Anodic oxidations and polarity: exploring the chemistry of olefinic radical cations

Article abstract of DOI:10.1016/j.tet.2009.09.028

The cyclization chemistry of radical cations derived from electron-rich olefins has been examined and the relationship between the polarization of the radical cation and the chemoselectivity of the reaction probed. It was found that more polarized radical

Full text of DOI:10.1016/j.tet.2009.09.028

Tetrahedron 65 (2009) 10863–10875
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Anodic oxidations and polarity: exploring the chemistry of olefinic radical cations
*
Feili Tang, Kevin D. Moeller
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2009
Received in revised form 15 August 2009
Accepted 7 September 2009
Available online 11 September 2009
The cyclization chemistry of radical cations derived from electron-rich olefins has been examined and the
relationship between the polarization of the radical cation and the chemoselectivity of the reaction probed. It
was found that more polarized radical cations favor carbon–carbon bond formation while less polarized
radical cations favor carbon–heteroatom bond formation. A new approach to the synthesis of quaternary
carbons was uncovered and the compatibility of ene diol ethers with anodic olefin coupling reactions
examined.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
To date, the reactions have been initiated by the oxidation of
enol ethers, ketene acetals, and electron-rich aromatic rings and
Anodic electrochemistry has proven to be an effective tool for
removing electrons from electron-rich functional groups and trig-
gering interesting new umpolung reactions.1 As part of an ongoing
effort to develop the synthetic utility of such reactions, we have
been studying transformations having the overall format illustrated
in Scheme 1.2 In the reactions, the one electron oxidation of an
electron-rich olefin forms a radical cation that is then trapped with
a nucleophile. After the addition of solvent and a second oxidation
step, the transformation affords a cyclic product that retains the
initial functionality used to trigger the cyclization. Both the
umpolung nature of the reactions that provides new opportunities
for generating bonds from existing functional groups and the
preservation of functionality that can be employed in subsequent
synthetic transformations suggest that the reactions have signifi-
cant potential for constructing complex molecules.
terminated with the use of simple olefins, enol ethers, allyl- and
vinylsilanes, electron-rich aryl rings, alcohols, amides, and sulfon-
amides.2,3 The reactions are compatible with the formation of fused
and bridged ring skeletons, the generation of quaternary carbons,
and the use of simple reaction setups.4 They have been used as key
reactions in total synthesis efforts.5
It was with this in mind that we turned our attention toward
a potential use of the reactions for the synthesis of the natural
product ineleganolide (Scheme 2).6 The plan called for an oxidative
cyclization reaction to form the final ring and join carbons C2 and
C20. This coupling reaction was intriguing because it involved the
oxidation of an electron-rich ene diol ether moiety to form a new
type of radical cation intermediate. Previous studies of more elec-
tron-rich ketene acetal derived radical cations led to very efficient
carbon–carbon bond forming reactions.7 Would the same be true
here? If the reactions were successful, then a second question
would be important. The proposed cyclization could lead to either
X
X
.
+
oxidation (- e-)
(
)
n
(
)
n
H
Me
O
H
Me
Nuc-H
Nuc-H
anodic oxid.
O
O
RO
H
2
3
O
RO
H
H
-H+
H
H
H
O
OR
2'
H
H
O
H
X
X
oxidation (- e-)
+ solvent (YH)
OR
.
Y
Ineleganolide
(
)
n
(
)
n
Nuc
Nuc
- H+
H
H
Me
O
OBzl
H
Scheme 1.
O
O
O
O
H
H
H
O
OR
Corey Lactone
* Corresponding author. Tel.: þ1 314 935 4270; fax: þ1 314 935 4481.
E-mail address: moller@wuchem.wustl.edu (K.D. Moeller).
Scheme 2.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.028

10864
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
the formation of a six- or a seven-membered ring. Would the
conformational requirements imposed on the cyclization by the
bicyclic nature of the substrate dictate this regiochemistry?
of compound 4a (Scheme 3), an effort that started with the conver-
sion of cyclopentenone to compound 29 followed by deprotection of
the alcohol and then an acid catalyzed cyclization to form tetrahy-
drofuranone 3.10 The resulting enone was reduced with an excess of
Support for the suggestion that the reaction might lead to seven-
membered ring formation was obtained from molecular modeling
studies using a simplified radical cation structure (Fig. 1). The
modeling study was conducted using SpartanÓ 02 on an SGI work-
station.8 Geometry optimization of the initial radical cation was
performed using the PM3 and HF/3-21G force fields with the single
point energy of the optimized structure calculated using B3LYP/6-
31G. The energy profile for the cyclization reaction was performed
using a semi-empirical method (PM3) in order to provide a rough
approximation of the transition state for the cyclization. For the
seven-membered ring, the drive distance for the calculation was set
from the initial distance in the optimized radical cation to 1.5 Å with
25 points chosen within this distance. The energy maximum point in
the energy profile was taken as the initial transition state structure.
This structure was then optimized using both the PM3 and HF/3-21G
force fields. The resulting transition state was confirmed with one
and only one imaginary frequency that indicates stretching along the
reaction coordinate of the forming bond. The single point energy of
the transition state was then calculated by B3LYP/6-31G. For the six-
membered ring cyclization, the same approach led to an energy
maximum that when followed again led to the seven-membered
ring product. Hence, for the six-membered ring cyclization the
transition state was found by modeling the reverse reaction with
a drive distance varying from 1.5 Å to 3.0 Å. The optimized transition
state energy was then calculated as described for the seven-mem-
bered ring cyclization. A large difference in energy was found for the
two pathways (6.4 kcal/mol using HF/3-21G and 11.9 kcal/mol using
B3LYP/6-31G to calculate the energy of the transition state) favoring
formation of the seven-membered ring. It appeared that the con-
formation constraints of the bicyclic ring system would indeed im-
pose seven-membered ring formation on the cyclization. That is, of
course, if the new radical cation led to any cyclization at all.
L
-Selectride to afford a mixture of two alcohols (4a,b).11 The stereo-
chemistry of the isomers was assigned using an NOE experiment after
oxidation of the alcohols to ketones. For isomer a, the methine proton
at C3 showed roughly equal NOE couplings to both the methine at C4
and the methine at C7. For isomer b, no interaction was observed for
the methine at C3 with the methine at C7.
With 4a in hand, the bicyclic oxidation substrate (7) was syn-
thesized as outlined in Scheme 4. To this end, 4a was converted to 5
using an ozonolysis reaction followed by reduction of the second-
ary ozonide with sodium borohydride, selective protection of the
primary alcohol, and then a Swern oxidation to form the ketone.
Conversion of the ketone to a dimethoxy ketal followed by an
elimination led to formation of the ene diol ether needed for the
electrolyis.12 Deprotection of the primary alcohol, oxidation to form
an aldehyde, and a Wittig reaction installed the necessary trapping
group for the anodic cyclization.
1) a) O3, CH2Cl2, MeOH
H
H
H
H
b) NaBH4, 67%
O
O
2) PivCl, Et3N, DMAP
CH2Cl2, 92%
3) Swern, 96%
O
OH
4a
5
PivO
4) a) CH(OMe)3, MeOH,
TsOH (cat.), 2h
b) TMSOTf, DiPEA,
CH2Cl2, 20 h, 58%
H
H
5) LiAlH4, Et2O, -78 °C
6) Corey-Kim oxidation
O
H
O
7) Ph3P=CHOMe
THF, 0 °C, 12 h,
40% (3 steps)
OMe
H
OMe
7
6
PivO
MeO
H
H
Scheme 4.
O
MeO
MeO
.
+
2
The oxidation of 7 was conducted at a reticulated vitreous car-
bon (RVC) anode using an electrolyte solution containing 0.05 M
tetraethylammonium tosylate in 25% methanol/dichloromethane,
2,6-lutidine as a proton scavenger, a carbon cathode, and a constant
current of 8 mA. A total of 2.0–2.2 F/mol of charge was passed
through the cell (Scheme 5). To our surprise, no cyclized product
was observed. Instead, a 60–70 % yield of product resulting from
solvent trapping was obtained.13 Initially, two products (8 and 9)
were observed. However, with a careful workup the formation of
the methanol elimination product 9 could be avoided and a 59%
yield of the pure methanol trapping product 8 isolated. A proton
NMR of the crude reaction indicated that 8 was the only product
formed in the reaction. The methyl enol ether trapping group was
H3
H
H
OMe
OMe
Figure 1.
2'
H
2. Initial studies
With this in mind, a model substrate for the electrolysis was
designed and synthesized. The synthesis beganwith the construction
1a)
MgBr
O
O
2) TFAA, DMSO
Et3N, CH2Cl2
O
Bu3P, CuI
O
O
OH
H
b)
H
H
RVC Anode
carbon cathode
Et4NOTs
O
85%
O
OTBS
H
OTBS
OMe
OMe
OMe
OTBS
1
2
53%
+
H
O
2,6-lutidine
3) a) 1% HCl, EtOH
b) TsOH, C6H6
reflux
25% MeOH/CH2Cl2
2.2 F/mole
8
7
MeO
(60-70%)
MeO
73% (two steps)
H
O
H
O
4) 3 eq. L-selectride
THF, -78 °C, 3 h
O
OMe
H
OH
OMe
O
80%
4a. C7 = β, 55%
4b. C7 = α, 25%
3
9
MeO
Scheme 3.
Scheme 5.

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10865
completely intact. Clearly, either the presence of the bicyclic ring
skeleton or the use of the ene diol ether completely stopped the
cyclization.
anodic oxidation of 17 smoothly led to the formation of a new car-
bon–carbon bond, a quaternary center, and a bicyclic ring skeleton
(Scheme 9).13a
3. Removing the conformational constraint
1) Ph3P=CH2, THF
-78 °C to rt, 24 h, 79%
Me
4) (Ph P) RuCl , DIPEA
PhCH3, 65 °C, 8h
Me
O
3
3
2
O
2) LiAlH4, Et2O, -78 °C,
2h, 94%
In order to separate the effect of the bicyclic ring skeleton on the
cyclization from that of the ene diol ether, monocyclic substrate 13
was synthesized (Scheme 6). While we understood that removing
the conformational constraint from the substrate would lead to
six-membered ring formation, we wanted to know if the ene diol
ether derived radical cation was compatible with carbon–carbon
bond formation. How would this electron-rich radical cation
compare with the one generated from the oxidation of a ketene
acetal?7
11
CH2
79%
CH3
3) a) Swern oxidation
b) Ph3P=CHOMe, THF
68% (two steps)
17
16
OMe
OMe
Scheme 8.
RVC Anode
carbon cathode
LiClO4
Me
O
Me
H
O
OMe
Me
1) Na, acetone, PhCH3
H
Me
2,6-lutidine
OMe
OMe
18. 75% (6:1 ratio)
- 78 °C to rt, 10 h, 53%
2) PivO(CH2)4-I, K2CO3, acetone
Me
O
50% MeOH/THF
2.2 F/mole
O
OTBS
MeO
reflux, 12 h, 72%
17
MeO
O
3) HCl (conc.), THF, rt, 15 min, 94%
4) L-selectride, THF, -78 °C,
1 h, 79%
PivO
11
10
Scheme 9.
5) a) CH(OMe)3, MeOH,
cat. TsOH, 0.5 h
A 75% isolated yield of the cyclic product was obtained as a 6:1
ratio of diastereomers. The major diastereomer had the dimethoxy
acetal group on the convex face of the bicyclic ring skeleton. From
a synthetic standpoint, the reaction was intriguing because it
formed a functionalized bicyclic product having four contiguous
stereogenic atoms one of which was the central quaternary carbon.
Clearly, the formation of the quaternary carbon was not a problem
for the electrolysis reaction. The lack of cyclization resulting from
substrate 13 must have been due to the ene diol ether derived
radical cation.
b) TMSOTf, DiPEA, CH2Cl2,
20 h, 77% (two steps)
Me
O
6) LiAlH4, Et2O, 2 h, 93%
7) Corey-Kim oxidation
Me
O
OMe
13
8) Ph3PCHOMe, 0 °C, 12 h
45% (two steps)
OMe
PivO
OMe
12
Scheme 6.
The synthesis began with the conversion of 10 into a 1,3-dicar-
bonyl14 that was then alkylated,15 cyclized using the acid catalyzed
conditions employed in the synthesis of the bicyclic substrate,10b
4. Polarization and carbon–carbon bond formation
and the resulting enone reduced with L-Selectride to form furanone
So why did the use of an ene diol ether derived radical cation stop
the cyclization reaction when the earlier use of an electron-rich
olefin had favored carbon–carbon bond formation?7 Two sugges-
tions arose from looking at trends associated with the radical cations
studied to date (Fig. 2). Our studies started with the examination of
enol ether derived radical cations. These intermediates proved adept
at forming both carbon–carbon and carbon–oxygen bonds.2 Two
types of ketene acetal derived radical cations were then studied.
Ketene dithioacetal derived radical cations were shown to be less
effective than the enol ether derived radical cations for generating
carbon–carbon bonds but very effective for use in generating car-
bon–oxygen bonds.17 N,O-Ketene acetal derived radical cations be-
haved in the opposite fashion and proved to be more efficient at
generating carbon–carbon bonds than their enol ether derived
counterparts.5a,7b Cyclic voltammetry studies showed that this later
11. Compound 11 was converted into the electrolysis substrate us-
ing the chemistry described previously for the synthesis of 7.
The electrolysis of 13 was conducted using nearly identical con-
ditions to those employed for the earlier oxidation of substrate 7
(Scheme 7).13a Once again, no cyclic product resulting from carbon–
carbon bond formation was obtained, and the only observable
products resulted from either methanol trapping of, or elimination of
a proton from, the radical cation. In this case, the products could not
be readily separable from the crude reaction mixture. However, the
conclusion of the experiment was obvious. Either the use of the ene
diol ether derived radical cation was preventing cyclization or there
was some undetermined reason that formation of the tetrasub-
stituted carbon was in this case preventing the cyclization. The
compatibility of the cyclization with forming the tetrasubstituted
carbonwas quickly demonstrated by replacing the methoxy group of
the ene diol ether with a methyl substituent. To this end, a substrate
(17) was synthesized (Scheme 8). The synthesis took advantage of
the previously synthesized furanone ring by converting the ketone
into an olefin that was subsequently migrated into the ring.16 The
OR
OR
O
S
.
+
+
N
H
S
.
.
O
+
Increased C-C bond formation
Increased oxygen trapping
Intermediate
Less
More
Polar
Me
O
Me
O
RVC Anode
carbon cathode
LiClO4
Me
O
Polar
OMe
OMe
OMe
OR
OR
+
OMe
OMe
+
H
OMe
+
H
2,6-lutidine
50% MeOH/THF
2.2 F/mole
.
.
Me
OR
MeO
MeO
13
MeO
14
15
C-O bond formation
C-C bond formation
Scheme 7.
Figure 2.

10866
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
1
O
H
H
observation was a result of the N,O-ketene acetal derived radical
cations being more stable to methanol solvent trapping.7b
H
H
H
H
H
H
Me
R
Me
R
O
Me
R
O
2
Me
R
O
H2
H2
3
H2
O
H2
At the time, it was thought that the tendency toward carbon–
carbon bond formation might be dependent on the ‘electron-rich-
ness’ of the radical cation. It was suggested that the more the groups
on the initial double bond stabilized a cation, the more the radical
cation would behave as a radical and favor carbon–carbon bond
formation.7b,18 This description of the reactions is not consistent
with the oxidation chemistry of substrates 7, 13, and 17. In these
cases, the more electron-rich double bond did not lead to carbon–
carbon bond formation, but instead favored carbon–oxygen bond
formation. The reactions were more consistent with a second pos-
sibility suggesting that more polarized radical cations favor car-
bon–carbon bond formation and less polarized radical cations favor
carbon–heteroatom formation. This view of the reactions was con-
sistent with all five radical cations shown in Figure 2.
OMe
Me
17
O
OTf
21
Ot-Bu
20
13
R = CH=CHOMe
E
p/2 = + 0.81
δ H2 5.82
+1.10
5.96
+1.25
6.50
+1.44
6.56
=
R = CH2OPiv
p/2 = + 0.84
E
+1.18
+1.30
+1.92
Scheme 11.
In order to probe this idea in more detail, two new substrates
were constructed (Scheme 10). The first (20) replaced the OMe
substituent in substrate 13 with a t-butylcarbonate group. Since
acyloxy type substituents are known to be ‘neutral’ from an elec-
tron-donation perspective,19 substrate 20 should be less electron-
rich but more polar than either the previously studied 13 or 17. In
the second substrate (21) the OMe substituent in substrate 13 was
replaced with an electron-withdrawing triflate group. Again, the
plan was to build a less electron-rich but more polar substrate. The
’electron-richness’ versus polarity of all the substrates in the series
was examined using a combination of cyclic voltammetry and
proton NMR chemical shift data (Scheme 11).13a The cyclic vol-
tammetry data was used to gauge the ‘electron-richness’ of the
substrates. The lower the oxidation potential (easier to oxidize)
measured for the substrate, the more electron-rich the substrate.
The trend established for the initial olefin was assumed to be the
same as that for the radical cation intermediate following the oxi-
dation. In other words, a more electron-rich olefin was assumed to
give rise to a more electron-rich radical cation intermediate. Two
sets of data are presented, one for the preparative electrolysis
substrates themselves (R]CH]CHOMe) and a second for a model
cyclic voltammetry substrate containing the five-membered ring
functional group but lacking the side chain enol ether (R]CH2O-
Piv). All of the CV data reported was measured relative to a Ag/AgCl
reference electrode using identical conditions.20 The ‘electron-
richness’ of the double bond used to generate the radical cation can
be best assessed with the model substrate. For this series, the
oxidation potential depends directly on the electron-donating
ability of the substituent at C3 of the substrates. From left to right in
the Scheme, the substrates go from being more electron-rich to less
electron-rich. When the enol ether trapping group is added to the
side chain of the substrates two changes can be noticed. First, for
substrates 13, 17, and 20, a slight drop in potential is observed. This
drop in potential is consistent with a rapid cyclization of the radical
cation.21 For substrate 13, the cyclic voltammogram was run in the
absence of methanol solvent. Hence, there was no chance for
competitive solvent trapping of the radical cation as observed in
the preparative electrolysis. The drop in potential for 13 suggests
the possibility for a preparative cyclization from 13 if the methanol
solvent could be removed from the reaction. Second, for substrate
21 a dramatic drop in potential is observed relative to the model
substrate. In this case, the oxidation potential measured is for the
methoxy enol ether group, an observation that suggests that
a preparative oxidation of this substrate will not lead a radical
cation derived from the five-membered ring double bond.
The polarity of the five-membered ring double bond was gauged
by looking at the proton NMR chemical shift observed for H2 in each
of the substrates. The chemical shift of this proton reflects the
ability of the group at C3 to donate electron density to the double
bond. The better the electron–donor at C3 the more upfield the
chemical shift of the proton at C2. Since the donation of electron
density to the double bond by the group at C3 opposes the donation
of electron density to the double bond by the oxygen in the ring, the
more electron density donated by the group at C3 the less polar
the p-system. Hence, the lower the chemical shift observed for the
proton at C2 the less polar the double bond. The more polar the
double bond, the more downfield the chemical shift for H2. As in
the case of electron-richness, it was assumed that the trends ob-
served for the p-system in the starting material would remain the
same for the radical cation intermediates generated by the oxida-
tion reaction.
For the substrates in Scheme 11, the polarity of the five-mem-
bered ring double bond increased from lowest polarity to highest
polarity from left to right in the Scheme. Hence, an oxidation of
substrate 13 would be expected to lead to the least polarized radical
cation while an oxidation of substrate 21 would be expected lead to
the most polarized radical cation (if the five-membered ring double
bond was oxidized in this case instead of the side chain enol ether).
When taken in context with the earlier ketene acetal studies,7
the series of substrates highlighted in Scheme 11 provide a nice test
of whether the ‘electron-richness’ or polarization of a radical cation
favors carbon–carbon bond formation. The preparative oxidation of
substrates 13 and 17 clearly supports the idea of polarization fa-
voring carbon–carbon bond formation (Fig. 2).13a If this trend is
general, then the preparative oxidation of substrate 20 should also
lead to carbon–carbon formation. This turned out to be the case
(Scheme 12). The anodic oxidation of substrate 20 at an RVC anode
led to a 64% unoptimized yield of two cyclized products. No
uncyclized material was observed in the proton NMR of the crude
reaction mixture. This was easy to determine because no signal
1) LiAlH4, THF, rt
2 h, 90%
2) a) Swern oxidation
O
O
b) Ph3P=CHOMe
THF, -78 °C to rt,
12 h, 48% (two steps)
O
O
11
19
PivO
OMe
3) LDA, TMEDA, Boc2O
THF, -78 °C to
rt, 69%
4) LDA, Tf2N, THF
-78 °C to rt,
71%
O
O
OBoc
OTf
21
20
OMe
OMe
Scheme 10.

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10867
1) Swern oxidation, 96%
2) a) O3, CH2Cl2
b) PPh3
remained for either the five-membered ring double bond or the
H
H
O
side chain enol ether. The two cyclic products formed arose from
the expected initial cyclization followed by a subsequent reaction
involving the carbonate group. The products were not stable (the
reason for the unoptimized yields) and had a tendency to form
furan products derived from elimination. The use of 10% MeOH/
CH3CN as the solvent for the reaction reduced these side reactions.
A closely related reaction using an electrolysis substrate having
a pivaloyl group in place of the carbonate led almost exclusively to
furan products. As in the case of 20, no uncyclized products were
observed following oxidation of the pivaloyl-containing substrate.
O
H
3) Ph3P=CHOMe, THF
64% (two steps)
H
O
OH
4a
24
OMe
4) a) LDA, TMEDA, THF
b) Boc2O, 57%
H
O
anodic oxidation
No
Cyclized
Products
O
H
O
H
RVC Anode
carbon cathode
LiClO4
Ot-Bu
Me
O
25
H
H
MeO
Me
H
O
Me
O
O
OMe
O
O
O
H
O
O
Scheme 13.
+
2,6-lutidine
10% MeOH/CH3CN
2.0 F/mole
OMe
OMe
O
Ot-Bu
Ot-Bu
OMe
H
H
H
1) Ph3P=CH2, THF, 6h
0 °C to rt, 92%
MeO
O
O
20
22. 38%
Scheme 12.
23. 26%
2) (Ph3P)3RuCl2, DIPEA,
PhCH3, 65 °C, 8h, 86%
H
O
Me
24
26
An attempt to probe the chemistry of an even more electron-
poor but highly polarized radical cation using substrate 21 met with
failure when the preparative reaction did indeed lead to side chain
oxidation. In this reaction, the only products observed were derived
from methoxylation of the methoxy enol ether. During the reaction,
the vinyl triflate group remained intact. The lack of cyclized prod-
ucts in this oxidation is consistent with both the cyclic voltammetry
data shown above and earlier cyclization attempts demonstrating
that like radical intermediates, radical cations are sensitive to ste-
rics at the terminating end of a cyclization.17c
From these studies, two things were clear. First, one cannot
simply improve the yield of carbon–carbon bond formation in an
anodic olefin coupling reaction by adding a heteroatom to the enol
ether starting material. In the case of a ketene acetal, such a change
does help the cyclization, but in the case of an ene diol ether the
change hurts the cyclization. In other words, it matters where the
heteroatom is added to the substrate with the success of a cycliza-
tion tracking the polarity of the resulting double bond rather than
how electron-rich it is. Second, ene diol ether type substrates can be
compatible with the anodic olefin coupling reaction as long as they
are substituted in a manner that leads to a polarized radical cation.
OMe
OMe
anodic oxidation
No
Cyclized
Products
Scheme 14.
The failure the anodic oxidation arising from substrate 26 was
not that surprising. From our earlier calculations, we knew that the
formation of a six-membered ring product from the bicyclic sub-
strate was unlikely. We hoped that the result would be initial
trapping of the radical cation by methanol at C3 followed by a rad-
ical cyclization that would form a seven-membered ring at C2 (the
alpha carbon of the radical cation). However, to date no anodic
cyclization has led to the formation of a carbon–carbon bond to the
alpha carbon of an enol ether derived radical cation. With this in
mind, one final test of the anodic cyclization was attempted. In this
case, a substrate was built that would enable seven-membered ring
formation from an enol ether–enol ether coupling reaction at the
beta carbons of the two enol ethers. Similar anodic cyclizations
have been used to generate seven-membered ring products.21a,22
The synthesis of the substrate for the cyclization is shown in
Scheme 15.23 Once again, the anodic oxidation of 30 failed to afford
any cyclized product. A variety of conditions were utilized.
5. A return to bicyclic substrates
Having determined the substituent pattern necessary for trig-
gering cyclizations with ene diol ether type substrates, attention
was returned to the bicyclic substrate, the synthesis of inelegano-
lide, and the key question of whether or not the ring skeleton can
be used to channel the anodic cyclization toward the formation of
a seven-membered ring. To this end, the methoxy group on the
five-membered ring of 7 was replaced with a t-butylcarbonyloxy
group (25) using the synthesis illustrated in Scheme 13. The syn-
thesis started from 4a and capitalized on the chemistry developed
previously.
H
H
1) TBSCl, imidazole, DMF, 85%
2) TBSO-(CH2)3-Li, THF, 79%
H
O
OH
TBSO
H
3) SOCl2, pyridine, THF
CuSO4, 75%
OTBS
27
28
4) a) Pd/C, EtOAc, 71%
b) 5% aq. HCl, 73%
5) Swern oxidation
6) Ph3P=CHOMe, THF,
12 h, -78 °C to rt
57% (two steps)
Unfortunately, the anodic oxidation of 25 did not lead to either
a six- or a seven-membered ring product. In this case, evidence for
polymerization of the radical cation was obtained. While the re-
action led to an inseparable mixture of products, the side chain enol
ether appeared to be unchanged in all of them. Clearly, the con-
straints associated with the bicyclic ring skeleton stopped the cy-
clization. The same observation was made for a bicyclic substrate
based upon the earlier successful cyclization of 17 (Scheme 14).
Once again, no cyclized products were observed from the anodic
oxidation reaction.
H
H
7) a) LDA, THF
b) TBSOTf, 85%
MeO
MeO
H
30
OTBS
H
O
29
Scheme 15.
In the end, it was clear that the bicyclic ring skeleton would not
allow the cyclization reaction to occur. Evidently, it is simply too
difficult for the enol ether to approach the radical cation in a fashion

10868
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
that allows an intramolecular trapping reaction to compete with
decomposition or polymerization of the radical cation.
7. Experimental
7.1. General
6. Long range implications and conclusions
7.1.1. 3-(But-3-enyl)-2-(2-(tert-butyldimethylsilyloxy)-1-hydroxy-
ethyl)cyclopentanone. A flame-dried 250 mL three-neck flask under
argon was charged with magnesium turnings (2.12 g, 87 mmol) in
anhydrous ether (50 mL). A solution of 4-bromobut-1-ene (10.0 g,
74 mmol) in anhydrous ether (50 mL) was placed in the additional
funnel and a small portion of the solution was added to the flask.
The mixture was heated to reflux and the remaining solution
added dropwise at a rate to maintain reflux. After complete addi-
tion, the mixture was refluxed for another 30 min and then cooled
to rt.
A flame-dried 500 mL three-neck flask under argon was charged
with CuI (14.1 g, 74 mmol) in anhydrous ether (200 mL). To the
suspension was added Bu3P (18.3 mL, 74 mmol) and the mixture
stirred for 30 min. The resulting slightly yellow solution was added
to the Grignard reagent made above at ꢀ78 ꢁC and the resulting
solution stirred for 30 min. A solution of 2-cyclopenten-1-one
(4.2 mL, 50 mmol) in anhydrous ether (30 mL) was then added
dropwise. The reaction was stirred for 1.5 h at ꢀ78 ꢁC. A solution of
2-dimethyl-t-butylsiloxyacetaldehyde (17.2 g, 99 mmol) in anhy-
drous ether (30 mL) was added over 30 min. The resulting solution
was warmed to room temperature for 3 h and then quenched by
satd NH4Cl (200 mL). The aqueous layer was extracted with ether
(2ꢂ200 mL). The combine organic phase was washed with brine
(300 mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was chromatographed through a silica gel col-
umn packed with 1% Et3N in hexane (gradient elution from 5% to
35% EtOAc in hexane) to afford desired product in 53% yield (8.30 g,
27 mmol) as a yellow oil. The spectral data were as follows: 1H NMR
While the work reported above indicates that the approach to
ineleganolide is fatally flawed, the successful cyclization of 17
suggests a new method for the construction of functionalized
quaternary carbons,24 and the mechanistic insight gained has had
an immediate impact on our continuing studies. Two recent ex-
amples are particularly useful for highlighting this later point.
The first capitalized on the observation that polarized radical
cations lead to more efficient carbon–carbon bond forming re-
actions (Scheme 16). During efforts to synthesize the arteannuin
ring skeleton,5a we examined the coupling of electron-rich olefins
with substituted furan rings. Two cyclization reactions are shown
in Scheme 16. In the first, the coupling reaction was attempted
utilizing a silyl enol ether substrate. In the second, an N,O-ketene
acetal was used. Of the two oxidation reactions, the one utilizing
the N,O-ketene acetal (31b) led to a far superior yield. A yield for the
reaction obtained by NMR using an internal standard showed that
this reaction proceeded very cleanly. The lower isolated yield was
due to the instability of the furan product. Once again, the use of
a more polarized radical cation led to more efficient carbon–carbon
bond formation. The total synthesis is being pursued using the
ketene acetal-based strategy.
OMe Me
X
O
Me
Me
O
RVC anode, C cathode
0.1 M Et4NOTs
X
Y
N
O
or
O
O
O
20% MeOH/CH2Cl2
20 mA, 2.1 F/mole
Ph
Me
32. 30%
Me
MeO
Me
(CDCl3/300 MHz) d 5.85–5.70 (m, 1H), 5.03, 4.97 (d plus d with fine
O
31a. X = OTIPS, Y = H
31b. X = OTBS, Y =
N.A.
N.A.
33. 65% (90% by NMR)
coupling, J¼17.1 Hz, 10.2 Hz, 2H), 3.94 (p, J¼5.1 Hz, 0.35H), 3.87 (dd,
J¼9.6 Hz, 7.5 Hz, 0.65H), 3.78 (p, J¼3.6 Hz, 0.65H), 3.70–3.58 (m,
1.35H), 3.47 (d, J¼6.6 Hz, 0.35H), 2.74 (d, J¼3.6 Hz, 0.65H), 2.30–
1.90 (m, 6H), 1.86–1.71 (m, 2H), 1.41–1.27 (m, 2H), 0.85, 0.84 (s plus
N
O
Ph
Scheme 16.
s, 9H), 0.03, 0.01 (s plus s, 6H); 13C NMR (CDCl3/75 MHz)
d 220.9,
219.5, 138.2, 138.1, 114.8, 114.7, 71.7, 71.4, 65.2, 64.8, 55.8, 55.7, 39.0,
38.7, 38.5, 37.2, 34.6, 34.0, 31.2, 27.0, 25.8, 18.2, 18.1, ꢀ5.4, ꢀ5.5,
ꢀ5.6; IR (neat/KBr) 3459, 2928, 2856, 1738, 1640, 1471, 1254, 1105,
The second example capitalized on the relationship between
radical cation polarization and chemoselectivity in the opposite
direction (Scheme 17). In this case, the trapping of a radical cation by
a sulfonamide group was examined.3 When the reaction was initi-
ated by oxidation of an enol ether, a very low yield of cyclic product
was obtained (Scheme 17, substrate 34a). A switch to a less polar
thioenol ether substrate fixed this problem and led to a significantly
higher yield of cyclic product. The yield of both reactions could be
dramatically improved by using LiOMe as a base to deprotonate the
sulfonamide group. Still, the use of the less polarized radical cation
led to a higher yield of the desired cyclic product.
837, 777 cmꢀ1
; HRMS (ESI) m/z calculated for C17H32O3NaSi
[MþNa]þ 335.2018, found 335.2000.
7.1.2. 3-(But-3-enyl)-2-(2-(tert-butyldimethylsilyloxy)-acetyl)cyclo-
pentanone (2). To a ꢀ78 ꢁC solution of DMSO (15 mL, 0.21 mol) in
dry CH2Cl2 (150 mL) was added TFAA (115 mL, 0.11 mol). The re-
action was stirred for 40 min at this temperature, a solution of the
alcohol made above (8.3 g, 27 mmol) in dry CH2Cl2 (50 mL) added
at ꢀ78 ꢁC, and the mixture stirred for 40 min (at ꢀ78 ꢁC). Trie-
thylamine (59 mL, 0.43 mol) was then added to the solution and the
reaction stirred for 0.5 h. The reaction was warmed to 0 ꢁC, stirred
for 40 min, and quenched with satd NH4Cl (200 mL). HCl (0.5 N)
was added until the mixture reached pH¼4. The aqueous layer was
extracted by ether (3ꢂ40 mL), and then the combined organic
phase washed with brine (200 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was chromatographed
through a silica gel column (gradient elution from 5% to 10% EtOAc
in hexane) to afford the desired product in 85% yield (7.0 g,
22 mmol, 85%) as a pale reddish oil. The spectral data were as fol-
RVC anode, Pt cathode
X
0.1 M Et4NOTs, 6 mA
Y
X
R
2.2 F/mole, 2,6-lutidine
Y
R
NHTs
OMe
30% MeOH/ THF
N
Ts
34a. X = H, Y = OMe, R = H
34b. X = H, Y = SMe, R = H
35a. 20% (82% with n-BuLi/MeOH)
35b. 54% (90% with n-BuLi/MeOH)
Scheme 17.
The chemistry outlined in Schemes 16 and 17 demonstrate how
important it is to account for the nature of the radical cation in-
termediate when planning an anodic cyclization reaction. The key
is to match the nature of the radical cation intermediate with the
type of trapping group being used, an idea that will be imple-
mented in all future anodic olefin coupling reactions.
lows: 1H NMR (CDCl3/300 MHz)
d 5.82–5.67 (m, 1H), 5.07–4.92 (m,
2H), 4.51 (d, J¼18 Hz, 1H), 4.28 (d, J¼18 Hz, 1H), 3.24 (d, J¼10.8 Hz,
1H), 2.80 (m, 1H), 2.41–2.19 (m, 3H), 2.13–1.95 (m, 2H), 1.60–1.42
(m, 3H), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (CDCl3/75 MHz)
d 212.1,
204.6, 137.8, 114.9, 69.9, 64.6, 38.9, 38.6, 34.2, 31.5, 27.2, 25.8, 25.7,
18.3, ꢀ5.5, ꢀ5.6; IR (neat/KBr) 2954, 2929, 2856, 1747, 1723, 1641,

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10869
1471, 1254, 1151, 838, 780 cmꢀ1; HRMS (ESI) m/z calculated for
C17H31O3Si [MþH]þ 311.2042, found 311.2038.
7.1.5. (3S*,3aR*,4S*,6aR*)-4-(3-Hydroxypropyl)-hexahydro-2H-cy-
clopenta[b]furan-3-ol. Ozone was bubbled through a ꢀ78 ꢁC so-
lution of compound 4a (0.56 g, 3.1 mmol) in CH2Cl2 (20 mL) until
the solution turned a persistent pale blue. The excess ozone was
removed by flushing the solution with Ar. NaBH4 (0.72 g,
19 mmol) and MeOH (20 mL) were added and the mixture stirred
for 0.5 h at ꢀ78 ꢁC. The reaction was warmed to 0 ꢁC and stirred
for 1 h. The solution was quenched by H2O (10 mL). The aqueous
layer was extracted by CH2Cl2 (3ꢂ40 mL) and then the combined
organic layers dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was chromatographed through a silica
gel column (gradient elution from 0% to 2% methanol in EtOAc) to
afford the desired product in 67% yield (0.38 g, 2.0 mmol) as
a colorless oil. The spectral data were as follows: 1H NMR (CDCl3/
7.1.3. 4-(But-3-enyl)-5,6-dihydro-2H-cyclopenta[b]furan-3(4H)-one
(3). To a 25-mL round-bottom flask was added the ketone made
above (1.0 g, 3.22 mmol) and a solution of 5% HCl in THF (20 mL).
The reaction was stirred for 3 h and then neutralized by NaHCO3.
The aqueous phase was extracted with ether (3ꢂ40 mL), and the
combined organic layer dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was used in next step without
further purification.
To this end, the crude product was taken up in benzene
(80 mL) and tosylic acid monohydrate (0.80 g, 4.2 mmol) added.
The resulting solution was refluxed using a Dean Stark trap for
20 min. Ether (200 mL) was added and the crude product washed
with satd Na2CO3 (2ꢂ20 mL). The organic layer was dried over
Na2SO4, filtered and concentrated in vacuo to give a crude product
that was chromatographed through a silica gel column (gradient
elution from 10% to 25% EtOAc in hexane) to afford the desired
product 3 in 73% yield (0.42 g, 2.4 mmol) as a pale reddish oil. The
300 MHz)
d
4.41 (t, J¼7.5 Hz, 1H), 4.37 (dd, J¼2.4 Hz, 5.7 Hz, 1H),
3.82 (d, J¼9.6 Hz, 1H), 3.67 (q, J¼6.3 Hz, 2H), 3.52 (dd, J¼2.7 Hz,
9.6 Hz, 1H), 2.50 (m, 3H), 1.96–1.86 (m, 3H), 1.78–1.57 (m, 6H); 13C
NMR (CDCl3/75 MHz) d 84.9, 76.8, 74.9, 62.9, 50.7, 43.4, 32.4, 32.2,
31.6, 26.1; IR (neat/KBr) 3400, 2931, 2865, 1653, 1059, 997 cmꢀ1
;
HRMS (ESI) m/z calculated for C10H18NaO3 [MþNa]þ 209.1154,
spectral data were as follows: 1H NMR (CDCl3/300 MHz)
d
5.89–
found 209.1154.
5.76 (ddt, J¼17.1 Hz, 10.2 Hz, 6.6 Hz, 1H), 5.07 (dq, J¼17.1 Hz, 1H),
4.97 (d with fine coupling, J¼10.2 Hz, 1H), 4.90 (d with fine cou-
pling, J¼1.2 Hz, 2H), 2.88 (m, 1H), 2.63–2.53 (m, 3H), 2.22–2.14 (q
with fine coupling, J¼8.1 Hz, 2H), 2.05–1.94 (m, 1H), 1.79–1.73 (m,
7.1.6. 3-((3S*,3aR*,4S*,6aR*)-3-Hydroxy-hexahydro-2H-cyclo-
penta[b]-furan-4-yl)propyl pivalate. To a solution of the diol syn-
thesized above (0.30 g, 1.6 mmol), Et3N (270 mL, 1.9 mmol), and
1H), 1.54–1.41 (m, 1H); 13C NMR (CDCl3/75 MHz)
d
200.8, 194.6,
DMAP (20 mg, 0.16 mmol) in anhydrous CH2Cl2 (10 mL) was added
in a dropwise fashion a solution of trimethylacetic chloride
(194 mg, 1.61 mmol) in anhydrous CH2Cl2 (3 mL). The reaction was
stirred overnight. Ethyl acetate (20 mL) was added and the mixture
washed with satd NH4Cl (20 mL), H2O (20 mL), and brine (20 mL).
The organic layer was dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was chromatographed through
a silica gel column (gradient elution from 10% to 25% EtOAc in
hexane) to afford the desired product in 92% yield (0.40 g,
1.48 mmol) as a colorless oil. The spectral data were as follows: 1H
138.3, 122.9, 114.4, 84.0, 35.1, 34.5, 32.9, 31.7, 26.5; IR (neat/KBr)
3075, 2920, 2852, 1693, 1613, 1435, 1200, 997, 912 cmꢀ1; HRMS
(ESI) m/z calculated for C11H15O2 [MþH]þ 179.1072, found
179.1067.
7.1.4. (3S*,3aR*,4S*,6aR*)-4-(But-3-enyl)-hexahydro-2H-cyclo-
penta[b]-furan-3-ol (4a) and (3R*,3aS*,4S*,6aS*)-4-(but-3-enyl)hexa-
hydro-2H-cyclopenta[b]furan-3-ol (4b). To a flame-dried 100 mL
round-bottom flask under an argon atmosphere was added a solu-
tion of compound 3 (1.0 g, 5.6 mmol) in anhydrous THF (20 mL).
NMR (CDCl3/300 MHz)
d
4.38 (t, J¼6.9 Hz, 1H), 4.31 (t with fine
The reaction was cooled to ꢀ78 ꢁC and a 1 M
L-Selectride solution in
coupling, J¼6 Hz, 1H), 4.05 (t with fine coupling, J¼6.6 Hz, 2H),
3.78 (d, J¼9.6 Hz, 1H), 3.48 (dd, J¼2.1 Hz, 9.6 Hz, 1H), 2.48 (q,
J¼7.2 Hz, 1H), 1.91–1.60 (m, 9H), 1.17 (s, 9H); 13C NMR (CDCl3/
THF (17 mL, 17 mmol) added dropwise. The resulting solution was
stirred for 6 h and quenched with 30% H2O2 (10 mL), followed by
satd NaHCO3 (10 mL). The mixture was stirred for 1 h at rt. Ethyl
acetate (50 mL) was added and washed by satd Na2S2O3. The
aqueous layer was extracted with ethyl acetate (3ꢂ20 mL) and the
combined organic layer dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was chromatographed through
a silica gel column (gradient elution from 10% to 25% EtOAc in
hexane) to afford the desired product 4a in 55% yield (0.57 g,
3.1 mmol) as a colorless oil. The spectral data were as follows: 1H
75 MHz)
d 178.6, 84.8, 76.9, 74.9, 64.5, 50.8, 43.1, 38.7, 32.2, 31.5,
28.5, 27.1, 26.0; IR (neat/KBr) 3445, 2959, 1726, 1480, 1285,
1162 cmꢀ1; HRMS (ESI) m/z calculated for C15H27O4 [MþH]þ
271.1909, found 271.1903.
7.1.7. 3-((3aS*,4S*,6aR*)-3-Oxo-hexahydro-2H-cyclopenta[b] furan-
4-yl) propyl pivalate (5). To a flame-dried 50-mL round-bottom
flask under argon was added a solution of oxalyl chloride (508 mL,
NMR (CDCl3/300 MHz)
d
5.62–5.78 (m, 1H), 5.06 (d with fine cou-
6 mol) in anhydrous CH2Cl2 (15 mL). The reaction was cooled to
pling, J¼17.1 Hz,1H), 4.93 (d with fine coupling, J¼10.2 Hz, 1H), 4.41
(t, J¼7.2 Hz, 1H), 4.34 (t with fine coupling, J¼5.7 Hz, 1H), 3.78 (d,
J¼9.6 Hz, 1H), 3.51 (dd, J¼2.1 Hz, 9.6 Hz, 1H), 2.52 (q, J¼7.2 Hz, 1H),
2.16 (q, J¼6.6 Hz, 2H), 1.97–1.80 (m, 4H), 1.71–1.51 (m, 3H); 13C NMR
ꢀ78 ꢁC and DMSO (840
mL, 12 mmol) added dropwise over 5 min.
The reaction was stirred 10 min and then a solution of the alcohol
synthesized above (0.40 g, 1.5 mmol) in anhydrous CH2Cl2 (5 mL)
added. The reaction was stirred for 0.5 h before triethylamine
(2.1 mL, 15 mmol) was added, the reaction allowed to warm to
room temperature, and then the mixture stirred for 0.5 h. EtOAc
(100 mL) was added and the reaction washed with satd NH4Cl
(30 mL), H2O (30 mL), and brine (30 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. The crude
product was chromatographed through a silica gel column (gradi-
ent elution from 10% to 20% EtOAc in hexane) to afford the desired
product 5 in 96% yield (0.38 g, 1.4 mmol) as a colorless oil. The
(CDCl3/75 MHz) d 139.1, 114.2, 84.8, 76.8, 75.0, 50.8, 42.8, 33.5, 32.1,
31.4, 29.0; IR (neat/KBr) 3399, 3078, 2924, 2856, 1639, 1453, 1227,
1048, 998 cmꢀ1
; HRMS (ESI) m/z calculated for C11H18NaO2
[MþNa]þ 205.1204, found 205.1208.
Diastereomer 4b was isolated in a 25% yield (0.25 g,1.4 mmol) as
a colorless oil. The spectral data were as follows: 1H NMR (CDCl3/
300 MHz)
d
5.90–5.76 (m, 1H), 5.06–4.94 (dq, J¼1.8 Hz, 17.1 Hz and
d with fine coupling, J¼10.2 Hz, 2H), 4.44 (m, 1H), 4.32 (septet,
J¼3.9 Hz, 1H), 3.73 (dq, J¼4.2 Hz, 9.6 Hz, 2H), 2.27–2.06 (m, 5H),
1.93–1.86 (m, 2H), 1.69 (m, 1H), 1.49–1.34 (m, 3H); 13C NMR (CDCl3/
spectral data were as follows: 1H NMR (CDCl3/300 MHz)
d 4.85 (t,
J¼5.1 Hz, 1H), 4.06 (t, J¼6.3 Hz, 2H), 3.89 (AB, J¼17.1 Hz, 2H), 2.75
(dd, J¼5.7 Hz, 10.8 Hz, 1H), 2.20–2.09 (m, 2H), 1.93 (dt, J¼11.7 Hz,
6.6 Hz, 1H), 1.79–1.62 (m, 4H), 1.48–1.35 (m, 1H), 1.22–1.18 (m
75 MHz)
d 138.8, 114.3, 85.8, 75.4, 72.7, 54.0, 37.1, 34.7, 32.4, 32.3,
32.2; IR (neat/KBr) 3399, 3078, 2924, 2856, 1639, 1453, 1227, 1048,
998 cmꢀ1; HRMS (ESI) m/z calculated for C11H18NaO2 [MþNa]þ
205.1204, found 205.1199.
buried s at 1.20, 10H); 13C NMR (CDCl3/75 MHz)
d
216.9, 178.4, 85.2,
72.4, 64.1, 52.6, 43.7, 38.6, 34.0, 30.9, 27.8, 27.7, 27.0; IR (neat/KBr)

10870
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
2958, 1750, 1726, 1480, 1285, 1158, 1072 cmꢀ1; HRMS (ESI) m/z
calculated for C15H24NaO4 [MþNa]þ 291.1572, found 291.1567.
(d with fine coupling, J¼6.0 Hz, 0.3H), 4.84 (m,1H), 4.75 (dt, J¼7.2 Hz,
12.6 Hz, 0.7H), 4.45 (q, J¼7.2 Hz, 0.3H), 3.20–3.08 (s at 3.20; s at 3.15; s
at 3.09; s at 3.08; m, 7H), 2.46–2.35 (m, 0.7H), 2.07–1.97 (m, 2.3H),
1.89–1.68 (m, 2.3H), 1.61–1.43 (m, 2.7H), 1.40–1.27 (m, 1H); 13C NMR
7.1.8. 3-((3aS*,4S*,6aR*)-3-Methoxy-4,5,6,6a-tetrahydro-3aH-cyclo-
penta[b] furan-4-yl)propyl pivalate (6). To a solution of compound 5
(0.36 g, 1.3 mmol) in anhydrous MeOH (5 mL) was added trimethyl
orthoformate (5 mL), followed by p-toluenesulfonic acid mono-
hydrate (25 mg, 0.13 mmol). The reaction was heated at reflux for
2 h, and then quenched with satd Na2CO3 (20 mL). The aqueous
layer was extracted with ether (4ꢂ30 mL) and then the combined
organic layers dried over K2CO3, filtered, and concentrated in vacuo.
The crude product was used in next step.
(C6D6/75 MHz)
d 147.5, 146.4, 143.3, 122.9, 122.8, 107.2, 102.9, 86.3,
58.8, 56.7, 55.2, 49.7, 49.6, 45.3, 44.9, 35.0, 34.9, 32.2, 31.1, 29.8, 29.7,
27.5, 23.8; IR (neat/KBr) 2931, 2855,1654,1451,1254,1209,1095,1026,
933 cmꢀ1; HRMS (ESI) m/z calculated for C13H20NaO3 [MþNa]þ
247.1310, found 247.1308.
7.1.10. (3aS*,4S*,6aR*)-2,3,3-Trimethoxy-4-(4-methoxybut-3-enyl)-
hexahydro-2H-cyclopenta[b]furan (8). A solution of
7 (38 mg,
To a 0 ꢁC solution of the crude dimethyl ketal in anhydrous
dichloromethane (5 mL) was added diisopropylethylamine (0.89 mL,
3.5 mmol), followed by TMSOTf (0.92 mL, 3.5 mmol). The reaction
was stirred for 12 h at ambient temperature and quenched by sat-
urated Na2CO3 (20 mL). To the reaction mixture was added 50 mL of
ether and then the reaction washed with water (2ꢂ30 mL) and brine
(30 mL). The organic layer was dried over K2CO3, filtered, and con-
centrated in vacuo. The crude product was chromatographed
through a silica gel column packed with 1% Et3N in hexane (5% EtOAc
in hexane) to afford the desired product 6 in 58% yield over two steps
(0.21 g, 0.74 mmol) as a colorless oil. The spectral data were as fol-
0.17 mmol), 2,6-lutidine (0.18 g, 1.7 mmol), and Et4NOTs (0.23 g,
0.75 mmol) in 25% MeOH/CH2Cl2 (15 mL) was placed in a flame-
dried 25 mL three-necked round-bottom flask equipped with a re-
ticulated vitreous carbon (RVC) anode and a carbon rod cathode. The
reaction was electrolyzed at a constant current of 8 mA until 2.0 F/
mol of charge was passed. The solution was diluted with 50 mL ether
and then washed with water (3ꢂ20 mL) and brine (20 mL). The or-
ganic layer was dried over Na2SO4, filtered and, concentrated in
vacuo. The residue was chromatographed through a silica gel col-
umn packed with 1% Et3N in hexane (gradient elution with 2.5%–5%
EtOAc in hexane) to afford product 8 (28 mg, 0.10 mmol, 59%) as
a colorless oil. The spectral data were as follows: 1H NMR (C6D6/
lows: 1H NMR (CDCl3/300 MHz)
d
5.93 (s, 1H), 4.97 (dd, J¼5.1 Hz,
8.4 Hz, 1H), 4.05 (dt, J¼3.3 Hz, 6.3 Hz, 2H), 3.49 (s, 3H), 3.29 (t,
300 MHz)
d
6.35 (d, J¼12.6 Hz, 0.6H), 5.69 (d with fine coupling,
J¼7.8 Hz,1H),1.97–2.88 (m, 2H),1.79–1.56 (m, 5H),1.46–1.34 (m, 2H),
J¼6.3 Hz, 0.4H), 4.76–4.63 (m, 2.6H), 4.42–4.35 (m, 0.4H), 3.22–2.97
(s at 3.22, s at 3.21, s at 3.17, s at 3.16, s at 3.15, s at 3.09, s at 2.99, s at
2.97,12H), 2.57 (t, J¼7.8 Hz,1H), 2.39–1.50 (m, 8H),1.37–1.24 (m,1H);
1.20 (s, 9H); 13C NMR (C6D6/75 MHz)
d 177.6, 143.0, 122.9, 86.2, 64.6,
56.7, 49.5, 45.1, 38.6, 34.9, 29.9, 28.4, 27.2, 27.1; IR (neat/KBr) 2956,
1727, 1480, 1285, 1159, 1095 cmꢀ1; HRMS (ESI) m/z calculated for
C16H26NaO4 [MþNa]þ 305.1729, found 305.1726.
13C NMR (C6D6/75 MHz)
d 147.5, 146.4, 111.4,107.1,103.4, 103.3, 102.9,
84.1, 83.9, 58.8, 55.3, 54.0, 52.0, 50.5, 49.2, 49.1, 44.2, 43.9, 32.3, 32.2,
32.1, 31.0, 29.5, 28.4, 24.7; IR (neat/KBr) 2941, 1654, 1453, 1210,
1147 cmꢀ1; HRMS (ESI) m/z calculated for C15H26NaO5 [MþNa]þ
309.1678, found 309.1672.
7.1.9. (3aS*,4S*,6aR*)-3-Methoxy-4-(4-methoxybut-3-enyl)-4,5,6,6a-
tetra-hydro-3aH-cyclopenta[b]furan (7). To a solution of compound
6 (0.21 g, 0.74 mmol) in anhydrous ether (3 mL) was added a 1 M
lithium aluminum hydride solution in ether (2 mL, 2 mmol) at
ꢀ78 ꢁC. The reaction was stirred for 2 h at this temperature and
then quenched by the addition of ethyl acetate (2 mL). To the
resulting solution was added ether (100 mL) followed by saturated
sodium potassium tartrate (100 mL). The solution was stirred for
1 h, the layers separated, and the aqueous layer extracted with
ether (30 mLꢂ2). The combined organic layers were dried over
Na2SO4, filtered through a short silica plug, and concentrated in
vacuo. The crude product was used in the next step without further
purification.
7.1.11. 1-(tert-Butyldimethylsilyloxy) pentane-2,4-dione. A flame-
dried 250 mL round-bottom flask under argon was charged with
freshly cut sodium (4.71 g, 200 mmol) in anhydrous toluene
(100 mL). A solution of 3.3 (20.8 g, 100 mmol) in anhydrous toluene
(25 mL) was added at room temperature. The resulting solution was
cooled to ꢀ78 ꢁC, followed by a solution of 10 (20.8 g, 100 mmol) and
anhydrous acetone (15 mL, 200 mmol) in anhydrous toluene (25 mL).
The mixture was stirred overnight at ambient temperature. The re-
action was quenched with satd NH4Cl (200 mL). The layers were
separated and theaqueous layeracidified with 0.5 M HCl untilpH¼4–
5. The aqueous layer was extracted with ether (2ꢂ100 mL) and then
the combined organic layers were washed with brine (200 mL), dried
by Na2SO4, filtered, and concentrated invacuo. The crude product was
chromatographed through a silica gel column (gradient elution from
0% to 10% EtOAc in hexane) afford the desired product in 51% yield
(24 g, 100 mmol) as a pale reddish oil. The NMR spectrum met
spectral data reported in literature.14
To a stirred suspension of N-chlorosuccinimide (0.20 g, 1.5 mmol)
in dry toluene (4 mL) was added dimethyl sulfide (0.13 mL,1.8 mmol)
at 0 ꢁC. The reaction was stirred for 20 min at this temperature, a so-
lution of crude product made above in dry toluene (4 mL) added, and
then the reaction stirred for an additional 30 min. Triethylamine
(0.42 mL, 3.0 mmol) was added and the mixture stirred further for
0.5 h at ambient temperature. At this point hexane (20 mL) was
added, the resulting mixture filtered, and thefiltrate usedinnextstep.
A flame-dried50 mL round-bottom flaskunderargonwascharged
witha stirred suspension of (methoxymethyl)triphenylphosphonium
chloride (0.72 g, 2.1 mmol) in anhydrous THF (10 mL) at 0 ꢁC. A 1 M
NaHMDS solution inTHF (2.0 mL, 2.0 mmol) was added dropwise and
stirred for 1 h. The crude aldehyde synthesized above was added via
cannula. The mixturewasallowed towarm to rtand stirredovernight.
The reactionwas quenched by the addition of satd NH4Cl (25 mL). The
aqueous layer was extracted with ether (3ꢂ30 mL) and the combined
organic layers dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was chromatographed through a silica gel column
packed with 1% Et3N in hexane (gradient elution using 5% EtOAc in
hexane) to afford the desired product 7 in 40% yield over three steps
(67 mg, 0.3 mmol) as a colorless oil. The spectral datawere as follows:
7.1.12. 5-Acetyl-7-(tert-butyldimethylsilyloxy)-6-oxoheptyl pivalate. A
solution of the 1,3-dicarbonyl made above (30 g, 0.13 mol), 4-iodo-1-
pivoyloxybutane (37 g, 0.13 mol), and K2CO3 (19.8 g, 0.14 mol) in
acetone (200 mL) was refluxed overnight. The reaction was filtered
and concentrated in vacuo. The residue was dissolved in ether
(400 mL) and washed with satd NH4Cl (3ꢂ100 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo. The
crude product was chromatographed through a silica gel column in
1:8 EtOAc/hexane to afford the desired product in 72% yield (36.2 g,
0.094 mol) as a yellow oil. The spectral data were as follows: 1H NMR
(CDCl3/300 MHz)
d
4.11 (s with shoulder, 2H), 3.96 (t, J¼6.6 Hz, 2H),
3.87–3.82 (dd, J¼7.5 Hz, 7.7 Hz, 1H), 2.12 (s, 3H), 1.85–1.51 (m, 4H),
1.30–1.22 (m, 2H), 1.09 (s, 9H), 0.83 (s, 9H), 0.01 (s, 6H); 13C NMR
1H NMR (C6D6/300 MHz)
d
6.42 (d, J¼12.6 Hz, 0.7H), 5.85 (s, 1H), 5.73
(CDCl3/75 MHz) d 206.3, 203.1, 178.1, 68.7, 63.5, 61.9, 38.4, 28.9, 28.3,

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10871
26.9, 25.6, 23.9,18.1, ꢀ5.8, ꢀ5.9; IR (neat/KBr) 3430, 2956, 2858,1730,
1606, 1480, 1462, 1361, 1284, 1156, 839, 781 cmꢀ1; HRMS (ESI) m/z
calculated for C20H38O5NaSi [MþNa]þ 409.2381, found 409.2386.
49.4, 38.7, 32.1, 28.8, 27.2, 22.9, 21.8; IR (neat/KBr) 2970, 2935, 2869,
1727, 1666, 1480, 1460, 1285, 1157, 1098, 1031 cmꢀ1; HRMS (EI) m/z
calculated for C15H26O4 [M]þ 270.1831, found 270.1831.
7.1.13. 4-(2-Methyl-4-oxo-4,5-dihydrofuran-3-yl)butyl pivalate. Con-
centrated hydrochloric acid (10 mL, 12 M) was added dropwise to
a 250 mL round-bottom flask containing the alkylated product
made above (36 g, 93 mmol) in THF (100 mL) until the reactant was
completely converted to product by TLC. The reaction was quenched
by satd Na2CO3 (50 mL). The aqueous layer was extracted with ether
(3ꢂ200 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The crude product was chro-
matographed through a silica gel column in 1:3 EtOAc/hexane to
afford the desired product in 94% yield (22.2 g, 88 mmol) as a yellow
oil. The spectral data were as follows: 1H NMR (CDCl3/300 MHz)
7.1.16. (2R*,3R*)-4-Methoxy-3-(5-methoxypent-4-enyl)-2-methyl-
2,3-dihydrofuran (13). Compound 12 was converted into 13 using
the same sequence used to convert 6–7. In this case, a 42% yield was
obtained for the three step sequence. 1H NMR (CDCl3/300 MHz)
d
6.31 (dt, J¼12.6 Hz, 0.9 Hz, 0.6H), 5.89 (dt, J¼6.3 Hz, 1.2 Hz, 0.4H),
5.82 (m, 1H) 4.73 (dt, J¼12.3 Hz, 7.5 Hz, 0.6H), 4.34 (m, 0.4H), 4.16
(m, 1H), 3.57 (s, 1.2H), 3.54, 3.52 (two s, 3H), 3.50 (s, 1.8H), 2.53 (m,
1H), 2.06 (m, 0.6H),1.92 (m,1.4H),1.44–1.34 (m, 3H),1.32 (d, J¼6 Hz,
3H); 13C NMR (CDCl3/75 MHz)
d 147.2, 146.2, 145.8, 145.7, 119.3,
119.2, 106.5, 102.6, 81.7, 81.6, 59.4, 57.4, 55.8, 49.4, 49.3, 32.0, 31.8,
27.8, 27.7, 26.7, 23.9, 21.8; IR (neat/KBr) 2931, 2857, 1655, 1450,1310,
1258, 1209, 1102, 1031, 935 cmꢀ1; HRMS (EI) m/z calculated for
C12H20O3[M]þ 212.1412, found 212.1409.
d
4.43 (d, J¼0.9 Hz, 2H), 4.06 (t, J¼6.3 Hz, 2H), 2.20–2.15 (t, J¼7.2 Hz,
buried with s at 2.20, 5H), 1.68–1.59 (m, 2H), 1.55–1.45 (m, 2H), 1.19
(s, 9H); 13C NMR (CDCl3/300 MHz)
202.7, 186.3, 178.5, 115.6, 73.7,
d
63.9, 38.7, 28.3, 27.1, 24.9, 20.642, 14.9; IR (neat/KBr) 2958, 1725,
1698, 1630, 1480, 1409, 1284, 1161, 1028, 934 cmꢀ1; HRMS (EI) m/z
calculated for C14H22O4 [M]þ 254.1518, found 254.1516.
7.1.17. 4-((2R*,3S*)-2-Methyl-4-methylene-tetrahydrofuran-3-yl)butyl
pivaloate and 4-((2R*,3S*)-2-methyl-4-methylene-tetrahydrofuran-3-
yl)butan-1-ol. A flame-dried 50 mL round-bottom flask under argon
was charged with
a stirred suspension of methyltriphenyl-
7.1.14. 4-((2R*,3R*)-2-Methyl-4-oxo-tetrahydrofuran-3-yl)butyl piv-
alate (11). To a flame-dried 250 mL round-bottom flask under argon
were added a solution of the product made above (4.0 g,16 mmol) in
anhydrous THF (50 mL). The reactionwas cooled to ꢀ78 ꢁC and a 1 M
phosphonium bromide (2.79 g, 7.8 mmol) in anhydrous THF (25 mL)
at 0 ꢁC. A 1.6 M solution of n-butyllithium in hexane (4.6 mL, 7.4 mol)
was added dropwise and stirred for 1 h. The reaction was cooled to
ꢀ78 ꢁC, followed by a solution of 11 (1.00 g, 3.9 mmol) in anhydrous
THF (5 mL). The mixture was allowed to warm to room temperature
and stirred overnight. The reaction was quenched by addition of satd
NH4Cl (50 mL), the layers separated, and the aqueous layer was
extracted with ether (3ꢂ100 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was chromatographed through a silica gel column (gradient
elution from 5% to 40% EtOAc in hexane) to afford the desired product
in a 49% yield (0.48 g, 1.9 mmol) as a colorless oil. The spectral data
L-Selectride solution in THF (17 mL, 17 mmol) was added dropwise.
The resulting solution was stirred for 1 h and quenched by satd
NH4Cl (100 mL). The aqueous layer was extracted with ether
(3ꢂ100 mL) and then the combined organic layer dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was chro-
matographed through a silica gel column in 1:8 EtOAc/hexane to
afford the desired product 11 in 79% yield (3.18 g, 12 mmol) as
a slightly yellow oil. The spectral data were as follows: 1H NMR
(CDCl3/300 MHz)
d
4.14 (d with fine coupling, J¼16.8 Hz,1H), 4.04 (t,
were as follows: 1H NMR (CDCl3/300 MHz)
d
4.92 (q, J¼2.4 Hz, 1H),
J¼6.3 Hz, 2H), 3.92–3.87 (m, 1H), 3.80 (d, J¼16.8 Hz, 1H), 1.96–1.92
(m,1H),1.69–1.58 (m, 3H),1.55–1.37 (m buried with d at 1.41, J¼6 Hz,
4.89 (q, J¼2.4 Hz, 1H), 4.37 (dt, J¼13.2 Hz, 1.8 Hz, 1H), 4.22 (dq,
J¼13.2 Hz, 2.1 Hz, 1H), 4.07 (t, J¼6.3 Hz, 2H), 3.72 (p, J¼6.9 Hz, 1H),
2.16 (m,1H),1.68–1.56 (m, 3H),1.53–1.41 (m, 3H),1.28 (d, J¼6 Hz, 3H),
6H); 1.17 (s, 9H); 13C NMR (CDCl3/300 MHz)
d 216.9, 178.5, 79.3, 71.3,
63.7, 53.8, 38.7, 28.7, 27.1, 26.4, 23.5, 20.4; IR (neat/KBr) 2972, 2935,
1761, 1726, 1480, 1459, 1387, 1284, 1158, 1070, 848 cmꢀ1; HRMS (EI)
m/z calculated for C14H24O4 [M]þ 256.1675, found 256.1675.
1.20 (s, 9H); 13C NMR (CDCl3/75 MHz)
d 178.5,152.5,103.5, 80.6, 70.6,
64.0, 50.1, 38.7, 31.1, 28.9, 27.2, 23.4, 20.1; IR (neat/KBr) 2969, 1726,
1479,1383,1283,1152, 1036, 882 cmꢀ1; HRMS (EI) m/z calculated for
C15H26O3 [M]þ 254.1882, found 254.1868. In addition, the alcohol
product having lost the pivaloyl protecting group (the desired
product for the next reaction) was obtained in a 30% yield (0.20 g,
1.2 mmol) as a slightly yellow oil. The spectral data were as follows:
7.1.15. 4-((2R*,3R*)-4-Methoxy-2-methyl-2,3-dihydrofuran-3-yl)butyl
pivalate (12). To a solution of 11 (0.53 g, 2.1 mmol) in anhydrous
MeOH (5 mL) was added trimethyl orthoformate (5 mL) followed by
p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The re-
action was heated at reflux for 0.5 h and then quenched by saturated
Na2CO3 (20 mL). The aqueous layer was extracted with ether
(3ꢂ20 mL) and the combined organic layers dried over K2CO3, fil-
tered, and concentrated in vacuo to afford a residue (0.59 g) that was
used in next step without further purification.
1H NMR (CDCl3/300 MHz)
d
4.86 (m, 2H), 4.31 (dt, J¼13.2 Hz, 2.1 Hz,
1H), 4.16 (dq, J¼13.2 Hz, 2.1 Hz, 1H), 3.68 (p, J¼6.6 Hz, 1H), 3.57 (t,
J¼6.6 Hz, 2H), 2.37 (br, 1H), 2.12 (m, 1H), 1.55–1.35 (m, 6H), 1.21 (d,
J¼6 Hz, 3H); 13C NMR (CDCl3/75 MHz)
d 152.4,103.5, 80.6, 70.4, 62.3,
50.1, 32.9, 31.4, 23.2, 20.1; IR (neat/KBr) 3400, 2933, 2861,1666,1459,
1384, 1037, 884 cmꢀ1; HRMS (ESI) m/z calculated for C10H19O2
[MþH]þ 170.1380, found 170.1379.
To a 0 ꢁC solution of crude dimethyl ketal (0.59 g) in anhydrous
dichloromethane (2.5 mL) was added diisopropylethylamine
(0.89 mL, 5.1 mmol) followed by TMSOTf (0.92 mL, 5.1 mmol). The
reaction was stirred for 12 h at ambient temperature and then
quenched by saturated 20 mL of Na2CO3. To the reaction mixture
was added 50 mL ether and the resulting mixture washed with
water (2ꢂ30 mL) and brine (40 mL). The organic layer was dried
over K2CO3, filtered, and concentrated in vacuo. The crude product
was chromatographed through a silica gel column packed with 1%
Et3N in hexane (10% EtOAc in hexane) to afford product 12 in 77%
yield over 2 steps (0.43 g,1.6 mmol) as a yellow oil. The spectral data
7.1.18. (2R*,3S*)-3-(5-Methoxypent-4-enyl)-2-methyl-4-methyl-
enetetrahydrofuran (16). Compound 16 was synthesized using the
same three step sequence employed in the conversion of 6–7. In
this case a Swern oxidation (procedure described for the synthesis
of 5) was used in place of the Corey Kim oxidation. The yield for the
three step sequence was 64%. The spectral data for 16 were as
follows: 1H NMR (CDCl3/300 MHz)
d
6.32 (d, J¼12.6 Hz, 0.7H), 5.89
(dt, J¼6.3 Hz, 1.2 Hz, 0.3H), 4.91 (m, 2H), 4.71 (dt, J¼12.6 Hz, 7.5 Hz,
0.7H), 4.406–4.205 (m, 2.3H), 3.71 (p, J¼6.6 Hz, 1H), 3.575 (s, 0.9H),
3.50 (s, 2.1H), 2.15–2.04 (m, 1.7H), 1.98–1.91 (m, 1.3H), 1.61–1.63 (m,
were as follows: 1H NMR (CDCl3/300 MHz)
d
5.83 (d, J¼2.1 Hz, 1H),
4.15 (p, J¼6.6 Hz,1H), 4.06 (t, J¼6.6 Hz, 2H), 3.53 (s, 3H), 2.54 (m,1H),
4H), 1.26 (d, J¼6.3 Hz, 3H); 13C NMR (CDCl3/75 MHz)
d 152.8, 152.7,
1.67–1.60 (m, 3H), 1.45–1.38 (m, 3H), 1.33 (d, J¼6.3 Hz, 3H), 1.20 (s,
147.2, 146.2, 106.3, 103.3, 103.2, 102.4, 80.7, 80.6, 70.5, 59.3, 55.8,
50.0, 49.9, 31.0, 30.9, 28.1, 27.9, 27.1, 23.9, 20.1; IR (neat/KBr) 2929.
9H); 13C NMR (CDCl3/75 MHz)
d 178.6, 145.6, 119.5, 81.6, 64.1, 57.4,

10872
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
1651, 1455, 1384, 1209, 1106, 934, 883, 737, 665, 542 cmꢀ1; HRMS
round-bottom flask under argon was placed freshly distilled diiso-
propylamine (0.87 mL, 6.2 mmol) and anhydrous THF (15 mL). The
mixture was cooled to ꢀ78 ꢁC, a 1.6 M solution of n-butyllithium in
hexane (3.4 mL, 5.4 mmol) added, and then allowed to warm to 0 ꢁC
over 30 min. The reaction was re-cooled to ꢀ78 ꢁC, a solution of 19
(0.47 g, 2.4 mmol) in anhydrous THF (10 mL) added via cannula, and
the mixture stirred for 0.5 h. While the reaction was still at ꢀ78 ꢁC,
TMEDA (4.1 mL, 28 mmol) was added, the resulting solution stirred
further for 30 min, and then a solution of 1 M ditertbutyldicarbonate
in THF (23 mL, 23 mmol) added. The reaction was allowed to slowly
warm to rt over 2 h and quenched by saturated NH4Cl (15 mL). The
aqueous phase was extracted with ether (2ꢂ30 mL) and then the
combined organic layers were washed with brine (2ꢂ40 mL), dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
chromatographed through a silica gel column packed with 1% Et3N in
hexane (gradient elution from 10% to 50% methylene chloride in
hexane) to afford product 20 in 69% yield (0.49 g, 1.6 mmol) as a yel-
low oil. The spectral data were as follows: 1H NMR (CDCl3/300 MHz)
(EI) m/z calculated for C12H20O2 [M]þ 196.1463, found 196.1455.
7.1.19. (2R*,3S*)-3-(5-Methoxypent-4-enyl)-2,4-dimethyl-2,3-dihy-
drofuran (17). To a stirred solution of 16 (0.14 g, 0.71 mmol) in dry
toluene(4 mL)wasaddeddiisopropylethylamine(123 mL,0.71 mmol)
and dichlorotris(triphenylphosphine) ruthenium (II) (134 mg,
0.14 mmol). The reaction was heated at 65 ꢁC for 8 h and then con-
centrated. The residue was chromatographed through a silica gel
column packed with 1% Et3N in hexane (gradient elution from 10% to
50% dichloromethane in hexane) to afford the desired product 17 in
79% yield (0.11 g, 0.56 mmol) as a colorless oil. The spectral data were
as follows: 1H NMR (CDCl3/300 MHz)
d
6.30 (dt, J¼12.6 Hz, 1.2 Hz,
0.64H), 5.66 (m, 1H), 5.86 (dt, J¼6.3 Hz, 1.5 Hz, 0.36H), 4.69 (dt,
J¼12.3 Hz, 7.5 Hz, 0.64H), 4.357–4.287 (m, 0.36H), 4.24–4.17 (m, 1H),
3.57 (s,1.08H), 3.50 (s,1.92H), 2.31–2.27 (m,1H), 2.11–2.02 (m, 0.64H),
1.97–1.89 (m,1.36H),1.62–1.55(m, buried with s at1.57, 4H),1.36–1.24
(m, buried with d at 1.26, J¼6.3 Hz, 6H); 13C NMR (CDCl3/75 MHz)
d
147.2, 146.3, 138.7, 138.6, 112.3, 112.2, 106.5, 102.7, 83.0, 82.9, 59.4,
d
6.50 (m,1H), 6.30 (d, J¼12.6 Hz, 0.7H), 5.88 (d, J¼6.3 Hz, 0.3H), 4.72
55.9, 52.7, 52.6, 32.1, 31.9, 27.9, 27.7, 26.7, 23.9, 22.1, 9.7; IR (neat/KBr)
(dt, J¼12.9 Hz, 7.2 Hz, 0.7H), 4.26 (m, 1.3H), 3.57 (s, 0.9H), 3.50 (s,
2.1H), 2.27 (m, 1H), 2.09 (m, 0.7H), 1.95 (q, J¼6.9 Hz, 1.3H), 1.70–1.55
(m,1H),1.51 (s, 9H),1.43–1.30 (m, buried with d at 1.36, J¼6.6 Hz, 6H);
2925, 2855, 1668, 1655, 1454, 1374, 1259, 1209, 1107, 934, 841 cmꢀ1
;
HRMS (EI) m/z calculated for C12H20O2 [M]þ 196.1463, found 196.1473.
13C NMR (CDCl3/75 MHz)
d 151.1, 147.2, 146.3, 134.8, 134.7, 132.1, 132.0,
7.1.20. (1R*,3R*,3aS*,4S*,7aS*)-4-(Dimethoxymethyl)-3-methoxy-
1,3a-dimethyl-octahydroisobenzofuran (18). A solution of 17 (80 mg,
0.41 mmol), 2,6-lutidine (0.43 g, 4.1 mmol), and LiClO4 (0.65 g,
6 mmol) in 50% MeOH–THF (20 mL) was placed in a flame-dried, 25-
mL three-necked round-bottom flask equipped with a reticulated
vitreous carbon (RVC) anode and a carbon rod cathode. The reaction
was electrolyzed at a constant current of 10 mAuntil 2.2 F/mol charge
was passed. The solution was diluted with Et2O (80 mL) and washed
with H2O (3ꢂ20 mL) and brine (40 mL). The organic layer was dried
over Na2SO4, filtered, and concentrated. The residue was column
chromatographed (silica gel, packed with 1% Et3N in CH2Cl2, gradient
elution from 2% to 10% EtOAc–CH2Cl2) to afford 18 in 75% yield
(79 mg, 0.31 mmol) as a colorless oil. The spectral data were as fol-
106.2, 102.4, 83.2, 83.1, 82.5, 82.4, 55.8, 48.1, 31.9, 31.7, 27.9, 27.7, 27.6,
27.5, 27.5, 26.5, 23.8, 21.9; IR (neat/KBr) 2978, 2931, 2857, 1756, 1655,
1456,1370,1254,1153, 935, 872, 780 cmꢀ1; HRMS (ESI)m/z calculated
for C12H19O5 [M-isobutyleneþH]þ 243.1227, found 243.1229.
7.1.23. (4R*,5R*)-4-(5-Methoxypent-4-enyl)-5-methyl-4,5-dihy-
drofuran-3-yl trifluoromethanesulfonate (21). Into a flamed-dried,
25 mL round-bottom flask under argon was placed freshly distilled
diisopropylamine (0.12 mL, 1.2 mmol) and anhydrous THF (4 mL).
The reaction was cooled to ꢀ78 ꢁC, a 1.6 M solution of n-butyl-
lithium in hexane (0.68 mL, 1.1 mmol) added, and then allowed to
warm to 0 ꢁC over 30 min. The reaction was cooled to ꢀ78 ꢁC,
a solution of 19 (0.10 g, 0.39 mmol) in anhydrous THF (2 mL) added
via cannula, and stirred for 0.5 h. While the reaction was stirred at
ꢀ78 ꢁC, a solution of N-phenyltrifluoromethanesulfonimide (0.28 g,
0.78 mmol) in THF (3 mL) was added. The reaction was allowed to
slowly warm to room temperature over 2 h before being quenched
with satd NaHCO3 (10 mL). The aqueous phase was extracted with
ether (30 mLꢂ2) and then the combined organic layers washed
with brine (2ꢂ20 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. The residue was chromatographed through a silica
gel column packed with 1% Et3N in hexane (gradient elution from
20% to 50% dichloromethane in hexane) to afford the desired
product 21 in 71% yield (91 mg, 0.28 mmol) as a slightly yellow oil.
lows: 1H NMR (CDCl3/500 MHz)
d 4.96 (s, 0.86H), 4.90 (s, 0.14H), 4.44
(d, J¼4 Hz, 0.14H), 4.14 (d, J¼7 Hz), 4.07 (m, 0.86H), 3.81 (m, 0.14H),
3.40 (s, 0.42H), 3.37–3.33 (s plus s, 6H), 3.26 (s, 2.58H), 1.78–1.65 (m,
3H),1.60–1.48 (m, 3H),1.42–1.35 (m, 1H), 1.31 (d, J¼6 Hz, 0.42H),1.24
(d, J¼6 Hz, 2.58H), 1.18–1.09 (m, buried with s at 1.147,1.42H), 0.98 (s,
2.58H); 13C NMR (CDCl3/75 MHz)
d 109.9, 107.7, 106.9, 105.5, 78.2,
76.3, 55.9, 55.1, 54.6, 54.3, 53.5, 51.4, 50.6, 50.4, 47.0, 45.3, 44.6, 39.1,
25.5, 23.1, 22.7, 22.3, 21.5 21.2, 20.5, 20.1, 14.0; IR (neat/KBr) 2925,
2855, 1668, 1655, 1454, 1374, 1259, 1209, 1107, 934, 841 cmꢀ1; HRMS
(EI) m/z calculated for C13H23O3 [M-OMe]þ 227.1647, found 227.1644.
7.1.21. (4R*,5R*)-4-(5-Methoxypent-4-enyl)-5-methyl-dihydrofuran-
3(2H)-one (19). Compound 19 was made from 11 using the same
three step procedure used to convert 6 into 7. In this case, the
Swern oxidation (see the synthesis of 5) was used in place of the
Corey Kim oxidation. The overall yield for the three step sequence
was 43%. The spectral data for 19 were as follows: 1H NMR (CDCl3/
The spectral data were as follows: 1H NMR (CDCl3/300 MHz)
d 6.56
(m, 1H), 6.32 (d, J¼12.9 Hz, 0.7H), 5.91 (d with fine coupling,
J¼6.3 Hz, 0.3H), 4.71 (dt, J¼12.6 Hz, 7.5 Hz, 0.7H), 4.41 (m, 1.3H),
3.58 (s, 0.9H), 3.51 (s, 2.1H), 2.74 (m, 1H), 2.08 (m, 0.7H), 1.97 (m,
1.3H), 1.68 (m, 1H), 1.48–1.32 (m, buried with d at 1.36, J¼6.3 Hz,
6H); 13C NMR (CDCl3/75 MHz)
d 147.6, 146.7, 137.2, 137.1, 134.6,
300 MHz)
d
6.31 (dt, J¼12.3 Hz, 1.2 Hz, 0.7H), 5.90 (dt, J¼6.3 Hz,
134.5, 120.7 (q, J¼319 Hz), 105.7, 102.0, 84.4, 59.4, 55.9, 48.1, 48.0,
31.4, 31.3, 27.5, 27.2, 26.1, 23.5, 21.7; IR (neat/KBr) 2977, 2934, 1656,
1423, 1245, 1211, 1140, 935, 908, 845 cmꢀ1; HRMS (ESI) m/z calcu-
lated for C12H18O5F3S [MþH]þ 331.0822, found 331.0821.
1.5 Hz, 0.3H), 4.71 (dt, J¼12.6 Hz, 5.1 Hz, 0.7H), 4.32 (m, 0.3H), 4.15
(d with fine coupling, J¼17.1 Hz, 1H), 3.94 (m, 1H), 3.83 (d with fine
coupling, J¼17.1 Hz, 1H), 3.57 (s, 0.9H), 3.50 (s, 2.1H), 2.11–1.88 (m,
3H), 1.72–1.62 (m, 1H), 1.55–1.37 (m, buried with d at 1.46, J¼5.7 Hz,
6H); 13C NMR (CDCl3/75 MHz)
d
217.3, 217.2, 147.4, 146.5, 105.7,
7.1.24. tert-Butyl methoxy(3-methoxy-1-methyl-1,3,4,5,6,7-hexahy-
droiso-benzofuran-4-yl)methyl carbonate (22) and 9-(dimethoxy-
methyl)octahydroindeno[1-d][1,3]dioxol-2-one (23). The electrolysis
was conducted using the same procedure reported above or the
oxidation of 17. The only change was in the electrolyte solution
used. In this case, the electrolyte solution was made by dissolving
LiClO4 (0.65 g, 6 mmol) in 10% MeOH/CH3CN (20 mL). The reaction
led to product 22 in 38% yield (36 mg, 0.13 mmol) and 23 in 26%
102.0, 79.4, 79.3, 71.2, 59.3, 55.8, 53.7, 53.6, 28.0, 27.7, 26.9, 26.2,
26.0, 23.6, 20.4; IR (neat/KBr) 2971, 2933, 2859, 1759, 1655, 1459,
1388, 1209, 1132, 1108, 935, 852 cmꢀ1; HRMS (EI) m/z calculated for
C11H18O3 [M]þ 198.1256, found 198.1256.
7.1.22. tert-Butyl (4R*,5R*)-4-(5-methoxypent-4-enyl)-5-methyl-4,5-
dihydro-furan-3-yl carbonate (20). Into
a flamed-dried 25 mL

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10873
yield (29 mg, 0.09 mmol), both as colorless oils. The spectral data
were as follows: For 22: 1H NMR (CDCl3/300 MHz)
6.17 (s, 0.6H),
a dropwise fashion at ꢀ78 ꢁC. The reaction was stirred until the
aldehyde was consumed completely by TLC. The mixture was
allowed to warm to room temperature and stirred for 2 h before
being quenched by the addition of saturated NH4Cl (50 mL). The
aqueous layer was extracted with EtOAc (4ꢂ40 mL) and the com-
bined organic layers were washed by brine (50 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
chromatographed through a silica gel column packed with 1% Et3N
in hexane (gradient elution from 5 to 10% EtOAc in hexane) to afford
product 24 in a 64% yield (0.35 g, 1.7 mmol) as a slightly yellow oil.
d
5.99 (s, 1H), 4.40 (d, J¼8.1 Hz, 1H), 4.28 (d, J¼4.2 Hz, 0.6H), 4.15–
4.00 (q plus p, J¼7.2 Hz, 6.6 Hz, 1.6H), 3.41 (s, s, 4.8H), 3.40 (s, 1.8H),
3.36 (s, 3H), 2.26 (m, 1.2H), 2.14–1.92 (m, 3.2H), 1.85–1.68 (m, 3.6H),
1.55–1.45 (m, 2H), 1.43–1.15 (m, buried with d at 1.42, J¼6.9 Hz, and
d at 1.37, J¼6.6 Hz, 7H); 13C NMR (CDCl3/75 MHz)
d 153.9, 153.5
108.1, 105.3, 104.8, 104.1, 93.8, 90.9, 85.0, 80.6, 56.0, 55.9, 55.2, 52.8,
49.7, 48.6, 43.5, 40.2, 30.8, 22.8, 22.5, 21.9, 21.7, 21.0, 19.1; IR (neat/
KBr) 2930, 1795, 1533, 1449, 1367, 1282, 1209, 1023, 972, 859,
765 cmꢀ1; HRMS (EI) m/z calculated for C12H17O5 [M-OMe]þ
The spectral data were as follows: 1H NMR (CDCl3/300 MHz)
d 6.33
241.1076, found 241.1076. For 22: 1H NMR (CDCl3/300 MHz)
d
5.69
(d, 12.6 Hz, 0.7H), 5.89 (dt, J¼6 Hz, 1.2 Hz, 0.3H), 4.83 (t, J¼5.1 Hz,
1H), 4.71 (dt, J¼12.3 Hz, 7.5 Hz, 0.7H), 4.32 (q, J¼6.3 Hz, 0.3H), 3.91
(d, J¼17.1 Hz, 1H), 3.88 (d, J¼17.1 Hz, 1H), 3.57 (s, 0.9H), 3.49 (s,
2.1H), 2.76 (dd, J¼11.1 Hz, 6 Hz, 1H), 2.23–1.87 (m, 5H), 1.78–1.60
(m, 2H), 1.46–1.31 (dq, J¼6 Hz, 12 Hz, 1H), 1.26–1.11 (m, 1H); 13C
(d with fine coupling, J¼3.6 Hz, 1H), 5.61 (d with fine coupling,
J¼3.6 Hz, 1.2H), 5.58 (d, J¼5.7 Hz, 1.2H), 5.51 (d, J¼5.7 Hz, 1H), 4.78
(m, 2.2H), 3.46 (s, 3.2H), 3.45 (s, 3H), 3.42 (s, 6.2H), 2.67 (m, 2.2H),
1.96 (m, 4.4H), 1.83–1.54 (m, 8.8H, water peak at 1.62), 1.50, 1.49 (s,
s, 19.8H), 1.26 (d, d, J¼6.6 Hz, 6.6 Hz, 6.6H); 13C NMR (CDCl3/
NMR (CDCl3/75 MHz)
d 217.3, 147.2, 146.4, 106.1, 102.2, 85.4, 85.3,
75 MHz)
d
153.3, 153.2, 144.3, 144.2, 129.2, 128.3, 109.3, 108.9, 103.3,
72.5, 59.4, 55.7, 52.9, 52.8, 43.5, 43.2, 34.1, 34.0, 32.5, 31.4, 30.7, 30.6,
26.7, 23.0; IR (neat/KBr) 2931, 2854, 1749, 1654, 1452, 1438, 1268,
1209, 1071, 934 cmꢀ1; HRMS (ESI) m/z calculated for C12H18NaO3
[MþNa]þ 233.1154, found 233.1162.
102.6, 82.3, 82.1, 81.8, 81.7, 77.4, 56.8, 56.7, 54.9, 54.7, 36.7, 27.7, 23.5,
23.1, 21.4, 20.4, 20.2; IR (neat/KBr) 2933, 1739, 1449, 1369, 1287,
1254, 1162, 1060, 940, 850 cmꢀ1; HRMS (EI) m/z calculated for
C16H25O5 [M-OMe]þ 297.1702, found 297.1701.
7.1.27. tert-Butyl (3aS*,4S*,6aR*)-4-(4-methoxybut-3-enyl)-4,5,6,6a-
tetra-hydro-3aH-cyclopenta[b]furan-3-yl carbonate (25). Compound
25 was synthesized from 24 using the same conditions used to
construct substrate 20. In this case, a 57% yield (0.10 g, 0.32 mmol)
of the product was obtained as a slightly yellow oil. The spectral
7.1.25. (3aS*,4S*,6aR*)-4-(But-3-enyl)-tetrahydro-2H-cyclopenta[b]-
furan-3(3aH)-one (from 4a). To a flame-dried 25 mL round-bottom
flask under an argon atmosphere was added a solution of oxalyl
chloride (0.38 mL, 4.5 mmol) in anhydrous dichloromethane (12 mL).
The reaction was cooled to ꢀ78 ꢁC and then DMSO (0.91 mL,
13 mmol) added dropwise over 5 min. The reaction was stirred
10 min, a solution of compound 4a (0.20 g, 1.1 mmol) in anhydrous
dichloromethane (8 mL) added, and the reaction stirred for 0.5 h.
Triethylamine (2.7 mL, 19 mmol) was added and stirred further for
0.5 h at 0 ꢁC. The reactionwas quenched by H2O (20 mL). The aqueous
layer was extracted with EtOAc (3ꢂ20 mL) and then the combined
organic phase washed with brine (30 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. The crude product was chromatographed
through a silica gel column (gradient elution from 5% to 10% EtOAc in
hexane) to afford the desired ketone in 96% yield (0.19 g,1.1 mmol) as
a yellow solid. The spectral data were as follows: 1H NMR (CDCl3/
data were as follows: 1H NMR (CDCl3/300 MHz)
d 6.58 (d, 1.2 Hz,
0.7H), 6.56 (d, J¼0.9 Hz, 0.3H), 6.34 (d, J¼12.6 Hz, 0.7H), 5.88 (d
with fine coupling, J¼6.3 Hz, 0.3H), 5.10 (dd, J¼8.4 Hz, 5.4 Hz, 1H),
4.74 (dt, J¼12.9 Hz, 6.9 Hz, 0.7H), 4.34 (q, J¼6.9 Hz, 0.3H), 3.58–3.49
(m buried s at 3.57 and s at 3.49, 4H), 2.16–1.89 (m, 4H), 1.79–1.40
(m buried with s at 1.48, 14H); 13C NMR (CDCl3/75 MHz)
d 151.3,
151.2, 147.0, 146.1, 135.6, 135.5, 132.1, 106.8, 102.8, 87.6, 87.5, 83.0,
82.9, 59.3, 55.7, 47.8, 47.7, 45.0, 44.7, 34.7, 34.6, 31.5, 30.2, 29.3, 29.3,
27.6, 27.0, 23.2; IR (neat/KBr) 2931, 2858, 1756, 1654, 1456, 1370,
1278, 1256, 1155, 1112, 876 cmꢀ1; HRMS (ESI) m/z calculated for
C17H26NaO5 [MþNa]þ 333.1678, found 333.1675.
500 MHz)
d
5.83–5.75 (ddt, J¼17 Hz, 10 Hz, 7 Hz, 1H), 5.04
7.1.28. (3aR*,4S*,6aR*)-4-(4-Methoxybut-3-enyl)-3-methylene-hexa-
hydro-2H-cyclopenta[b]furan. A Wittig reaction was used to convert
the ketone in 24 into an exocyclic methylene using the same
chemistry described above for the monocyclic substrate. The yield
of the methylene product was 92% yield (92 mg, 0.44 mmol of
a colorless oil). The spectral data were as follows: 1H NMR (CDCl3/
(dq, J¼17 Hz,1.5 Hz,1H), 4.96 (d with fine coupling, J¼10 Hz,1H), 4.84
(t, J¼5.5 Hz, 1H), 3.95 (d, J¼17.5 Hz, 1H), 3.87 (d, J¼17.5 Hz, 1H), 2.75
(dd,J¼11 Hz,5.5 Hz,1H),2.21–2.07(m, 4H),1.93(dt,J¼12.5 Hz, 6.5 Hz,
1H), 1.83–1.76 (m, 1H), 1.71–1.63 (m, 1H), 1.44–1.35 (dq, J¼5.5 Hz,
12 Hz,1H),1.25–1.18 (m,1H);13C NMR (CDCl3/125 MHz)
d 217.3,183.2,
114.7, 85.3, 72.5, 52.8, 43.4, 34.1, 32.8, 30.8, 30.6; IR (neat/KBr) 3075,
2930, 1749, 1639, 1437, 1175, 1071, 911 cmꢀ1; HRMS (ESI) m/z calcu-
lated for C11H17O2 [MþH]þ 181.1229, found 181.1223.
300 MHz)
d
6.32 (d with fine coupling, d¼12.6 Hz, 0.7H), 5.89 (dt,
J¼6 Hz, 1.5 Hz, 0.3H), 4.99 (m, 1H), 4.94 (m, 1H), 4.76 (dt, J¼12.6 Hz,
7.2 Hz, 0.7H), 4.61 (t, J¼5.1 Hz, 1H), 4.34 (q, J¼7.2 Hz, 0.3H), 4.22
(m, 2H), 3.57 (s, 0.9H), 3.50 (s, 2.1H), 3.05 (dd, J¼9 Hz, 6 Hz, 1H),
2.11–1.88 (m, 4H),1.84–1.74 (m,1H),1.63–1.50 (m, 2H),1.27–1.11 (m,
7.1.26. (3aS*,4S*,6aR*)-4-(4-Methoxybut-3-enyl)-tetrahydro-2H-cy-
clopenta-[b]furan-3(3aH)-one (24). Ozone was bubbled through
a ꢀ78 ꢁC solution of the compound made above (0.47 g, 2.6 mmol)
in CH2Cl2 (10 mL) until the solution turned a persistent blue color.
The excess ozone was removed by flushing the solution with Ar. To
the reaction was added PPh3 (1.37 g, 5.2 mmol) and the reaction
then stirred for 1 h at ambient temperature. The solution was dried
over MgSO4, filtered and concentrated in vacuo. To the residue was
added THF (20 mL). This solution was used in the next step without
further purification.
A flame-dried 100 mL round-bottom flask under an argon at-
mosphere was charged with a stirred suspension of (methoxy-
methyl)triphenylphosphonium chloride (1.52 g, 4.4 mmol) in
anhydrous THF (20 mL) at 0 ꢁC. To this mixture was added a 1 M
NaHMDS solution in THF (3.9 mL, 3.9 mmol) in a dropwise fashion.
The resulting solution was stirred for 1 h. The Wittig reagent made
in this fashion was added to the crude aldehyde generated above in
2H); 13C NMR (CDCl3/75 MHz)
d 149.8, 149.7, 146.9, 146.0, 106.7,
106.1, 102.8, 86.5, 86.4, 73.0, 72.9, 59.3, 55.8, 50.8, 50.7, 42.6, 42.2,
34.1, 34.0, 32.6, 31.5, 30.9, 30.8, 26.9, 23.1; IR (neat/KBr) 2929, 1851,
1654, 1451, 1209, 1109, 1054, 932 cmꢀ1; HRMS (ESI) m/z calculated
for C13H21O2 [MþH]þ 209.1542, found 209.1536.
7.1.29. (3aR*,4S*,6aR*)-4-(4-Methoxybut-3-enyl)-3-methyl-4,5,6,6a-
tetrahydro-3aH-cyclopenta[b]furan (26). Compound 26 was syn-
thesized using the same procedure described for the synthesis of
substrate 17. An 86% yield of the rearranged olefin (79 mg,
0.38 mmol) was obtained as a colorless oil. The spectral data were
as follows: 1H NMR (CDCl3/300 MHz)
d
6.30 (d, J¼12.3 Hz, 0.6H),
6.06 (s, 1H), 5.87 (d, J¼6.3 Hz, 0.4H), 5.01 (dd, J¼8.1 Hz, 5.4 Hz, 1H),
4.73 (dt, J¼12.3 Hz, 7.5 Hz, 0.6H), 4.33 (q, J¼6.6 Hz, 0.4H), 3.56 (s,
1.2H), 3.49 (s, 1.8H), 3.07 (t, J¼8.1 Hz, 1H), 2.12–1.86 (m, 4H), 1.74–
1.52 (m buried with s at 1.65, 6H), 1.41–1.24 (m, 2H); 13C NMR

10874
F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
(CDCl3/75 MHz)
d
146.9, 146.0, 142.5, 142.4, 109.5, 106.8, 102.9, 88.5,
J¼5.4 Hz, 1H), 3.59 (dt, J¼3.6 Hz, 6.9 Hz, 2H), 2.91 (t with fine cou-
pling, J¼7.2 Hz, 1H), 2.68–2.49 (m, 2H), 2.56–1.94 (m, 3H), 1.81–1.37
(m, 6H), 0.89 (s, 9H), 0.86 (s, 9H), 0.05, 0.03 (s, s, 12H); 13C NMR
88.4, 59.4, 55.8, 52.8, 52.7, 46.0, 45.6, 34.3, 34.3, 32.3, 31.3, 29.2,
29.1, 27.3, 23.5,12.2,12.1; IR (neat/KBr) 2929,1855,1656,1454,1436,
1209, 1106, 933 cmꢀ1; HRMS (ESI) m/z calculated for C13H21O2
[MþH]þ 209.1542, found 209.1537.
(CDCl3/75 MHz)
d 143.1, 124.8, 75.6, 63.4, 57.6, 41.2, 40.3, 35.5, 31.2,
31.0, 27.2, 26.0, 25.9, 18.4, 18.1, ꢀ4.4, ꢀ5.0, ꢀ5.3; IR (neat/KBr) 2953,
2938, 2889, 1471, 1387, 1253, 1102, 1060, 834, 773 cmꢀ1; HRMS (ESI)
m/z calculated for C23H47O2Si2 [MþH]þ 411.3115, found 411.3118.
7.1.30. (3aS*,6S*,6aR*)-6-(tert-Butyldimethylsilyloxy)-hexahy-
dropentalen-1(2H)-one. To a 0 ꢁC solution of compound 27 (2.70 g,
19 mmol) in DMF (40 mL) was added imidazole (1.97 g, 29 mmol)
and TBS-Cl (4.05 g, 27 mmol). The reaction was stirred for 12 h at
ambient temperature and then EtOAc (250 mL) added. The solution
was washed with H2O (3ꢂ50 mL) and brine (50 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was chromatographed through a silica gel col-
umn (gradient elution from 5% to 10% EtOAc in hexane) to afford the
protected alcohol in 85% yield (4.20 g, 16.5 mmol) as a colorless oil.
7.1.33. tert-Butyl(3-((1S*,3aR*,6S*,6aR*)-6-(tert-butyldimethyl-sily-
loxy)-octahydropentalen-1-yl)propoxy)dimethylsilane and (3aR*,6S*,
6aR*)-6-(3-(tert-butyldimethylsilyloxy)propyl)octa hydropentalen-1-
ol. To a solution of compound 28 (1.10 g, 2.7 mmol) in EtOAc (7 mL)
was added Pd/C (0.30 g). After three vacuum/H2 cycles, the reaction
was charged with atmosphere H2 and stirred for 24 h. The reaction
was filtered through Celite and the filtrate concentrated in vacuo.
The crude product was chromatographed through a silica gel col-
umn (gradient elution from 2.5% to 12.5% EtOAc in hexane) to afford
the hydrogenated product in 47% yield (0.52 g, 1.3 mmol) as a col-
orless oil. The spectral data were as follows: 1H NMR (CDCl3/
The spectral data were as follows: 1H NMR (CDCl3/300 MHz)
d 4.40
(t with fine coupling, J¼3.9 Hz, 1H), 2.71 (p, J¼7.5 Hz, 1H), 2.54 (dd,
J¼9.6 Hz, 6 Hz, 1H), 2.31–2.20 (m, 1H), 2.12–1.93 (m, 3H), 1.78–1.65
(m, 3H), 1.61–1.53 (m, 1H), 0.77 (s, 9H), ꢀ0.3, ꢀ0.4 (s, s, 6H); 13C
300 MHz)
d
4.26 (m, 1H), 3.64 (t, J¼6.6 Hz, 2H), 2.43 (p, J¼6.9 Hz,
NMR (CDCl3/75 MHz)
d
218.5, 75.7, 58.2, 40.6, 40.3, 37.9, 31.4, 28.4,
1H), 2.17 (m, 1H), 1.92 (m, 1H), 1.77–1.57 (m, 9H), 1.42 (m, 3H), 0.91,
25.6, 17.7, ꢀ5.0, ꢀ5.4; IR (neat/KBr) 2953, 2856, 1741, 1471, 1253,
0.88 (sþs, 18H), 0.09, 0.05 (sþs, 12H); 13C NMR (CDCl3/75 MHz)
1051, 1034, 836, 777 cmꢀ1
;
HRMS (ESI) m/z calculated for
d 75.9, 63.4, 52.6, 43.6, 42.2, 37.7, 32.9, 32.8, 32.0, 31.8, 26.0, 25.9,
C14H27O2Si [MþH]þ 255.1780, found 255.1775.
25.6, 17.8, ꢀ3.6, ꢀ3.9, ꢀ4.8; IR (neat/KBr) 2953, 2930, 2858, 1471,
1252, 1099, 1043, 912, 833 cmꢀ1; HRMS (ESI) m/z calculated for
C23H49O2Si2 [MþH]þ 413.3271, found 413.3268.
7.1.31. (1S*,3aS*,6S*,6aR*)-6-(tert-Butyldimethylsilyloxy)-1-(3-(tert-
butyldimethylsilyloxy)propyl)-octahydropentalen-1-ol. To
a
ꢀ78 ꢁC
In addition, a monodeprotected product was obtained in 24%
yield (0.19 g, 0.64 mmol) as a colorless oil. The spectral data were as
solution of (3-bromopropoxy)(tertbutyl)-dimethylsilane (4.48 g,
17.7 mmol) in anhydrous ether (50 mL) was added a 1.7 M solution
of tert-butyllithium in pentane (20.8 mL, 35 mmol). The reaction
was stirred at ꢀ78 ꢁC for 0.5 h and then warmed to 0 ꢁC for 1 h. A
flame-dried 250 mL round-bottom flask under argon was charged
with a ꢀ78 ꢁC solution of starting ketone (1.50 g, 5.9 mmol) in an-
hydrous ether (50 mL). The alkyl lithium solution above was added
to this solution via cannula. The reaction was stirred for 1 h and then
warmed to 0 ꢁC for 2 h. The reaction was quenched by satd NH4Cl
(40 mL), the layers separated, and the aqueous layer extracted with
CH2Cl2 (3ꢂ30 mL). The combined organic layer was washed with
brine (50 mL), dried over Na2SO4, filtered, and concentrated in
vacuo. The crude product was chromatographed through a silica gel
column (gradient elution from 0% to 3% EtOAc in hexane) to afford
the desired addition product in 79% yield (2.00 g, 4.7 mmol) as
a colorless oil. The spectral data were as follows: 1H NMR (CDCl3/
follows: 1H NMR (CDCl3/300 MHz)
d
4.28 (m, 1H), 3.66 (t, J¼6.6 Hz,
2H), 2.46 (m, 1H), 2.19 (m, 1H), 1.95 (m, 1H), 1.85–1.55 (m, 9H), 1.53–
1.37 (m, 3H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3/75 MHz)
d
75.9, 63.4, 52.5, 43.6, 42.2, 37.7, 32.9, 32.8, 32.0, 31.8, 26.0, 25.9,
17.8, ꢀ3.9, ꢀ4.8; IR (neat/KBr) 3338, 2930, 2857, 1471, 1360, 1253,
1044, 912, 833, 773 cmꢀ1; HRMS (ESI) m/z calculated for C17H35O2Si
[MþH]þ 299. 2401, found 299.2408.
7.1.34. (1S*,3aR*,6S*,6aR*)-6-(3-Hydroxypropyl)-octahydropentalen-
1-ol. The products above were deprotected to form the diol using
aqueous HCl. For example, to a solution of the disilated material
(0.2 g, 0.5 mmol) in THF (6 mL) was added concentrated HCl (1 mL)
at 0 ꢁC. The reaction was stirred at ambient temperature for 12 h
and then quenched carefully with satd NaHCO3 (5 mL). The reaction
was then neutralized with K2CO3 until pH>7. The layers were
separated and the aqueous layer extracted with CH2Cl2 (5ꢂ20 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was chromatographed
through a silica gel column (gradient elution from 20% to 35% EtOAc
in hexane) to afford the diol in 73% yield (64 mg, 0.35 mmol) as
a white solid. The spectral data were as follows: 1H NMR (CDCl3/
300 MHz)
d 4.31–4.23 (m, 2H), 3.63–3.50 (m, 2H), 2.40 (t with fine
coupling, J¼9 Hz, 1H), 2.13 (t, J¼9.3 Hz, 1H), 1.97–1.61 (m, 6H), 1.58–
1.40 (m, 5H), 1.28 (dtd, J¼6.6 Hz, 12.3 Hz, 2.1 Hz, 1H), 0.88, 0.86 (s, s,
18H), 0.08, 0.07 (s, s, 6H), 0.01 (s, 6H); 13C NMR (CDCl3/75 MHz)
d
84.6, 78.1, 64.0, 52.8, 42.5, 39.8, 39.3, 34.1, 32.4, 28.3, 27.5, 26.0,
25.8, 18.3, 17.8, ꢀ4.8, ꢀ5.2, ꢀ5.28, ꢀ5.32; IR (neat/KBr) 3507, 2953,
2858, 1471, 1361, 1253, 1090, 836, 776 cmꢀ1; HRMS (ESI) m/z cal-
culated for C23H49O3Si2 [MþH]þ 429.3220, found 429.3216.
300 MHz)
d
4.30 (m, 1H), 3.66 (q with fine coupling, J¼6 Hz, 2H),
2.46 (p, J¼8.7 Hz, 1H), 2.24–2.17 (m buried with br, 2H), 2.00–1.91
(m, 1H), 1.83–1.76 (m, 1H), 1.71–1.40 (m, 10H); 13C NMR (CDCl3/
7.1.32. tert-Butyl(3-((6S*)-6-(tert-butyldimethylsilyloxy)3,3a,4,5,6,6a-
hexa-hydropentalen-1-yl)propoxy)dimethylsilane (28). To a ꢀ40 ꢁC
solution of the alcohol made in the previous step (1.00 g, 2.3 mmol)
in THF (50 mL) was added pyridine (5 mL, 60 mmol) and SOCl2
(5 mL, 70 mmol). The reaction was stirred at this temperature for
0.5 h and then poured into satd aqueous solution of CuSO4 (150 mL)
at 0 ꢁC. The layers were separated and the aqueous layer extracted
with CH2Cl2 (3ꢂ30 mL). The combined organic layers were washed
with satd NaHCO3 (2ꢂ30 mL) and brine (30 mL), dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was chro-
matographed through a silica gel column (gradient elution from 0%
to 2.5% EtOAc in hexane) to afford product 28 in 75% yield (0.72 g,
1.8 mmol) as a colorless oil. The spectral data of major isomer were
75 MHz) d 75.8, 63.2, 51.8, 43.8, 42.1, 37.9, 32.7, 32.6, 32.4, 31.9, 26.8;
IR (neat/KBr) 3368, 2936, 2863, 1458, 1057, 1000, 979 cmꢀ1; HRMS
(ESI) m/z calculated for C11H21O2 [MþH]þ 185.1536, found 185.1525.
7.1.35. (3aR*,6R*,6aR*)-6-(4-Methoxybut-3-enyl)-hexahydropentalen-
1(2H)-one (29). Product 29 was generated from the diol using the
two step Swern oxidation–Wittig sequence described above in 57%
yield (123 mg, 0.59 mmol) as a pale yellow oil. The spectral data
were as follows: 1H NMR (CDCl3/300 MHz)
d
6.27 (d, J¼12.6 Hz,
0.7H), 5.82 (d, J¼3.3 Hz, 0.3H), 4.68 (dt, J¼12.6 Hz, 7.5 Hz, 0.7H), 4.29
(q, J¼7.2 Hz, 0.3H), 3.52 (s, 0.9H), 3.44 (s, 2.1H), 2.78 (m, 1H), 2.45
(t, J¼9 Hz, 1H), 2.15–1.89 (m, 6H), 1.89–1.52 (m, 5H), 1.21–1.06 (m,
2H); 13C NMR (CDCl3/75 MHz)
d 221.9, 146.8, 146.0, 106.6, 102.3,
as follows: 1H NMR (CDCl3/300 MHz)
d
5.31 (m, 1H), 4.21 (q,
59.3, 55.6, 54.3, 54.1, 44.4, 44.1, 40.7, 40.6, 39.9, 32.9, 32.8, 32.4, 32.3,

F. Tang, K.D. Moeller / Tetrahedron 65 (2009) 10863–10875
10875
2. For a recent account see: Moeller, K. D. Synlett 2009, 1208; For reviews of early
work see: (a) Moeller, K. D. Tetrahedron 2000, 56, 9527; (b) Moeller, K. D. Top.
Curr. Chem. 1997, 185, 49.
3. For recent work with sulfonamide trapping groups see: Xu, H.-C.; Moeller, K. D.
J. Am. Chem. Soc. 2008, 130, 13542.
32.0, 30.9, 29.8, 28.1, 26.9, 23.1; IR (neat/KBr) 2941, 2863,1731,1654,
1452, 1410, 1390, 1265, 1207, 1145, 1107, 933, 741 cmꢀ1; HRMS (ESI)
m/z calculated for C13H21O2 [MþH]þ 209.1536, found 209.1529.
4. Frey, D. A.; Wu, N.; Moeller, K. D. Tetrahedron Lett. 1996, 37, 8317.
5. (a) For the synthesis of the arteannuin ring skeleton see: Wu, H.; Moeller, K. D.
Org. Lett. 2007, 9, 4599; (b) For the synthesis of alliacol a see: Mihelcic, J.;
Moeller, K. D. J. Am. Chem. Soc. 2004, 126, 9106; (c) For a synthesis of the cyathin
core skeleton see: Wright, D. L.; Whitehead, C. R.; Sessions, E. H.; Ghiviriga, I.;
Frey, D. A. Org. Lett. 1999, 1, 1535; (d) For the synthesis of guanacastepene see:
Miller, A. K.; Hughes, C. C.; Kennedy-Smith, J. J.; Gradl, S. N.; Trauner, D. J. Am.
Chem. Soc. 2006, 128, 17057.
7.1.36. tert-Butyl((3aR*,6R*,6aR*)-6-(4-methoxybut-3-enyl)-
3,3a,4,5,6,6a-hexahydropentalen-1-yloxy)dimethylsilane (30). Into
a flamed-dried 25 mL round-bottom flask under an argon atmo-
sphere was introduced freshly distilled diisopropylamine (0.20 mL,
1.43 mmol) and anhydrous THF (5 mL). To this mixture was added
a 1.6 M solution of n-butyllithium in hexane (0.73 mL, 1.2 mmol) at
ꢀ78 ꢁC. The reaction was allowed to warm to 0 ꢁC over 30 min and
then it was recooled to ꢀ78 ꢁC before adding a solution of com-
pound 29 (0.12 g, 0.59 mmol) in anhydrous THF (5 mL) via cannula.
The mixture was stirred for 0.5 h. While the reaction was still at
6. Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron Lett.1999, 40, 6033.
7. (a) Huang, Y.; Moeller, K. D. Organic Lett. 2004, 6, 4199; (b) Huang, Y.; Moeller,
K. D. Tetrahedron 2006, 62, 6536.
8. Wavefunction, Inc.: Irvine, CA, USA.
9. For the Michael – aldol sequence see: (a) Li, C. C.; Liang, S.; Zhang, X. H.; Xie, Z.
X.; Chen, J. H.; Wu, Y. D.; Yang, Z. Org. Lett. 2005, 7, 3709; For the use of the
Grignard reagent in the Michael reaction see: (b) Ihara, M.; Makita, K.; Toku-
naga, Y.; Fukumoto, K. J. Org. Chem. 1994, 59, 6008; Crimmins, M. T.; Gould, L. D.
J. Am. Soc. Chem. 1987, 109, 6199.
10. For the acid catalyzed cyclization see: (a) Domazon, R. J. J. Heterocyclic Chem.
1988, 2, 751; (b) Smith, A. B., III; Liverton, N. J.; Hrib, N. J.; Sivaramakrishnan, H.;
Winzenbeg, K. J. J. Am. Chem. Soc. 1986, 108, 3040.
ꢀ78 ꢁC, TBS-OTf (270
mL, 1.2 mmol) was added. The resulting so-
lution was stirred for 1 h at ꢀ78 ꢁC and 1 h at 0 ꢁC. The reaction
was quenched with saturated NaHCO3 (20 mL). The aqueous phase
was extracted with ether (4ꢂ20 mL) and the combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was chromatographed through a silica gel column
packed with 1% Et3N in hexane (gradient elution from 0% to 5%
methylene chloride in hexane) to afford product 30 in 85% yield
(0.16 g, 0.50 mmol) as a colorless oil. The spectral data were as
11. Kulesza, A.; Ebetino, F. H.; Mishra, R. K.; Cross-Doersen, D.; Mazur, A. W. Org.
Lett. 2003, 5, 1163.
12. Gassman, P. G.; Burns, S. J.; Pfister, K. B. J. Org. Chem. 1993, 58, 1449.
13. (a) For a preliminary account of this work see: Tang, Feili; Moeller, Kevin D. J. Am.
Chem. Soc. 2007, 129, 12414; (b) For examples see: Solvent trapping and elimi-
nation are the typical products generated from failed cyclizations, New, D. G.;
Tesfai, Z.; Moeller, K. D. J. Org. Chem. 1996, 61, 1578–1598; Reddy, S. H. K.; Chiba,
K.; Sun, Y.; Moeller, K. D. Tetrahedron 2001, 57, 5183.
14. For the use of Na in toluene see: Bode, R. H.; Bol, J. E.; Driessen, W. L.;
Hulsbergen, F. B.; Reedijk, J.; Spek, A. L. Inorg. Chem. 1999, 1239.
15. For a synthesis of the iodide see: Oku, A.; Harada, T.; Kita, K. Tetrahedron Lett.
1982, 23, 681.
16. Hu, Y. J.; Dominique, R.; Das, S.; Roy, R. Can. J. Chem. 2000, 78, 838.
17. For evidence that ketene dithioacetal derived radical cations are less efficient at
generating carbon–carbon bonds see Ref. 7b. For recent uses in synthesis see:
(a) Sun, Y.; Liu, B.; d’Avignon, D. A.; Moeller, K. D. Org. Lett. 2001, 3 , 1729; (b) Liu,
B.; Duan, S.; Sutterer, A. C.; Moeller, K. D. J. Am. Chem. Soc. 2002, 124, 10101; (c)
Sun, Y.; Moeller, K. D. Tetrahedron Lett. 2002, 43, 7159; (d) Brandt, J. D.; Moeller,
K. D. Org. Lett. 2005, 7, 3553; (e) Xu, H.-C.; Brandt, J. D.; Moeller, K. D. Tetra-
hedron Lett. 2008, 49, 3868.
follows: 1H NMR (CDCl3/300 MHz)
d
6.30 (d, J¼12.6 Hz, 0.7H), 5.84
(d, J¼3.3 Hz, 0.3H), 4.74 (dt, J¼12.6 Hz, 6.3 Hz, 0.7H), 4.53 (s, 1H),
4.33 (q, J¼7.2 Hz, 0.3H), 3.56 (s, 0.9H), 3.48 (s, 2.1H), 2.83 (m, 2H),
2.54 (dd, J¼9.3 Hz, 15.6 Hz, 1H), 2.21–1.75 (m, 5H), 1.66–1.56 (m,
2H), 1.42–1.08 (m, 3H), 0.92 (s, 9H), 0.15 (s, 6H); 13C NMR (CDCl3/
75 MHz)
d 154.9, 154.8, 146.6, 145.6, 107.6, 103.5, 102.8, 102.7, 59.3,
55.6, 52.4, 52.3, 44.7, 44.3, 39.4, 39.3, 37.0, 34.3, 32.4, 31.3, 30.4,
27.5, 25.8, 23.8, 18.0, ꢀ2.7, ꢀ4.7, ꢀ4.8; IR (neat/KBr) 2932, 2856,
1643, 1471, 1462, 1252, 1228, 1208, 1110, 933, 839, 780 cmꢀ1; HRMS
(ESI) m/z calculated for C19H35O2Si [MþH]þ 323.2401, found
323.2398.
18. For a related study showing the relative abilities of S and N to stabilize radical
cations see: Murphy, J. A.; Khan, T. A.; Zhou, S.; Thomson, D. W.; Mahesh, M.
Angew. Chem. Int. Ed. Eng. 2005, 44, 1356.
Acknowledgments
19. For examples see: Moeller, K. D.; Wang, P. W.; Tarazi, S.; Marzabadi, M. R.;
Wong, P. L. J. Org. Chem. 1991, 56, 1058.
20. All CV data was measured using a BAS 100B Electrochemical Analyzer, Pt
working and auxiliary electrodes, a Ag/AgCl reference electrode, a 0.1 M LiClO4
in acetonitrile electrolyte solution, a substrate concentration of 0.025 M, and
a sweep rate of 25 mV/s.
21. For examples see Ref. 7b as well as: (a) Moeller, K. D.; Tinao, L. V. J. Am. Chem.
Soc. 1992, 114, 1033; (b) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Tetra-
hedron 2001, 57, 5183.
We thank the National Science Foundation (CHE-0809142) for
their generous support of our work. We also gratefully acknowl-
edge the Washington University High Resolution NMR facility,
partially supported by NIH grants RR02004, RR05018, and RR07155,
and the Washington University Mass Spectrometry Resource Cen-
ter, partially supported by NIHRR00954, for their assistance.
22. For enol ether–furan couplings leading to seven-membered rings see Ref. 5d as
well as: (a) New, D. G.; Tesfai, Z.; Moeller, K. D. J. Org. Chem. 1996, 61, 1578; (b)
Sperry, J. B.; Wright, D. L. J. Am. Chem. Soc. 2005, 127, 8034.
References and notes
23. (a) Tsantali, G. G.; Takakis, I. M. J. Org. Chem. 2003, 68, 6455; (b) Bal, S. A.;
Marfat, A.; Helquist, P. J. Org. Chem. 1982, 47, 5045.
24. Tang, F.; Chen, C.; Moeller, K. D. Synthesis 2007, 3411.
1. For a recent reviews of the use of electrochemistry in synthesis see: (a) Sperry,
J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605; (b) Yoshida, J.; Kataoka, K.;
Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265.