Cyclopropanation of 5-methylene galactopyranosides by dihalo-, ethoxycarbonyl-, and unsubstituted carbenes

Article abstract of DOI:10.1016/j.tet.2008.07.013

Cyclopropanation reactions of 6-deoxyhex-5-enopyranosides by methylene-zinc-iodide complex, dichlorocarbene, and rhodium ethoxycarbonyl complex addition afford optimum yields of the corresponding spirocyclopropanes. Surprisingly, a stereospecific spirocyclopropane derivative with the two halogens on the upper face of the 4-hydroxy substituent is obtained. To get more insight on the dichlorocarbene cyclopropanation process a computational study, based on DFT quantomechanic calculation was conducted.

Full text of DOI:10.1016/j.tet.2008.07.013

Tetrahedron 64 (2008) 8652–8658
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Tetrahedron
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Cyclopropanation of 5-methylene galactopyranosides by dihalo-, ethoxycarbonyl-,
and unsubstituted carbenes
*
*
`
Antonino Corsaro, Maria Assunta Chiacchio, Venerando Pistara , Antonio Rescifina , Elisa Vittorino
`
Universita degli Studi di Catania, Dipartimento di Scienze Chimiche, Viale A. Doria 6, 95125 Catania, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclopropanation reactions of 6-deoxyhex-5-enopyranosides by methylene-zinc-iodide complex, di-
chlorocarbene, and rhodium ethoxycarbonyl complex addition afford optimum yields of the corre-
sponding spirocyclopropanes. Surprisingly, a stereospecific spirocyclopropane derivative with the two
halogens on the upper face of the 4-hydroxy substituent is obtained. To get more insight on the di-
chlorocarbene cyclopropanation process a computational study, based on DFT quantomechanic calcu-
lation was conducted.
Received 31 March 2008
Received in revised form 17 June 2008
Accepted 3 July 2008
Available online 8 July 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Ketopyranose glycals
Cyclopropanation
Spirosugar
DFT calculation
1. Introduction
to the 5-methylene pyranoside was used to obtain the corre-
sponding 5-spirohalocyclopropyl adducts as diastereoisomeric
C-Glycosydenes and 5-methylene pyranosides are unsaturated
sugar derivatives with a exo-double bond near the pyranoid-ring
oxygen; the first ones, called exo-glycals, with a double bond at the
anomeric centre, have been largely studied,1 and are very useful
compounds in relation to the reduction of their double bond, since
they are precursor of hydrolytically stable C-glycosides;1 the second
ones, frequently termed as 6-deoxyhex-5-enopyranosides, are
further enol ethers with exo-glycal functionality and are also in-
teresting intermediates for the formation of a carbon–carbon
bond,2 for the well known Ferrier-II carbocyclization,3 and in other
rearrangement reactions with Lewis acid.4 Recently, the chemistry
of 5,6-unsaturated pyranosides has found interesting de-
velopments in the reduction of their double bond and functional-
izations such as oxidation to epoxides.5 However, their chain
extension by the cyclopropanation of the exo-double bond has not
been thoroughly explored, though the resulting spirocyclopropyl-
functionalized sugars are very important as synthetic building
blocks, glycosidase inhibitors, or useful scaffolds for carbohydrates
mimics.
mixtures,7 which were then reduced with lithium aluminum hy-
dride in order to afford the unsubstituted spirocyclopropanes.
Within our research on chemical valorisation of lactose,8 we
needed to prepare its 50-spirocyclopropane together with the cor-
responding derivatives of
a- and b-galactopyranoside, on the
analogy of 4,5-cyclopropanated galactopyranosides,9 with the aim
to obtain 1,5-dicarbonyl intermediates. From these latter, through
further reactions, interesting sugars derivatives such as cyclitols8a–c
or aza-sugars10 can be synthesized.
2. Results and discussion
5-Methylene galactopyranosides 1,11 2,5,12 and 3,13 were pre-
pared with good global yields starting from commercial methyl-
and methyl- -galactopyranoside, and lactose, respectively,
following our previously reported method.13
a-
b-D
These 5,6-unsaturated pyranosides were then subjected to the
cyclopropanation reaction with the Furukawa modification14 of the
Simmons–Smith15 reaction, addition of halocarbene,16 already
Indeed, very few 5-spirocyclopropyl pyranosides6 were pre-
pared directly with the Simmons–Smith cyclopropanation reaction
because their synthesis resulted arduous under the several used
variations. Therefore, the addition of dichloro- or dibromocarbene
employed for L
-threo-hex-4-enopyranosides,8d and furthermore to
the addition of methoxycarbonyl-carbene,17 with the aim at con-
firming that these methods are also applicable to methylene gal-
actopyranose derivates and establishing the stereochemical course
of the cyclopropanation reactions.
Therefore, the Furukawa cyclopropanation of 5-methylene gal-
actopyranosides 1–3 with diethyl zinc and diiodomethane, per-
formed in dry diethyl ether as a solvent and in a sealed vessel at
* Corresponding authors. Tel.: þ39 095 7385017; fax: þ39 095 580138.
`
E-mail addresses: vpistara@unict.it (V. Pistara), arescifina@unict.it (A. Rescifina).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.013

A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
8653
40 ꢀC, gave after 2 h a nearly quantitative yield of cycloadducts 4–6
(Scheme 1).
Scheme 1. (i) CH2I2, Et2Zn, dry Et2O, 40 ꢀC, 2 h.
Scheme 3. (i) EDA, dry CH2Cl2, Rh2(OAc)4, N2, rt, 5 h.
The structures of spiroadducts 4–6 were unambiguously con-
firmed on the basis of their spectral data. Particularly, their 1H and
13C NMR spectra show the characteristics signals of the two
methylenic protons of the spirocyclopropane moiety in the range
0.62–1.39 ppm, analogous to those reported in the literature7c for
the 5-spiroderivative of glucopyranose.
The dichlorocyclopropanation reactions of 1–3 were performed
in chloroform by adding 50% aqueous sodium hydroxide in the
presence of benzyltriethylammonium chloride as phase-transfer
catalyst and then allowing the mixture to react at room tempera-
ture for 5 h (Scheme 2).
15%), the stereoisomers 13 (30%) and 17 (10%) were separated from
the two crude reaction mixtures, while the residual stereoisomers
10–12 and 14–16 were obtained as pure samples by the HPLC pu-
rification in the sequence 12 (37%), 10 (12%), and 11 (14%) from 1,
and 16 (37%), 14 (12%), and 15 (14%) from 2.
The formation of the spirocyclopropane ring in adducts 10–13
and 14–17 was evident from their mono- and bi-dimensional 1H
NMR spectra, which showed the
d and J reported in Table 1 easily
attributable to the protons directly bonded to carbon atoms of the
two rings, while NOE experiments (Table 2) have allowed us to
assign their stereochemistry. 13C NMR confirmed structural
assignments.
3. Computational studies
To get more insight on the dichlorocarbene cyclopropanation
process in which an unexpected stereospecificity was observed, we
conduct an in silico study, employing density functional theory
(DFT) quantomechanic calculations. It is well known that in-
termolecular cyclopropanations of alkenes by carbenoid species,
such as those derived from diazoacetates, are not particularly dia-
stereoselective,19 because can be regarded as triplet species.20
Then, we have focused our attention on the process concerning the
Scheme 2. (i) CHCl3, 50% aq NaOH, BTEAC, rt, 5 h.
addition of dichlorocarbene to b-5-hexenopyranosides 2 upon the
Surprisingly, in spite of previously reported dihalocyclopropa-
nation reactions of differently protected galactose,7a the reactions
of compounds 1–3 were highly stereospecific affording exclusively
considerations that the dichlorocarbene exists undoubtedly as
a singlet21 and its reactivity is independent of the method used to
generate it.22
the corresponding spirocycloadducts 7–9; only
a single di-
After a conformational Monte Carlo analysis23 at the molecular
mechanics level and successive refinement of lower energy con-
formers, such as located, at semiempirical PM3 level of calcula-
tion,24 the two lowest energy conformers A and B of 2 were used for
high level computational studies (Fig. 1). The lower conformer A
adopts a twist conformation with the benzyl substituent in axial
position and conformer B has a boat-like conformation with the
benzyl group in an equatorial position.
astereoisomer was observed in the 1H NMR spectra of the crude
reaction mixtures.
The structures of the spirocyclopropane adducts 7–9 were
assigned on the basis of their 1H NMR spectra, which show one AB
system for the cyclopropane methylene protons in the range be-
tween 1.91 and 1.64 ppm (J¼9.0 Hz). NOE experiments easily
allowed the stereochemical assignation of these adducts, since, for
example, in the case of spiroderivative 8, a positive enhancement
(about 2.9%) was apparent on the H-6a proton (at 1.82 ppm) by
irradiating the H-4 proton (at 4.46 ppm) and vice versa, whereas
the H-6b proton, which is near the pyranoside oxygen atom, res-
onates at upper fields (1.64 ppm) and does not show any appre-
ciable NOE effect.
Geometry optimizations of the critical points (reactants, tran-
sition structures, and products) were studied at the DFT level,
Table 1
Selected 1H NMR chemical shifts (ppm) and coupling constants (Hz) of spi-
rocyclopropanecarboxylates 10–17 (CDCl3, 500 MHz)
Finally, we investigated the cyclopropanation reactions of
a- 1
H-6a
H-6b
H-7
Jcis
Jtrans
Jgem
and -5-hexenopyranosides 2 with ethyl diazoacetate in dry
b
10
11
12
13
14
15
16
17
1.12
1.24
1.31
1.40
1.08
1.66
1.51
1.60
1.46
1.66
2.03
2.07
1.86
1.97
2.21
1.88
1.84
1.88
7.0
7.0
7.0
7.5
7.0
8.0
6.5
8.0
9.0
9.0
9.0
9.5
9.0
9.0
8.5
9.2
6.0
5.5
6.0
6.5
6.0
6.5
6.0
6.5
dichloromethane in the presence of a large excess of rhodium ac-
etate (Scheme 3).
From 1, a mixture of the four spirocyclopropanecarboxylate
stereoisomers 10–13, in the 1.0:1.1:0.5:0.55 ratio,18 respectively,
was obtained with a 82% global yield; while stereoisomers 14–17 in
the ratio 1.2:0.8:2.0:1.8,18 respectively, were obtained with a global
yield of 89% from 2. By flash chromatography (silica gel, Cy/AcOEt
1.66
1.67
1.39
1.89

8654
A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
Table 2
NOE experiments: positive enhancements on irradiation of H-4, H-6a, H-6b, and/or
H-7 protons of spirocyclopropanecarboxylates 10–17
Irradiated H (
d
)
NOE with (%)
10
11
12
13
14
15
16
17
H-6a (1.12)
H-6b (1.66)
H-4 (3.92)
H-7 (2.07)
H-4 (3.91)
H-7 (1.86)
H-4 (4.20)
H-7 (1.97)
H-6b (1.66)
H-6a (1.08)
H-6b (1.66)
H-7 (1.88)
H-6a (1.39)
H-4 (3.84)
H-6a,b (1.67)
H-7 (1.88)
H-7 (6.1), H-4 (7.0)
OCH3 (4.4)
H-6b (4.25)
H-1 (4.1), H-6a (3.4)
H-7 (8.8)
H-4 (8.2), H-6a (3.5)
H-6b (3.1)
OCH3 (5.8), H-6a (3.3)
H-1 (4.5)
H-4 (4.9), H-7 (3.1)
H-4 (2.8)
Figure 2. Transition state structures for dichlorocarbene approach to Re-face of con-
former A and Si-face of conformer B. Only olefinic hydrogens are shown for clarity.
Distances are in Å.
OCH3 (4.6)
H-6b (27.1), H-7 (4.1), H-4 (3.0)
H-7 (6.7), H-6a (2.6)
H-7 (1.9), H-4 (3.5)
H-1 (5.2)
Finally, the reaction shows an inverse
45–51 kcal/mol and thus it can be considered irreversible. Then,
based on the predicted low and realistically identical activation
values and knowledge of the rate constant in the order of
6.00ꢁ10ꢂ4 sꢂ1 for this type of reaction,31 we can expect that the
ratio between the two diastereomeric products coincides with that
DG energetic barrier of
employing the B3LYP exchange correlation functional and
6-311þG(d) basis set.25 Frequency calculation was used to confirm
the nature of the stationary points. Transition structures were
found to have only one negative eigenvalue with the corresponding
eigenvector involving the formation of the newly created C–C
bonds. Vibrational frequencies were calculated (1 atm, 298.15 K) for
all B3LYP/6-311þG(d) optimized structures and used, unscaled, to
compute both ZPVE and activation energies. The electronic struc-
tures of critical points were studied by the natural bond orbital
(NBO) method.26 The enthalpy and entropy changes were calcu-
lated from standard statistical thermodynamic formulas.27 The in-
trinsic reaction coordinates28 (IRC analysis) were also calculated to
analyze in detail the mechanism for all the obtained transition
structures. DFT calculations were carried out with the G03 system
of programs.29 In all the cases, full geometry optimization was
carried out without any symmetry constraints.
From inspection of the two conformers, it was apparent that the
dichlorocarbene moiety can approach conformer A only from the
upper side of alkene moiety (Re-face), because the lower one is very
crowded; on the contrary, for the same reason, conformer B can be
approached only from the lower side of double bond (Si-face). So,
the two possible products of the cyclopropanation reaction, 8-(Re)
and 8-(Si) can be originated through the two transition states TSA
and TSB as shown in Figure 2.
DG
one of A and B conformers at equilibrium. Introducing the DD
G
value of 1.11 kcal/mol, relative to the energy difference between the
two conformers A and B, in the Boltzman’s distribution equation,
we get 95.77% of conformer A at the equilibrium (A/B ratio of
22.64:1). Moreover, observing that the dipole moment of the two
conformers is considerably different (
D
D¼1.17 D), it is plausible to
presume that the solvent polarity affects the conformer ratio. So, in
order to obtain more insight on the solvent influence, we mini-
mized the two conformers in the presence of a continuum model of
chloroform solvation (PCM model)32 at the same level of calcula-
tion (Table 3).
The obtained results confirm that in the most polar environ-
ment (chloroform vs gas phase) the amount of conformer A in-
creases with respect to conformer B (A¼98.13%; A/B ratio of
52.47:1), and on this basis, we must expect to practically observe
only one product, namely that one derived from the attack of
dichlorocarbene to the Re-face of conformer A, in agreement to the
experimental results.
Insofar as concerns the reaction mechanism, transition struc-
tures and IRC analysis showed that the formation of the two new
The energetic of the whole process, reported in Table 3, shows
that the reaction is very exothermic with an activation free energy
of 11.1 kcal/mol for both the transition state pathways, which is
almost exclusively imputable to entropic contributions rather than
enthalpic ones. All these parameters are in good agreement with
those reported in the literature for similar reactions.30
s
-bonds proceeds via a concerted pathway in which the carbene
approaches to the olefin in an asymmetric fashion. The results
provide unambiguous evidence for a nonlinear attack in which
bond formation is more advanced at the terminal alkene unsub-
stituted carbon in accord with the non-least-motion approach34 of
Table 3
B3LYP/6-311þG(d,p) relative electronic (
D
E), enthalpic (
DH), and free (
DG) energies
(kcal/mol), and molecular dipole moments (D) (Debye)
Direct Direct Direct
Ea Ha Ga
D
D
D
Inverse
D
Gb
D
A
B
0.00
0.00
0.00
1.74
0.00c
0.85
0.00c
0.85
0.00c
1.11
2.19c
0.57
0.78c
5.07
3.13
4.48
2.50
1.86c
1.86c
2.36c
11.10
TSA
TSB
P1
ꢂ0.05
ꢂ0.64
45.77
51.04
1.10
0.51
11.13
ꢂ48.53
ꢂ53.42
ꢂ49.12
ꢂ54.01
ꢂ34.67
P2
ꢂ39.91
a
Since 2 exists in equilibrium between A and B conformers, the Curtin–Hammett
principle33 was applied and their relative energies were calculated with reference to
Aþdichlorocarbene.
b
Referred to the corresponding products.
Figure 1. Conformers A and B of compound 2 with only olefinic hydrogens shown for
clarity.
c
Values calculated in chloroform as solvent.

A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
8655
the TS is reached near the starting point of the nucleophilic phase
(Fig. 4).
4. Conclusions
Besides the reactions of 1–3 under Furukawa conditions, which
afford optimum yields of expected spirocyclopropanes 4–6, the
synthetic strategy of the dihalocarbene addition to the 5,6-double
bond of the pyranose ring provides a stereospecific method for
obtaining spirocyclopropanated galactopyranosides with the two
halogens on the upper face containing the 4-hydroxy substituent,
which were never reported for the differently protected gal-
actopyranosides. On the contrary, the reaction of 1 and 2 with the
rhodium ethoxycarbonyl complex does not present any significant
endo/exo, nor facial stereoselectivity.
Figure 3. TSA displayed the
cyclic double bond and dichloromethane moieties depicted by PNBO framework.
p/p (left) and s/p (right) interactions between exo-
*
a carbene to a double bond, first proposed by Skell35 and succes-
sively experimentally demonstrated by Houk.36
The Second Order Perturbation Theory Analysis (SOPT) of Fock
Matrix in NBO Basis evidenced that, at the transition state, two
pairs of orbital interactions exist between :CCl2 carbene and C]C
double bond (Fig. 3). For TSA, the primary one, which is the most
important, involves the
finic double bond with the empty p-like orbital of dichlorocarbene
moiety (41.95 kcal/mol), whereas the secondary one, of type /p*
(11.41 kcal/mol), is established between the carbon lone pair of
:CCl2 carbene and the antibonding orbital of the olefinic double
bond; this last orbital interaction explains why the carbene ap-
proach is asymmetric, exhibiting concerted, but asynchronous,
Moreover this is, at our best knowledge, the first in silico study
of a dichlorocyclopropanation reaction upon a 5-methylene py-
ranoside at this level of theory.
These synthetic reactions assume a considerable importance
since the cyclopropane ring can be open to various manipulations,
which can lead to natural and unnatural ketoses, higher sugars,
3-deoxy-2-glyculosonates, and 2-amino sugars. Furthermore, the
application of these cyclopropanation reactions to unsaturated
lactose allows a further chemical valorisation of this natural di-
saccharide, obtainable in great amounts from whey (a by-product
of cheese industry), opening new prospects for its utilization.
p/p stabilizing delocalization of the ole-
s
formation of the new two
s bonds. So, the addition trajectory be-
5. Experimental
gins as an electrophilic attack, but it involves a subsequent rotation
of the carbene to achieve a final nucleophilic stage, which com-
pletes product formation as previously evidenced in similar
reactions.30b,c,37
5.1. General methods
Melting points were determined with a Kofler hot-stage appa-
ratus and are uncorrected. Optical rotations were measured on
a Perkin–Elmer 241 polarimeter at 25ꢃ2 ꢀC. 1H NMR spectra were
recorded with a Varian Unity INOVA instrument at 200 and
500 MHz in the stated solvent (Me4Si was used as the internal
standard). 13C NMR spectra were recorded at 50 MHz. Assignments
were made, when possible, with the aid of DEPT experiments, for
comparison with values for known compounds. High-resolution
mass spectra were recorded on a VG ZAB-2SE double focusing
magnetic sector mass spectrometer operating at 70 eV. All re-
actions were followed by TLC on Kieselgel 60 F254 with detection by
UV light and/or with ethanolic 10% phosphomolybdic or sulfuric
acid, and heating. Kieselgel 60 (E. Merck, 70–230 and 230–400
mesh, respectively) was used for column and flash chromatogra-
phy. HPLC purifications were made with a Microsorb silica Dina-
max-100 Å preparative column (250ꢁ21 mm) at a flow rate of
21 mL/min with a Varian Pro Star instrument. Solvents were dried
by distillation according to standard procedure,39 and stored over
4 Å molecular sieves activated for at least 24 h at 400 ꢀC. MgSO4
was used as the drying agent for solutions.
Moreover, the charge transfer between the two reactant at the
TS geometry, evaluated by natural population analysis,38 in terms of
the residual charge on dichlorocarbene is of ꢂ0.188 electrons (a.u.)
for TSA and it is indicative of an electron flow from the pyranose
HOMO to the dichlorocarbene LUMO, in agreement with the pri-
mary dichloromethane electrophilic attack. The same consider-
ations can be applied to TSB.
Further, the charge transfer analysis along the IRC pathway
provide an additional and clear evidence for the two-phase (elec-
trophilic/nucleophilic) mechanism, in that, for both TSA and TSB
pathways, there is a distinct turning point (charge minimum) in the
charge/IRC curves, which occurs just before the TS. In other words,
5-Methylene galactopyranosides 1,11 2,5,12 and 313 were pre-
pared from commercially available methyl-a- and methyl-b-D-gal-
actopyranoside and lactose, respectively, following our previously
reported method.13
5.2. General procedures for the cyclopropanation of 6-
deoxyhex-5-enopyranosides 1–3
5.2.1. Procedure using the Simmons–Smith modified method
To
(0.78 mmol) in Et2O (3 mL), diethyl zinc (520
hexane, 4.2 mmol) and diiodomethane (340
a
suspension of 6-deoxyhex-5-enopyranosides 1–3
L of a 1 M solution in
L, 4.2 mmol) were
m
m
added at room temperature. The solution was then heated at 40 ꢀC
in a sealed vessel. After 2 h, a saturated solution of NaHCO3 (2 mL)
was added to the reaction mixture, which was then neutralized
Figure 4. Charge analysis along the IRC for :CCl2 cycloaddition to 2; (,) and (C)
correspond to the transition state and turning point, respectively; electrophilic phase-
region right to the turning point and nucleophilic ones left.

8656
A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
with diluted HCl (5%, 2 mL) and extracted twice with diethyl ether
(10 mL); the combined organic layers were washed with brine
(20 mL), water (20 mL), and dried (Na2SO4). Flash chromatography
of the crude gave the cyclopropanated pyranosides 4–6.
as pure samples together with a little amount of starting unreacted
5-methylene galactopyranosides.
5.2.2.1. (1S,3a0R,60S,70R,7a0S)-70-(Benzyloxy)-2,2-dichloro-60-methoxy-
20,20-dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]py-
25
5.2.1.1. (3a0R,60S,70R,7a0S)-70-(Benzyloxy)-60-methoxy-20,20-dimethyl-
ran] 7. Yield 80%; colourless solid: mp 52–54 ꢀC (from hexane); [
a]
D
tetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran] 4. Yield
þ25.89 (c 0.55, CHCl3); 1H NMR (CDCl3, 500 MHz):
d 7.40–7.28 (m,
25
90%; amorphous solid; [
200 MHz):
a
]
D
þ22.38 (c 0.21, CHCl3); 1H NMR (CDCl3,
5H, aromatic H), 4.87 (d, 1H, J¼3.0 Hz, H-1), 4.76 and 4.69 (AB, 2H,
J¼12.0 Hz, CH2Ph), 4.46 (t, 1H, J¼6.5 Hz, H-4), 4.44 (1H, dd, J¼6.0,
6.5 Hz, H-3), 3.70 (dd, 1H, J¼3.0, 6.5 Hz, H-2), 3.49 (s, 3H, OCH3), 1.82
(1/2 AB system, 1H, J¼9.0 Hz, H-6b), 1.64 (1/2 AB system, 1H,
J¼9.0 Hz, H-6a), 1.40 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C NMR (CDCl3,
d
7.35–7.26 (m, 5H, aromatic H), 4.83 and 4.69 (AB
system, 2H, J¼12.5 Hz, CH2Ph), 4.60 (d, 1H, J¼3.5 Hz, H-1), 4.43–
4.39 (m, 1H, H-3), 3.71–3.69 (m, 1H, H-4), 3.64–3.61 (m, 1H, H-2),
3.44 (s, 3H, OCH3), 1.24–1.21, 0.93–0.88, 0.79–0.75, and 0.71–0.67
(4m, each 1H, 2ꢁCH2); 13C NMR (CD3CN, 50 MHz):
d
138.5 (aro-
50 MHz): d 138.1 (aromatic C), 128.9, 127.9, and 127.7 (aromatic CH),
matic C), 128.4, 128.3, and 127.2 (aromatic CH), 109.4 (C(CH3)2), 98.4
(C-1), 83.6, 75.3, and 74.8 (C-2, C-3, and C-4), 73.1 (CH2Ph), 56.6
(OCH3), 54.8 (C-5), 27.5 (CH3), 26.3 (CH3), 11.7 (CH2), 9.5 (CH2). Anal.
Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.44; H, 7.52.
109.1 (C(CH3)2), 100.0 (C-1), 75.5, 74.5, and 73.4 (C-2, C-3, C-4), 73.1
(CH2Ph), 63.5 (CCl2), 63.2 (C-5), 58.4 (OCH3), 29.6 (C-6), 27.3 (CH3),
25.5 (CH3). Anal. Calcd for C18H22Cl2O5: C, 55.54; H, 5.70. Found: C,
55.62; H, 5.71; HRMS (EI) m/z: calcd for C18H22Cl2O5, 389.2703;
found, 389.2706.
5.2.1.2. (3a0R,60R,70R,7a0S)-70-(Benzyloxy)-60-methoxy-20,20-dimethyl-
tetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran] 5. Yield
5.2.2.2. (1S,3a0R,60R,70R,7a0S)-70-(Benzyloxy)-2,2-dichloro-60-methoxy-
25
98%; colourless solid: mp 39–41 ꢀC (from hexane); [
a
]
D
ꢂ9.26 (c
20,20-dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]py-
25
0.11, CHCl3); 1H NMR (CDCl3, 500 MHz):
d
7.41–7.25 (m, 5H, aro-
ran] 8. Yield 65%; amorphous solid; [
a
]
ꢂ16.24 (c 0.55, CHCl3); 1H
D
matic H), 4.82 (s, 2H, CH2Ph), 4.31 (d, 1H, J¼7.8 Hz, H-1), 4.23 (dd,
1H, J¼5.8, 7.1 Hz, H-3), 3.72 (d,1H, J¼5.8 Hz, H-4), 3.53 (dd,1H, J¼7.1,
7.8 Hz, H-2), 3.42 (s, 3H, OCH3), 1.16–1.11, 0.93–0.88, 0.78–0.73, and
NMR (CDCl3, 500 MHz): d 7.41–7.25 (m, 5H, aromatic H), 4.79 and
4.84 (AB system, J¼11.8 Hz, CH2Ph), 4.58 (d, 1H, J¼7.5 Hz, H-1), 4.36
(d, J¼6.0 Hz, H-4), 4.32 (dd, 1H, J¼6.0, 7.5 Hz, H-3), 3.54 (s, 3H,
OCH3), 3.51 (d, 1H, J¼7.5 Hz, H-2), 1.91 and 1.87 (AB system, 1H,
J¼9.1 Hz, CH2), 1.41 (s, 3H, CH3), 1.35 (s, 3H, CH3); 13C NMR (CDCl3,
0.66–0.61 (4m, each 1H, 2ꢁCH2); 13C NMR (CDCl3, 50 MHz):
d 138.4
(aromatic C), 128.2, 128.1, and 127.5 (aromatic CH), 109.8 (C(CH3)2),
103.2 (C-1), 88.2, 78.7, and 78.5 (C-2, C-3, and C-4), 73.5 (CH2Ph),
56.2 (OCH3), 55.1 (C-5), 27.7 (CH3), 26.1 (CH3), 11.3 (CH2), 9.6 (CH2).
Anal. Calcd for C18H24O5: C, 67.48; H, 7.55. Found: C, 67.52; H, 7.57;
HRMS (EI) m/z: calcd for C18H24O5, 320.3801; found, 320.3803.
50 MHz): d 138.0 (aromatic C), 128.2, 128.0, and 127.6 (aromatic CH),
110.1 (C(CH3)2), 104.0 (C-1), 78.8, 77.8, and 73.8 (C-2, C-3, C-4), 73.6
(CH2Ph), 61.6 (C-5), 61.5 (CCl2), 57.0 (OCH3), 30.1 (CH2), 27.6 (CH3),
26.2 (CH3). Anal. Calcd for C18H22Cl2O5: C, 55.54; H, 5.70. Found: C,
55.69; H, 5.68.
5.2.1.3. (1S,3a0R,60R,70R,7a0S)-70-(Benzyloxy)-2,2-dichloro-60-{(R)[(4S,5R)-
5-(dimethoxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl][(4R)-2,2-dimeth-
yl-1,3-dioxolan-4-yl]methoxy}-20,20-dimethyltetrahydrospiro[cyclo-
5.2.2.3. (1S,3a0R,60R,70R,7a0S)-70-(Benzyloxy)-2,2-dichloro-60-{(R)[(4S,5R)-
5-(dimethoxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl][(4R)-2,2-di-
methyl-1,3-dioxolan-4-yl]methoxy}-20,20-dimethyltetrahydrospiro[cy-
propane-1,40-[1,3]dioxolo[4,5-c]pyran] 6. Yield 96%; amorphous
25
25
solid; [
d
a]
ꢂ17.04 (c 0.17, CHCl3); 1H NMR (CDCl3, 500 MHz):
clopropane-1,40-[1,3]dioxolo[4,5-c]pyran] 9. Yield 70%; syrup; [
a]
D
D
7.39–7.25 (m, 5H, aromatic H), 4.84 and 4.76 (AB system, 2H,
ꢂ2.95 (c 1.18, CHCl3); 1H NMR (CDC13, 500 MHz):
d 7.40–7.26 (m,
J¼12.0 Hz, CH2Ph), 4.64 (d, 1H, J¼8.0 Hz, H-10), 4.45 (dd, 1H, J¼6.2,
7.8 Hz, H-2), 4.33 (d, 1H, J¼6.2 Hz, H-1), 4.26 (dd, 1H, J¼6.0, 8.8 Hz,
H-5), 4.20 (dd, 1H, J¼5.8, 7.2 Hz, H-30), 4.17 (dd, 1H, J¼6.0, 8.8 Hz, H-
6b), 4.02 (dd, 1H, J¼1.4, 7.8 Hz, H-3), 3.94 (dd, 1H, J¼6.0, 7.0 Hz, H-
6a), 3.73 (dd, 1H, J¼1.4, 5.5 Hz, H-4), 3.61 (d, 1H, J¼5.8 Hz, H-40),
3.47 (dd, 1H, J¼8.0, 7.2 Hz, H-20), 3.30 (s, 6H, 2ꢁOCH3), 1.41 (s, 3H,
CH3), 1.40 (s, 6H, 2ꢁCH3), 1.35, 1.32, and 1.30 (3s, each 3H, CH3),
1.15–1.12, 0.89–0.85, 0.78–0.73, and 0.74–0.69 (4m, each 1H, CH2);
5H, aromatic H), 4.93 (d, 1H, J¼7.9 Hz, H-l0), 4.86 and 4.75 (AB
system, 2H, J¼11.8 Hz, CH2Ph), 4.44 (dd, 1H, J¼6.2, 7.5 Hz, H-2), 4.33
(d, 1H, J¼6.2 Hz, H-l), 4.29–4.21 (m, 3H, H-30, H-40, H-5), 4.20
(dd, 1H, J¼1.2, 5.2 Hz, H-4), 4.14 (dd, J¼6.2, 7.0 Hz, H-6b), 4.05 (d,
1H, J¼1.2 Hz, H-3), 3.99 (dd, 1H, J¼7.0, 8.7 Hz, H-6a), 3.47 (dd, 1H,
J¼6.0, 7.9 Hz, H-20), 3.38 (2s, each 6H, 2ꢁOCH3), 1.86 and 1.82 (AB
system, 2H, J¼8.9 Hz, CH2), 1.41 (s, 6H, 2ꢁCH3), 1.39 (s, 3H, CH3),
1.34 (s, 3H, CH3), 1.33 (2s, each 6H, 2ꢁCH3); 13C NMR (CD3CN,
13C NMR (CD3CN, 50 MHz):
d
138.4 (C aromatic), 128.8, 128.0, and
50 MHz): d 138.6 (aromatic C), 128.2,128.1, and 127.6 (aromatic CH),
127.4 (aromatic CH), 110.9, 110.7, and 109.2 (3ꢁC(CH3)2), 106.9 (C-
1), 104.2 (C-10), 88.1 (C-30), 80.2, 78.5, 77.9, 77.8, and 76.9 (C-2, C-3,
C-4, C-20, C-40), 76.3 (C-2), 73.2 (CH2Ph), 72.6 (C-6), 55.0 and 54.1
(2ꢁOCH3), 54.5 (C-50), 27.9, 27.5, 26.1, 26.2, 27.4, and 26.1 (6ꢁCH3),
11.1 and 9.5 (2ꢁCH2). Anal. Calcd for C31H46O11: C, 63.05; H, 8.04.
Found: C, 63.28; H, 8.07; HRMS (EI) m/z: calcd for C31H46O11,
594.6903; found, 594.6905.
110.8, 110.4, and 108.9 (3ꢁC(CH3)2), 105.9 (C-1), 103.7 (C-10), 89.0
(C-30), 81.7, 77.8, 76.9, and 75.5 (C-2, C-3, C-4, C-20, C-40), 75.8 (C-2),
73.2 (CH2Ph), 71.5 (C-6), 61.6 (C-50), 61.5 (CCl2), 57.0 and 56.1
(2ꢁOCH3), 32.5 (CH2), 27.9, 27.2, 26.8, 26.3, 26.0, and 25.9 (6ꢁMe).
Anal. Calcd for C31H44Cl2O11: C, 56.11; H, 6.68. Found: C, 55.99; H,
6.70; HRMS (EI) m/z: calcd for C31H44Cl2O11, 663.5804; found,
663.5802.
5.2.2. Cyclopropanation by dichlorocarbene addition
5.2.3. Cyclopropanation by addition of ethoxycarbonyl-carbene
to 1 and 2
To a suspension of 1–3 (0.98 mmol) in CHCl3 (5 mL) containing
benzyltriethylammonium chloride (BTEAC) (0.007 g, 0.037 mmol)
as phase-transfer catalyst, a 50% aqueous NaOH (4 mL) was added
under agitation. The suspension was stirred for 5 h and the reaction
course was monitored by TLC (cyclohexane/AcOEt 70:30). Water
(10 mL) and CHCl3 (10 mL) were added and the layers separated.
The aqueous layer was further extracted with CHCl3. The combined
organic extracts were washed with water and dried (Na2SO4), and
the solvent was removed under reduced pressure. Flash chroma-
tography (cyclohexane/AcOEt 90:10) of the residual syrup gave 7–9
To a suspension of 1 or 2 (0.456 g, 1.47 mmol) in anhydrous
CH2Cl2 (3 mL), containing Rh2(OAc)4 (0.013 g, 0.027 mmol) as cat-
alyst, a solution of ethyl diazoacetate (0.47 mL, 1.5 mmol) in anhy-
drous CH2Cl2 (15 mL) was slowly added under constant agitation
and under a nitrogen atmosphere. The reaction was monitored by
TLC (cyclohexane/AcOEt 70:30) until starting 1, 2 disappeared
(about 5 h). A mixture of four products 10,11,12, and 13 was formed
in the ratio 1.2:0.8:2.0:1.8, respectively, as it appeared from the 1H
NMR spectra of the crude. After filtration of catalyst, the solvent

A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
8657
was removed under reduced pressure. The flash chromatography
(cyclohexane/AcOEt 85:15) of the residue gave 13 and a mixture
of the other diastereoisomers 10, 11, and 12; preparative HPLC
(hexane/isopropanol 10%) of this latter mixture yielded isomeri-
cally pure samples of 12 (tR 15 min), 10 (tR 18 min) and 11 (tR
19 min).
An analogous procedure was followed for the cyclopropanation
of 2, which yielded 14, 15, 16, and 17 in the ratio 0.5:0.5:1.1:1.0 after
the flash chromatography, which gave only 17 and preparative
HPLC, which afforded in the sequence 16 (tR 13 min), 14 (tR 16 min),
and 15 (tR 17 min) as pure samples.
4.80 and 4.68 (AB system, 2H, J¼12.5 Hz, CH2Ph), 4.60 (d, 1H,
J¼3.5 Hz, H-1), 4.35 (d, 1H, J¼6.0 Hz, H-4), 4.26 (dd, 1H, J¼6.0, 7.5 Hz,
H-3), 4.08 and 4.03 (2dq, J¼11.0, 7.0 Hz, CH3CH2O), 3.61 (dd,1H, J¼3.5,
7.5 Hz, H-2), 3.41 (s, 3H, OCH3), 1.97 (dd, 1H, J¼7.5, 9.5 Hz, H-7), 1.46
(dd, 1H, J¼6.5, 9.5 Hz, H-6b), 1.42 (s, 3H, CH3), 1.40 (dd, 1H, J¼6.5,
7.5 Hz, H-6a), 1.32 (s, 3H, CH3), 1.20 (t, 3H, J¼7.0 Hz, CH3CH2O); 13C
NMR (CDCl3, 50 MHz): d 171.0 (C]O), 139.0 (aromatic C), 128.3, 127.8,
and 127.7 (aromatic CH), 108.6 (C(CH3)2), 99.9 (C-1), 75.8, 74.3, and
72.8 (C-2, C-3, C-4), 72.7 (CH2Ph), 60.7 (CH3CH2O), 58.9 (C-5), 56.9
(OCH3), 27.9 (CH3ꢁ2), 26.1 (C-7), 15.3 (C-6), 14.1 (CH3CH2O). Anal.
Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C, 64.44; H, 7.21.
5.2.3.1. Ethyl
(1R,2R,3a0R,60S,70R,7a0S)-70-(benzyloxy)-60-methoxy-
5.2.3.5. Ethyl (1R,2R,3a0R,60R,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
20,20-dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]-
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-
25
25
pyran]-2-carboxylate 10. Yield 10%; amorphous solid; [
a
]
D
þ17.2 (c
2-carboxylate 14. Yield 12%; amorphous solid; [
a
]
ꢂ64.5 (c 1.21,
D
0.8, CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d
7.37–7.27 (m, 5H, aro-
CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d 7.34–7.25 (m, 5H, aromatic
matic H), 4.84 and 4.68 (AB, 2H, J¼12.5 Hz, CH2Ph), 4.67 (d, 1H,
J¼3.0 Hz, H-1), 4.49 (dd, 1H, J¼6.5, 7.5 Hz, H-3), 4.15 and 4.08 (2dq,
2H, J¼6.5, 7.5 Hz, CH3CH2O), 4.07 (d, 1H, J¼6.5 Hz, H-4), 3.77 (dd,
1H, J¼3.0, 7.5 Hz, H-2), 3.41 (s, 3H, OCH3), 2.03 (dd,1H, J¼7.0, 9.0 Hz,
H-7), 1.66 (dd, 1H J¼6.0, 9.0 Hz, H-6b), 1.48 (s, 3H, CH3), 1.34 (s, 3H,
CH3), 1.20 (t, 3H, J¼7.5 Hz, CH3CH2O), 1.12 (dd, 1H, J¼6.0, 7.0 Hz, H-
H), 4.83 and 4.78 (AB system, 2H, J¼12.0 Hz, CH2Ph), 4.52 (d, 1H,
J¼7.5 Hz, H-1), 4.25 (t, 1H, J¼7.5 Hz, H-3), 4.20 (d, 1H, J¼6.0 Hz, H-
4), 4.17 and 4.08 (2dq, 2H, J¼6.5, 7.0 Hz, CH3CH2O), 3.69 (t, 1H,
J¼7.5 Hz, H-2), 3.35 (s, 3H, OCH3), 2.21 (dd, 1H, J¼7.0, 9.0 Hz, H-7),
1.66 (dd, 1H, J¼6.0, 7.0 Hz, H-6b), 1.44 (s, 3H, CH3), 1.33 (s, 3H, CH3),
1.27 (t, 3H, J¼7.5 Hz, CH3CH2O), 1.08 (dd, 1H, J¼6.0, 9.0 Hz, H-6a);
6a); 13C NMR (CDCl3, 50 MHz):
d
169.7 (C]O), 138.1 (aromatic C),
13C NMR (CDCl3, 50 MHz):
d 169.6 (C]O), 138.5 (aromatic C), 128.2,
128.3, 127.9, and 127.7 (CH aromatic), 109.6 (C-(CH3)2), 99.5 (C-1),
76.3, 75.9, and 75.3 (C-2, C-3, C-4), 72.5 (CH2Ph), 61.0 (C-5), 60.7
(CH3CH2O), 56.3 (OCH3), 27.1 (C-7), 25.5 (CH3), 22.5 (CH3), 16.2 (C-
6), 14.2 (CH3CH2O). Anal. Calcd for C21H28O7: C, 64.27; H, 7.19.
Found: C, 64.39; H, 7.22.
127.9, and 127.8 (CH aromatic), 110.5 (C(CH3)2), 103.2 (C-1), 79.4,
78.2 (C-2 and C-3), 73.5 (CH2Ph), 73.1 (C-4), 61.2 (CH3CH2O), 60.8
(C-5), 56.6 (OCH3), 27.3 (CH3), 27.0 (CH3), 23.6 (C-7), 18.1 (C-6), 14.2
(CH3CH2O). Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C,
64.35; H, 7.17.
5.2.3.2. Ethyl
(1R,2S,3a0R,60S,70R,7a0S)-70-(benzyloxy)-60-methoxy-
5.2.3.6. Ethyl (1R,2S,3a0R,60R,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
20,20-dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]-
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-
25
25
pyran]-2-carboxylate 11. Yield 13%; amorphous solid; [
a
]
ꢂ18.1 (c
2-carboxylate 15. Yield 14%; amorphous solid; [
a
]
þ41.2 (c 0.98,
D
D
1.1, CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d
7.37–7.28 (m, 5H, aro-
CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d 7.39–7.28 (m, 5H, aromatic
matic H), 4.82 and 4.72 (AB system, 2H, J¼11.5 Hz, CH2Ph), 4.29 (d,
1H, J¼3.5 Hz, H-1), 4.03 (dd, 1H, J¼5.5, 8.0 Hz, H-3), 3.98 (2dq, 2H,
J¼6.0, 7.5 Hz, CH3CH2O), 3.92 (d, 1H, J¼5.5 Hz, H-4), 3.63 (dd, 1H,
J¼3.5, 8.0 Hz, H-2), 3.37 (s, 3H, OCH3), 2.07 (dd, 1H, J¼7.0, 9.0 Hz, H-
7), 1.51 (dd, 1H, J¼5.5, 9.0 Hz, H-6b), 1.39 (s, 3H, CH3), 1.30 (s, 3H,
CH3), 1.26 (t, 3H, J¼7.5 Hz, CH3CH2O), 1.24 (dd, 1H, J¼5.5, 7.0 Hz, H-
H), 4.79 (s, 2H, CH2Ph), 4.29 (d, 1H, J¼8.5 Hz, H-1), 4.26 (dd, 1H,
J¼6.5, 7.5 Hz, H-3), 4.16 (d, 1H, J¼6.5 Hz, H-4), 4.08 and 4.15 (2dq,
2H, J¼6.0, 7.0 Hz, CH3CH2O), 3.51 (dd,1H, J¼7.5, 8.5 Hz, H-2), 3.46 (s,
3H, OCH3), 1.88 (dd, 1H, J¼8.0, 9.0 Hz, H-7), 1.66 (2dd, 1Hꢁ2, J¼6.5,
8.0, 9.0 Hz, H-6a, H-6b), 1.42 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.27 (t,
3H, J¼7.0 Hz, CH3CH2O); 13C NMR (CDCl3, 50 MHz):
d 169.9 (C]O),
6a); 13C NMR (CDCl3, 50 MHz):
d
169.8 (C]O), 139.0 (aromatic C),
138.1 (aromatic C), 128.0, 127.6, and 127.5 (aromatic CH), 110.7
(C(CH3)2), 103.6 (C-1), 80.2, 77.7, and 75.2 (C-2, C-3, and C-4), 73.5
(CH2Ph), 61.2 (CH3CH2O), 60.8 (C-5), 56.0 (OCH3), 27.8 (CH3), 27.2
(CH3), 26.3 (C-7), 15.1 (C-6), 14.2 (CH3CH2O). Anal. Calcd for
129.1, 129.0, and 128.1 (aromatic CH), 110.1 (C(CH3)2), 101.0 (C-1),
78.8, 77.1, and 76.1 (C-2, C-3, C-4), 73.4 (CH2Ph), 62.0 (C-5), 60.5
(CH3CH2O), 57.1 (OCH3), 27.9 (CH3), 27.2 (CH3), 27.0 (C-7), 18.2 (C-6),
14.2 (CH3CH2O). Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C,
64.19; H, 7.23.
C21H28O7: C, 64.27; H, 7.19. Found: C, 64.36; H, 7.16.
5.2.3.7. Ethyl (1S,2S,3a0R,60R,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
5.2.3.3. Ethyl (1S,2S,3a0R,60S,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-2-
25
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-2-
carboxylate 16. Yield 37%; amorphous solid; [
a
]
ꢂ4.0 (c 0.1, CH2Cl2);
D
25
carboxylate 12. Yield 22%; amorphous solid; [
a
]
ꢂ16.1 (c 0.9,
1H NMR (500 MHz, CDCl3):
d 7.40–7.25 (m, 5H, aromatic H), 4.80 (s,
D
CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d
7.37–7.27 (m, 5H, aromatic H),
2H, CH2Ph), 4.29 (dd, J¼6.5, 8.0 Hz, H-3), 4.20 (d, 1H, J¼7.5 Hz, H-1),
4.12 and 4.18 (2dq, 2H, J¼7.0, 7.5 Hz, CH3CH2O), 3.84 (d, 1H, J¼6.5 Hz,
H-4), 3.55 (dd, 1H, J¼7.5, 8.0 Hz, H-2), 3.42 (s, 3H, OCH3), 1.89 (dd, 1H,
J¼6.0, 8.5 Hz, H-6b), 1.84 (dd, 1H, J¼6.5, 8.5 Hz, H-7), 1.40 (s, 3H, CH3),
1.39 (dd,1H, J¼6.0, 8.5 Hz, H-6a),1.32 (s, 3H, CH3),1.29 (t, 3H, J¼7.5 Hz,
4.82 and 4.70 (AB system, 2H, J¼12.5 Hz, CH2Ph), 4.77 (dd, 1H, J¼6.5,
7.5 Hz, H-3), 4.68 (d, 1H, J¼3.5 Hz, H-1), 4.20 and 4.08 (2dq, 2H,
J¼11.0, 7.5 Hz, CH3CH2O), 3.91 (d, 1H, J¼6.5 Hz, H-4), 3.71 (dd, 1H,
J¼3.5, 7.5 Hz, H-2), 3.31 (s, 3H, OCH3), 1.86 (dd, 1H, J¼7.0, 9.0 Hz, H-7),
1.60 (dd, 1H, J¼6.0, 7.0 Hz, H-6b), 1.44 (s, 3H, CH3), 1.32 (s, 3H, CH3),
CH3CH2O); 13C NMR (CDCl3, 50 MHz):
d 168.6 (C]O), 138.4 (aromatic
1.31 (dd, 1H, J¼6.0, 9.0 Hz, H-6a), 1.26 (t, 3H, J¼7.5 Hz, CH3CH2O); 13
C
C), 128.2, 128.1, and 127.6 (aromatic CH), 110.2 (C(CH3)2), 103.2 (C-1),
79.9, 78.1, and 77.5 (C-2, C-3, and C-4), 73.6 (CH2Ph), 60.9 (CH3CH2O),
60.7 (C-5), 56.4 (OCH3), 27.4 (CH3), 25.9 (CH3), 24.9 (C-7), 15.7 (C-6),
14.2 (OCH2CH3). Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C,
64.08; H, 7.22; HRMS (EI) m/z: calcd for C21H28O7, 392.44282; found,
392.44291.
NMR (CDCl3, 50 MHz): d 171.9 (C]O), 138.1 (aromatic C), 128.4, 127.8,
and 127.7 (aromatic CH), 109.2 (C(CH3)2), 100.1 (C-1), 77.4, 76.0, and
75.1 (C-2, C-3, C-4), 72.8 (CH2Ph), 61.1 (C-5), 60.6 (CH3CH2O), 57.4
(OCH3), 27.41 (CH3), 25.5 (CH3), 25.7 (C-7),14.9 (C-6),14.2 (CH3CH2O).
Anal. Calcd for C21H28O7: C, 64.27; H, 7.19. Found: C, 64.13; H, 7.22.
5.2.3.4. Ethyl (1S,2R,3a0R,60S,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
5.2.3.8. Ethyl (1S,2R,3a0R,60R,70R,7a0S)-70-(benzyloxy)-60-methoxy-20,20-
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-2-
dimethyltetrahydrospiro[cyclopropane-1,40-[1,3]dioxolo[4,5-c]pyran]-2-
25
25
carboxylate 13. Yield 20%; amorphous solid; [
a
]
þ4.8 (c 0.17,
carboxylate 17. Yield 30%; amorphous solid; [
a
]
D
þ6.9 (c 0.13,
D
CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d
7.34–7.24 (m, 5H, aromatic H),
CH2Cl2); 1H NMR (CDCl3, 500 MHz):
d 7.40–7.26 (m, 5H, aromatic H),

8658
A. Corsaro et al. / Tetrahedron 64 (2008) 8652–8658
16. (a) Brimacombe, J. S.; Evans, M. E.; Forbes, E. J.; Foster, A. B.; Webber, J. M.
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18. Determined by 1H NMR integration of the signals of OCH3 protons in the crude
reaction mixture.
19. Doyle, M. P.; Dorow, R. L.; Buhro, W. E.; Griffin, J. H.; Tamblyn, W. H.; Trudell, M.
L. Organometallics 1984, 3, 44–52; Doyle, M. P.; Bagheri, V.; Wandless, T. J.;
Harn, N. K.; Brinker, D. A.; Eagle, C. T.; Loh, K. L. J. Am. Chem. Soc. 1990, 112,
1906–1912.
20. Chen, C.-H.; Tsai, M.-L.; Su, M.-D. Organometallics 2006, 25, 2766–2773; (b)
Gaspar, P. P.; Lin, C. T.; Dunbar, B. L. W.; Mack, D. P.; Balasubramanian, P. J. Am.
Chem. Soc. 1984, 106, 2128–2139; (c) Aydogan, C.; Anac, O. Chim. Acta Turc. 1982,
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4.83–4.78 (AB system, 2H, J¼11.5 Hz, CH2Ph), 4.29 (d, 1H, J¼8.0 Hz, H-
1), 4.25 (d, 1H, J¼6.0 Hz, H-4), 4.20 and 4.11 (2dq, 2H, J¼7.0, 7.5 Hz,
CH3CH2O), 4.10 (dd, 1H, J¼6.0, 7.5 Hz, H-3), 3.51 (dd, 1H, J¼7.5, 8.0 Hz,
H-2), 3.46 (s, 3H, OCH3), 1.88 (dd, 1H, J¼8.0, 9.2 Hz, H-7),1.67 (2dd, 2H,
J¼6.5, 8.0, 9.2 Hz, H-6a, H-6b), 1.42 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.27
(t, 1H, J¼7.5 Hz, CH3CH2O); 13C NMR (CDCl3, 50 MHz):
d 169.9 (C]O),
138.0 (aromatic C), 128.2 and 127.6 (aromatic CH), 109.8 (C(CH3)2),
103.6 (C-1), 79.4 and 78.2 (C-2, C-4), 73.7 (CH2Ph), 73.1 (C-3), 61.1
(CH3CH2O), 61.0 (C-5), 56.6 (OCH3), 27.8 (CH3), 27.2 (CH3), 26.3 (C-7),
18.1 (C-6), 14.2 (CH3CH2O). Anal. Calcd for C21H28O7: C, 64.27; H, 7.19.
Found: C, 64.10; H, 7.21.
Acknowledgements
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Financial supports from the University of Catania and from
MIUR (Rome) are gratefully acknowledged. CPU time support from
CINECA is also acknowledged.
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