Cleavage of the 1,6-anhydro bridge in the levoglucosenone adduct with isoprene and its derivatives

Article abstract of DOI:10.1134/S1070428010010148

Methods of opening of the 1,6-anhydro bridge in levoglucosenone (ZnCl ₂-Ac₂O), its adducts with isoprene (ZnCl ₂-Ac₂O, HCl-MeOH), and hydroxy derivatives (H ₃PO₄-Ac_{2 O}

Full text of DOI:10.1134/S1070428010010148

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 1, pp. 129–137. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © B.T. Sharipov, O.Yu. Krasnoslobodtseva, L.V. Spirikhin, F.A. Valeev, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 1, pp. 128–135.
Cleavage of the 1,6-Anhydro Bridge in the Levoglucosenone
Adduct with Isoprene and Its Derivatives
B. T. Sharipov, O. Yu. Krasnoslobodtseva, L. V. Spirikhin, and F. A. Valeev
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: sinvmet@anrb.ru
Received December 3, 2008
Abstract—Methods of opening of the 1,6-anhydro bridge in levoglucosenone (ZnCl2–Ac2O), its adducts with
isoprene (ZnCl2–Ac2O, HCl–MeOH), and hydroxy derivatives (H3PO4–Ac2O) were studied. Cleavage of the
1,6-anhydro bridge in anomeric acetoxy derivatives of levoglucosenone–isoprene adduct by the action of
BF3·Et2O–Ac2O was accompanied by acetylation at the allylic C6 position.
DOI: 10.1134/S1070428010010148
in organic synthesis is cleavage of the 1,6-anhydro
bridge. We believed that study on such transformation
of levoglucosenone–isoprene adduct II as an example
would give rise to procedures applicable to all other
levoglucosenone adducts, which should extend the
series of available chiral substrates. Known methods
for opening of the 1,6-anhydro bridge involved the
corresponding protected hydroxy derivatives rather
Levoglucosenone (I) as dienophile undergoes
thermal Diels–Alder reaction with butadiene to give
the corresponding adduct at the α-side with high
stereoselectivity [1]. Analogous reactions of I with
cyclopentadiene [2, 3], isoprene [4], and piperilene [5]
lead to the formation of mixture of regioisomeric pairs
of endo and exo diastereoisomers. An important prob-
lem related to further application of the above adducts
Scheme 1.
OAc
11
O10
Me
O
O
H
O
H
O
CH2
1
7
10
6
9
2
1
H2C
Ac2O, ZnCl2, 2 h
9
8
OAc
3
4
2
3
8
7
5
6
4
5
O
H
O
H
O
Me
Me
I
II
IIIa, IIIb, 67%
α :β = 4:5
Ac2O, ZnCl2
Ac2O, ZnCl2, 48 h
OAc
OAc
O
H
O
OAc
OAc
OAc
OAc
H
OAc
OAc
Me
Me
O
V, 60%
[α]D20 = –140.4°
IV, 60%
129

SHARIPOV et al.
130
Scheme 2.
OH
OH
H
O
H
O
HCl, MeOH
OMe
OMe
OMe
H
OMe
II
+
H
O
Me
Me
VI, 57%
VII, 14%
HCl, MeOH–H2O
80%
VII
VI
than the adducts themselves [6]. Development of proce-
dures for direct cleavage of the 1,6-anhydro bridge
should shorten the necessary transformation sequence.
We made attempts to open the 1,6-anhydro bridge in
adduct II with the use of the following systems: Ac2O–
BF3 · Et2O, isopropenyl acetate–BF3 · Et2O, Ac2O–
H2SO4, and Ac2O–H3PO4; however, in all cases, the
reaction was accompanied by strong tarring. Treatment
of II with acetic anhydride in the presence of a softer
Lewis acid (ZnCl2, 2 h) gave a mixture of α- and
β-anomeric products IIIa and IIIb (yield 67%) which
were difficult to separate (Scheme 1).
tion of the 8-H proton; signal from the corresponding
(more shielded) proton of α-anomer IIIb is located
at δ 5.59 ppm.
Increase of the reaction time (48 h) leads to acetyla-
tion of compound II at the more accessible allylic po-
sition (C6), and the oxo group is converted into acylal
moiety (compound IV). It is known that opening of the
1,6-anhydro bridge in highly reactive levoglucosenone
(I) involves difficulties. Nevertheless, treatment of
compound I with ZnCl2–Ac2O resulted in stereoselec-
tive formation of acylal V.
Another procedure for cleavage of oxygen bridges
in carbohydrates involves treatment with a solution of
hydrogen chloride in methanol. The reaction of adduct
II with a 15% solution of HCl in MeOH in 5 h gave
57% of methyl acetal VI and up to 14% of dimethyl
ketal VII (Scheme 2). The latter underwent hydrolysis
to compound VI on addition of water, so that the
overall yield of VI reached 70%.
The ratio of anomers IIIa and IIIb was determined
1
on the basis of the H NMR data, and they were
assigned to α- or β-series* using 13C NMR spectros-
copy. The C8 and C10 atoms in the major anomer (IIIa)
resonated in a stronger field (δC 90.10 and 72.61 ppm)
than those of minor anomer IIIb (δC 90.23 and
74.03 ppm, respectively). The observed upfield shift
indicated syn interaction between the substituents on
C8 and C10, i.e., β-orientation of the acetoxy group.
This conclusion is confirmed by the 1H NMR data: the
8-H signal of major β-anomer IIIa appears in a weaker
field (δ 6.09 ppm), in keeping with equatorial orienta-
Opening of the 1,6-anhydro bridge was more effec-
tive in diastereoisomeric hydroxy derivatives VIIIa
and VIIIb. The oxo group in adduct II was reduced
using (i-Bu)2AlH, NaBH4, or LiAlH4. In all cases, the
corresponding α-hydroxy derivative VIIIa was formed
Scheme 3.
O
O
a: (i-Bu)2AlH, PhMe, –70°C
b: NaBH4, EtOH, 0°C
c: LiAlH4, THF, 0°C
H
O
H
O
II
+
H
OH
H
OH
Me
Me
VIIIa
VIIIb
a:
b:
c:
71%
57%
53%
10%
21%
17%
* Atom numbering in the NMR spectra corresponds to that shown
in the respective scheme.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

CLEAVAGE OF THE 1,6-ANHYDRO BRIDGE IN THE LEVOGLUCOSENONE ADDUCT
131
as the major product (Scheme 3). Spectral identifica-
tion of epimers VIIIa and VIIIb was based initially on
general relations holding in the spectra of epimeric
alcohols derived from levoglucosenone [7]. The most
informative signal is that belonging to the 1-H proton.
It is located at δ 5.48 ppm (J1,2 = 2.5 Hz) for the major
presumed that closure of tetrahydrofuran ring occurs at
the stage of formation of β-oriented iodonium cation
via nucleophilic attack by the hydroxy group. This is
possible only in the structure with α-oriented hydroxy
group. After cleavage of the iodine-containing ring, the
1
iodine atom appears β-configured. The H NMR spec-
threo isomer (2S-epimer) and at δ 5.52 ppm (J1, 2
=
trum of compound IX is consistent with stereochem-
1.6 Hz) for the erythro isomer (2R-epimer). The pyran
ring in hydroxy derivatives VIIIa and VIIIb may
adopt both chair and boat conformation, depending on
the substituent on C8. Correspondingly, couplings be-
tween 8-H and the neighboring protons change. In the
1H NMR spectrum of the major epimer, the 9-H signal
appears at δ 5.37 ppm (J8,9 = 2.5 Hz), while the 8-H
ical aspects of the above transformation. The most in-
formative H NMR signals characterizing the structure
1
of IX are those belonging to 6-H (δ 4.27 ppm, d.d, J =
10.3, 4.0 Hz), 7-Hax (δ 2.22 ppm, d.d.d, J7,8 = 2.2 Hz)
2
and 7-Heq (δ 2.67 ppm, d.d, J = 10.8 Hz), and 8-H
(δ 1.72 ppm, d.d, J = 2.2 Hz). The observed couplings
may occur only in the structure with β-orientation of
the iodine atom in the gauche conformation of IX.
proton resonates at δ 3.44 ppm (J8, 9 = 2.5, J8, 7
=
3.1 Hz). In the spectrum of the minor epimer, the 9-H
and 8-H signals are located at δ 5.35 (overlapped
The hydroxy group in VIIIa can be protected via
transformation into p-toluenesulfonate, acetate, and
trimethylsilyl or methyl ether moieties (Scheme 5).
Although the methoxy group in XIII cannot be
hydrolyzed directly, methyl protection can be removed
by complete opening of the sugar fragment and α-ketol
rearrangement.
by the 4-H signal) and 3.35 ppm (J8, 9 = 1.4, J8, 7
=
10.0 Hz), respectively.
Thus, on the basis of only J8, 9 values we can
presume that the major stereoisomer is characterized
by S configuration at the C8 atom, as in other alcohols
derived from levoglucosenone [7]. On the other hand,
the large coupling constant J8,7 = 10.0 Hz for the minor
isomer indicates axial orientations of 7-H and 8-H,
which is also possible for the (8S)-epimer with chair
conformation of the pyran ring. By contrast, small
value of J8,7 (3.1 Hz) for the major diastereoisomer
suggests axial–equatorial interaction possible for the
(8R)-epimer in both chair and boat conformations.
Therefore, additional spectral studies are necessary to
unambiguously assign stereochemical structure of the
newly formed asymmetric center.
Treatment of acetates XI and XIV with BF3 ·Et2O
in acetic anhydride results in more effective (as com-
pared to adduct II) acetylation at the allylic C6 position
with simultaneous opening of the 1,6-anhydro bridge
(Scheme 6). Analogous reactions with H2SO4–Ac2O or
BF3 ·Et2O–isopropenyl acetate give only mixtures of
anomeric products XV and XVII, but the efficiency of
cleavage of the 1,6-anhydro bridge is lower. The reac-
tions of alcohols VIIIa and VIIIb with H3PO4–Ac2O
afforded anomeric acetates XV and XVII in high
yields. Here, (8R)-epimer VIIIb reacted almost instan-
taneously, while the transformation of (8S)-epimer
VIIIa required 1 h.
In order to elucidate this problem, both epimers
were subjected to iodocyclization. The results showed
that only the major (8S)-epimer (VIIIa) underwent
intramolecular cyclization with closure of tetrahydro-
furan ring (compound IX, Scheme 4) and that minor
(8R)-epimer VIIIb failed to react. Taking into account
the mechanism of this reaction proposed in [8], we
Thus, opening of the 1,6-anhydro bridge is possible
both in adduct II with conservation of the oxo group
and in its 8-hydroxy and 8-acetoxy derivatives.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Scheme 4.
a Bruker AM-300 spectrometer at 300 (1H) and
75.47 MHz (13C) using CDCl3 as solvent unless other-
wise stated. The melting points were measured on
a Kofler S 30A/G melting point apparatus (DDR).
Analytical thin-layer chromatography was performed
on Sorbfil PTSKh-AF-A plates (Sorbpolimer Ltd.,
Krasnodar, Russia). The elemental compositions were
determined on an Evro-2000 CHNS(O) analyzer. The
O11
10
H
1O2
9
I2, Et2O–H2O, NaHCO3
1
H
7
5
8
4
VIIIa
2
6
3
I
O 13
Me
IX, 92%
20
[α]D = –143.0°
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

SHARIPOV et al.
132
Scheme 5.
O
O
H
O
H
O
TsCl, pyridine
Me3SiCl, pyridine
H
OTs
O
H
OSiMe3
O
Me
Me
X, 76%
XII, 78%
VIIIa
H
O
H
O
a: Ac2O, pyridine
b: CH2=C(Me)OAc, TsOH
NaH, MeI, THF, imidazole
H
OAc
H
OMe
Me
Me
XI, 99% (a), 65% (b)
XIII, 82%
O
H
O
Ac2O, pyridine
VIIIb
H
OAc
Me
XIV, 98%
Scheme 6.
OAc
OAc
a: Ac2O, BF3 ·Et2O
b: Ac2O, H2SO4
H
O
H
O
c: H2C=C(Me)OAc, BF3 ·Et2O
OAc
OAc
XI
+
H
OAc
H
OAc
Me
Me
Me
O
XV
XVI
a, 30 min:
a, 60 min:
b:
c:
41%
0%
75%
57%
42%
98%
0%
0%
OAc
OAc
H
O
H
O
a: Ac2O, BF3 ·Et2O
b: Ac2O, H2SO4
OAc
OAc
XIV
+
H
OAc
H
OAc
Me
Me
Me
O
XVII
XVIII
a, 60 min:
b:
0%
70%
98%
0%
Ac2O, H3PO4, 1 h
Ac2O, H3PO4, 1 min
98%
VIIIa
XV
VIIIb
XVII
97%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

CLEAVAGE OF THE 1,6-ANHYDRO BRIDGE IN THE LEVOGLUCOSENONE ADDUCT
133
mass spectra (atmospheric pressure chemical ioniza-
tion) were obtained on a Shimadzu 2010EV GC–MS
instrument. The optical rotations were measured on
a Perkin–Elmer 341 polarimeter.
20.89 (COCH3), 21.36 (COCH3), 21.71 (C2), 22.90
(4-CH3), 28.20 (C2″), 30.07 (C1), 33.94 (C6), 53.08
(C5), 63.57 (C1′), 68.65 (C10), 88.38 (C8), 99.65 (C7),
121.94 (C3), 135.40 (C4), 167.49 (COCH3), 167.75
(COCH3), 167.75 (COCH3), 170.53 (COCH3), 208.05
(C1″). Found, %: C 57.47; H 6.21. C21H28O10. Calculat-
ed, %: C 57.27; H 6.41.
(1S,3RS,4aR,8aS)-1-Acetoxymethyl-6-methyl-4-
oxo-3,4,4a,5,8,8a-hexahydro-1H-isochromen-3-yl
acetate (IIIa/IIIb). A solution of 1.0 g (5.15 mmol) of
compound II in 10 ml of acetic anhydride was cooled
to 0°C, 0.70 g (5.15 mmol) of anhydrous zinc(II)
chloride was added, and the mixture was stirred for 2 h
at 0°C, poured onto ice, neutralized with a saturated
solution of sodium hydrogen carbonate, and extracted
with ethyl acetate (3×50 ml). The extract was dried
over MgSO4 and evaporated, and the residue was
purified by chromatography. Yield 1.03 g (67%),
IIIa:IIIb = 5:4, oily substance, Rf 0.3 (petroleum
Acetyl 2,2,6-tri-O-acetyl-3,4-dideoxy-β-D-hex-3-
enopyranoside (V) was synthesized in a similar way
from 1.0 g (7.93 mmol) of levoglucosenone (I); the
reaction mixture was stirred for 12 h at room tempera-
ture. Yield 1.57 g (60%), mp 112–113°C, Rf 0.3 (petro-
leum ether–ethyl acetate, 1:1), [α]D20 = –140.4° (c =
1
0.95, CHCl3). H NMR spectrum, δ, ppm: 2.05 s (3H,
CH3), 2.10 s (3H, CH3), 2.12 s (3H, CH3), 2.18 s (3H,
CH3), 4.22 d (1H, 6-H, J = 7.7 Hz), 4.23 d.d (1H, 6-H,
J = 7.7, 5.7 Hz), 4.38 d.d (1H, 5-H, J = 5.7, 2.4 Hz),
5.39 d.d (1H, 4-H, J = 6.2, 2.4 Hz), 6.08 d (1H, 3-H,
J = 6.2 Hz), 6.38 s (1H, 1-H). Found, %: C 50.85;
H 5.55. C14H18O9. Calculated, %: C 50.91; H 5.49.
1
ether–ethyl acetate, 5:1). H NMR spectrum,* δ, ppm:
1.60 s [1.60 s] (3H, 4-CH3), 1.83–2.10 m [1.83–
2.10 m] (3H, CH, CH2), 1.95 s [2.05 s] (3H, CH3),
2.08 s [2.12 s] (3H, CH3), 2.48 m [2.48 m] (1H, CH2),
2.60 m [2.60 m] (1H, CH2), 3.08 m [3.08 m] (1H, CH),
4.03 d [4.05 d] (1H, 1-H, J = 7.1 Hz), 4.08 d [4.11 d]
(1H, 1-H, J = 7.1 Hz), 4.22 m [4.40 m] (1H, 10-H),
5.35 m [5.35 m] (1H, 3-H), 6.09 s [5.59 s] (1H, 8-H).
13C NMR spectrum, δC, ppm: 20.54 [20.88] (COCH3),
21.68 [22.52] (C2), 23.27 [20.81] (4-CH3), 32.64
[30.76] (C5), 33.71 [31.43] (COCH3), 34.11 [35.75]
(C1), 41.01 [39.92] (C6), 64.99 [64.84] (C1), 72.61
[74.03] (C10), 90.10 [90.23] (C8), 118.59 [118.33] (C3),
130.64 [131.02] (C4), 168.76 [167.97] (COCH3),
170.53 [168.54] (COCH3), 204.49 [202.01] (C7).
Found, %: C 60.57; H 7.03. C15H20O6. Calculated, %:
C 60.80; N 6.80.
(1S,3R,4aR,8aS)-1-Hydroxymethyl-6-methyl-
4a,5,8,8a-tetrahydro-1H-isochromen-4(3H)-one
(VI) and [(1S,3R,4aR,8aS)-3,4,4-trimethoxy-6-meth-
yl-3,4,4a,5,8,8a-hexahydro-1H-isochromen-1-yl]-
methanol (VII). A solution of 10.0 g (51.54 mmol) of
compound II in 30 ml of methanol was cooled to 0°C,
90 ml of a 20% solution of HCl in methanol was ad-
ded, and the mixture was stirred for 5 h at room tem-
perature. When the reaction was complete (TLC), the
mixture was neutralized with a saturated solution of
NaHCO3 and extracted with ethyl acetate (3×50 ml),
the extracts were combined, dried over MgSO4, and
evaporated, and the residue was subjected to chroma-
tography on silica gel to isolate 6.64 g (57%) of hy-
droxy ketone VI and 1.96 g (14%) of compound VII.
(1S,3S,4aS,5R,8aS)-1-Acetoxymethyl-5-acetyl-6-
methyl-3,4,4a,5,8,8a-hexahydro-1H-isochromene-
3,4,4-triyl triacetate (IV) was synthesized in a similar
way from 1.0 g (5.15 mmol) of compound II; the reac-
tion mixture was stirred for 48 h at room temperature.
Yield 1.36 g (60%), oily substance, Rf 0.3 (petroleum
Compound VI. Oily substance. Rf 0.4 (petroleum
1
ether–ethyl acetate, 2:1). H NMR spectrum, δ, ppm:
1.60 s (3H, CH3), 1.86 m (2H, CH2), 1.98–2.17 m (3H,
CH, CH2), 2.43 br.s (1H, OH), 2.68 d.d.d (1H, 6-H,
J 12.1, 9.1, 6.6 Hz), 3.42 s (3H, OCH3) 3.62 d.d (1H,
1′-H, J = 12.0, 5.6 Hz), 3.78 d.d (1H, 1′-H, J = 12.0,
2.4 Hz), 4.0 m (1H, 10-H), 4.58 s (1H, 8-H), 5.38 m
(1H, 3-H). 13C NMR spectrum, δC, ppm: 23.17 (C2),
23.35 (CH3), 32.33 (C5), 40.50 (C1), 43.37 (C6), 55.17
(OCH3), 62.15 (C1′), 73.50 (C10), 100.57 (C8), 119.50
(C3), 131.26 (C4), 203.32 (C7). Mass spectrum: m/z
227 [M + H]+. Found, %: C 63.79; H 7.93. C12H18O4.
Calculated, %: C 63.70; H 8.02.
1
ether–ethyl acetate, 2:1). H NMR spectrum, δ, ppm:
1.68 s (3H, 4-CH3), 1.90–2.00 m (2H, CH2), 2.0 s (3H,
CH3), 2.04 s (3H, CH3), 2.07 s (3H, CH3), 2.11 s (3H,
CH3), 2.20 s (3H, CH3), 2.28 d.d (1H, 6-H, J = 6.8,
3.6 Hz), 2.64 d.d.d (1H, 1-H, J = 15.6, 11.0, 3.6 Hz),
3.09 d (1H, 5-H, J = 6.8 Hz), 3.88 d.d.d (1H, 10-H, J =
11.0, 4.7, 2.9 Hz), 4.22 d.d (1H, 1′-H, J = 5.2, 4.7 Hz),
4.24 d.d (1H, 1′-H, J = 5.2, 2.9 Hz), 5.55 d (1H, 3-H,
J = 5.1 Hz), 6.69 d (1H, 8-H, J = 1.3 Hz). 13C NMR
spectrum, δC, ppm: 20.45 (COCH3), 20.62 (COCH3),
Compound VII. Oily substance, Rf 0.2 (petroleum
1
** Hereinafter, the data for α-epimer are given in brackets.
ether–ethyl acetate, 2:1). H NMR spectrum, δ, ppm:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

SHARIPOV et al.
134
of water, the solution was cooled to 0°C, and 0.52 g
(5.1 mmol) of NaHCO3 and 1.30 g (5.1 mmol) of
iodine were added. The mixture was allowed to warm
up to room temperature, stirred for 1 h, diluted with
a saturated solution of sodium chloride, and extracted
with ethyl acetate (3×30 ml). The extracts were com-
bined, washed with a solution of Na2S2O3 and water,
dried over MgSO4, and evaporated, and the residue
was subjected to chromatography. Yield 0.75 g (92%),
oily substance, Rf 0.45 (petroleum ether–ethyl acetate,
1.55 s (3H, CH3), 1.70–2.30 m (6H, CH, CH2), 3.31 s
(3H, OCH3), 3.35 s (3H, OCH3), 3.40 s (3H, 8-OCH3),
3.43 m (1H, 10-H), 3.55 d.d (1H, 1′-H, J = 11.4,
5.5 Hz), 3.68 d.d (1H, 1′-H, J = 11.4, 1.4 Hz), 4.60 s
(1H, 8-H), 5.31 m (1H, 3-H). 13C NMR spectrum, δC,
ppm: 23.25 (CH3), 23.63 (C2), 32.03 (C5), 33.50 (C1),
38.85 (C6), 50.22 (OCH3), 50.61 (OCH3), 54.74
(8-OCH3), 62.90 (C1'), 73.59 (C10), 97.25 (C7), 97.93
(C8), 120.11 (C3), 130.75 (C4). Mass spectrum: m/z 273
[M + H]+. Found, %: C 61.57; H 8.73. C14H24O5. Cal-
culated, %: C 61.74; H 8.88.
5:1), [α]D20 = –143.0° (c = 1.58, CHCl3). H NMR spec-
1
trum, δ, ppm: 1.28 s (3H, CH3), 1.72 d.d (1H, 8-H, J =
2.6, 2.2 Hz), 1.92 d.d (1H, 3-H, J = 10.8, 2.0 Hz),
2.06 d.d (1H, 4-H, J = 14.1, 10.8 Hz), 2.22 d.d.d (1H,
7-H, J = 10.8, 10.3, 2.2 Hz), 2.52 d.d (1H, 4-H, J =
14.1, 2.0 Hz), 2.67 d.d (1H, 7-H, J = 10.8, 4.0 Hz),
3.70 d (1H, 2-H, J = 3.0 Hz), 3.72 d.d (1H, 10-H, J =
7.3, 4.7 Hz), 3.82 d (1H, 10-H, J = 7.3 Hz), 4.21 d.d
(1H, 9-H, J = 4.7, 2.6 Hz), 4.27 d.d (1H, 6-H, J = 10.3,
(1S,2S,7R,8R,9R)-5-Methyl-10,12-dioxatricyclo-
[7 . 2 . 1 . 0 2 , 7 ] d o d e c - 4 - e n - 8 - o l ( V I I I a ) a n d
(1S,2S,7R,8S,9R)-5-methyl-10,12-dioxatricyclo-
[7.2.1.02,7]dodec-4-en-8-ol (VIIIb). a. A solution of
1.0 g (5.15 mmol) of compound II in 30 ml of THF
was cooled to –78°C, 1.5 ml (6.2 mmol) of a 73%
solution of (i-Bu)2AlH in toluene was slowly added
under argon, and the mixture was stirred for 30 min at
that temperature. The mixture was then diluted with
5 ml of ethyl acetate and allowed to warm up to 0°C,
20 ml of 10% hydrochloric acid was added, and the
mixture was stirred until it became homogeneous and
extracted with ethyl acetate (3×30 ml). The extracts
were combined and dried over MgSO4, the solvent was
distilled off on a rotary evaporator, and the residue was
subjected to chromatography on silica gel to isolate
0.71 g (71%) of VIIIa and 0.10 g (10%) of VIIIb.
13
4.0 Hz), 5.27 d (1H, 1-H, J = 3.0 Hz). C NMR spec-
trum, δC, ppm: 25.55 (CH3), 27.38 (C6), 31.80 (C7),
32.31 (C8), 34.22 (C3), 38.64 (C4), 65.56 (C10), 70.96
(C5), 72.61 (C2), 75.88 (C9), 99.89 (C1). Found, %:
C 41.21; H 4.59. C11H15IO3. Calculated, %: C 41.01;
H 4.69.
(1S,2S,7R,8R,9R)-5-Methyl-10,12-dioxatricyclo-
[7.2.1.02,7]dodec-4-en-8-yl p-toluenesulfonate (X).
A solution of 0.50 g (2.55 mmol) of alcohol VIIIa
in 10 ml of pyridine was cooled to 0°C, 0.58 g
(3.06 mmol) of p-toluenesulfonyl chloride was added,
and the mixture was stirred for 12 h at room tempera-
ture. The mixture was diluted with water and extracted
with ethyl acetate (3×50 ml). The extracts were com-
bined, washed with 5% hydrochloric acid, a saturated
solution of NaCl, and water, dried over MgSO4, and
concentrated. Yield 0.68 g (76%), mp 152–155°C,
b. A solution of 1.0 g (5.15 mmol) of compound II
in 20 ml of ethanol was cooled to 0°C, and 0.20 g
(5.15 mmol) of sodium tetrahydridoborate was added
in small portions under vigorous stirring. When the
reaction was complete (TLC), the mixture was diluted
with 5 ml of acetone and evaporated, and the residue
was subjected to chromatography to isolate 0.57 g
(57%) of VIIIa and 0.21 g (21%) of VIIIb.
Rf 0.6 (petroleum ether–ethyl acetate, 2:1), [α]D20
=
–7.9° (c = 1.0, CHCl3). 1H NMR spectrum (CD2Cl2), δ,
ppm: 1.50 d (1H, CH2, J = 16.1 Hz), 1.60 s (3H, CH3),
1.78 m (1H, CH2, J = 16.1, 3.1 Hz), 2.20 m (1H, CH2),
2.35 m (1H, CH), 2.45 m (2H, CH, CH2), 2.45 s (3H,
C6H4CH3), 3.78 d.d (1H, 11-H, J = 7.4, 5.1 Hz), 3.88 d
(1H, 11-H, J = 7.4 Hz), 4.22 d (1H, 8-H, J = 2.2 Hz),
4.33 d (1H, 1-H, J = 5.1 Hz), 5.10 m (1H, 4-H), 5.32 d
(1H, 9-H, J = 2.2 Hz), 7.32 m and 7.72 d (2H each,
c. A solution of 1.0 g (5.15 mmol) of compound II
in 20 ml of THF was cooled to 0°C, and 0.20 g
(5.15 mmol) of lithium tetrahydridoaluminate was
added in small portions under vigorous stirring. When
the reaction was complete (TLC), the mixture was
diluted with 5 ml of acetone and evaporated, and the
residue was subjected to chromatography to isolate
0.53 g (53%) of VIIIa and 0.21 g (17%) of VIIIb. The
spectral parameters of compounds VIIIa and VIIIb
were identical to those reported in [4].
H
arom). 13C NMR spectrum (CD2Cl2), δC, ppm: 21.63
(C6H4CH3), 23.71 (5-CH3), 25.96 (C7), 26.21 (C3),
30.11 (C6), 35.20 (C2), 67.49 (C11), 76.71 (C1), 79.46
(C8), 100.39 (C9), 118.24 (C4), 127.89 (Carom), 129.91
(Carom), 132.63 (C5), 133.98 (Carom), 145.28 (Carom).
Found, %: C 61.79; H 6.35. C18H22O5S. Calculated, %:
C 61.70; H 6.33.
(1R,2R,3R,5S,6S,8S,9S)-6-Iodo-5-methyl-
11,12,13-trioxatetracyclo[7.2.1.12,5.03,8]tridecane
(IX). Compound VIIIa, 0.50 g (2.55 mmol), was dis-
solved in a mixture of 15 ml of diethyl ether and 3 ml
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CLEAVAGE OF THE 1,6-ANHYDRO BRIDGE IN THE LEVOGLUCOSENONE ADDUCT
135
(1S,2S,7R,8R,9R)-5-Methyl-10,12-dioxatricyclo-
[7.2.1.02,7]dodec-4-en-8-yl acetate (XI). a. Acetic an-
hydride, 0.48 ml (5.1 mmol), was added to a solution
of 0.50 g (2.55 mmol) of compound VIIIa in 10 ml of
anhydrous pyridine, and the mixture was left overnight
at 20°C. Methanol, 5 ml, was slowly added, the mix-
ture was stirred for 30 min, 20 ml of 10% hydrochloric
acid was added, and the mixture was extracted with
ethyl acetate (3×20 ml). The extracts were combined,
washed with 5% hydrochloric acid and a saturated
solution of sodium chloride, and dried over MgSO4.
The solvent was distilled off on a rotary evaporator,
and the residue was subjected to chromatography on
silica gel. Yield 0.60 g (99%). The product was
identical to that described in [4].
were added in succession under argon to a solution of
0.10 g (4.1 mmol) of sodium hydride in 10 ml of tetra-
hydrofuran. The mixture was stirred for 5 h at 50°C
and cooled to room temperature, and 0.32 ml
(5.1 mmol) of methyl iodide was added. When the re-
action was complete (TLC), the mixture was carefully
treated with water and extracted with ethyl acetate
(3×15 ml). The extract was dried over MgSO4, the
solvent was distilled off on a rotary evaporator, and the
residue was subjected to chromatography on silica gel.
Yield 0.44 g (82%), mp 66–68°C, Rf 0.4 (petroleum
1
ether–ethyl acetate, 5:1). H NMR spectrum (CCl4–
C6D6), δ, ppm: 1.48 m (1H, CH2), 1.50 m (1H, CH),
1.55 s (3H, 5-CH3), 1.72 br.d (1H, CH2, J = 16.4 Hz),
2.07 m (1H, CH), 2.12 m (1H, CH2), 2.48 d (1H, CH2,
J = 16.4 Hz), 2.73 br.s (1H, 8-H), 3.14 s (3H, OCH3),
3.55 m (2H, 11-H), 3.98 d (1H, 1-H, J = 4.0 Hz),
5.15 m (1H, 4-H), 5.27 br.s (1H, 9-H). 13C NMR spec-
trum, δC, ppm: 23.57 (5-CH3), 26.22 (C7), 26.31 (C3),
30.23 (C6), 35.66 (C2), 58.73 (OCH3), 66.69 (C11),
76.07 (C1), 80.87 (C8), 99.76 (C9), 118.13 (C4), 132.33
(C5). Found, %: C 68.32; H 8.86. C12H18O3. Calculat-
ed, %: C 68.55; H 8.63.
b. A catalytic amount of p-toluenesulfonic acid was
added to a solution of 0.50 g (2.55 mmol) of alcohol
VIIIa in 5 ml of isopropenyl acetate, and the mixture
was stirred for 1 h. Excess reagent was distilled off on
a rotary evaporator, and the residue was purified by
chromatography on silica gel. Yield 0.40 g (65%).
(1S,2S,7R,8R,9R)-5-Methyl-8-trimethylsiloxy-
10,12-dioxatricyclo[7.2.1.02,7]dodec-4-ene (XII).
Chloro(trimethyl)silane, 0.98 ml (7.65 mmol), was
added to a solution of 0.50 g (2.55 mmol) of alcohol
VIIIa in 10 ml of anhydrous pyridine, and the mixture
was left overnight at 20°C. The mixture was then
slowly treated with 20 ml of 10% hydrochloric acid
and extracted with ethyl acetate (3×20 ml). The ex-
tracts were combined, washed with a saturated solution
of sodium chloride and water, and dried over MgSO4.
The solvent was distilled off on a rotary evaporator,
and the residue was purified by chromatography on
silica gel. Yield 0.53 g (78%), oily substance, Rf 0.6
(petroleum ether–ethyl acetate, 10:1), [α]D20 = +21.4°
(1S,2S,7R,8S,9R)-5-Methyl-10,12-dioxatricyclo-
[7.2.1.02,7]dodec-4-en-8-yl acetate (XIV) was synthe-
sized as described above for compound XI from 0.30 g
(1.53 mmol) of alcohol VIIIb. Yield 0.36 g (98%); the
product was identical to that described in [4].
(1S,3RS,4R,4aR,8aS)-1-Acetoxymethyl-6-methyl-
3,4,4a,5,8,8a-hexahydro-1H-isochromene-3,4-diyl
diacetate (XV) and (1S,3RS,4R,4aS,5R,8aS)-1-acet-
oxymethyl-5-acetyl-6-methyl-3,4,4a,5,8,8a-hexa-
hydro-1H-isochromene-3,4-diyl diacetate (XVI).
a. A solution of 0.30 g (1.26 mmol) of acetate XI in
5 ml of acetic anhydride was cooled to 0°C, 0.31 ml
(2.52 mmol) of BF3·Et2O was added dropwise under
stirring, and the mixture was allowed to warm up to
room temperature. After 30 min (or 1 h), the mixture
was neutralized with a saturated solution of NaHCO3
and extracted with methylene chloride (3×15 ml), the
extracts were combined and washed with a saturated
solution of sodium chloride, the solvent was distilled
off on a rotary evaporator, and the residue was sub-
jected to chromatography on silica gel to isolate 0.18 g
(41%) of epimeric triacetates XV and 0.20 g (42%) of
epimeric acetyl derivatives XVI (in 30 min) or only
0.42 g (98%) of XVI (in 1 h).
1
(c = 1.4, CHCl3). H NMR spectrum, δ, ppm: 0.02 s
(9H, SiCH3), 1.62 s (3H, 5-CH3), 1.60–1.90 m (3H,
CH, CH2), 2.12 m (1H, CH), 2.30 d (1H, CH, J =
2.8 Hz), 2.60 d (1H, CH2, J = 11.8 Hz), 3.47 d.d (1H,
8-H, J = 2.8, 2.1 Hz), 3.82 d.d (1H, 11-H, J = 7.0,
4.9 Hz), 3.92 d (1H, 11-H, J = 7.0 Hz), 4.32 d (1H,
1-H, J = 4.9 Hz), 5.15 d (1H, 9-H, J = 2.1 Hz), 5.28 m
(1H, 4-H). 13C NMR spectrum, δC, ppm: 0.01 (SiCH3),
23.57 (5-CH3), 26.90 (C3), 26.91 (C7), 30.78 (C6),
35.78 (C2), 66.89 (C11), 72.14 (C8), 76.34 (C1), 103.07
(C9), 118.14 (C4), 132.60 (C5). Found, %: C 62.52;
H 9.12. C14H24O3Si. Calculated, %: C 62.64; H 9.01.
(1S,2S,7R,8R,9R)-8-Methoxy-5-methyl-10,12-di-
oxatricyclo[7.2.1.02,7]dodec-4-ene (XIII). Compound
VIIIa, 0.55 g (2.55 mmol), and imidazole, 0.01 g,
b. A solution of 0.30 g (1.26 mmol) of acetate XI in
10 ml of acetic anhydride was cooled to 0°C, a solu-
tion of 0.2 ml of H2SO4 in 1.5 ml of Ac2O was added,
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SHARIPOV et al.
136
and the mixture was stirred for 20 min at 0°C. The
mixture was poured into an ice–water mixture contain-
ing 45 g of NaHCO3, stirred until gas no longer
evolved, and extracted with ethyl acetate (3×50 ml).
The extracts were combined, washed with a saturated
solution of NaHCO3, a saturated solution of NaCl, and
water, dried over MgSO4, and evaporated, and the
residue was subjected to chromatography to isolate
0.33 g (75%) of epimeric acetates XV.
170.70 [169.80] (COCH3). Found, %: C 60.19; H 6.91.
C17H24O7. Calculated, %: C 59.99; H 7.11.
Compound XVI. Oily substance, Rf 0.26 (petro-
1
leum ether–ethyl acetate, 2:1), β:α = 1:1. H NMR
spectrum, δ, ppm: 1.64 s [1.61 s] (3H, CH3), 1.93–
2.07 m [1.93–2.07 m] (1H, CH), 1.99 s [2.00 s] (3H,
CH3), 2.02 s [2.05 s] (3H, CH3), 2.06 s [2.09 s] (3H,
CH3), 2.19–2.24 m [2.19–2.24 m] (2H, CH2), 2.19 s
[2.20 s] (3H, COCH3), 2.45 m [2.45 m] (1H, CH),
3.12 m [3.12 m] (1H, 5-H), 3.80 d.t [3.71 m] (1H,
10-H, J = 10.9, 3.4 Hz), 4.20 m [4.20 m] (2H, 1′-H),
[4.94 d.d (1H, 7-H, J = 8.8, 5.9 Hz)], 5.07 d.d (1H,
7-H, J = 4.6, 3.8 Hz), [5.45 d (1H, 3-H, J = 3.7 Hz)],
5.50 d (1H, 3-H, J = 5.1 Hz), [5.78 d (1H, 8-H, J =
8.8 Hz)], 6.19 d (1H, 8-H, J = 3.8 Hz). 13C NMR spec-
trum, δC, ppm: 20.36 [20.36] (COCH3), 20.45 [20.65]
(COCH3), 20.84 [21.80] (4-CH3), 21.71 [20.18] (C2),
22.99 [22.90] (C2″), 28.88 [28.70] (COCH3), 29.40
[31.20] (C1), 35.0 [35.41] (C6), 52.56 [52.09] (C5),
63.47 [60.01] (C1′), 68.62 [70.16] (C10), 68.86 [74.39]
(C7), 89.56 [89.88] (C8), 122.20 [121.83] (C3), 135.33
[135.03] (C4), 166.77 [166.11] (COCH3), 169.37
[169.0] (COCH3), 170.56 [169.11] (COCH3), 208.75
[208.23] (C1″). Found, %: C 59.57; H 6.96. C19H26O8.
Calculated, %: C 59.68; H 6.85.
c. A solution of 1.26 mmol of compound XI in
3.0 ml of methylene chloride–isopropenyl acetate (1:1)
was cooled to 0°C, 0.2 ml (2.52 mmol) of BF3·Et2O
was slowly added, and the mixture was stirred until the
reaction was complete. The mixture was then treated
with 5 ml of water and extracted with methylene
chloride (3×15 ml), the extracts were combined and
dried over MgSO4, the solvent was distilled off on
a rotary evaporator, and the residue was subjected to
chromatography. Yield of triacetate XV 0.25 g (57%).
d. A solution of 0.50 g (2.55 mmol) of compound
VIIIa in 10 ml of acetic anhydride was cooled to 0°C,
a mixture of 0.5 ml of H3PO4 and 0.5 ml of Ac2O was
added dropwise under stirring, and the mixture was
stirred for 1 h at room temperature. The mixture was
then poured into an ice–water mixture containing
40.0 g of NaHCO3, stirred until gas no longer evolved,
and extracted with ethyl acetate (3×100 ml). The ex-
tracts were combined, washed with a solution of
NaHCO3, a saturated solurtion of NaCl, and water,
dried over MgSO4, and evaporated, and the residue
was subjected to chromatography to isolate 0.84 g
(97%) of epimers XV.
(1S,3RS,4S,4aR,8aS)-1-Acetoxymethyl-6-methyl-
3,4,4a,5,8,8a-hexahydro-1H-isochromene-3,4-diyl
diacetate (XVII) and (1S,3RS,4S,4aS,5R,8aS)-1-
acetoxymethyl-5-acetyl-6-methyl-3,4,4a,5,8,8a-
hexahydro-1H-isochromene-3,4-diyl diacetate
(XVIII). The reactions were performed as described
above for compounds XV and XVI.
Compound XV. Oily substance, Rf 0.55 (petroleum
ether–ethyl acetate, 3:1), β:α = 2:1. H NMR spec-
a. BF3 ·Et2O–Ac2O. From 0.30 g (1.26 mmol) of
acetate XIV (reaction time 1 h) we obtained 0.42 g
(98%) of acetyl derivative XVIII.
1
trum, δ, ppm: 1.63 s [1.63 s] (3H, CH3), 1.80 m
[1.80 m] (1H, CH2), 2.0–2.22 m [2.0–2.22 m] (4H,
CH, CH2), 2.02 s (6H, CH3), 2.08 s [2.09 s] (3H, CH3),
[2.10 s (3H, CH3)], [2.12 s (3H, CH3)], 2.52 m
[2.36 m] (1H, CH2), 3.89 m [4.04 m] (1H, CH), 4.20 m
[4.20 m] (2H, 1′-H), 4.89 d.d (1H, 10-H, J = 7.6,
5.3 Hz) [5.12 d.d (1H, 10-H, J = 5.1, 4.7 Hz)], 5.36 m
[5.40 m] (1H, 3-H), 6.0 d (1H, 8-H, J = 7.5 Hz) [6.24 d
(1H, 8-H, J = 4.2 Hz)]. 13C NMR spectrum, δC, ppm:
20.67 [20.58] (COCH3), 20.93 [21.08] (COCH3),
22.11 [22.11] (C2), 23.33, [23.33] (4-CH3), 30.37
[29.49] (C5), 32.03 [32.03] (COCH3), 33.21 [33.21]
(C6), 33.61 [33.61] (C1), 64.44 [64.12], (C1′), [70.06
(C10)], 72.15 [67.73] (C7), [72.39 (C10)], 90.28 [90.12]
(C8), 118.08 [119.28] (C3), 131.27 [130.32] (C4),
169.29 [169.09] (COCH3), 169.69 [169.29] (COCH3),
b. H2SO4–Ac2O. From 0.30 g (1.26 mmol) of ace-
tate XIV we obtained 0.30 g (70%) of triacetate XVII.
c. H3PO4–Ac2O. From 0.30 g (1.53 mmol) of
alcohol VIIIb we obtained 0.51 g (98%) of triacetate
XVII.
Compound XVII. Oily substance, Rf10.5 (petroleum
ether–ethyl acetate, 3:1), β:α = 1:1. H NMR spec-
trum, δ, ppm: 1.66 s [1.70 s] (3H, CH3), 1.98 m
[1.98 m] (1H, CH2), 2.0–2.20 m [2.0–2.20 m] (3H,
CH, CH2), [2.10 s (3H, CH3)], [2.12 s (3H, CH3)],
2.13 s [2.06 s] (3H, CH3), 2.14 s (6H, CH3), 2.30 m,
[2.30 m] (1H, CH2), 2.42 m [2.42 m] (1H, CH2),
3.88 m, [4.06 m] (1H, CH), 4.32 m [4.25 m] (2H,
1′-H), 4.74 d.d (1H, 10-H, J = 3.6, 2.7 Hz) [4.98 d.d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

CLEAVAGE OF THE 1,6-ANHYDRO BRIDGE IN THE LEVOGLUCOSENONE ADDUCT
137
(COCH3), 170.59 (COCH3), 208.59 (C1″). Found, %:
C 60.57; H 7.03. C15H20O6. Calculated, %: C 60.80;
H 6.80.
(1H, 10-H, J = 9.7, 3.1 Hz)], 5.37 m [5.30 m] (1H,
3-H), 6.0 d (1H, 8-H, J = 2.4 Hz), [6.22 d (1H, 8-H,
J = 3.2 Hz)]. 13C NMR spectrum, δC, ppm: 20.92
[20.74] (COCH3), 21.00 [21.08] (COCH3), 23.36
[23.36] (4-CH3), 23.63 [24.34] (C2), 27.86 [27.86]
(COCH3), 30.07 [30.07] (C6), 30.19, [30.38] (C5),
32.75 [32.17] (C1), 64.90 [64.21] (C1′), 67.07 [69.47]
(C7), 70.07 [74.50] (C10), 89.76 [91.91] (C8), 118.76
[117.64] (C3), 131.10 [131.94] (C4), 168.62 [169.23]
(COCH3), 169.83 [170.18] (COCH3), 170.81 [170.67]
(COCH3). Found, %: C 59.77; H 7.33. C17H24O7. Cal-
culated, %: C 59.99; H 7.11.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 08-03-97033-r_povolzh’e_a, NSh-1725.2008.3).
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122.55 (C3), 134.65 (C4), 168.01 (COCH3), 169.48
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