Variations of solvent and substitution pattern in Pb(OAc)4 mediated domino reactions

Article abstract of DOI:10.1016/j.tetasy.2004.11.097

The effect of solvent on oxidative cleavage of the Hajos-Parrish ketone derived hydrindene-diols 1, and Wieland-Miescher ketone derived octaline-diols 2 with Pb(OAc)₄ is presented. Various solvents were screened and compared for these domino reactions. Changing the solvent influenced the reaction rate, product distribution, and chemical yield in the octalin-diol series, while no-effect was detected in the lower homologue hydrindene-diol series. The use of a cheap, readily available chiral carboxylic acid, such as (S)-2-acetoxypropionic acid gave diastereomeric mixtures when performed in the racemic series, offering the potential of a chemical resolution. The influence of the substitution pattern on the substrate was also investigated on variously substituted derivatives of 1. Diols 38 failed to give any detectable amount of IMDA type ring closure, leading only to dialdehyde 39. For the compounds studied, alkyl or carboxyalkyl substituents on the olefin 41 and 44 led to incomplete cascade transformation due to steric interference caused by the alkyl or acyl groups. The oxidative cleavage of unsaturated diols 46 and 48 derived from monocyclic precursors, used as templates to determine whether any unsaturated 1,2-diol could be regarded as a substrate, is also described.

Full text of DOI:10.1016/j.tetasy.2004.11.097

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 995–1015
Variations of solvent and substitution pattern in Pb(OAc)4
mediated domino reactions
¨
Ozge Sesenoglu, Jose I. Candela Lena, Ertan Altınel,
´
Nicolas Birlirakis and Simeon Arseniyadis
*
´
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 17 November 2004; accepted 30 November 2004
Abstract—The effect of solvent on oxidative cleavage of the Hajos–Parrish ketone derived hydrindene–diols 1, and Wieland–Mie-
scher ketone derived octaline–diols 2 with Pb(OAc)4 is presented. Various solvents were screened and compared for these domino
reactions. Changing the solvent influenced the reaction rate, product distribution, and chemical yield in the octalin–diol series, while
no-effect was detected in the lower homologue hydrindene–diol series. The use of a cheap, readily available chiral carboxylic acid,
such as (S)-2-acetoxypropionic acid gave diastereomeric mixtures when performed in the racemic series, offering the potential of a
chemical resolution. The influence of the substitution pattern on the substrate was also investigated on variously substituted deriv-
atives of 1. Diols 38 failed to give any detectable amount of IMDA type ring closure, leading only to dialdehyde 39. For the com-
pounds studied, alkyl or carboxyalkyl substituents on the olefin 41 and 44 led to incomplete cascade transformation due to steric
interference caused by the alkyl or acyl groups. The oxidative cleavage of unsaturated diols 46 and 48 derived from monocyclic pre-
cursors, used as templates to determine whether any unsaturated 1,2-diol could be regarded as a substrate, is also described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
namely acetonitrile, benzene, trifluorotoluene, toluene,
anisole, 1,2-dichlorobenzene, acetone, methylene chlo-
ride, chloroform, DME, DMF, THF, acetic acid, and
(S)-2-acetoxypropionic acid. While focusing on the
mechanistic rationale of these interesting domino reac-
tions we briefly examined the scope and limitations of
the process through a series of selected examples.
Unsaturated bicyclic diol system 1 (2) has proven to be a
versatile archetype for domino1 transformations initi-
ated by Pb(OAc)4-mediated oxidative cleavage.2 The
effectiveness of this methodology with regard to the syn-
thesis of biologically active natural products was
demonstrated by the large-scale preparation of a
conveniently functionalized taxoid C-ring precursor,3
which in turn was elaborated into the highly oxygenated
taxoid ABC tricyclic system.4 The oxidative cleavage of
selected unsaturated bicyclic 1,2-diols, derived from ste-
roidal diols5 and carvone based octalin–diols6 proved
advantageous for the synthesis of elaborated six- and
seven-membered ring compounds. A less toxic version of
this process, using only 1 equiv of Pb(OAc)4, was the
two-reagent consecutive7 hetero-domino reaction initi-
ated by iodobenzene diacetate (oxidative/pericyclic
transformation), and completed by Pb(OAc)4 (ring
expansion) all in one pot.8 Exploring the solvent effect
on the above mentioned transformations, we examined
a number of solvents compatible with the reagent used,
To explain the formation of the products, a series of
transformations in a row was proposed (Scheme 1)
involving the oxidative cleavage leading to internally
linked hetero-diene–hetero-dienophiles 3 or 4, subse-
quent IMDA furnishing the half-cascade intermediates
5 or 6, and finally an oxyplumbation/deplumbation/ring
expansion sequence (i, ii, iii) giving rise to either 7,
whose structure was secured by X-ray analysis or 8.
The particularly significant role, which Pb(OAc)4 plays,
as a multipurpose reagent, at all stages of these one-pot
multistage transformations deserves attention. The use
of other oxidants invariably resulted in either an inter-
rupted domino process or simple allylic oxidation.9
The structural changes occurring during the conversion
of 1 to 7 and 2 to 8 have been corroborated by a
computational study where the thermodynamic features
for the proposed mechanistic rationale supported the
*
Corresponding author. Fax: +33 1 69 82 30 29; e-mail: simeon.
arseniyadis@icsn.cnrs-gif.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.097

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
996
OtBu
OtBu
OtBu
OtBu
4+2
Pb(OAc)4
HO
HO
PhI(OAc)2
O
O
O
O
O
O
O
n
MeCN
n
n
n
O
O
1 n=1
2 n=2
25°C
3 n=1
4 n=2
5 n=1
6 n=2
Pb(OAc)3
OAc
O
Pb
i
OAc
OtBu
OtBu
OtBu
OtBu
AcO
-Pb(OAc)2
n=1
AcO
H
-Pb(OAc)2
H
O
H
O
O
H
O
O
n=2
n
O
O
AcO
OAc
AcO
OAc
O
OAc
AcO
8
iii
ii
7
Scheme 1. Proposed mechanism for the consecutive hetero-domino reactions of 1 and 2 via oxidative cleavage/intramolecular 4 + 2 cycloaddition/
oxyplumbation/ring expansion.
experimental findings.10 Herein we report examples
showing the scope and limitations, including the ques-
tion of ring size, nature of the substituents on the bicy-
clic framework, and the more general question of
whether other than bicyclic or steroidal unsaturated
1,2-diols will undergo similar domino reactions.
respectively, were chosen to start this study because they
offered optimum opportunities to examine the process,
as the resulting domino products are fully characterized.
We first examined a number of solvents, compatible
with the reagent used. Then, we focused our attention
on a brief scope and limitation study, varying several
reaction parameters such as the substitution pattern
and the nature of the unsaturated diol.
2. Results and discussion
2.1. The solvent
The ready availability of the above cited unsaturated
diols, and various derivatives, in their enantiomerically
pure forms (both antipodes) provided incentive for anal-
ysis of the scope of this domino process. To gain insight
into the mechanistic course, it was essential to this study
that a series of other solvents and substrates be em-
ployed. The Hajos–Parrish and Wieland–Miescher
ketones derived unsaturated diol systems, 1 and 2,
To examine the solvent effect, we studied the Pb(OAc)4
mediated domino transformations in a dozen solvents
(Tables 1 and 2). The choice of solvent resulted partly
from a literature survey but equally importantly from
consideration of how the cleavage reaction would incor-
porate into the subsequent process (Scheme 1, mechanis-
tic rationale).
Table 1. Product distribution on oxidation of vicinal unsaturated diols in the hydrindene–diol series using various solvents
OtBu
OtBu
OtBu
OtBu
4+2
HO
HO
H
Pb(OAc)4
O
O
O
O
O
O
Solvent
RT
AcO
OAc
7
1
3
5
Entry
Solvent
% Yield of 3 + 5
% Yield of 7
1
MeCN
AcOH
Acetone
—
—
82
88
85
97
85
92
97
89
86
84
—
—
78
2
3
—
—
4
Benzene
Toluene
5
—
—
6
Trifluorotoluene
Anisole
7
—
—
8
1,2-Dichlorobenzene
CHCl3
CH2Cl2
9
—
—
10
11
12
13
THF
DMF
DME
3 ꢀ 5 only
3 ꢀ 5 only
—
Conditions: 2.4 equiv of Pb(OAc)4, solvent (5 mL/mmol) at room temperature for 20 h.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
997
Table 2. Product distribution on oxidation of vicinal unsaturated diols in the octaline–diol series using various solvents
OtBu
OtBu
OtBu
OtBu
AcO
HO
HO
H
Pb(OAc)4
O
O
O
O
O
O
Solvent
RT
AcO
O
2
6
8
9
Entry
Solvent
Time (h)
Yield (%)
6
8
9
1
MeCN
AcOH
48
15
45
78
78
78
29
50
50
45
48
24
48
25
5
60
68
9
<5
11
5
2
3
Acetone
Benzene
Toluene
64
63
68
68
57
66
40
30
98
40
55
4
24
10
12
11
12
30
31
—
—
3
12
—
—
5
5
6
Trifluorotoluene
Anisol
7
8
1,2-Dichlorobenzene
CHCl3
CH2Cl2
22
10
10
—
—
—
9
10
11
12
13
THF
DMF
DME
Conditions: 2.4 equiv of Pb(OAc)4, solvent (5 mL/mmol) at room temperature.
2.1.1. Solvent variations in the Hajos–Parrish series. In
the hydrindene–diol series 1, the initially formed cyclic
ene–acetal 5 (the half-cascade intermediate) was not iso-
lable in most cases but observed by NMR (in equilib-
rium with the ring opened dialdehyde 3). The
equilibrium mixture underwent oxymetalation and sub-
sequent ring opening upon addition of a second equiva-
lent of Pb(OAc)4, to give the ring-enlarged compound 7.
It is yet unclear whether oxyplumbation/ring-expansion/
acetoxylation occur simultaneously11 through the postu-
lated intermediate i (with intramolecular assistance to
ring expansion) or in a stepwise manner via ii (Scheme
1).
(85%), TFT (92%), CH2Cl2 (84%), anisol (97%), chloro-
form (86%), acetone (85%), but less so in THF or DMF.
Utilization of an excess of Pb(OAc)4 was beneficial to the
process. The use of as much as 5 equiv of the oxidant
rather than the theoretical 2 equiv did not increase the
yield, although shortened significantly the reaction time
(the reaction was completed in less than 5 h). The solvent
profile study in hydrindene–diol series revealed that a
wide range of solvents can be employed with no evidence
of significant alteration in the product composition.
2.1.2. Solvent variations in the Wieland–Miescher ser-
ies. The effect of solvent was then investigated in the
reaction of 2 (octalin–diol series) with Pb(OAc)4. The
choice of solvent was found to be important in these ser-
ies where reaction rates varied depending upon the nat-
ure of the solvent used. A brief study of the reaction
conditions with Pb(OAc)4 established that, acetic acid
is the most effective solvent. Unsurprisingly, we have a
faster cascade in acetic acid than in benzene. While most
of the domino reactions took approximately 50 h to
complete in MeCN, PhH, PhMe, CHCl3, CH2Cl2 it only
required 15 h to 2 to be converted into ring-expanded 8,
cyclic ene–acetal 6, and the corresponding lactone 9. The
ring-expanded fused bicycle 8, where a seven-membered
ring is fused to an a,a0-functionalized tetrahydropyran
ring, was not always the major component of the reac-
tion crude although the half-cascade intermediate 6
can be cleanly recycled to yield slightly higher yields of
8, compared to the yields obtained via the unsaturated
diols 2. Changing to DME, DMF, or THF as solvent
was ineffective in promoting the ring expansion step of
the domino process. The reaction sequence can be mon-
itored by TLC with all intermediates possessing distinct
Rf values. The results of solvent effect on the yields, reac-
tion time and on product distribution in the octaline–
diol series are summarized in Table 2.
Changing the solvent in the hydrindene–diol series
showed only marginal effects on the reaction rate and
chemical yield, while in two solvents (entries 11 and 12)
the process was interrupted in the half-cascade stage.
For the solvents listed in entries 1–10 (Table 1), the
half-cascade intermediate 5 was obtained in equilibrium
with its open counterpart 3 if only 1 equiv of Pb(OAc)4
was employed. Upon addition of one more equivalent,
even after long-time conservation of the equilibrium mix-
ture in solution, the process was completed with the for-
mation of 7. As can be seen from Table 1, this domino
reaction works well not only in acetonitrile (82% yield,
95% average yield per transformation) but also in many
other solvents. The optimal conditions employed
2.4 equiv of commercial Pb(OAc)4 (used as supplied
commercially, contains acetic acid in ca. 5–10%), room
temperature stirring in various solvents. High isolated
yields (>82%) of full-cascade product 7 are obtained in
entries 1–10 at room temperature with reaction times
of 12–15 h, whatever the solvent is. With optimum con-
ditions established, the oxidative cleavage of unsaturated
1,2-diols 1 was examined and results are given in Table 1.
The reaction works very well in benzene (97%), toluene

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
998
In these series, the rate increases dramatically with car-
boxylic solvents (vide infra) and also with increased
amounts of the oxidant. The best isolated yields of
ring-enlarged product 8 are obtained in carboxylic sol-
vents at room temperature with reaction times of 12–
15 h. When the reaction was attempted at reflux, exten-
sive degradation was observed.
one-pot transformation, the yield is remarkably high
(the only loss appeared to be due to the work-up condi-
tions). The way we proceeded is different from the one
used in the literature. Our purpose was to test the syn-
thetic viability of just mixing selected carboxylic acids
with Pb(OAc)4 and the unsaturated diols, without caring
about completion of the ligand exchange or the easy
ligand equilibration. Conditions allowing for lead tetra-
benzoate formation were chosen because the latter is a
widely known reagent,17 while the tetralactate was tar-
geted for a domino process offering potential for resolu-
tion. Deuterium labeled acetic acid, the use of which led
to the exclusive formation of CD3-labeled compounds
such as 10, could help in mechanistic rationale.
2.1.3. Other carboxylic species used as solvent or co-
solvent. We elected to use a solid achiral carboxylic
acid, namely benzoic acid, to investigate (and compare
to) practical aspects of ligand exchange and a chiral-
liquid carboxylic acid to study the feasibility of a domino
process allowing for resolution. Previously12 we re-
ported preliminary details on the applicability of
Pb(OAc)4 mediated hetero-domino transformations in
chiral solvents, compatible with the reagent. Lead(IV)
acetate undergoes a rapid ligand exchange with carbox-
ylic acids and several lead(IV) carboxylates can be easily
prepared by metathesis of the acetate with the corre-
sponding acid.13 The synthesis, characterization, and
reactivity of a number of lead(IV) carboxylates have
been reported by Moloney et al. These authors found
that replacement of the acetate ligands of Pb(OAc)4 by
other carboxylic functions gives the corresponding lead
tetracarboxylates, which resist hydrolysis better than
Pb(OAc)4.14 In their elegant studies concerning the effect
of ligands on the structure and reactivity of lead(IV)
compounds, they provided a wealth of information,
which is of capital importance for the understanding
of the chemistry involving lead tetracarboxylates.15
Under Rubottomꢀs conditions, 12 can be obtained
cleanly, while just mixing the unsaturated diol 1
(1 equiv) with Pb(OAc)4 (2.4 equiv), and benzoic acid
(36 equiv) in dichloromethane (co-solvent) and stirring
under argon at room temperature, 12 remains by far
the major component (65% isolated yield) of a mixture
containing also 13 (16%) and 7 (6%), which are easily
separable by flash chromatography, while the C-2
OAc/C-4 OBz analog 14 present in small amounts (ca.
3%) could not be obtained pure. The connectivity in
1
the NMR spectrum was confirmed by H–1H COSY,
HMQC, and HMBC experiments. For 13, the broad
proton singlet at d 6.60 correlated to the methine carbon
resonating at d 92.5 and was assigned H-2. This proton
1
signal showed H–1H COSY coupling to the broad sin-
glet at d 3.21, which correlated to the methine carbon at
d 37.6 and was assigned H-3. Long-range hetero-nuclear
coupling observed in the HMBC spectrum confirmed
the location of the OBz substituent at C-2 and the acet-
oxy substituent at C-4. Thus, proton H-2 showed diag-
nostic 3J-HMBC correlations to the C-4 quaternary
carbon at d 105.1 and to the benzoate carbonyl carbon
at d 166.0. Stereochemical assignments for 13 were
based on our previous observations (Scheme 2).18
(S)-2-Acetoxypropionic acid was found to be an optimal
solvent for this process as it is liquid, it boils much high-
er than acetic acid and it is easy to prepare on a large
scale from commercially available inexpensive lactic
acid. We found that enantiomerically pure 1 underwent
domino transformations when treated with 2.4 equiv of
Pb(OAc)4 in (S)-2-acetoxypropionic acid16 under re-
duced pressure, in less than 10 h at room temperature,
to give 11 in 87% isolated yield. Taking into account
the high level of molecular complexity attained in a
As part of the efforts to arrive at the optimal set of reac-
tion parameters and choice of appropriate precursors,
OtBu
OtBu
OtBu
HO
HO
H
a
b
H
O
O
O
O
O
O
O
O
D3C
O
O
O
1
10
O
AcO
AcO
11
CD3
c
OtBu
H
OtBu
OtBu
H
9
7
6
10
2
8
3
H
5
O
O
O
O
4
O
O
O
O
O
O
Ph
O
O
O
Ph
O
O
O
O
O
12
13
14
Ph
Ph
Scheme 2. Reagents and conditions: (a) Pb(OAc)4, (S)-2-acetoxypropionic acid, 25 ꢁC; (b) Pb(OAc)4, CD3COOD, 25 ꢁC; (c) PhCO2H-DCM, 25 ꢁC.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
999
we undertook a spectroscopic study to monitor the for-
mation of chiral lead tetracarboxylates. However, our
efforts to fully characterize Pb(OCOCH(OAc)CH3)4, re-
mained fruitless as we did not succeed in getting mole-
cular ions whatever the ionization technique used (EI, CI,
FAB, ESI spectra). Instead, we repeatedly obtained ions
corresponding to m/z Pb(OCOCH(OAc)CH3)3 as the
highest lead containing mass fragment, indicating either
that complete metathesis did not occur (in that case we
should be dealing with the M–OAc peak), or impossibil-
ity of getting molecular ion. In some cases, as for exam-
ple, in the progression of transient organolead
intermediate i (Scheme 1), mechanisms may be drawn
formally involving either in situ metathesis or direct car-
boxylate attack from the solvent and considerable work
may be needed to establish the correct mechanism.
of OBz, which confirmed the location of this substituent
at C-2. The identification of the H-2 proton (d 6.67) was
secured from a COSY experiment from the coupling of
H-2 with H-1. Complementary long-range hetero-nucle-
ar couplings between H-4 proton (d 6.46) and OAc-car-
bonyl carbon at d 168.9, as well as H-4/C-6 carbonyl
carbon at d 209.0 confirmed the regiochemical assign-
ment for 18 locating the OBz group at C-2 and OAc
group at C-4, as depicted in Scheme 3. Experimental evi-
dence favoring the structure of 19 came again from diag-
nostic long-range hetero-nuclear couplings observed in
the HMBC spectrum. H-2 (d 6.48) and H-4 (d 6.60) dis-
3
play J-HMBC correlation to the carbonyl carbons res-
onating at d 164.6 and 169.4, assigned to the carbonyls
of OAc and OBz groups, respectively. The proton dou-
blet H-4 also displayed a 3J-HMBC correlation to the C-
6 carbonyl group at d 209.3. Further evidence for the
location of the acetate carbonyl group was obtained
We next carried out the ligand exchange experiments
using benzoic acid as well as (S)-2-acetoxypropionic acid
in the octalin–diol series. Under Rubottomꢀs conditions,
17 can be obtained cleanly upon treatment with freshly
prepared Pb(OBz)4, along with half-cascade 6 and lac-
tone 9. Proceeding as in hydrindene–diol series, simply
mixing the unsaturated diol 2 (1 equiv) with Pb(OAc)4
(2.4 equiv), but diminishing the amount of benzoic acid
(10 equiv), in dichloromethane (co-solvent), 17 is no
more the major component (8% isolated yield) of the
crude reaction mixture. The latter contains 18 (15%)
and 19 (9%), which are easily separable by flash chroma-
tography, along with 8 (12%) and 9 (28%). The results
clearly show that simply mixing the ingredients when
using a nonliquid carboxylic acid, which clearly needs
a co-solvent, could not be a method of choice for such
endeavors. In common with the above products, the
gross structures of 18 and 19, as well as the stereochem-
istry, was proven in the following manner. Firstly,
1H–1H, 1H–13C correlation spectra allowed a definite
assignment of the respective resonances due to the
a,a0-functionalized tetrahydropyran part of the mole-
cule. The structure of 18 was apparent from long-range
hetero-nuclear coupling observed in the HMBC spec-
trum between H-2 and the carbonyl carbon at d 164.7
2
from the J-HMBC correlation with the methyl protons
resonating at d 2.14.
In the enantiomerically pure octalin–diol series, pro-
ceeding as in the lower homologue, bis-lactyloxy acetal
16 and lactone 9 were obtained in 70% and 11% yields,
respectively. It was interesting to observe that the use of
(S)-2-acetoxypropionic acid as solvent gave rise to a dra-
matic acceleration in these series, furnishing a high iso-
lated yield of 16 after less than 3 h stirring at room
temperature. It should be reminded that using acetoni-
trile, toluene or benzene as solvent the corresponding
bis-acetoxy acetal 8 required 50 h of stirring at room
temperature for completion.
When performed in the racemic series, the use of a chiral
carboxylic acid as solvent gives diastereomeric mixtures,
offering the possibility for a resolution. By far the most
promising application of these domino reactions would
have been the rapid synthesis of complex chiral mole-
cules using inexpensive chiral solvents. It was then of
interest to investigate the applicability of this
approach for the synthesis of chiral nonracemic cyclo-
heptane derivatives using in situ generated chiral lead
OtBu
H
OtBu
H
OtBu
OAc
D3C
O
HO
HO
O
O
a
b
O
O
O
+
9
+
O
O
6
+
9
2
D3C
O
O
O
O
15
16
c
AcO
O
OtBu
H
OtBu
OtBu
H
O
Ph
Ph
O
10
9
1
4
10a
2
+
9
+
8
8
H
+
+
5
O
O
O
O
O
O
O
O
7
6
Ph
O
O
Ph
O
O
O
O
18
19
O
17
Scheme 3. Reagents and conditions: (a) Pb(OAc)4–(S)-2-acetoxypropionic acid, 25 ꢁC; (b) Pb(OAc)4–CD3CO2D, MeCN, 25 ꢁC; (c) Pb(OAc)4–
PhCO2H–CH2Cl2, 25 ꢁC.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1000
OtBu
OAc
OtBu
H
OAc
O
O
10
9
OtBu
O
O
1
10a
2
8
H
5
HO
HO
O
O
7
4
6
O
O
a
+
O
O
O
O
[ ]-2
16
d-ent-16
AcO
AcO
d
b, c
OtBu
OtBu
O
O
7
HO
HO
OtBu
6
H
OtBu
H
H
1
H
HO
8
2
4
+
+
5
4
9
6
3
O
O
O
O
20
OH
22
21
23
Scheme 4. Reagents and conditions: (a) Pb(OAc)4, (S)-2-acetoxypropionic acid, 25 ꢁC; (b) LiAlH4, THF, reflux; (c) acetone, H+; (d) K2CO3, MeOH–
H2O, 25 ꢁC.
carboxylates, in a chiral carboxylate rich medium. This
would be of great synthetic use, especially for the
Wieland–Miescher ketone derived diols of type 2, as
the enantiomeric excess obtained via the proline-
catalyzed Robinson annulation remains modest (ca.
63%) and tedious recrystallization processes are required
for further enrichment.19
recrystallization, when performed in the racemic series.
So far, these promising results have a shortcoming: only
very few cases proved synthetically interesting, allowing
for diastereomeric separation via recrystallization. In
most cases investigated, chromatographic separation is
required, and this can be often tedious.
An exchange mechanism that does involve transesterifi-
cation on stirring 7 or 8 with deuterated acetic acid or
with (S)-2-acetoxypropionic acid in the presence of
Pb(OAc)4 as Lewis acid is ruled out by experiments per-
formed on 8. The latter was stirred in excess CD3CO2D
and in (S)-2-acetoxypropionic acid at room temperature
for 24 h after which the starting material was recovered
intact. This clearly eliminates exchange processes during
the domino reaction, as neither 15 nor 16 are observed
after prolonged treatment (several days) (Scheme 5).
Upon treatment with 2.4 equiv of Pb(OAc)4 in (S)-2-
acetoxypropionic acid and proceeding as above, racemic
diol 2 gave, following chromatographic separation, 16
(36%) and d-ent-16 (34%) in 70% combined isolated
yield, along with lactone 9 (8%, Scheme 4). Reduction
of 16 with LiAlH4 in THF afforded the diastereomeric
mixture of the corresponding, enantiomerically pure,
cycloheptane–triols (1:1 ratio, 91% isolated yield). Selec-
tive protection of the C-4, C-6 hydroxy groups (anhy-
drous acetone, cat. pTsOH, in CH2Cl2) afforded cis-
fused acetonide 22 along with the trans-fused isomer
23 (85% combined yield). The bicyclo[3.2.2]nonane aldol
derivatives 20 and 21 were easily obtained in one step
from the cis-fused bicyclic derivative 16, by dissolving
the latter in methanol–water (8:1) and stirring the reac-
tion mixture in the presence of K2CO3 (nearly 1:1 ratio,
87% yield).
A similar one-pot sequence was successfully employed
for the conversion of 24 into the 7-nor taxoid C-ring
precursor 25 in 67% isolated yield, but also for the con-
version of carvone derived and steroidal unsaturated
diols into 266 and 27,20 respectively (Scheme 6).
It should be noted however, that using O-acetyl man-
delic acid in various solvents failed to produce a compa-
rable yield of the corresponding ring-expanded
intermediate, the reaction being sluggish. This observa-
tion is in agreement with the statement that the nature
(S)-2-Acetoxypropionic acid proved compatible with the
domino transformations; the process offers the possibil-
ity for a resolution, via chromatographic separation or
OtBu
H
OtBu
OAc
OtBu
O
O
AcO
D3C
O
a
b
H
O
O
O
O
O
O
O
D3C
O
H
O
O
AcO
O
8
15
16
AcO
Scheme 5. Reagents and conditions: (a) (S)-2-acetoxypropionic acid, Pb(OAc)4, 25 ꢁC, 24 h; (b) CD3CO2D, Pb(OAc)4, 25 ꢁC, 24 h.

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1001
OTBS
CN
AcO
HO
HO
O
a
H
H
O
O
O
O
O
O
O
O
O
O
O
H
O
O
AcO
24
O
25
O
27
AcO
AcO
26
AcO
Scheme 6. Reagents and conditions: (a) (S)-2-acetoxypropionic acid, Pb(OAc)4, 25 ꢁC, 24 h.
of ligand could influence the reactivity of the lead
carboxylate.
ing the reaction outcome.21 Side product formation and
solvent induced rate increase in the octaline–diol series is
partially due to the fused-ring size effect. By visualizing
the Chem3D output of the lowest energy conformers
(PM3), portrayed in Figure 1 (arbitrary numbering),
the effect of ring size in orbital alignment, is obvious.
That is smaller ring (Pb–C4–C5–C9 = ꢀ179ꢁ) in i, pro-
vides better orbital alignment than larger ring (Pb–C4–
C5–C10 = ꢀ147ꢁ) in ii. This can help in rationalizing,
in part, the diverging behavior of the organolead
intermediates.10
2.1.4. On the diverging behavior in the Hajos–Parrish and
Wieland–Miescher ketone series: ring size effects. The
size of the ring annulated to the ene–diol portion proved
to be an important structural change as it can be seen
that the five-membered ring system in the Hajos–Parrish
series allows for the fastest and cleanest domino trans-
formations. In brief, neither side product nor a solvent
effect was detected when started from hydrindene–diols
1. In octalin–diol 2 series, on the other hand, much
slower reaction, solvent dependence, and side product
formation (lactone) was observed. For the hydrindene
series, which are of particular interest in taxoid con-
struction, and six-membered ring manufacture in gen-
eral, only a single product was observed by high-field
NMR control of the reaction crude. A simple filtration
through a pad of silica gel can be used in these series,
while in the higher homologue, the octaline–diol series,
a flash chromatography is required for product separa-
tion. The influence of ring size in cyclization reactions
has been frequently addressed, and we briefly considered
its impact on the results presented below. In this regard,
we found that there was significant change in product
distribution when 1 and 2 were subjected to the
Pb(OAc)4-mediated domino process, the ring size affect-
Ring expansion requires alignment of C4–Pb bond with
the C9–C-5 and C10–C5 bond in transient organolead
intermediates i and ii, respectively (Fig. 1). Increasing
the size of the B-ring moiety, significantly decreases
the rate of the domino transformations and allows
for the production of a side product, the lactone, which
is totally absent in the lower homologue series.
2.2. The substitution pattern
2.2.1. Allylic substitution. Practical syntheses of enan-
tiopure taxoid subunits, which possess oxygenation at
sites appropriate for further elaboration into various
members of the major taxoid families continue to
provide challenges to the synthetic chemist. We had
3
10
3
4
5
4
9
5
Pb
Pb
Pb-C4-C5-C10 -147˚
Pb-C4-C5-C9
OtBu
-179˚
n=1
OtBu
9
5
OtBu
O
O
10
O
7
8
HO
HO
5
3
n=2
AcO
4
n
3
AcO
4
Pb(OAc)3
1 n=1
2 n=2
Pb(OAc)3
i
ii
Figure 1. The effectiveness of orbital overlap depends on the initial alignment of relevant bonds (shown in bold blue color). Hydrindene–diol derived
transient organolead intermediate i can more easily attain the required transition state, than ii.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1002
developed an attractive approach that relies on an A+C
fragment coupling.3,4 The route followed, a four-step
preparation of homochiral taxoid ABC diterpene frame-
work, represents one of the most straightforward routes
to these compounds, is operationally simple and serves
to further validate the synthetic utility of our domino
reaction. A second generation of substrates, in the Ha-
jos–Parrish diol derived series, should contain a pro-
tected a-hydroxy functionality at C-5. These molecules
were targeted for an improved taxoid A+C approach,
as we hypothesized that an additional functionalization
sequence could be inserted prior to the beginning of the
linear synthesis, and this hypothesis was tested by pre-
paring C5a-OR 33 and 35. The hoped for complex het-
ero-cycles 34 and 36 could prove a challenging synthetic
aim due to the presence of the C5a-OH group, necessary
for esterification,22 thus avoiding post-coupling opera-
tions. As a consequence, we decided to synthesize these
allylic benzyl ethers or acetate esters. The substrates 28a
and 28b used in this investigation were prepared accord-
ing to our earlier work.23 To synthesize the necessary
test reactants, we generated the allylic alcohols 30 from
the corresponding enone 28 by way of the intermediate
dienol acetate species 29 as depicted in Scheme 7.24
(21% isolated yield), it is far too inefficient to be synthet-
ically useful as the desired compound is accompanied by
a substantial loss of weight. The choice of diol 35 (and/
or 33) was dictated by the importance of compounds
like 36 (a fully functionalized enantiopure taxoid C-ring
unit) in taxane synthesis. If the yields of this domino
reaction were improved, it would offer an attractive
step-efficient approach to a fully functional taxoid
ABC-diterpene framework. Regrettably, this reaction
could not be driven to complete conversion without sig-
nificant degradation of the desired product. Allylic a-
hydroxy compound 33 did undergo cascade
transformations proceeding as above (preheated oil bath
at 100 ꢁC); however the yield (26% of 34) was substan-
tially reduced relative to 85% yield obtained upon reac-
tion of Pb(OAc)4 and diol 1. Clearly, despite the high
oxygenation degree of 34/35 their synthetic utility is
compromised by the significant yield lowering and the
dirty nature of the reaction crude, due in part to high
temperatures required for the domino transformation
to occur (Scheme 8).
For comparison purposes we have also investigated the
chemistry of the closely related diols 38 where the allylic
functionality has been switched from the C-5a to the C-
5b-position. The precursor of the b-OH containing sub-
strate 37a was obtained by means of a microbial trans-
formation, using Rhizopus arrhizus ATCC 11145.23
The fungus acts as a nearly quantitative oxidizing re-
agent (>95% isolated yields, large-scale preparations),
albeit with poor stereoselectivity (5a-OH:5b-OH,
88:12), and therefore a chromatographic separation is
needed. The C-5b hydroxy group was protected as its
tBu-ether upon treatment with isobutylene, in the pres-
ence of boron trifluoride etherate and phosphoric acid
before lithium aluminum hydride reduction, as above.
Dienol-acetates were then treated with methyltrioxorhe-
nium (MTO) as catalyst and aqueous hydrogen peroxide
as terminal oxidant to give exclusively the C5a-OH epi-
mer (taxoid numbering), and in ca. 60% yield along with
recovered starting material (ca. 36%). Complete reduc-
tion of the acetoxy–hydroxy enones with LiAlH4 in
Et2O at 0 ꢁC, afforded triols 30. Diols 33 and 35 were
prepared by selective acetonide formation and installa-
tion of the appropriate protective group. Finally, re-
moval of the acetonide protection set the stage for the
crucial domino reaction. Through a series of experi-
ments on 33 and 35, the influence of the substitution
at C5a-position was investigated. Neither the optimal
procedure (room temperature stirring under argon in
any of the solvents depicted in Table 1) nor harsh con-
ditions (prolonged reaction time, more equiv of the re-
agent) delivered the desired ring-expanded target
molecule 34 or 36. In an attempt to force the formation
of the ring-expanded, full-cascade intermediate 36, diol
35 was heated straightforwardly in a preheated oil bath
at 100 ꢁC. Although the aforementioned reaction did
provide some of the desired ring-expanded product
All efforts to induce the C-5, C-7 bis-OtBu substituted
unsaturated diol 38 to undergo a domino transforma-
tion (oxidative/pericyclic) failed to generate even a trace
of the required cycloadduct 40, necessary to complete
the process (even after prolonged heating, 90–100 ꢁC,
for 72 h). These results indicate that cyclic ene–acetal
40 is not formed or, if it is formed, unlike its C5a–
OBn and C5a–OAc counterparts, is unreactive toward
electrophilic attack of the olefin by the metal. On the
other hand, we do know that in these series, except for
OtBu
OtBu
OtBu
OtBu
HO
HO
AcO
AcO
AcO
O
O
OtBu
O
OH
a
28a
OtBu
29a
OtBu
30a
31a
HO
HO
b, c
OH
d
OtBu
OtBu
AcO
O
AcO
AcO
HO
HO
O
O
OR
33 R=Ac
35 R=Bn
OH
OH
28b
29b
30b
31b
Scheme 7. Reagents and conditions: (a) Ac2O, Py, DMAP, 100 ꢁC; (b) MTO, 30% H2O2, Py, CH2Cl2, 25 ꢁC; (c) LiAlH4, Et2O, 0 ꢁC; (d) acetone,
pTsOH, 25 ꢁC.

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1003
OtBu
OtBu
5
OtBu
OtBu
7
HO
HO
O
O
O
O
9
a
d, b
10
10
8
8
H
5
O
4
2
O
OH
OBn
OAc
31
35
32
AcO
OAc
ref.5
7
c
b
OtBu
OtBu
19
19
MOMO
HO
OtBu
7
OtBu
5
7
6
5
4
7
6
10
9
10
2
10
2
8
3
8
3
c
HO
HO
5
O
O
8
8
10
4
O
5
4
OAc
OBn
O
O
AcO
OAc
AcO
OAc
2
33
H
OAc
20
36
34
I
O
Scheme 8. Reagents and conditions: (a) Ac2O, Py, DMAP, CH2Cl2, 0 ꢁC; (b) 12% HCl–THF, 25 ꢁC; (c) Pb(OAc)4, MeCN, 100 ꢁC; (d) BnBr, NaH–
DMF.
a few exceptions, the equilibrium mixture persists and
upon longer reaction times at high temperatures Z/E
isomerization and decomposition occurs to a consider-
able extent. Insofar as a mechanistic rationale is con-
cerned, the results obtained are consistent with the
sequence of events proposed in Scheme 1. For an
organolead derived from 5a–OBn the conformation re-
quired for formation of the C4–Pb bond eclipses the
thus allowing for enal isomerization, which in turn pre-
vents the 4+2 step (Schemes 9).
For 38, intra-molecular Diels–Alder type ring closure to
form the tricyclic enol ether 40 should have a consider-
ably higher energy transition state, than ring closure to-
ward 5a–OBn with an a-substituent at C-5 (taxoid
numbering).
C6a–OBn substitution as portrayed in Figure
2
(Chem3D output). One possible reason for the failure
of diol 38 to give the desired ring-expanded product
may be due to its crowded b-face on the five-membered
ring resulting in a slow cycloaddition step toward 40,
2.2.2. Substitution at the double bond. Alongside the
work just described we were also pushing forward a
vinylically substituted model system as depicted in
Scheme 10. To evaluate the part of electronic versus
1
3
9
1
4
3
2
9
2
8
5
4
7
8
8
6
5
9
7
6
1
4
6
5
3
Pb(OAc)4
Pb(OAc)4
2
OtBu
OtBu
OtBu
1
2
8
7
1
2
Pb(OAc)4
8
7
1
2
8
7
9
5
9
5
9
5
O
O
3
O
6
O
3
O
6
O
6
4
3
4
4
OtBu
OBn
40
5
5-αOBn
Figure 2. Rationalizing the encountered difficulties and the complete interruption of the domino process: lowest energy conformers of 5, 5a–OBn,
and 40.
OtBu
OtBu
OtBu
OtBu
OtBu
HO
HO
O
AcO
O
7
6
c
a, b
8
10
O
5
O
O
O
OtBu
OtBu
OR
OtBu
OtBu
37a R=H
37b R=OtBu
38
39E
39Z
40
O
Scheme 9. Reagents and conditions: (a) isobutylene, BF3ÆEt2O, H3PO4, P2O5, ꢀ78 ꢁC; (b) LiAlH4–Et2O, 0 ꢁC; (c) Pb(OAc)4, MeCN, 100 ꢁC.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1004
OtBu
OtBu
OtBu
OtBu
OtBu
HO
HO
HO
HO
a
O
a
O
O
O
+
O
O
44
CO2Me
CO2Me
45
43
41
42
Scheme 10. Reagents and conditions: (a) Pb(OAc)4, MeCN, ꢀ25 to 25 ꢁC.
steric factors we elected to examine two additional cases,
the methyl and carbomethoxy substituted derivatives, 41
and 44, containing a donor and an acceptor substituent,
respectively, on the olefin, which could have an adverse
effect on the process. The requisite diols were prepared
from their corresponding acetoxy enones, intermediates
in our previous work,23 by lithium aluminum hydride
reduction in ether at 0 ꢁC. When the carbomethoxy
substituted 44 was subjected to domino conditions with
Pb(OAc)4 an 89% conversion to the Diels–Alder adduct
45 was observed. The failure of the latter to yield the
corresponding ꢁfull-cascadeꢀ ring-enlarged product when
exposed to an excess reagent is postulated to be a com-
bination of the steric and the electron-withdrawing ef-
fects of the carbomethoxy group.
peared that donation of electron density to the olefinic
linkage was not important, and this suggested that the
donor properties of the substituent were less significant
then its steric contribution. Both diols, 41 and 44, failed
to give any trace of ring-enlarged product when treated
with Pb(OAc)4 in any of the solvents figuring in Table 1,
including acetic acid or (S)-2-acetoxypropionic acid.
2.3. Pushing the limits: monocyclic ene–diols
To answer the question whether any unsaturated diol
can be regarded as a substrate, we decided to perform
further experiments and carry out a proper study. To
this aim, we reduced the complexity of the requisite tem-
plate, the unsaturated-1,2 diol, to a simple cyclohexene–
diol of type 4625 and 48. Their synthesis began with the
corresponding, commercially available, enones and used
the acetoxylation (Pb(OAc)4, PhH, reflux)-reduction
(LiAlH4, Et2O, 0 ꢁC) protocol.26 The limits of the
Pb(OAc)4-mediated domino transformations are illus-
trated with these two examples. In the first case, mono-
cyclic unsaturated diol 46, only the dialdehyde 47
derived from a simple oxidative cleavage is obtained.
Upon treatment with Pb(OAc)4, monocyclic unsatu-
rated diol 46 failed to yield any cyclic ene–acetal (such
as 52, Scheme 11). Instead, 46 furnished only the dialde-
hyde 47, which remained essentially unchanged even
after 60 h at 75 ꢁC in acetic acid or acetonitrile. All
efforts to induce 46 to undergo a full-cascade transform-
ation under a variety of conditions, several solvents,
excess of the reagent, and elevated temperatures, failed
to generate even a trace of 52 and hence the correspond-
When a donor substituent was situated on the olefin, the
process again stopped half the way through, on the cyc-
lic ene–acetal stage. Treatment of 41 with 2 equiv of
Pb(OAc)4 in MeCN at ꢀ25 ꢁC to rt afforded, after chro-
matography, 42 (72%) and 43 (15%), both unstable on
standing. When operating at reflux temperatures and
prolonged reaction time, workup provided extensive
decomposition products, which could not be character-
ized. The results indicate that when a methyl group is
present as opposed to a carbomethoxy group, the oxida-
tive/pericyclic transformation still proceeds smoothly.
The initially formed cycloadduct 43 was isolable and
thus characterized by NMR, although decomposed
through its opened form 42 on standing. Both 42 and
43 were unstable, while 45 was stable (resonance stabi-
lized) and could be stored for long periods of time. It ap-
HO
HO
a, b
c
+
O
O
O
O
HO
HO
46a
52
46b
a, b
c
HO
HO
HO
O
H
H
O
O
O
O
HO
H
H
O
48
47
48-trans
47
c
47-anti
Me
H
H
H
H
O
O
Me
O
50
+
51
Me
Me
O
O
O
O
O
49-gauche
49
49-anti
49
Scheme 11. Reagents and conditions: (a) Pb(OAc)4, PhH, 90 ꢁC, 4 days; (b) LiAlH4–Et2O, 0 ꢁC; (c) 2.4 equiv Pb(OAc)4, MeCN, ꢀ30 to 25 ꢁC.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1005
ing ring-expanded intermediate. In the second case,
monocyclic unsaturated diol 48, containing the gem-di-
methyl group27 in the connecting chain, higher popula-
tion of reactive syn rotamers due to methyl
substituents on the chain connecting the hetero-diene
to the hetero-dienophile, enabled the transformation.28
The system also possesses ring strain to act as a driving
force and full domino transformation occurs to give 50
and 51 in 62% combined yield. No intermediate bicyclic
enol ether was isolated, although characterized by
NMR. In the absence of a gem-dimethyl group the dom-
ino reaction does not proceed and this could be attrib-
uted to the conformational freedom of the acyclic
chain of the resulting dialdehyde product 47 and its
reluctance to adopt the required conformation for fur-
ther reaction.
led to enhancements of the H-3 (H-5) (d 6.43), H-4 (d
2.12), and H-7 (d 1.78) signals. Hence these sets of pro-
tons must lie on the same face of the molecule confirm-
ing the location and the stereochemistry of the 3 a-(5a)-
acetoxy group. The minor isomer was assigned as 51 on
the basis of diagnostic NOEs for the protons attached
to C-3 and C-5 observed upon irradiation of the gem-
methyl-a and gem-methyl-b group signal, respectively.
Thus, transannular enhancements were observed be-
tween H-3 (d 6.49) and methyl-a for which the chemical
shift was unequivocally established at d 1.23 on the
minor dioxa-bicyclo[2.2.2]octane derivative 51. Failure
to observe an enhancement at the C-5 H (d 6.53) on
irradiation of the C-8 methyl-b (d 1.40) group provides
evidence that they are on opposite faces of the molecule,
an observation in agreement with NMR data, where in
1
the H and 13C NMR spectra, resonances for all pro-
For the unsaturated ene–diol 48, the cycloaddition is in-
deed facilitated by the increased population of the reac-
tive conformer since the anti-form could be essentially
iso-energetic to the gauche form, therefore the crucial
cyclization to the half-cascade intermediate does occur.
The higher population of reactive syn rotamers can be
verified graphically via Newman projections portrayed
in Scheme 11. The one-pot conversion of 48 to 50 and
51 is best explained by the 3D representation shown in
Figure 3.
tons and carbons were observed due to the lack of
symmetry.
A plausible mechanistic pathway to rationalize these
observations is shown in Scheme 12 and Figure 3. The
initially formed half-cascade intermediate i, the transi-
tion structures ii and iii, as well as the final products
50 and 51 were optimized using the semi-empirical
PM3 method (Chem3D drawings, Fig. 3).
As a consequence of the control originating from the
geminal methyl group on cyclic ene–acetal i, the tran-
sient organolead intermediate ii has the C6–C5 bond
in a trans coplanar arrangement to the C4–Pb bond.
The resulting geometry gives ring-expansion leading to
cation iii. Transition state representations illustrating
the relationship of these two factors (steric i ! ii,
iii ! 50, 51 and stereoelectronic ii ! iii) are depicted
in Figure 3. Thus, we assume that the gem-dimethyl
group will first favor an entire a-face attack of the
metal on i, creating the geometry, which favors ring
Domino reactions of 48 conducted in CD3CO2D also
proceeded smoothly with the deuterium labeled dioxa-
bicyclo[2.2.2]octane derivatives 50-d6 and 51-d6, ob-
tained in 66% isolated yield. The ESI mass spectrum
of 50-d6 exhibited a molecular ion at m/z 287 (M+Na)
and m/z 303 (M+K) consistent with the molecular for-
mula C12H12D6O6.
The C-3 (C-5) stereochemistry of 50 followed from
NOE experiments where irradiation of methyl (d 1.30)
6
5
1
H
3
4
i
OAc
O
O
51 Minor
H
OAc
Pb(OAc)4
OAc
H
51
3
6
H
1
O
O
4
5
H
H
OAc
OAc
iii
OAc
Pb
ii
50
Ring expanded "cation"
Transient Organolead
intermediate
50 Major
Figure 3. Stereodrawing depicting the source of control for domino transformations starting from diol 48; possible transition state structures for the
likely intermediates ii and iii.

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1006
H
H
7
H
O
Me
Me
H
O
[4+2]
O
8
O
O
O
O
O
O
1
H
O
H
4
H
H
i
3
O
5
O
Pb
O
49
O
D3C
O
O
O
OAc
AcO
HO
HO
O
O
O
CD3
50
50-d6
b
a
O
O
O
Ha
O
Hb
7
H
O
48
O
Mea
Meb
H
O
O
OAc
AcO
8
H
O
O
1
Pb
O
OAc
O
iii
4
ii
H
O
AcO
3
O
H
5
CD3
O
D3C
O
H
O
O
51-d6
51
Scheme 12. Reagents and conditions: (a) 2.4 equiv Pb(OAc)4, MeCN, ꢀ30 to 25 ꢁC; (b) 2.4 equiv Pb(OAc)4, CD3CO2D, ꢀ30 to 25 ꢁC.
expansion, then will ensure a net preference for an a-
face attack on cation iii.
range of 1H and 13C NMR data (1 and 2D experiments)
and corroborated by spatial proximity studies using
mainly the 1D NOEDIFF technique.29 For all com-
pounds investigated, multiplicities of 13C resonances
were assigned by the SEFT technique.30 Electron spray
mass spectra were obtained in instances where electron
impact and chemical ionization failed to produce mole-
cular ions. Mass spectra acquired in the positive ion
mode under electron spray ionization (ES+) using a mo-
bile phase of methanol, will be abbreviated as ESIMS
(MeOH). ꢁUsual work-upꢀ 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
under vacuum in the reaction vessel. Optical rotations
were measured in CHCl3.
3. Conclusion
A solvent profile study revealed that a wide range of sol-
vents can be employed. It was demonstrated that chang-
ing the solvent influenced the domino reaction rate,
product distribution and chemical yield in the Wie-
land–Miescher series while no appreciable change was
observed in the Hajos–Parrish series. The use of acetic
acid as solvent, in the octalin–diol series shortens the
time required for the ring-expanded compound from
50 h to ca. 15 h. An even more important acceleration
was observed when (S)-2-acetoxypropionic acid was
used (ca. 3 h). The domino reaction is sensitive to alter-
ations made to the substitution pattern. The process suc-
cessfully accommodated both hydrindene and octaline–
diol bicyclic ring systems, 1 and 2, respectively, while
attempts with allylically or vinylically substituted tem-
plates met with partial or total failure. This study
revealed an important limitation to the method: any
unsaturated diol cannot be regarded as a substrate.
4.2. General procedures
4.2.1. General procedure for acetoxylation of bicyclic
enones with Pb(OAc)4. A dry three-necked flask,
equipped with a Dean–Stark apparatus was charged
with 1 or 2 (12.76 mmol) and Pb(OAc)4 (22.62 g,
51.02 mmol, 4 equiv) put under vacuum, flushed with
argon before dry benzene (80 mL) was added and the
reaction mixture was heated at 90 ꢁC (oil bath tempera-
ture should not exceed 100 ꢁC) for 3 days. After cooling
a large volume of ether was added, and the reaction mix-
ture stirred for an additional hour, filtered, and the fil-
trate washed with brine and water, dried on MgSO4,
concentrated, and purified by chromatography on silica
with heptane–EtOAc 5:1 as eluent afforded 95% of the
desired bicyclic acetoxy enones as a nearly 1:1 epimeric
mixture.
4. Experimental
4.1. General
General experimental details were as previously de-
scribed.8 NMR spectra were run in CDCl3 and specific
rotations were measured in chloroform, unless otherwise
noted. 1H (600/800 MHz) and 13C NMR (150/200 MHz)
experiments were carried out on a Bruker Avance DRX-
600/800 spectrometer, equipped with triple resonance H/
C/N probehead and a three-axis pulsed field gradient
module. Gradients were used for the coherence transfer
pathway selection in HMBC and HMQC experiments.
In the latter, broadband decoupling was performed by
using GARP sequence. Experimental evidence favoring
the structures investigated came from a comprehensive
4.2.2. General procedure for reduction of acetoxy-
enones. To
a magnetically stirred suspension of
LiAlH4 (8.0 mmol, 2.0 equiv) in 50 mL of anhydrous
Et2O, cooled to nearly 0 ꢁC, was added dropwise a solu-
tion of the acetoxyenone (4.0 mmol, 1.0 equiv) in anhy-

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1007
drous ether (50 mL). After stirring at this temperature
for 30–40 min (TLC monitoring) the mixture was di-
luted with wet Et2O and treated with a small amount
of 6 N NaOH solution (for each 1 g of LiAlH4: 1 mL
of water, 1 mL of 6 N NaOH, and 3 mL more water
were added). The organic layer was worked up as usual
to give, after silica gel chromatography (eluent: hep-
tane–EtOAc), >95% of the desired diols.
J = 1.5, 2.4), 6.42 (1H, d, J = 1.3). 13C NMR
(75 MHz): 21.0 (2C, J = 19.5), 25.3, 25.6, 28.3, 28.7
(3C), 36.0, 36.5, 39.5, 72.5, 73.4, 90.6, 92.5, 104.1,
169.1, 169.5. CIMS: 380 ([M+NH4]+, 47), 317 (18),
300 (100), 297 (23), 52 (41). Anal. Calcd for
C18H22D6O7: C, 59.65; H, 6.11. Found: C, 59.84; H,
5.83.
4.3.2. Domino reactions in chiral solvent
4.2.3. General procedure for domino transformations in
the hydrindene–diol series. A dry flask was charged
with unsaturated diols 1 (603 mg, 2.42 mmol, diastereo-
meric mixture) and Pb(OAc)4 (2.57 g, 5.80 mmol,
2.4 equiv) put under vacuum, flushed with argon, and
cooled to 0 ꢁC. Solvent (10 mL) was added, the cooling
bath removed soon after and the reaction mixture was
stirred for 19 h at room temperature (TLC monitoring).
Upon completion, the reaction mixture was diluted with
Et2O or EtOAc, filtered through a path of Celite and sil-
ica gel, and flash chromatographed using heptane as elu-
ent, to remove most of the solvent, then heptane–Et2O,
1:1 as eluent to afford pure 7.
4.3.2.1. (20S)-Acetoxy-propionic acid 3-[(20S)-acetoxy-
propionyloxy]-(6S)-tert-butoxy-(7S)-methyl-2,10-dioxa-
tricyclo[5.3.1.0]undec-(9S)-yl ester 11. (S)-2-Acetoxy-
propionic acid (8 mL), Pb(OAc)4 (1374 mg, 3.10 mmol),
and diol 1 (240 mg, 1.0 mmol) were stirred under vac-
uum at 25 ꢁC for 18 h (TLC monitoring). Upon comple-
tion, the reaction mixture was diluted with Et2O, washed
with water and 15% NaOH, dried over MgSO4, and
chromatographed on silica gel (heptane–EtOAc
20
D
CHCl3). IR (film): 2973, 1750, 1461, 1370, 1236, 1144,
2:1) gave 436 mg (87%) of 11: ½aꢁ ¼ ꢀ35 (c 1.76,
1103, 989 cmꢀ1 1H NMR (600 MHz): 1.20 (9H, s),
.
1.30 (3H, s), 1.54 (3H, d, J = 7.0), 1.56 (3H, d,
J = 8.0), 1.61 (1H, dd, J = 1.2, 14.2), 1.68–1.73 (1H,
m), 1.75 (1H, dd, J = 2.6, 14.2), 1.86–1.93 (1H, m),
2.13 (3H, s), 2.14 (3H, s), 2.16–2.25 (2H, m), 2.69 (1H,
s), 3.28 (1H, t, J = 2.4), 5.06 (1H, q, J = 7.1), 5.12 (1H,
q, J = 7.1), 5.31 (1H, br s), 6.5 (1H, s). 13C NMR
(75 MHz): 16.7, 20.6, 20.7, 25.3, 25.8, 27.8, 28.9 (3C),
36.4, 38.5, 39.7, 68.7, 69.0, 72.6, 73.7, 77.2, 91.8, 92.7,
104.8, 168.4, 170.2, 170.3 (2C). ESIMS (MeOH): 539
([MK]+, 20), 523 ([MNa]+, 100).
4.2.4. General procedure for domino transformations in
the octaline–diol series. A dry flask was charged with
unsaturated diols
2
(1.0 mmol) and Pb(OAc)4
(2.4 mmol, 2.4 equiv) vacuumed, flushed with argon,
and cooled to 0 ꢁC. Acetic acid (5 mL) was added, the
cooling bath removed soon after, and the reaction mix-
ture was stirred for 17 h at room temperature. The mix-
ture was diluted with EtOAc and washed carefully with
satd NaHCO3 solution till neutral pH and brine. The
organic layer was concentrated under reduced pressure,
dried over MgSO4, and purified through flash chroma-
tography using heptane–EtOAc as eluent affording the
ring-expanded intermediate 8 as the major component
of a mixture of three compounds. The half-cascade 6,
which can be recycled, and the lactone derivative 9.
4.3.2.2. (20S)-Acetoxy-propionic acid 9-[(20S)-acetoxy-
propionyloxy]-(7R)-methyl-2,10-dioxa-tricyclo[5.3.1.0]undec-
(3S)-yl ester 25. (S)-2-Acetoxypropionic acid (10 mL)
was added to
a mixture of hydrindene–diol 24
(270 mg, 1.60 mmol) and Pb(OAc)4 (1.78 g, 4.01 mmol).
The reaction mixture was stirred under vacuum over-
night. Dilution with ether and washing with 6 N NaOH
For other solvents, see reaction time in Table 2.
solution and brine afforded, after column chromatogra-
20
D
phy using heptane–EtOAc 3:1, 67% of 25: ½aꢁ ¼ þ6 (c
4.3. Solvent variations in the Hajos–Parrish series
1.41, CHCl3). IR (film): 2942, 1744, 1451, 1373, 1309,
1237, 1177, 1130, 1093, 1068, 1049, 1027, 976,
4.3.1. Domino reactions in labeled solvent: Trideuterium-
acetic acid (6S)-tert-butoxy-(7S)-methyl-3-trideuterium-
841 cmꢀ1 1H NMR (300 MHz): 1.29 (3H, s), 1.31–
.
1.69 (4H, m), 1.46 (3H, d, J = 7.0), 1.55 (3H, d,
J = 7.0), 1.65 (1H, d, J = 11.9), 1.73 (1H, d, J = 11.9),
1.83 (1H, dd, J = 2.7, 14.0), 1.89–1.98 (1H, m), 2.13
(3H, s), 2.14 (3H, s), 2.55 (1H, s), 5.11 (1H, q,
J = 7.1), 5.29 (1H, q, J = 7.1), 5.30–5.33 (1H, m), 6.40
(1H, s). 13C NMR (75 MHz): 16.8, 17.1, 18.9, 20.5,
20.7, 27.9, 32.0, 33.3, 38.1, 39.6, 42.6, 68.6, 68.8, 91.4,
92.2, 105.1, 169.1, 169.9, 170.3, 170.8. ESIMS (MeOH):
467 ([MK]+, 70), 451 ([MNa]+, 100).
acetoxy-2,10-dioxa-tricyclo[5.3.1.0]undec-(9S)-yl
ester
10. CD3COOD (2.5 mL) was added to an evacuated
argon flashed mixture of 1 (85 mg, 0.35 mmol, 1 equiv)
and Pb(OAc)4 (471 mg, 1.06 mmol, 3 equiv) under
argon. The reaction mixture was stirred for 18 h at room
temperature (TLC monitoring), then diluted with
EtOAc, washed with NaHCO3 and brine, dried over
MgSO4, and concentrated. Crude product was chro-
matographed on silica gel (heptane–EtOAc 3:1 to 1:1)
to give 109 mg (85%) of 10: mp: 142 ꢁC (heptane–
20
ether), ½aꢁ ¼ ꢀ14 (c 1.10, CHCl3), IR (film): 2975,
4.3.3. Domino reactions in the presence of benzoic acid in
DCM. Dichloromethane (30 mL) was added to a stir-
ring mixture of 1 (340 mg, 1.42 mmol, 1.0 equiv), LTA
(1.884 g, 4.25 mmol, 3.0 equiv), and benzoic acid
(6300 mg, 51.55 mmol, 36.3 equiv) under argon. The
reaction mixture was stirred for 26 h at room tempera-
ture (controlled by TLC monitoring), then diluted with
DCM, washed with water, brine and NaHCO3, dried
D
1737, 1464, 1446, 1372, 1322, 1308, 1277, 1250, 1229,
1187, 1171, 1142, 1126, 1099, 1078, 1044, 1025, 977,
962, 911, 850, 831 cmꢀ1 1H NMR (250 MHz): 1.21
.
(9H, s), 1.29 (3H, s), 1.62–1.77 (2H, m), 1.64 (1H, dd,
J = 1.6, 14.3), 1.77 (1H, dd, J = 2.6, 14.3), 1.89 (1H,
ddt, J = 2.3, 4.8, 14.6), 2.7 (1H, td, J = 5.0, 13.0), 3.14
(1H, d, J = 1.2), 3.29 (1H, t, J = 2.5), 5.32 (1H, dd,

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1008
over MgSO4, and concentrated. The reaction crude was
chromatographed on silica gel (heptane–EtOAc 3:1 to
1:1) to give 27 mg (6%) of 7, 437 mg (65%) of 12, and
93 mg (16%) of 13.
J = 5.8, 15.1), 2.76 (1H, d, J = 18.8), 3.28 (1H, dd,
J = 3.5, 11.4), 5.81 (1H, d, J = 5.8). 13C NMR
(62.5 MHz): 14.5, 19.4, 29.0, 29.2 (3C), 31.2, 40.3,
47.4, 47.8, 73.3, 74.3, 85.8, 100.9, 168.3. CIMS: 269
([MH]+, 95), 195 (100), 177 (27), 57 (83). HRCIMS:
calcd for C15H24O4 m/z 269.1753, found 269.1739.
4.3.3.1. Benzoic acid (9S)-benzoyloxy-(6S)-tert-but-
oxy-(7S)-methyl-2,10-dioxa-tricyclo[5.3.1.0]undec-(3R)-yl
20
D
ester 12. Mp: 195 ꢁC (heptane–ether), ½aꢁ ¼ ꢀ14 (c
4.4.1.2. Trideuterium-acetic acid (5S)-tert-butoxy-
(4aS)-methyl-9-oxo-3-trideuteriumacetoxy-decahydro-cyclo-
1.02, CHCl3), IR (film): 3067, 2972, 2664, 2547, 1720,
1692, 1602, 1586, 1452, 1368, 1323, 1295, 1234, 1228,
1222, 1189, 1144, 1110, 1091, 1071, 1047, 1025, 973,
hepta[c]pyran-(1S)-yl ester 15. Mp: 140 ꢁC (heptane–
20
ether), ½aꢁ ¼ ꢀ64 (c 0.92, CHCl3), IR (film): 2973,
D
2931, 1757, 1714, 1461, 1398, 1363, 1342, 1236, 1173,
1
919, 711 cmꢀ1. H NMR (600 MHz): 1.25 (9H, s), 1.41
(3H, s), 1.75–1.83 (3H, m), 1.87 (1H, dd, J = 2.7,
14.1), 2.00 (1H, ddt, J = 2.2, 4.8, 13.8), 2.90 (1H, dt,
J = 4.8, 13.3), 3.36 (1H, t, J = 2.5), 3.50 (1H, s), 5.45
(1H, t, J = 1.6), 6.70 (1H, d, J = 0.9), 6.89 (2H, t,
J = 7.7), 7.28 (3H, m), 7.46 (1H, t, J = 7.4), 7.60 (2H,
d, J = 7.7), 7.99 (2H, d, J = 7.7). 13C NMR
(150 MHz): 25.2, 25.5, 28.2, 28.6 (3C), 36.2, 37.2, 39.6,
72.5, 73.2, 91.8, 92.4, 104.9, 127.3, 127.8, 128.1, 128.6,
129.2, 129.5, 129.7, 130.9, 132.4, 133.3, 164.6, 165.7,
169.7, 171.2. CIMS: 498 ([M+NH4]+, 41), 359 (100).
Anal. Calcd for C28H32O7: C, 69.98; H, 6.71. Found:
C, 70.11; H, 6.71.
1110, 1068, 997, 955, 913, 737 cmꢀ1 1H NMR
.
(300 MHz): 1.15 (9H, s), 1.65 (3H, s), 1.50–2.14 (6H,
m), 2.42–2.55 (2H, m), 2.93 (1H, d, J = 3.3), 3.06 (1H,
d, J = 8.7), 6.34 (1H, d, J = 3.4), 6.39 (1H, dd, J = 2.0,
3.7). 13C NMR (75 MHz): 19.7 (2C, J = 40.2), 20.3,
22.4, 28.5 (3C), 30.4, 35.0, 37.2, 45.2, 53.6, 73.5, 79.2,
88.2, 91.9, 168.5, 168.7, 208.6. CIMS: 394 ([M+NH4]+,
100), 331 (18), 314 (36), 118 (13), 105 (27), 88 (27). Anal.
Calcd for C19H24D6O7: C, 60.62; H, 6.43. Found: C,
60.89; H, 6.18.
4.4.2. Domino reactions in the presence of benzoic acid in
DCM. Dichloromethane (4 mL) was added to a mix-
ture of 2 (305 mg, 1.21 mmol, 1.0 equiv), LTA
4.3.3.2. Benzoic acid (3R)-acetoxy-(6S)-tert-butoxy-
(7S)-methyl-2,10-dioxa-tricyclo[5.3.1.0]undec-(9S)-yl
(1073 mg, 2.42 mmol, 2.0 equiv), and benzoic acid
(1476 mg, 12 mmol, 10 equiv) under argon. The reaction
mixture was stirred for 61 h at room temperature (TLC
monitoring), then diluted with EtOAc, washed with
water and NaHCO3, dried over MgSO4, and concen-
trated. Crude product was chromatographed on silica
gel (toluene–ether 15:1 to 4:1) to give 20 mg (12%) of
compound 8, 92 mg (28%) of lactone 9, 45 mg (8%) of
compound 17, 47 mg (9%) of compound 19, 75 mg
(15%) of compound 7.
20
D
(c 0.80, CHCl3), IR (film): 2979, 1729, 1695, 1460, 1370,
ester 13. Mp: 173–175 ꢁC (heptane–ether), ½aꢁ ¼ ꢀ13
1
1325, 1286, 1185, 1090, 1028, 910, 730 cmꢀ1. H NMR
(600 MHz): 1.22 (9H, s), 1.37 (3H, s), 1.66–1.95 (5H,
m), 1.91 (3H, s), 2.59 (1H, dt, J = 4.6, 13.1, H-5), 3.21
(1H, br s, H-3), 3.32 (1H, t, J = 2.4), 5.39 (1H, t,
J = 1.9, H-10), 6.60 (1H, br s, H-2), 7.48 (2H, t,
J = 7.7), 7.62 (1H, m), 8.13 (2H, dd, J = 1.3, 8.3). 13C
NMR (150 MHz): 22.8, 25.4, 25.8, 28.2, 28.8 (3C),
36.2, 37.6, 39.7, 72.7, 73.5, 92.5, 92.7, 104.2, 128.2,
128.3, 129.7, 129.8, 130.0, 133.6, 166.0, 169.5. CIMS:
436 ([M+NH4]+, 100), 359 (54), 297 (38), 254 (17), 105
(46). Anal. Calcd for C23H30O7: C, 66.01; H, 7.23.
Found: C, 65.77; H, 7.09.
4.4.2.1. Benzoic acid (5S)-tert-butoxy-(4aS)-methyl-
9-oxo-3-benzyloxy-decahydro-cyclohepta[c]pyran-(1S)-yl
20
D
(c 1.50, CHCl3), IR (film): 2980, 1727, 1606, 1453, 1267,
ester 17. Mp: 166–168 ꢁC (heptane–ether), ½aꢁ ¼ ꢀ21
1174, 1114, 1086, 1064, 950, 911, 736, 649 cmꢀ1 1H
.
4.4. Solvent variations in the Wieland–Miescher series
NMR (600 MHz): 1.17 (9H, s), 1.48 (3H, s), 1.60–2.10
(6H, m), 2.45–2.60 (2H, m), 3.11 (1H, d, J = 9.0), 3.16
(1H, d, J = 3.6), 6.72 (1H, d, J = 3.4), 6.75 (1H, t,
J = 4.1), 7.42 (2H, t, J = 7.5), 7.48 (2H, t, J = 7.5),
7.56 (1H, t, J = 7.5), 7.59 (1H, t, J = 7.5), 7.97 (2H, d,
J = 8.3), 8.09 (2H, d, J = 8.3). 13C NMR (150 MHz):
20.7, 22.9, 28.7 (3C), 30.6, 35.4, 37.6, 45.6, 53.7, 73.9,
80.0, 89.1, 93.3, 128.4 (4C), 128.9 (2C), 129.7 (2C),
129.8 (2C), 133.2, 133.5, 164.4, 164.7, 209.0. CIMS:
512 ([M+NH4]+, 100), 450 (40), 390 (78), 373 (86). Anal.
Calcd for C29H34O7: C, 70.43; H, 6.93. Found: C, 69.92;
H, 6.89.
4.4.1. Domino reactions in labeled solvent. CD3COOD
(5 mL) was added to mixture of 2 (241 mg, 0.95 mmol,
1 equiv) and Pb(OAc)4 (1.05 g, 2.37 mmol, 2.5 equiv)
under argon. The reaction mixture was stirred for 15 h
at room temperature (TLC monitoring), then diluted
with EtOAc, washed with NaHCO3 and water, dried
over MgSO4, and concentrated. Crude product was
chromatographed on silica gel (heptane–EtOAc 4:1 to
1:1) to give 12 mg (5%) of 6, 27.5 mg (11%) of 9, and
241 mg (68%) of 15.
4.4.1.1. (5S)-tert-Butoxy-(6R)-methyl-9,12-dioxa-tri-
cyclo[6.3.1.0]dodecan-10-one 9. ½aꢁ ¼ þ13 (c 1.38,
4.4.2.2. Benzoic acid (3S)-acetoxy-(5S)-tert-butoxy-
(4aS)-methyl-9-oxo-decahydro-cyclohepta[c]pyran-(1S)-yl
ester 19. Mp: 175–177 ꢁC (heptane–ether), ½aꢁ ¼ ꢀ47
20
D
CHCl3). IR (film): 2980, 2938, 2875, 1757, 1462, 1370,
20
D
(c 1.25, CHCl3), IR (film): 2981, 2942, 1729, 1449, 1366,
1223, 1068, 1019, 991, 962, 941, 878, 843 cmꢀ1
.
1H
NMR (600 MHz): 1.09 (3H, s), 1.19 (9H, s), 1.15–1.8
(3H, m), 1.32 (1H, ddd, J = 6.0 12.1, 16.6), 1.45 (1H,
dd, J = 15.1, 18.1), 1.79 (1H, d, J = 15.1), 1.88 (1H, br
d, J = 15.1), 2.48 (1H, d, J = 18.8), 2.63 (1H, dd,
1265, 1231, 1176, 1108, 1086, 1069, 985, 946, 712 cmꢀ1
.
1H NMR (600 MHz): 1.14 (9H, s), 1.36 (3H, s), 1.55
(1H, dd, J = 9.2, 14.0, H-1), 1.65 (1H, m), 1.76 (1H,
td, J = 4.3, 15.2), 1.85 (1H, d, J = 14.0, H-1), 1.96 (1H,

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1009
dd, J = 4.3, 14.0), 2.04 (1H, m), 2.14 (3H, s), 2.49 (1H,
m), 2.51 (1H, dd, J = 6.50, 10.6), 3.08 (1H, d, J = 3.5,
H-5), 3.08 (1H, d, J = 10.1, H-10), 6.48 (1H, dd,
J = 1.7, 4.1, H-2), 6.60 (1H, d, J = 3.5, H-4), 7.42 (1H,
t, J = 7.8), 7.48 (1H, t, J = 7.8), 7.59 (1H, dt, J = 7.8,
8.0), 7.98 (1H, d, J = 8.0), 8.12 (1H, d, J = 8.0). 13C
NMR (150 MHz): 20.6, 21.2, 22.8, 28.8 (3C), 30.7,
35.3, 37.7, 45.5, 54.0, 73.9, 79.8, 89.1, 92.6, 128.4 (2C),
129.0, 129.8, 130.1, 133.5, 164.6, 169.4, 209.3. CIMS:
450 ([M+NH4]+, 100), 390 (8), 373 (19), 328 (98), 311
(31), 105 (53). Anal. Calcd for C24H32O7: C, 66.65; H,
7.46. Found: C, 66.58; H 7.41.
9b}: Me-10a, H-5, H-9a (NOE gem). 13C NMR
(75 MHz): 16.4 (MeCH), 16.7 (MeCH), 20.1 (Me-10a),
20.5 (CH3CO), 20.6 (CH3CO), 22.9 (C-8), 28.7 (tBu),
30.5 (C-9), 35.0 (C-1), 37.6 (Cq-10a), 45.5 (C-7), 53.2
(C-5), 68.3 (C H), 68.4 (C H), 73.9 (Cq–tBu), 80.0 (C-
*
*
10), 88.8 (C-4), 93.1 (C-2), 168.8 (2·C, MeCO), 170.2
(MeCO), 170.4 (MeCO), 208.7 (C-6). ESIMS (MeOH):
537 ([MNa]+, 100), 553 ([MK]+, 12), 1051 ([2MNa]+,
20).
4.4.3.2. (20S)-Acetoxy-propionic acid (1R)-[(20S)-acet-
oxy-propionyloxy]-(5R)-tert-butoxy-(4aR)-methyl-9-oxo-
deca hydro-cyclohepta[c]pyran-(3R)-yl ester d-ent-
20
4.4.2.3. Benzoic acid (1S)-acetoxy-(5S)-tert-butoxy-
(4aS)-methyl-9-oxo-decahydro-cyclohepta[c]pyran-(3S)-yl
16. ½aꢁ ¼ ꢀ4 (c 1.20, CHCl3). IR (film): 2975, 2941,
D
1747, 1716, 1583, 1455, 1372, 1344, 1303, 1237, 1189,
20
D
1
ester 18. ½aꢁ ¼ ꢀ49 (c 0.75, CHCl3), IR (film): 2977,
1174, 1127, 1097, 1049, 994, 941, 736 cmꢀ1. H NMR
2936, 1757, 1722, 1606, 1455, 1396, 1367, 1269, 1228,
1187, 1170, 1112, 1089, 1065, 1048, 1025, 996, 943,
(600 MHz): 1.13 (9H, s), 1.21–2.59 (9H, m), 1.29 (3H,
s), 1.49 (3H, d, J = 6.9), 1.53 (3H, d, J = 6.9), 2.09
(3H, s), 2.13 (3H, s), 2.96 (1H, t, J = 3.4), 5.07 (1H, q,
J = 6.9), 5.18 (1H, q, J = 6.9), 6.33 (1H, d, J = 3.2),
6.47 (1H, br s). 13C NMR (75 MHz): 16.7, 16.8, 20.5
(3C), 23.1, 28.8 (3C), 30.5, 35.1, 37.4, 45.6, 53.1, 68.5
(2C), 74.0, 80.2, 89.2, 93.7, 168.6, 168.9, 170.1, 170.5,
208.7. CIMS: 532 ([M+NH4]+, 97), 460 (47), 400 (100),
383 (6).
711 cmꢀ1 1H NMR (600 MHz): 1.15 (9H, s), 1.42
.
(3H, s), 1.55–2.11 (6H, m), 2.08 (3H, s), 2.40–2.60
(2H, m), 3.01 (1H, d, J = 3.4, H-5), 3.07 (1H, d,
J = 8.9, H-10), 6.46 (1H, d, J = 3.4, H-4), 6.67 (1H,
dd, J = 1.8, 4.1, H-2), 7.44–7.49 (2H, m), 7.56–7.63
(1H, m), 8.04–8.11 (2H, m). 13C NMR (150 MHz) 20.9
(2C), 22.8, 28.8 (3C), 30.7, 35.4, 37.5, 45.5, 53.7, 73.9,
79.8, 88.6, 93.1, 128.4 (2C), 128.9, 129.7 (2C), 133.2,
164.7, 168.9, 209.0. CIMS: 450 ([M+NH4]+, 75), 390
(100), 373 (26), 328 (27), 311 (27), 105 (19).
4.5. One pot fused to bridged ring system interchange:
preparation of bicyclo[3.2.2]nonane derivatives 20 and 21
4.4.3. Domino reactions in chiral solvent. A dry flask
was charged with 700 mg (2.92 mmol) of ( )-2 and
2.7 g (6.1 mmol) of Pb(OAc)4, vacuumed, flushed with
argon and then again vacuumed for 1 h. (S)-2-Acetoxy-
propionic acid (10 mL) was then added at room temper-
ature and stirring continued for 30 min under argon and
an additional 30 min under reduced pressure (ca.
4 mmHg). The reaction mixture was then diluted with
ether (200 mL), washed with water (3 · 20 mL), 6 N
NaOH (3 · 10 mL), and water again (2 · 20 mL). The
organic layer was dried over magnesium sulfate and
the solvent evaporated under reduced pressure. The res-
idue was purified on silica gel (toluene–ether 4:1) to yield
536 mg of 16 (36%), 506 mg of d-ent-16 (34%) along with
62 mg of lactone 9 (8%).
To a stirred solution of 16 (1.0 g, 2.7 mmol) in a mixture
of methanol (40 mL) and water (5 mL), was added
potassium carbonate (2.1 g, 15 mmol). The resulting
mixture was stirred at room temperature for 15 h, di-
luted with water, and extracted with methylene chloride.
Following usual work up the residue was purified by
flash chromatography on silica gel affording 550 mg
(2.29 mmol, 85%) of a diastereomeric mixture of 20
and 21 in a nearly 1:1 ratio. Elution with ethyl ace-
tate–heptane–methanol (1:1:0.01) allowed separation;
higher eluting isomer (2S)-tert-butoxy-(9R)-a-hydroxy-
20
D
(1S)-methyl-bicyclo[3.2.2]nonane-6-one
21:
½aꢁ ¼
þ70 (c 1.12, CHCl3). IR (film): 3422, 2971, 2934, 2871,
1705, 1458, 1387, 1364, 1189, 1057, 1024, 991 cmꢀ1
.
1H NMR (400 MHz): 1.02 (3H, s, Me-1), 1.15 (9H, s,
tBu), 1.45 (1H, m, H-3aax), 1.55–1.75 (2H, m, H-4),
1.66 (1H, dd, J = 3.9, 14.7, H8a), 1.68 (1H, d,
J = 18.7, H-7b), 1.93 (1H, m, H-4), 2.06 (1H, dd,
J = 9.5, 14.7, H-8b), 2.07 (1H, m, H-4), 2.60 (1H, m,
H-5), 2.63 (1H, dd, J = 2.6, 18.7, H-7a), 3.44 (1H, t,
J = 5.7, H-2), 4.20 (1H, ddd, J = 3.9, 6.7, 9.5, H-9).
Diagnostic NOEs: {Me-1}: H-8b, H-7a, H-7b, H-2;
{H-9}: H-5, H8b; {H-2}: H-8a; {H-5}: H-9, H-4, 40;
{H-8a}: H-2. 13C NMR (75 MHz): 19.8 (CH2), 29.1
(tBu), 29.3 (Me-1), 30.4 (CH2), 37.6 (Cq-1), 41.6 (C-8),
45.2 (C-7), 54.1 (C-5), 66.6 (C-9), 73.2 (Cq–tBu), 77.6
(C-2), 214.6 (C-6). EIMS: 240 (M+Æ, 89), 184 (100), 166
(34), 57 (89). HREIMS: calcd for C14H24O3: m/z
240.1725, found: 240.1729.
4.4.3.1. (20S)-Acetoxy-propionic acid (1S)-[(20S)-acet-
oxy-propionyloxy]-(5S)-tert-butoxy-(4aS)-methyl-9-oxo-
20
D
deca hydro-cyclohepta[c]pyran-(3S)-yl ester 16. ½aꢁ
¼
ꢀ80 (c 1.70, CHCl3). IR (film): 2982, 2943, 1746, 1456,
1371, 1345, 1312, 1246, 1187, 1127, 1101, 1062, 1049,
989, 943, 910, 737 cmꢀ1 1H NMR (600 MHz): 1.14
.
(9H, s, tBu), 1.30 (3H, s, Me-10a), 1.48 (3H, d,
J = 7.2), 1.55 (3H, d, J = 6.7), 1.62 (1H, m, H-8a),
1.72 (1H, dt, J = 4.3, 14.9, H-9a), 1.84 (1H, dd,
J = 1.4, 14.8, H-1b), 1.88 (1H, dd, J = 4.2, 14.8, H-1a),
1.93 (1H, m, H-8b), 2.00 (1H, dq, J = 2.6, 14.9, H-9b),
2.08 (3H, s, MeCO), 2.11 (3H, s, MeCO), 2.42 (1H, m,
H-7), 2.54 (1H, m, H-70), 2.93 (1H, d, J = 3.4, H-5),
2.95 (1H, d, J = 8.9, H-10), 4.92 (1H, q, J = 7.2), 5.08
(1H, q, J = 7.2), 6.30 (1H, d, J = 3.4, H-4), 6.47 (1H,
dd, J = 1.4, 3.8, H-2). Diagnostic NOEs: {Me-10a}: H-
4, H-1beq, H-5, H-9bax; {H-4}: H-5, Me-10a; {H-10}:
H1aax, H-8a; {H-5}: H-4, H7b, H-9b, Me-10a; {H-
Lower eluting isomer (2S)-tert-butoxy-(9S)-b-hydroxy-
(1S)-methyl-bicyclo[3.2.2]nonane-6-one 20: mp 76–
20
D
(film): 3422, 2957, 2871, 1705, 1458, 1392, 1361, 1235,
78 ꢁC (ether–heptane). ½aꢁ ¼ þ92 (c 1.10, CHCl3). IR

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1010
1192, 1108, 1060, 1024, 991, 895 cmꢀ1
.
1H NMR
J = 6.1, 9.4, 14.4), 2.11 (1H, ddd, J = 5.6, 9.6, 15.0),
2.15 (1H, td, J = 7.9, 14.1), 2.29 (1H, q, J = 5.5), 3.47
(1H, dd, J = 1.7, 4.8), 3.70 (1H, td, J = 6.1, 10.0), 3.79
(1H, dd, J = 5.4, 10.2), 3.80 (1H, dd, J = 6.1, 11.7),
3.86 (1H, dd, J = 6.3, 11.9), 4.19 (1H, ddd, J = 5.5,
9.5, 15.0). 13C NMR (200 MHz) 16.8, 21.3, 25.2, 26.3,
29.1 (3C), 33.2, 34.6, 38.3, 38.9, 42.9, 59.4, 61.5, 71.5,
73.0, 76.1, 99.2. EIMS: m/z 314 (M+Æ, 0.5), 299 (1), 256
(3), 225 (18), 89 (80), 57 (100). Anal: calcd for
C18H34O4: C 68.75, H 10.90. Found: C 68.86, H 10.91.
(400 MHz): 1.03 (3H, s, Me-1), 1.14 (9H, s, tBu), 1.57
(1H, dd, J = 15.5, 1.5, H-8b), 1.52–1.62 (3H, m, H-4,
3), 1.75 (2H, m, H-3, 4), 1.97 (1H, d, J = 18.7, H-7b),
2.20 (1H, ddd, J = 2.4, 7.9, 15.5, H-8a), 2.57 (1H, ddd,
J = 3.1, 4.7, 4.8, H-5), 2.72 (1H, dd, J = 2.7, 18.7, H-
7a), 3.39 (1H, dd, J = 4.2, 5.1, H-2), 4.26 (1H, ddd,
J = 1.5, 3.1, 8.0, H-9). Diagnostic NOEs: {Me-1}: H-
8b, H-7a, H-7b, H-2; {H-9}: H8a; {H-2}: H-8a; {H-
5}: H-4, 40; {H-8a}: H-2, H-9. 13C NMR (75 MHz):
21.7 (CH2), 29.1 (tBu), 29.6 (Me-1), 30.5 (CH2), 36.9
(Cq-1), 41.8 (C-8), 45.1 (C-7), 54.5 (C-5), 69.2 (C-9),
73.1 (Cq–tBu), 76.6 (C-2), 215.5 (C-6). EIMS: 240
(M+Æ, 18), 184 (30), 166 (64), 57 (100). HREIMS: calcd
for C14H24O3: m/z 240.1725, found: 240.1716.
4.7. Preparation and domino reactions of the allylically
substituted substrates 33, 35, 37a
Starting from the known C-2b acetoxy enone 28a, ob-
tained as described in Ref. 23, the required C-6 hydr-
oxylated derivative 30a was synthesized in four
straightforward steps as follows. To a magnetically stir-
red solution of acetoxy enone 28a (3.145 g, 7.82 mmol)
and DMAP (521 mg, 4.26 mmol) in pyridine (12 mL),
acetic anhydride (12 mL, 108 mmol) was added at
0 ꢁC. The reaction mixture was allowed to reach room
temperature, then heated at 100 ꢁC for 27 h after what
solvent was removed under reduced pressure. Usual
work-up gave after silica gel chromatography (using
heptane–EtOAc, 8:1 to 3:1 as eluent) 2.39 g (69%) of
the desired dienol acetate 29a along with unreacted
starting material (21%).
4.6. Reduction of 16 and selective acetonide formation
To
a stirred suspension of 500 mg (13.18 mmol,
7.8 equiv) of LiAlH4 in THF (10.0 mL) a solution of
500 mg (1.35 mmol) of 16 in THF (10.0 mL) was added
at room temperature. The reaction mixture was then re-
fluxed for 30 min, cooled, quenched with 0.5 mL of
water, 0.50 mL of 15% NaOH, 1.5 mL of water, and
stirring was continued at room temperature for an addi-
tional 1 h. Filtration and concentration under reduced
pressure gave a mixture of triols. The latter without
purification, was dissolved in acetone (1.0 mL) and
methylene chloride (10.0 mL) and 20 mg of pTsOH
was added. The mixture was stirred at room tempera-
ture for 1 h, filtered through aluminum oxide with ethyl
acetate, and concentrated under reduced pressure.
Rapid filtration on silica gel with a mixture of ethyl
acetate–heptane (1:1) gave 22 and 23 (386 mg, 91%) as
a diastereomeric mixture in 1:1 ratio. The lower eluting
isomer 22 (cis acetonide) was precipitated from hexane at
room temperature. Pure sample of the higher eluting
isomer was obtained by silica gel flash chromatogra-
phy (elution with methylene chloride–methanol, 98:2).
Data for higher eluting isomer 2-[(6S)-tert-butoxy-2,2,
4.7.1. 5-(Acetoxy)-(1S)-tert-butoxy-(7aS)-methyl-2,6,7,7a-
20
D
(c 2.42, CHCl3). IR (film): 2975, 2359, 2347, 1759,
tetrahydro-1H-inden-(6R)-yl acetate 29a. ½aꢁ ¼ þ20
1739, 1366, 1239, 1197, 1124, 1087, 1016, 665 cmꢀ1
.
1H NMR (300 MHz): 1.07 (3H, s), 1.17 (9H, s), 1.53
(1H, t, J = 10.8), 2.07 (3H, s), 2.11 (3H, s), 2.24 (1H,
dd, J = 6.5, 11.7), 2.41 (2H, m), 3.84 (1H, t, J = 7.9),
5.44 (1H, t, J = 3.0), 5.81 (1H, t, J = 7.5), 6.02 (1H, d,
J = 1.7). 13C NMR (75 MHz): 16.5, 20.7, 21.0, 28.6
(3C), 39.0, 39.8, 46.1, 67.8, 72.7, 79.8, 115.1, 122.4,
142.2, 146.2, 168.6, 170.3. TOFESIMS 361 ([MK]+,
100), 345 ([MNa]+, 12).
5-trimethyl-octahydro-cyclohepta[1,3]dioxin-(5S)-yl]-etha-
20
D
nol 23 (trans acetonide): ½aꢁ ¼ þ30 (c 1.17, CHCl3), IR
(film): 3440, 2976, 2940, 2873, 1462, 1380, 1364, 1268,
1256, 1228, 1190, 1168, 1118, 1085, 1054, 1019, 874,
Starting from 28b and proceeding as above dienol ace-
tate 29b was obtained along with recovered starting
material.
738 cmꢀ1 1H NMR (800 MHz): 0.94 (3H, s), 1.18
.
(9H, s), 1.35 (3H, s), 1.40 (3H, s), 1.46–1.52 (1H, m),
1.58–1.64 (2H, m), 1.72 (1H, td, J = 7.5, 14.0), 1.75–
1.89 (5H, m), 2.02 (1H, ddd, J = 5.6, 7.8, 9.9), 3.36
(1H, dd, J = 1.2, 5.3), 3.73 (2H, dd, J = 7.9, 9.7),
3.74 (1H, dd, J = 5.6, 7.6), 3.78 (1H, dd, J = 5.6, 11.7),
3.84 (1H, ddd, J = 4.7, 7.1, 11.7). 13C NMR (200 MHz):
19.8, 21.0, 23.4, 27.9, 29.1 (3C), 29.4, 35.8, 37.4, 40.7,
45.6, 59.5, 60.5, 70.1, 73.4, 76.8, 98.2. EIMS: 314 (M+Æ,
2), 299 (20), 285 (3), 256 (10), 57 (100). HREIMS: calcd
for C18H34O4 m/z 314.2457, found 314.2462. Lower
eluting isomer 2-[(6S)-tert-butoxy-2,2,5-trimethyl-octa-
4.7.2. 5-(Acetoxy)-(1S)-tert-butoxy-(7aS)-methyl-2,6,7,7a-
20
tetrahydro-1H-inden-(6S)-yl acetate 29b. ½aꢁ ¼ ꢀ88
D
(c 3.09, CHCl3). IR (film): 2973, 2952, 2359, 2349,
1759, 1739, 1366, 1239, 1197, 1122, 1087, 1014,
668 cmꢀ1 1H NMR (300 MHz): 1.10 (3H, s), 1.17
.
(9H, s), 1.80 (1H, dd, J = 5.4, 14.6), 2.08 (3H, s), 2.14
(3H, s), 2.40–2.50 (3H, m), 3.78 (1H, t, J = 8.3), 5.53
(1H, t, J = 5.5), 5.55 (1H, t, J = 5.4), 6.14 (1H, s). 13C
NMR (75 MHz): 17.2, 20.8, 21.1, 28.6 (3C), 38.8, 39.5,
43.5, 67.1, 72.7, 81.0, 116.8, 123.9, 142.7, 145.6, 169.1,
170.4. TOFESIMS 361 ([MK]+, 100). 345 ([MNa]+,
18). HRESIMS: calcd for C18H26O5Na m/z 345.1678,
found 345.1674.
hydro-cyclohepta[1,3]dioxin-(5S)-yl]-ethanol 22 (cis ace-
20
D
tonide): mp 135–137 ꢁC (hexane), ½aꢁ ¼ þ33 (c 0.86,
CHCl3), IR (CHCl3): 3440, 2978, 2938, 2882, 1467,
1388, 1366, 1227, 1191, 1099, 1080, 1041, 1024,
983 cmꢀ1
.
1H NMR (800 MHz): 0.98 (3H, s), 1.15
Installation of the C-6 hydroxy group was then carried
out using methyltrioxorhenium developed by the Her-
mann group.31 To a stirred solution of dienol acetate
(9H, s), 1.36 (3H, s), 1.37 (3H, s), 1.44–1.49 (1H, m),
1.58–1.71 (3H, m), 1.87–1.91 (1H, m), 2.05 (1H, ddd,

¨
O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1011
29a (1.82 g, 4.09 mmol) in 4.0 mL of CH2Cl2, pyridine
(0.04 mL, 0.49 mmol), 30% H2O2 (0.63 mL, 6.14 mmol),
and MeReO3 (5.0 mg, 0.02 mmol) were added and the
reaction mixture stirred under argon at room tempera-
ture for 26 h. Upon dilution with CH2Cl2, and washings
with Na2S2O3 and brine, the organic layers were dried,
concentrated, and chromatographed (SiO2, heptane–
EtOAc, 6:1 to 1:1) to afford 1.21 g (71% yield) of the
corresponding 5a-OH derivative as a single epimer, at
this position. The allylic a- and b-hydroxy substituent
bearing acetoxy enones were described in our earlier
publications.23 Using mCPBA as the oxidant (834 mg,
2.9 mmol) in 16 mL of dioxane/phosphate buffer
pH = 8 (1:1) at 0 ꢁC, 29a (468 mg, 1.45 mmol) was oxi-
dized in 70% isolated yield. Standard LiAlH4 reduction
using the general procedure afforded the corresponding
triol, which was selectively protected as its acetonide
(acetone, methylene chloride, pTsOH) without purifica-
tion. Acetonide formation allowed for the isolation of
31a for characterization purposes.
residue (hexane–EtOAc, 1:1) gave the desired benzyl-
protected product (252 mg, 99%). 1H NMR
(300 MHz): 0.85 (3H, s), 1.14 (9H, s), 1.25 (1H, m),
1.37 (3H, s), 1.46 (3H, s), 1.85–2.12 (3H, m), 3.71
(1H, t, J = 8.7), 4.40 (2H, m), 4.49 (ABq, J = 11.9),
4.55 (1H, m), 6.00 (1H, dd, J = 2.2, 3.2), 7.31–7.35
(5H, m). 13C NMR (75 MHz): 17.9, 25.3, 28.0, 28.5
(3C), 38.1, 39.2, 45.1, 71.1, 71.3, 72.9, 75.5, 78.2,
108.7, 117.7, 127.5, 127.6 (2C), 128.3 (2C), 137.3,
138.4, 152.4.
4.9. Acetonide cleavage
The isopropylidene-benzyl alcohol (112 mg, 0.29 mmol)
thus obtained was stirred at room temperature in 4 mL
12% HCl–THF (1:1) while TLC monitored. Quenched
with a saturated NaHCO3 solution, evaporated to dry-
ness, and extracted in CH2Cl2 the reaction crude was
worked-up as usual to give quantitatively the unsatu-
rated diols 35 as an undefined diastereomeric mixture
1
(characterized as such). 35: H NMR (300 MHz): 0.91
4.7.3.
hexahydro-3aH-indeno[5,6-d][1,3]dioxol-(5S)-ol
½aꢁ ¼ þ92 (c 0.74, CHCl3). IR (CHCl3): 3400, 2975,
(7S)-tert-Butoxy-2,2,7a-trimethyl-5,6,7,7a,8,8a-
31a.
(3H, s), 1.14 (9H, s), 1.40 (1H, m), 1.76 (1H, m), 1.90–
2.06 (2H, m), 3.67 (1H, t, J = 8.8), 3.75 (2H, br
s), 4.09 (1H, m), 4.42 (2H, m), 4.53 (2H, ABq,
J = 11.9), 5.92 (1H, br s), 7.20–7.40 (5H, m). 13C
NMR (75 MHz): 18.5, 28.6 (3C), 38.1, 38.6, 45.9, 65.6,
67.4, 71.6, 72.9, 75.7, 78.1, 119.8, 127.6 (3C), 128.4
(2C), 138.1, 151.5.
20
D
2940, 1720, 1452, 1360, 1190, 1090, 1025, 889, 870,
756 cmꢀ1 1H NMR (300 MHz): 0.88 (3H, s), 1.16
.
(9H, s), 1.40 (3H, s), 1.48 (3H, s), 1.87–2.18 (5H, m),
3.71 (1H, t, J = 8.7), 4.41 (1H, dt, J = 5.7, 11.4), 4.60
(1H, m), 4.67 (1H, br s), 5.91 (1H, dd, J = 2.0, 3.2).
13C NMR (75 MHz): 18.0, 25.4, 28.1, 28.6 (3C), 39.4,
42.0, 45.5, 69.3, 71.2, 72.8, 73.0, 77.8, 108.9, 116.7,
156.4.
4.10. Oxidative cleavage
A dry flask was charged with unsaturated diols 35
(45 mg, 0.13 mmol, diastereomeric mixture) and
Pb(OAc)4 (173 mg, 0.39 mmol, 3 equiv) put under vac-
uum, flushed with argon, dry MeCN (5 mL) was added,
and the reaction mixture was immediately immersed
into a preheated oil bath (oil bath temperature
100 ꢁC). Following 24 h stirring at this temperature the
reaction was stopped by dilution with hepatane–ether,
1:1 and filtration through a pad of silica gel. Flash chro-
matography afforded 12 mg of 36 (21%) along with dial-
dehyde mixture (10 mg, 22%) and 6 mg of the
corresponding unstable half-cascade.
Starting from 28b and proceeding as above, 31b was ob-
tained pure for characterization.
4.7.4.
hexahydro-3aH-indeno[5,6-d][1,3]dioxol-(5S)-ol
(7S)-tert-Butoxy-2,2,7a-trimethyl-5,6,7,7a,8,8a-
31b.
20
D
2940, 1750, 1450, 1380, 1360, 1252, 1200, 1146, 1105,
½aꢁ ¼ þ70 (c 0.90, CHCl3). IR (CHCl3): 3450, 2975,
1
1040, 990, 904, 848 cmꢀ1. H NMR (300 MHz): 1.12
(3H, s), 1.15 (9H, s), 1.36 (3H, s), 1.44 (3H, s), 1.54
(1H, dd, J = 3.4, 14.7), 1.83 (1H, m), 2.08 (1H, m),
2.28 (1H, dd, J = 2.3, 14.7), 3.62 (1H, t, J = 8.7), 4.47
(1H, dt, J = 2.8, 6.0), 4.64 (1H, m), 4.69 (1H, m), 5.74
(1H, dd, J = 1.8, 3.6). 13C NMR (75 MHz): 19.1, 25.2,
27.5, 28.6 (3C), 38.6, 41.3, 42.4, 69.5, 72.4, 72.5, 72.9,
79.1, 108.5, 117.8, 153.2.
4.10.1. Acetic acid (9S)-acetoxy-(4S)-benzyloxy-
(6S)-tert-butoxy-(7S)-methyl-2,10-dioxa-tricyclo[5.3.1.0]-
20
D
undec-(3S)-yl ester 36. ½aꢁ ¼ þ3 (c 0.74, CHCl3). IR
(CHCl3): 3065, 3032, 2976, 2938, 2875, 1740, 1680,
1456, 1370, 1248, 1235, 1216, 1197, 1067, 1028, 996,
4.8. Benzylation
737, 705 cmꢀ1 1H NMR (400 MHz): 1.23 (9H, s),
.
1.25 (3H, s), 1.65 (1H, dd, J = 1.5, 14.2, H-9b); 1.74
(1H, dd, J = 2.6, 14.2, H-9a), 1.86 (1H, ddd, J = 2.3,
11.2, 13.8, H-6ax), 1.96 (1H, ddd, J = 3.2, 5.2, 13.8,
H-6eq), 2.10 (3H, s, MeC@O), 2.13 (3H, s, MeC@O),
3.17 (1H, d, J = 1.2, H-3), 3.33 (1H, t, J = 2.7, H-7),
4.56 (2H, ABq, J = 11.9, OCH2Bn), 4.57 (1H, dd,
J = 5.2, 11.2, H-5), 5.34 (1H, dd, J = 1.5, 2.5, H-10),
6.38 (1H, d, J = 1.2, H-2), 7.3 (5H, m). Diagnostic
NOEs: {H-2}: H-3, H-9b, Me-19; {H-10}: H-9a, H-
9a; {H-5}: H-3, H-6eq; {H-3}: H-2, H-5, Me-19;
{Me-19}: H-2, H-7, H-3, H-9b. 13C NMR (75 MHz):
21.2 (MeC@O), 22.4 (MeC@O), 25.4 (Me-19), 28.7
(3C), 32.5 (C-6), 35.9 (C-8), 36.4 (C-3), 39.5 (C-9),
Sodium hydride (60% w/w in mineral oil; 53.00 mg,
1.33 mmol) was washed twice with dry hexane under
argon atmosphere and the remainder of the hexane re-
moved via syringe and the flask put under vacuum then
filled with argon. N,N-Dimethylformamide (3.0 mL)
and isopropylidene–alcohol 31a (195 mg, 0.66 mmol)
were added. After stirring for 0.5 h the reaction mix-
ture was cooled to 0 ꢁC, BnBr (0.125 g, 0.73 mmol)
and N,N-dimethylformamide (1.0 mL) were added,
and the mixture was stirred for 20 h. Water and ether
were added, the two phases separated and the organic
phase was worked-up as usual. Chromatography of the

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1012
72.6 (OCH2Bn), 72.7 (C-5), 73.6 (C-7), 73.8 (Cq–OtBu),
90.6 (C-2), 92.3 (C-10), 103.7 (C-4), 127.7, 128.2 (2C),
128.3 (2C), 137.9 (Cq-Ph), 169.7 (2C, MeC@O). ESIMS
(MeOH): 501 ([MK]+, 28), 485 ([MNa]+, 100), 947
([2MNa]+, 14).
(1H, dd, J = 1.2, 14.4, H-9b); 1.80 (1H, dd, J = 2.6,
14.3, H-9a), 1.95 (1H, ddd, J = 2.2, 11.6, 13.7, H-6ax),
2.12 (1H, m, H-6eq), 2.08 (3H, s, MeC@O), 2.09 (3H,
s, MeC@O), 2.10 (3H, s, MeC@O), 3.44 (1H, t,
J = 2.7, H-7), 3.45 (1H, d, J = 1.1, H-3), 5.37 (1H, d,
J = 1.8, H-10), 5.86 (1H, dd, J = 5.3, 11.4, H-5), 6.40
(1H, d, J = 1.2, H-2). 13C NMR (75 MHz): 20.9
(MeC@O), 21.2 (MeC@O), 22.1 (MeC@O), 25.4 (Me-
19), 28.7 (3C), 31.6 (C-6), 35.9 (Cq-8), 36.1 (C-3), 39.5
(C-9), 68.6 (C-5), 73.2 (C-7), 74.4 (Cq–OtBu), 90.3 (C-
2), 92.4 (C-10), 102.1 (Cq-4), 169.6 (MeC@O), 169.7
(MeC@O), 170.0 (MeC@O). ESIMS (MeOH): 453
([MK]+, 42), 437 ([MNa]+, 100), 851 ([2MNa]+, 8).
HRESIMS calcd for C20H30O9Na: 437.1787, found:
437.1782.
4.11. Acetylation
Acetic anhydride (0.1 mL, 1.24 mmol) was added to a
stirring mixture of isopropylidene alcohol 31 (125 mg,
0.41 mmol) and DMAP (catalytic) in dry CH2Cl2
(5.0 mL) and pyridine (0.1 mL) under argon at 0 ꢁC.
The reaction mixture was stirred for 1 h 30 min at 0 ꢁC
(TLC monitoring), diluted with dichloromethane,
washed with saturated sodium bicarbonate then 1 N
hydrochloric acid, and worked-up as usual to give, after
silica gel flash column chromatography (eluent: hep-
tane–EtOAc 8:1), 112 mg (92%) of the corresponding
acetate 32 as a diastereomeric mixture, which was used
as such for the next step.
4.13. Preparation of 37b, the precursor of 5b-OtBu
substituted diol 38
Starting from the O–tBu-protected hydrindenone deriv-
ative 37a and proceeding as described in Ref. 23 the C-5,
C-7 bis-OtBu-protected acetoxyenone 37b was obtained
pure after a silica gel flash chromatography (eluent hep-
tane–EtOAc, 4:1) and was further reduced with lithium
aluminum hydride in ether at 0 ꢁC to afford the desired
unsaturated diol 38 as a diastereomeric mixture in 90%
combined yield.
Isopropylidene acetate 32 (105 mg, 0.31 mmol) were dis-
solved in 6 mL of a 1:1 mixture of 12% HCl–THF at
room temperature. The reaction was complete at nearly
1 h; quenched with a saturated solution of NaHCO3 and
the residue evaporated to dryness, diluted with water
and extracted in CH2Cl2. Usual work-up gave a 92%
yield of the expected unsaturated 1,2-diols 33 as a diaste-
reomeric mixture (all characteristic peaks present). 33:
IR (film): 3400, 2973, 2936, 1741, 1364, 1243, 1196,
4.13.1. (1R,3S)-Di-tert-butoxy-(3aS)-methyl-6-oxo-
2,3,3a,4,5,6-hexahydro-1H-inden-(5R)-yl acetate 37b.
20
½aꢁ ¼ þ18 (c 0.92, CHCl3). IR (CHCl3): 2982, 2930,
1098, 1056, 1039 cmꢀ1
.
1H NMR (300 MHz): 0.99
D
2356, 2337, 1750, 1689, 1463, 1367, 1237, 1192, 1138,
(3H, s), 1.13 (18H, s), 1.15 (3H, s), 1.60–2.30 (m), 2.08
(3H, s), 2.09 (3H, s), 3.02 (m), 3.59 (1H, t, J = 7.9),
3.69 (1H, t, J = 8.8), 3.92 (m), 4.19 (m), 5.54 (m). 13C
NMR (75 MHz): 18.3 (Me), 20.8 (Me), 21.0 (Me), 28.5
(tBu), 37.3 (CH2), 38.2 (CH2), 38.9 (CH2), 39.4 (CH2),
43.3 (Cq), 46.0 (Cq), 65.4 (CHO), 67.2 (CHO), 67.6
(CHO), 67.7 (CHO), 71.3 (CHO), 71.4 (CHO), 72.9
(Cq–tBu), 73.0 (Cq–tBu), 76.4 (CHO), 77.7 (CHO),
118.5 (@CH), 119.6 (@CH), 147.7 (@Cq), 148.9
(@Cq), 170.7 (MeCO), 170.9 (MeCO).
1
1095, 1067, 887 cmꢀ1. H NMR (300 MHz): 1.17 (9H,
s), 1.20 (9H, s), 1.36 (3H, s), 1.85 (2H, m), 2.17 (3H,
s), 2.30 (2H, m), 3.45 (1H, dd, J = 7.3, 10.3), 4.29 (1H,
t, J = 7.7), 5.61 (1H, dd, J = 5.4, 13.4), 5.95 (1H, s).
13C NMR (75 MHz): 16.5, 20.7, 28.5 (6C), 40.9, 41.7,
45.4, 69.1, 70.9, 73.0, 74.1, 76.7, 123.7, 169.9, 173.7,
194.2. EIMS: m/z 352 (M+, 5), 296 (100), 279 (3), 254
(5), 223 (13), 193 (20), 57 (60).
4.14. Domino reactions of vinylically substituted sub-
strates 41, 44
4.12. Oxidative cleavage
A dry flask was charged with unsaturated diols 33
(47 mg, 0.16 mmol, diastereomeric mixture) and
Pb(OAc)4 (210 mg, 0.47 mmol, 3 equiv) vacuumed,
flushed with argon, dry MeCN (5 mL) was added and
the reaction mixture was immediately immersed into a
preheated oil bath (oil bath temperature 100 ꢁC). Fol-
lowing 24 h stirring at this temperature the reaction
was stopped by dilution with hepatane–ether, 1:1 and fil-
tration through a pad of silica gel. Flash chromatogra-
phy afforded 18 mg of 34 (26%) along with the
corresponding dialdehyde mixture (8 mg) and 5 mg of
half-cascade, both unstable.
The synthesis of 41 started from the corresponding acet-
oxyenone, a known intermediate. To a stirred solution
of 41 (170 mg, 0.7 lmol) in MeCN (3 mL) was added
Pb(OAc)4 (890 mg, 2.0 mmol, 3 equiv) at ꢀ25 ꢁC. The
mixture was stirred at room temperature for 1 h, (TLC
monitoring) till no evolution of the 42:43 ratio observed.
The residue was purified by flash chromatography on
silica gel. Elution with heptane–ethyl acetate (10:1)
afforded 27 mg (15%) of 43 (unstable) along with
128 mg (72%) of dialdehyde 42 (also unstable on
standing).
4.14.1. (2Z)-2-[(3S)-tert-Butoxy-2-methyl-(2S)-(2-oxo-
20
D
1.03, CHCl3). IR (film) 2972, 2940, 2870, 1635, 1364,
4.12.1. Acetic acid (4S,9S)-diacetoxy-(6S)-tert-butoxy-
(7S)-methyl-2,10-dioxa-tricyclo[5.3.1.0]undec-(3S)-yl ester
34. ½aꢁ ¼ ꢀ21 (c 0.77, CHCl3). IR (CHCl3): 2974,
ethyl)cyclopentylidene]propanal 42. ½aꢁ ¼ þ56 (c
.
1213, 1202, 1138, 1095, 1070, 1024, 987 cmꢀ1 1H
20
D
1751, 1748, 1369, 1267, 1250, 1232, 1216, 1198, 1150,
NMR (300 MHz): 1.19 (9H, s), 1.25 (3H, s), 1.71 (3H,
s), 1.90–2.10 (2H, m), 2.40–2.70 (2H, m), 2.98 (2H, m),
3.98 (1H, dd, J = 6.0, 10.2), 9.69 (1H, s), 10.18 (1H, s).
1140, 1094, 1070, 1047, 1021, 991, 971, 952, 937 cmꢀ1
.
1H NMR (600 MHz): 1.24 (9H, s), 1.30 (3H, s), 1.71

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1013
13C NMR (75 MHz): 11.8, 22.9, 28.5 (3C), 28.6, 29.3,
47.3, 53.4, 73.5, 77.5, 130.5, 167.2, 189.5, 200.2. EIMS:
m/z 252 (M+Æ, 8), 251 (34), 237 (21), 209 (18), 197 (48),
196 (98), 195 (55), 179 (31), 178 (100), 167 (97), 154
(65), 153 (57), 151 (47), 150 (100), 123 (89), 109 (82),
106 (95), 98 (81), 90 (92). HREIMS calcd for
C15H24O3 252.1725, found 252.1708.
4.06 (1H, br s), 5.44 (1H, br s). 13C NMR (75 MHz):
23.2, 25.7, 28.5, 66.7, 68.7, 121.6, 139.3. EIMS: 128
([M]+, 16), 84 (100), 83 (51). HREIMS: calcd for
C7H12O2 m/z 128.0837, found 128.0831.
4.15.2. Slower eluting trans-4-methylcyclohex-3-ene-1,2-
diol-( )-46b. Mp: 58–60 ꢁC (heptane–ether). IR (film):
3435, 2914, 1673, 1651, 1434, 1377, 1264, 1227, 1155,
4.14.2. (4S)-tert-Butoxy-5,10-dimethyl-8,11-dioxatricy-
1062, 1029, 1007, 970, 937, 905, 875, 807 cmꢀ1 1H
.
20
clo[5.3.1.01,5]undec-9-ene 43. ½aꢁ ¼ þ44 (c 1.0,
NMR (300 MHz): 1.67 (3H, s), 1.63–2.20 (4H, m),
3.51–3.61 (1H, m), 3.96–4.31 (2H, m), 4.05 (1H, br s),
5.27 (1H, br s). 13C NMR (75 MHz): 22.7, 28.7, 29.6,
73.5 (2C), 123.1, 136.9. EIMS: 128 ([M]+, 10), 84
(100), 83 (55). Anal. Calcd for C7H12O2: C, 65.60; H,
9.44. Found: C, 65.54; H, 9.38.
D
CHCl3). IR (film) 2971, 2931, 2884, 1802, 1717, 1654,
1621, 1458, 1415, 1387, 1364, 1281, 1189, 1110, 1074,
900 cmꢀ1 1H NMR (200 MHz): 1.04 (3H, s), 1.14
.
(9H, s), 1.00–2.20 (4H, m), 1.55 (3H, br s), 1.91 (1H,
d, J = 14.0), 2.31 (1H, dd, J = 5.1, 14.0), 3.90 (1H, t,
J = 8.2), 5.61 (1H, d, J = 5.1), 6.04 (1H, br s). 13C
NMR (50 MHz): 13.8, 15.7, 24.8, 28.8 (3C), 32.6, 47.8,
53.5, 72.5, 78.9, 93.9, 100.7, 112.2, 135.3. EIMS: m/z
252 (M+Æ, 9), 219 (39), 167 (45), 149 (100), 57 (50).
4.16. Oxidative cleavage of unsaturated diols 46
A dry flask was charged with unsaturated diol 46
(90 mg, 0.70 mmol) and Pb(OAc)4 (342 mg, 0.77 mmol,
1.1 equiv) vacuumed, flushed with argon, and cooled
to ꢀ25 ꢁC. Acetonitrile (3.5 mL) was then added and
the reaction mixture was stirred at ꢀ30 ꢁC for 15 min.
Direct column chromatography with heptane first to re-
move the acetonitrile and then with heptane–EtOAc 1:1
afforded 72 mg, 81% of the dialdehyde 47. (2Z)-3-Meth-
ylhex-2-enedial 47: IR (film): 2978, 2835, 2734, 1722,
1668, 1644, 1444, 1402, 1324, 1261, 1211, 1170, 1117,
Diol 44 was obtained in 69% yield from its correspond-
ing acetoxy enone by a Luche reduction (NaBH4–CeCl3,
0 ꢁC, 30 min) and used as a crude diastereomeric mix-
ture for the next operation. Oxidative cleavage using
the general procedure afforded (4S)-tert-butoxy-5-
methyl-8,11-dioxa-tricyclo[5.3.1.00,0]undec-9-ene-10-carb-
oxylic acid methyl ester 45.
20
½aꢁ ¼ þ75 (c 1.01, CHCl3). IR (film): 3021, 2976, 2953,
1
1059, 1023, 847, 734 cmꢀ1. H NMR (300 MHz): 1.99
D
2360, 1701, 1604, 1438, 1216, 1186, 1146, 1103, 1071,
(3H, d, J = 1.4), 2.74 (2H, dt, J = 0.9, 7.4), 2.91 (2H, t,
J = 7.4), 5.91 (1H, d, J = 7.7), 9.83 (1H, t, J = 0.9),
9.98 (1H, d, J = 7.7). 13C NMR (75 MHz): 24.5, 24.7,
42.0, 128.6, 161.2, 190.3, 199.9. ESIMS (MeOH): 127
([MH]+, 100).
1026 cmꢀ1 1H NMR (250 MHz): 1.04 (3H, s), 1.15
.
(9H, s), 1.60–1.90 (2H, m), 1.90 (1H, d, J = 14.3),
2.00–2.20 (1H, m), 2.37 (1H, dd, J = 5.0, 14.3), 2.85–
3.05 (1H, m), 3.68 (3H, s), 3.85 (1H, t, J = 8.0), 5.72
(1H, d, J = 5.0), 7.44 (1H, s); 13C NMR (62.5 MHz):
13.9, 25.2, 28.8 (3C), 33.0, 48.2, 50.9, 62.9, 72.5, 78.7,
93.7, 102.2, 110.0, 153.2, 165.5. EIMS: m/z 296 (M+Æ,
14), 196 (77), 154 (99), 57 (100). HREIMS: calcd for
C16H24O5 m/z 296.1624, found 296.1629.
4.17. Preparation and oxidative cleavage of unsaturated
diols 48
Starting from the commercially available 4,4-dimethyl-
cyclohex-2-enenone and proceeding as above the requi-
site diol was obtained in 95% combined yield.
The tricyclic enol ether intermediate, unlike most other
vinylically substituted analogs, is stable and easily
isolable.
4.17.1. ( )-trans 5,5-Dimethylcyclohex-3-ene-1,2-diol
48. Mp: 56–58 ꢁC (heptane–ether). IR (film): 3418,
2956, 2920, 2864, 1651, 1645, 1633, 1469, 1455, 1361,
4.15. Preparation and domino reactions of racemic
unsaturated diols 46 and 48
1
1257, 1058, 946, 876 cmꢀ1. H NMR (300 MHz): 1.03
(3H, s), 1.05 (3H, s), 1.49 (1H, t, J = 12.7), 1.74 (1H,
dd, J = 3.2, 12.7), 3.44–3.87 (2H, m), 3.72 (1H, ddd,
J = 3.2, 7.8, 12.7), 4.04 (1H, d, J = 7.8), 5.38 (1H, d,
J = 10.6), 5.42 (1H, d, J = 10.6). 13C NMR (75 MHz):
28.8, 31.0, 34.9, 43.2, 71.7, 74.3, 125.5, 139.0. EIMS:
142 ([M]+, 0.03), 124 (1.5), 109 (1), 98 (100), 86 (20),
83 (10), 55 (10), 41 (10). Anal. Calcd for C8H14O2: C,
67.57; H, 9.92. Found: C 67.24; H, 10.12.
The general procedure for acetoxylation with Pb(OAc)4
and subsequent LiAlH4 reduction of the corresponding
enones was used for the large-scale synthesis of the req-
uisite unsaturated diols 46 and 48 in 82% and 95% com-
bined yields, respectively. Given the fact that Pb(OAc)4
mediated domino transformations are insensitive to diol
stereochemistry, the starting diols [ ]-46 and [ ]-48 were
used as diastereomeric mixtures. However, we separated
the racemic cis and trans diols for characterization
purposes.
A dry flask was charged with starting diols ( )-48–trans
(123 mg, 0.87 mmol) and Pb(OAc)4 (960 mg, 2.16 mmol,
2.5 equiv), vacuumed, and flushed with argon several
times. Dry acetic acid (3 mL) was then added and the
reaction mixture was stirred at room temperature for
5 h, at which point TLC indicated complete consump-
tion of starting diols. Dilution with ether followed by
washing with saturated aqueous NaHCO3, till neutral
4.15.1. Faster eluting cis-4-methylcyclohex-3-ene-1,2-
diol-46a. IR (film): 3391, 2913, 1667, 1432, 1377,
1262, 1218, 1155, 1119, 1071, 1049, 995, 961, 902,
848 cmꢀ1 1H NMR (300 MHz): 1.69 (3H, s), 1.73–
.
2.19 (4H, m), 3.26–3.58 (2H, m), 3.67–3.82 (1H, m),

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O. Sesenoglu et al. / Tetrahedron: Asymmetry 16 (2005) 995–1015
1014
pH, and brine, drying over MgSO4, and concentration
under reduced pressure afforded 139 mg (62%) of a mix-
ture of 50 and 51. A careful silica gel flash column chro-
matography, eluent heptane–EtOAc, 3:1, allowed
separation and hence identification of pure 50: IR (film):
References
1. Tietze proposed the following definition: ꢁa domino
reaction is a process involving two or more bond-forming
transformations (usually C–C bonds), which take place
under the same reaction conditions without adding
additional reagents and catalysts, and in which the
subsequent reactions result as a consequence of the
functionality formed in the previous step.ꢀ (a) Tietze, L.
F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131;
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115; (c) Tietze, L. F.;
Modi, A. Med. Res. Rev. 2000, 20, 304; (d) Tietze, L. F.;
Haunert, F. In Stimulating Concepts in Chemistry; Shiba-
saki, M., Stoddart, J. F., Vogtle, F., Eds.; Wiley-VCH:
Weinheim, 2000; pp 39–64.
2968, 1735, 1369, 1223, 1178, 1127, 1050, 962, 872 cmꢀ1
.
1H NMR (300 MHz): 1.30 (6H, s), 1.77–1.79 (2H, m),
2.12 (1H, dd, J = 0.9, 3.2), 2.14 (6H, s), 4.98 (1H, t,
J = 2.1), 6.43 (2H, d, J = 1.7). 13C NMR (75 MHz):
21.2 (2C), 28.4 (2C), 29.0, 41.7, 41.8, 91.9 (2C), 92.9,
169.8 (2C). ESIMS: 297 ([MK]+, 5), 281 ([MNa]+,
100), 539 ([2MNa]+, 18). 51 was contaminated with
some 50 thus, it was better characterized in its deuterium
labeled form, as pure 51-d6.
2. The reaction of Pb(OAc)4 with olefins as well as the glycol
fission was originally investigated by Criegee and subse-
quently studied by several other chemists: Criegee, R. Ber.
1931, 64, 260; Criegee, R. Angew. Chem. 1958, 70, 173;
Criegee, R. In Oxidation in Organic Chemistry, Part A;
Wiberg, K. B., Ed.; Academic: New York, 1965; p 277.
3. Arseniyadis, S.; Martin Hernando, J. I.; Quilez del Moral,
J.; Rico Ferreira, M.; Birlirakis, N.; Potier, P. Tetrahedron
Lett. 1998, 39, 9011–9014; Arseniyadis, S.; Martin Her-
nando, J. I.; Quilez del Moral, J.; Yashunsky, D. V.;
Proceeding as above, 48 (152 mg, 1.07 mmol), and
Pb(OAc)4 (1185 mg, 2.67 mmol, 2.5 equiv) were stirred
at room temperature in a large excess of deuterated ace-
tic acid (10 mL) for 22.5 h. The large excess of labeled
acetic acid (high-quality standards of the commercial
solvent sold in sealed tubes for NMR studies was used)
is to ensure metathesis of the acetate by the labeled car-
boxylate, while the extra stirring time is to remove as
much as possible the left-over nonlabeled acetoxy group,
by exchange (and hence to measure the extent of ex-
change). Work-up and flash chromatography using hep-
tane–EtOAc 3:1 as eluent afforded 169 mg (60%) of 50-
d6 and 18 mg (6%) of 51-d6. The unlabeled 50 is present
as could be seen from proton, contribution from the
unlabeled counterpart at 2.15 (MeCO), from carbon,
at 21.2 (MeCO) and Electron Spray Ionization Mass
spectra, C12H18O6 at m/z 281 ([MNa]+, 12), 297
([MK]+, 5).
´
Potier, P. Synlett 1998, 1010–1012; Martın Hernando, J.
I.; Quılez del Moral, J.; Rico Ferreira, M.; Candela Lena,
´
J. I.; Arseniyadis, S. Tetrahedron: Asymmetry 1999, 10,
783–797.
´
4. Rico Ferreira, M.; Martın Hernando, J. I.; Candela-Lena,
J. I.; Birlirakis, N.; Arseniyadis, S. Synlett 2000, 113–115;
´
Martın Hernando, J. I.; Rico Ferreira, M.; Candela Lena,
J. I.; Birlirakis, N.; Arseniyadis, S. Tetrahedron: Asymme-
try 2000, 11, 951–973.
´
5. Rico Ferreira, M.; Martın Hernando, J. I.; Candela Lena,
J. I.; Quılez del Moral, J.; Arseniyadis, S. Tetrahedron:
´
Asymmetry 1999, 10, 1527–1537.
6. Sanchez Fernandez, E. M.; Candela Lena, J. I.; Altinel, E.;
Birlirakis, N.; Barrero, A.; Arseniyadis, S. Tetrahedron:
Asymmetry 2003, 14, 2277–2290.
4.17.2. 5-(Trideuteriumacetoxy)-8,8-dimethyl-2,6-dioxa-
bicyclo[2.2.2]oct-3-yl trideuteriumacetate 50-d6. IR
(film): 2966, 2875, 1725, 1638, 1447, 1368, 1278, 1229,
7. According to Tietzeꢀs classification1 the process is a
consecutive reaction, as another reagent is added after
the first transformation without isolation of the first
formed product.
1
1178, 1127, 1047, 999, 944 cmꢀ1. H NMR (600 MHz):
1.30 (6H, s, Me-gem), 1.78 (2H, d, J = 2.0, H-7), 2.12
(1H, t, J = 1.5, H-4), 5.27 (1H, t, J = 2.0, H-1), 6.43
(2H, d, J = 1.5, H-3, H-5). 13C NMR (150 MHz): 20.5
(CD3), 28.4 (Me-gem), 29.0 (Cq-8), 41.7 (C-4), 41.8 (C-
7), 91.9 (C-3, C-5), 93.0 (C-1), 169.9 (MeCO). ESIMS:
303 ([MK]+, 12), 287 ([MNa]+, 100).
8. Finet, L.; Candela Lena, J. I.; Kaoudi, T.; Birlirakis, N.;
Arseniyadis, S. Chem. Eur. J. 2003, 9, 3813–3820.
´
9. DMP: Candela Lena, J. I.; Martın Hernando, J. I.; Rico
Ferreira, M.; Altınel, E.; Arseniyadis, S. Synlett 2001,
597–600; , IBD: Candela Lena, J. I.; Altınel, E.; Birlirakis,
N.; Arseniyadis, S. Tetrahedron Lett. 2002, 43, 1409–1412;
1
51-d6: H NMR (600 MHz): 1.23 (3H, s, Me-a), 1.40
´
Mn(OAc)3: Candela Lena, J. I.; Rico Ferreira, M.; Martın
(3H, s, Me-b), 1.81 (1H, dd, J = 3.0, 13.7, H-7a), 1.87
(1H, t, J = 13.7, H-7b), 2.08–2.24 (1H, m, H-4), 5.31
(1H, br s, H-1), 6.49 (1H, d, J = 2.9, H-3), 6.53 (1H, d,
J = 2.9, H-5). 13C NMR (150 MHz): 20.5 and 20.7
(CD3), 28.0, 30.6 (Me-b), 30.7 (Me-a), 41.3 (C-7), 41.6
(C-4), 91.2 (C-5), 91.6 (C-3), 93.9 (C-1), 169.5 (MeCO),
170.2 (MeCO). ESIMS: 287 ([MNa]+, 100).
Hernando, J. I.; Altınel, E.; Arseniyadis, S. Tetrahedron
Lett. 2001, 42, 3179–3182.
10. Unaleroglu, C.; Aviyente, V.; Arseniyadis, S. J. Org.
Chem. 2002, 67, 2447–2452.
11. The absence of solvent effects in a reaction has generally
been correlated with transition states in which no net
charge develops (ex: concerted reactions).
¨
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Acknowledgements
The authors thank the Scientific and Technical Research
Council of Turkey (TUBITAK) and CNRS (France) for
¨
a grant to Ms Ozge Sesenoglu, the European Commis-
sion for a Research Training Grant to Dr J. I. Candela
Lena and Professor Jean-Yves Lallemand for his kind
interest and constant encouragements.
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