Stereoselective synthesis of highly substituted 8-oxabicyclo[3.2.1]octanes and 2,7-dioxatricyclo[4.2.1.03,8]nonanes

Article abstract of DOI:10.1016/j.tet.2012.05.029

The synthesis of new polyhydroxylated 8-oxabicyclo[3.2.1]octanes and 2,7-dioxatricyclo[4.2.1.0^3,8]nonanes is described. These structures is an interesting synthetic blocks for potential bioactive molecules. The precursor, 3-chloro-8-oxabicyclo[

Full text of DOI:10.1016/j.tet.2012.05.029

Tetrahedron 68 (2012) 5785e5792
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Tetrahedron
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Stereoselective synthesis of highly substituted 8-oxabicyclo[3.2.1]octanes
and 2,7-dioxatricyclo[4.2.1.03,8]nonanes
,
a
a
a,b
Dmitry A. Khlevin a , Sergey E. Sosonyuk , Marina V. Proskurnina , Nikolay S. Zefirov
*
a Department of Chemistry, Moscow State Lomonosov University, Lenin Hills, 1, Moscow 119992, Russian Federation
b Institute of Physiologically Active Compounds RAS, Severny proezd, 1, Chernogolovka 142432, Russian Federation
a r t i c l e i n f o
a b s t r a c t
The synthesis of new polyhydroxylated 8-oxabicyclo[3.2.1]octanes and 2,7-dioxatricyclo[4.2.1.03,8]non-
anes is described. These structures is an interesting synthetic blocks for potential bioactive molecules.
The precursor, 3-chloro-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione was obtained from reaction of tetra-
chlorocyclopropene with furan, then it was involved in carbonyl groups reduction and double bond
oxidation, resulted in the formation of a polyhydroxylated derivatives, differently substituted at C-3
position, with five new stereocenters.
Using intramolecular transannular hydroxycyclization, bicyclic epoxy diacetate was transformed into 2,7-
dioxatricyclo[4.2.1.03,8]nonane in high yield through an alkoxide intermediate. Compounds thus obtained
have a structure close to certain molecules with antitumor and glycosidase inhibitors activity.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 10 February 2012
Received in revised form 25 April 2012
Accepted 8 May 2012
Available online 15 May 2012
Keywords:
8-Oxabicyclo[3.2.1]octanes
2,7-Dioxatricyclo[4.2.1.03,8]nonanes
Hydride reduction
Transannular hydroxycyclization
Diastereoselectivity
1. Introduction
endocyclic oxygen atom in monosaccharides are thought to be
more promising drug candidates than natural sugars, since they are
Our research interests lie in the synthesis of new poly-
hydroxylated cycloheptane scaffolds, which could possess various
biological activities, and act as linkers for the building of complex
hybrid structures through hydroxyl group functionalization. Here,
we describe the application of some simple chemical trans-
formation (carbonyl group reduction, double bond oxidation,
intramolecular hydroxycyclization) in high diastereoselectivity, to
create five new stereocenters in oxabicyclooctane structures.
8-Oxabicyclo[3.2.1]octane derivatives can be considered as
structural analogs and synthetic precursors of tropane alkaloids
(e.g., calystegines1 and scopoline,2 see Fig. 1), and other bioactive
compounds (e.g., polyketides3 and tetrahydropyrans4). Calyste-
gines and other tropane alkaloids show remarkable inhibitory ac-
tivities against several glycosidase enzymes, so the same activity is
expected from their analogs. Glycosidase inhibitors were a subject
of a number of works in the past decade, most of which has been
reviewed.5 These compounds have already been used or tested in
the treatment of diabetes and HIV infection, as antifungal agents
and are expected to arouse increasing interest as therapeutic agents
as our understanding of the role of glycosidases in recognition
processes improves. It is also worth mentioning that carba-analogs
of oligosaccharides (carbasugars) generated by replacing the
hydrolytically stable.6
Hoffmann et al. used 8-oxabicyclo[3.2.1]octanes to generate the
2,7-dioxatricyclo[4.2.1.03,8]nonane core of the antitumor terpenic
natural product dictyoxetane.7 The elaboration of the oxetane and
oxolane rings of ingenol and thromboxane A2 analogs has been
elegantly carried out.8 Recently several 8-oxabicyclo[3.2.1]octanes
have been found to possess moderate anti-HIV activity.9 Moreover,
8-oxabicyclo[3.2.1]octane derivatives have shown broad utility as
chiral building blocks for construction of C-linked nucleosides10
and disaccharides.11 De novo synthesis of a full set of hybrid C-
glycosides and thymine polyoxin C starting with the unsaturated 8-
oxabicyclo[3.2.1]octane framework was reported.12
Lautens et al. showed that 8-oxabicyclo[3.2.1]octane derivatives
can be readily transformed to non-bridged cycloheptane de-
rivatives.13 Thus, our methodology could be an efficient way to
wide range of non-natural carbasugar molecules.
Here, we report on concise stereoselective way to poly-
hydroxylated bridged cycloheptane derivatives as potential glyco-
sidase inhibitors, antitumor agents and building blocks for complex
nature-type carbasugars.
2. Results and discussion
There are several synthetic ways to 8-oxabicyclo[3.2.1]octane
* Corresponding author. Tel.: þ7 916 278 8275; fax: þ7 495 939 0290; e-mail
address: khlevindmitry@yahoo.com (D.A. Khlevin).
core. The [4þ3]-cycloaddition reaction is the most common.14 An
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.029

5786
D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
(pKw5). It caused the vigorous decomposition of hydrides and low
HN
O
HO
HN
conversion of starting materials (5e15%), but fortunately, we have
found that the use of diisobutylaluminum hydride (DIBAL-H) al-
lows to overcome those problem.16
=
OH
OH
O
N
H
OH
Here we describe two other ways to avoid the difficulties by
modification of the C-3 position in diketone 2, namely, alkylation
and chlorine reduction. Early, methylation of 2 was investigated by
Wright et al.17 It has been shown that the activated proton in 2 is
acidic enough to use Et3N as a base for alkylation, and compound 3
was readily obtained. Its configuration was proved by X-ray dif-
fraction analysis with methyl group in exo-position. We increased
the yield of methylation using methyl iodide in acetone with K2CO3
as a base (Scheme 2).
Calystegine B2
Scopoline
O
OR
O
O
R
N
O
HO
O
HO
R
Hal
Boc
Ingenol and
Scopoline
Dictyoxetane
thromboxane
analogue (ref. 2e)
OAc
precursor (ref. 7)
precursor (ref. 8)
O
O
O
MeI, K2CO3
N
N
CH3
Cl
O
O
O
NHBoc
Cl
O
acetone, 20 o
36 h, 83%
C
OH
N
N
O
O
2
3
C-linked
anti-HIV activity (ref. 9)
nucleoside (ref.10)
NMe2
O
Zn, AcOH
50 oC, 30 min
68%
Zn, AcOH
50 oC, 30 min
80%
RO
O
OAc
MeOOC
OBz
H
O
O
C-linked
disaccaride (ref. 11)
O
O
CH3
PhS
OTBS
OBn
OR
AcO
O
O
4
5
Scheme 2. Synthesis of diketones 3e5.
Fig. 1. Examples of some bioactive bridged cycloheptane derivatives.
The same authors described the dechlorination protocol using
zinc in acidic media, however, the isolation of diketone 4 was
mentioned to be difficult owing to high water solubility and ready
deprotonation. We applied flash chromatography for purification,
and compound 4 was isolated in good yield (Scheme 2). Using the
same conditions for dechlorination of diketone 3, compound 5 was
obtained in high yield. Compared with the diketone 4, it was much
more stable and easy to isolate.
As already mentioned above, the reduction of diketone 2 by
complex hydrides was complicated. Many reducers were tested,
among them NaBH4, LiAlH4, LiAl(OR)3H, LiR3BH and others, but the
best conditions tested so far was treatment with DIBAL-H. Straight
reduction was unsuccessful, in all cases complex mixture were
afforded, so two-steps methodology was proposed (Scheme 3).
Thus, reduction of 2 was performed with 1 equiv of DIBAL-H in
anhydrous THF at ꢀ40 ꢁC, obtaining the ketoalcohol 6 in 68% yield.
Then, a further reduction of 6 with the 2 equiv of DIBAL-H afforded
the mixture of diastereomeric diols 7a and 7b in 2:1 ratio, which
were separated.
alternative approach is the Tobey and Law synthesis of the 1,3-
diketone 2 (Scheme 1) in just two steps from commercially avail-
able tetrachlorocyclopropene.15
O
[4+3]-cycloaddition
O
O
O
Cl
Cl
O
O
CCl4
Cl Cl
Cl
H2SO4 (conc.)
O
Cl
Cl
O
O
80 oC, 18 h
92%
55 oC, 1 h
78%
Cl
Cl
1
2
Scheme 1. Synthesis of 8-oxabicyclo[3.2.1]octanes core.
Cyclocondensation of tetrachlorocyclopropene and furan pro-
ceeds through an initial DielseAlder reaction to produce 1 in high
yield. Direct hydrolysis of 1 under strongly acidic conditions and
elevated temperatures delivers the 1,3-dione 2. Reported yield for
this step was moderate (42%) but we optimized the conditions to
get 78% of yield so 2 could be easily produced in multigram
quantities. As mentioned above, the main objective of our work is
the synthesis of polyhydroxylated cycloheptane core, with the se-
lective creating of new stereocenters. Therefore, following trans-
formations of diketone 2 should involve reduction of the carbonyl
groups and oxidation of the double bond. As far as we know,
diketone 2 never been used for constructing of polyhydroxylated
cycloheptane derivatives, probably because of difficulties with
carbonyl group reduction.
OH
Cl
OH
OH
Cl
OH
O
DIBAL-H
(1,1 eq.)
DIBAL-H
(2 eq.)
O
O
O
Cl
2
hexane/THF
hexane/THF
40 oC
40 oC, 68%
−
−
7b
7a
OH
OH
6
(25%)
(50%)
LiAlH4 (1 eq.)
+ 6 (20%)
7a
2
O
Cl
OH
+
(12%) + other products
THF, 40 oC
−
30 min
7c
(15%)
Actually, the reduction of diketone 2 by complex hydride re-
agents (NaBH4, LiAlH4) was challenging due to its high CeH acidity
Scheme 3. Reduction of diketone 2.

D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
5787
The stereochemistry of both compounds has been established
O
OH
CH3
Cl
OH
by careful 1H and 13C NMR correlation studies. However, NMR
spectroscopic studies did not allow to assign exact configuration of
all stereocenters in the six-membered ring so isomer 7a was sub-
jected to X-ray analysis,16 resulted in the proposed structure with Cl
and OH-groups in equatorial positions (Fig. 2).
CH3 NaBH4, MeOH
20 oC, 30 min
O
O
Cl
75%
O
3
7d
The corresponding coupling constants are 1,2J¼4.3 and
2,3J¼8.1 Hz for eea and aea pairs, respectively. Small coupling
constant 4,5J¼1.0 Hz in the trans-isomer 7b associated with eee
configuration. These configurational assignments were confirmed
with NOE experiments: positive effect (1.5e3%) in case of eea and
eee proton pairs corroborate it once again (Fig. 3).
LiAlH4
THF
60 oC
−
OH
CH3
7e OH
other
7d
O
products
(25%)
Configuration of ketoalcohol 6 could be established easily by
similar NMR data with the diol 7a. One more Cl-containing isomer
7c was isolated from the reaction mixture of diketone 2 with LiAlH4
in anhydrous THF (Scheme 3).
Subsequently the reduction of diketones 3e5 was investigated.
As expected, methylated diketone 3 was smoothly reduced with
NaBH4 in methanol at room temperature obtaining the only di-endo
diol isomer 7d in 75% yield (Scheme 4). Attempting the LiAlH4 re-
duction led to a complex mixture even at ꢀ60 ꢁC, from which the
diols 7d and 7e were isolated in poor yields.
(20%)
OAc
CH3
OAc
OH
CH3
NaBH4, MeOH
Ac2O, Py
O
5
O
0 oC to rt
52%
rt, 24h
92%
OH
OH
7e
8e
OH
Diol 7e was the major product of diketone 5 reduction with
NaBH4 (Scheme 4). Several other isomers were detected in
NMR spectra of reaction mixture, but they were not isolated.
Coupling constant 1,2J¼4.3 Hz was in good agreement with pro-
posed configuration of OH-groups, but stereochemistry of methyl
group was ambiguous and recourse was made to X-ray crystallog-
raphy. Since diol 7e was isolated as an oil we synthesized crystalline
diacetate 8e.
NaBH4, MeOH
0 oC to rt
O
O
4
OH
OH
7f
7g
(54%)
(32%)
Scheme 4. Reduction of diketones 3e5 with NaBH4.
X-ray diffraction analysis showed the axial position of methyl
group (Fig. 4), thus the configuration of diol 7e was completely
defined.18
Finally, diketone 4 was reduced with NaBH4 in methanol at
room temperature to produce mixture of two isomeric diols
7f and 7g in 3:2 ratio (Scheme 4). They were separated and
purified by column chromatography and spectroscopically
characterized.
For further transformations we carried out protection of the
OH-groups. A benzyl ether was the protecting group of choice here
because of its stability and the simplicity of its removal. Alcohols
were thus treated with NaH and BnBr in anhydrous THF under the
classical Williamson reaction conditions (Scheme 5). In most
cases, corresponding benzyl derivatives 9 was synthesized in high
yields. As an exception, diols 7c and 7d containing axial Cl atom
failed in the Williamson reaction. Complex mixtures were
obtained with only traces of benzyl ethers. Most probably, the
intramolecular nucleophilic attack was preferable in these cases
though corresponding epoxides were not isolated. At the same
time acylation of diols 7c and 7d proceed smoothly under the
same conditions as those applied for 7e to afford acetates 8c and
8d in high yield.
Fig. 2. X-ray structure of diol 7a.
NOE = 1.5%
NOE = 1.5%
J = 4.3 Hz
J = 4.8 Hz
H4
O
H5
H5
O
O
H2
HO
H2
Cl
Cl
H1
H1
HO
H3
HO
H3
NOE ~ 0 %
NOE~0%
J = 7.3 Hz
J = 8.1 Hz
6
7a
NOE = 2.5%
NOE = 0%
J = 3.5 Hz
J = 1 Hz
NOE = 1.5%
NOE = 3.5%
H4
J = 5.8 Hz
J = 5.3 Hz
OH
H5
H5
O
O
H4
HO
H3
H2
H2
J = 4.5 Hz
Cl
NOE = 1%
H1
H1
HO
HO
H3
Cl
NOE = 0%
J = 9 Hz
7b
7c
Fig. 3. NOE dif. couplings of some Cl-containing alcohols.
Fig. 4. X-ray structure of diacetate 8e.

5788
D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
Scheme 6. Synthesis of oxetane diol 14.
Thus we demonstrated the concise and practical route to dif-
ferent polyhydroxylated polycyclic scaffolds, based on cheap and
easy available substrates and reagents. High stereoselectivity was
observed.
3. Conclusions
In summary, we have established a methodology to obtain 3-
functionalized polyhydroxylated 8-oxabicyclo[3.2.1]octanes with
good yield and a high stereoselectivity. By this method it is possible
to prepare a wide variety of derivatives (alkyl, chloro) under mild
conditions. Acetyl protected epoxy alcohol was successfully con-
verted to tricyclic oxetane diol. Substances thus obtained could
possess different biological activity and be precursors of other
carbasugars and complex structures.
All compounds synthesized have been isolated, purified and
physically and spectroscopically characterized. The stereochemis-
try has been unequivocally assigned by a careful correlation of 1H,
13C and NOE NMR data and confirmed by X-ray diffraction analysis.
Scheme 5. Protection of OH-groups and oxidation of double bond.
Further functionalization of 8-oxabicyclo[3.2.1]octane skeleton
was achieved by the double bond oxidation. According to the
symmetry in the molecule, the hydroxylation reagent can approach
with the endo- as well as from the exo-face. Previous research
consider this reaction proceed with high exo-stereoselectivity.19
Actually, treatment of symmetrical ethers 9a, 9e and 9f with
OsO4/NMO gave only a single exo-isomers 10 (Scheme 5) without
considerable 1,7J or 2,6J coupling constants. Epoxidation of ethers 9a,
9e and 9f was performed by m-CPBA in anhydrous CH2Cl2 at room
temperature. The reaction was completed after 48 h, affording
single stereoisomers of epoxides 11 in 76e85% yield.
Removal of the benzyl protecting groups with H2 and Pd/C in
methanol gave the tetraol 12a in almost quantitative yield. Notably,
Cl atom was retained after hydrogenation. Thereby we suggest
versatile way to create five new stereocenters in the 8-oxabicyclo
[3.2.1]octane core. Our approach is flexible providing different
polyhydroxylated compounds in stereocontrolled fashion, that
could act as glycosidase inhibitors. Frameworks thus obtained
could be convenient linkers for construction of complex molecules
as well. Hydroxyl groups introduced step by step might be func-
tionalized in different manner.
4. Experimental section
4.1. General methods
All the solvents were distilled prior to use. Dry solvents were
prepared according to the standard procedures. Reactions requiring
an inert atmosphere were carried out under argon. All reactions
were monitored by TLC using Merck 60 F254 precoated silica gel
plates (0.25 mm thickness). Flash and column chromatography was
performed by using silica gel 60 from MachereyeNagel. 1H and 13
C
NMR spectra were recorded in CDCl3 or DMSO-d6 with a Bruker
Avance 400 (400 MHz for 1H NMR, 100 MHz for 13C NMR) in-
strument. Data for 1H NMR spectra are reported as chemical shift (
d
[ppm]), number of protons, multiplicity (s¼singlet, d¼doublet,
t¼triplet, m¼multiplet) and coupling constant (J [Hz]). Data for 13C
NMR spectra are reported as chemical shift (d [ppm]). Chemical
In order to use synthetic potential of the epoxide ring moiety
compounds 11a, 11e, 11f were treated with some basic and acidic
reagents. All attempts of nucleophilic ring opening with NaOH or
NaN3 were unsuccessful: even after refluxing in DMF or aqueous
media only starting materials were recovered. Reactions with Ac2O
in the presence of Lewis acids (BF3eEt2O or ZnCl2) afforded the
complex mixture of rearrangement products. Thus we decided to
explore the intramolecular nucleophilic reaction.
shifts were reported in parts per million from the residual solvent
as an internal standard. Infrared (IR) spectra were recorded in KBr
pellets on a Thermo Nicolet IR-200 spectrometer. Elemental anal-
yses were carried on Vario MICRO cube analyzer.
Crystallographic data for the structures in this paper have been
deposited at the Cambridge Crystallographic Data Center and al-
located the deposit numbers CCDC 741610 for 7a and 841294 for 8e.
As already mentioned above, Hoffmann et al. reported the
synthesis of the 2,7-dioxatricyclo[4.2.1.03,8]nonane core from some
8-oxabicyclo[3.2.1]octanes. These oxetanes can be considered as
structural analogs of antitumor terpenic natural product dictyox-
etane.7 We decided to apply this methodology to our substrates.
We synthesized the diacetate 13 using the same procedures as
described above to indirectly generate the alkoxide from hydroxyl
group by using NaOH. Treating with 10 equiv NaOH in MeOH at
room temperature after 24 h gave the dioxatricycle 14 in 72% yield
(Scheme 6) with the structure close to dictyoxetane analogs in-
vestigated by Hoffmann.
4.2. 3-Chloro-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione (2)
It was prepared by the modified procedure of Tobey and Law.15
Compound 1 (9.00 g, 37.0 mmol) was mixed with 130 mL of conc.
H2SO4 (d¼1.84 g/mL) and heated at 50e55 ꢁS with good stirring
during 1 h (until the intensive gas evolving stopped). The resulting
mixture was cooled to room temperature and poured into the ice-
cold water (500 mL) followed by extraction with methylene chlo-
ride (5ꢂ20 mL). The combined organic layers were dried over an-
hydrous Na2SO4 and evaporated under reduced pressure to yield

D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
5789
crude product, which after recrystallization from chloroform gave
J 6.1 Hz), 6.44 (1H, d, J 6.1 Hz), 5.06 (1H, d, J 4.8 Hz), 4.78 (1H, s),
4.68 (1H, d, J 7.3 Hz), 4.23 (1H, dd, J 4.8, 7.3 Hz); 13S NMR
diketone 2 (5.04 g, 78%) as a white crystalline solid, mp 137e138 ꢁC
(CHCl3). (lit. 139e140 ꢁC15); 1O NMR (400 MHz, CDCl3):
d
6.40 (2O,
6.88
192.0, 132.3, 86.6,
(100 MHz, CDCl3): d 191.7, 134.2, 131.4, 85.0, 82.2, 75.9, 65.1; IR
s), 5.91 (1H, s), 5.49 (2H, s); 1O NMR (400 MHz, DMSO-d6):
d
(cmꢀ1):
3380e3460, 3090, 2960, 1747, 1733, 1660, 1322, 1050,
~
n
(2H, s), 5.20 (2H, s); 13S NMR (100 MHz, CDCl3):
d
935; Anal. Calcd for S7O7O3Cl: S, 48.14; O, 4.01. Found: S, 47.97;
O, 4.22.
72.6; IR (cmꢀ1):
3100, 2920, 1770, 1740, 1675, 1145, 1068, 941.
~
n
4.3. 3-endo-Chloro-3-exo-methyl-8-oxabicyclo[3.2.1]oct-6-
ene-2,4-dione (3)
4.7. Reduction of ketoalcohol (6) with DIBAL-H
1
M hexane solution of DIBAL-H (8.00 mL, 8.00 mmol) was
To a solution of diketone 2 (0.50 g, 2.90 mmol) in acetone
(10 mL) K2CO3 (0.83 g, 6.01 mmol) and MeI (1.38 g, 9.72 mmol)
were added. The mixture was stirred at room temperature for 36 h,
then concentrated under reduced pressure. The residue was puri-
fied via silica gel flash chromatography (EtOAc/CH2Cl2¼1:9), to give
a pale yellow crystalline solid of diketone 3 (0.45 g, 83%); mp
97e98 ꢁC (diethyl ether); Rf 0.5 (CH2Cl2); 1O NMR (400 MHz,
added dropwise during 10 min at ꢀ60 ꢁS to a solution of ketoal-
cohol 6 (700 mg, 4.01 mmol) in 30 mL of dry THF under argon
atmosphere followed by stirring for 30 min. After that MeOH
(10 mL) was added, resulting mixture was stirred at room tem-
perature for 6 h, concentrated in vacuum, and filtered through
a plug of silica gel with EtOAc as an eluent. Solvent was removed
under reduced pressure. The residue consisting of a mixture of
diols 7a and 7b was separated by column chromatography on silica
gel with CH2Cl2/Et2O/EtOAc (1:4:1) as an eluent to give diol 7a as
the first fraction (Rf 0.55) and diol 7b as the second fraction
(Rf 0.32).
CDCl3):
CDCl3):
d
6.47 (2H, s), 5.35 (2H, s), 1.98 (3H, s); 13S NMR (100 MHz,
~
n
d
195.0, 132.5, 86.3, 75.8, 27.6; IR (cmꢀ1):
3100,
2920e2960, 1745, 1650, 1470, 1380, 1210, 1090, 935; Anal. Calcd for
S8O7ClO3: S, 51.50; O, 3.78. Found: S, 51.48; O, 3.76.
4.4. 8-Oxabicyclo[3.2.1]oct-6-ene-2,4-dione (4)
4.7.1. 1R(S),2S(R),3R,4R(S),5S(R)-3-Chloro-8-oxabicyclo[3.2.1]oct-6-
ene-2,4-diol (7a). Yield 352 mg (50%), colorless crystals from
CH2Cl2/Et2O/EtOAc (1:4:1), mp 115e117 ꢁS. Crystals suitable for
diffraction analysis were obtained by slow evaporation of chloro-
form solution. For crystallographic data see ref. 16; 1O NMR
To a solution of diketone 2 (0.50 g, 2.90 mmol) in 5 mL of glacial
acetic acid Zn powder (0.28 g, 4.28 mmol) was added with stirring.
After the beginning of heating-up the mixture was stirred at 50 ꢁS
for 30 min and then concentrated under reduced pressure. The
residue was filtered through a plug of silica gel with CH2Cl2/EtOAc
(5:1) mixture as eluent to give after removal of the solvent com-
pound 4 as a yellow oil (0.27 g, 68%); Rf 0.6 (CH2Cl2/EtOAc¼5:1); 1O
(400 MHz, DMSO-d6): d 6.29 (2H, s), 4.53 (2H, d, J 4.3 Hz), 3.50 (2H,
dd, J 4.3, 8.1 Hz), 3.44 (1H, t, J 8.1 Hz); 13S NMR (100 MHz, DMSO-
~
n
d6):
d
130.5, 81.0, 70.6, 68.0; IR (cmꢀ1):
3300e3450, 2965, 2940,
1655, 1285, 1050, 940; Anal. Calcd for S7O9O3Cl: S, 47.61; O, 5.14.
Found: S, 47.64; O, 5.26.
NMR (400 MHz, CDCl3):
d 6.38 (2H, s), 5.15 (2H, s), 3.80 (1H, d, J
19.7 Hz), 3.45 (1H, d, J 19.7 Hz); 13S NMR (100 MHz, CDCl3):
d 197.8,
132.0, 86.8, 52.8; IR (cmꢀ1):
n
3090, 2980, 1720, 1680, 1220, 1085,
~
4.7.2. 1R(S),2S(R),3R(S),4S(R),5S(R)-3-Chloro-8-oxabicyclo[3.2.1]oct-
950; Anal. Calcd for S7O6O3: S, 60.87; O, 4.48. Found: S, 60.62; O,
4.63.
6-ene-2,4-diol (7b). Yield 175 mg (25%), colorless oil. 1O NMR
(400 MHz, DMSO-d6):
d 6.32 (1H, d, J 6.3 Hz), 6.22 (1H, d, J 6.3 Hz),
4.56 (1H, d, J 1.0 Hz), 4.54 (1H, d, J 5.8 Hz), 3.92 (1H, dd, J 4.5,
4.5. 3-Methyl-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione (5)
9.0 Hz), 3.63 (1H, dd, J 5.8, 9.0 Hz), 3.59 (1H, dd, J 1.0, 4.5 Hz); 13S
NMR (100 MHz, DMSO-d6):
d 132.7, 131.8, 83.7, 81.7, 68.9, 66.6,
To a solution of diketone 3 (0.40 g, 2.14 mmol) in 4 mL of glacial
acetic acid Zn powder (0.23 g, 3.52 mmol) was added. The mixture
was then heated to 50 ꢁS and stirred for 30 min. Then 20% aqueous
NaOH was added dropwise till producing of the solid. The solid was
dissolved by addition of 1 mL 0.1 N HCl, the mixture was extracted
with CH2Cl2 (5ꢂ20 mL), the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under reduced pressure to
yield compound 5 (0.26 g, 80%) as a pale yellow crystalline solid, mp
87e88 ꢁC; Rf 0.55 (CH2Cl2/EtOAc¼4:1); 1O NMR (400 MHz, CDCl3):
65.9; IR (cmꢀ1):
3250e3450, 2970, 2940, 1660, 1290, 1055, 940;
~
n
Anal. Calcd for S7O9O3Cl: S, 47.61; O, 5.14. Found: S, 47.64;
O, 5.26.
4.8. Reduction of diketone (2) with LiAlH4
To a solution of diketone 2 (0.50 g, 2.90 mmol) in anhydrous THF
(20 mL) a suspension of LiAlH4 (75.0 mg, 1.97 mmol) in THF was
added dropwise at ꢀ40 ꢁS under the argon atmosphere followed
by stirring for 30 min. To the resulting mixture methanol (5 mL) and
d
6.33 (2H, s), 5.24 (2H, s), 4.05 (1H, q, J 6.8 Hz),1.26 (3H, d, J 6.8 Hz);
13S NMR (100 MHz, CDCl3): 200.5, 132.1, 77.9, 58.9, 7.4; IR (cmꢀ1):
d
~
n
3100, 3010, 2880, 1730, 1670, 1315, 1190, 1095, 950; Anal. Calcd for
1 M aqueous solution of AcOH (20 mL) were added and it was
S8O8O3: S, 63.15; O, 5.30. Found: S, 63.21; O, 5.42.
allowed to reach the room temperature. The mixture was extracted
with EtOAc (5ꢂ20 mL), the combined organic layers were dried
over anhydrous Na2SO4 and evaporated under reduced pressure to
yield a mixture of ketoalcohol 6 and diols 7a and 7c. Pure com-
pounds were obtained by column chromatography on silica gel
with CH2Cl2/Et2O/EtOAc (1:4:1) as an eluent to give ketoalcohol 6
(100 mg, 20%) as the first fraction (Rf 0.72), diol 7a (60.0 mg, 12%) as
the second fraction (Rf 0.55) and diol 7c as the third fraction
(Rf 0.45).
4.6. 1S(R),3R(S),4S(R),5R(S)-3-Chloro-4-hydroxy-8-oxabicyclo
[3.2.1]oct-6-en-2-one (6)
1
M hexane solution of DIBAL-H (6.00 mL, 6.00 mmol) was
added dropwise during 10 min at ꢀ30 ꢁS to a solution of diketone
2 (1.00 g, 5.75 mmol) in 30 mL of dry THF under argon atmosphere,
followed by stirring for 30 min. After that the methanol (10 mL)
was added, resulting mixture was stirred at room temperature for
6 h and concentrated in vacuum, then filtered through a plug of
silica gel with CH2Cl2/EtOAc mixture (1:1). Removal of the solvents
under reduced pressure yielded crude ketoalcohol 6, which was
purified by flash chromatography (CH2Cl2/Et2O¼2:3) to give a pale
4.8.1. 1R(S),2S(R),3S,4R(S),5S(R)-3-Chloro-8-oxabicyclo[3.2.1]oct-6-
ene-2,4-diol (7c). Yield 75.0 mg (15%), colorless oil. 1O NMR
(400 MHz, DMSO-d6):
d 6.22 (2H, s), 4.55 (1H, t, J 5.3 Hz), 4.40 (2H,
d, J 3.6 Hz), 3.92 (2H, dd, J 3.6, 5.3 Hz); 13S NMR (100 MHz, DMSO-
yellow oil (682 mg, 68%); 1O NMR (400 MHz, CDCl3):
d
6.56 (1H, d,
d6):
d
133.1, 80.3, 65.5, 65.3; IR (cmꢀ1):
n
3300e3500, 2975, 2950,
~

5790
D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
1655, 1290, 1050, 940; Anal. Calcd for S7O9O3Cl: S, 47.61; O, 5.14.
Found: S, 47.75; O, 5.31.
stirred for 24 h at room temperature, then concentrated under
reduced pressure (1 mmHg) to give thick brown oil. Chromato-
graphic purification of the crude compound using silica gel (gra-
dient elution with 10e50% EtOAc in CH2Cl2) yielded pure diacetates
as colorless crystals.
4.9. 1R(S),2S(R),4R(S),5S(R)-3-endo-Chloro-3-exo-methyl-8-
oxabicyclo[3.2.1]oct-6-ene-2,4-diol (7d)
To a solution of diketone 3 (0.37 g, 1.98 mmol) in anhydrous
MeOH (10 mL) the NaBH4 powder (0.50 g, 13.2 mmol) was added
portionwise at room temperature followed by stirring for 30 min.
Then, a saturated aqueous solution of NH4Cl (10 mL) was added at
0 ꢁC and the reaction mixture was extracted with EtOAc (5ꢂ20 mL),
combined organic layers were dried over anhydrous Na2SO4 and
evaporated under reduced pressure to yield a 0.33 g (75%) of diol 7d
as pale yellow crystals: mp 106e108 ꢁS; Rf 0.45 (CH2Cl2/Et2O¼1:2);
4.11.1. 1R(S),2S(R),3S,4R(S),5S(R)-3-Chloro-8-oxabicyclo[3.2.1]oct-6-
ene-2,4-diyl diacetate (8c). It was prepared from 7c. Yield 145 mg
(93%), colorless crystals: mp 162e163 ꢁS; Rf 0.6 (CH2Cl2/Et2O¼6:1);
1O NMR (400 MHz, CDCl3):
d 6.29 (2H, s), 5.15 (2H, dd, J 4.1, 5.9 Hz),
13
4.52 (2H, d, J 4.1 Hz), 4.41 (1H, t, J 5.9 Hz), 2.09 (6H, s); C NMR
~
n
(100 MHz, CDCl3):
d
170.1, 134.4, 81.1, 72.2, 59.2, 21.1; IR (cmꢀ1):
2920e2980, 2880, 1745, 1735, 1650, 1460, 1380, 1230, 1080; Anal.
Calcd for S11O13O5Cl: S, 50.68; O, 5.03. Found: S, 51.06; O, 5.13.
1O NMR (400 MHz, CDCl3):
d 6.33 (2H, s), 4.63 (2H, d, J 4.3 Hz), 3.79
(2H, dd, J 4.3, 7.0 Hz), 2.21 (2H, d, J 11.4 Hz), 1.76 (3H, s); 13S NMR
4.11.2. 1R(S),2S(R),4R(S),5S(R)-3-endo-Chloro-3-exo-methyl-8-
oxabicyclo[3.2.1]oct-6-ene-2,4-diyl diacetate (8d). It was prepared
from 7d. Yield 148 mg (0.54 mmol, 90%), colorless crystals: mp
142e144 ꢁS; Rf 0.5 (CH2Cl2/Et2O¼8:1); 1O NMR (400 MHz, CDCl3):
~
n
(100 MHz, CDCl3):
d
132.8, 81.0, 80.8, 71.8, 30.4; IR (cmꢀ1):
3250e3500, 2960, 2915,1680, 1400,1260,1050, 930; Anal. Calcd for
S8O11O3Cl: S, 50.41; O, 5.82. Found: S, 50.29; O, 5.95.
d
6.33 (2H, s), 5.11 (2H, d, J 4.0 Hz), 4.69 (2H, d, J 4.0 Hz), 2.18 (6H, s),
4.10. Reduction of diketones (4) and (5) with NaBH4
1.54 (3H, s); 13C NMR (100 MHz, CDCl3):
d 170.1, 132.5, 78.6, 71.3,
69.4, 31.4, 20.8; IR (cmꢀ1): 3010, 2956, 2945, 1740, 1730, 1650,
1250, 1035; Anal. Calcd for S12O15O5Cl: S, 52.47; O, 5.50. Found: S,
52.66; O, 5.38.
~
n
To a stirred solution of diketone (1.30 mmol) in MeOH (15 mL)
NaBH4 powder (0.50 g, 13.2 mmol) was added portionwise during
3 h, reaction temperature was kept between 0 and 5 ꢁS (avoiding
vigorous gas evolution). Afterward, the reaction was stirred at room
temperature for 12 h, then solid NH4Cl (0.50 g, 9.35 mmol) was
added followed by 1 N HCl (0.5 mL). The solvents were evaporated
under reduced pressure, the residue was eluted by EtOAc/Me2CO
(1:1) through a silica gel plug to give a yellow oil after evaporation.
Mixture of isomers thus obtained was separated by column chro-
matography on silica gel eluting with EtOAc/Me2CO mixture of
increased polarity. In the case of diketone 4 diols 7f and 7g were
afforded. For diketone 5 only one isomer was isolated, diol 7e.
4.11.3. 1R(S),2R(S),3r,4S(R),5S(R)-3-Methyl-8-oxabicyclo[3.2.1]oct-6-
ene-2,4-diyl diacetate (8e). It was prepared from 7e. Yield 132 mg
(0.55 mmol, 92%), colorless crystals: mp 157e159 ꢁS; Rf 0.55
(CH2Cl2/Et2O¼6:1). Crystals suitable for diffraction analysis were
obtained by slow evaporation of dichloromethaneehexane solu-
tion. For crystallographic data see ref. 18; 1O NMR (400 MHz,
CDCl3):
d 6.30 (2H, s), 5.03 (2H, dd, J 4.5, 7.3 Hz), 4.69 (2H, d, J
4.5 Hz), 2.92e3.02 (1H, m), 2.06 (6H, s) 0.90 (3H, d, J 7.6 Hz); 13C
NMR (100 MHz, CDCl3): d 170.0, 133.3, 79.1, 67.9, 32.3, 20.8, 11.4; IR
(cmꢀ1):
3023, 2942, 2940, 1740, 1660, 1230, 1048; Anal. Calcd for
~
n
4.10.1. 1R(S),2R(S),4S(R),5S(R)-8-Oxabicyclo[3.2.1]oct-6-ene-2,4-diol
S12O16O5: S, 59.99; O, 6.71. Found: S, 60.23; O, 6.71.
(7f). Yield 100 mg (54%), colorless oil; Rf 0.6 (EtOAc/Me2CO¼5:1);
1O NMR (400 MHz, DMSO-d6):
d
6.21 (2H, s), 4.37 (2H, d, J 4.0 Hz),
4.11.4. 1R(S),2R(S),4R(S),5S(R)-8-Oxabicyclo[3.2.1]oct-6-ene-2,4-diyl
diacetate (8g). It was prepared from 7g. Yield 125 mg (92%), col-
orless oil; Rf 0.4 (CH2Cl2/Et2O¼6:1); 1O NMR (400 MHz, CDCl3):
3.49 (2H, ddd, J 4.0, 5.7, 9.9 Hz), 1.93 (1H, dd, J 9.9, 10.1 Hz), 1.25 (1H,
d, J 5.7, 10.1 Hz); 13C NMR (100 MHz, DMSO-d6):
d 135.1, 82.7, 63.2,
35.9; IR (cmꢀ1):
n
3200e3550, 2970, 2945, 1650, 1290, 1060, 935;
d
¼6.37 (1H, dd, J 1.8, 6.1 Hz), 6.29 (1H, dd, J 1.8, 6.3 Hz), 5.11e5.16
~
Anal. Calcd for S7O10O3: S, 59.14; O, 7.09. Found: S, 58.85; O, 7.24.
(1H, m), 4.82 (1H, d, J 4.3 Hz), 4.72e4.75 (1H, m), 4.73 (1H, d, J
1.3 Hz), 2.13 (3H, s), 2.03 (3H, s), 1.96e2.11 (2H, m); 13C NMR
4.10.2. 1R(S),2R(S),4R(S),5S(R)-8-Oxabicyclo[3.2.1]oct-6-ene-2,4-diol
(100 MHz, CDCl3):
d
170.8, 170.0, 132.4, 131.8, 80.8, 78.9, 66.9, 64.6,
(7g). Yield 58 mg (32%), colorless oil; Rf 0.4 (EtOAc/Me2CO¼5:1);
28.6, 21.3, 21.0; IR (cmꢀ1):
n
3080, 2985, 2960, 1735, 1650, 1255,
~
1O NMR (400 MHz, DMSO-d6):
d
6.32 (1H, d, J 6.1 Hz), 6.17 (1H, d,
1234, 1050, 1030; Anal. Calcd for S11O14O5: S, 58.40; O, 6.24.
Found: S, 58.55; O, 6.15.
J 6.1 Hz), 4.73 (1H, d, J 4.3 Hz), 4.63 (1H, d, J 3.8 Hz), 4.45 (1H, d,
J 3.8 Hz), 4.33 (1H, s), 3.79e3.84 (1H, m), 3.38e3.42 (1H, m),
1.55e1.70 (2H, m); 13C NMR (100 MHz, DMSO-d6):
d
133.23, 131.4,
4.12. General procedure for benzylation of diols
83.3, 81.9, 63.9, 62.1, 35.4; IR (cmꢀ1):
n
3250e3550, 2980,
~
2945, 1660, 1290, 1075, 940; Anal. Calcd for S7O10O3: S, 59.14; O,
7.09. Found: S, 58.85; O, 7.24.
The diol (1.50 mmol) was dissolved in anhydrous THF (15 mL)
and treated with NaH (96.0 mg, 4.00 mmol) and BnBr (600 mg,
3.51 mmol) at 0 ꢁS. Then reaction mixture was stirred for 24 h at rt
and quenched with MeOH (2 mL) and H2O (15 mL). Organic sol-
vents were evaporated at reduced pressure. The residue was
extracted with MTBE (4ꢂ10 mL), and the combined organic phases
were washed with brine (10 mL), dried (Na2SO4), and concentrated.
The benzyl ethers were purified by flash chromatography on silica
gel (gradient elution with 5e20% EtOAc in CH2Cl2).
4.10.3. 1R(S),2R(S),3R,4S(R),5S(R)-3-Methyl-8-oxabicyclo[3.2.1]oct-
6-ene-2,4-diol (7e). Yield 105 mg (52%), colorless oil; Rf 0.7
(EtOAc/Me2CO¼5:1); 1O NMR (400 MHz, DMSO-d6):
d 6.25 (2H, s),
4.31 (2H, d, J 4.1 Hz), 3.80 (2H, dd, J 4.1, 7.6 Hz), 2.33e2.43 (1H, m),
0.91 (3H, d, J 7.8 Hz); 13C NMR (100 MHz, DMSO-d6):
d 134.2, 81.6,
66.2, 38.3, 11.1; IR (cmꢀ1):
3200e3500, 2965, 2945, 1665, 1285,
~
n
1060, 935; Anal. Calcd for S8O12O3: S, 61.52; O, 7.74. Found: S,
61.40; O, 7.82.
4.12.1. 1R(S),2S(R),3r,4R(S),5S(R)-2,4-Bis(benzyloxy)-3-chloro-8-
oxabicyclo[3.2.1]oct-6-ene (9a). It was prepared from 7a. Yield
364 mg (68%), pale yellow oil; Rf 0.65 (CH2Cl2); 1O NMR (400 MHz,
4.11. General procedure for acetylation of diols
CDCl3):
(2H, d, J 11.6 Hz), 4.65 (2H, d, J 4.3 Hz), 3.90 (1H, t, J 8.6 Hz), 3.64 (2H,
dd, J 4.3, 8.1 Hz); 13S NMR (100 MHz, CDCl3):
137.9, 130.9, 128.4,
d 7.32e7.45 (10H, m), 6.26 (2H, s), 4.81 (2H, d, J 11.6 Hz) 4.69
Diol (0.60 mmol) was dissolved in dry pyridine (5 mL) and acetic
anhydride (3.00 mL, 30.0 mmol) was added. The mixture was
d

D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
5791
127.9, 127.9, 78.8, 78.4, 73.7, 64.4; Anal. Calcd for S21O21O3Cl: S,
70.68; O, 5.93. Found: S, 70.74; O, 5.80.
d
~
n
137.5, 128.5, 128.2, 128.0, 83.6, 79.0, 73.7, 70.6, 62.8; IR (cmꢀ1):
3400, 3300, 3090, 3030, 2960, 2900, 1360, 1210, 1100, 1090,
950; Anal. Calcd for S21O23O5Cl: S, 64.53; O, 5.93. Found: S,
64.62; O, 5.80.
4.12.2. 1R(S),2S(R),3R(S),4S(R),5S(R)-2,4-Bis(benzyloxy)-3-chloro-8-
oxabicyclo[3.2.1]oct-6-ene (9b). It was prepared from 7b. Yield
347 mg (65%), pale yellow oil; Rf 0.55 (CH2Cl2); 1O NMR (400 MHz,
4.13.2. 1R(S),2R(S),3r,4S(R),5S(R),6S(R),7R(S)-2,4-Bis(benzyloxy)-3-
methyl-8-oxabicyclo[3.2.1]octane-6,7-diol (10e). It was prepared
from 9e. Yield 89.2 mg (80%), colorless oil; Rf 0.50 (CH2Cl2/
CDCl3):
d
7.31e7.42 (10H, m), 6.29 (1H, d, J¼6.1 Hz), 6.21 (1H, d, J
6.1 Hz), 4.69e4.88 (4H, m), 4.77 (1H, d, J 4.3 Hz), 4.74 (1H, d, J
1.7 Hz), 4.26 (1H, dd, J 4.8, 8.8 Hz), 3.86 (1H, dd, J 4.3, 8.8 Hz), 3.58
EtOAc¼3:2); 1O NMR (400 MHz, CDCl3):
d 7.31e7.42 (10H, m), 4.61
(2H, s, CHOH), 4.59 (2H, d, J 11.9 Hz, OCH2Ph) 4.56 (2H, d, J 11.9 Hz,
OCH2Ph); 4.16 (2H, d, J 4.6 Hz), 3.68 (2H, dd, J 4.6, 7.3 Hz), 2.71e2.81
(1H, dd, J 1.7, 4.8 Hz); 13S NMR (100 MHz, CDCl3):
d
138.1, 137.9,
132.6, 131.4, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 81.1, 79.6, 77.1,
74.4, 73.9, 73.4, 61.6; Anal. Calcd for S21O21O3Cl: S, 70.68; O, 5.93.
Found: S, 70.74; O, 5.80.
(1H, m), 1.03 (3H, d, J 7.8 Hz); 13S NMR (100 MHz, CDCl3):
d
138.1,
128.5, 127.8, 127.5, 84.2, 73.9, 71.1, 71.0, 33.6, 8.3; IR (cmꢀ1):
~
n
3350e3450, 3300, 3090, 3050, 2900, 1340, 1230, 1210, 1120, 1085,
950; Anal. Calcd for S22O26O5: S, 71.33; O, 7.07. Found: S, 71.52; O,
6.90.
4.12.3. 1R(S),2R(S),3r,4S(R),5S(R)-2,4-Bis(benzyloxy)-3-methyl-8-
oxabicyclo[3.2.1]oct-6-ene (9e). It was prepared from 7e. Yield
418 mg (83%), pale yellow oil; Rf 0.6 (CH2Cl2); 1O NMR (400 MHz,
CDCl3):
d
7.28e7.38 (10H, m), 6.33 (2H, s), 4.63 (2H, d, J 4.1 Hz),
4.13.3. 1R(S),2R(S),4S(R),5S(R),6S(R),7R(S)-2,4-Bis(benzyloxy)-8-
oxabicyclo[3.2.1]octane-6,7-diol (10f). It was prepared from 9f.
Yield 83.3 mg (78%), colorless oil; Rf 0.45 (CH2Cl2/EtOAc¼3:2); 1O
4.60 (2H, d, J 11.9 Hz) 4.49 (2H, d, J 11.9 Hz), 3.80 (2H, dd, J 4.1,
7.1 Hz), 2.82e2.91 (1H, m), 1.17 (3H, d, J 7.6 Hz); 13S NMR
(100 MHz, CDCl3):
d
138.4, 133.7, 128.4, 127.7, 127.5, 80.0, 73.8, 71.1,
NMR (400 MHz, CDCl3): d 7.32e7.43 (10H, m), 4.58 (2H, d, J 11.9 Hz,
33.5, 10.6; Anal. Calcd for S22O24O3: S, 78.54; O, 7.19. Found: S,
78.66; O, 7.05.
OCH2Ph) 4.57 (2H, d, J 11.9 Hz, OCH2Ph), 4.40 (2H, s, CHOH), 4.24
(2H, d, J 4.3 Hz), 3.50e3.55 (2H, m), 2.35e2.41 (1H, m), 1.01e1.10
(1H, m); 13S NMR (100 MHz, CDCl3):
d
~
n
138.0, 128.5, 127.9, 127.7,
3250e3400, 3070, 3040,
4.12.4. 1R(S),2R(S),4S(R),5S(R)-2,4-Bis(benzyloxy)-8-oxabicyclo
[3.2.1]oct-6-ene (9f). It was prepared from 7f. Yield 377 mg (78%),
pale yellow oil; Rf 0.5 (CH2Cl2); 1O NMR (400 MHz, CDCl3):
83.4, 71.8, 71.2, 71.0, 32.2. IR (cmꢀ1):
2850e2900, 1320, 1200, 1100, 960; Anal. Calcd for S21O24O5: S,
70.77; O, 6.79. Found: S, 70.62; O, 6.90.
d
7.32e7.43 (10H, m), 6.29 (2H, s), 4.73 (2H, d, J 4.0 Hz), 4.60 (2H, d, J
11.9 Hz), 4.52 (2H, d, J 11.9 Hz), 3.57 (2H, ddd, J 4.0, 5.8, 9.9 Hz), 2.35
4.14. General procedure for epoxidation
(1H, dd, J 5.8, 12.4 Hz), 1.64 (1H, dd, J 9.9, 12.4 Hz); 13S NMR
(100 MHz, CDCl3):
29.3; Anal. Calcd for S21O22O3: S, 78.23; O, 6.88. Found: S, 78.29; O,
6.78.
d
137.0, 130.7, 129.3, 127.1, 126.3, 78.0, 69.7, 69.3,
Alkene (0.30 mmol) was dissolved in methylene chloride
(10 mL) and m-CPBA (86.0 mg, 0.50 mmol) was added, then the
reaction was stirred at room temperature for 2e3 days (every
day a small portion (10.0 mg) of m-CPBA was added). The
progress of the reaction was monitored by thin layer chroma-
tography. After completion of the reaction, 10 mL of methylene
chloride was added, and reaction mixture was washed with
saturated aqueous solution of Na2SO3 and then aqueous NaHCO3.
The aqueous solution was extracted with methylene chloride,
combined organic phases were washed with brine and dried
(Na2SO4). Evaporation of solvent under reduced pressure and
purification of product by flash chromatography on silica gel
(gradient elution with 10e20% EtOAc in CH2Cl2) gave epoxides as
colorless oils.
4.12.5. 1R(S),2R(S),4R(S),5S(R)-2,4-Bis(benzyloxy)-8-oxabicyclo
[3.2.1]oct-6-ene (9g). It was prepared from 7g. Yield 362 mg (75%),
pale yellow oil; Rf 0.4 (CH2Cl2); 1O NMR (400 MHz, CDCl3):
d
¼7.30e7.45 (10H, m), 6.31 (1H, d, J 6.1 Hz), 6.28 (1H, d, J 6.1 Hz),
4.90 (1H, d, J 3.6 Hz), 4.79 (1H, d, J 1.4 Hz), 4.60e4.65 (4H, m),
3.98e4.03 (1H, m), 3.43 (1H, d, J 5.1 Hz), 2.20e2.25 (1H, m),
1.86e1.93 (1H, m); 13S NMR (100 MHz, CDCl3):
d 138.5, 138.4, 132.1,
128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 80.8, 79.7, 71.5, 71.2,
70.6, 70.2, 29.7; Anal. Calcd for S21O22O3: S, 78.23; O, 6.88. Found:
S, 78.29; O, 6.78.
4.13. General procedure for syn-hydroxylation
4.14.1. 1R(S),2S(R),4R(S),5S(R),6R(S),7s,8S(R)-6,8-Bis(benzyloxy)-7-
chloro-3,9-dioxatricyclo[3.3.1.02,4]nonane (11a). It was prepared
from 9a. Yield 85.4 mg (76%), colorless oil; Rf 0.6 (CH2Cl2/
O-Benzyl protected diol (0.30 mmol) was dissolved in acetone
(5 mL). Water (2 mL), OsO4 (0.01 mmol, 0.25 mL of 2.5 wt % so-
lution in tBuOH) and NMO (200 mg, 1.50 mmol) were added. The
mixture was stirred at room temperature for 72 h, and an aque-
ous solution of Na2SO3 (10 wt %, 10 mL) was added. From the
resulted mixture acetone was removed by evaporation under
reduced pressure. The residue was extracted with EtOAc
(4ꢂ10 mL), organic phase was washed with brine (10 mL), dried
(Na2SO4), and concentrated. The syn-diols were purified by flash
chromatography on silica gel (gradient elution with 10e50%
EtOAc in CH2Cl2).
EtOAc¼5:1); 1O NMR (400 MHz, CDCl3):
d 7.24e7.45 (10H, m, Ph),
4.84 (2H, d, J 11.6 Hz, OCH2Ph), 4.72 (2H, d, J 11.6 Hz, OCH2Ph), 4.14
(2H, d, J 4.6 Hz, bridgehead), 4.06 (1H, t, J 8.6 Hz, SOCl), 3.77 (2H,
dd, J 4.6, 8.6 Hz, SOPBn), 3.75 (2H, s, oxiran ring); 13S NMR
(100 MHz, CDCl3):
d 137.5, 128.6, 128.3, 128.0, 80.9, 74.2, 72.8, 63.8,
51.0; IR (cmꢀ1):
n
¼3070, 2950e3000, 2920, 1470, 1250, 1210, 1060;
~
Anal. Calcd for S21O21O4Cl: S, 67.65; O, 5.68. Found: S, 67.74;
O, 5.80.
4.14.2. 1R(S),2R(S),4S(R),5S(R),6R(S),7s,8S(R)-6,8-Bis(benzyloxy)-7-
methyl-3,9-dioxatricyclo[3.3.1.02,4]nonane (11e). It was prepared
from 9e. Yield 93.0 mg (88%), colorless oil; Rf 0.55 (CH2Cl2/
4.13.1. 1R(S),2S(R),3r,4R(S),5S(R),6S(R),7R(S)-2,4-Bis(benzyloxy)-3-
chloro-8-oxabicyclo[3.2.1]octane-6,7-diol (10a). It was prepared
from 9a. Yield 84.0 mg (72%), colorless oil; Rf 0.55 (CH2Cl2/
EtOAc¼5:1); 1O NMR (400 MHz, CDCl3):
d 7.26e7.45 (10H, m, Ph),
4.64 (2H, d, J 11.9 Hz, OCH2Ph) 4.54 (2H, d, J 11.9 Hz, OCH2Ph), 4.25
(2H, d, J 4.3 Hz, bridgehead), 3.86 (2H, dd, J 4.3, 6.8 Hz, SOPBn),
3.77 (2H, s, oxiran ring), 2.79e2.86 (1H, m), 1.23 (3H, d, J
EtOAc¼3:2); 1O NMR (400 MHz, CDCl3):
d 7.32e7.43 (10H, m),
4.78 (2H, d, J 11.6 Hz, OCH2Ph) 4.71 (2H, d, J 11.6 Hz, OCH2Ph),
4.32 (2H, s, CHOH), 4.16 (2H, d, J 4.8 Hz), 3.56 (2H, dd, J 4.8,
9.4 Hz), 3.45 (1H, t, J 9.4 Hz, SOCl); 13S NMR (100 MHz, CDCl3):
7.6 Hz, CH3); 13S NMR (100 MHz, CDCl3):
d
129.8, 128.6, 127.9,
127.5, 75.4, 73.7, 71.3, 52.6, 33.4, 9.9; IR (cmꢀ1):
3070, 3040,
~
n

5792
D.A. Khlevin et al. / Tetrahedron 68 (2012) 5785e5792
2930e2960, 2880,1480,1280,1100,1080; Anal. Calcd for S22O24O4:
S, 74.98; O, 6.86. Found: S, 75.14; O, 6.80.
Supplementary data
These data include MOL files of the most important compounds
described in the article and copies of 1H and 13C NMR spectra of all
new compounds. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2012.05.029.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.14.3. 1R(S),2R(S),4S(R),5S(R),6R(S),8S(R)-6,8-Bis(benzyloxy)-3,9-
dioxatricyclo[3.3.1.02,4]nonane (11f). It was prepared from 9f. Yield
86.5 mg (85%), colorless oil; Rf 0.45 (CH2Cl2/EtOAc¼5:1); 1O NMR
(400 MHz, CDCl3):
d 7.32e7.42 (10H, m), 4.62 (2H, d, J 11.9 Hz,
OCH2Ph) 4.59 (2H, d, J 11.9 Hz, OCH2Ph), 4.22 (2H, d, J 4.1 Hz,
bridgehead), 3.82 (2H, s), 3.73e3.78 (2H, m, SOPBn), 2.39e2.46
(1H, m), 1.61e1.69 (1H, m). 13S NMR (100 MHz, CDCl3):
d 137.9,
References and notes
128.6, 128.0, 127.7, 73.5, 72.1, 71.3, 51.5, 32.1; IR (cmꢀ1) 3050e3100,
2950, 2920, 1460, 1300, 1245, 1150; Anal. Calcd for S21O22O4: S,
74.54; O, 6.55. Found: S, 75.44; O, 6.50.
1. (a) Derwick, P. M. Medicinal Natural Products; Wiley: Chichester, UK, 1998; (b)
Iminosugars: From Synthesis to Therapeutic Applications; Compain, P., Martin, O.
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R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645e1680; (d) Re, D. L.;
ꢀ
Franco, F.; Sanchez-Cantalejo, F.; Tamayo, J. A. Eur. J. Org. Chem. 2009, 74,
4.14.4. 1R(S),2R(S),4S(R),5S(R),6S(R),8R(S)-3,9-Dioxatricyclo
[3.3.1.02,4]non-6,8-diyl diacetate (13). It was prepared from 8g. Yield
61.2 mg (84%), colorless crystals: mp 143e144 ꢁS; Rf 0.55 (CH2Cl2/
€
1984e1993; (e) Drager, B. Nat. Prod. Rep. 2004, 21, 211e223; (f) Biastoff, S.;
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Drager, B. Alkaloids 2007, 64, 49e102.
2. (a) Heusner, A. Chem. Ber. 1954, 87, 1063e1067; (b) Fodor, G.; Kovacs, O. J. Chem.
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Proemmel, S.; Beil, W.; Wartchow, R.; Hoffmann, H. M. R. Org. Lett. 2004, 6,
4155e4158.
EtOAc¼3:1); 1O NMR (400 MHz, CDCl3):
d 5.16 (1H, m), 4.98 (1H, d, J
5.2 Hz), 4.26 (1H, d, J 4.5 Hz), 4.24 (1H, s), 3.72 (1H, d, J 2.9 Hz), 3.62
(1H, d, J 2.9 Hz), 2.12e2.18 (1H, m), 2.11 (3H, s), 2.08 (3H, s)
1.77e1.84 (1H, m); 13C NMR (100 MHz, CDCl3):
d 170.4, 169.8, 73.8,
3. (a) Schwenter, M. E.; Vogel, P. Chem.dEur. J. 2000, 6, 4091e4103; (b) Csaky, A.
G.; Vogel, P. Tetrahedron: Asymmetry 2000, 11, 4935e4944; (c) Schwenter, M. E.;
Vogel, P. J. Org. Chem. 2001, 66, 7869e7872; (d) Gerber-Lemaire, S.; Vogel, P. Eur.
J. Org. Chem. 2003, 2959e2963; (e) Meilert, K. M.; Schwenter, M. E.; Shatz, Y.;
Dubbaka, S. R.; Vogel, P. J. Org. Chem. 2003, 68, 2964e2967; (f) Coste, G.;
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Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096e1109; (c) Candy, M.;
Audran, G.; Bienayme, H.; Bressy, C.; Pons, J.-M. Org. Lett. 2009, 11, 4950e4953.
5. (a) Asano, N. Glycobiology 2003, 13, 93e104; (b) Heightman, T. D.; Vasella, A. T.
Angew. Chem., Int. Ed. 1999, 38, 750e770; (c) Ogawa, S. In Carbohydrate Mimics:
ConceptandMethods;Chapleur, Y., Ed.; Wiley-VCH: Weinheim, Germany,1998; (d)
Dwek, A. Chem. Rev.1996, 96, 683e720; (e) Varki, A. Glycobiology 1993, 3, 97e130.
6. (a) Ogawa, S.; Hirai, K.; Odagiri, T.; Matsunaga, N.; Yamajaki, T.; Nakajima, A.
Eur. J. Org. Chem. 1988, 1099e1109; (b) Ogawa, S.; Ohmura, M.; Hisamatsu, S.
Synthesis 2000, 312e316; (c) Saumi, T. Top. Curr. Chem. 1990, 154, 257e283; (d)
Saumi, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 21e90.
7. (a) Reinecke, J.; Hofmann, H. M. R. Chem.dEur. J. 1995, 1, 368e373; (b) Wit-
tenberg, J.; Beil, W.; Hofmann, H. M. R. Tetrahedron Lett. 1998, 39, 8259e8262;
(c) Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1998, 37,
1266e1268; (d) Stark, C. B. W.; Pierau, S.; Warthhow, R.; Hoffmann, H. M. R.
Chem.dEur. J. 2000, 6, 684e691; (e) Beck, H.; Stark, C. B. W.; Hoffmann, H. M. R.
Org. Lett. 2000, 2, 883e886; (f) Proemmel, S.; Warthhow, R.; Hoffmann, H. M. R.
Tetrahedron 2002, 58, 6199e6206.
71.6, 68.1, 65.5, 51.3, 50.2, 29.6, 21.1, 21.0; IR (cmꢀ1): 3000, 2970,
1730, 1430, 1255, 1240; 1045, 970; Anal. Calcd for S11O14O6: S,
54.54; O, 5.83. Found: S, 54.48; O, 5.64.
~
n
4.15. 1R(S),2S(R),3r,4R(S),5S(R),6S(R),7R(S)-3-Chloro-8-
oxabicyclo[3.2.1]octane-2,4,6,7-tetraol (12a)
To a solution of compound 10a (100 mg, 0.26 mmol) in MeOH
(10 mL) PdeC (10%, 3.0 mg, 0.026 mmol) was added under H2
atmosphere then the mixture was stirred for 24 h at rt. The
mixture was filtered through a short pad of Celite and washed
with MeOH (30 mL). The filtrate was evaporated under reduced
pressure to afford the unprotected tetraol 12a (53.0 mg) in 98%
yield as a colorless oil. 1O NMR (400 MHz, DMSO-d6):
d 4.94 (2H, s,
CHOH), 3.83 (2H, d, J 5.1 Hz, bridgehead), 3.44 (2H, dd, J 5.1,
9.6 Hz), 3.26 (1H, t, J 9.6 Hz, SOSl); 13C NMR (100 MHz, DMSO-
~
n
d6):
d
86.2, 72.1, 69.5, 67.2; IR (cmꢀ1):
3250e3400, 2950, 1400,
8. (a) Bowers, K. G.; Mann, J. Tetrahedron Lett. 1985, 26, 4411e4412; (b) Bowers, K.
G.; Mann, J.; Walsh, E. B.; Howarth, O. W. J. Chem. Soc. Perkin Trans. I 1987,
1657e1666; (c) Corey, E. J. Angew. Chem., Int. Ed. Engl. 1991, 30, 455e465; (d)
Grainger, R. S.; Owoare, R. B. Org. Lett. 2004, 6, 2961e2964.
1230, 1055; Anal. Calcd for S7O11O5Cl: S, 39.92; O, 5.26. Found: S,
40.14; O, 5.36.
9. Montana, A. M.; Barcia, J. A.; Kociok-Kohn, G.; Font-Bardia, M. Tetrahedron 2009,
65, 5308e5321.
4.16. 1S(R),3R(S),5R(S),6R(S),8S(R),9R(S)-2,7-Dioxatricyclo
10. (a) Gender, W. J.; Chan, S.; Ball, D. B. J. Org. Chem. 1981, 46, 3407e3415; (b)
Knapp, S. Chem. Rev. 1995, 95, 1859e1876; (c) Gethin, D. M.; Simpkins, N. S.
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Roy, B. G.; Drew, M. G. B.; Achari, B.; Mandal, S. B. J. Org. Chem. 2007, 72,
7427e7430; (f) Ghosh, R.; Maiti, J. K.; Achari, B.; Mandal, S. B. J. Org. Chem. 2010,
75, 2419e2422.
[4.2.1.03,8]nonane-5,9-diol (14)
Compound 13 (125 mg, 0.516 mmol) was dissolved in MeOH
(5 mL) and NaOH (206 mg, 5.16 mmol) was added. The reaction
mixture was stirred at rt for 48 h and afterward conc. HCl (0.5 mL)
was added. Evaporation of solvent under reduced pressure and
purification of product by flash chromatography on silica gel
(EtOAc/acetone¼1:2) gave diol 15. Yield 58.0 mg (72%), colorless
crystals: mp 67e69 ꢁS; Rf 0.35 (EtOAc/acetone¼1:1); 1O NMR
11. (a) Gerber, P.; Vogel, P. Tetrahedron Lett. 1999, 40, 3165e3168; (b) Gerber, P.;
Vogel, P. Helv. Chim. Acta 2001, 84, 1363e1395.
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9, 435e441; (b) Anzeveno, P. B.; Creemer, L. J.; Danile, J. K.; King, C.-H. R.; Liu, P.
S. J. Org. Chem. 1989, 54, 2539e2542; (c) Hoffmann, H. M. R.; Dunkel, R.;
Mentzel, M.; Reuter, H.; Stark, C. B. W. Chem.dEur. J. 2001, 7, 4771e4789.
13. (a) Lautens, M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 6478e6487.
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rahedron 1997, 53, 6235e6280; (c) Rigby, J. H.; Pigge, F. C. In Organic Reactions;
Paquette, L. A., Ed.; Wiley: New York, NY, 1997; 51, pp 351e478; (d) Hosomi, A.;
Tominaga, Y. In; Trost, B. M., Fleming, I., Eds. Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; vol. 5; (e) Mann, J. Tetrahedron 1986, 42, 4611e4659;
(f) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163e344.
(400 MHz, CDCl3):
d 4.98 (1H, d, J 4.3 Hz, OH), 4.79 (1H, d, J 5.7 Hz,
OH), 3.82e3.90 (2H, m), 3.86 (1H, d, J 12.0 Hz), 3.72 (1H, t, J 5.1 Hz),
3.61 (2H, dd, J 2.8, 4.8 Hz), 1.69e1.74 (1H, m), 1.46e1.53 (1H, m); 13C
NMR (100 MHz, CDCl3):
d 76.3, 74.4, 65.7, 62.9, 51.9, 50.4, 36.1; IR
(cmꢀ1):
n
3200e3550, 2955, 2940, 2890, 1335, 1275, 1075, 1020,
~
970, 910; Anal. Calcd for S7O10O4: S, 53.16; O, 6.37. Found: S,
53.02; O, 6.29.
15. (a) Law, D. C. F.; Tobey, S. W. J. Am. Chem. Soc. 1968, 90, 2376e2386; (b) Tobey, S.
W.; Law, D. C. F. U.S. Patent 3,538,117, Nov. 3, 1970.
16. Tafeenko, V. A.; Aslanov, L. A.; Proskurnina, M. V.; Sosonyuk, S. E.; Khlevin, D. A.
Acta Crystallogr. 2009, E65, 1580.
17. Batson, W. A.; Abboud, K. A.; Battiste, M. A.; Wright, D. L. Tetrahedron Lett. 2004,
45, 2093e2096.
Acknowledgements
18. Tafeenko, V. A.; Aslanov, L. A.; Proskurnina, M. V.; Sosonyuk, S. E.; Khlevin, D. A.
Acta Crystallogr. 2011, E67, 2127.
19. (a) Yang, W.; Koreeda, M. J. Org. Chem. 1992, 57, 3836e3839; (b) Daniels, R.;
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We are grateful to Russian Foundation for Basic Research (Pro-
ject No. 11-03-00641-a) and Russian Foundation for Scientific
Schools (Project No. 65546.2010.3)