Design, synthesis, and biological activities of some branched carbasugars: Construction of a substituted 6-oxabicyclo[3.2.1]nonane skeleton

Article abstract of DOI:10.1021/jo300655p

Transformation of cyclohexa-2,4-diene-1,2-diylbis(methylene) diacetate to various carbasugars is described. Photooxygenation of a cyclohexadiene derivative gave a bicyclicendoperoxide, which was reduced with thiourea to [2-[(acetyloxy)methyl]cyclohexa-2,4

Full text of DOI:10.1021/jo300655p

Article
pubs.acs.org/joc
Design, Synthesis, and Biological Activities of Some
Branched Carbasugars: Construction of a Substituted
6-Oxabicyclo[3.2.1]nonane Skeleton
Arif Baran,*,† Sinem Cambul,† Mehmet Nebioglu,† and Metin Balci*,‡
̧
†Department of Chemistry, Sakarya University, 54100 Sakarya, Turkey
‡Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
S
* Supporting Information
ABSTRACT: Transformation of cyclohexa-2,4-diene-1,2-diyl-
bis(methylene) diacetate to various carbasugars is described.
Photooxygenation of a cyclohexadiene derivative gave a bicyclic
endoperoxide, which was reduced with thiourea to [2-[(acetyloxy)-
methyl]cyclohexa-2,4-dien-1-yl]methyl acetate. Epoxidation of
the remaining double bond followed by epoxide ring-opening
and hydrolysis of the acetate groups gave one of the target
hexols. The bicyclic endoperoxide was rearranged to a di-
epoxide with CoTPP. The diepoxide was reacted with sulfamic
acid in acetic anhydride, resulting in the formation of a new
branched carbasugar as well as in the formation of cyclitols
with a 6-oxabicyclo[3.2.1]nonane skeleton. The mechanism
of the formation of the products is discussed. The inhibi-
tion activity of six cyclitol derivatives was tested against
α-glycosidase.
INTRODUCTION
■
Glycosidases are a family of essential enzymes in the human
body, and they catalyze the hydrolysis of glycosidic linkages to
release smaller sugars.1 Therefore, glycosidase inhibitors are
generally regarded as promising candidates for new drug
development. Inhibition of intestinal α-glycosidases can be
used to treat diabetes through the lowering of blood glucose
levels.2 Carba-analogues of oligosaccharides (carbasugar)
generated by replacing the endocyclic oxygen atom in
monosaccharides3 are thought to be more potent drug candi-
dates than natural sugars, since they are hydrolytically stable.
Figure 1. Representative cyclitols.
The first carbahexopyranose 1 found in nature5 was isolated as
a weak antibiotic from the fermentation broth of Streptomyces
species6 and synthesized by McCasland et al.7 Recently, we
synthesized two new carbasugars, namely, 5a-carba-6-deoxy-α-
DL-galacto-heptopyranose (2) and 5a-carba-6-deoxy-α-DL-gluco-
heptopyranose (3) (Figure 1).8 The pentol 2 showed inhibi-
tion of α-glycosidase and increased the activity of α-amylase,
whereas 3 did not. Furthermore, we prepared various branched
carbahexopyranose derivatives such as 4, which showed high
inhibition for α-glycosidase.9 Vogel et al. synthesized some
double-branched carbahexopyranose 5 and its amino deriva-
tives.10 After the pioneering work carried out by McCasland,11
oxanorbornene derivatives were extensively used for the
synthesis of carbasugars.12 The microbial oxidation of benzene
and its derivatives to cyclohexadiene has also been prevalent in
carbasugar chemistry.13−15
In the present paper, we describe the regio- and stereospecific
synthesis of new branched carbasugars 6−8 starting from a
cyclohexadiene derivative 13 (Figure 2). The applied synthetic
strategy was based on the photooxygenation of 13 followed by
transformation of the bicyclic endoperoxide formed.
RESULTS AND DISCUSSION
■
The starting material rel-(1R,2S)-cyclohex-4-ene-1,2-diylbis-
(methylene) diacetate (11) was prepared in three steps start-
ing with the addition of maleic anhydride to in situ generated
butadiene.
Received: March 30, 2012
Published: May 18, 2012
© 2012 American Chemical Society
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C-6 and the bromine atom is not suitable for trans-elimination to
give 14. However, allylic activation of the proton H-2 to be
abstracted for 1,4-elimination significantly accelerates the base-
induced elimination reaction. Therefore, 15 underwent syn-1,4-
elimination, and the unsymmetrical diene 13 was formed as the
major product. Furthermore, DFT calculations showed that the
diene 13 is about 3.7 kcal/mol more stable than the symmetrical
diene 14.
After the successful synthesis of diene 13, the next step was
functionalization of the diene unit. Photooxygenation21 of 13
in methylene chloride (500 W, projection lamp) at room tem-
perature using tetraphenylporphyrin as the sensitizer afforded
the bicyclic endoperoxide 16 in a yield of 82%. The diene unit
in 13 is not symmetric and can be attacked from both sides of the
diene. The repulsive interaction22 between the axial acetoxy-
methylene group in 13 and the singlet oxygen molecule is
directing the singlet oxygen to approach the diene unit from the
anti position.4a,23 Exclusive formation of the anti product 16 was
later supported by X-ray analysis.
Figure 2. Target compounds.
The reduction of the anhydride functionality in 916 followed
by acetylation of diol 1017 afforded the desired diacetate 11.18
The resulting compound 11 was brominated at room temper-
ature to give only the trans-dibromide 12 in high yield. The
unsymmetrical structure, confirmed by 13C NMR, was in
agreement with the trans-addition of bromine to the double
bond in 11. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)-induced
elimination furnished the unsymmetrical diene 13 and the
symmetrical diene 1419 in a ratio of 9:1 (Scheme 1).
Scheme 1. Preparation of Diene 13 from Anhydride 9
After the successful synthesis of the endoperoxide 16, we
turned our attention to the selective reduction of the peroxide
linkage in 16. Reaction of bicyclic endoperoxide 16 with
thiourea20,24 under very mild conditions followed by acetylation
in pyridine at room temperature afforded the tetraacetate 19
(Scheme 3). For synthesis of cyclitols, the tetraacetate 19 was
reacted with m-CPBA. Unfortunately, the desired epoxide 20 was
not formed due to the steric crowdedness hindering the approach
of m-CPBA.
After the failure of the epoxidation reaction, the diol 17 was
submitted to the selective acetylation reaction with acetic
anhydride in pyridine under milder reaction conditions. The
triacetate 21 was isolated as the sole product, where only the
secondary alcohol functionality was acetylated. In contrast to the
tetraacetate 19, the triacetate 21 reacted smoothly with m-CPBA
in methylene chloride at room temperature to give a mixture of
two separable epoxides 22 and 23 in 75% and 7% yields,
respectively (Scheme 4). For further characterization, the major
product 22 was transferred into the corresponding tetraacetate
syn-20 by reaction with acetic anhydride in the presence of a
catalytic amount of H2SO4 (Scheme 5).
The geometry-optimized (DFT, B3LYP at 6-31G** level)
structure of the trans-dibromide 12 is given in Figure 3. We
Geometry optimization calculations (DFT, B3LYP at 6-31+G*
level) for syn- and anti-epoxides with respect to the hydroxyl
group show dihedral angles of 52° and 105.5° between the vicinal
protons H-5 and H-6 (Figure 4). We calculated the vicinal
coupling constants25 between the protons H-5 and H-6 by
considering substituent electronegativities and found a value of
2.97 Hz for 22 and 0.81 Hz for 23. The measured coupling
constants 3.5 Hz for 22 and <1.0 Hz for 23 are in good agreement
with our configurational assignments. It is well established that
upon the treatment of cyclic allylic alcohols with m-CPBA the
formation of epoxides occurs mainly on the same side as the
hydroxyl group.26
Figure 3. Geometry-optimized structures of 12 and 15.
assume that the elimination of 2 mol of HBr takes place step by
step. DBU, a non-nucleophilic base, can easily approach the
axial-hydrogens H-6 in 12 since the proton H-3 is hindered
because of the steric effect caused by the axial acetoxymethylene
group in 12. Therefore, the elimination of the first mole of HBr is
chemoselective, and the axial-proton H-6 and bromine atom
attached to C-5 are first eliminated to give 15. The initially
formed monobromide 15 can undergo two types of elimina-
tion, namely, 1,2- and 1,4-elimination,20 to form 14 and 13,
respectively (Scheme 2). The geometry-optimized (DFT,
B3LYP at 6-31+G* level) structure of the monobromide 15
(Figure 3) shows that the conformation of the proton attached to
After the successful synthesis of the epoxides 22 and 23,
we turned our attention to the ring-opening reaction of the
major epoxide isomer 22. syn-Epoxide 22 was subjected to the
Scheme 2. Formation of Diene 13 from Dibromide 12
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Scheme 3. Formation of Tetrol 18 from Diene 13
Scheme 4. Synthesis of Epoxides 22 and 23
Scheme 5. Synthesis of Hexol 6 and Tetrol 26
the neighboring acetoxyl group was not involved (no anchimeric
assistance) in the ring-opening reaction. This can be attributed to
the cis-configuration of the acetoxyl group.9 Hydrolysis of 24 and
25 with ammonia in CH3OH resulted in the formation of
branched hexol 6 in 93% and 95% yields, respectively.
In the second part of this work, we turned our attention to the
synthesis of other isomeric branched cyclitols starting from the
bicyclic endoperoxide 16. Unsaturated bicyclic endoperoxides
can be easily converted to the corresponding diepoxides upon
treatment with cobalt(II) tetraphenylporpyrin (CoTPP).27,28
The reaction of the endoperoxide 16 with CoTPP in methylene
chloride gave the expected diepoxide 27 with syn-configuration in
80% yield (Scheme 6).
Bisepoxide 27 was subjected to an acid-catalyzed ring-opening
reaction in AcOH/Ac2O in the presence of sulfamic acid29 at
reflux resulting in the formation of four separable products 28−
31 in 30%, 10%, 19%, and 29% yields, respectively (Scheme 6).
However, when the reaction was carried out in acetic anhydride
in the presence of a catalytic amount of H2SO4, two products, 28
and 29, were formed in 47% and 24% yields, respectively (Scheme 7).
Moreover, the compound 28 was smoothly converted to 29 with
a catalytic amount of H2SO4. When the acid concentration was
increased, 28 was hydrolyzed to 30.
Figure 4. Geometry-optimized structures of 22 and 23.
acid-catalyzed ring-opening reaction in the presence of H2SO4
followed by acetylation with acetic anhydride in pyridine
resulting in the formation of a single isolable product, penta-
acetate 24. However, when the epoxide ring-opening reaction of
22 was carried out in acetic anhydride with H2SO4, the
hexaacetate 25 was isolated as the sole product in 75% yield.
The analysis of the NMR spectra of 24 and 25 showed that these
compounds have the same configuration. The configuration of
the three acetate groups attached directly to the cyclohexane ring
in 24 was found to be trans−trans. The resonance signal of
H-4 appears as a triplet at 5.32 ppm with a coupling constant of
J4,3 = J4,5 = 9.6 Hz, which clearly supports the trans relation of
protons H-4−H-5 as well as H-4−H-3. These configurational
assignments showed that the epoxide-ring in 22 underwent a
normal trans-ring-opening reaction. It was surprising to note that
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After the successful separation of compounds 28−31, we
determined the constitution of 28 by using NMR spectroscopic
data (COSY, HSQC, HMBC). The gated decoupled 13C NMR
spectrum of 28 clearly indicated that one of the epoxide rings,
where the acetoxymethylene group is attached, was retained. The
Scheme 6. Synthesis of Bisepoxide 27 and Its Acid-Catalyzed
Ring-Opening Reaction
1
large coupling constant observed in the signal at 52.7 (d, J =
184.0 Hz) indicated the presence of an epoxide ring, whereas the
other coupling constants observed between 13C and 1H (157.0−
128.8 Hz) lay within the expected ranges.30 Further analysis of
the HMBC spectrum of 28 showed that one of the acetyl groups
present in the starting material 27 was removed during the ring-
opening reaction, indicating that this group was involved in the
ring-opening reaction. After careful analysis of all possible
coupling constants, we assigned the cis-configuration to the
epoxide ring and the acetoxyl group attached to C-5 (Table 1).
This configuration was further proved later by comparison with
the structure of 30, which was obtained by single crystal X-ray
analysis.
The geometry-optimized (DFT, B3LYP at 6-31G** level)
structure of 27 (Figure 5) shows that one of the acetoxyl groups
Scheme 7. Reaction of Bisepoxide 27 in Ac2O with a Catalytic
Amount of H2SO4
Figure 5. Geometry-optimized structure of 27.
exists in a rigid conformation and is ideally aligned to effect
neighboring group participation. Probably, the initially proto-
nated epoxide ring 33 undergoes an attack by the ester oxygen
atom to form the intermediate 34. Removal of the acetoxyl group
from 34 followed by acetylation of the epoxide oxygen provides
the monoepoxide 28.31 This attack also explains the config-
urations of the acetate groups in 28−30 (Scheme 8).
The ring-opening reaction of 28 results in the formation of 29
and 30. Protonation of the second epoxide ring forms the
intermediate 35, which can undergo two different ring-opening
reactions. Since the configuration of the acetoxymethylene
Table 1. Selected 1H−1H Coupling Constants in 28 and 31
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Scheme 8. Mechanism of Formation of 28−30 by Hydrolysis of 27
Scheme 9. Synthesis of Hexaacetate 36 Starting from 28−30
groups in 29 and 30 are inverted, we assumed that the more
stable tertiary carbocation is formed during the epoxide ring-
opening reaction, which is then attacked by water and acetate
anion from the less crowded side to give 29 and 30. Finally, X-ray
analysis of 30 confirmed all structural findings in 30 as well as in
29 (Supporting Information).
(OAc and CH2OH) attached to the C-1 and C-5 carbon atoms
have a cis-configuration. The coupling constant between the
protons H1 and H2 (J = 10.5 Hz) indicates the trans configuration
of these protons. On the other hand, the smaller coupling
constant (J = 3.1 Hz) measured between the protons H2 and H3
shows the axial−equatorial orientation of the protons and the cis-
configuration of the substituent. All these data confirm the
proposed structural assignment of 31.
The formation of skeletons 28−30 is interesting. To
synthesize cyclitols derived from this skeleton, the bicyclic
compounds 28 and 29 were submitted to a hydrolysis reaction
with ammonia in methanol. The obtained epoxydiol 32 and
tetrol 8 were isolated, and their structures were determined
unambiguously (Scheme 7).
We then extended this synthetic scheme to the preparation of
the desired branched cyclitol 7 by cleavage of the oxomethylene
bridges in 28−30 followed by hydrolysis of acetate groups.
During the ring-opening reaction of 27 with sulfamic acid, 31 was
formed in only 29% yield. We were not able to decide at this stage
whether 31 was a primary product formed directly by ring-
opening of diepoxide 27 or was formed by subsequent ring-
opening of 28−30. To address this question, isolated isomers
28−30 having oxomethylene bridges were submitted to a
Finally, the structure of the ring-opening product 31 was found
to be rel-(1S,2R,3R,4S,5S)-4-hydroxy-4,5-bis(acetoxymethyl)-
cyclohexane-1,2,3-triyl triacetate based on the analysis of NMR
spectroscopic data (COSY, HSQC, HMBC). To determine the
exact configuration of 31, we analyzed the splitting pattern of
the AB system arising from methylene protons H6a and H6e
(Table 1). The diastereotopic methylene protons in 31 give rise
to an AB system. The A part (H6e) of this system is overlapped by
methyl ester resonances, whereas the B part (H6a) appears as a
doublet of triplets at 1.69 ppm with coupling constants of J =
11.5 and 12.3 Hz. Doublet splitting (12.3 Hz) is due to the
geminal coupling (J6a,6e) of protons H6a and H6e. Triplet splitting
(11.5 Hz) arises from the coupling between the methylene
proton H6a and the vicinal protons H1 and H5. The geminal
coupling is within the expected range.31 The large vicinal
couplings indicate that the coupled protons (H6a, H1, and H5)
have an axial conformation; in other words, the substituents
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Scheme 10. Mechanism of Formation of 36 from 28−30
Scheme 11. Synthesis of Hexol 7 Starting from 31 and 36
hydrolysis reaction with sulfamic acid in a mixture of Ac2O/
AcOH at reflux temperature. In all three cases, we observed the
formation of the same hexaacetate 36 in high yields (Scheme 9).
Acetylation of 31 also gave the same hexaacetate 36 (Scheme 11).
Since the configuration in 31 during acetylation of the hydroxyl
group will not change, we assigned the same configuration of the
substituents in 31 to those in 36.
The cis-opening of the oxomethylene bridge in 28−30 needs
explanation. It is likely that neighboring group participation
controls the mode of the reaction. The initially protonated bridge
oxygen in 37 can be attacked by the adjacent acetoxy group to
form cyclic oxolonium ion 38, which then can undergo ring-
opening by attack of the acetate anion. To determine the
involvement of any neighboring group participation, the acetate
groups in 29 were removed and the formed tetrol 8 was treated
with sulfamic acid under the same reaction conditions as shown
in Scheme 10. The formed hexaacetate 36 was identical to
those obtained from the reaction of 28−30 with sulfamic acid.
We concluded that the acetate group was not involved during the
ring-opening reaction. For the opening of the oxomethylene
bridge we suggest the following mechanism as shown in Scheme 10.
The acetate anion attacks the protonated oxomethylene
bridge in 37 from the back of methylene carbon so that the
original configuration at the bridgeheads will be retained in
the product.
Finally, deacetylation of 31 and 36 with ammonia gave the
same hexol 7, which furthermore indicated that 31 and 36 have
the same configuration (Scheme 11). The H6a proton in 7 reso-
nates as a doublet of triplets at 1.35 ppm with coupling constants
of 13.5 Hz (geminal coupling) and 11.1 Hz (vicinal coupling).
The large vicinal couplings between the protons H6a and the
protons H1 and H5 here also indicate the cis-configuration of the
hydroxyl group and the hydroxymethyl group attached to C-1
and C-5 in 7.
α-Glycosidase Inhibition Study. The inhibitory activities
of compounds 18, 26, 6, 32, 8, and 7 were screened against
α-glycosidase. The results are summarized in Table 2. While the
compounds 6, 7, 8, 26, and 32 were found to be weak inhibitors
of α-glucosidase, the tetrol 18 turned out to be a stronger
inhibitor toward α-glycosidase with an inhibition of 64.6 2.2%
for 30 μM concentration (IC50 = 24 μM). Although the activity
of 18 is lower when compared to commercially available
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Table 2. Inhibition of α-Glycosidase by Racemic 18, 26, 6, 32,
8, and 7
EXPERIMENTAL SECTION
rel-(4R,5S)-4,5-Bis(hydroxymethyl)cyclohexene (10). Com-
pound 10 was prepared according to the procedure described in the
literature.17
■
rel-(1R,2S)-[2-[(Acetyloxy)methyl]cyclohex-4-en-1-yl]methyl
Acetate (11).18 To a solution of diol 10 (40.0 g, 281.3 mmol), pyridine
(68 mL), and dichloromethane (500 mL) was added acetyl chloride
(42 mL, 2.1 equiv) dropwise. A colorless precipitate was formed, and
the mixture was stirred at room temperature overnight. The mixture was
washed with water, 1 N hydrochloric acid, and brine, dried, and
1
concentrated to give 11 as a colorless oil (63.22 g, 98%): H NMR
(300 MHz, CDCl3) δ 5.55 (bs, 2H, H-4 and H-5), 4.03 (dd, A part of AB
system, J = 11.0, 6.5 Hz, 2H, OCHH), 3.93 (dd, B part of AB system, J =
11.0, 7.3 Hz, 2H, OCHH), 2.17−2.06 (m, 4H, 2CH and 2 CHH), 2.03
(s, 6H, CH3), 1.86 (dd, B part of AB system, J = 16.4, 5.9 Hz, 2H, CHH);
13C NMR (75 MHz, CDCl3) 170.7, 125.0, 64.9, 33.6, 26.5, 20.8.
r e l - ((1 R , 2S , 4 S , 5S ) - [ 2 - [ ( A c e t y l o x y) meth yl]- 4, 5-
dibromocyclohexyl]methyl Acetate (12). Bromine (10.62 g, 66.6
mmol) in 100 mL of dichloromethane was added dropwise to a
magnetically stirred solution of diacetate 11 (10.0 g, 44.2 mmol) in
200 mL of dry dichloromethane at room temperature over a period
of 4 h. The mixture was then stirred at room temperature for 6 h. After
removal of the solvent, the oily dibromodiacetate 12 (16.06 g, 94%) was
1
used without purification for further reactions: H NMR (300 MHz,
CDCl3) δ 4.27 (dt, J = 10.0, 4.0 Hz, 1H), 4.15−3.95 (m, 5H), 2.48
(dt, J = 14.3, 4.2 Hz, 1H), 2.44−2.37 (m, 1H), 2.30−2.25 (m, 1H),
2.18−2.10 (m, 1H), 2.03−1.94 (m, 2H), 2.02 (s, 3H, CH3), 2.1 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3) 171.04, 170.99, 65.1, 62.8, 54.50,
53.4 (2C), 38.2, 35.2, 35.4, 21.2, 21.1; IR (KBr, cm−1) 2954, 2899, 1732,
1446, 1367, 1222, 1033, 979, 910, 848, 788, 744, 684, 605. Anal. Calcd
for C12H18Br2O4: C, 37.33; H, 4.70. Found: C, 37.57; H, 4.74.
[2-[(Acetyloxy)methyl]cyclohexa-2,4-dien-1-yl]methyl Ace-
tate (13). To a magnetically stirred solution of dibromodiacetate 12
(20.0 g, 51.82 mmol) in 300 mL of dry benzene was added a solution of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (19.72 g, 129.7 mmol) in
200 mL of dry benzene at room temperature. The resulting mixture was
heated at the reflux temperature of benzene for 12 h and then cooled to
room temperature. Water (200 mL) was added, and the organic phase
washed with saturated aqueous sodium bicarbonate (3 × 250 mL), dried
(MgSO4), and evaporated under reduced pressure to give a mixture
of the dienes 13 and 1419 (9.1 g, 78%) in a ratio of 9:1 as a colorless
liquid. An analytically pure sample of 13 was obtained by column
chromatography over silica gel eluting with n-hexane/EtOAc (5:1):
1H NMR (400 MHz, CDCl3) δ 6.02 (bd, J = 5 Hz, 1H), 5.94−5.90
(m, 1H), 5.75−5.71 (m, 1H), 4.63 (AB system, J = 11.0 Hz, 2H), 4.09
(dd, A part of AB system, J = 10.5, 5.4 Hz, 1H, CHH), 3.98 (dd, B part of
AB system, J = 10.5, 9.1 Hz, 1H, CHH), 2.53−2.49 (m, 1H), 2.38−2.34
(m, 2H), 2.09 (s, 3H, CH3), 2.05 (s, 3H, CH3); 13C NMR (100 MHz,
CDCl3) δ 170.9, 170.7, 126.2, 125.1, 124.4, 123.5, 66.6, 63.0, 32.8, 25.2,
20.9, 20.8; IR (KBr, cm−1) 3043, 2947, 2829, 1735, 1367, 1220, 1070,
1026, 974; HRMS-ESI (m/z) [M + H]+ calcd for C12H17O4 225.11268,
found 225.10966.
a
Four experiments were performed for all compounds in each
b
c
experiment duplicated. Inhibition by 30 μM compound. Inhibition
d
by 400 μM compound. Inhibition by 40 μM compound.
e
Concentration required for 50% inhibition of the enzyme activity
f
under the assay conditions. NT = not tested.
antidiabetics such as miglitol (IC50 = 1.3 μM), voglibose (IC50 =
0.11 μM), and acarbose (IC50 = 0.35 μM),32 the inhibitory
activity of tetrol 18 against α-glycosidase is comparable with
respect to newly synthesized carbasugars.8,33,34
CONCLUSION
■
rel-(1R,4R,5R)-[4-[(Acetyloxy)methyl]-2,3-dioxabicyclo-
[2.2.2]oct-7-en-5-yl]methyl Acetate (16). A stirred solution of diene
13 (10.0 g, 44.60 mmol) and 250 mg of tetraphenylporphyrin (TPP) in
250 mL of CH2Cl2 was irradiated with projection lamp (500 W) while
oxygen gas passed through the solution. The reaction was completed
after 12 h. The solvent was evaporated under reduced pressure. The
residue (9.94 g, 87%) was crystallized from diethyl ether to give pure
bicyclic endoperoxide 16 (9.37 g, 82%) as colorless crystals: mp 78−
79 °C; 1H NMR (300 MHz, CDCl3) δ 6.78 (dd, A part of AB system,
J7,8 = 8.5 Hz and J7,1 = 5.9 Hz, 1H, H-7) 6.37 (d, B part of AB system, J7,8
= 8.5, 1H, H-8), 4.75−4.70 (m, 1H, H-1)), 4.48 (d, A part of AB system,
The methodology detailed herein facilitated the convenient
conversion of the diene 13 into various carbasugar derivatives.
The oxygen functionalities were introduced by photooxygena-
tion of the diene unit to give an unsaturated bicyclic endo-
peroxide. Cleavage of the oxygen−oxygen bond followed by
epoxidation of the double bond and ring-opening of the formed
epoxide resulted in the formation of 6, 18, and 26. The
rearrangement of the unsaturated bicyclic endoperoxide 16 to
the corresponding diepoxide 28 with CoTPP followed by an
epoxide-ring-opening reaction in the presence of sulfamic acid
and removal of acetate groups gave bicylic carbasugars 32 and 8
and the monocyclic carbasugar 7. This methodology also
provides an entry to the synthesis of carbasugar derivatives as
well as for aminocarbasugars. Six compounds, 6, 7, 8, 18, 26, and
32, were screened against α-glycosidase. The tetrol 18 showed
comparable inhibition.
J10,10′ = 12.9 Hz, 1H, H-10 or H-10′), 4.35 (d, B part of AB system, J10,10′
=
12.9 Hz, 1H, H-10′ or H-10), 3.84 (dd, A part of AB system, J9,9′ = 11.8
Hz and J9,7(9′,7) = 5.9 Hz, 1H, H-9 or H-9′), 3.69 (dd, B part of AB- system
J9,9′ = 11.8 Hz and J9,6(9′,6) = 8.5 Hz, 1H, H-9 or H-9′), 2.82 (m, 1H, H-6),
2.53 (ddd, J5,5′ = 13.5 Hz, J = 9.4, 3.8 Hz, 1H, H-8 or H-8′), 2.14 (s, 3H,
CH3), 2.03 (s, 3H, CH3), 1.09 (ddd, J5,5′ = 13.5 Hz, J = 3.8, 2.0 Hz, 1H,
H-8 or H-8′); 13C NMR (75 MHz, CDCl3) δ 170.9 (2C), 134.0, 129.1,
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78.4, 70.9, 65.8, 63.8, 34.0, 27.1, 21.01, 20.97; IR (KBr, cm−1) 3016,
2970, 2941, 1726, 1365, 1222, 1035, 987, 956, 902, 877. Anal. Calcd for
C12H16O6: C, 56.24; H, 6.29. Found: C, 55.92; H, 6.35.
anhydride (5 mL). The resulting mixture was stirred magnetically at
room temperature for 6 h. The mixture was acidified with ice-cold HCl
(100 mL, 5%) and washed with water (2 × 300 mL) and saturated
NaHCO3 (2 × 100 mL). The organic phase was dried (Na2SO4), and
evaporation of the solvent gave triacetate 21 (1.2 g, 80%) as the sole
product as a colorless viscous oil. An analytical pure sample was obtained
by chromatography on a short silica gel column eluting with EtOAc/
n-hexane (2:1): 1H NMR (300 MHz, CDCl3) δ 5.88 (ddd, A part of AB
system, J4,3 = 10.3 Hz, J4,5 = 4.1 Hz and J4,6 = 1.2 Hz, 1H, H-4), 5.81
(dd, B part of AB system, J3,4 = 10.3 Hz, J3,5 = 0.6 Hz, 1H, H-3), 5.23
(bq, J5,4 = J5,6 = J5,6′ = 4.1 Hz 1H, H-5), 4.26 (dd, A part of AB system,
J7,7′ = 11.4 Hz and J(7,1′) = 6.2 Hz, 1H, H-7 or H-7′), 4.12 (dd, B part of AB
system, J7,7′ = 11.4 Hz and J(7,1) = 6.5 Hz, 1H, H-7 or H-7′), 4.08 (s, 2H,
H-8 and H-8′), 2.42−2.34 (m, 1H, H-1), 2.28 (s, 1H, OH), 2.07 (s, 3H,
CH3), 2.06 (s, 3H, CH3), 2.04 (s, 3H, 1.90 (ddd, A part of AB system, J =
14.6, 4.1, 1.2 Hz, 1H, H-6 or H-6′), 1.85 (ddd, J = 14.6, 11.4, 4.7 Hz, 1H,
H-6 or H-6′); 13C NMR (75 MHz, CDCl3) δ 171.2, 171.1, 170.8, 135.4,
127.2, 71.4, 67.0, 65.7, 64.0, 39.2, 28,6, 21.5, 21.2, 21.1; IR (KBr, cm−1)
3464, 3240, 3151, 2966, 1732, 1693, 1525, 1487, 1367,1230, 1211, 1020,
976. Anal. Calcd for C14H20O7: C, 55.99; H, 6.71. Found: C, 55.81;
H, 6.64.
rel-(1R,2S,5S)-[2-[(acetyloxy)methyl]-2,5-dihydroxycyclohex-
3-en-1-yl]methyl Acetate (17). Bicyclic endoperoxide 16 (4.0 g,
15.62 mmol) was dissolved in absolute methanol (150 mL). Thiourea
(1.43 g, 18.8 mmol) was added to the solution. After completion of the
addition (ca. 15 min), the mixture was stirred for 24 h at room
temperature. The solids were removed by filtration. After the removal of
the solvent, the residue was filtered on a short silica gel column (25.0 g)
eluting with dichloromethane to yield diol diacetate 17 (3.5 g, 87%).
Crystallization from ethyl acetate gave white crystals: mp 108−110 °C
(2.97 g, 74%); 1H NMR (300 MHz, CDCl3) δ 5.94 (ddd, A part of AB
system, J4,3 = 10.0 Hz, J4,5 = 4.1 Hz, and J4,6 = 1.0 Hz, 1H, H-4), 5.72
(dd, B part of AB system, J3,4 = 10.0 Hz and J3,5 = 0.6 Hz, 1H, H-3), 4.30
(dd, A part of AB system, J8,8′ = 11.3 Hz and J8,1(8′,1) = 6.0 Hz, 1H, H-8 or
H-8′), 4.25 (q, J5,4 = J5,4 = J5,6′ = 4.1 Hz, 1H, H-5), 4.09 (dd, B part of AB
system, J8,8′ = 11.3 Hz and J8,1(8′,1) = 7.0 Hz, 1H, H-8 or H-8′), 4.11−4.04
(AB- system, J7,7′ = 11.7 Hz, 2H, H-7 and H-7′), 3.3−2.9 (br s, 2H,
−OH), 2.41 (m, 1H, H-1), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.92
(ddt, A part of AB system, J6,6′ = 14.3 Hz, J6,5(6′,5) = 3.6 Hz, and J6,4(6′,4)
=
1.0 Hz, 1H, H-6 or H-6′), 1.82 (ddd, B part of AB system, J6,6′ = 14.3 Hz,
J = 11.1, 4.6 Hz, 1H, H-6 or H-6′). 13C NMR (75 MHz, CDCl3) δ
171.33, 171.31, 133.2, 131.2, 71.4, 67.1, 64.3, 63.3, 38.9, 31.7, 21.2, 21.1;
IR (KBr, cm−1) 3387, 3279, 2958, 2926, 2897, 1728, 1462, 1440,
1381,1363, 1305, 1228, 1105, 1035, 1004, 977, 927, 912, 812. Anal.
Calcd for C12H18O6: C, 55.81; H, 7.02. Found: C, 55.73; H, 6.69.
General Procedure for Hydrolysis of Acetates. Synthesis of
Cyclitols. Di-, tri-, or tetraacetates (3.0 mmol) were dissolved in 60 mL
of absolute methanol. Dry NH3(g) was passed through solution for 1 h.
Then, the flask was closed with a stopper. The solution was stirred for
12 h at room temperature. Evaporation of the solvent and formed
acetamide gave the corresponding cyclitols.
Reaction of Triacetate 21 with m-Chloroperbenzoic Acid.
Triacetate 21 (6.35 g, 21.14 mmol) was dissolved in 400 mL of
dichloromethane and m-CPBA (10.95 g, 44.4 mmol, 70%) was added.
The reaction mixture was stirred magnetically at room temperature
for one week. After completion of the reaction, saturated NaHSO3
(400 mL) was added and the mixture was stirred for 20 min. The organic
layer was separated, washed with saturated NaHCO3 (3 × 300 mL) and
dried (MgSO4). After removal of solvent, the residue was chromato-
graphed on silica gel eluting with EtOAc/hexane (1:4) to give two
separable fractions.
rel-((1R,2S,3R,5S,6R)-5-Acetoxy-2-hydroxy-7-oxabicyclo-
[4.1.0]heptane-2,3-diyl)bis(methylene) diacetate (23). Com-
pound 23 was isolated as the first fraction: colorless oil (470 mg, 1.48
mmol 7%); TLC (hexane/EtOAc, 1:1) Rf = 0.52; 1H NMR (300 MHz,
CDCl3) δ 5.15 (ddd, J5,4 = 11.0 Hz, J5,4′ = 5.7 Hz and J5,6 = 1.6 Hz, 1H, H-5),
4.25 (d, A part of AB system, J7,7′ =11.6 Hz, 1H, H-7 or H-7′), 4.27
(dd, A part of AB system, J8,8′ =11.4 Hz and J8,3 = 5.7 Hz, 1H, H-8 or H-8′),
4.17 (dd, B part of AB system, J7,7′ = 11.6 Hz, 1H, H-7 or H-7′), 3.91
(dd, B part of AB system, J8,8′ = 11.4 Hz and J8′,3 = 7.0 Hz, H-8 or H-8′), 3.53
(bdt, J6,1 = 4.0, and J6,5 = J6,4 = 1.6 Hz, 1H, H-6), 3.36 (d, J1,6 = 4.0 Hz, 1H,
H-1), 2.70(bs, 1H, −OH), 2.10(s, 3H, CH3), 2.09 (s, 3H, CH3), 2.02 (s, 3H,
CH3), 1.84−1.65 (m, 2H), 1.56 (dd, J4,4′ = 12.7 Hz and J4,5 = 11.0 Hz, 1H,
H-4 or H-4′); 13C NMR (75 MHz, CDCl3) δ 171.1, 170.9, 170.7, 70.2, 68.4,
67.0, 63.8, 59.4, 56.3, 38.4, 22.8, 21.3, 21.2, 21.1; IR (KBr, cm−1) 3466, 2947,
1732, 1433, 1367, 1226, 1028, 979, 912, 815, 734, 702. Anal. Calcd for
C14H20O8: C, 53.16; H, 6.37. Found: C, 53.20; H, 6.25.
rel-(1S,4S,6R)-2,3-Bis(hydroxymethyl)cycloheptane-2,5-diol
(18). Diacetate 17 (4.0 g, 15.5 mmol) was hydrolyzed as described
above to give tetrol 18 (2.62 g, 97%) as a colorless viscous oil: 1H NMR
(300 MHz, CD3OD) δ 5.83 (ddd, 1H, A part of AB system, J3,2
=
10.1 Hz, J3,4 = 3.8 Hz and J3,5 = 0.9 Hz, 1H, H-3), 5.63 (dd, B part of AB
system, J3,2 = 10.1 Hz, J2,4 = 1.0 Hz, 1H, H-2), 4.9 (s, 4H, −OH), 4.17
(q, J4,3 = J4,5 = J4,5′ = 3.8 Hz, 1H, H-4), 3.73 (dd, A part of AB system, J7,7′
=
10.8 Hz and J7,6(7′,6) = 5.8 Hz, 1H, H-7 or H-7′), 3.65 (dd, B part of AB
system, J7,7′ = 10.8 Hz and J7,6(7′,6) = 5.8 Hz, 1H, H-7 or H-7′), 3.53−3.42
(AB system, J8,8′ = 11.5 Hz, 2H, H-8 and H-8′), 2.17−2.09 (m, 1H, H-6),
1.92 (ddd, A part of AB system, J = 12.9, 10.8, 4.8 Hz, 1H, H-5 or H-5′),
1.82 (ddd, B part of AB system, J = 12.9, 3.8, 1.0 Hz, 1H, H-5 or H-5′);
13C NMR (75 MHz, CD3OD) δ 133.8, 130.7, 72.4, 65.0, 63.2, 61.5, 41.4,
31.3. IR (KBr, cm−1) 3305, 2931, 1662, 1402, 1203.58, 1043, 999, 756.
Anal. Calcd for C8H14O4: C, 55.16; H, 8.10. Found: C, 55.34; H, 8.31.
rel-(1S,4S,5R)-4-(Acetyloxy)-4,5-bis[(acetyloxy)methyl]-
cyclohex-2-en-1-yl Acetate (19). Dihydroxy diacetate 17 (1.0 g,
3.87 mmol) was dissolved in pyridine (2.5 mL) and acetic anhydride
Ac2O (3 mL). The resulting mixture was stirred magnetically at room
temperature for 72 h. The mixture was worked up as described above
rel-((1S,2S,3R,5S,6S)-5-Acetoxy-2-hydroxy-7-oxabicyclo-
[4.1.0]heptane-2,3-diyl)bis(methylene) Diacetate (22). Com-
pound 22 was isolated as the second fraction: colorless oil (5.01 g,
1
75%); TLC (hexane/EtOAc, 1:1) Rf = 0.38; H NMR (300 MHz,
CDCl3) δ 5.18 (dt, J = 5.0 and 3.6 Hz,1H, H-5), 4.25 (dd, A part of AB
system, J8,8′ = 11.4 Hz and J8,3 = 5.2 Hz, 1H, H-8 or H-8′), 4.23 (d, A part
1
to yield tetraacetate 19 (1.1 g, 83%) as a colorless liquid: H NMR
of AB system, J7,7′ = 11.6 Hz, 1H, H-7 or H-7′), 4.21 (AB system, J7,7′
=
(300 MHz, CDCl3) δ 6.13 (dd, A part of AB system, J3,2 = 10.3 Hz, J3,1
=
12.0 Hz, 2H, H-7 and H-7′), 4.02 (dd, B part of AB system, J8,8′ = 11.4 Hz
and J8′,3 = 6.7 Hz, H-8 or H-8′), 3.61 (t, J6,1 = J6,5 = 4.1, 1H, H-6), 3.31
(d, J1,6 = 4.1 Hz, 1H, H-1), 2.70−2.80 (bs, 1H, −OH), 2.33−2.24 (m,
1H, H-3), 2.12 (s, 3H, CH3), 2.119 (s, 3H, CH3), 2.07 (s, 3H, CH3),
1.84−1.65 (m, 2H, H-4 and H-4′); 13C NMR (75 MHz, CDCl3) δ 171.0,
170.94, 170.90, 70.9, 66.4, 65.9, 63.3, 57.6, 55.3, 37.7, 27.4, 21.2, 21.15,
21.1; IR (KBr, cm−1) 3468, 2958, 1732, 1433, 1369, 1226, 1028, 910,
875. Anal. Calcd for C14H20O8: C, 53.16; H, 6.37. Found: C, 53.58; H,
6.31.
rel-(1S,2S,3R,5S,6S)-2,5-Acetoxy-7-oxabicyclo[4.1.0]-
heptane-2,3-diyl)bis(methylene) Diacetate (syn-20). To a stirred
solution of monoepoxide 22 (1.2 g, 3.80 mmol) in Ac2O (5 mL) was
added a catalytic amount of H2SO4 (one drop). The solution was stirred
for 12 h at room temperature, and then CH2Cl2 (300 mL) was added.
The organic phase was extracted with saturated NaHCO3 (2 × 150 mL)
and then with water (3 × 300 mL), dried over MgSO4, and filtered. The
0.9 Hz, 1H, H-3), 5.91 (dd, B part of AB system, J2,3 = 10.3 Hz, J2,1 = 4.1,
1H, H-2), 5.23 (bq, J1,2 = J1,6 = J1,5′ = 4.1 Hz, 1H, H-1), 4.48 (d, A part of
AB system, J8,8′ = 12.1 Hz, 1H, H-8 or H-8′) 4.23 (dd, A part of AB
system, J7,7′ = 11.4 Hz, J7,5 = 5.2 Hz, 1H, H-7 or H-7′), 4.11 (d, B part of
AB system, J8,8′ = 12.1 Hz and, 1H, H-8 or H-8′), 3.98 (dd, B part of AB
system, J7,7′ = 11.4 Hz and J7,5 = 7.3 Hz, 1H, H-7 or H-7′), 2.92 (dq, J =
5.0, 7.1 Hz, 1H, H-5), 2.05 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.03 (s, 3H,
CH3), 2.02 (s, 3H, CH3), 1.97 (dd, J = 7.0, 4.7 Hz, 2H, H-6 and H-6′);
13C NMR (75 MHz, CDCl3) δ 171.1, 170.9, 170.5, 170.0, 131.6, 128.6,
79.6, 65.6, 64.0, 63.0, 36.3, 28.4, 22.2, 21.5, 21.1, 21.0; IR (KBr, cm−1)
2956, 1732, 1435, 1367, 1222, 1031, 1016, 972, 941, 858, 765, 638. Anal.
Calcd for C16H22O8: C, 56.13; H, 6.48. Found: C, 56.27; H, 6.40.
rel-[(1R,2S,5S)-5-(Acetyloxy)-2-[(acetyloxy)methyl]-2-hydroxy-
cyclohex-3-en-1-yl]methyl Acetate (21). Dihydroxy diacetate 17
(1.29 g, 5.0 mmol) was dissolved in pyridine (3 mL) and acetic
5093
dx.doi.org/10.1021/jo300655p | J. Org. Chem. 2012, 77, 5086−5097

The Journal of Organic Chemistry
Article
solution was evaporated under reduced pressure to give the tetraacetate
1H, H-6 or H-6′); 13C NMR (75 MHz, D2O) δ 76.3, 76.1, 72.9, 69.2,
64.8, 60.3, 41.3, 28.6; IR (KBr, cm−1) 3446, 3342, 3155, 2956, 2927,
2893, 1384, 1363, 1327,1151, 1089, 1058, 1033, 1014, 975, 941. Anal.
Calcd for C8H16O6: C, 46.15; H, 7.75. Found: C, 46.01; H, 7.78.
rel-(1S,2S,3R,5S,6S)-2,3-Bis(hydroxymethyl)-7-oxabicyclo-
[4.1.0]heptane-2,5-diol (26). Epoxy triacetate 22 (0.30 g, 0.95 mmol)
was hydrolyzed with NH3(g) as described above to give epoxy tetrol 26
syn-20 (1.0 g, 74%), which was crystallized from EtOAc to give colorless
prisms: mp 85−88 °C; 1H NMR (300 MHz, CDCl3) δ 5.20 (dt, J5,4
J5,4′ = 7.3 Hz and J5,6 = 2.9, 1H, H-5), 4.97 (d, A part of AB system, J7,7′
=
=
12.3 Hz, 1H, H-7 or H-7′), 4.18 (dd, A part of AB system, J8,8′ = 11.4 Hz
and J8,3 = 5.3 Hz, 1H, H-8 or H-8′), 4.16 (d, B part of AB system, J7,7′
=
12.3 Hz, 1H, H-7 or H-7′), 3.97 (dd, B part of AB system, J8,8′ = 11.4 Hz
and J8′,3 = 7.9 Hz, 1H, H-8 or H-8′), 3.67 (d, J1,6 = 3.5 Hz, 1H, H-1), 3.54
(dd J6,1 = 3.5 Hz and J6,5 = 2.9 Hz, 1H, H-6), 2.41−2.49 (m, 1H, H-3),
2.11 (s, 3H, CH3), 2.09 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.06 (s, 3H,
CH3), 1.76−1.84 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 170.9 (2C),
170.3 (2C), 78.2, 67.1, 62.6, 62.4, 54.7, 54.5, 37.5, 24.3, 21.7, 21.3, 21.1,
21.0; IR (KBr, cm−1) 2947, 2852, 1733, 1435, 1367, 1222, 1031, 906,
873, 815, 734. Anal. Calcd for C16H22O9: C, 53.63; H, 6.19. Found: C,
53.58, H, 5.96.
1
(0.15 g, 86%) as a colorless viscous oil: H NMR (300 MHz, D2O) δ
4.06 (m, 1H), 3.57−3.39 (m, 3H), 3.34 (t, J = 3.3 Hz, 1H, H-6), 3.24
(dd, B part of AB system, J = 11.0, 8.0 Hz, 1H, H-8 or H-8′), 3.15 (d, 1H,
J = 4.0 Hz, 1H, H-1), 1.70−1.60 (m, 1H, H-3), 1.59−1.45 (m, 1H, H-4
or H-4′), 1.42−1.37 (m, 1H, H-4 or H-4′); 13C NMR (75 MHz, D2O) δ
72.6, 62.9 (2C), 60.5, 58.5, 57.2, 38.7, 29.5; IR (KBr, cm−1) 3331, 3298,
3286, 2933, 1406, 1332, 1257, 1031. Anal. Calcd for C8H14O5: C, 50.52;
H, 7.42. Found: C, 50.16; H, 7.07.
rel-(1S,2S,3R,4S,6R)-1,6-Bis(acetoxymethyl)cyclohexane-
1,2,3,4-tetrayl Tetraacetate (25). Epoxy triacetate 22 (3.0 g, 9.49
mmol) was dissolved in Ac2O (15 mL), and H2SO4 (12 drops) was
added. The reaction was carried out as reported in the synthesis of syn-
20. A dark residue was formed that was chromatographed on silica
Deacetylation of Hexaacetate with NH3(g) in MeOH. Hexa-
acetate 25 (1.0 g, 2.17 mmol) was hydrolyzed with MeOH in the
presence of NH3(g) as described above to give hexol 6 (0.43 g, 95%) as
colorless crystals. The spectral data of this compound was the same as
the compound, which was obtained by hydrolysis of 24 with ammonia.
rel-(1S,2S,4S,5R,7S)-[4-[(Acetyloxy)methyl]-3,8-dioxatricyclo-
[5.1.0.02,4]oct-5-yl]methyl Acetate (27). To a magnetically stirred
solution of bicyclic endoperoxide 16 (5.0 g, 19.5 mmol) in 150 mL
of CH2Cl2 was added a solution of cobalt meso-tetraphenylporphyrin
(180 mg) in 25 mL of CH2Cl2 at 0 °C. After complete addition (20 min),
the mixture was allowed to stir for 30 min at room temperature. Removal
of solvent and chromatography of the residue on 50 g silica gel eluting
with hexane/EtOAc (5:1) gave bisepoxide 27 (4.0 g, 80%) as colorless
liquid: 1H NMR (300 MHz, CDCl3) δ 4.53 (d, J7,7′ = 12.6 Hz, 1H, H-8 or
H-8′), 4.24 (dd, A part of AB system, J7,7′ =11.6 Hz and J7,6 = 5.8 Hz, 1H,
(50 g), eluting with hexane/ethyl acetate (4/1) to give 25 (3.28 g, 75%)
1
as a colorless liquid: H NMR (300 MHz, CDCl3) δ 5.51 (d, J3,4
=
9.9 Hz, 1H, H-3), 5.40 (t, J4,3 = J4,5 = 9.9 Hz, 1H, H-4), 5.20 (ddd, J5,6
=
11.7 Hz, J5,4 = 9.9 Hz, and J5,6′ = 5.3 Hz, 1H, H-5), 4.65 (d, A part of AB
system, J8,8′ = 11.7 Hz, 1H, H-8 or H-8′), 4.56, (d, B part of AB system,
J8,8′ = 11.7 Hz, 1H, H-8 or H-8′), 4.33 (dd, A part of AB system, J7,7′
=
12.0 Hz and J7,1 = 5.9 Hz, 1H, H-7 or H-7′), 4.20 (dd, B part of AB
system, J7,7′ =12.0 Hz and J7′,1 = 5.0 Hz, 1H, H-7 or H-7′), 3.27 (m, 1H,
H-1), 2.16 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.02 (s, 3H, CH3), 2.00
(s, 3H, CH3), 1.99 (s, 3H, CH3), 1.97 (s, 3H, CH3), 2.16−2.08 (m, 1H,
H-6 or H-6′), 1.87−1.75 (m, 1H, H-6 or H-6′); 13C NMR (75 MHz,
CDCl3) δ 170.5, 170.28, 170.23, 169.9 (2C), 169.8, 84.2, 72.6, 70.0,
69.8, 63.4, 63.1, 37.0, 28.7, 21.9, 21.1 (2C), 20.9, 20.83, 20.76; IR (KBr,
cm−1) 2970, 1737, 1433, 1367, 1217, 1029, 952, 898, 864, 734 700, 640.
Anal. Calcd for C20H28O12: C, 52.17; H, 6.13. Found: C, 52.12, H, 6.08.
rel-(1S,2R,3S,4S,5R)-4,5-Bis(acetoxymethyl)-4-hydroxycyclo-
hexane-1,2,3-triyl Triacetate (24). To a suspension of epoxy acetate
22 (570 mg, 1.8 mmol) in water (20 mL) was added H2SO4 (2 mL), and
the resulting mixture was stirred for 24 h at room temperature. After
neutralization of the solution with saturated NaHCO3, the water was
evaporated, the residue was dissolved in MeOH, and the solid was
filtered off. MeOH was evaporated, and without any purification,
pyridine (1.5 mL) and acetic anhydride (2 mL) were added to the
residue. The mixture was stirred for 12 h, and ethyl acetate (150 mL)
was added. The mixture was hydrolyzed with ice-cooled HCl (100 mL,
5%), neutralized with saturated NaHCO3 solution, dried (Na2SO4), and
evaporated. The residue was chromatographed on silica gel (10.0 g)
eluting with hexane/ethylacetate (6:1) to yield pentaacetate 24
(600 mg, 80%), which was crystallized from hexane/EtOAc to give
colorless crystals: mp 132−135 °C; 1H NMR (300 MHz, CDCl3) δ 5.32
(t, A part of AB system, J4,3 = J4,5 = 9.6 Hz, 1H, H-4), 5.17 (d, B part of
AB system, J3,4 = 9.6, 1H, H-3), 5.03 (ddd, J5,6 = 11.7 Hz, J5,4 = 9.6 Hz,
and J5,6′ = 5.3 Hz, 1H, H-5), 4.14 (dd, A part of AB system, J7,7′ =11.9 Hz
H-7 or H-7′), 4.17 (dd, B part of AB system, J7,7′ =11.6 Hz and J7,6
=
5.3 Hz, 1H, H-7 or H-7′), 3.94 (d, J8,8′ = 12.6 Hz, 1H, H-8 or H-8′), 3.39
(d, A part of AB system, J2,3 = 2.6 Hz, 1H, H-2), 3.31 (dd, B part of AB
system J3,4 = 4.1 Hz and J3,2 = 2.6 Hz, 1H, H-3), 3.03 (dt, 1H, J = 5.6, 3.8
Hz, 1H, H-5), 2.5−2.42 (m, 1H, H-6), 2.08 (s, 3H, CH3), 2.07 (s,3H,
CH3), 1.94−1.88 (m, 2H, H-5 and H-5′); 13C NMR (75 MHz, CDCl3) δ
171.0, 170.7, 65.3, 64.5, 57.3, 51.6, 48.0, 46.3, 33.1, 24.5, 21.2, 21.0; IR
(KBr, cm−1) 2956, 1735, 1431, 1365, 1224, 1103, 1029, 975. Anal. Calcd
for C12H16O6: C, 56.24; H, 6.29. Found: C, 56.27; H, 6.40.
Ring Opening of Bisepoxide 27 with Sulfamic Acid. Bisepoxide
27 (3.0 g,11.71 mmol) was dissolved in 10 mL of Ac2O/AcOH (1:1),
and then sulfamic acid (100 mg) was added. The resulting solution was
heated at reflux temperature for 12 h. After the mixture was cooled to
room temperature, ice-cooled HCl solution (150 mL, 5%) was added,
and the solution was extracted with methylene chloride (3 × 75 mL).
The organic phase was washed with water and dried (MgSO4). After
removal of the solvent under reduced pressure, the residue was
chromatographed on a silica gel column (120 g) eluting with hexane/
EtOAc (4:1). Four compounds 28, 29, 30, and 31 were isolated in the
following order:
rel-((1R,2S,4S,5S,6R)-5-Acetoxy-3,7-dioxatricyclo[4.2.1.02,4]-
nonan-2-yl)methyl acetate (28): 0.9 g, 30% as colorless needles from
1
ether; mp 92−94 °C; TLC (hexane/EtOAc, 1:1) Rf = 0.84, H NMR
and J7,1 = 6.2 Hz, 1H, H-7 or H-7′), 4.08 (dd, B part of AB system, J7,7′
=
(300 MHz, CDCl3) δ 4.73 (ddd, J = 4.2, 2.8, 1.5 Hz, 1H, H-5), 4.53
(d, A part of AB system, J = 12.5 Hz, 1H, H-10), 4.06 (dt, J = 6.2, 2.1 Hz,
1H, H-6), 3.98 (dd, A part of AB system, J = 8.4, 0.9 Hz, 1H, H-8endo),
3.96 (d, B part of AB system, J = 12.5 Hz, 1H, H-10′), 3.80 (dd, B part of
AB system, J = 8.4, 3.9 Hz, 1H, H-8exo), 3.33 (ddd, J = 4.1, 1.9, 0.6 Hz,
1H, H-4), 2.74 (bt, J = 4.1 Hz, 1H, H-1), 2.31 (d, J = 12.1 Hz, 1H,
H-9endo), 1.58 (dddd, J = 12.1, 6.1, 4.4, 1.5 Hz, 1H, H-9exo); 13C NMR
(75 MHz, CDCl3) δ 170.8, 170.3, 74.5, 70.0, 69.9, 64.1, 60.0, 52.7, 35.6,
27.4, 21.0, 20.96; gated decoupled 13C NMR (75 MHz, CDCl3) only
one bond C−H couplings are given δ 170.8 (s), 170.3 (s), 74.5 (t, 1J =
157.0 Hz), 70.0 (d, 1J = 150.0 Hz), 69.9 (t, 1J = 149.0 Hz), 64.1 (t, 1J =
148.0 Hz), 60.0 (s), 52.7 (d, 1J = 184.0 Hz), 35.6 (d, 1J = 141.0 Hz), 27.4
(t, 1J = 136.2 Hz), 21.0 (q, 1J = 129.8 Hz), 20.96 (q, 1J = 128.8 Hz); IR
(KBr, cm−1) 3001, 2962, 2949, 2879, 1745, 1726, 1433, 1367, 1232,
1220, 1197, 1095, 1031, 1006, 974, 883. Anal. Calcd for C12H16O6: C,
56.24; H, 6.29. Found: C, 56.08; H, 6.35.
11.9 Hz and J7,7′ = 4.9 Hz, 1H, H-7 or H-7′), 3.97 (bs, 2H, H-8 and H-8′),
2.24−2.27 (m, 1H, H-1), 2.20−1.57 (m, 2H, H-6 and H-6′), 2.03 (s, 3H,
CH3), 1.97 (s, 3H, CH3), 1.95 (s, 3H, CH3), 1.91 (s, 3H, CH3), 1.89
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 170.8, 170.7, 170.4, 170.3,
169.9, 74.6, 72.7, 72.2, 70.0, 66.0, 63.6, 40.0, 28.0, 21.1(2C), 20.9 (2C),
20.7; IR (KBr, cm−1) 3493, 2949, 1726, 1456, 1367, 1220, 1029, 983,
881. Anal. Calcd for C18H26O11: C, 51.67; H, 6.26. Found: C, 52.11;
H, 6.53.
rel-(1S,2S,3R,4S,6R)-1,6-Bis(hydroxymethyl)cyclohexane-
1,2,3,4-tetraol (6). Pentaacetate 24 (1.0 g, 2.39 mmol) was dissolved in
50 mL of absolute methanol and hydrolyzed with dry NH3(g) for 3 h as
described above. Evaporation of methanol and formed acetamide gave
hexol 6 (0.47 g, 93%) as colorless plates from ethanol/n-hexane (1:1):
1
mp 195−198 °C; H NMR (300 MHz, D2O) δ 4.65 (bs, 6H, OH),
3.59−3.22 (m, 7H), 1.93 (m, 1H, H-5), 1.79 (ddd, 1H, J6,6′ = 12.2 Hz,
J = 5.3, 2.8 Hz, 1H, H-6 or H-6′), 1.59 (dt, J6,6′ = 12.2 Hz and J = 4.4 Hz,
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rel-(1R,2S,3S,4S,5R)-2-(Acetoxymethyl)-6-oxabicyclo[3.2.1]-
octane-2,3,4-triyl triacetate (29): 0.42 g, 10% as colorless crystals
from EtOAc/n-hexane; mp 97−99 °C; TLC (hexane/EtOAc, 1:1) Rf =
0.64; 1H NMR (300 MHz, CDCl3) δ 5.38 (d, J = 5.2 Hz, 1H, H-3), 5.27
(dt, J = 5.0, 1.2 Hz, 1H, H-4), 5.17 (d, A part of AB system, J = 12.7 Hz,
1H, H-9), 4.56 (d, B part of AB system, J = 12.7 Hz, 1H, H-9′), 4.27
(t, J = 5.1 Hz, 1H, H-5), 4.11 (bd, A part of AB system, J = 9.1, 1H,
H-7endo), 3.77 (dd, B part of AB system, J = 9.1, 4.5 Hz, 1H, H-7exo), 3.31
(bt, J = 4.5 Hz, 1H, H-1), 2.22 (bd, A part of AB system, J = 13.2 Hz, 1H,
H-8endo), 2.13 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.02 (s, 3H, CH3), 1.99
(s, 3H, CH3), 1.85 (ddt, J = 13.2, 5.1, 1.2 Hz, 1H, H-8exo); 13C NMR (75
MHz, CDCl3) δ 170.4, 169.9, 169.8, 169.5, 84.3, 74.1, 71.7, 70.2, 68.7,
62.4, 40.3, 28.6, 22.2, 21.11, 21.07, 20.8; IR (KBr, cm−1) 2970, 2893,
1737, 1456, 1435, 1367, 1218, 1055, 1039, 952, 894, 813, 777, 734, 705,
638. Anal. Calcd for C16H22O9: C, 53.63; H, 6.19. Found: C, 53.79;
H, 6.34.
rel-(1R,2S,3S,4S,5R)-2-(Acetoxymethyl)-2-hydroxy-6-
oxabicyclo[3.2.1]octane-3,4-diyl Diacetate (30): 0.71 g, 19% as
colorless crystals from ether; mp 174−176 °C; TLC (hexane/EtOAc,
1:1) Rf = 0.51, 1H NMR (300 MHz, CDCl3) δ 5.25 (dt, J = 5.2, 1.2 Hz,
1H, H4), 5.15 (d, J = 5.2 Hz, 1H, H-3), 4.45 (d, A part of AB system J =
12.3 Hz, 1H, H-9), 4.35 (d, B part of AB system, J = 12.3 Hz, 1H, H-9′),
4.27 (t, J = 5.2 Hz, 1H, H-5), 4.23 (bd, J = 8.8 Hz, 1H, H-7endo), 3.75 (dd,
J = 8.8, 4.4 Hz, 1H, H-7exo), 3.4−3.0 (1H, −OH), 2.55 (bt, J = 4.4 Hz,
1H, H-1), 2.15 (bd, A part of AB system, J = 13.0 Hz, 1H, H-8endo) 2.13
(s, 3H, CH3), 2.09 (s, 3H, CH3). 2.04 (s, 3H, CH3), 1.81 (dddd, J = 13.0,
5.2, 4.4, 1.2 Hz, 1H, H-8exo); 13C NMR (75 MHz, CDCl3) δ 171.5,
171.0, 169.7, 75.2, 74.6, 74.2, 70.0, 68.7, 66.5, 42.1, 28.9, 21.1, (2C),
21.0; IR (KBr, cm−1) 3481, 2972, 2900, 1735, 1716, 1373, 1232, 1217,
1195,1134, 1056, 1037, 883. Anal. Calcd for C14H20O8: C, 53.16; H,
6.37. Found: C, 53.49; H, 6.31.
rel-(1R,2S,3S,4R,5R)-4,5-Bis(acetoxymethyl)-4-hydroxycyclo-
hexane-1,2,3-triyl Triacetate (31): 1.41 g, 29% as colorless crystals
from ether; mp 138−140 °C; TLC (hexane/EtOAc, 1:1) Rf = 0.25, 1H
NMR (300 MHz, CDCl3) δ 5.33 (bd, A part of AB system, J = 3.1 Hz,
1H, H-3), 5.26 (bdd, B part of AB system J = 10.5, 3.2 Hz, 1H, H-2), 5.08
(b dt, J = 10.5 and 5.1 Hz, H-1), 4.21 (dd, A part of AB system, J =
11.5 and 6.4 Hz, 1H, CHCHHO), 4.17 (d, A part of AB system J = 12.0
Hz, 1H, OCHH), 4.14 (d, B part of AB system, J = 12.0 Hz, 1H,
OCHH), 3.98 (dd, B part of AB system, J = 11.5, 5.9 Hz, 1H,
HCCHHO), 3.41 (bs, 1H, OH), 2.25−2.15 (m, 1H, H-5), 2.12−1.98
(m, 1H, CHH), 2.05 (s, 3H, CH3), 2.03 (s, 2 × CH3), 2.00 (s, 3H, CH3),
1.94 (s, 3H, CH3), 1.69 (q, B part of AB system, J = 12.3 Hz, 1H, CHH);
13CNMR (75 MHz, CDCl3) δ 171.6, 170.9, 170.8, 170.7, 169.7, 73.9,
anhydride was added a catalytic amount of H2SO4 (one drop), and the
mixture was stirred for 12 h at room temperature. The same workup was
applied as described above. After column chromatography over silica gel,
the tetraacetate 29 (0.9 g, 80%) was isolated as the sole product.
rel-(1R,2S,4S,5S,6R)-2-(Hydroxymethyl)-3,7-dioxatricyclo-
[4.2.1.02,4]nonan-5-ol (32). Epoxy diacetate 28 (0.27 g, 1.05 mmol)
was hydrolyzed with NH3(g) as described above to give epoxy tetrol 32
(0.14 g, 79%) as a colorless viscous oil after column chromatography
eluting with EtOAc: 1H NMR (300 MHz, D2O) δ 3.84−3.75 (m, 3H),
3.58 (m, 2H), 3.35 (d, J = 13.1 Hz1H,), 3.09 (m, 1H), 2.62 (t, J = 3.8 Hz,
1H,), 1.97 (bd, J = 12.3 Hz, 1H), 1.41−1.34 (m, 1H); 13C NMR
(75 MHz, D2O) δ 76.6, 69.5, 67.6, 63.3, 61.4, 54.7, 34.5, 26.1; IR
(KBr, cm−1) 3327, 3313, 3300, 2941, 2883, 1558, 1435, 1332, 1288,
1253, 1116, 1097, 1045, 1024, 993. Anal. Calcd for C8H12O4: C, 55.81;
H, 7.02; Found: C, 55.39; H, 6.57.
rel-(1R,2R,3S,4R,5R)-2-(Hydroxymethyl)-6-oxabicyclo[3.2.1]-
octane-2,3,4-triol (8). Tetraacetate 29 (0.33 g 0.92 mmol) was
hydrolyzed with NH3(g) as described above to give tetrol 8 (0.18 g, 92%)
as a colorless powder: mp 256−258 °C from ethanol; 1H NMR
(300 MHz, D2O) δ 4.6 (bs, 4H, OH), 4.09 (t, J = 5.0 Hz, 1H, H-4), 3.83
(d, J = 8.5 Hz, 1H, H-4), 3.72 (m, 2H), 3.53 (m, 3H), 2.35 (t, J = 4.7 Hz,
1H, H-1), 1.98 (bd, J = 12.9 Hz, 1H, H-8), 1.53 (dt, J = 12.9, 5.3 Hz, 1H,
H-8′); 13C NMR (75 MHz, D2O) δ 77.1, 76.7, 73.3, 70.5, 68.2, 63.4,
40.3, 27.5; IR (KBr, cm−1) 3334, 3213, 2937, 2893, 1392, 1350, 1323,
1251, 1060, 1033, 977. Anal. Calcd for C8H14O5: C, 50.52; H, 7.42.
Found: C, 50.16; H, 7.33.
General Procedure for Ring-Opening of Bicyclic Acetates 28−
30. To a stirred solution of tetraacetate 29 (1.0 g, 2.79 mmol) in Ac2O/
AcOH (7 mL, 1:1) was added sulfamic acid (70 mg) at room
temperature, followed by heating at reflux for 72 h. After the mixture was
cooled to room temperature, HCl was added (50 mL, 5%), and the
mixture was extracted with EtOAc (3 × 100 mL). The organic phase was
washed with saturated NaHCO3 (2 × 100 mL) and then with water (2 ×
100 mL) and dried (MgSO4). The organic phase was concentrated, and
the residue was chromatographed on silica gel (50.0 g) eluting with
hexane/ethyl acetate 4:1 to afford hexaacetate 36.
rel-(1R,2S,3S,4R,6R)-1,6-Bis(acetoxymethyl)cyclohexane-
1,2,3,4-tetrayl tetraacetate (36): 1.02 g, 80% as colorless liquid;
1H NMR (CDCl3, 300 MHz) 5.97 (d, J = 2.0 Hz, 1H, H-2), 5.2−5.03
(m, 2H, H-3 and H-4), 4.78 (d, A part of AB system, J = 12.3 Hz, 1H,
OCHH), 4.34 (d, B part of AB system, J = 12.3 Hz, 1H, OCHH), 4.26
(dd, A part of AB system, J = 11.4, 5.3 Hz, 1H, HCCHHO), 3.96 (dd, B
part of AB system, J = 11.4, 8.0 Hz, 1H, HCCHHO), 2.56−2.40 (m, 1H,
H-6), 2.19−2.1 (H-5), 2.12 (s, 3H, CH3), 2.08 (s, 3H, CH3), 2.03 (s, 3H,
CH3), 2.02 (s, 3H, CH3), 2.00 (s, 3H, CH3), 1.96 (s, 3H, CH3), 1.64−
1.50 (m, 1H, H-5′); 13C NMR (75 MHz, CDCl3) δ 170.91, 170.6,
170.19, 170.15, 169.3, 169.27, 81.7, 70.4, 69.25, 68.9, 63.5, 63.3, 37.9,
28.6, 21.8, 21.3, 21.1, 20.95, 20.9, 20.86; IR (KBr, cm−1) 2966, 1737,
1367, 1209, 1078, 1031, 902. Anal. Calcd for C20H28O12: C, 52.17; H,
6.13. Found: C, 52.19; H, 6.25.
Ring Opening of 28. Epoxy diacetate 28 (1.0 g 3.90 mmol) was
hydrolyzed, acetylated, and chromatographed as described above for 29
to give 36. The hexaacetate 36 was isolated as a colorless liquid (1.28 g,
71%).
Ring Opening of 30. Compound 30 (1.0 g 3.17 mmol) was
hydrolyzed, acetylated, and chromatographed as described above to give
36 as colorless liquid (0.96 g, 66%).
Acetylation of Pentaacetate 32 with Ac2O/AcOH/H2NSO3H.
Pentaacetate 31 (1.0 g, 2.39 mmol) was dissolved in Ac2O/AcOH
(8 mL, 1:1), and H2NSO3H (20 mg) was added. The mixture was stirred
at reflux temperature for 12 h at room temperature. Dichloromethane
(200 mL) was added, and then ice-cooled HCl (50 mL, 5%) was added.
The organic phase was washed with saturated NaHCO3 solution (2 ×
100 mL) and water (3 × 100 mL) and then dried (MgSO4). Removal of
the solvent under reduced pressure gave hexaacetate 36 almost in
quantitative yield (1100 mg).
rel-(1R,2S,3S,4R,6R)-1,6-Bis(hydroxymethyl)cyclohexane-
1,2,3,4-tetraol (7). Hexaacetate 36 (1.5 g 3.26 mmol) was dissolved in
absolute methanol (60 mL), and dry NH3(g) was passed through the
solution for 45 min. NH3 gas streaming was stopped, and the mixture
71.1, 70.3, 69.2, 67.0, 63.5, 36.9, 28.4, 21.3, 21.2, 21.0, 20.99, 20.9; IR
(KBr, cm−1) 3462 3441, 2966, 1730, 1456, 1433, 1365, 1220, 1178,
1076, 1028, 987. Anal. Calcd for C18H26O11: C, 51.67; H, 6.26. Found:
C, 51.98; H, 6.55.
Ring-Opening Reaction of the Bisepoxide 27 in Acetic
Anhydride with a Catalytic Amount of H2SO4. To a stirred
solution of bisepoxide 27 (3.0 g, 11.71 mmol) in 10 mL of acetic
anhydride was added H2SO4 (4 drops), and then the mixture was stirred
for 12 h at room temperature. After completion of the reaction,
dichloromethane (350 mL) was added. The solution was extracted first
with HCl (100 mL, 5%), then with saturated NaHCO3 (2 × 350 mL),
and next with water (4 × 350 mL) and then dried (MgSO4). The solvent
was evaporated, and the residue was chromatographed on silica gel
(60 g), eluting with hexane and ethyl acetate (1/3) to give the
monoepoxide 28 (1.4 g, 47%) as the first fraction. The second fraction
was identified as the tetraacetate 29 (1.02 g, 24%).
Ring-Opening Reaction of the Monoepoxide 28 in Acetic
Anhydride with H2SO4: Synthesis of 30. To a stirred solution of 28
(0.75 g, 2.93 mmol) in 8 mL of acetic anhydride was added H2SO4
(8 drops) and the mixture stirred for 12 h at room temperature. The
same workup was applied as described above. After column
chromatography over silica gel, the hydroxytriacetate 30 (0.87 g, 94%)
was isolated as the sole product.
Ring-Opening Reaction of the Monoepoxide 28 in Acetic
Anhydride with a Catalytic Amount of H2SO4: Synthesis of 29.
To a stirred solution of 28 (0.8 g, 3.12 mmol) in 8 mL of acetic
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was stirred additionally for 6 h. Evaporation of the solvent and formed
acetamide gave hexol 7 (0.60 g, 89%) as a colorless powder from EtOH/
n-hexane (5:3): mp 176−179 °C.
(5) (a) Toyokuni, T.; Abe, Y.; Ogawa, S.; Suami, T. Bull. Chem. Soc. Jpn.
1983, 56, 505−513. (b) Ogawa, S.; Shibata, Y. Carbohydr. Res. 1986,
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Pentaacetate 31 (1 g, 2.39 mmol) was hydrolyzed with dry NH3(g) in
MeOH as described above. The hexol 7 (0.45 g, 91%) was obtained as a
colorless powder: 1H NMR (300 MHz, D2O) δ 4.67 (s, 6H, OH), 3.72
(d, J = 3.2 Hz, 1H, H-2), 3.67−3.49 (m, 5H), 3.39 (dd, J = 11.4, 6.2 Hz,
1H, CHCHHOH), 1.79−1.70 (m, 2H), 1.35 (dt, J = 13.5, 11.1 Hz, 1H,
H-6); 13C NMR (75 MHz, D2O) δ 110.0, 76.2, 73.0, 69.2, 65.0, 61.5,
37.6, 31.0; IR (KBr, cm−1) 3296, 2935, 2899, 1643, 1415, 1301, 1244,
1060, 1028. Anal. Calcd for C8H16O6: C, 46.15; H, 7.75. Found: C,
46.11; H, 7.77.
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra (1H and 13C) for all new compounds and X-ray
structure and CIF of 30, experimental details for the glycosidase
inhibition assay, and tables of atom coordinates and absolute
energies of the calculated compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Rev. 1996, 96, 1195−1220. (b) Duchek, J.; Adams, D. R.; Hudlicky, T.
Chem. Rev. 2011, 111, 4223−4258.
AUTHOR INFORMATION
■
(14) Pilgrim, S.; Kociok-Kohn, G.; Lloyd, M. D.; Lewis, S. E. Chem.
̈
Corresponding Author
*E-mail: baranarif@yahoo.com, mbalci@metu.edu.tr.
Commun. 2011, 47, 4799−4801.
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1990, 46, 4995−4520. (b) Ley, S. V.; Sternfeld, F. Tetrahedron 1989, 30,
3463−3476. (c) Ley, S. V.; Sternfeld, F.; Taylor, S. Tetrahedron Lett.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are indebted to the Scientific and Technological Research
Council of Turkey (TUBITAK, Grant Nos. 109T817 and 108-
M-168), the Departments of Chemistry at Sakarya University
and Middle East Technical University, and the Turkish Academy
of Sciences (TUBA) for financial support of this work.
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