Pb(OAc)4 mediated transannular oxidative ring cleavage

Article abstract of DOI:10.1016/j.tetasy.2007.06.025

Pb(OAc)₄ oxidation of homoallylic alcohols at room temperature leads to the formation of a variety of fragmentation products, whose formation requires spatial proximity of the alcohol and the olefin moieties.

Full text of DOI:10.1016/j.tetasy.2007.06.025

Tetrahedron: Asymmetry 18 (2007) 1589–1602
Pb(OAc)4 mediated transannular oxidative ring cleavage
*
´
Zobida Elkhayat, Imad Safir, Mohamed Dakir and Simeon Arseniyadis
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 12 June 2007; accepted 20 June 2007
Abstract—Pb(OAc)4 oxidation of homoallylic alcohols at room temperature leads to the formation of a variety of fragmentation prod-
ucts, whose formation requires spatial proximity of the alcohol and the olefin moieties.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
OtBu
OtBu
HO
HO
a
The potential interest of Pb(OAc)4 in organic chemistry lies
in its ability to bring about various reactions under mild
conditions and its low cost.1 Apart from the widely used
oxidative cleavage (C–C bond cleavage),2 decarboxyl-
ations,3 acetoxylation,4 and formation of cyclic ethers
(C–O bond formation),5 Pb(OAc)4 is also used in C–C
bond formation,6 aziridination (C–N bond formation),7
and various other transformations.8 We have previously re-
ported that Pb(OAc)4 in a variety of solvents initiated a
domino reaction9 influenced by the stoichiometry,10 the
solvent,11 or the substitution pattern.12 At the outset, inter-
est in this work arose out of a need to perform a practical
synthesis of a conveniently functionalized taxoid C-ring
precursor.13 Thus, the unsaturated bicyclic vic. diols 1 were
converted, via a domino sequence, into ring-expanded
cycloalkane 2, which was used as a C-ring precursor in tax-
oid total synthesis.14 On the other hand, the bicyclic aldol
framework 3, which could also be used as more elaborate
taxoid C-ring precursor was prepared from 2 or directly
from 1, in one pot, using a consecutive domino reaction
(Scheme 1).15
O
O
2
1
AcO
OAc
c
b
R3
C2-C3
3
R2
C1-C2
O
OtBu
OtBu
2
4
5
8
1
7
HO
R7
6
3
I
C1-C7
Scheme 1. Reagents and conditions: (a) 2.4 equiv Pb(OAc)4, PhMe, 25 ꢁC;
(b) K2CO3, MeOH, H2O, 25 ꢁC; (c) 2.4 equiv Pb(OAc)4, PhMe then
K2CO3, MeOH, H2O, 25 ꢁC, one pot.
(R3), and C7 (R7), accessed from 3 using published proce-
dures.16 Of special interest for our ongoing synthetic
endeavors are the C1–C7 and C1–C2 cleavage products
with the highest possible regioselectivity.
It has been shown long ago, that introduction of remote
double bonds into alcohols oxidized with Pb(OAc)4 gives
the opportunity for neighboring group participation,17
and a radical mechanism was claimed, based on the early
explorations of Rao et al., reporting on the lead tetraace-
tate mediated fragmentation of pulegol (possessing a
homoallylic olefin segment) upon heating in benzene.18 In
their work dealing with new coupling processes upon treat-
ment of x-functionalized carboxylic acids with various lead
tetracarboxylates, Moloney et al. proposed a mechanistic
rationale based on the formation of a p-allyl type Pb(IV)
species II (Fig. 1) as an intermediate.6c More recently, Pre-
ite et al.19 reported the reaction of homoallylic alcohols
In the course of these studies, we found that starting from
the key intermediate 3 and using the appropriate sequenc-
ing of the steps, the reaction conditions can be tailored to
fit a particular type of transformation. The probe used is
a bicyclo[2.2.2]octane framework of general type I, having
a variable substitution pattern at the positions C2 (R2), C3
*
Corresponding author. Fax: +33 1 69 82 30 29; e-mail: Simeon.
Arseniyadis@icsn.cnrs-gif.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.025

1590
Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
O
O
O
Pb(OAc)4
H
O
O
Pb
L
n
R1
Bu
OAc
O
OH
PhH, r.
ref.18
Pb(OAc)3
L
II
III
R2
R2
3
3
HO
2
O
tBu
2
O
t
4
C1-C2
4
5
8
1
5
8
1
7
HO
6
O
O
7
6
V
IV
C1-C7
Figure 1. Proposed mechanistic rationale for the interaction of an olefin (p base) with Pb(OAc)4 (a Lewis acid).
with Pb(OAc)4 in refluxing benzene, ending with atom loss;
these results were suggestive of the involvement of an
organolead intermediate III similar to the one proposed
by Moloney et al.20
ious substrates and reaction conditions, in an attempt to
study the scope and selectivity of the process. Since elabo-
rated six-membered rings are present in a large variety of
biologically important natural products, establishing the
relative configuration of a quaternary carbon still remains
a major synthetic challenge. To that end, a synthetic route
had to be examined for suitable intermediates that might
allow the desired inversion or retention of the relative con-
figuration at quaternary centers, with the unsaturated diol
1 (Scheme 1) taken as reference. The purpose of this work
is to put forward routes, allowing for a substrate controlled
transannular ring opening and hence a modular construc-
tion of functionalized cyclohexanes, starting from the
variously substituted bridged-bicyclic frameworks of type
IV and V as portrayed in Figure 1. We now report
the fast, room temperature reaction of Pb(OAc)4 with
bicyclic homoallylic alcohols leading to transannular ring
opening.
A hint as to the potential use of this type of rearrangement
arose from previous work in our laboratory upon at-
tempted domino transformation of substrate 6 (Scheme
2). Prepared from hydrindenone 4 in two steps (AllylMgBr,
THF, ꢀ78 ꢁC, 1 h, 88% then TBAF, 60 ꢁC, 1 h, 80%), the
unsaturated diol 6 was subjected to our standard domino
conditions [2.4 equiv Pb(OAc)4, PhMe, 25 ꢁC, 15 h] aimed
at the corresponding ring-expanded domino product 7b.
Instead, the loss of the allylic fragment was observed with
concomitant oxidation of the hydroxyl moiety. Although
free-hydroxyl bearing carbinols exhibited good reactivity
in reactions with Pb(OAc)4, domino substrate 6 gave rear-
ranged ketone 7a in 71% isolated yield. The latter could
also be accessed from 4 via a fluoride induced deprotection
and subsequent treatment with Pb(OAc)4 in toluene at
room temperature. The same phenomenon was also de-
tected upon treatment of the bis-TBS-protected unsatu-
rated diol 5, which, unable to undergo an oxidative
cleavage induced domino transformation, under the stan-
dard conditions (2 equiv of the oxidant in AcOH or PhMe
or else, at 25 ꢁC), afforded 4.
2. Results and discussion
Methods for the synthesis of 8, 12 (Scheme 3), 14
(Scheme 4), 34 and 36 (Scheme 8) are described in previous
papers.15,16
OH
OH
HO
HO
O
OtBu
O
t
Bu
Bu
HO
O
t
Bu
TBSO
a
2
1
4
a, b, c, d
TBSO
7
HO
HO
TBSO
6
8
5
12
9
d
c, d
HO
c
b
b
b
OH
H
O
O
t
Bu
b
Ot
O
t
Bu
O
2
1
4
TBSO
TBSO
a, b
TBSO
H
HO
7
O
O
11
10
O
13
O
AcO
OAc
AcO
OAc
4
7a
7b
Scheme 3. Reagents and conditions: (a) MeLi, THF, ꢀ78 ꢁC; (b) TBAF,
60 ꢁC, 1 h; (c) DMP, py, CH2Cl2, 25 ꢁC, 2.5 h; (d) MeP+Ph3Brꢀ, t-BuOK,
THF, 25 ꢁC, 6 h.
Scheme 2. Reagents and conditions: (a) TBAF, 60 ꢁC, 1 h; (b) 2.4 equiv
Pb(OAc)4, PhMe, 25 ꢁC, 15 h; (c) AllylMgBr, THF, ꢀ78 ꢁC, 1 h.
The observed fragmentation pathway for the conversion of
homoallylic alcohols 5 to 4 and 6 to 7a is precedented18 and
similar to the one described by Preite et al.,19 who reported
the reaction of homoallylic alcohols with Pb(OAc)4 in
refluxing benzene, which was accompanied with atom loss.
These preliminary results encouraged us to investigate var-
2.1. Elaboration of the substrates
The necessary test reactants, homoallylic alcohols 9 and 11,
were prepared uneventfully, in their enantiomerically pure
form, from the known key intermediate 8, the two-direc-
tional transformation of which was accomplished by func-

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1591
AcO
tional group interconversion. Thus, by using known proce-
MOMO
HO
dures and by partially reversing the order of the reactions,
both target products can be synthesized efficiently (Scheme
3). Wittig olefination (MeP+Ph3Brꢀ, t-BuOK, THF, 25 ꢁC,
6 h, 90%) and subsequent fluoride deprotection (TBAF,
60 ꢁC, 1 h, 90%) cleanly afforded 11. The second target
homoallylic alcohol 9 was obtained via a four-step se-
quence starting with methyl carbinol formation (MeLi,
THF, ꢀ78 ꢁC) followed by desilylation as above, subse-
quent Dess–Martin oxidation (DMP, py, CH2Cl2, 25 ꢁC,
2.5 h, 60% three steps) and finally a Wittig olefination as
above (75%).
3
O
e, d
a, b
OtBu
O
t
Bu
O
t
Bu
Bu
TBSO
HO
TBSO
14
15
16
d
O
c, d
HO
Ot
OtBu
HO
HO
18
17
Scheme 4. Reagents and conditions: (a) MeP+Ph3Brꢀ, t-BuOK, THF,
25 ꢁC, 6 h; (b) K2CO3, MeOH–H2O (10:1), 25 ꢁC, 72 h; (c) DMP, py,
CH2Cl2, 25 ꢁC, 1.5 h; (d) TBAF, 60 ꢁC, 1 h; (e) MOMCl, i-Pr2NEt,
CH2Cl2, 25 ꢁC, 3 h.
The known compound 1216 was converted into the
bis-homoallylic alcohol substrate 13 by a Dess–Martin oxi-
dation (DMP, py, CH2Cl2, 25 ꢁC, 2.5 h, 82%) and a subse-
quent Wittig olefination (MeP+Ph3Brꢀ, t-BuOK, THF,
25 ꢁC, 6 h, 75%). With a satisfactory domino approach to
the synthesis of both homo-allylic carbinol types 9 and
11 in hand, attention was directed to the C3 oxygenated
substrates, to examine the effect of substitution at C3.
The substrates were prepared as shown in Scheme 4. The
known C3-acetoxy derivative 1416 served as a common
intermediate for the synthesis of substrates 15–18. Starting
from 14, the target allylic alcohol derivative 15 was
ing maneuvers, into 19/20 and 21/22, respectively (Scheme
5). C1–C2 ring opening on 9 would afford reversal at C4
quaternary center (compared to 1) while applying the same
conditions to 11 would ensure retention at C4 via a C1–C7
ring opening, thus enabling a straightforward preparation
of taxoid C-ring segments. The bicyclic rings in 9 and 11
hold the hydroxyl groups at C2 and C7, respectively, and
the newly formed olefin in a favorable orientation for inter-
action. The process was initiated by the exposure of homo-
allylic alcohol 11 to Pb(OAc)4 successively in acetone,
toluene, acetic acid, dichloromethane or acetonitrile at
25 ꢁC resulting, in all cases, in quantitative conversion of
the bicyclic framework into the ring-opened 21/22. After
screening several temperatures in one of the above cited
solvents, as well as mixed solvent systems such as ace-
tone–AcOH, 1:1, we found that all these solvents, at room
temperature, afforded similar product distribution and in
comparable isolated yields, although in slightly different
ratios. Selected typical reaction conditions involve the use
of 2 M equiv of Pb(OAc)4 in AcOH at room temperature
and stirring under an inert atmosphere, until TLC control
indicated consumption of the starting material (from 5 min
to 6 h, depending on the substrate investigated). Transan-
nular oxidative ring cleavage on homoallylic alcohol 11
under these conditions afforded, after only 5 min, 21a
(41%) along with 22a (20%) and its free-hydroxyl derivative
22c (18%). Performing the reaction in acetonitrile at 25 ꢁC
with 2 equiv of Pb(OAc)4 led to the formation of 21a, 22a
and 22c in 78% combined isolated yield, after nearly an
hour of stirring. This reaction was performed at a variety
prepared straightforwardly by
a
Wittig olefination
(MeP+Ph3Brꢀ, t-BuOK, THF, 25 ꢁC, 6 h, 86%) followed
by a mild base treatment (K2CO3, MeOH–H2O (10:1),
25 ꢁC, 72 h, 95%).21 Upon Dess–Martin oxidation of 15
(DMP, py, CH2Cl2, 25 ꢁC, 1.5 h, 79%) and subsequent
desilylation (TBAF, DMF, 2 h at 60 ꢁC, 85%), the desired
C3-oxo homoallylic alcohol 17 was obtained in good over-
all yield.
The required mono-protected allylic–homoallylic carbinol
16 was prepared by a two-step route starting with 15, via
a MOM-protection (MOMCl, i-Pr2NEt, CH2Cl2, 25 ꢁC,
3 h, 88%) and subsequent desilylation (TBAF, 60 ꢁC, 1 h,
80%) (Scheme 4). The target free allylic–homoallylic alcohol
18 was prepared from 15 by fluoride deprotection under the
same conditions than for 17, in 95% isolated yield.
2.2. Selective C1–C7/C1–C2 cleavage
It was anticipated that the TBS-protected domino product,
bicyclic aldol 8, could be further elaborated to either 9 or
11 (Scheme 3) and hence through transannular ring open-
OtBu
O
t
Bu
H
AcO
AcO Pb
O
O
O
O
OtBu
2
1
a
4
4
9
2 h
C1-C2
OH
19
20
7
AcO
R
9i
O
OtBu
OtBu
OtBu
O
O
O
O
4
a
O
Pb
HO
11
AcO
R
H
22c
C1-C7
OAc
OH
OtBu
5 min
2
AcO
4
AcO
b
1
21a
22a
22b
R = H
R = Me
b
7
11i
21b
Scheme 5. Reagents and conditions: (a) Pb(OAc)4, AcOH, 25 ꢁC; (b) (i) Me3Al (2 M in hexane), CH2Cl2, 0 ꢁC, 20 min, (ii) DMP, py, CH2Cl2, 25 ꢁC,
30 min.

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Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
of temperatures from 0 ꢁC to 60 ꢁC with negligible differ-
ences in the product ratio, while large amounts of starting
material were recovered at 0 ꢁC and extensive degradation
at 60 ꢁC.
The homoallylic alcohol 16 when subjected to the fragmen-
tation conditions (AcOH, 25 ꢁC, 45 min) afforded 57% iso-
lated yield of pure 25 along with 36% of an inseparable
mixture of 26a and its acetylated derivative 26b, which were
not characterized as pure. Inserting a carbonyl into the
bicyclic ring system a-to the olefin at the C3 position,
caused a large rate retarding effect and modified the reac-
tion outcome affording a single compound. Thus, under
the typical procedure (Pb(OAc)4, AcOH, 25 ꢁC, 6 h), 27
was produced in 66% isolated yield, to the exclusion of
its corresponding exocyclic olefin, along with recovered
17 (13%, Scheme 6). Steric energy for 27 was calculated
(MM3) to be 29.8 kcal/mol while that for its corresponding
exocyclic olefin containing isomer was considerably higher
(35.5 kcal/mol). Satisfactory yields were achieved in
Schemes 5 and 6, with 66–75% combined yields for the
transannular cleavage. The results obtained using 13, 16,
and 17 as substrates were very similar to those obtained
with 9 and 11 again suggesting a reaction pathway as
depicted in Scheme 5.
The initially obtained aldehydes 21a and 22a were treated
with Me3Al (2 M in hexane, CH2Cl2, 0 ꢁC, 20 min, 78%
and 74%, respectively) and subsequently with Dess–Martin
periodinane (DMP, py, CH2Cl2, 25 ꢁC, 30 min) to afford
21b (80%) and 22b (79%). As with 11, different reaction
conditions were used to optimize the yields of individual
products from 9. Treatment of the former with 2 equiv of
Pb(OAc)4 for 45 min afforded 45% of 19 and 25% of 20,
along with recovered starting material 9 (10%). A pro-
longed reaction time (2 h at room temperature) gave a
two-component mixture 19 (53%) and 20 (40%), which
was stable and easily separable. Presumably, the transition
state required for production of the transannularly cleaved
products 21, 22 can be attained with much less steric strain
than the one for 19 and 20.
A speculative mechanism, inspired by Moloney’s p-allyl
type Pb(IV) species II (Fig. 1), already adapted to the
homoallylic carbinol III, involves an initial ligand exchange
followed by an electrophilic plumbation (the olefin acting
as a p-base), and a subsequent skeletal rearrangement
accompanying the C–C bond cleavage as illustrated in
Scheme 5. The overall stereochemical outcome was such
that it could be accommodated via homoallylic alcohol
containing substrates, in which the olefin and the hydroxyl
group are disposed in a cis fashion, affording an intermedi-
ate generalized as 9i or 11i. The results support that the
reaction involves the formation of a p-allyl type Pb(IV) spe-
cies III (Fig. 1) followed by ring opening and acyl anion
addition leading to 19 and 21a. This transformation, in
addition to creating a reversal at quaternary center (19 vs
21b and 20 vs 22b) provides a useful functional handle
for further manipulation.
O
tBu
OtBu
HO
OtBu
+
a
O
O
OAc
24
15 min
13
23
AcO
O
t
Bu
MOMO
OtBu
O
t
Bu
O
O
+
a
OR
HO
MOMO
MOMO
45 min
16
25 OAc
26a R = H
26b R = Ac
O
O
t
Bu
O
O
t
Bu
a
HO
O
6 h
17
To evaluate the scope of the process we set out to apply the
method to some more complex bicyclic frameworks,
including bis-homoallylic alcohol 13, the mono-protected
alcohol 16, and enone 17. We pursued this study at room
temperature in AcOH using 2 equiv of Pb(OAc)4, and
found that the reaction was complete (all starting material
consumed) in 15 min for 13, 45 min for 16, while it required
6 h for 17 (Scheme 5). The regiochemical issue, when two
homoallylic alcohols are in competition, such as 13, was
resolved unambiguously upon subjection of the latter to
the standard conditions. The starting material 13 was con-
sumed after only 15 min, while the initially formed allyl-
ketones were converted into the corresponding crotyl-
ketones 23 and 24, following an in situ olefin migration
(by stirring for an additional 1 h before work up or even
by standing in the NMR tube in the presence of CDCl3).
Under these conditions reproducibly good yields of 23
(42%) and 24 (25%) were readily obtained. Evidence that
olefinic products 23 and 24 have the E-geometry came from
the coupling constants and spatial proximity measure-
ments. NOE difference spectra showed strong enhance-
ments between the vinylic methyl group and the relevant
vinylic proton in both cases.
27
OAc
Scheme 6. Reagents and conditions: (a) Pb(OAc)4, AcOH, 25 ꢁC (15 min
to 6 h).
It was reasoned that if 25/26 resulted from 16 by treatment
with Pb(OAc)4 (Scheme 6), then 32/33 should be accessible
by the reaction of Pb(OAc)4 with the allylic–homoallylic
template 18. Treatment of the latter with 2 equiv of
Pb(OAc)4 for 45 min at room temperature in AcOH, gave
four rearrangement products, 28 (13%), 29 (14%), 30
(60%), and 31 (13%), which were stable and isolable,
although 29, 30, and 31 were characterized as anomeric
mixtures. The structure of 28 was assigned by extensive
spectroscopic investigations (HMBC, NOESY) and further
supported by X-ray crystallographic analysis (Fig. 2).
Apparently the cyclic acetal 28, was formed spontaneously
from its parent dihydroxy-aldehyde upon subjection of 18
to the reaction conditions. In assigning the structure for
this product only one possible orientation of the hydroxyl
groups (both a) at C3, C5, could be conceived (taxoid
numbering).

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1593
and 36b (Scheme 8). Homoallylic alcohol 12b, when sub-
jected to transannular cleavage conditions, gave after 1 h
at room temperature in acetic acid, starting material 12b
along with the bicyclic ketone 8 in a 4:1 ratio, while
extended stirring (15 h) afforded 8 quantitatively. The allyl-
ically positioned hydroxyl group (C3) on 15 remains a spec-
tator insofar as the transannular oxidative ring cleavage is
concerned, since allylic alcohol 15, subjected to the stan-
dard conditions, [2 equiv of Pb(OAc)4, in AcOH, at
25 ꢁC, for more than 1 h] remained intact. Homoallylic
alcohol 35, prepared straightforwardly from the known
3415 via a two-step sequence (Wittig olefination followed
by a fluoride deprotection, 78% combined yield) and sub-
jected to transannular oxidative ring opening conditions
(2 equiv, 25 ꢁC, 1 h) was recovered intact. Thus, while the
homoallylic alcohol 11 upon treatment with the oxidant
(2 equiv, 5 min, 25 ꢁC) led to the C1–C7 bond cleavage
affording cyclohexane derivatives 21 and 22 (Scheme 5),
the homoallylic alcohol 35 with an inverted C7 hydroxyl
configuration remained unchanged, even under prolonged
reaction time (Scheme 8). The fact that the a-hydroxyl con-
taining bicyclic framework 35 was unreactive upon subjec-
tion to the reaction conditions suggests that alcohol
stereochemistry is a critical factor. An example of a stereo-
selective cleavage was described by Preite et al. who also
found that the corresponding anti-isomer exhibited virtu-
ally no reactivity.19
Figure 2. X-ray structure of 28 (Chem3D output).
In order to simplify the isolation of the products, the num-
ber of compounds can be produced by treatment of the
anomeric mixtures 30 and 31 with PCC. Thus, upon oxida-
tion (PCC, CH2Cl2, 25 ꢁC, 1 h) lactol 30 furnished 32 (71%)
and 31 afforded 33 (66%), which were fully characterized.22
As a result we have a precursor for the taxoid C-ring moi-
ety, compound 33, which contains three out of four stereo-
genic centers (C5, C7, and C8) with the correct relative
and absolute stereochemistry. It, therefore, becomes unnec-
essary to block the secondary hydroxyl function at C3 tem-
porarily, unless its further use in intramolecular lactone
formation (Scheme 7) is undesired. Moreover, it is expected
that the allyl acetate 32 could be transformed in a separate
step to the exocyclic olefin containing isomer 33, or to even
more elaborate C-ring precursors using osmylation or
Sharpless epoxidation.
Upon treatment with Pb(OAc)4 (2 equiv, 25 ꢁC, 1 h) the
homoallylic alcohol 36a gave back the hydrindenone 38,
from which it originated, in 81% isolated yield. Interest-
ingly, when treated in toluene with 2.4 equiv of Pb(OAc)4
at room temperature for 12 h, its free-diol derivative 36b,
led to the domino product 3712 in 72% isolated yield, with-
out re-forming the carbonyl. On the other hand 37, itself
stayed inert under the standard conditions (2 equiv
Pb(OAc)4, AcOH, 1 h), and even after prolonged reaction
times.
HO
In summary we have described a simple method for the
ring cleavage of bicyclo[2.2.2]homoallylic alcohols toward
endocyclic cyclohexenes and their in situ allylic rearrange-
ment to partially form exocyclic cyclohexanes. Complete
dependence on topology (15) and stereochemistry (35)
of the hydroxy group versus the olefinic moiety was ob-
served. The apparent region- and stereocontrol in product
distribution, is supportive of the mechanistic reasoning
advanced in Scheme 5. The results obtained using type
9 and 11 as substrates were very similar to those obtained
with all additional structures investigated in this paper
suggesting a reaction pathway as depicted in Scheme 5.
OtBu
HO
18
O
t
Bu
a
OtBu
7
8
3
7
Me
8
3
HO
5
5
+
O
O
OH
Bu
O
29
28
+
H
O
t
OtBu
HO
+
HO
O
O
OAc
O
31
30
OAc
Bu
b
b
O
t
OtBu
3. Conclusion
O
O
O
33
OAc
32
OAc
The bridged-bicyclic aldol 3, which is available in quantity
from fused-bicyclic diol 1, can be readily elaborated to the
variously substituted cyclohexanes (Schemes 5–7), by
Pb(OAc)4 mediated transannular cleavage of the related
homoallylic alcohols at room temperature. It was found
that the overall result can be strongly influenced by subtle
variations of the substrate; the reaction conditions for this
Scheme 7. Reagents and conditions: (a) Pb(OAc)4, AcOH, 25 ꢁC, 45 min;
(b) PCC, CH2Cl2, 25 ꢁC, 1 h.
Finally, in order to obtain supporting evidence for the pro-
posed mechanism, we examined substrates 12b, 15, 35, 36a,

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Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
HO
HO
3
O
O
t
Bu
OtBu
O
t
Bu
O
t
Bu
a, b
TBSO
TBSO
7
15
12b
34
35
HO
TBSO
OH
O
MOMO
MOMO
TBSO
OH
O
c
d
RO
RO
O
O
R = H
d
37
AcO
TBSO
38
R = TBS
36a
R = TBS
b
36bR = H
Scheme 8. Reagents and conditions: (a) MeP+Ph3Brꢀ, t-BuOK, THF, 25 ꢁC; (b) TBAF, 60 ꢁC, 1 h; (c) AllylMgBr, THF, ꢀ78 ꢁC; (d) Pb(OAc)4, AcOH,
25 ꢁC.
transformation are mild and tolerate various solvents but
also various substituents. Consistently good combined
yields (70–80%) were observed for a range of homoallylic
alcohols. For maximum efficiency, control of the regio-
chemical outcome (endo/exo double bond in 19/20, 21/22,
and 25/26) of the process must be improved. Equally, an
efficient method for the endo/exo double bond interconver-
sion will be necessary if this synthetic route is to meet pro-
gram objectives. Both of these problems are currently
under investigation and results will be reported in due
course.
1.0 mmol of substrate homoallylic alcohol and 2.0 mmol
of Pb(OAc)4, evacuated and flashed with argon, were
added 5 mL of dry acetic acid at room temperature. After
consumption of starting material (TLC monitoring, from
5 min to 6 h), the reaction mixture was diluted with ethyl
acetate, washed with aqueous saturated NaHCO3, worked
up as usual, and chromatographed on SiO2 column
chromatography.
4.2.2. General procedure for fluoride deprotection. To a
magnetically stirred solution of TBS-protected alcohol
(1.0 mmol) was added tetrabutylammonium fluoride
(2.0 mmol). The reaction was stirred at 60 ꢁC until TLC
monitoring showed no starting material left (usually ca.
1 h). After dilution with EtOAc, usual work up and chro-
matography on SiO2 gave the expected compound.
4. Experimental
4.1. General
General experimental details were as previously described.
NMR spectra were run in CDCl3 and specific rotations
were measured in chloroform. Experimental evidence
favoring the structures investigated came from a compre-
4.2.3. General procedure for oxidation with Dess–Martin’s
periodinane. To a stirred solution of alcohol (1 mmol) in
15 mL of dry methylene chloride and 2 mL of dry pyridine
3 equiv of Dess–Martin periodinane reagent were added
and the reaction mixture was stirred at room temperature
until TLC analysis indicated that the reaction was complete
(ca. 1–3 h). The mixture was diluted with methylene chlo-
ride, washed with a saturated aqueous solution of sodium
bicarbonate, then sodium thiosulfate solution, worked up
as usual, and chromatographed on SiO2 (eluent heptane–
EtOAc) to give the desired ketone.
1
hensive range of H and 13C NMR data (1 and 2D exper-
iments) and corroborated by spatial proximity studies
using mainly the 1D NOEDIFF technique.23 For all com-
pounds investigated, multiplicities of 13C resonances were
assigned by the SEFT technique.24 Electron spray mass
spectra were obtained in instances where electron impact
and chemical ionization failed to produce molecular ions.
Mass spectra acquired in the positive ion mode under elec-
tron spray ionization (ES+) using a mobile phase of meth-
anol, will be abbreviated as ESIMS (MeOH). HR will be
added for the high resolution mass measurements (HRE-
SIMS). ‘Usual work up’ means washing of the organic
layer with brine, drying over anhydrous magnesium sul-
fate, and evaporating in vacuo with a rotary evaporator
at aspirator pressure. Commercial Pb(OAc)4 was used
without purification. The acetic acid content of the latter
(introduced in excess of 0.2 equiv) was mostly removed un-
der vacuum in the reaction vessel. Optical rotations were
measured in CHCl3.
4.2.4. General procedure for Wittig methylenation.
A
solution of potassium tert-butoxide (5.6 mmol) in 6 mL
of dry THF was stirred under argon at room tempera-
ture as methyltriphenylphosphonium bromide (6 mmol)
was added. The resulting bright yellow solution was stir-
red for 1 h, cooled to 0 ꢁC before the ketone (1 mmol)
was added in dry THF (6 mL). The ice bath was re-
moved and the solution stirred at room temperature
while the reaction progress was monitored by TLC.
After TLC analysis indicated consumption of the start-
ing ketone, the reaction mixture was diluted with hep-
tane and worked up as usual. Rapid filtration on silica
gel with heptane–EtOAc as eluent afforded the desired
compound.
4.2. General procedures
4.2.1. General procedure for the lead tetraacetate mediated
oxidative cleavage. To a flame dried flask containing

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1595
1
4.3. Preparation and oxidative cleavage of unsaturated
diols 6
1062, 1019, 996 cmꢀ1; H NMR (500 MHz): d = 1.47 (s,
3H), 1.93 (d, J = 14.2 Hz, 1H), 2.11 (s, 3H), 2.12 (s, 3H),
2.30 (dd, J = 3.3, 14.2 Hz, 1H), 2.51 (m, 1H), 2.61 (dd,
J = 12.9, 4.2 Hz, 1H), 2.66 (m, 1H), 2.73 (dd, J = 5.3,
13.0 Hz, 1H), 3.03 (dd, J = 0.9, 3.0 Hz, 1H), 5.40 (d,
J = 3.3 Hz, 1H), 6.40 (d, J = 3.0 Hz, 1H); 13C NMR
(125 MHz): d = 21.3, 22.0, 22.8, 32.0, 34.5, 40.0, 41.5,
42.3, 90.0, 93.1, 102.9, 169.1, 169.4, 211.1; ESIMS
(MeOH): 321.1 ([M+Na]+, 100); HRESIMS: calcd for
C14H18O7Na m/z 321.0950, found 321.0947.
To a solution of hydrindenone 4 (200 mg, 0.48 mmol) in
dry THF (3 mL) was added allylmagnesium bromide
(1.0 M in ether, 1.9 mL, 1.92 mmol), at ꢀ78 ꢁC, and the
mixture stirred for 1 h under argon. The reaction mixture
was poured into a saturated aqueous solution of NH4Cl
at 0 ꢁC. This was then extracted with EtOAc, washed with
saturated aqueous NaHCO3, worked up as usual, and
chromatographed on silica gel (heptane–EtOAc, 95:5) to
give the expected compound 5 (190 mg, 88%).
4.4. Preparation of target molecules 9, 11, 13, and their
transannular oxidative ring cleavage
4.3.1. (1R,5S,6R,7aS)-1-Allyl-5,6-bis(tert-butyldimethyl-
silyloxy)-7a-methyl-2,3,5,6,7,7a-hexahydro-1H-inden-1-ol 5.
20
Colorless oil; ½aꢁD ¼ ꢀ96 (c 1.5, CHCl3); IR (film):
4.4.1. Homoallylic alcohol 9. The target homoallylic alco-
hol 9 was synthesized from 8 by the addition of methyl-
lithium16 on followed by desilylation (TBAF, 60 ꢁC, 1 h)
and oxidation of the resulting alcohol (485 mg, 2.0 mmol)
with a Dess–Martin periodinane (2.54 g, 6.0 mmol) in dry
pyridine (1.6 mL) using the general procedure affording
after SiO2 chromatography (heptane–EtOAc, 2:1) the cor-
responding ketone (280 mg, 60%).
m = 3365, 1639, 1471, 1462, 1407, 1386, 1360, 1251, 1101,
1071, 1030, 1005, 880, 869, 834, 773 cmꢀ1 1H NMR
;
(300 MHz): d = 0.09 (s, 3H), 0.10 (s, 6H), 0.11 (s, 3H),
0.90 (s, 9H), 0.91 (s, 9H), 1.19 (s, 3H), 1.70 (m, 3H), 2.08
(m, 3H), 2.26 (dd, J = 6.5, 13.1 Hz, 1H), 2.42 (m, 2H),
3.92 (ddd, J = 3.6, 6.8, 11.0 Hz, 1H), 4.07 (m, 1H), 5.09
(d, J = 2.2, 1H), 5.15 (b, 1H), 5.19 (d, J = 2.2 Hz, 1H),
5.91 (m, 1H); 13C NMR (75 MHz): d = ꢀ4.5, ꢀ4.4, ꢀ3.9,
ꢀ3.8, 18.0, 18.2, 21.2, 24.8, 26.0 (3C), 26.8 (3C), 32.6,
37.3, 40.6, 49.1, 73.1, 75.4, 81.3, 119.0, 122.2, 134.4,
146.8; ESIMS (MeOH): 475.3 ([M+Na]+, 100); HRE-
SIMS: calcd for C25H48O3Si2Na m/z 475.3040, found:
475.3050; Anal. Calcd for C25H48O3Si2 (452.31): C, 66.31;
H, 10.68. Found: C, 66.16; H, 10.91.
4.4.1.1. (1R,4R,5S,7S)-5-tert-Butoxy-7-hydroxy-4,7-di-
¼
20
methylbicyclo[2.2.2]octan-2-one. Colorless oil; ½aꢁD
þ52 (c 0.6, CHCl3); IR (film): m = 3426, 2972, 2933, 1737,
1719, 1457, 1389, 1369, 1230, 1204, 1190, 1131,
1071 cmꢀ1 1H NMR (500 MHz): d = 0.93 (s, 3H), 1.14
;
(s, 9H), 1.31 (d, J = 14.4 Hz, 1H), 1.41 (s, 3H), 1.56 (s,
1H), 1.66 (ddd, J = 2.0, 2.9, 14.8 Hz, 1H), 1.91 (dd,
J = 2.8, 18.8 Hz, 1H), 2.07 (m, 1H), 2.12 (dd, J = 2.9,
14.2 Hz, 1H), 2.17 (t, J = 2.9 Hz, 1H), 2.24 (t,
J = 18.8 Hz, 1H), 3.30 (ddd, J = 1.5, 3.5, 8.9 Hz, 1H);
13C NMR (125 MHz): d = 23.5, 28.5, 28.7 (3C), 33.5,
37.6, 42.5, 46.9, 56.6, 69.7, 72.3, 73.3, 213.9; ESIMS
(MeOH): 263.2 ([M+Na]+, 100); HRESIMS: calcd for
C14H24O3Na m/z 263.1623, found: 263.1607; Anal. Calcd
for C14H24O3 (240.17): C, 69.96; H, 10.07. Found: C,
69.26; H, 10.15.
Fluoride deprotection was carried out on 5 (190 mg,
0.42 mmol) using the general procedure (1 h, 60 ꢁC) to give
after chromatography (SiO2, heptane–EtOAc, 2:1) 6
(75 mg, 80%).
4.3.2. (1R,5S,6R,7aS)-1-Allyl-7a-methyl-2,3,5,6,7,7a-hexa-
20
hydro-1H-indene-1,5,6-triol 6. Colorless oil; ½aꢁD ¼ ꢀ78
(c 1.2, MeOH); IR (film): m = 3336, 1638, 1435, 1373,
1
1308, 1270, 1185, 1114, 1034, 1007, 911 cmꢀ1; H NMR
(300 MHz): d = 1.19 (s, 3H), 1.66 (m, 3H), 1.96 (m, 3H),
2.37 (m, 4H), 3.32 (t, J = 3.2 Hz, 1H), 3.88 (m, 2H), 5.05
(m, 2H), 5.20 (dd, J = 3.1, 4.3 Hz, 1H), 5.93 (m, 1H); 13C
NMR (75 MHz): d = 22.3, 25.6, 32.3, 37.5, 42.2, 50.8,
73.3, 75.8, 82.5, 118.0, 122.0, 136.5, 150.0; ESIMS
(MeOH): 247.2 ([M+Na]+, 100); HRESIMS: calcd for
C13H20O3Na m/z 247.1310, found: 247.1301.
Wittig methylenation of the ketone thus obtained (270 mg,
1.12 mmol) in dry THF (6 mL) with potassium tert-butox-
ide (700 mg, 6.25 mmol) and methyltriphenylphosphonium
bromide (2.40 g, 6.75 mmol) using the general procedure
afforded after SiO2 chromatography (heptane–EtOAc,
8:2) 9 (200 mg, 75%).
Placed in a flame dried flask, 6 (70 mg, 0.31 mmol) and
Pb(OAc)4 (329 mg, 0.74 mmol) were vacuumed, flashed
with argon and cooled to 0 ꢁC. Toluene (2 mL) was added,
the ice bath removed soon after, and the mixture was stir-
red at room temperature while TLC monitored. The reac-
tion mixture was diluted with Et2O and filtered through
Celite. The filtrate was concentrated and purified by SiO2
flash column chromatography (heptane–EtOAc, 3:1 as elu-
ent) affording 7a (65.6 mg, 71%).
4.4.1.2. (1S,4S,5S,7S)-5-tert-Butoxy-4,7-dimethyl-2-meth-
20
ylenebicyclo[2.2.2]octan-7-ol 9. Colorless oil; ½aꢁD ¼ þ72
(c 1.0, CHCl3); IR (film): m = 3453, 2972, 2925, 1649, 1461,
1437, 1387, 1363, 1244, 1189, 1067, 989, 897, 880 cmꢀ1; 1H
NMR (500 MHz): d = 0.79 (s, 3H), 1.04 (d, J = 14.5 Hz,
1H), 1.10 (s, 9H), 1.33 (s, 3H), 1.66 (td, J = 2.6, 14.2 Hz,
1H), 1.90 (m, 2H), 1.96 (m, 3H), 2.09 (td, J = 1.9, 17.4 Hz,
1H), 3.15 (ddd, J = 1.5, 2.6, 9.0 Hz, 1H), 4.79 (dd, J = 1.9,
3.9 Hz, 1H), 4.84 (dd, J = 1.9, 3.9 Hz, 1H); 13C NMR
(125 MHz): d = 24.0, 27.1, 28.6 (3C), 35.5, 36.4, 39.4, 44.8,
49.6, 70.5 (2C), 72.7, 109.3, 147.6; ESIMS (MeOH): 261.2
([M+Na]+, 100); HRESIMS: calcd for C15H26O2Na m/z
261.1830, found: 261.1849.
4.3.3. (1R,3R,7S,8R,9S)-Acetic acid-9-acetoxy-7-methyl-6-
oxo-2,10-dioxa-tricyclo[5.3.1.03,8]undec-3-yl ester 7a. Col-
20
orless oil; ½aꢁD ¼ þ17 (c 1.3, CHCl3); IR (film): m = 2941,
1731, 1715, 1450, 1368, 1325, 1219, 1170, 1105, 1083,

1596
Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
Transannular oxidative ring cleavage of
9
(40 mg,
Fluoride deprotection of 10 (448 mg, 1.32 mmol) using the
general procedure (1 h, 60 ꢁC) afforded after SiO2 chroma-
tography (heptane–EtOAc, 2:1) the target homoallylic
alcohol 11 (287 mg, 90%).
0.16 mmol) was achieved using the general procedure
(45 min, AcOH, 25 ꢁC) to afford 19 (21.3 mg, 45%) and
20 (10.2 mg, 25%) after SiO2 flash column chromatography
(heptane–EtOAc, 9:1). Yields were higher (19, 53% and 20,
40%) while no starting material was recovered upon pro-
longed stirring (2 h at room temperature).
4.4.2.2. (1R,2S,4R,5S)-5-tert-Butoxy-4-methyl-7-methyl-
20
enebicyclo[2.2.2]octan-2-ol 11. Colorless oil; ½aꢁD ¼ þ48
(c 0.9, CHCl3); IR (film): m = 3293, 2971, 2919, 1651,
4.4.1.3. ((4S,5S)-4-tert-Butoxy-5-methyl-5-(2-oxoprop-
yl)cyclohex-1-enyl)methyl acetate 19. Colorless oil;
1450, 1434, 1384, 1359, 1309, 1232, 1192, 1094, 1048,
1
1008, 887, 878, 742, 742, 694 cmꢀ1; H NMR (500 MHz):
20
½aꢁD ¼ þ46 (c 1.6, CHCl3); IR (film): m = 2971, 1740,
d = 0.80 (s, 3H), 1.11 (s, 9H), 1.14 (m, 1H), 1.58 (td,
J = 3.3, 14.0 Hz, 1H), 1.72 (s, 1H), 1.80 (m, 2H), 1.99
(ddd, J = 2.9, 9.2, 13.9 Hz, 1H), 2.17 (dd, J = 2.9, 6.0 Hz,
1H), 2.60 (ddd, J = 2.6, 5.3, 17.2 Hz, 1H), 3.20 (ddd,
J = 1.6, 3.3, 9.2 Hz, 1H), 3.81 (td, J = 3.3, 9.2 Hz, 1H),
4.84 (dd, J = 1.3, 3.2 Hz, 2H); 13C NMR (125 MHz):
d = 24.1, 28.7 (3C), 34.2, 35.1, 36.9, 43.8, 44.4, 68.3, 70.2,
72.7, 109.6, 146.2; ESIMS (MeOH): 247.2 ([M+Na]+,
100); HRESIMS: calcd for C14H24O2Na m/z 247.1674,
found: 247.1686; Anal. Calcd for C14H24O2 (224.17): C,
74.95; H, 10.78. Found: C, 75.37; H, 10.14.
1710, 1457, 1362, 1192, 1072, 1023, 959, 895, 842 cmꢀ1
;
1H NMR (500 MHz): d = 1.07 (s, 3H), 1.15 (s, 9H), 1.81
(dd, J = 2.5, 17.1 Hz, 1H), 2.06 (s, 3H), 2.07 (m, 1H),
2.14 (s, 3H), 2.28 and 2.61 (ABquartet, J = 14.7 Hz, 2H),
2.30 (m, 2H), 3.45 (dd, J = 5.6, 7.5 Hz, 1H), 4.42 (d,
J = 12.4 Hz, 2H), 5.60 (m, 1H); 13C NMR (125 MHz):
d = 20.9, 24.1, 29.0 (3C), 31.9, 32.7, 36.7, 36.8, 45.8, 68.0,
72.7, 73.3, 123.5, 131.3, 170.9, 209.6; ESIMS (MeOH):
319.2 ([M+Na]+, 100); HRESIMS: calcd for C17H28O4Na
m/z 319.1885, found: 319.1890; Anal. Calcd for C17H28O4
(296.19): C, 68.89; H, 9.52. Found: C, 68.17; H, 9.49.
Transannular oxidative ring cleavage of 11 (90 mg,
0.41 mmol) was achieved using the general procedure to
afford after 5 min of stirring, 21a (46.2 mg, 41%), 22a
(22 mg, 20%), and 22c (17.2 mg, 18%) after SiO2 flash col-
umn chromatography (heptane–EtOAc, 9:1).
4.4.1.4. 1-((1S,2S,4S)-2-tert-Butoxy-4-hydroxy-1-meth-
yl-5-methylenecyclohexyl)propan-2-one 20. Colorless oil;
20
½aꢁD ¼ ꢀ7 (c 0.9, CHCl3); IR (film): m = 3424, 2971, 1708,
1654, 1456, 1364, 1233, 1191, 1090, 1058, 1023, 898 cmꢀ1
;
1H NMR (500 MHz): d = 1.01 (s, 3H), 1.21 (s, 9H), 1.75
(d, J = 13.4 Hz, 1H), 1.90 (m, 2H), 2.11 (s, 3H), 2.34 and
2.65 (ABquartet, J = 16.6 Hz, 2H), 2.62 (d, J = 13.4 Hz,
1H), 3.71 (t, J = 4.0 Hz, 1H), 3.85 (s, 1H), 4.09 (dd,
J = 4.7, 9.3 Hz, 1H), 4.76 (s, 1H), 4.96 (s, 1H); 13C NMR
(125 MHz): d = 22.1, 28.8 (3C), 32.2, 35.8, 38.9, 39.4,
49.3, 72.0, 74.0, 74.7, 110.1, 147.1, 208.7; ESIMS (MEOH):
277.2 ([M+Na]+, 100); HRESIMS: calcd for C15H26O3Na
m/z 277.1779, found: 277.1781.
4.4.2.3. ((4S,5R)-4-tert-Butoxy-5-methyl-5-(2-oxoethyl)-
cyclohex-1-enyl)methyl ethanoate 21a. Colorless oil;
20
½aꢁD ¼ þ55 (c 1.3, CHCl3); IR (film): m = 2975, 2928,
1740, 1714, 1465, 1433, 1364, 1230, 1192 1074, 1024,
1
961 cmꢀ1; H NMR (500 MHz): d = 1.10 (s, 3H), 1.15 (s,
9H), 1.94 (d, J = 17.3 Hz, 1H), 2.06 (s, 3H), 2.09 (m,
2H), 2.17 (dd, J = 1.7, 15.5 Hz, 1H), 2.36 (dd, J = 8.4,
14.2 Hz, 1H), 2.41 (dd, J = 3.7, 15.5 Hz, 1H), 3.50 (dd,
J = 5.6, 8.3 Hz, 1H), 4.39 and 4.43 (ABquartet,
J = 12.3 Hz, 2H), 5.60 (m, 1H), 9.85 (m, 1H); 13C NMR
(125 MHz): d = 17.9, 20.9, 28.9 (3C), 31.8, 36.8, 39.2,
54.3, 68.0, 72.0, 73.9, 123.9, 130.5, 170.7, 203.2; ESIMS
(MeOH): 305.2 ([M+Na]+, 100); HRESIMS: calcd for
C16H26O4Na m/z 305.1729, found: 305.1722.
4.4.2. Homoallylic alcohol 11. Wittig methylenation of 8
(500 mg, 1.46 mmol) in dry THF (10 mL) with potassium
tert-butoxide (918 mg, 8.18 mmol) and methyltriphenyl-
phosphonium bromide (3.13 g, 8.76 mmol) using the gen-
eral procedure gave after SiO2 chromatography (heptane–
EtOAc, 8:2) 10 (448 mg, 90%).
4.4.2.4. (1S,4R,5S)-5-tert-Butoxy-4-methyl-2-methylene-
4-(2-oxoethyl)cyclohexyl ethanoate 22a. Colorless oil;
4.4.2.1. (1R,4R,5S,7S)-(5-tert-Butoxy-4-methyl-2-methyl-
enebicyclo[2.2.2]octan-7-yloxy)(tert-butyl)dimethylsilane 10.
20
½aꢁD ¼ þ30 (c 1.5, CHCl3); IR (film): m = 2973, 1737,
20
Colorless oil; ½aꢁD ¼ þ49 (c 0.6, CHCl3); IR (film):
1718, 1653, 1365, 1237, 1191, 1070 cmꢀ1 1H NMR
;
m = 2928, 2856, 1654, 1462, 1387, 1362, 1255, 1201, 1059,
(500 MHz): d = 1.06 (s, 3H), 1.18 (s, 9H), 1.88 (dddd,
J = 3.6, 7.3, 12.4, 13.9 Hz, 1H), 2.07 (s, 3H), 2.24 (m,
4H), 2.46 (dd, J = 3.4, 15.3 Hz, 1H), 3.70 (dd, J = 3.6,
8.2 Hz, 1H), 4.84 (s, 1H), 4.99 (s, 1H), 5.43 (t,
J = 5.0 Hz, 1H), 9.86 (dd, J = 2.2, 3.4 Hz, 1H); 13C
NMR (125 MHz): d = 19.2, 21.2, 28.8 (3C), 35.3, 39.6,
42.0, 53.2, 71.5, 73.2, 73.9, 112.6, 141.8, 169.9, 202.8;
ESIMS (MeOH): 305.2 ([M+Na]+, 100); HRESIMS: calcd
for C16H26O4Na m/z 305.1729, found: 305.1700.
1
1005, 936, 907, 870, 835, 802, 773, 695 cmꢀ1; H NMR
(500 MHz): d = 0.01 (s, 6H), 0.79 (s, 3H), 0.86 (s, 9H),
1.11 (s, 9H), 1.20 (dd, J = 3.4, 14.0 Hz, 1H), 1.48 (td,
J = 3.4, 13.8 Hz, 1H), 1.68 (ddd, J = 3.0, 9.1, 14.0 Hz,
1H), 1.84 (dd, J = 1.6, 16.8 Hz, 1H), 1.92 (ddd, J = 2.8,
9.0, 13.8 Hz, 1H), 2.08 (dd, J = 2.8, 5.8 Hz, 1H), 2.53 (dd,
J = 2.3, 16.8 Hz, 1H), 3.18 (ddd, J = 1.6, 3.2, 9.0 Hz, 1H),
3.82 (td, J = 3.4, 9.1 Hz, 1H), 4.70 (dd, J = 2.3, 4.2 Hz,
2H); 13C NMR (125 MHz): d = ꢀ4.7, ꢀ4.5, 18.1, 24.2,
25.8 (3C), 28.7 (3C), 33.4, 35.2, 37.7, 44.0, 44.7, 69.6, 70.6,
72.6, 107.4, 146.9; ESIMS (MeOH): 361.2 ([M+Na]+,
100); HRESIMS: calcd for C20H38O2SiNa m/z 361.2539,
found: 361.2564; Anal. Calcd for C20H38O2Si (338.26): C,
70.94; H, 11.31. Found: C, 70.93; H, 11.23.
4.4.2.5. 2-((1R,2S,4S)-2-tert-Butoxy-4-hydroxy-1-methyl-
20
5-methylenecyclohexyl)ethanal 22c. Colorless oil; ½aꢁD
¼
þ46 (c 1.8, CHCl3); IR (film): m = 3409, 2973, 2359, 1715,
1654, 1469, 1389, 1364, 1230, 1191, 1069, 1024, 899 cmꢀ1
1H NMR (500 MHz): d = 1.04 (s, 3H), 1.18 (s, 9H), 1.83
;

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1597
(m, 3H), 1.60 and 2.32 (ABquartet, J = 13.5 Hz, 2H), 2.16
and 2.43 (ABquartet, J = 15.3 Hz, 2H), 3.76 (dd, J = 3.9,
7.6 Hz, 1H), 4.37 (t, J = 5.2 Hz, 1H), 4.77 (s, 1H), 4.97
(s, 1H), 9.85 (t, J = 2.8 Hz, 1H); 13C NMR (125 MHz):
d = 19.4, 28.9 (3C), 38.0, 39.8, 41.5, 53.2, 71.0, 71.4, 73.9,
110.2, 147.0, 203.1; ESIMS (MeOH): 263.1 ([M+Na]+,
100); HRESIMS: calcd for C14H24O3Na m/z 263.1623,
found: 263.1607.
4.4.3. Preparation of bis-homoallylic alcohol 13 and its
transannular oxidative ring cleavage. Dess–Martin oxida-
tion of the known diol 1216 (260 mg, 0.97 mmol) was
carried out with DMP (1.23 g, 2.91 mmol) in pyridine
(0.75 mL) for 2.5 h using the general procedure to give,
after chromatography, (heptane–EtOAc, 1:1) the corre-
sponding ketone (210 mg, 82%).
4.4.3.1. (1R,4R,5S,7S)-7-Allyl-5-tert-butoxy-7-hydroxy-
4-methylbicyclo[2.2.2]octan-2-one. White solid; mp: 88–
Aldehydes 21a and 22a (140 mg, 0.49 mmol scale each)
were dissolved in dry CH2Cl2 (5 mL), chilled to 0 ꢁC, trea-
ted dropwise with Me3Al (2.0 M in hexane, 5 mL) and stir-
ring was continued, at 0 ꢁC, for 20 min. The reaction
mixtures were diluted with CH2Cl2, and quenched by the
addition of a saturated aqueous solution of NH4Cl.
The aqueous layer was back-extracted with CH2Cl2. The
extracts were worked up as usual and chromatographed
on silica gel (heptane–EtOAc, 4:1) to give the correspond-
ing methyl carbinols as a mixture of diastereomers (122 mg,
78% for 21a and 116 mg, 74% for 22a).
20
89 ꢁC (heptane); ½aꢁD ¼ þ66 (c 1.0, CHCl3); IR (film):
m = 3444, 3073, 2973, 2930, 2360, 2340, 1718, 1639, 1451,
1389, 1364, 1202, 1191, 1126, 1071, 1042, 1023, 1000,
973, 913 cmꢀ1 1H NMR (500 MHz): d = 0.93 (s, 3H),
;
1.15 (s, 9H), 1.26 (dd, J = 1.4, 14.2 Hz, 1H), 1.68 (t, d,
J = 3.0, 14.9 Hz, 1H), 1.85 (s, 1H), 1.93 (dd, J = 2.8,
18.8 Hz, 1H), 2.05 (ddd, J = 3.5, 9.1, 14.9 Hz, 1H), 2.13
(dd, J = 2.8, 14.2 Hz, 1H), 2.25 (m, 2H), 2.46 (m, 2H),
3.32 (ddd, J = 1.8, 3.6, 9.2 Hz, 1H), 5.19 (ddd, J = 1.5,
3.4, 9.0 Hz, 1H), 5.23 (dd, J = 2.2, 10.2, Hz, 1H), 5.84
(tdd, J = 7.5, 10.2, 17.5 Hz, 1H); 13C NMR (125 MHz):
d = 23.5, 28.7 (3C), 32.8, 37.3, 41.7, 44.1, 47.3, 53.9, 69.6,
73.0, 73.3, 120.4, 132.4, 213.5; ESIMS (MeOH): 289.2
([M+Na]+, 100); HRESIMS: calcd for C16H26O3Na m/z
289.1780, found: 289.1791; Anal. Calcd for C16H26O3
(266.18): C, 72.14; H, 9.84. Found: C, 72.25; H, 9.82.
The methyl carbinols thus obtained (116 mg, 0.388 mmol
scale each) in dry CH2Cl2 (4 mL) and pyridine (0.3 mL)
were oxidized with Dess–Martin periodinane (516.5 mg,
1.16 mmol) at room temperature for 30 min. The reaction
mixtures were then diluted with CH2Cl2, quenched with a
saturated aqueous solution of sodium bicarbonate, usual
work up and chromatography (heptane–EtOAc, 4:1) to
afford 21b (94 mg, 80%) and 22b (91 mg, 79%).
Wittig methylenation of the ketone thus obtained (210 mg,
0.78 mmol) in dry THF (2 mL) with potassium tert-butox-
ide (489 mg, 4.36 mmol) and methyltriphenylphosphonium
bromide (1.67 g, 4.68 mmol) using the general procedure
gave after SiO2 chromatography (heptane–EtOAc, 8:2) 13
(154 mg, 75%).
4.4.2.6. ((4S,5R)-4-tert-Butoxy-5-methyl-5-(2-oxoprop-
¼
20
yl)cyclohex-1-enyl)methylacetate 21b. Colorless oil; ½aꢁD
þ38 (c 1.1, CHCl3); IR (film): m = 2974, 2934, 1740, 1716,
1362, 1229, 1195, 1069, 1022, 957, 772 cmꢀ1 1H NMR
;
4.4.3.2. (1S,4S,5S,7S)-7-Allyl-5-tert-butoxy-4-methyl-2-
methylenebicyclo[2.2.2]octan-7-ol
(500 MHz): d = 0.96 (s, 3H) 1.15 (s, 9H), 2.02 (m, 1H),
2.05 (s, 3H), 2.11 (s, 3H), 2.15 (m, 2H), 2.29 (m, 1H), 2.35
and 2.58 (ABquartet, J = 16.2 Hz, 2H), 3.66 (dd, J = 5.5,
7.2 Hz, 1H), 4.41 (s, 2H), 5.56 (s, 1H); 13C NMR
(125 MHz): d = 19.0, 21.0, 29.1 (3C), 31.8, 32.4, 36.5, 36.7,
51.7, 57.2, 70.7, 73.2, 123.2, 131.2, 170.9, 208.9; ESIMS
(MeOH): 319.2 ([M+Na]+, 100); HRESIMS: calcd for
C17H28O4Na m/z 319.1885, found: 319.1872; Anal. Calcd
for C17H28O4 (296.19): C, 68.89; H, 9.52. Found: C, 69.47;
H, 9.53.
13. Colorless
oil;
20
½aꢁD ¼ þ79 (c 1.0, CHCl3); IR (film): m = 3559, 3070,
2972, 2924, 1640, 1451, 1432, 1388, 1363, 1249, 1229,
1186, 1170, 1058, 1023, 1000, 962, 908, 887 cmꢀ1 1H
;
NMR (500 MHz): d = 0.83 (s, 3H), 1.01 (dd, J = 1.5,
14.2 Hz, 1H), 1.14 (s, 9H), 1.69 (td, J = 2.7, 14.3 Hz,
1H), 1.91 (ddd, J = 3.2, 9.2, 14.3 Hz, 1H), 2.02 (m, 3H),
2.10 (t, J = 3.0 Hz, 1H), 2.16 (td, J = 2.1, 17.3 Hz, 1H),
2.49 (tdd, J = 1.3, 5.1, 7.7 Hz, 2H), 3.21 (ddd, J = 1.6,
2.7, 9.0 Hz, 1H), 4.82 (dd, J = 2.0, 4.0 Hz, 1H), 4.85 (dd,
J = 2.1, 4.2 Hz, 1H), 5.12 (t, J = 1.2 Hz, 1H), 5.15 (m,
1H), 5.95 (tdd, J = 7.3, 11.2, 16.2 Hz, 1H); 13C NMR
(125 MHz): d = 24.0, 28.8 (3C), 35.3, 35.8, 39.7, 43.7,
43.8, 47.1, 70.4, 71.8, 72.8, 109.2, 117.7, 134.5, 147.5;
ESIMS (MeOH): 287.2 ([M+Na]+, 100); HRESIMS: calcd
for C17H28O2Na m/z 287.1987, found: 287.1980.
4.4.2.7. (1S,4R,5S)-5-tert-Butoxy-4-methyl-2-methylene-
4-(2-oxopropyl)cyclohexyl acetate 22b. Colorless oil;
20
½aꢁD ¼ þ82 (c 0.7, CHCl3); IR (film): m = 2974, 2933,
1739, 1716, 1364, 1239, 1064, 1027, 901, 772 cmꢀ1 1H
;
NMR (500 MHz): d = 0.97 (s, 3H), 1.18 (s, 9H), 1.77
(ddd, J = 3.2, 8.1, 13.6 Hz, 1H), 1.89 (ddd, J = 4.6, 6.6,
13.5 Hz, 1H), 2.09 (s, 3H), 2.12 (s, 3H), 2.19 (d,
J = 13.5 Hz, 1H), 3.34 (d, J = 9.3 Hz, 1H), 2.36 and 2.55
(ABquartet, J = 16.2 Hz, 2H), 3.90 (dd, J = 3.1, 6.7 Hz,
1H), 4.78 (s, 1H), 4.89 (s, 1H), 5.46 (dd, J = 4.6, 7.9 Hz,
1H); 13C NMR (125 MHz): d = 20.6, 21.3, 28.9 (3C),
32.5, 35.6, 39.5, 41.3, 50.9, 68.4, 70.7, 73.6, 110.1, 143.2,
170.1, 208.6; ESIMS (MeOH): 319.2 ([M+Na]+, 100);
HRESIMS: calcd for C17H28O4Na m/z 319.1885, found:
319.1871; Anal. Calcd for C17H28O4 (296.19): C, 68.89;
H, 9.52. Found: C, 68.12; H, 9.67.
Oxidative cleavage of 13 (200 mg, 0.75 mmol) was achieved
using the general procedures to afford 23 (85 mg, 42%) and
24 (45 mg, 25%) after SiO2 flash column chromatography
(heptane–EtOAc, 4:1 as eluent).
Transannular oxidative ring cleavage of 13 (200 mg,
0.75 mmol) was achieved using the general procedure to
afford after 15 min stirring 23 (85 mg, 42%) and 24
(45 mg, 25%) after SiO2 flash column chromatography
(heptane–EtOAc, 4:1).

1598
Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
4.4.3.3. ((4S,5S)-4-tert-Butoxy-5-methyl-5-((E)-2-oxo-
pent-3-enyl)cyclohex-1-enyl)methylethanoate 23. Colorless
419.2550; Anal. Calcd for C22H40O4Si (396.26): C, 66.62;
H, 10.16. Found: C, 66.52; H, 10.23.
20
oil; ½aꢁD ¼ þ46 (c 0.3, CHCl3); IR (film): m = 2971, 2925,
1740, 1687, 1661, 1628, 1456, 1438, 1387, 1366, 1227,
To a stirred solution of the C3-acetoxy olefin (380 mg,
0.95 mmol) in methanol (10 mL) and water (1 mL), was
added potassium carbonate (1322 mg, 9.58 mmol). The
resulting mixture was stirred at room temperature for
3 days. After removing the solvents without heating and
dilution with EtOAc, usual work up and chromatography
on silica gel (heptane–EtOAc, 9:1) afforded the allylic alco-
hol 15 (322 mg, 95%).
1192, 1071, 1023, 969, 895 cmꢀ1 1H NMR (500 MHz):
;
d = 1.02 (s, 3H), 1.17 (s, 9H), 1.78 (d, J = 17.0 Hz, 1H),
1.87 (dd, J = 2.1, 6.8 Hz, 3H), 2.06 (s, 3H), 2.12 (m, 1H),
2.30 (d, J = 17.0 Hz, 1H), 2.34 (m, 1H), 2.42 and 2.68
(ABquartet, J = 14.0 Hz, 2H), 3.45 (dd, J = 5.3, 7.4 Hz,
1H), 4.40 and 4.45 (ABquartet, J = 13.7 Hz, 2H), 5.60 (s,
1H), 6.10 (qd, J = 1.7, 15.6 Hz, 1H), 6.78 (qd, J = 6.7,
15.7 Hz, 1H); 13C NMR (125 MHz): d = 18.1, 20.9, 24.2,
29.0 (3C), 31.9, 36.4, 36.9, 42.0, 68.0, 72.8, 73.2, 123.2,
131.3, 133.9, 141.7, 170.9, 201.1; ESIMS (MeOH): 345.2
([M+Na]+, 100); HRESIMS: calcd for C19H30O4Na m/z
345.2042; found: 345.2023.
4.5.1.2. (1S,2S,4R,5S,7R)-2-tert-Butoxy-5-(tert-butyl-
dimethylsilyloxy)-1-methyl-8-methylenebicyclo[2.2.2]octan-
20
7-ol 15. White solid; mp: 50–51 ꢁC (heptane); ½aꢁD ¼ ꢀ16
(c 1.3, CHCl3); IR (film): m = 3514, 2954, 2927, 2856, 1462,
4.4.3.4. (1S,4S,5S)-5-tert-Butoxy-4-methyl-2-methylene-
4-((E)-2-oxopent-3-enyl)cyclohexyl ethanoate 24. Color-
1388, 1363, 1250, 1201, 1098, 1053, 997, 948, 897, 878, 836,
1
775 cmꢀ1; H NMR (500 MHz): d = 0.03 (s, 3H), 0.04 (s,
20
less oil; ½aꢁD ¼ þ19 (c 0.4, CHCl3); IR (film): m = 2976,
3H), 0.86 (s, 9H), 0.98 (s, 3H), 1.10 (s, 9H), 1.48 (m, 1H),
1.52 (m, 2H), 1.80 (ddd, J = 1.9, 8.4, 13.9 Hz, 1H), 2.32
(s, 1H), 2.37 (d, J = 10.2 Hz, 1H), 3.28 (d, J = 8.3 Hz,
1H), 3.86 (ddd, J = 1.2, 4.2, 8.1 Hz, 1H), 4.06 (d,
J = 10.0 Hz, 1H), 4.98 (s, 1H), 5.20 (s, 1H); 13C NMR
(125 MHz): d = ꢀ4.9, ꢀ4.7, 18.0, 20.7, 25.8 (3C), 28.6
(3C), 36.6, 37.0, 38.9, 43.5, 69.1, 71.0, 71.8, 72.9, 113.2,
150.5; ESIMS (MeOH): 377.2 ([M+Na]+, 100); HRE-
SIMS: calcd for C20H38O3NaSi m/z 377.2488, found:
377.2489; Anal. Calcd for C20H38O3Si (354.25): C, 68.10;
H, 10.92. Found: C, 68.24; H, 11.21.
2930, 2360, 2330, 1738, 1695, 1659, 1439, 1367, 1238,
1194, 1059, 1026, 969, 897, 773, 669 cmꢀ1 1H NMR
;
(500 MHz): d = 1.03 (s, 3H), 1.18 (s, 9H), 1.77 (m, 1H),
1.87 (dd, J = 1.5, 6.8 Hz, 3H), 1.94 (m, 1H), 1.99 and
2.51 (ABquartet, J = 13.5 Hz, 2H), 2.08 (s, 3H), 2.43 and
2.66 (ABquartet, J = 15.3 Hz, 2H), 3.71 (dd, J = 7.0,
14.0 Hz, 1H), 4.80 (s, 1H), 4.91 (s, 1H), 5.47 (dd, J = 4.5,
8.0 Hz, 1H), 6.08 (dd, J = 1.5, 15.6 Hz, 1H), 6.78 (qd,
J = 6.8, 15.6 Hz, 1H); 13C NMR (125 MHz): d = 18.0,
21.2, 23.0, 28.9 (3C), 35.3, 39.7, 41.0, 44.4, 72.6, 72.9,
73.6, 110.4, 133.6, 141.5, 143.0, 170.0, 200.4; ESIMS
(MeOH): 345.2 ([M+Na]+, 100); HRESIMS: calcd for
C19H30O4Na m/z 345.2042; found: 345.2020; Anal. Calcd
for C19H30O4 (322.21): C, 70.83; H, 10.30. Found: C,
69.71; H, 10.14.
To an ice-cold solution of allylic alcohol 15 (540 mg,
1.52 mmol) in 6.5 mL of dry CH2Cl2, under argon, were
added chloromethyl methylether (269.7 mg, 3.35 mmol)
and diisopropylethylamine (490 mg, 3.8 mmol). The reac-
tion mixture was allowed to warm and stirred at room tem-
perature for 3 h while TLC-monitored. Quenched with
water, extracted with CH2Cl2, washed with diluted 1 M
HCl, a saturated aqueous solution of NaHCO3, the crude,
after the usual work up and silica gel chromatography
(heptane–EtOAc, 9:1) gave the corresponding MOM-pro-
tected product (531 mg, 88%).
4.5. Preparation of target molecules 16, 17, 18, and their
transannular oxidative ring cleavage
4.5.1. Homoallylic alcohol 16. Wittig methylenation of 14
(1.9 g, 4.7 mmol) in dry THF (10 mL) with potassium
tert-butoxide (2.9 g, 26.3 mmol) and methyltriphenylphos-
phonium bromide (10.0 g, 28.2 mmol) using the general
procedure (6 h) gave after SiO2 chromatography (hep-
tane–EtOAc, 8:2) the C3-acetoxy olefin (1.6 g, 86%).
4.5.1.3. ((1R,3R,4R,5S,7S)-5-tert-Butoxy-3-(methoxy-
methoxy)-4-methyl-2-methylenebicyclo[2.2.2]octan-7-yloxy)-
20
4.5.1.1. (1R,2S,4R,5S,7S)-2-tert-Butoxy-5-(tert-butyl-
dimethylsilyloxy)-1-methyl-8-methylenebicyclo[2.2.2]octan-
(tert-butyl)dimethylsilane. Colorless oil; ½aꢁD ¼ þ23 (c
1.6, CHCl3); IR (film): m = 2955, 2927, 2856, 2360, 1462,
20
7-yl ethanoate. Colorless oil; ½aꢁD ¼ þ83 (c 1.5, CHCl3);
1364, 1251, 1100, 1060, 1045, 835, 773, 668 cmꢀ1 1H
;
IR (film): m = 2957, 2928, 2856, 1737, 1462, 1366, 1245,
NMR (500 MHz): d = 0.01 (s, 6H), 0.85 (s, 9H), 0.90 (s,
3H), 1.11 (s, 9H) 1.39 (ddd, J = 1.7, 9.2, 14.1 Hz, 1H),
1.46 (td, J = 3.6, 13.7 Hz, 1H), 1.65 (dd, J = 4.2, 14.1 Hz,
1H), 1.91 (ddd, J = 2.9, 9.2, 13.6 Hz, 1H), 2.15 (q,
J = 2.9 Hz, 1H), 3.28 (dd, J = 3.6, 9.2 Hz, 1H), 3.43 (s,
3H), 3.76 (ddd, J = 2.8, 4.2, 9.2 Hz, 1H), 4.23 (d,
J = 1.8 Hz, 1H), 4.69 and 4.79 (ABquartet, J = 6.8 Hz,
2H), 5.0 (t, J = 1.8 Hz, 1H), 5.12 (t, J = 1.8 Hz, 1H); 13C
NMR (125 MHz): d = ꢀ4.6, ꢀ4.5, 18.1, 20.5, 25.8 (3C),
28.7 (3C), 37.4, 37.8, 39.7, 45.2, 55.9, 69.7, 71.2, 72.9,
76.9, 96.9, 112.4, 147.5; ESIMS (MeOH): 421.2
([M+Na]+, 100); HRESIMS calcd for C22H42O4NaSi m/z
421.2750; found: 421.2721.
1102, 1062, 1008, 836 cmꢀ1
;
1H NMR (500 MHz):
d = 0.00 (s, 3H), 0.01 (s, 3H), 0.80 (s, 3H), 0.85 (s, 9H),
1.11 (s, 9H), 1.48 (m, 2H), 1.63 (ddd, J = 0.7, 3.9,
14.2 Hz, 1H), 1.92 (ddd, J = 2.9, 9.2, 13.8 Hz, 1H), 2.15
(q, J = 3.0 Hz, 1H), 2.07 (s, 3H), 3.30 (dd, J = 3.5,
9.2 Hz, 1H), 3.80 (ddd, J = 3.0, 3.9, 9.1 Hz, 1H), 4.93
(dd, J = 1.3, 2.5 Hz, 1H), 5.01 (t, J = 1.5 Hz, 1H), 5.65
(dd, J = 1.8, 3.7 Hz, 1H); 13C NMR (125 MHz):
d = ꢀ4.6, ꢀ4.5, 18.0, 20.1, 21.2, 25.7 (3C), 28.6 (3C),
36.9, 37.8, 38.2, 44.7, 69.1, 70.9, 72.0, 73.0, 112.8, 146.0,
171.4; ESIMS (MeOH): 419.2 ([M+Na]+, 100); HRE-
SIMS: calcd for C22H40O4NaSi m/z 419.2594, found:

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1599
Fluoride deprotection was carried out on the silyl ether
thus obtained (449 mg, 1.12 mmol) using the general proce-
dure (1 h, 60 ꢁC) to give, after chromatography (heptane–
EtOAc, 2:1), the desired homoallylic alcohol 16 (255 mg,
80%).
8.6 Hz, 1H), 4.94 (td, J = 2.8, 8.6 Hz, 1H), 5.13 (d,
J = 1.5 Hz, 1H), 6.07 (d, J = 1.5 Hz, 1H); 13C NMR
(125 MHz): d = ꢀ4.8, ꢀ4.6, 17.4, 18.0, 25.7 (3C), 28.6
(3C), 36.9, 41.7, 44.5, 48.2, 68.4, 72.4, 76.4, 119.3, 143.1,
201.5; ESIMS (MeOH): 375.2 ([M+Na]+, 100); HRESIMS
calcd for C20H36O3NaSi m/z 375.2340; found: 375.2331.
4.5.1.4. (1R,2S,4R,5S,8R)-5-tert-Butoxy-8-(methoxy-
methoxy)-4-methyl-7-methylenebyciclo[2,2,2]octan-2-ol 16.
Fluoride deprotection was carried out on TBS-protected
enone thus obtained (180 mg, 0.64 mmol) using the general
procedure (2 h, 60 ꢁC) to give after SiO2 chromatography
(heptane–EtOAc, 2:1) the homoallylic alcohol 17 (90 mg,
85%).
20
White solid; mp: 62–63ꢁC (heptane); ½aꢁD ¼ þ11 (c
0.9, CHCl3); IR (film): m = 3473, 2973, 1458, 1389, 1364,
1194, 1143, 1098, 1039, 926, 754 cmꢀ1
;
1H NMR
(500 MHz): d = 0.98 (s, 3H), 1.10 (s, 9H), 1.57 (m, 3H),
1.86 (ddd, J = 2.1, 8.6, 12.8 Hz, 1H), 2.37 (d,
J = 12.8 Hz, 1H), 2.44 (s, 1H), 3.27 (dd, J = 1.7, 8.5 Hz,
1H), 3.41 (s, 3H), 3.76 (s, 1H), 4.18 (dd, J = 1.4, 3.1 Hz,
1H), 4.68 and 4.84 (ABquartet, J = 6.7 Hz, 2H), 5.18 (dd,
J = 1.4, 7.6 Hz, 2H); 13C NMR (125 MHz): d = 21.0,
28.6 (3C), 37.4, 37.3, 38.9, 43.7, 56.0, 68.2, 71.6, 73.1,
76.7, 95.8, 115.4, 146.6; ESIMS (MeOH): 307.2
([M+Na]+, 100); HRESIMS (MeOH) calcd for
C16H28O4Na m/z 307.1885; found: 307.1896.
4.5.2.2. (1R,2S,4R,5S)-2-tert-Butoxy-5-hydroxy-1-meth-
yl-8-methylenebicyclo[2.2.2]octan-7-one 17. White solid;
20
mp: 137–138 ꢁC (heptane); ½aꢁD ¼ þ5 (c 0.5, CHCl3); IR
(film): m = 3315, 2925, 2969, 2358, 1714, 1640, 1362, 1096,
1024 cmꢀ1 1H NMR (500 MHz): d = 1.04 (s, 3H), 1.10
;
(s, 9H), 1.43 (ddd, J = 0.9, 2.8, 15.2 Hz, 1H), 1.53 (d,
J = 6.8 Hz, 1H), 1.76 (ddd, J = 2.5, 4.0, 14.2 Hz, 1H),
2.12 (m, 2H), 2.77 (dd, J = 3.8, 6.1 Hz, 1H), 3.55 (ddd,
J = 1.0, 2.3, 6.2 Hz, 1H), 4.01 (m, 1H), 5.25 (d,
J = 1.58 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H); 13C NMR
(125 MHz): d = 17.2, 28.5 (3C), 36.8, 41.1, 44.1, 48.3,
67.8, 72.1, 73.7, 120.7, 142.1, 201.0; ESIMS (MeOH):
261.1 ([M+Na]+, 100); HRESIMS: calcd for C14H22O3Na
m/z 261.1467, found: 261.1468; Anal. Calcd for
C14H22O3 · 0.15 H2O (238.32): C, 69.77; H, 9.33. Found:
C, 69.73; H 9.23.
Transannular oxidative ring cleavage of 16 (110 mg,
0.38 mmol) was achieved using the general procedure
(45 min, AcOH, 25 ꢁC) affording after SiO2 flash column
chromatography (heptane–EtOAc, 4:1) pure25 (74 mg,
57%) along with an inseparable mixture of 26a and 26b
(45 mg, 36%).
4.5.1.5. ((4S,5R,6S)-4-tert-Butoxy-6-(methoxymethoxy)-
5-methyl-5-(2-oxoethyl)cyclohex-1-enyl)methyl
ethanoate
Transannular oxidative ring cleavage of 17 (95 mg,
0.54 mmol) was achieved using the general procedure
(6 h, AcOH, 25 ꢁC) to afford 27 (105 mg, 66%) and the
recovered starting material 17 (16 mg, 13%) after SiO2 flash
column chromatography (heptane–EtOAc, 9:1).
20
25. Colorless oil; ½aꢁD ¼ þ55 (c 1.3, CHCl3); IR (film):
m = 2973, 2925, 1738, 1713, 1463, 1364, 1227, 1193, 1146,
1
1073, 1021, 919, 754 cmꢀ1; H NMR (500 MHz): d = 1.05
(s, 3H), 1.16 (s, 9H), 2.05 (s, 3H), 2.08 (m, 1H), 2.37 (d,
J = 16.2 Hz, 1H), 2.46 (td, J = 5.5, 18.5 Hz, 1H), 2.56
(dd, J = 3.8, 16.2 Hz, 1H), 3.34 (s, 3H), 3.75 (s, 1H), 3.86
(dd, J = 5.5, 8.6 Hz, 1H), 4.57 (m, 2H), 4.62 (s, 2H), 5.77
(d, J = 2.9 Hz, 1H), 9.89 (dd, J = 1.3, 3.8 Hz, 1H); 13C
NMR (125 MHz): d = 16.2, 20.9, 28.9 (3C), 32.7, 41.9,
50.0, 56.0, 65.8, 68.3, 74.2, 81.7, 98.4, 128.9, 131.5, 170.7,
203.2; ESIMS (MeOH): 365.2 ([M+Na]+, 100); HRESIMS
calcd for C18H30O6Na m/z 365.1940; found: 365.1929;
Anal. Calcd for C18H30O6 (342.2): C, 63.14; H, 8.83.
Found: C, 63.13; H, 9.03.
4.5.2.3. ((4S,5R)-4-tert-Butoxy-5-methyl-6-oxo-5-(2-oxo-
ethyl)cyclohex-1-enyl)methyl ethanoate 27. Colorless oil;
20
½aꢁD ¼ þ15 (c 1.1, CHCl3); IR (film): m = 2974, 2933,
1743, 1720, 1671, 1458, 1366, 1228, 1192, 1072, 1023,
965, 885 cmꢀ1 1H NMR (500 MHz): d = 1.12 (s, 3H),
;
1.14 (s, 9H), 2.06 (s, 3H), 2.46 (dddd, J = 2.1, 4.4, 9.5,
18.9 Hz, 1H), 2.67 (td, J = 5.8, 18.9 Hz, 1H), 2.76 and
2.80 (ABquartet, J = 17.9 Hz, 2H), 4.07 (dd, J = 5.3,
9.5 Hz, 1H), 4.73 (s, 2H), 6.81 (tdd, J = 1.3, 2.5, 6.4 Hz,
1H), 9.72 (s, 1H); 13C NMR (125 MHz): d = 16.8, 20.9,
28.9 (3C), 32.3, 47.9, 49.9, 61.3, 69.8, 74.3, 132.9, 144.2,
170.7, 200.6, 201.0; ESIMS (MeOH): 319.1 ([M+Na]+,
100); HRESIMS: calcd for C16H24O5Na m/z 319.1521,
found: 319.1517.
4.5.2. Homoallylic alcohol 17. Dess–Martin oxidation of
15 (250 mg, 0.89 mmol) was carried out with DMP
(1.13 g, 2.67 mmol) in pyridine (0.75 mL) for 1.5 h using
the general procedure, to give after chromatography (hep-
tane–EtOAc, 1:1), the corresponding enone (195 mg, 79%).
4.5.3. Allylic–homoallylic diol 18. Fluoride deprotection
was carried out on TBS-protected allylic alcohol 15
(425 mg, 1.20 mmol) using the general procedure (1 h,
60 ꢁC) to give after chromatography (SiO2, heptane–
EtOAc, 1:1) 18 (270 mg, 95%).
4.5.2.1. (1R,2S,4R,5S)-2-tert-Butoxy-5-(tert-butyldi-
methylsilyloxy)-1-methyl-8-methylenebicyclo[2.2.2]octan-7-
20
one. White solid; mp: 76–77 ꢁC (heptane); ½aꢁD ¼ ꢀ12 (c
0.8, CHCl3); IR (film): m = 2959, 2338, 2360, 1732, 1715,
1637, 1363, 1250, 1100, 1066, 1030, 775, 668 cmꢀ1 1H
;
NMR (500 MHz): d = 0.00 (s, 3H), 0.01 (s, 3H), 0.82 (s,
9H), 1.02 (s, 3H), 1.09 (s, 9H), 1.43 (ddd, J = 1.0, 2.8,
14.6 Hz, 1H), 1.69 (ddd, J = 2.5, 4.3, 14.1 Hz, 1H), 2.00
(dd, J = 8.9, 14.6 Hz, 1H), 2.08 (ddd, J = 2.2, 8.6,
13.9 Hz, 1H), 2.62 (d, J = 2.6 Hz, 1H), 3.52 (dd, J = 2.3,
4.5.3.1.
(1R,2S,4S,5S,8R)-5-tert-Butoxy-4-methyl-7-
methylenebicyclo[2,2,2]octane-2,8-diol 18. White solid;
20
mp: 107–108 ꢁC (heptane); ½aꢁD ¼ þ10 (c 0.7, CHCl3); IR
(film): m = 3303, 2971, 2929, 1389, 1362, 1203, 1095, 1057,
997, 900, 742, 996 cmꢀ1; H NMR (500 MHz): d = 0.90
1

1600
Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
(s, 3H), 1.04 (s, 9H), 1.47 (m, 2H), 1.50 (m, 1H), 1.84 (ddd,
J = 2.4, 8.9, 13.8 Hz, 1H), 2.08 (br s, 2H), 2.30 (dd, J = 3.6,
6.1 Hz, 1H), 3.25 (dd, J = 2.4, 8.8 Hz, 1H), 3.76 (td,
J = 3.6, 7.6 Hz, 1H), 4.19 (s, 1H), 5.04 (s, 1H), 5.2 (s,
1H); 13C NMR (125 MHz): d = 19.4, 27.7 (3C), 35.5,
35.6, 37.9, 42.9, 67.3, 69.5, 70.4, 72.1, 112.6, 149.1; ESIMS
(MeOH): 263.2 ([M+Na]+, 100); HRESIMS: calcd for
C14H24O3Na m/z 263.1623 found: 263.1613.
4.5.4.1. ((3aR,4S,7aS)-4-tert-Butoxy-3a-methyl-2-oxo-
2,3,3a,4,5,7a-hexahydrobenzofuran-7-yl)methyl ethanoate
20
32. Colorless oil; ½aꢁD ¼ ꢀ40 (c 1.2, CHCl3); IR (film):
m = 2974, 2941, 1782, 1742, 1459, 1364, 1224, 1195, 1153,
1077, 1024, 944, 753, 667 cmꢀ1 1H NMR (500 MHz):
;
d = 1.08 (s, 3H), 1.19 (s, 9H), 2.08 (s, 3H), 2.17 (dd,
J = 9.7, 18.3 Hz, 1H), 2.42 (td, J = 5.3, 18.3 Hz, 1H),
2.30 and 2.80 (ABquartet, J = 17.4 Hz, 2H), 3.50 (dd,
J = 5.3, 9.5 Hz, 1H), 4.48 (s, 1H), 4.55 and 4.68 (AB quar-
tet, J = 12.8 Hz, 2H), 5.97 (d, J = 5.6 Hz, 1H); 13C NMR
(125 MHz): d = 16.1, 21.0, 29.0 (3C), 31.1, 41.2, 42.7,
65.4, 67.2, 74.1, 82.9, 128.3, 131.2, 170.6, 175.6; ESIMS
(MeOH + CH2Cl2): 319.1 ([M+Na]+, 100); HRESIMS:
calcd for C16H24O5Na m/z 319.1521, found: 319.1509;
Anal. Calcd for C16H24O5 (296.16): C, 64.84; H, 8.16.
Found: C, 64.24; H, 8.25.
Transannular oxidative ring cleavage of 18 (100 mg,
0.41 mmol) was achieved using the general procedure
(45 min, AcOH, 25 ꢁC) to afford 28 (12 mg, 13%), 29 (ano-
meric mixture, 13.2 mg, 14%), 30 (anomeric mixture,
12.6 mg, 13%), and 31 (anomeric mixture, 69 mg, 60%)
after SiO2 flash column chromatography (heptane–EtOAc,
4:1). Compounds 30 and 31 were characterized as pure lac-
tones 32 and 33, respectively (see below).
To a stirred solution of lactol 31 (anomeric mixture, 21 mg,
0.07 mmol), in dry CH2Cl2 (0.7 mL), were added 55 mg of
Celite and PCC (75.4 mg, 0.35 mmol). The reaction mix-
ture was stirred at room temperature for 1 h, and Et2O
added. The suspension was applied to a Celite column,
eluting with further diethyl ether. The solution was concen-
trated and the residue was purified by silica gel flash chro-
matography (heptane–EtOAc, 2:1) to give the
corresponding lactone 33 (13.6 mg, 66%).
4.5.3.2.
(1S,3S,4S,6R,8R)-4-tert-Butoxy-3-methyl-7-
methylene-9,10-dioxa-tricyclo[4.3.1.03,8]decane 28. White
20
solid; mp: 54–55 ꢁC (heptane); ½aꢁD ¼ ꢀ27 (c 0.5, CHCl3);
IR (film): m = 2974, 2868, 1457, 1362, 1231, 1136, 1076,
ꢀ1
974, 896, 761 cm
;
1H NMR (500 MHz): d = 1.11 (s,
9H), 1.30 (s, 3H), 1.79 (dd, J = 3.8, 12.8 Hz, 1H), 1.97
(dd, J = 6.2, 15.4 Hz, 1H), 2.09 (d, J = 12.8 Hz, 1H), 2.52
(dd, J = 6.2, 15.4 Hz, 1H), 3.74 (d, J = 6.1 Hz, 1H), 4.25
(d, J = 6.2 Hz, 1H), 4.41 (d, J = 6.1 Hz, 1H), 4.81 (s,
1H), 4.86 (s, 1H), 5.43 (d, J = 3.8 Hz, 1H); 13C NMR
(125 MHz): d = 25.1, 27.5 (3C), 41.1, 44.5, 45.6, 69.5,
72.2, 72.4, 84.5, 98.9, 104.5, 143.5; ESIMS (MeOH):
261.1 ([M+Na]+, 20); HRESIMS: calcd for C14H22O3Na
m/z 261.1467, found: 261.1447; Anal. Calcd for C14H22O3
(238.32): C, 70.56; H, 9.30. Found: C, 69.93; H, 9.31.
4.5.4.2.
methylene-2-oxooctahydrobenzofuran-6-yl-ethanoate
(3aR,4S,6S,7aS)-4-tert-Butoxy-3a-methyl-7-
33.
20
Colorless oil; ½aꢁD ¼ ꢀ32 (c 0.5, CHCl3); IR (film):
m = 2972, 2936, 1782, 1738, 1367; 1234; 1189, 1023, 1011,
947, 938 cmꢀ1 1H NMR (500 MHz): d = 1.11 (s, 3H),
;
1.21 (s, 9H), 1.85 (m, 1H), 2.02 (ddd, J = 3.4, 5.2,
14.1 Hz, 1H), 2.07 (s, 3H), 2.22 and 2.70 (AB quartet,
J = 17.0 Hz, 2H), 3.85 (dd, J = 3.4, 9.9 Hz, 1H), 4.55 (s,
1H), 5.42 (s, 1H), 5.48 (s, 1H), 5.53 (dd, J = 3.2, 5.2 Hz,
1H); 13C NMR (125 MHz): d = 17.2, 21.2, 29.0 (3C),
34.8, 41.5, 45.3, 66.6, 71.7, 74.3, 87.6, 122.1, 137.5, 170.2,
175.7; ESIMS (MeOH + CH2Cl2): 319.1 ([M+Na]+, 100);
HRESIMS calcd for C16H24O5Na m/z 319.1521 found:
319.1526; Anal. Calcd for C16H24O5 (296.16): C, 64.84;
H, 8.16. Found: C, 65.11; H, 8.15.
X-ray data for 28: CCDC deposited number: CCDC
620079. A needle of 0.30 · 0.125 · 0.125 mm was used for
data
collection.
Empirical
formula
C14H22O3,
M = 238.32, T = 293 K. Orthorhombic system, space
group P212121, Z = 4, a = 6.386(4), b = 10.977(6),
c = 19.482(12) A, V = 1365.7 A , dcalc = 1.159 g cmꢀ3
,
3
˚
˚
F(000) = 520, l = 0.080 mmꢀ1, k(Mo Ka) = 0.71073 A.
A total of 4496 intensity data was measured with a Nonius
Kappa-CCD diffractometer up to h = 20.89ꢁ, reduced to
1427 orthorhombic unique reflections.1 The structure was
solved with program SHELXS86.2 Refinement of 167 para-
meters on F2, using program SHELXL97,3 leaded to
R1(F) = 0.0623, calculated with the 1173 observed reflec-
tions having I P 2r(I) and wR2(F2) = 0.1112 considering
all the 1427 data. Goodness of fit = 1.054. Residual elec-
˚
4.6. Preparation of homoallylic alcohol 35
Wittig methylenation was carried out on known 3415
(160 mg, 0.47 mmol) in dry THF (4 mL) with potassium
tert-butoxide (295 mg, 2.63 mmol) and methyltriphenyl-
phosphonium bromide (1008 mg, 2.82 mmol) using the
general procedure to give, after SiO2 chromatography
(heptane–EtOAc, 4:1), the desired TBS-protected olefin
(142 mg, 90%).
3
˚
tronic density between ꢀ0.11 and 0.11 e A .
4.5.4. PCC oxidation of lactols 30 and 31. To a stirred
solution of lactol 30 (anomeric mixture, 35 mg, 0.11 mmol),
in dry CH2Cl2 (1.3 mL), were added 92 mg of Celite and
PCC (126 mg, 0.58 mmol). The reaction mixture was stir-
red at room temperature for 1 h, Et2O was added, the sus-
pension was applied to Celite column, eluting with further
diethyl ether. The solution was concentrated and the resi-
due was purified by silica gel flash chromatography (hep-
tane–EtOAc, 4:1) to give the corresponding lactone 32
(23.3 mg, 71%).
4.6.1. ((1R,4R,5S,7R)-5-tert-Butoxy-4-methyl-2-methylene-
bicyclo[2.2.2]octan-7-yloxy)(tert-butyl)dimethylsilane. Col-
20
orless oil; ½aꢁD ¼ þ12 (c 1.2, CHCl3); IR (film): m = 2970,
2950, 2928, 2856, 1362, 1063, 1042, 869, 833, 774 cmꢀ1
;
1H NMR (500 MHz): d = 0.04 (s, 3H), 0.05 (s, 3H), 0.83
(s, 3H), 0.91 (s, 9H), 1.10 (t, J = 2.8 Hz, 1H), 1.15 (s,
9H), 1.31 (dddd, J = 1.1, 2.6, 3.7, 12.3 Hz, 1H), 1.62
(ddd, J = 1.8, 3.6, 16.6 Hz, 1H), 1.75 (dd, J = 8.9,
14.1 Hz, 1H), 2.18 (dd, J = 3.2, 6.4 Hz, 1H), 2.42 (ddd,

Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
1601
J = 3.2, 9.8, 12.9 Hz, 1H), 2.51 (ddd, J = 2.7, 5.4, 16.6 Hz,
1H), 3.39 (ddd, J = 1.6, 3.6, 9.1 Hz, 1H), 3.77 (ddd,
J = 2.6, 5.2, 6.2 Hz, 1H), 4.66 (dd, J = 2.0, 4.1 Hz, 1H),
4.81 (dd, J = 2.2, 4.4 Hz, 1H); 13C NMR (125 MHz):
d = ꢀ4.8, ꢀ4.7, 18.1, 24.1, 25.9 (3C), 28.8 (3C), 33.4,
34.5, 35.5, 44.7, 45.2, 69.3, 70.9, 72.5, 106.5, 149.9; ESIMS
(MeOH): 361.2 ([M+Na]+, 100); HRESIMS: calcd for
C20H38O2SiNa m/z 361.2539, found: 361.2564; Anal. Calcd
for C20H38O2Si (338.26): C, 70.94; H, 9.45. Found: C,
71.56; H, 10.55.
100); HRESIMS: calcd for C15H24O5Na m/z 307.1521,
found 307.1517; Anal. Calcd for C15H24O5 (284.16): C,
63.36; H, 8.51. Found: C, 63.10; H, 8.13.
Placed in a flame dried flask, 36b (40 mg, 0.14 mmol) and
Pb(OAc)4 (149 mg, 0.34 mmol) were vacuumed, flashed
with argon and cooled to 0 ꢁC. 2 mL of toluene were
added, and the ice bath removed soon after; the mixture
was stirred at room temperature for 12 h. The reaction
mixture was diluted with Et2O and filtered through Celite.
The filtrate was concentrated and purified by SiO2 flash
column chromatography (heptane–EtOAc, 1:1 as eluent)
to afford 37 (29.8 mg, 72%).
Fluoride deprotection was carried out on the TBS-pro-
tected intermediate thus obtained (120 mg, 0.35 mmol)
using the general procedure (1 h, 60 ꢁC) to give, after SiO2
chromatography (heptane–EtOAc, 1:1), 35 (68 mg, 86%).
4.8. Domino product 37
20
4.6.2. (1R,2R,4R,5S)-5-tert-Butoxy-4-methyl-7-methylene-
Colorless oil; ½aꢁD ¼ ꢀ30 (c 0.7, CHCl3); IR (film):
20
bicyclo[2.2.2]octan-2-ol 35. Colorless oil; ½aꢁD ¼ þ42 (c
m = 3491, 2961, 2884, 2360, 2334, 1738, 1367, 1243, 1131,
1088, 980, 939, 924, 785 cmꢀ1 1H NMR (500 MHz):
;
1.1, CHCl3); IR (film): m = 3340, 2972, 2927, 1462, 1387,
1362, 1305, 1252, 1227, 1192, 1167, 1131, 1091, 1068,
d = 1.75 (dd, J = 2.7, 12.2 Hz, 1H), 1.90 (m, 1H), 1.95
(dd, J = 6.5, 12.3, Hz, 1H), 2.01 (ddd, J = 5.7, 11.2,
17.2 Hz, 2H), 2.09 (d, J = 2.9 Hz, 1H), 2.12 (s, 3H), 2.33
(dq, J = 7.5, 14.2 Hz, 2H), 3.81 (d, J = 9.1 Hz, 1H), 4.12
(s, 1H), 4.52 (d, J = 9.1 Hz, 1H), 5.10 (qd, J = 1.7, 17.0,
1H), 5.14 (dd, J = 2.0, 10.2 Hz, 1H), 5.73 (d, J = 2.8 Hz,
1H), 5.77 (m, 1H), 5.92 (s, 1H); 13C NMR (125 MHz):
d = 21.3, 31.0, 40.2, 41.8, 42.8, 63.5, 75.4, 80.1, 80.9,
93.2, 102.0, 102.1, 119.9, 132.9, 169.8; ESIMS (MeOH):
319.1 ([M+Na]+, 100); HRESIMS: calcd for C15H20O6Na
m/z 319.1158; found 319.1160; Anal. Calcd for C15H20O6
(296.12): C, 60.80; H, 6.80. Found: C, 59.48; H, 6.64.
1049, 1022, 988, 874, 754 cmꢀ1 1H NMR (500 MHz):
;
d = 0.75 (s, 3H), 0.99 (t, J = 2.9 Hz, 1H), 1.04 (s, 9H),
1.27 (dddd, J = 1.2, 2.5, 5.1, 13.7 Hz, 1H), 1.53 (ddd,
J = 1.7, 3.6, 17.5 Hz, 1H), 1.67 (br s, 1H), 1.73 (dd,
J = 9.3, 14.4 Hz, 1H), 2.16 (dd, J = 3.2, 6.2 Hz, 1H), 2.23
(ddd, J = 3.2, 9.4, 13.5 Hz, 1H), 2.42 (ddd, J = 2.9, 5.6,
17.5 Hz, 1H), 3.29 (ddd, J = 1.6, 3.6, 9.1 Hz, 1H), 3.82
(tdd, J = 1.1, 3.6, 9.3 Hz, 1H), 4.57 (dd, J = 2.0, 4.1 Hz,
1H), 4.71 (dd, J = 2.2, 4.4 Hz, 1H); 13C NMR (75 MHz):
d = 24.0, 28.8 (3C), 33.2, 34.1, 35.3, 43.8, 44.5, 68.9, 70.8,
72.7, 106.9, 149.1; ESIMS (MeOH): 247.2 ([M+Na]+,
100); HRESIMS: calcd for C14H24O2Na m/z 247.1674
found: 247.1673; Anal. Calcd for C14H24O2 (224.17): C,
74.95; H, 10.78. Found: C, 75.26; H 10.57.
Acknowledgments
4.7. Preparation and oxidative cleavage of diol 36b
The authors wish to thank Professor Jean-Yves Lallemand
´
for his kind interest and constant encouragements, Angele
Proceeding as above, treatment of 38 (100 mg, 0.2 mmol)
with allylmagnesium bromide (1.0 M in ether, 0.8 mL,
0.8 mmol) in dry THF (5 mL) for 1 h, furnished, after chro-
matography (SiO2, heptane–EtOAc, 95:5), 36a (98 mg,
90%).
Chiaroni for X-ray crystallographic assistance and Sridhar
R. Iyer for some preliminary experiments and running the
reaction on substrate 17.
References
4.7.1. (1R,5R,6R,7aS)-1-Allyl-5,6-bis(tert-butyldimethylsil-
yloxy)-7a-((methoxymethoxy)methyl)-2,3,5,6,7,7a-hexahy-
dro-1H-inden-1-ol 36a. Characterized as a diastereomeric
mixture, colorless oil; IR (film): m = 3351, 1638, 1435, 1373,
1300, 1270, 1181, 1110, 1030, 1005, 880, 860, 834,
773 cmꢀ1; ESIMS (MeOH): 535.3 ([M+Na]+, 100); HRE-
SIMS: calcd for C27H52O5Si2Na m/z 535.3251, found
535.3210; Anal. Calcd for C27H52O5Si2 (512.34): C, 63.23;
H, 10.22, Found: C, 62,98; H, 9.95.
1. Articles dealing with specific aspects of organolead chemistry:
Criegee, R. In Oxidation in Organic Chemistry, Part A;
Wiberg, K. B., Ed.; Academic Press: New York, 1965; pp
277–366; Rubottom, G. M. In Oxidation in Organic Chem-
istry; Trahanovsky, W. H., Ed.; Academic Press: London,
1982; Vol. D, Chapter 1.
2. Criegee, R. Chem. Ber. 1931, 64, 260–266; For cleavage of
1,2-glycols with other oxidants, see: Malaprade, M. L. Bull.
Soc. Chim. Fr. 1928, 43, 683–696; Rigby, W. J. Chem. Soc.
1950, 1907–1913.
3. Starnes, W. H., Jr. J. Am. Chem. Soc. 1964, 86, 5603–5611;
Kochi, J. J. Am. Chem. Soc. 1965, 87, 3609–3619.
4. (a) Criegee, R. Angew. Chem. 1958, 70, 173–179;
(b) Rawlinson, D.; Sosnovsky, G. Synthesis 1973, 567–603;
(c) Arseniyadis, S.; Rodriguez, R.; Cabrera, E.; Thompson,
A.; Ourisson, G. Tetrahedron 1991, 47, 7045–7058; (d)
Floresca, R.; Kurihara, M.; Watt, D. S.; Demir, A. S.
J. Org. Chem. 1993, 58, 2196–2200.
Fluoride deprotection of 36a (90 mg, 0.17 mmol) using the
general procedure (1 h, 60 ꢁC) afforded after chromatogra-
phy (heptane–EtOAc, 2:1), 36b (42 mg, 87%).
4.7.2.
(1R,5R,6R,7aS)-1-Allyl-7a-((methoxymethoxy)-
methyl)-2,3,5,6,7,7a-hexahydro-1H-indene-1,5,6-triol 36b.
Characterized as a diastereomeric mixture, colorless oil;
IR (film): m = 3332, 3318, 1430, 1353, 1300, 1260, 1111,
1014, 997, 910 cmꢀ1; ESIMS (MeOH): 307.1 ([M+Na]+,
5. Mihailovic, M.; Cekovic, Z. Synthesis 1970, 209–224.

1602
Z. Elkhayat et al. / Tetrahedron: Asymmetry 18 (2007) 1589–1602
´
6. (a) Masuda, Y.; Hoshi, M.; Arase, A. Chem. Lett. 1980, 413;
hedron Lett. 2000, 41, 863–866; Rico Ferreira, M.; Martın
Hernando, J. I.; Candela-Lena, J. I.; Birlirakis, N.; Arseniy-
adis, S. Synlett 2000, 113–115.
(b) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353–1382; (c)
Moloney, M.; Nettleton, E.; Smithies, K. Tetrahedron Lett.
2002, 43, 907–909, and references cited therein.
15. The whole potential of this consecutive hetero-domino
transformation for rapidly generating molecular complexity
is not yet realized. Finet, L.; Candela Lena, J. I.; Kaoudi, T.;
Birlirakis, N.; Arseniyadis, S. Chem. Eur. J. 2003, 9, 3813–
3820, and references cited therein.
7. Anderson, D. J.; Gilchrist, T. L.; Horweil, D. C.; Rees, C. W.
J. Chem. Soc. 1970, 576; Kapron, J. T.; Santarsiero, B. D.;
Vederas, J. C. J. Chem. Soc., Chem. Commun. 1993, 1074;
Yang, K.-S.; Chen, K. Org. Lett. 2002, 7, 1107.
8. As stated by Mark Moloney, ‘lead(IV) has been significantly
under-utilized in synthesis and further novel applications are
likely to emerge, by making use of our developing under-
standing of the principles governing these unusual reactions.’
Moloney, M. G. Main Group Metal Chem. 2001, 24, 653–660.
9. (a) Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 32, 115–136;
Angew. Chem., Int. Ed. Engl. 1993, 32, 131–163; (b) Tietze,
L. F. Chem. Rev. 1996, 96, 115–136; (c) Tietze, L. F.; Modi,
A. Med. Res. Rev. 2000, 20, 304–322; (d) Tietze, L. F.;
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´
´
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¨
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´
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