had passed ofr cases 31a and
31b :Scheme 10) and at least 6.0 F/mol had been passed
for the case of 31c :Scheme 11). The extra electricity was
passed in order to ensure cleavage ofthe initially ofrmed
silated acetal to either an ortho ester or methyl ester product.
In the case of 31c enough current was passed to ensure
cyclization :2 F/mol) and removal ofboth silyl groups
:2 F/mol each).
Having established the ability ofthe silated enol ether to
participate in anodic carbon±carbon bond forming reac-
tions, attention was turned toward seeing ifthe ketene acetal
equivalent could be used to construct a bridged bicyclic ring
skeleton. Because ofthe di®fculties associated with doing
Peterson ole®nation reactions on ketones, the initial
The anodic oxidation of 31a led to the formation of a 79%
isolated yield ofcyclized product :Scheme 10). A 64% yield
ofthe methyl ester product : 32a) was obtained :presumably
by hydrolysis ofan ortho ester upon aqueous workup) along
with approximately 15% :cis/transˆ1.7) ofa product tenta-
tively assigned as the ortho ester :33a). The presumed ortho
ester could not be unambiguously assigned because it was
contaminated with the methyl ester products. The ester
product 32a was obtained as a 15:1 ratio of cis to trans
isomers. This assignment was made based on the chemical
shift difference between the gem methyl groups on the ®ve-
membered ring. Normally, for a ®ve-membered ring
product of this type the difference in chemical shifts for
the gem methyl groups is signi®cantly larger for the cis-
isomer than for the trans-isomer. In this case, the chemical
shift difference between the gem methyl was approximately
10 times greater in the major product than in the minor
product. The assignment ofthe major product as the cis-
isomer was supported by hydrolysis ofthe dimethoxy acetal
which slowly converted the aldehyde ester obtained from
the major isomer into the aldehyde ester obtained from the
minor isomer.
Scheme 12.

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S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
substrate designed :37) placed the ketene acetal on the side
chain and the enol ether group on the ring :Scheme 12). To
synthesize this substrate, the side chain hydroxyl group in 9
was protected with a t-butyldiphenylsilyl group, the ketone
converted to an enol ether using a Wittig reaction, and then
the silyl group removed. Oxidation ofthe alcohol using
TPAP followed by the Peterson ole®nation afforded the
desired electrolysis substrate.
Figure 3.
This is exactly the scenario outlined in Scheme 13. For
the cyclization resulting from the oxidation of 10 the
extra substituents would be on the carbon bearing the
`radical'. For the cyclization resulting from 37 the extra
substituent would be on the internal carbon ofthe ole®n to
be attacked.
Unfortunately, all attempts to cyclize 37 met with failure.
In no case was the desired bicyclo[3.2.1]octane ring
skeleton observed. This result was puzzling because the
presence ofthe trimethylsilyl substituent had not interfered
with the cyclization in any ofthe model systems. While the
formation of the quaternary carbon would slow the cycliza-
tion, why would the presence ofthe trimethylsilyl sub-
stituent lower the ef®ciency of the cyclization relative to
substrate 10? One possible explanation for this observation
was that the presence ofthe silicon group caused the ole®n
on the side chain to be oxidized and hence changed the site
ofinitial radical cation ofrmation. This suggestion was
consistent with cyclic voltammetry data that gave rise to
an Ep/2 of 11.0 V vs. Ag/AgCl for substrate 37. Recall
that the oxidation potential measured for 10 was 11.13 V
vs. Ag/AgCl. Ifthe oxidation of 37 did take place on the side
chain, then the resulting cyclization reaction would run in
the opposite direction to one that originated from 10.
Previous ole®n coupling reactions had demonstrated that
the cyclization reactions were `radical-like' in their
behavior.3 What this meant was that the radical cation
attacked the ole®n in a fashion that led to the formation of
a radical intermediate at the terminating end ofthe cycliza-
tion. It was possible that the problems associated with the
cyclization resulting from 37 simply represented further
evidence for this mechanism. For 10, such a mechanism
would involve initial formation of a radical cation from
the ring enol ether and then a subsequent 6-exo-trig type
cyclization onto the disubstituted ole®n ofthe side chain
:Scheme 13 :1)). Ifthe presence ofthe silyl group in 37
were to reverse the direction ofthis cyclization reaction,
then the radical cation would be generated on the side
chain :Scheme 13 :2)). The ensuing radical-like cyclization
would then require a 6-exo-trig cyclization onto the tri-
substituted ring enol ether. For radical cyclization reactions,
it is known that substituents at the radical center :R1 in
Fig. 3) have little effect on the cyclization.24 However,
substituents on the internal carbon ofthe ole®n being
attacked :R2 in Fig. 3) dramatically slow the cyclization.
Ifsuch a scenario were the case, then moving the ketene
acetal equivalent to the position on the ring should lead to a
successful cyclization. Unfortunately, Peterson ole®nation
reactions often do not work well with ketone substrates. In
the current case, all attempts to build a substrate with a silyl
substituent on the ring enol ether of 10 met with failure and
a direct test ofthe theory above was not possible. It became
clear that an alternative ketene acetal equivalent was
needed.
4. The use of a ketene dithioacetal initiating group
What was required was a ketene acetal equivalent that could
be readily generated from a ketone, could be isolated and
puri®ed, and could be introduced into an electrolysis cell.
To this end, a ketene dithioacetal seemed ideal.25 While
oxidative cyclization reactions using this substrate were
rare,26 the combination ofhydrolytic stability and the low
oxidation potential ofthe sulufr groups suggested that
such an initiating group would be very effective for the
anodic reactions. To investigate this idea, substrate 40 was
built from alcohol 9 as outlined in Scheme 14. This was
accomplished by ®rst protecting the alcohol as the t-butyl-
diphenylsiloxy ether and then adding a dithiane anion to
the ketone. The tertiary alcohol was converted to a
chloride and followed by an elimination reaction to
complete formation of the ketene dithioacetal group.27
The synthesis ofthe substrate was completed by cleav-
ing the silyl ether, oxidizing the resulting alcohol, and
introducing the enol ether terminating group with a
Wittig reaction.
The anodic oxidation of 40 proceeded smoothly to the
desired bridged bicyclic product in a 75% isolated yield
:Scheme 15). One major product was isolated along with
5% ofwhat looked to be a minor isomer. The structure ofthe
minor isomer could not be unequivocally assigned because
the majority ofits signals in the proton NMR were buried
underneath those observed for the major isomer. The stereo-
chemistry ofthe major product also proved to be dif®cult to
assign in an unambiguous fashion because the proton NMR
signal for the methine proton on the carbon bearing the
dimethoxy acetal group was obscured by other signals. A
hydrolysis reaction ofthe major product moved this proton
to a position where it could be observed by converting the
acetal to an aldehyde :see Section 6 for details). In this case,
the methine proton alpha to the aldehyde appeared as a
doublet ofdoublets with 11.3 and 4.8 Hz coupling
Scheme 13.

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5189
Scheme 14.
6. Experimental28
6.1. Data for compounds
3-130-Hydroxypropyl)cyclopentan-1-one
6.1.1.
19).
Initially, 3-:20-propenyl)cyclopentanone :8) was synthe-
sized as follows.14 CuBr/Me2S :20.6 g, 20 mmol) and dry
LiCl :4.32 g, 20 mmol) were placed in a two-necked
100 mL round-bottom ¯ask equipped with a stir bar and
sealed with two septa. The ¯ask was evacuated with a
vacuum pump and then purged with Ar while drying with
a heat gun. Heating was continued for several hours until the
solid became a pale green or blue. This process was repeated
three times. At that point, THF :150 mL) was added and the
resulting mixture stirred for 3 min to yield a dark yellow,
homogeneous solution which was then cooled to 2788C.
Next, 90 mL ofa 1.0 M solution ofallyl magnesium bro-
mide in THF was added in a dropwise fashion. TMSCl
:12.7 mL, 100 mmol) was then added followed immediately
by the neat addition ofcyclopentenone :3.70 mL, 45 mmol).
The reaction was allowed to proceed for 5 min before being
quenched at 2788C with a saturated aqueous NH4OH/
NH4Cl solution :1:9). The mixture was extracted four
times with 100 mL ofether. The combined organic layers
were then dried over MgSO4 and then concentrated in
vacuo. The resulting liquid was treated with THF
:150 mL) and tetrabutylammonium ¯uoride :100 mL,
100 mmol, 1.0 M sol. in THF) for 10 min.
Scheme 15.
constants. Clearly, the methine proton was in an axial
position and the aldehyde was in the equatorial position.
A second aldehyde isomer was not observed. At this
point, we believe that the major product from the cyclization
reaction had the dimethoxy acetal group in the equatorial
position as well.
5. Conclusions
While the anodic cyclization resulting from 40 did not
directly address what went wrong with the planned cycliza-
tion of 37, it did clearly indicate that the use ofa ketene
acetal initiating group on the ring could be employed to
build bicyclo[3.2.1]octane products having the ends differ-
entiated for further synthetic transformations. Of course, the
success ofthis cyclization reaction immediately led to a
number ofquestions. Can the ketene dithioacetal group be
used to directly probe the mechanistic suggestion made in
connection with Scheme 13? Can a cyclization reaction
utilizing a ketene dithioacetal be used to complete the
synthesis ofscopadulcic acid B? How general are anodic
cyclization reactions using initiating groups ofthis nature?
What other ketene acetal groups can be used to trigger
anodic cyclization reactions? Efforts to address these ques-
tions and exploit the reactions for use in total synthesis are
currently underway.
The solution was again concentrated in vacuo and the oil
was subjected to ¯ash chromatography :hexane/ether 8:1) to
yield the known 3-:20-propenyl)cyclopentanone :80%). As
an important sidenote the product is volatile. In our hands, it
was best to dissolve the crude product in THF, add silica gel
to the solution, and then remove the THF in vacuo. The
coated silica gel was then added to the top ofthe chromato-
graphy column.
Once the allyl substituted cyclopentanone was generated, it

5190
S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
was converted into 9 using a three-step procedure as
follows. A slurry of 2.15 g :20.0 mmol) of trimethylortho-
formate and 1.4 g of montmorillonite K-10 clay :dried in an
oven at 1208C for 16 h) was allowed to stir for 30 min at
room temp. under N2. Following this step, a solution of0.5 g
temperature was 2508C. The reaction was then stirred for
10 min before being cooled back down to 2788C and
quenched with triethylamine :8.55 mL, 61.2 mmol). The
resulting solution was stirred for another 10 min, diluted
with 100 mL oftetrahydroufran, and allowed to warm to
room temperature. The white solids were removed by ®ltra-
tion and then washed with tetrahydrofuran. The combined
washings were concentrated in vacuo. The crude aldehyde
generated in this step was diluted with 50 mL oftetrahydro-
furan and then cannulated into the stirred 08C solution of
methoxymethyltriphenylphosphonium ylide generated
above. The reaction mixture was allowed to warm to
room temperature. After 48 h, the reaction was diluted
with ether and quenched with brine. The layers were sepa-
rated and the aqueous layer was extracted with ether. The
combined organic extracts were dried over MgSO4, con-
centrated in vacuo, and chromatographed through silica
gel that was slurry packed using 1% triethylamine/hexane
solution. Gradient elution with hexane followed by 5%
ether/hexane afforded 1-:10-methoxymethylene)-3-:40-
methoxy-30-butenyl)cyclopentane :2.0 g, 50%, over two
steps). IR :NaCl, neat) 2929, 2848, 1694, 1654, 1456,
0
:4.0 mmol) of3-:2 -propenyl)cyclopentanone in 5.0 mL of
pentane was added and the reaction mixture allowed to stir
for 6 h. The reaction was monitored by TLC. If starting
material remained, then additional premixed trimethyl-
orthoformate and MK-10 was added until the reaction was
forced to completion. The reaction mixture was then suction
®ltered through a glass ®lter, dried over MgSO4, and
concentrated in vacuo in order to obtain the corresponding
acetal.
The acetal was directly used for the next step without puri-
®cation. To a stirred 08C mixture of7.2 mL :72.0 mmol) of
a 10 M borane dimethysul®de complex in THF solution
with 20 mL ofTHF was added 15 mL :144 mmol) of2-
methyl-2-butene over 10 min. The reaction was warmed to
room temperature and stirred for 2 h. The reaction mixture
was then cooled back to 08C and a solution of7.92 g
1
:48.0 mmol) of3-:2 -propenyl)cyclopentanone dimethyl-
1221, 1119 cm21; H NMR :CDCl3, 300 MHz) 6.27 :d,
0
acetal in 20 mL ofTHF was added dropwise. The reaction
mixture was warmed to room temperature and stirred for an
additional 2 h. The reaction mixture was cooled back to 08C.
Jˆ12.6 Hz, 0.5H), 5.85 :m, 1.5H), 4.70 :td Jtˆ12.5 Hz,
Jdˆ7.5 Hz, 0.5H,), 4.32 :dt, JdˆJtˆ6.0 Hz, 0.25H), 4.31
:dt, JdˆJtˆ6.0 Hz, 0.25H), 3.55, 3.53, 3.47 :three singlets,
6H), 2.25±1.65 :series ofm, 6H), 1.45±1.25 :m, 3H), 1.25±
1.05 :m, 2H); 13C NMR :CDCl3, 75 MHz) 146.9, 146.00,
138.7, 138.6, 120.5, 120.2, 107.0, 103.0, 59.4, 59.3, 55.8,
40.2, 39.8, 39.4, 36.8, 36.3, 35.7, 35.2, 33.6, 33.5, 33.00,
32.4, 28.4, 28.4, 26.6, 26.3, 22.9; HRMS :EI) m/e calcd for
C11H17O :M12OMe) 165.1279, found 165.1278.
A mixture of84 mL of30% H O2 and 48 mL of3 M NaOH
2
solution was slowly added. The reaction was allowed to stir
at room temperature for 16 h, diluted with ether, washed
with sat. Na2SO3 and aq. K2CO3. The aqueous fractions
were combined and extracted with ether. The combined
organic fractions were washed with brine, dried over
MgSO4, and concentrated in vacuo.
6.1.3. 3-Formylmethylcyclopentan-1-one. 3-:20-Propenyl)-
cyclopentanone :1.0 g) was dissolved in 100 mL ofa 1:1
mixture ofmethanol/methylene chloride and cooled to
2788C. Ozone gas was bubbled through the solution until a
pale blue color persisted. Nitrogen was then bubbled through
the reaction until no blue color remained. Dimethyl sul®de
:4.0 equiv.) was added and the reaction warmed to room
temperature. After 12 h, the solvent was removed in vacuo
and the crude product directly subjected to hydrolysis reac-
tion by dissolving it in a mixture of1.5% water/acetone.
Excess montmorillonite K-10 was added and the mixture
stirred for 2 h at room temperature. The reaction mixture
was then ®ltered through MgSO4, concentrated in vacuo,
and the residue chromatographed through a silica gel column.
Elution with 50% ether/hexane furnished 3-formylmethyl-
cyclopentan-1-one in a 60% yield :0.61 g). Due to volatility
the product was not fully characterized until after the subse-
quent Wittig reaction. IR :neat/NaCl) 2959, 2897, 1739,
The acetal was then removed by dissolving the crude
alcohol in wet acetone and adding 16.8 g ofmontmorillonite
K-10 clay. The resulting suspension was stirred at room
temperature for 12 h, ®ltered through MgSO4, concentrated
in vacuo, and the residue chromatographed through a silica
gel column. Elution with ether furnished 3-:30-hydroxy-
propyl)cyclopentan-1-one :4.12 g, 60% over three steps).
IR :NaCl, neat) 3424, 2931, 1734, 1163, 1057, 731 cm21
;
1H NMR :CDCl3, 300 MHz) 3.483 :td, Jtˆ6.0 Hz,
Jdˆ3.0 Hz, 2H), 3.03±3.00 :br s, 1H), 2.35±1.90 :series
ofm, 5H), 1.68 :dd, J1ˆ18.2 Hz, J2ˆ9.0 Hz, 1H), 1.60±
1.25 :series ofm, 5H); 13C NMR :CDCl3, 75 MHz) 220.3,
62.1, 45.0, 38.3, 36.8, 31.6, 30.6, 29.2; HRMS :EI) m/e
calcd for C8H15O2 :M11H) 143.1072, found 143.1071.
6.1.2. 1-110-Methoxymethylene)-3-140-methoxy-30-but-
enyl)cyclopentane 110). In a ¯ame dried ¯ask, under
1
argon blanket, to
a
stirred suspension of34.9 g
1718, 1406, 1158 cm21; H NMR :CDCl3, 300 MHz) 9.67
:101.9 mmol) ofmethoxymethyltriphenylphosphonium
chloride in 100 mL oftetrahydroufran at 0 8C was added
dropwise 78.4 mL :101.9 mmol) of1.3 M sec-butyllithium
in cyclohexane. The dark red mixture was allowed to warm
to room temperature, stirred for 1 h, and then cooled to 08C.
:s, 1H, CHO), 2.65±2.45 :m, 3H), 2.37 :dd, Jdˆ18.0, 6.9 Hz,
1H), 2.25±1.95 :m, 3H), 1.72 :dd, Jdˆ18.0, 8.5 Hz, 1H),
1.55±1.35 :m, 1H); 13C NMR :CDCl3, 75 MHz) 218.1,
200.7, 49.2, 44.4, 38.1, 30.9, 29.2.
0
In a second ¯ask, 2.895 g :20.4 mmol) of3-:3 -hydroxypro-
6.1.4. 1-110-Methoxymethylene)-3-130-methoxy-20-pro-
penyl)cyclopentane 111). The keto aldehyde generated in
the preceding reaction was converted into substrate 11 using
a Wittig reaction that was identical to the reaction used to
build substrate 10 above. In this case, a 60% yield
:scaleˆ1.73 g ofproduct) ofthe desired substrate 11 was
pyl)cyclopentane and 1.88 mL :26.5 mmol) ofdimethyl
sulfoxide in 40.0 mL of abs. tetrahydrofuran were cooled
to 2788C under nitrogen atmosphere. Oxalyl chloride
:2.13 mL, 24.5 mmol) was added dropwise and the resulting
mixture warmed slowly with stirring over 30 min until the

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5191
obtained. IR :NaCl, neat) 2932, 2832, 1653, 1457, 1222,
1119 cm21 1H NMR :CDCl3, 300 MHz) 6.25 :d,
ofmethanol ofllowed by isoprenyl bromide :2.15 mL,
;
18.5 mmol) was added to the ¯ask. The reaction mixture
was re¯uxed for 16 h and then cooled in an ice-bath,
quenched with water, and diluted with ether. The organic
layer was separated and then washed with saturated NaCl.
The combined aqueous layers were extracted with ether.
The combined organic layers were then washed with
brine, dried over magnesium sulfate, and concentrated in
vacuo. The crude product was chromatographed through a
silica gel column :packed with 1% triethylamine). Elution
with 10% ether/hexane afforded a 50% yield of 1,1-
dimethoxy-3-:1,10-bis-carbomethoxy-40-methyl-30-pentenyl)-
cyclopentane :3.02 g, 50%) along with 40% ofthe
recovered starting material. IR :NaCl, neat) 2965, 2832,
Jdˆ12.6 Hz, 0.3H), 6.24 :d, Jdˆ12.6 Hz, 0.3H), 5.84 :m,
1.4H), 4.75±4.60 :m, 0.6H), 4.33 :m, 0.4H), 3.53 :s), 3.51
:s), 3.50 :s), 3.46 :s), 2.52±1.68 :series ofm, 8H), 1.35±1.10
:m, 1H); 13C NMR :CDCl3, 75 MHz) 147.4, 146.4, 138.8,
138.7, 120.3, 120.1, 105.6, 101.8, 101.7, 59.3, 59.2, 55.7,
55.7, 41.3, 41.0, 40.6, 40.2, 35.3, 35.0, 33.3, 33.2, 33.1,
32.8, 32.5, 32.4, 31.9, 31.7, 29.2, 28.8, 28.2, 28.2, 26.2,
26.0; HRMS :EI) m/e calcd for C11H19O2 :M11H)
183.1385, found 183.1384.
6.1.5. 3-1Bis-carbomethoxymethyl)-1-cyclopentanone. In
a ¯ame-dried ¯ask under nitrogen atmosphere, to a suspen-
sion of9.9 g :180 mmol) ofsodium methoxide in 50 mL of
methanol was slowly added dimethyl malonate :20.9 mL,
183 mmol). The mixture was stirred for 1 h at room
temperature. Cyclopentenone :10.2 mL, 122 mmol) was
then added very slowly and the reaction stirred for an addi-
tional 18 h at room temperature. The reaction mixture was
quenched with brine, the methanol removed under reduced
pressure, and the remaining material diluted with water and
extracted with ether. The combined organic layers were then
washed with brine, dried over magnesium sulfate, and
concentrated in vacuo. The crude product was chromato-
graphed through a silica gel column. Elution with ether
furnished 3-:bis-carbomethoxymethyl)-1-cyclopentanone
in a 95% yield :24.8 g). IR :NaCl, neat) 2959, 1738, 1433,
1157, 1021, 730 cm21; 1H NMR :CDCl3, 300 MHz) 3.73 :s,
3H), 3.70 :s, 3H), 3.35 :d, Jˆ9.6 Hz, 1H), 2.92±2.73 :m,
1H), 2.54±2.40 :dd, Jdˆ18.3, 8.1 Hz, 1H), 2.40±2.07 :series
ofm, 3H), 2.05±1.90 :dd, Jdˆ18.6, 11.1 Hz, 1H), 1.72±1.50
:m, 1H); 13C NMR :CDCl3, 75 MHz) 216.9, 216.8, 168.5,
168.4, 56.0, 55.9, 52.5, 42.8, 42.7, 38.1, 38.0, 36.3, 36.2,
27.4, 27.3; HRMS :EI) m/e calcd for C10H15O5 :M11H)
215.0919, found 215.0910.
1737, 1433, 1240, 1048, 736 cm21 1H NMR :CDCl3,
;
300 MHz) 4.96 :t, Jˆ7.3 Hz, 1H), 3.69 :s, 6H), 3.17 :s,
3H), 3.16 :s, 3H), 2.72±2.55 :m, 1H), 2.53 :d, Jˆ7.2 Hz,
2H), 2.06 :dd, Jdˆ13.2, 8.13 Hz, 1H), 1.90±1.45 :series of
m, 5H), 1.67 :s, 3H), 1.59 :s, 3H); 13C NMR :CDCl3,
75 MHz) 171.2, 171.0, 134.9, 117.9, 110.1, 60.3, 51.8,
48.9, 48.6, 39.39, 36.0, 33.2, 32.4, 25.8, 24.9, 17.5;
HRMS :EI) m/e calcd for C16H25O5 :M12OMe)
297.1702, found 297.1692.
6.1.8. 3-110,10-Bis-carbomethoxy-40-methyl-30-pentenyl)-
cyclopentanone 113). The dimethoxy ketal in the product
formed during the previous step was removed using the
same procedure employed in the synthesis of 9. In this
case, a near quantitative yield ofproduct was obtained
:scaleˆ1.18 g ofproduct). IR :NaCl, neat) 2943, 1728,
1
1654, 1232, 908, 730 cm21; H NMR :CDCl3, 300 MHz)
4.93 :t, Jˆ7.3 Hz, 1H), 3.69 :s, 6H), 2.86±2.69 :m, 1H),
2.69±2.56 :m, 2H), 2.43 :dd, J1ˆ18.5 Hz, J2ˆ7.8 Hz, 1H),
2.34±2.04 :series ofm, 5H), 1.66 :s, 3H), 1.59 :s, 3H); 13C
NMR :CDCl3, 75 MHz) 217.2, 170.7, 170.7, 135.6, 117.3,
59.9, 52.0, 40.9, 39.5, 38.2, 32.2, 25.8, 24.8, 17.6; HRMS
:EI) m/e calcd for C15H23O5 :M11H) 283.1545, found
283.1546.
6.1.6. 1,1-Dimethoxy-3-1bis-carbomethoxymethyl)cyclo-
a stirred suspension of4.99 g
pentane 112). To
:47.0 mmol) oftrimethyl orthofrmate and 3.3 g of
montmorillinite K-10 clay was added a solution of2.0 g
:9.4 mmol) ofthe keto diester made above in 20 mL of
pentane at room temperature. The mixture was stirred for
1 h. The dark reaction was then ®ltered, dried over MgSO4,
concentrated in vacuo, and the residue chromatographed
through a silica gel column :packed with 1% triethylamine).
Elution with 50% ether/hexane furnished 1,1-dimethoxy-3-
:bis-carbomethoxymethyl)cyclopentane in near quantitative
yield :2.43 g, 100%). IR :NaCl, neat) 2953, 2832, 1738,
6.1.9.
3-110,10-Bis-carbomethoxy-30-oxo-propyl)cyclo-
pentanone. The ole®n in 13 was cleaved using an ozo-
nolysis in a fashion identical to that described above for
the synthesis of3-ofrmylmethylcyclopentan-1-one. In this
case, a 95% yield :0.95 g ofproduct) ofthe desired keto
aldehyde was obtained. IR :NaCl, neat) 3470, 2960, 2848,
1
1736, 1432, 1272, 1167, 916, 736 cm21; H NMR :CDCl3,
300 MHz) 9.66 :br s, 1H), 3.71 :s, 6H), 2.96 :s, 2H), 2.94±
2.80 :m, 1H), 2.50±2.00 :series ofm, 5H), 1.76±1.58 :m,
1H); 13C NMR :CDCl3, 75 MHz) 216.1, 198.1, 169.8, 169.7,
72.6, 56.4, 52.7, 45.7, 40.8, 40.7, 38.1, 24.9; HRMS :EI) m/e
calcd for C12H17O6 :M11H) 257.1025, found 257.1028.
1
1436, 1140, 1050 cm21; H NMR :CDCl3, 300 MHz) 3.63
:s, 6H), 3.21 :d, Jˆ10.2 Hz, 1H), 3.08 :s, 6H), 2.66±2.48
:m, 1H), 1.99 :dd, J1ˆ13.3 Hz, J2ˆ7.8 Hz, 1H), 1.88±1.58
:series ofm, 3H), 1.48±1.22 :m, 2H); 13C NMR :CDCl3,
75 MHz) 168.9, 168.9, 110.7, 56.7, 52.2, 52.2, 49.1, 49.0,
38.7, 36.5, 33.5, 27.8; HRMS :EI) m/e calcd for C12H21O6
:M11H) 261.1338, found 261.1358.
6.1.10.
methoxy-40-methoxy-30-butenyl)cyclopentanone
1-110-Methoxymethylene)-3-110,10-bis-carbo-
114).
The synthesis ofsubstrate 14 was completed in a fashion
identical to that reported for the synthesis of substrate 10. In
this case, the bis-Wittig reaction led to the formation of a
60% yield :0.73 g) ofthe desired bis enol ether substrate. IR
:NaCl, neat) 2948, 2835, 1736, 1656, 1438, 1286, 1219,
6.1.7. 1,1-Dimethoxy-3-11,10-bis-carbomethoxy-40-methyl-
30-pentenyl)cyclopentane. To 5 mL ofdry methanol in a
¯ame-dried ¯ask under nitrogen atmosphere was slowly
added 426 mg :18.5 mmol) ofsodium metal. Atfer the
sodium completely reacted, 1,1-dimethoxy-3-:bis-carbo-
methoxymethyl)cyclopentane :4.80 g, 18.4 mmol) in 5 mL
;
1120 cm21 1H NMR :CDCl3, 300 MHz) 6.29 :d,
Jˆ12.6 Hz, 0.5H), 5.92 :d with ®ne coupling, Jˆ6.3 Hz,
0.5H), 5.84 :br s, 1H), 4.66±4.48 :m, 0.5H), 4.26±4.13
:m, 0.5H), 3.68 :s, 3H), 3.67 :s, 3H), 3.54 :s, 1.5H), 3.51

5192
S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
:s, 1.5H), 3.50 :s, 1.5H), 3.45 :s, 1.5H), 2.78±1.84 :series of
m, 7H), 1.48±1.28 :m, 2H); 13C NMR :CDCl3, 75 MHz)
171.4, 171.2, 149.6, 148.6, 139.1, 138.9, 102.3, 100.4,
100.2, 96.5, 96.4, 61.3, 61.1, 60.1, 59.6, 59.4, 55.8, 52.0,
43.1, 43.0, 42.9, 42.8, 33.2, 31.0, 29.1, 29.0, 28.6, 28.5,
28.2, 27.7, 26.0, 25.9; HRMS :EI) m/e calcd for C16H25O6
:M11H) 313.1651, found 313.1653.
to the general procedure described for the oxidation of 10. In
this example, 45 mg ofthe substrate was oxidized in order to
obtain 35 mg :65%) ofthe cyclized product. IR :NaCl, neat)
1
2954, 2835, 1736, 1438, 1240, 1193, 1081 cm21; H NMR
:CDCl3, 300 MHz) 4.38 :d, Jˆ3.3 Hz, 1H), 4.08 :s, 1H),
3.70 :s, 3H), 3.65 :s, 3H), 3.50 :s, 3H), 3.44 :s, 3H), 3.39
:s, 3H), 3.36 :s, 3H), 2.85 :t, Jtˆ6.0 Hz, 1H), 2.43 :dd with
®ne coupling, Jdˆ15.4, 4.4 Hz, 1H), 2.25 :dt, Jdˆ15.4 Hz,
Jtˆ4.4 Hz, 1H), 2.02±1.73 :series ofm, 2H), 1.71±1.52 :m,
3H), 1.43±1.29 :m, 1H), 1.27±1.16 :m, 1H); 13C NMR
:CDCl3, 75 MHz) 171.7, 171.7, 111.3, 106.4, 59.1, 58.7,
57.2, 55.4, 54.8, 52.6, 52.4, 50.7, 40.3, 40.3, 37.3, 27.3,
26.0, 23.8; HRMS :EI) m/e calcd for C17H27O7
:M12OMe) 343.1757, found 343.1760.
6.2. General procedure for the preparative electrolysis
reactions
6.2.1. Synthesis of 1,2-1bis-carboxaldehydedimethyl-
acetal)bicyclo[3.2.1]heptane 115). To a dry three neck
round bottom ¯ask equipped with a nitrogen inlet, a reticu-
lated vitreous carbon anode, and a Pt cathode were added
364 mg :1.86 mmol) of1-:1 0-methoxymethylene)-3-:40-
methoxy-30-butenyl)cyclopentane, 62 mL ofa 50% metha-
nol/tetrahydrofuran solvent mixture, 660 mg of lithium
perchlorate :1 M solution), and 1.194 g :11.14 mmol) of
2,6-lutidine. The resulting solution was degassed under
nitrogen atmosphere with the aid ofa sonicator ofr
30 min. The electrolysis was then carried out at constant
current of28.6 mA until 395.4 C :2.2 F/mol) ofelectricity
had been passed. Following the passage ofcurrent, the reac-
tion mixture was diluted with ether and then washed with
brine. The aqueous layers were extracted with ether. The
combined organic layers were dried over MgSO4 and
concentrated in vacuo. The crude product was chromato-
graphed through a silica gel column that was slurry packed
using a 1% triethylamine/hexane solution. Elution with 30%
ether/hexane solution afforded product 15 in an 82% yield
as a 1:1 mixture ofstereoisomers :392 mg). IR :NaCl, neat)
2928, 1454, 1076 cm21; 1H NMR for a 4:1 ratio of isomers
:CDCl3, 300 MHz) 4.57 :d, Jˆ6.0 Hz, 0.5H), 4.36 :d,
Jˆ3.0 Hz, 0.5H), 4.07 :s, 1H), 3.51 :s), 3.47 :s), 3.44 :s),
3.42 :s), 3.37 :s), 3.34 :s), 3.33 :s, 7 `s', 12H), 2.16 :m, 1H),
2.00±1.78 :m, 2H), 1.78±1.55 :m, 3H), 1.55±1.10 :series of
m, 6H); 13C NMR :CDCl3, 75 MHz) 112.1, 110.9, 107.2,
106.4, 59.2, 58.9, 57.0, 56.8, 55.7, 55.1, 54.2, 53.8, 51.1,
50.8, 44.0, 41.5, 41.0, 35.3, 35.3, 34.8, 31.9, 30.9, 29.8,
29.0, 28.7, 27.0, 19.4, 18.3; HRMS :EI) m/e calcd for
C13H23O3 :M12OMe) 227.1647, found 227.1647.
6.2.4.
1-1Trimethylsilyl)-1,7-dimethoxy-4,4-dimethyl-
hepta-1,6-diene 131a). To a solution ofbis:trimethylsilyl)-
methoxymethane29 :2.27 g, 12.0 mmol) in 10 mL ofabs.
tetrahydrofuran at 2788C was added dropwise 4.78 mL
:12.0 mmol) of2.5 M n-butyllithium in hexanes. The
mixture was warmed slowly to room temperature and then
stirred for 45 min. In a second ¯ask, 1-:methoxy)-4,4-
dimethyl-1-en-hexan-6-ol17 :755 mg, 4.78 mmol) was
dissolved in 10.0 mL ofmethylene chloride. N-Methyl-
morpholine oxide :842 mg, 7.17 mmol) and molecular
Ê
sieves :4 A) powder :1.51 g, 2.0 equiv. by wt.) were
added and cooled to 08C. Tetrapropylammonium perruthi-
nate :84 mg, 0.239 mmol) was added very slowly, warmed
to room temperature and stirred for 90 min. The reaction
mixture was ®ltered through small silica gel pad packed
with 1% triethylamine, and then the solvent removed in
vacuo. The crude aldehyde was dissolved in 10 mL oftetra-
hydrofuran and transferred via cannulae into a stirred
2788C solution ofthe anion generated above. The reaction
mixture was allowed to warm to room temperature. After
20 h, the reaction mixture was diluted with ether and
quenched with brine. The layers were separated and the
aqueous layer was extracted with ether. The combined
organic extracts were dried over MgSO4, concentrated in
vacuo, and chromatographed through a silica gel column
that was slurry packed using 1% triethylamine/hexane
solution. Elution with 10% ether/hexane afforded 1-
:trimethylsilyl)-1,7-dimethoxy-4,4-dimethylhepta-1,6-diene
31a :856 mg, 70%, over two steps). IR :NaCl, neat) 2954,
6.2.2. 1,2-1Bis-carboxaldehydedimethylacetal)bicyclo-
[2.2.1]hexane 116). Substrate 11 was electrolyzed using
the general procedure described for the oxidation of
substrate 10. In this example, 100 mg ofthe starting material
was electrolyzed in order to form 87 mg :65%) of the
isolated product as a 1:1 mixture ofisomers. IR :NaCl,
1
2900, 2828, 1655, 1462, 1249, 1116, 837 cm21; H NMR
:CDCl3, 300 MHz) 6.24 :d, Jˆ12.5 Hz, 0.2H), 5.95 :d,
Jˆ6.2 Hz, 0.8H), 5.22 :t, Jˆ7.8 Hz, 0.8H), 5.20±5.04 :m,
0.2H), 4.72 :td, Jdˆ12.6 Hz, Jtˆ7.8 Hz, 0.2H), 4.48±4.28
:m, 0.8H), 3.55 :s, 2.4H), 3.51 :s, 0.6H), 3.46 :s, 3H), 2.10±
1.85 :m, 4H), 0.85 :s, 4.8H), 0.83 :s, 1.2H), 0.16 :s, 9H); 13C
NMR :CDCl3, 75 MHz) 148.4, 147.2, 109.7, 109.2, 103.5,
99.3, 59.4, 55.9, 54.4, 40.4, 38.7, 36.2, 34.2, 26.8, 26.6,
26.5, 20.4; HRMS calcd for C14H29O2Si :M11H)
257.1937, found 257.1935.
neat) 2925, 1460, 1077, 733 cm21 1H NMR :CDCl3,
;
300 MHz) 4.48 :s, 0.5H), 4.38 :s, 0.5H), 4.29 :d,
Jˆ9.0 Hz, 0.5H), 4.27 :d, Jˆ6.1 Hz, 0.5H), 3.52 :s), 3.49
:s), 3.48 :s), 3.44 :s), 3.34 :s), 3.33 :s), 3.31 :s), 3.28 :s, 8 `s',
12H), 2.35±2.08 :series ofm, 3H), 1.92±1.00 :series ofm,
7H); 13C NMR :CDCl3, 75 MHz) 108.9, 108.8, 106.7, 105.7,
58.4, 56.5, 54.0, 53.8, 53.3, 45.0, 41.0, 39.3, 37.6, 36.0,
35.7, 33.9, 32.8, 32.0, 30.0, 29.8, 29.7, 29.5, 29.3; HRMS
:EI) m/e calcd for C12H21O3 :M12OMe) 213.1491, found
213.1489.
6.2.5. 1-1Trimethylsilyl)-1,8-dimethoxyocta-1,7-diene 131b).
In a fashion identical to that described for the synthesis of
31a 1-:methoxy)heptan-1-en-7-ol :1.0 g, 6.94 mmol) was
converted into substrate 31b in a 60% isolated yield. IR
:NaCl, neat) 2936, 2856, 1659, 1459, 1251, 1104, 842,
762 cm21
;
1H NMR :CDCl3, 300 MHz) 6.26 :d,
6.2.3. 1,2-1Bis-carboxaldehydedimethylacetal)-4,4-bis-
carbomethoxy-bicyclo[3.2.1]heptane 117). The elec-
trolysis ofsubstrate 14 was conducted in a fashion identical
Jˆ12.6 Hz, 0.5H), 5.84 :d, Jˆ6.2 Hz, 0.5H), 5.11 :t,
Jˆ7.8 Hz, 1H), 4.70 :td, Jdˆ12.6 Hz, Jtˆ7.3 Hz, 0.5H),

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5193
4.30 :q, Jˆ7.3 Hz, 0.5H), 3.54 :s, 1.5H), 3.47 :s, 1.5H), 3.41
:s, 3H), 2.20±1.82 :m, 4H), 1.50±1.20 :m, 4H), 0.14 :s, 9H);
13C NMR :CDCl3, 75 MHz) 147.0, 146.0, 112.8, 112.6,
106.9, 102.9, 59.3, 58.2, 55.7, 54.2, 31.1, 30.9, 30.4, 29.4,
27.6, 27.3, 23.8, 20.7; HRMS :EI) m/e calcd for C10H17O2
:M12SiMe3) 169.1228, found 169.1074.
:d, Jˆ6.8 Hz, 0.06H), 3.65 :s, 0.18H), 3.64 :s, 2.82H), 3.30
:s, 0.18H), 3.28 :s, 0.18H), 3.26 :s, 2.82H), 3.23 :s, 2.82H),
3.05±2.92 :m, 1H), 2.74±2.58 :m, 1H), 1.80±1.45 :series of
m, 4H), 1.08 :s, 2.82H), 1.02 :s, 0.18H), 0.99 :s, 0.18H),
0.93 :s, 2.82H); 13C NMR :CDCl3, 75 MHz) 176.0, 107.8,
105.4, 53.5, 52.4, 51.4, 46.2, 45.5, 44.9, 43.9, 43.7, 43.1,
42.3, 39.0, 29.8, 29.5, 29.2, 28.0; HRMS :EI) m/e calcd for
C11H19O3 :M12OMe) 199.1334, found 199.1331.
6.2.6. 1-1Trimethylsilyl)-1-methoxy-4,4-dimethylhexan-
1-en-6-ol. To a solution ofbis:trimethylsilyl)methoxy-
methane :10.13 g, 53.3 mmol) in 30.0 mL ofabs. tetra-
hydrofuran at 2788C was added dropwise 21.31 mL
:53.3 mmol) of2.5 M n-butyllithium in hexanes. The
mixture was warmed slowly to room temperature and stirred
for 45 min. The solution was cooled to 2788C and then
2-hydroxy-4,4-dimethyltetrahydropyran :2.31 g, 17.76 mmol)
in 20.0 mL ofabs. tetrahydrofuran added with the use ofa
cannula. The reaction was allowed to warm to room
temperature and stirred for 20 h. The reaction mixture was
then diluted with ether, quenched with brine, the layers were
separated, and the aqueous layer was extracted with ether.
The combined organic extracts were dried over MgSO4 and
concentrated in vacuo. The crude product was chromato-
graphed through a silica gel column that was slurry packed
using 1% triethylamine/hexane solution. Elution with 50%
ether/hexane furnished 1-:trimethylsilyl)-1-methoxy-4,4-
dimethylhexan-1-en-6-ol :2.45 g, 60%, over two steps). IR
:NaCl, neat) 3346, 2956, 2896, 1470, 1245, 1120,
6.2.9. Preparative electrolysis of 31b. Using the setup
described for the oxidation of substrate 10, compound 31a
:106 mg) was electrolyzed. In this case, pure methanol
solvent and a constant current of8 mA were used. The
reaction was stopped after 4.3 F/mol of electricity was
passed. All other conditions were the same. The cyclization
reaction produced 34.4 mg :30%) ofthe ortho ester product
33b along with 33.1 mg :35%) ofthe methyl ester product
32b. The spectral data for the relatively unstable 33b were
as follows: 1H NMR :CDCl3, 300 MHz) 4.49 :d, Jˆ8.6 Hz,
0.6H), 4.03 :d, Jˆ6.1 Hz, 0.4H), 3.65 :s), 3.64 :s), 3.47 :s,
three S's, 9H)), 3.33 :s), 3.30 :s), 3.29 :s, three S's, 6H),
2.73 :q, Jˆ4.7 Hz, 1H), 2.24±2.13 :m, 1H), 2.30±1.00
:series ofm, 8H); 13C NMR :CDCl3, 75 MHz) 111.4,
107.8, 105.5, 55.4, 54.4, 53.7, 53.3, 51.4, 51.2, 45.5, 41.7,
41.2, 40.9, 29.9, 27.7, 25.9, 25.2, 25.0, 24.6, 24.5, 23.1. The
spectral data for 32b were as follows: IR :NaCl, neat) 2829,
2754, 2728, 1663, 1134, 1110, 1079, 1059, 1016, 998 cm21
;
836 cm21
;
1H NMR :CDCl3, 300 MHz) 5.18, :t,
1H NMR :CDCl3, 300 MHz) 4.48 :d, Jˆ8.6 Hz, 0.4H), 4.02
:d, Jˆ5.8 Hz, 0.6H), 3.64 :s), 3.63 :s, two S's, 3H)), 3.32
:s), 3.29 :s), 3.28 :s, three S's, 6H), 2.72 :q, Jˆ4.7 Hz,
0.6H), 2.45±2.25 :m, 0.4H), 2.18 :dt, Jtˆ11.8 Hz,
Jdˆ3.7 Hz, 1H), 2.05±0.95 :series ofm, 8H); 13C NMR
:CDCl3, 75 MHz) 176.7, 107.8, 105.5, 55.3, 54.4, 53.7,
53.3, 51.4, 51.2, 45.4, 41.7, 41.2, 40.9, 29.9, 27.7, 25.9,
25.2, 24.9, 24.6, 24.5, 23.0; HRMS :EI) m/e calcd for
C10H17O3 :M12OMe) 185.1178, found 185.1180.
Jˆ7.7 Hz, 0.7H), 5.12 :t, Jˆ7.7 Hz, 0.3H), 3.73±3.64 :m,
2H), 3.57 :s, 0.9H), 3.47 :s, 2.1H), 2.40±2.10 :br s, 1H),
2.08 :d, Jˆ7.5 Hz, 0.6H), 1.99 :d, Jˆ7.7 Hz, 1.4H), 1.55 :t,
Jˆ8.5 Hz, 1.4H), 1.49 :t, Jˆ7.2 Hz, 0.6H), 0.91 :s, 6H),
0.17 :s, 9H); 13C NMR :CDCl3, 75 MHz) 162.9, 161.8,
122.7, 108.7, 59.1, 58.5, 54.3, 44.3, 43.8, 38.6, 36.9, 32.7,
32.6, 27.4, 26.9, 20.5; HRMS :EI) m/e calcd for C11H23OSi
:M12OMe) 199.1518, found 199.1508.
6.2.7.
1,7-1Bis-trimethylsilyl)-1,7-dimethoxy-4,4-di-
6.2.10. Preparative electrolysis of 31c. Using the setup
described for the oxidation of substrate 10, compound 31c
:110 mg) was electrolyzed. In this case, pure methanol
solvent and a constant current of8 mA were used. The
reaction was stopped after 6.0 F/mol of electricity was
passed. All other conditions were the same. The cyclization
led to the formation of43.6 mg :50%) ofthe trans-isomer as
the ortho ester 34 and 7.2 mg :10%) ofthe cis-isomer as the
methyl ester 35. The ortho ester 34 was not stabilized and
was therefore hydrolyzed :water, montmorillonite K-10) to
the corresponding methyl ester prior to characterization.
The spectral data for the methyl ester obtained from 34
were as follows: IR :NaCl, neat) 2954, 2869, 1735, 1436,
1174, 1029, 733 cm21; 1H NMR :CDCl3, 300 MHz) 3.68 :s,
6H), 3.36±3.23 :m, 2H), 1.94±1.60 :m, 4H), 1.03 :s, 6H);
13C NMR :CDCl3, 75 MHz) 175.5, 52.0, 46.5, 44.5, 39.4,
29.0; HRMS :EI) m/e calcd for C10H15O3 :M12OMe)
183.1021, found 183.1019. The spectral data for 35 were
as follows: IR :NaCl, neat) 2958, 2872, 1744, 1433, 1207,
1041, 842 cm21; 1H NMR :CDCl3, 300 MHz) 3.65 :s, 6H),
3.30±3.16 :m, 2H), 2.00±1.70 :m, 4H), 1.13 :s, 3H), 0.98 :s,
3H); HRMS calcd for C10H15O3 :M12OMe) 183.1021,
found 183.1019.
methylhepta-1,6-diene 131c). In a fashion identical to
that described for the synthesis of 31a 1-:trimethylsilyl)-1-
:methoxy)-4,4-dimethyl-1-en-hexan-6-ol :888 mg, 3.86
mmol) was converted into substrate 31c in a 70% isolated
yield. IR :NaCl, neat) 3025, 2958, 2898, 2825, 1605, 1465,
1253, 1114, 842 cm21; 1H NMR :CDCl3, 300 MHz) 5.22 :t,
Jˆ7.8 Hz, 1.6H), 5.12 :t, Jˆ7.4 Hz, 0.4H), 3.57 :s, 1.2H),
3.47 :s, 4.8H), 2.09 :d, Jˆ7.4 Hz, 0.4H), 2.00 :d, Jˆ7.9 Hz,
1.6H), 0.87 :s, 6H), 0.17 :s, 18H); 13C NMR :CDCl3,
75 MHz) 163.7, 161.8, 161.6, 122.8, 109.4, 108.9, 58.6,
54.3, 39.4, 38.9, 37.3, 34.2, 34.1, 26.7, 26.5, 2.5, 20.3;
HRMS :EI) m/e calcd for C16H33O2Si2 :M12Me)
313.2019, found 313.2020.
6.2.8. Preparative electrolysis of 31a. Using the setup
described for the oxidation of substrate 10, compound 31a
:110 mg) was electrolyzed. In this case, pure methanol
solvent and a constant current of8 mA were used. The
reaction was stopped after 4.0 F/mol of electricity was
passed. All other conditions were the same. The cyclization
reaction produced 14.3 mg :15%) ofthe ortho ester product
33a along with 50.9 mg :64%) ofthe methyl ester product
32a. The spectral data for 32a were as follows: IR :NaCl,
neat) 2952, 2868, 1733, 1436, 1369, 1178, 1062 cm21; H
NMR :CDCl3, 300 MHz) 4.39 :d, Jˆ8.7 Hz, 0.94H), 4.16
6.2.11. 3-130-t-Butyldiphenylsilyloxypropyl)cyclopentan-
1
0
1-one. To a stirred solution of3-:3 -hydroxypropyl)cyclo-

5194
S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
1
pentane :2.84 g, 20 mmol) and imidazole :2.95 g, 44 mmol)
in 40 mL ofDMF was slowly added t-butyldiphenylsilyl
chloride :6.1 g, 22 mmol). The reaction mixture was stirred
for 12 h at room temperature, diluted with ether, and then
washed with water. The aqueous layers were combined and
extracted with ether. The combined ether fractions were
washed with brine, dried over MgSO4, and concentrated in
vacuo. The crude product was chromatographed through a
silica gel column using 25% ether/hexane as eluant in order
neat) 2826, 2795, 2744, 2728, 1190, 1064, 789 cm21; H
NMR :CDCl3, 300 MHz) 5.92±5.83 :m, 1H), 5.14 :dt
Jdˆ7.8 Hz, Jtˆ1.77 Hz, 1H), 3.54 :s, 3H), 3.43 :s, 3H),
2.62±1.98 :series ofm, 7H), 1.50±1.08 :series ofm, 4H),
0.16 :s, 9H); 13C NMR :CDCl3, 75 MHz) 160.8, 138.8,
120.3, 112.8, 59.4, 54.4, 40.4, 40.0, 37.6, 37.1, 35.8,
33.7, 33.1, 32.5, 28.4, 26.6, 26.3, 14.2, 20.6; HRMS :EI)
m/e calcd for C15H29O2Si :M11H) 269.1937, found
269.1945.
0
to afford 6.08 g :80%) of the protected alcohol 3-:3-t-butyl-
diphenylsilyloxypropyl)cyclopentan-1-one. IR :NaCl, neat)
3071, 2931, 2853, 1741, 1111, 703 cm21; 1H NMR :CDCl3,
300 MHz) 7.74±7.64 :m, 4H), 7.50±7.35 :m, 6H), 3.68 :t,
Jˆ6.2 Hz, 2H, CH2OH), 2.32 :dt, Jtˆ18.0 Hz, Jdˆ7.2 Hz,
2H), 2.22±2.02 :m, 3H), 1.88±1.70 :m, 1H), 1.70±1.40
:series ofm, 6H), 1.06 :s, 9H); 13C NMR :CDCl3,
75 MHz) 219.8, 135.6, 134.0, 129.7, 127.7, 63.8, 45.3,
38.6, 36.9, 31.9, 30.8, 29.6, 27.0, 19.3; HRMS :EI) m/e
calcd for C24H31O2Si :M11H2H2) 379.2093, found
379.2094.
6.2.14. 1-Hydroxy-1-120,60-dithiocyclohexyl)-3-130-t-butyl-
diphenylsilyloxypropyl)cyclopentane 138). In a ¯ame-
dried ¯ask, dithiane :320 mg, 2.7 mmol) was placed under
argon atmosphere. Tetrahydrofuran was added and the
mixture cooled to 08C. A 2.5 M solution of n-BuLi in
hexanes :1.36 mL, 3.4 mmol) was added, and then the reac-
tion raised to room temperature and stirred for one hour. The
reaction was then cooled back down to 08C and 3-:30-t-
butyldiphenylsilyloxypropyl)cyclopentan-1-one :380 mg,
1.0 mmol) in 5 mL ofTHF added. The reaction was allowed
to warm to room temperature and stirred for 1 h. The reac-
tion was then diluted with ether and washed with brine. The
aqueous layer was extracted with ether. The combined
organic layers were then dried over MgSO4 and concen-
trated in vacuo. The crude product was chromatographed
through a silica gel column using 20% ether/hexane as
eluant to afford 400 mg :80%) of the desired product. IR
:NaCl, neat) 3463, 3066, 2934, 2862, 1432, 1108,
6.2.12. 1-110-Methoxymethylene)-3-130-hydroxypropyl)-
cyclopentane 136). To a stirred suspension of8.57 g
:25 mmol) ofmethoxymethyltriphenylphosphonium chlo-
ride in 25 mL oftetrahydrofuran at 0 8C was added dropwise
19.3 mL :25 mmol) of1.3 M sec-butyllithium in cyclo-
hexane. The dark red mixture was allowed to warm to
room temperature and stirred for 1 h. After cooling the
solution back to 08C, 3-:30-t-butyldiphenylsilyloxypropyl)-
cyclopentan-1-one :3.8 g, 10 mmol) in 20 mL oftetrahydro-
furan was added via a cannula. The reaction was allowed to
warm to room temperature. After 16 h, the reaction mixture
was diluted with ether and quenched with brine. The layers
were separated and the aqueous layer was extracted with
ether. The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. The crude silyl protected
enol ether was then dissolved in tetrahydrofuran :20 mL)
and 1 M tetrabutylammonium ¯uoride :20.0 mL, 20 mmol)
was added. After 12 h, the reaction was diluted with ether
and washed with water and brine. The aqueous fractions
were combined, saturated with sodium chloride, and
extracted with ether. The combined organic fractions were
dried over MgSO4 and concentrated in vacuo. The crude
product was chromatographed through a silica gel column
that was slurry packed using 1% triethylamine/hexane
710 cm21 1H NMR :CDCl3, 300 MHz) 7.70±7.63 :m,
;
4H), 7.46±7.34 :m, 6H), 4.30 :br s, 1H), 4.26 :s, 1H),
3.64 :t, Jˆ6.3 Hz, 2H), 2.96±2.84 :m, 4H), 2.30±1.65
:series ofm, 8H), 1.64±1.12 :series ofm, 5H), 1.04 :s,
9H); 13C NMR :CDCl3, 75 MHz) 135.6, 134.2, 129.6,
127.6, 84.2, 74.8, 64.1, 59.3, 47.5, 45.5, 37.9, 37.5, 32.0,
31.5, 30.8, 30.5, 27.9, 27.2, 27.0, 25.8, 25.5, 19.3; HRMS
:EI) m/e calcd for C24H31S2O2Si :M12CMe3) 443.1535,
found 443.1543.
6.2.15. 1-Chloro-1-120,60-dithiocyclohexyl)-3-130-t-butyl-
diphenylsilyloxypropyl)cyclopentane. In a ¯ame-dried
¯ask,
1-hydroxy-:20,60-dithiacyclohexyl)-3-:30-t-butyl-
diphenylsilyloxypropyl)cyclopentane 38 :150 mg, 0.3
mmol) was dissolved in CH2Cl2 :10 mL). 1.5 equiv. of
N,N-dimethylaminopyridine :58.6 mg, 0.45 mmol) and
3.0 equiv. oftriethylamine :0.13 mL, 0.9 mmol) were
added and cooled to 08C. 2.0 equiv. ofMsCl :0.6 mmol)
was added very slowly and stirred for 3 h at room tempera-
ture. When complete, the reaction was poured into the ice
water. The aqueous layer was extracted with ether. The
organic layer was then washed with brine, dried over
MgSO4 and concentrated in vacuo. The crude product was
chromatographed through a silica gel column using 20%
ether/hexane as eluant to afford 93 mg :60%) of the chlori-
nated product along with 20 mg :14%) ofthe ketene dithio-
acetal product from elimination of the chloride. This
reaction afforded a 40% yield of the chloride when done
on a large scale :5.27 g ofproduct). The spectral data ofr
the chlorinated product were as follows: IR :NaCl, neat)
0
solution. Elution with 50% ether/hexane afforded 1-:1-
methoxymethylene)-3-:30-hydroxypropyl)cyclopentane
:0.85 g, 50%, over two steps). IR :NaCl, neat) 3263, 2826,
1
2760, 1625, 1373, 1064 cm21; H NMR :CDCl3, 300 MHz)
5.82 :br s, 1H), 3.55 :t, Jˆ6.6 Hz, 2H), 3.49 :s, 3H), 2.52±
2.00 :series ofm, 3H), 1.90±1.65 :m, 3H), 1.65±1.45 :m,
3H), 1.45±1.25 :m, 2H), 1.25±1.02 :m, 1H); 13C NMR
:CDCl3, 75 MHz) 138.6, 138.6, 120.3, 62.9, 59.3, 40.3,
39.9, 35.6, 33.6, 33.0, 32.4, 31.6, 31.5, 31.1, 28.3, 26.2;
HRMS calcd for C10H18O2Li :M11Li) 177.1467, found
177.1461.
6.2.13. 1-110-Methoxymethylene)-3-140-methoxy-40-tri-
methylsilyl-30-butenyl)cyclopentane 137). Using the
procedure described above for the synthesis of substrate
31a, 100 mg of1-:2 0-methoxymethylene)-3-:30-hydroxy-
propyl)cyclopentane was converted into 94.6 mg :60%
over two steps) ofthe desired substrate 37. IR :NaCl,
;
3067, 2927, 2861, 1396, 1109, 697 cm21 1H NMR
:CDCl3, 300 MHz) 7.76±7.60 :m, 4H), 7.50±7.40 :m,
6H), 4.32 :d, Jˆ12.0 Hz, 1H), 3.65 :t, Jˆ6.0 Hz, 2H),
3.00±2.86 :m, 4H), 2.65±1.75 :series ofm, 8H), 1.75±
1.20 :series ofm, 5H), 1.05 :s, 9H); 13C NMR :CDCl3,

S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5195
75 MHz) 135.6, 134.1, 134.1, 129.6, 127.7, 82.6, 81.6, 63.9,
60.8, 60.5, 48.7, 47.5, 42.4, 40.9, 38.6, 37.5, 32.9, 32.1,
31.7, 31.5, 31.4, 31.0, 30.1, 27.0, 25.7, 19.3; HRMS :EI)
m/e calcd for C28H40S2OSi35Cl :M1) 519.1978, found
519.1939.
Jdˆ6.3 Hz, Jtˆ1.5 Hz, 0.6H), 4.71 :dt, Jdˆ12.6 Hz,
Jtˆ7.2 Hz, 0.4H), 4.32 :q, Jˆ7.2 Hz, 0.6H), 3.58 :s,
1.8H), 3.50 :s, 1.2H), 2.89±2.76 :m, 4H), 2.74±2.43 :m,
2H), 2.35±2.18 :m, 1H), 2.18±2.02 :m, 3H), 2.02±1.81
:m, 4H), 1.46±1.18 :series ofm, 3H); 13C NMR :CDCl3,
75 MHz) 148.1, 147.7, 147.1, 146.2, 113.3, 106.9, 103.0,
59.6, 56.0, 40.1, 39.6, 39.6, 36.5, 35.4, 32.6, 32.6, 30.1,
26.6, 25.4, 22.8; HRMS :EI) m/e calcd for C14H23S2O
:M11H) 271.1190, found 271.1188.
6.2.16.
1-120,60-Dithiocyclohexylidene)-3-130-t-butyldi-
phenylsilyloxypropyl)cyclopentane 139). In a ¯ame-
dried ¯ask, 1-chloro-1-:20,60-dithiacyclohexyl)-3-:30-t-
butyldiphenylsilyloxypropyl)cyclopentane :6.3 g, 12.2
mmol) was dissolved in tetrahydrofuran under argon
atmosphere and cooled to 08C. A 2.5 M solution of n-
BuLi in hexanes :5.8 mL, 14.6 mmol) was added and then
the reaction warmed to room temperature. The resulting
mixture was stirred for 1 h, diluted with ether and quenched
with brine. The aqueous layer was then extracted with ether.
The combined organic layers were washed with water and
brine before being dried over magnesium sulfate and
concentrated in vacuo. The crude product was chromato-
graphed through a silica gel column using 10% ether/hexane
as eluant to afford 3.51 g :60%) of the desired ketene
dithioacetal. IR :NaCl, neat) 3064, 2932, 2859, 1465,
6.2.19. Preparative electrolysis of 40: 1-110-methoxy-
20,60-dithiacyclohexyl)-2-1carboxaldehyde
dimethoxy
acetal)bicyclo[3.2.1]heptane 144). Using the setup
described for the oxidation of substrate 10, compound 40
:299 mg, 1.11 mmol) was electrolyzed. In this case, 30%
methanol/THF was used as solvent. A current of8 mA
was applied until 2.2 F/mol ofelectricity was passed. All
other conditions were the same. The cyclization led to the
formation of276 mg :75%) ofthe desired bicyclic product
was obtained. The product was predominately one
isomer. IR :NaCl, neat) 2821, 1385, 1049, 1042, 1012,
1
994 cm21; H NMR :CDCl3, 300 MHz) 4.85 :br s, 1H),
1
1426, 1114, 696 cm21; H NMR :CDCl3, 300 MHz) 7.72±
3.53 :s, 3H), 3.42 :s, 3H), 3.39 :s, 3H), 3.30±3.10 :m,
1H), 2.80±2.55 :m, 3H), 2.25±1.20 :series ofm, 14H);
13C NMR :CDCl3, 75 MHz) 107.5, 56.6, 56.3, 56.1, 52.6,
46.2, 45.6, 44.1, 36.2, 35.0, 30.7, 30.2, 28.7, 28.0, 27.6,
27.4, 27.3, 24.0, 23.2, 22.7, 18.8, 11.2; HRMS :EI) m/e
calcd for C16H28O3S2Li :M11Li) 339.1640, found,
339.1653.
7.63 :m, 4H), 7.47±7.34 :m, 6H), 3.66 :t, Jˆ6.3 Hz, 2H),
2.92±2.76 :m, 4H), 2.72±2.45 :m, 2H), 2.34±2.19 :m, 1H),
2.19±2.06 :m, 2H), 1.96±1.78 :m, 3H), 1.66±1.52 :m, 2H),
1.48±1.33 :m, 2H), 1.33±1.18 :m, 1H), 1.05 :s, 9H); 13C
NMR :CDCl3, 75 MHz) 147.8, 135.6, 134.1, 129.6, 127.6,
113.5, 64.1, 40.1, 39.7, 32.7, 32.5, 31.4, 30.0, 30.0, 26.9,
25.3, 19.3; HRMS :EI) m/e calcd for C28H39S2OSi :M11H)
483.2212, found 483.2199.
6.2.20. Hydrolysis of 41: 1-110-oxo-20-thia-50-thiol-
pentyl)-2-1carboxaldehyde)bicyclo[3.2.1]heptane. In
a
6.2.17.
1-120,60-Dithiacyclohexylidene)-3-130-hydroxy-
round bottom ¯ask, 1-:10-methoxy-20,60-dithiacyclohexyl)-
2-:carboxaldehyde-dimethylacetal)bicyclo[3.2.1]heptane
:100 mg, 0.3 mmol) was dissolved in 1.5% water/acetone.
Amberlyst-15 :200 mg, 2.0 equiv. by weight) was added
and the mixture stirred for 1 h at room temperature. When
complete the reaction mixture was ®ltered through MgSO4,
concentrated in vacuo and the residue chromatographed
through a silica gel column. Elution with 20% ether/hexane
furnished 1-:10-oxo-20-thia-50-thiol-pentyl)-2-:carboxalde-
hyde)bicyclo[3.2.1]heptane :74 mg, 90%). IR :NaCl, neat)
2832, 2765, 1700, 1155 cm21; 1H NMR :CDCl3, 300 MHz)
9.59 :s, 0.1H), 9.57 :d, Jˆ1.5 Hz, 0.9H), 2.98 :t, Jˆ6.9 Hz,
2H), 2.88 :dd, Jdˆ11.3, 4.8 Hz, 1H), 2.57 :q, J1ˆ14.5 Hz,
J2ˆ7.5 Hz, 2H), 2.42±2.34 :m, 1H), 2.32±2.16 :m, 1H),
2.02±1.78 :series ofm, 6H), 1.70±1.36 :series ofm, 6H);
13C NMR :CDCl3, 75 MHz) 204.0, 202.3, 59.7, 55.3, 44.7,
35.3, 33.6, 30.8, 29.4, 28.8, 27.1, 23.5, 20.0; HRMS :EI) m/e
calcd for C13H20O2S2Li :M11Li) 279.1065, found
279.1061.
propyl)cyclopentane. In a dry ¯ask, compound 39 :4.3 g,
8.9 mmol) was dissolved in tetrahydrofuran and treated with
tetrabutylammonium ¯uoride :18.0 mL, 18.0 mmol) at
room temperature. The resulting mixture was stirred for
4 h, diluted with ether and quenched with brine. The
aqueous layer was extracted with ether, and then the
combined organic layers dried over magnesium sulfate
and concentrated in vacuo. The crude product was chroma-
tographed through a silica gel column using 75% ether/
hexane as eluant to afford 1.96 g :90%) of the deprotected
alcohol. IR :NaCl, neat) 3354, 2921, 1424, 1270, 1053,
914 cm21; H NMR :CDCl3, 300 MHz) 3.64 :t, Jˆ6.6 Hz,
1
2H), 2.90±2.78 :m, 4H), 2.75±2.45 :m, 2H), 2.36±2.19 :m,
1H), 2.19±2.06 :m, 2H), 2.00±1.82 :m, 3H), 1.66±1.53 :m,
2H), 1.48 :br s, 1H), 1.46±1.18 :m, 3H); 13C NMR :CDCl3,
75 MHz) 147.3, 113.6, 62.9, 40.1, 39.5, 32.6, 32.4, 31.5,
31.3, 29.9, 29.9, 25.2; HRMS :EI) m/e calcd for
C12H21S2O :M11H) 245.1034, found 245.1025.
6.2.18. 1-120,60-Dithiacyclohexylidene)-3-140-methoxy-30-
butenyl)cyclopentane 140). Using the two step oxidation±
Wittig reaction sequence outlined above for the synthesis of
substrate 10, 427 mg :1.75 mmol) ofthe alcohol synthesized
in the previous step was converted into 236 mg :50%) of
substrate 40. The procedure only differed from the one
reported above in that 2.5 equiv. ofthe ylide were used
for the Wittig reaction instead of the ®ve equivalents used
to make the bis enol ether substrate 10. IR :NaCl, neat)
Acknowledgements
We thank the National Science Foundation :CHE-9023698)
for their generous support of this work. We also gratefully
acknowledge the Washington University High Resolution
NMR facility, partially supported by NIH grants
RR02004, RR05018, and RR07155, and the Washington
University Mass Spectrometry Resource Center, partially
supported by NIHRR00954, for their assistance.
1
2923, 2850, 1654, 1424, 1206, 1100, 921 cm21; H NMR
:CDCl3, 300 MHz) 6.29 :d, Jˆ12.6 Hz, 0.4H), 5.86 :dt,

5196
S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
13. For a preliminary account ofthis work see: Reddy, S. H. K.;
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S. H. K. Reddy et al. / Tetrahedron 57 *2001) 5183±5197
5197
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