Efficient and shortcut syntheses of some novel eight-membered ring cyclitols starting from cycloocta-1,3-diene

Article abstract of DOI:10.1016/j.tet.2014.08.060

Cyclooctane-1,2,3,4-tetraols, aminocyclooctanetriol, and chlorocyclooctanetriol were synthesized starting from cis,cis-1,3-cyclooctadiene by a concise and efficient method. Cyclooctene endoperoxide and cyclooctene epoxide obtained by photooxygenation and epoxidation, respectively, of cis,cis-1,3-cyclooctadiene were used as the key intermediates. The other oxygen, nitrogen, and chloro functionalities were introduced via epoxidation of the remaining double bond, ring-opening of epoxide, and cis-hydroxylation reactions.

Full text of DOI:10.1016/j.tet.2014.08.060

Accepted Manuscript
Efficient and shortcut syntheses of some novel eight-membered ring cyclitols starting
from cycloocta-1,3-diene
Kadriye Ecer, Emine Salamci
PII:
S0040-4020(14)01266-6
10.1016/j.tet.2014.08.060
TET 25961
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 June 2014
Revised Date: 6 August 2014
Accepted Date: 27 August 2014
Please cite this article as: Ecer K, Salamci E, Efficient and shortcut syntheses of some novel
eight-membered ring cyclitols starting from cycloocta-1,3-diene, Tetrahedron (2014), doi: 10.1016/
j.tet.2014.08.060.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Efficient and shortcut syntheses of some novel eight-membered ring
cyclitols starting from cycloocta-1,3-diene
*
Kadriye Ecer, and Emine Salamci
Department of Chemistry, Faculty of Sciences, Atatürk University, 25240 Erzurum, Turkey
ABSTRACT
Cyclooctane-1,2,3,4-tetraols, aminocyclooctanetriol, and chlorocyclooctanetriol were
synthesized starting from cis,cis-1,3-cyclooctadiene by a concise and efficient method.
Cyclooctene endoperoxide and cyclooctene epoxide obtained by photooxygenation and
epoxidation, respectively, of cis,cis-1,3-cyclooctadiene were used as the key
intermediates. The other oxygen, nitrogen, and chloro functionalities were introduced
via epoxidation of the remaining double bond, ring opening of epoxide, and cis-
hydroxylation reactions.
Keywords: Cyclitol; 3-Aminocyclooctanetriol; Cyclooctanetetraol; 3-Chlorocyclooctanetriol;
Endoperoxide; Carbasugar.
*
Corresponding author. Tel: +90 442 231 4429; fax: +90 442 2314109 (E.S.).
E-mail address: esalamci@atauni.edu.tr (E. Salamci).
1

ACCEPTED MANUSCRIPT
1
. Introduction
Cyclitols containing eight-membered rings are polyhydroxycyclooctanes and
their derivatives. The cyclitol class of compounds has attracted considerable interest due
to the fact that many biologically important molecules and natural products contain a
1
-3
polyhydroxylated carbocycle. The most prominent cyclitols, such as inositols (1) and
their derivatives (2), have been synthesized and evaluated in particular for their
4
-6
biological activities, especially glycosidase inhibition.
Glycosidases are enzymes that catalyze the cleavage of glycosidic bonds and
play critical roles in a number of biological processes. Inhibitors of these enzymes have
garnered a great deal of attention and are currently used for the treatment of diabetes
and HIV infection, and as antifungal agents. Therefore, they are expected to arouse
increasing interest as therapeutic agents as our understanding of the role of glycosidases
7
in recognition processes improves. Some natural products or their analogues include
1
,6-diepicastanospermine (3) and gallic acid (4) (Figure 1), which have glycosidase
inhibitory activities and thus have potential utility as antiviral, anticancer, antidiabetic,
8
,9
and antiobesity drugs.
2

ACCEPTED MANUSCRIPT
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
OH
N
NH2
HO
OH
OH
OH
1
2
3
OH
HO
OH
OH
HO
O
HO
OH
HO
5
4
HO
HO
H N
Cl
2
HO
HO
HO
HO
6
7
Fig. 1. Structures of some cyclitols.
6
,10
Recently, interest in seven-, eight-, and nine-membered ring systems has been
increasing in order to study the effect of the enhanced flexibility and of the new spatial
distribution displayed by these structures. The configuration of the hydroxyl groups has
6
a, 6d, 6e
been reported to play an important role in the active site of the enzyme.
1
1
Synthetic methods have been previously reported for a cyclitol motif on six-,
1
2
3,6d,6f,13
10
seven-, eight-,
available for the synthesis of eight-membered
stereospecifically synthesized two stereoisomers of cyclooctane-1,2,3,4-tetraols starting
and nine-membered rings, but only a few approaches are
6
a,14
aminocyclitols. More recently, we
1
3e
from cis,cis-1,3-cyclooctadiene. The synthesis of isomeric cyclooctanetetrols 5 was
3
b,13e,13f
accomplished by three different methods,
but synthesis of 3-
aminocyclooctanetriol 6, which is an analogue of cyclooctanetetraol, and 3-
chlorocyclooctanetriol 7 has not been reported in the literature (Figure 1).
3

ACCEPTED MANUSCRIPT
Our aim in the present work was to design a concise synthetic route to new
cyclooctanoic carbasugar analogues 5, 6, and 7, using simple starting materials.
2
. Results and Discussion
For the synthesis of the key compound, cyclooctene epoxide 8, used in the
synthesis of 3-aminocyclooctanetriol and cyclooctanetetraols, cis,cis-1,3-cyclooctadiene
1
5
was reacted with m-CPBA to form epoxide 8 (Scheme 1). Our initial approach to
synthesize the 3-aminocyclooctanetriol was based on azidolysis of epoxide 8 with
1
6
sodium azide. As reported in the literature, vicinal azidohydrins have been extensively
utilized as precursors of 1,2-aminoalcohols in carbohydrate chemistry or in the
chemistry of carbocyclic nucleosides. For this purpose, treatment of epoxide 8 with
17
sodium azide in the presence of NH Cl produced azidoalcohol 9a. The acetylation of
4
azidoalcohol 9a with an excess of acetyl chloride in methylene chloride resulted in the
formation of azidoacetate 9b in 96% yield (Scheme 1). Cyclooctene azidoacetate 9b is a
unique substrate for the synthesis of aminocyclooctanetriol. For that reason, the double
bond in azidoacetate 9b was submitted to a cis-dihydroxylation reaction with OsO4-
1
8
NMO followed by acetylation to give triacetate 10b in 97% yield. The spectroscopic
data confirmed the formation of a single isomer. The exact configuration of 10b was
1
confirmed by both H NMR and 2D NMR spectroscopic data (COSY, NOESY). The
acetoxyl proton H-2 in 10b resonates as a doublet of doublets with coupling constants
of J = 7.6 and 2.6 Hz, clearly indicating that the neighboring protons H-2 and H-3 with
a large coupling constant (J2,3 = 7.6 Hz) are in the trans position. The azido proton H-3
also resonates as a doublet of doublets with coupling constants of J = 9.8 and 7.6 Hz.
Furthermore, the second large coupling between the protons H-3 and H-2 (J = 7.6 Hz)
2
,3
shows the trans relation between those protons. The fact that the proton H-4 appears as
a doublet of doublet of doublets with coupling constants of J = 9.8, 5.3, and 2.9 Hz also
supports the trans relation of the protons H-3 and H-4. The resonance signal of H-1
appears as a triplet of doublets with coupling constants of J = 7.7 and 2.6 Hz, which
clearly supports the cis relation of the protons H-1 and H-2 with a small coupling
constant (J1,2 = 2.6 Hz). On the basis of these findings, we assigned a trans-trans
relation to the azido group in 10b.
4

ACCEPTED MANUSCRIPT
RO
O
N3
1
. NaN , NH Cl
3 4
EtOH/H O, 12h, reflux, 94%
a: R = H
2
2
. AcCl, CH Cl , 96%
b: R = Ac
2
2
(±) 8
(±) 9
1
. OsO / NMO
4
2
. AcCl, CH Cl
2 2
97%
HO
AcO
N3
N3
4
NH /MeOH
3
3
2
30h, rt, 93%
1
HO
RO
HO (±) 11
RO
±) 10 a: R = H
b: R = Ac
(
H
2
/ Pd-C
MeOH, 2h, rt
1%
9
HO
HO
H N
2
HO
(±) 12
Scheme 1 Synthesis of (1R(S),2S(R),3R(S),4S(R))-3-Aminocyclooctane-1,2,4-triol
12).
(
The acetyl groups in (1R(S),2S(R),3R(S),4S(R))-3-azidocyclooctane-1,2,4-triyl
triacetate (10b) were removed using NH -MeOH to give (1R(S),2S(R),3R(S),4S(R))-3-
3
azidocyclooctane-1,2,4-triol (11) (93% yield). Hydrogenation of 11 gave
(1R(S),2S(R),3R(S),4S(R))-3-aminocyclooctane-1,2,4-triol (12) in 91% yield (Scheme
1
13
1
). H and C NMR spectroscopic data of the molecule are in agreement with the
proposed structure.
The formation of 10a from 9b as the sole product can be explained by
considering the steric effects. Since in relation to the azido group the cis-face of the
cyclooctene double bond is blocked by hindrance of the azido group, OsO approaches
4
5

ACCEPTED MANUSCRIPT
the double bond in 9b preferentially from the sterically less crowded face of the
molecule (Scheme 1).
O
O
8
3
OsO / NMO
4
1
2
98%
HO
(
±) 8
HO (±) 13
+
1
. H /H O, Dioxane
2
2
. Ac O/Pyr., DMAP
2
AcO
AcO
1
6
2
8
7
AcO
AcO
AcO
AcO
+
3
O
+
4
AcO
AcO
5
AcO
AcO
(
±) 14
(±) 15
(±) 16
Scheme 2 Reaction of Epoxy-diol 13 with H SO in Water.
2
4
For the synthesis of other polyhydroxylated cyclooctanes, epoxide 8 was reacted
with OsO -NMO to give 13 as the sole isomer (Scheme 2). The exact configuration of
4
1
1
3 was confirmed by both H NMR and 2D NMR spectroscopic data (COSY, NOESY).
The epoxide protons (H-1 and H-8) resonate as an AB system at δ 3.19 and 3.05 and
gave the most useful information for the configuration of 13. The A part of the AB
system (low field resonance, H-1) is split into a doublet of doublets (J = 8.5 and J =
1
,2
1,8
4
.7 Hz). The large coupling (J1,2 = 8.5 Hz) between the protons H-1 and H-2 shows the
trans relation between those protons. The small coupling (J1,8 = 4.7 Hz) also indicates a
relation between the neighboring epoxide protons H-1 and H-8. The high-field part of
the AB system resonates as a triplet of doublets (J = 9.6 and J1,8 = 4.7 Hz). Acid-
catalyzed ring opening of 13 followed by acetylation with acetic anhydride in pyridine
and 4-(dimethylamino)pyridine (DMAP) resulted in formation of the rearranged product
1
4 as the main product besides hydrolysis products 15 and 16. The reaction mixture was
chromatographed on a silica gel column with ethyl acetate/n-hexane (30:70) as the
eluent to give the rearrangement product 14 in 49% yield and the two isomers, 15 and
1
6, in 39% and 12% yields, respectively. The structures of 14, 15, and 16 were assigned
1
on the basis of H NMR spectra. The exact configuration of 14 was determined with the
6

ACCEPTED MANUSCRIPT
help of the corresponding coupling constants between the relevant protons and 2D NMR
spectroscopic data (COSY, NOESY). The acetoxy proton H-8 resonates as a doublet of
doublets with coupling constants of J = 4.6 and 2.6 Hz. The large coupling (J = 4.6
7
,8
Hz) between protons H-8 and H-7 shows the trans relation between those protons. In
1
8
addition to this, Dreiding models indicate that the dihedral angle between protons H-1
and H-8 is approximately 120° whereas the dihedral angle between H-6 and H-7 is 10°.
Consequently the high coupling constant value (J = 7.8 Hz) is uniquely accommodated
6
,7
by exo orientation of proton (endo orientation of acetoxy group) at C-7 atom, whereas,
the small value (J =2.6 Hz) indicate endo orientation of proton (exo orientation of
1
,8
acetoxy group) at C-8 atom. This also indicates the trans configuration of the
neighboring protons.
The structural assignment was made by comparison of the NMR spectra with
those of (1R(S),2S(R),3R(S),4S(R))-cyclooctane-1,2,3,4-tetraacetate (15) and
(1R(S),2R(S),3R(S),4S(R))-cyclooctane-1,2,3,4-tetraacetate (16). We have recently
1
2e
reported
the synthesis of tetraacetates 15 and 16 starting from cis,cis-1,3-
cyclooctadiene.
AcO
AcO
HO
HO
NH , MeOH
3
O
O
9
2%
(±) 14
(±) 17
AcO
HO
AcO
HCl-THF
NH , MeOH
HO
HO
3
AcO
9
8%
AcO
HO
HO
(
±) 15
(±) 18
AcO
AcO
HO
HO
HCl-THF
NH , MeOH
3
AcO
AcO
9
8%
HO
(
±) 16
(±) 19
Scheme 3 Synthesis of Diol 17, and Tetraols 18 and 19.
7

ACCEPTED MANUSCRIPT
The
1R(S),2R(S),3R(S),4S(R))-cyclooctane-1,2,3,4-tetrayl tetraacetate (15 and 16) were
removed using 10% HCl in THF and NH -MeOH to give (1R(S),2S(R),3R(S),4S(R))-
acetyl
groups
in
(1R(S),2S(R),3R(S),4S(R))-
and
(
3
1
3e
and (1R(S),2R(S),3R(S),4S(R))-cyclooctane-1,2,3,4-tetraol (18 and 19) (98% yield),
respectively. Diol 17 itself was readily obtained in 92% yield by ammonolysis of
diacetate 14 in methanol. The NMR spectroscopic data of the molecule are in agreement
with the proposed structure (Scheme 3).
1
3e
The formation of isomers 17 and 18 is reasonably understood in terms of the
1
3e
mechanism outlined in Scheme 4. Tetraols 18 and 21 were the expected products in
this reaction because epoxide 13 is an unsymmetrical structure. The formation of tetraol
1
3e
1
8
arises from the attack of water to the protonated epoxide ring (intermediate 20).
However, the other hydrolysis product, 21, was not formed (b attack), which can be
explained by considering steric effects. The formation of diol 17 arises from by an SN2
1
3b
attack of the hydroxyl group to the protonated epoxide ring (c attack). We assume
that the hydroxyl group prefers an attack to the protonated epoxide ring from the less
crowded side to produce furanoid 17.
a
H O
2
O
H O
HO
HO
+
H /H O
b
2
c attack
-H+
O
HO
HO
c
HO (±) 13
HO
(±) 17
b
a
t
ta
2
0
c
k
HO
-
H+
a attack -H+
HO
HO
HO
HO
HO
±) 21
(
HO
HO
±) 18
(
Scheme 4 Formation Mechanism of Diol 17 and Tetraol 18 from 13.
8

ACCEPTED MANUSCRIPT
1
3e
We also assume that the symmetrical tetraol 19 is formed by the bottom hydroxyl
group attacks the more hindered epoxide carbon to give an oxetane intermediate, which
is then opened by an SN2 attack of water on the bottom carbon (Scheme 5).
H
HO
O
O
+
H /H O
2
O H
22
H+
HO
HO
HO
H O
HO (±) 13
20
HO
2
-
HO
HO
HO
HO (±) 19
Scheme 5 Formation Mechanism of Tetraol 19 from 13.
2
0
For the synthesis of further cyclooctanetetraols, endoperoxide 23 was reacted
with m-CPBA to give the corresponding epoxy peroxide 24. The reaction was carried
out both in the presence of a NaHCO buffer and in the absence of the buffer, although
3
we were not able to isolate the epoxy peroxide 24. Although the formation of the epoxy
1
peroxide 24 was observed by H NMR spectroscopy, during the purification of the
reaction mixture, the rearrangement product 25 (in 53% yield) was obtained instead of
the desired epoxy peroxide 24. Probably, such as a Kornblum-DeLaMare
2
0a,21
rearrangement
the initial breaking of the peroxide linkage in 24 forms the
hydroxyketone intermediate 26 and the subsequent cyclization to give the epoxide 25 by
intramolecular cyclization (Scheme 6). When the reaction was carried out in neutral or
basic medium under concentrated reaction conditions, epoxide 25 was observed.
However, when the reaction concentration was decreased in the absence of a buffer, the
2
2
epoxy peroxide 24 did not rearrange to 25. Herz showed that "endo" endoperoxide-
epoxides are particularly susceptible to fragmentation, in six-membered rings.
9

ACCEPTED MANUSCRIPT
HO 1
2
m-CPBA/NaHCO3
8
9
7
3
O
O
O
10O 4
O
O
O
or
6
5
3%
5
m-CPBA
(
±) 23
24
(±) 25
m-CPBA
O
O
O
O
O
NaHCO3
(
±) 23
24
HO
HO
O
O
O
(
±) 25
O (±) 26
Scheme 6 Reaction of Endoperoxide 23 with m-CPBA.
1
The structure of compound 25 was assigned by both H NMR and 2D NMR
spectroscopic data (COSY, NOESY, and HMQC). The epoxide protons (H-7 and H-9)
of 25 resonating at δ 3.51 (d, JAB = 2.9 Hz) and 3.49 (d, JAB = 2.9 Hz) as an AB system
show no coupling with the adjacent proton H-6. There is no measurable coupling
between the alkoxy proton H-6 and the epoxide proton H-7 in 25. The exact
configuration of the epoxide ring in 25 was established by measuring the corresponding
coupling constants between the relevant protons. The alkoxy proton H-6 in 25 resonates
as a doublet of doublets with two coupling constants of J6,5 = 7.1 Hz and J6,5’ = 1.3 Hz.
For the exo orientation of the epoxide ring, inspection of Dreiding models indicates that
the dihedral angle between related protons is approximately 90°, and the coupling
constant between these protons is expected to be smaller than 1.0 Hz. In the case of an
endo orientation of the epoxy group, the dihedral angle between related protons is
approximately 0°, and a larger coupling constant (8-10 Hz) is expected. The geometry
of 25 shows the syn configuration of the neighboring protons H-6 and H-7.
Next, for the isolation of epoxy peroxide 24, endoperoxide 23 was also
2
3
submitted to reaction with dimethyldioxirane (DMDO). The reaction was carried out
1
0

ACCEPTED MANUSCRIPT
both in the presence of K CO and without K CO in neutral conditions. From this
2
3
2
3
1
reaction, formation of the mixture of 24 and 25 in a 1:1 ratio (from H NMR
spectroscopy) was observed, but all attempts to isolate 24 failed (Scheme 6). We
observed that, during the chromatography, compound 24 was fully rearranged to
compound 25.
HO
DMD
O
O
O
+
O
O
O
O
(
±) 23
24
(±) 25
HO
HO
m-CPBA, NaHCO3
CH Cl , 66%
2
2
O
O
O
or
DMD, 97%
(
±) 27
(±) 25
Scheme 7 Synthesis of Epoxide 25.
1
3e,20d,24
Independently, unsaturated oxabicycle 27
was submitted to an
epoxidation reaction both with DMDO and m-CPBA to confirm the structure of
compound 25. The formed epoxide 25 was identical to those obtained from the
epoxidation of endoperoxide 23. We assume that the oxidant prefers to approach the
double bond in 27 from the sterically less crowded side to produce 25 as a single isomer
(Scheme 7).
In the second part of this work, we turned our attention to the synthesis of
20
cyclooctanetetraol 18 starting from endoperoxide 23. Endoperoxide 23 was reacted
with m-CPBA to give the corresponding epoxy peroxide 24. The crude reaction mixture
without purification was subjected to hydrogenation to provide the corresponding epoxy
diol 28. Surprisingly, hydrogenation of 24 in absolute ethanol and in the presence of Pd-
C resulted in the formation of chlorotriol 29 as a single product, instead of the desired
epoxy diol 28. For further structural proof, chlorotriol 29 was converted into the
corresponding acetate 30 with an excess of acetic anhydride in pyridine and DMAP
(Scheme 8).
1
1

ACCEPTED MANUSCRIPT
AcO
Cl
AcO
AcO (±) 30
Ac O/Pyr.
2
DMAP
HO
HO
Cl
m-CPBA
CH Cl
H / Pd-C
2
O
O
O
+
HCl
O
O
(from CH Cl ) EtOH, rt, 5h
2
2
2
2
HO
(±) 23
24
(
±) 29
H / Pd-C
2
EtOH, rt, 5h
HO
HO
HO
HO
HO
HO
O
(
±) 28
(
±) 18
Scheme 8 Synthesis of Chlorotriol 29.
1
13
The H and C NMR spectra of the acetylation product 30 revealed that only three
acetate groups in 30 instead of the tetraacetate groups expected were formed in a total
yield of 66%.
In order to confirm the assigned structure and to establish the conformation of
the molecule, X-ray diffraction analysis of 30 was undertaken (Figure 2). cis and trans
stereochemistry of the substituted units can be seen explicitly in Figure 2. As shown in
Figure 2b, the molecules are ordered vertically along the b-axis in the unit cell.
Furthermore, there are closer Cl…Cl (3.355 Å) contacts in a certain direction. Short
intermolecular contact corresponds to a Cl…Cl separation of less than 3.52 Å. The
occurrence of Cl-Cl intermolecular contact, which is shorter than would be expected
from the conventional isotropic van der Waals radius, is shown to be most common in
the crystal structures of fully or highly chlorinated hydrocarbons, and is therefore a
1
2

ACCEPTED MANUSCRIPT
consequence of close packing of anisotropic atoms, rather than evidence of a specific
2
5
attractive force.
Fig. 2. a) The molecular structure of compound chlorotriacetate 30 showing the atom
numbering scheme. Thermal ellipsoids are drawn at the 40% probability level.
Fig. 2. b) The molecular packing of 30.
1
3

ACCEPTED MANUSCRIPT
We assume that 29 is formed by the HCl-catalyzed ring-opening reaction of epoxy diol,
which is the hydrogenation product of 24. It is clear that HCl comes from methylene
chloride which is epoxidation solvent. Similar results have also been observed more
recently by Balci et al in the synthesis of some cyclitols containing six-membered
2
6
rings. Hydrolysis of 30 with acetyl chloride in MeOH resulted in the formation of
chlorotriol 29 in 92% yield (Scheme 8).
3
. Conclusion
We have described here the synthesis of certain cyclitols and derivatives
containing eight-membered rings: 12, 18, 19, and 29, starting from the easily available
cis,cis-1,3-cyclooctadiene, concisely and efficiently. We are currently carrying out
further studies to synthesize new aminocyclitols through 9a.
4
4
. Experimental
.1. General experimental
Melting points are uncorrected. Infrared spectra were obtained from solution in
1
13
0
.1 mm cells or KBr pellets on an FT-IR Mattson 1000 instrument. The H and C
NMR spectra were recorded on 400 (100) MHz Varian or 400 (100) MHz Bruker
spectrometer and are reported in d units with SiMe as internal standard. HRMS spectra
4
were obtained on a Bruker microTOF-Q instrument. Elemental analyses were carried
out on a Carlo Erba 1108 model CHNS-O analyzer. Column chromatography was
performed on silica gel (60 mesh, Merck). TLC was carried out on Merck 0.2 mm silica
gel 60 F254 analytical aluminium plates.
4
.2. 7,8-Dioxabicyclo[4.2.2]dec-9-ene (23). Compound 23 was prepared as described in
1
3e
the literature.
4
.3. (Z)-9-Oxabicyclo[6.1.0]non-2-ene (8). Compound 8 was prepared as described in
1
5
the literature.
4
.4. (1R(S),2S(R),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraol (meso-19). Compound 19
1
3e
was prepared as described in the literature.
1
4

ACCEPTED MANUSCRIPT
1
1
H-NMR (400 MHz, D O): δ 3.72-3.63 (m, 4H), 1.77-1.66 (m, 2H), 1.53-1.38 (m, 6H).
2
3
-1
C-NMR (100 MHz, D O): δ 76.0, 72.5, 31.7, 23.8; IR (KBr, cm ): 3417, 2927, 2529,
2
2
393, 1441, 1403, 1344, 1277, 1160, 1069, 1042, 901, 715, 626. HRMS (ESI): calcd for
+
C H O Na (M +Na): 199.0941, found: 199.0932.
8
16
4
4
.5. (1R(S),2R(S),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraol (rac-18). Compound 18
1
3e
was prepared as described in the literature.
1
H-NMR (400 MHz, D O) δ 3.92-3.82 (m, 1H), 3.64-3.48 (m, 3H), 1.80-1.30 (series of
2
1
3
m, 8H); C-NMR (100 MHz, D O) δ 73.4, 72.9, 72.8, 70.9, 30.8, 29.3, 22.6, 20.7; IR
2
-1
(
KBr, cm ): 3398, 2918, 2854, 1639, 1441, 1357, 1217, 1155, 1069, 968, 893, 758,
+
6
26. HRMS (ESI): calcd for C H O Na (M +Na): 199.0946, found: 199.0952.
8
16
4
4
.6. (1S(R),2S(R),Z)-2-Azidocyclooct-3-enol (9a). To a stirred solution of epoxide 8
(
3.00 g, 24.16 mmol) in EtOH/H O (45/30 mL) was added NaN (9.42 g, 144.96 mmol)
2
3
and NH Cl 3.14 g (58.69 mmol). The reaction mixture was refluxed for 12 h and then
4
the solvent was rotoevaporated (40 °C, 20 mmHg). To the residue was added water (70
mL) and the mixture was filtered through a pad of 10.0 g of silica gel in a 50 mL
sintered glass funnel with ethyl acetate. The mixture was extracted with ethyl acetate
(
4x30 mL). The combined ethyl acetate layers were dried (Na SO ) and concentrated in
2 4
17
vacuo. Evaporation of the solvent gave 9a in 88% yield (3.60 g) as a colorless oil (lit.
1
6
8
2
7
0%). H-NMR (400 MHz, CDCl ) δ 5.82 (q, J= 9.0 Hz, 1H, H-4), 5.50 (dd, J= 10.6,
3
.1 Hz, 1H, H-3), 4.35-4.24 (m, 1H, H-2), 3.60-3.45 (m, 1H, H-1), 2.46 (bs, 1H, OH),
1
3
.21-2.14 (m, 2H), 1.82-1.24 (m, 6H); C-NMR (100 MHz, CDCl ) δ 133.8, 127.5,
3
4.7, 66.0, 32.4, 28.2, 27.2, 21.3.
4
.7. Acetylation of (1S(R),2S(R),Z)-2-azidocyclooct-3-enol (9a). To a magnetically
°
stirred solution of azidol 9a (1.60 g, 9.58 mmol) in CH Cl (10 mL) cooled to 0 C,
2
2
acetyl chloride (1.50 g, 19.16 mmol) was added and the mixture was stirred at room
temperature for 12 h. Evaporation of the solvents gave pure azidoacetate 9b (1.90 g, 96
1
%
); as a colorless oil. (1S(R),2S(R),Z)-2-azidocyclooct-3-enyl acetate (9b): H-NMR
(
400 MHz, CDCl ) δ 5.80-5.55 (m, 1H, H-4), 5.32 (dd, J=10.6, 8.1 Hz, 1H, H-3), 4.83
3
(dt, J= 10.3, 4.2 Hz, 1H, H-1), 4.47 (ddd, J= 9.7, 8.1, 1.5 Hz, 1H, H-2), 2.22-2.07 (m,
1
5

ACCEPTED MANUSCRIPT
1
3
2
H), 2.06 (s, 3H, CH ), 1.80-1.40 (m, 6H); C-NMR (100 MHz, CDCl ) δ 170.4, 133.9,
3 3
-1
1
26.9, 77.3, 62.2, 30.3, 28.4, 27.5, 22.0, 21.4; IR (KBr, cm ) 2933, 2860, 2101, 1742,
1
373, 1234, 1024, 964, 763. Anal. Calcd for C H N O : C, 57.40; H, 7.23; N, 20.08.
1
0
15
3
2
Found: C, 57.41; H, 7.29; N, 19.57.
4
.8. (1R(S),2(S)R,3R(S),4S(R))-3-Azidocyclooctane-1,2,4-triyl triacetate (10b). A 50
mL three necked, round-bottomed flask, equipped with a magnetic stirrer and a nitrogen
inlet, was charged with NMO (0.88 g, 6.52 mmol), water (11.5 mL), and acetone (11.5
mL). To this solution were added OsO (ca. 22.00 mg, 0.089 mmol) and azidoacetate 9b
4
(1.24 g, 5.93 mmol) at 0 °C. The resulting mixture was stirred vigorously under
nitrogen at room temperature and after 2 days, the reaction was stopped. Sodium
hydrosulfite (0.14 g) and Florisil (10.00 g) slurried in water (25 mL) were added, stirred
for 15 min, and then filtered through a pad of Celite (4.50 g) in a 50 mL sintered glass
funnel. The Celite cake was washed with acetone (3x50 mL). The filtrate was
neutralized to pH 7 with H SO . The organic layer was removed in vacuo. The pH of
2
4
the resulting aqueous solution was adjusted to pH 5 with sulfuric acid, and the solvents
were then removed in vacuo. Chromatography of the residue on a silica gel column (80
g) eluting with ethyl acetate/hexane (15:85) gave azidoacetoxy diol 10a (1.37 g, 95%)
as the sole product. The azidoacetoxy diol 10a was submitted to acetylation with AcCl
following the method described above for the acetylation of 9a to give 10b: 1.78 g,
1
9
7%; colorless solid; mp 114-116 °C, from CH Cl / n-hexane. H-NMR (400 MHz,
2
2
CDCl ) δ 5.20 (dt, J = 7.7, J = 2.6 Hz, 1H, H-1), 5.04 (dd, J = 7.7, J = 2.6 Hz, 1H,
3
1,8
1,2
2,3
1,2
H-2), 4.94 (ddd, J = 9.9, J = 5.5 Hz, J = 2.9 Hz, 1H, H-4), 4.06 (dd, J = 9.9, J =
3
,4
4,5
4,5’
3,4
2,3
7
8
2
7
6
.7 Hz, 1H, H-3), 2.05 (s, 3H, CH ), 2.08 (s, 3H, CH ), 2.10 (s, 3H, CH ), 2.00-1.42 (m,
3 3 3
1
3
H); C-NMR (100 MHz, CDCl ) δ 170.1, 170.0, 169.9, 73.9, 71.7, 71.6, 62.9, 28.5,
3
-1
8.4, 21.9, 21.6, 21.3, 20.8; IR (KBr, cm ) 2946, 2108, 1744, 1434, 1371, 1230, 1023,
60, 746. Anal. Calcd for C H N O : C, 51.37; H, 6.47; N, 12.84. Found: C, 51.14; H,
1
4
21
3
6
.27; N, 12.75.
4
.9.
(1R(S),2S(R),3R(S),4S(R))-3-Aminocyclooctane-1,2,4-triol
(12).
(1R(S),2(S)R,3R(S),4S(R))-3-Azidocyclooctane-1,2,4-triyl triacetate (10b) (600 mg,
1
.83 mmol) was dissolved in absolute methanol (25 mL). While dry NH3(g) was passed
1
6

ACCEPTED MANUSCRIPT
through the solution, the mixture was stirred for 30 h. Evaporation of solvent and the
formed acetamide gave azidotriol 11 (340 mg, 93 %). Into a 50-mL flask were placed
palladium on charcoal (40 mg, 10%) and 11 (340 mg, 1.69 mmol) in dry methanol (30
mL). The reaction mixture was hydrogenated for 2 h at room temperature under normal
pressure. The catalyst was removed by filtration. Evaporation of the solvent gave 12,
which was crystallized from absolute methanol/diethyl ether to give colorless crystals
1
(
270 mg, 91%). Mp 118.5-119.5 °C; H-NMR (400 MHz, CD OD) δ 3.91 (dt, J = 8.6,
3
2
2
3
9
5
4
.8 Hz, 1H, H-1), 3.50-3.43 (m, 2H, H-2 and H-4), 3.00 (dd, J = 8.2, 1.2 Hz, 1H, H-3),
1
3
.00-1.30 (series of m, 8H); C-NMR (100 MHz, CD OD) δ 73.2, 73.1, 71.7, 54.6,
3
-1
2.5, 30.1, 23.5, 21.1; IR (KBr, cm ) 3380, 2900, 2610, 1550, 1460, 1320, 1100, 1010,
70, 798, 690, 601. Anal. Calcd for C H NO : C, 54.84; H, 9.78; N, 7.99. Found: C,
8
17
3
4.52; H, 9.74; N, 7.96.
.10. (1R(S),2S(R),3S(R),8S(R))-9-Oxabicyclo[6.1.0]nonane-2,3-diol (13). The same
procedure as described above for 10b was applied for the oxidation of azidoacetate 9b
1
(
98%, colorless crystals, mp 88-89 °C, recrystallized from CH Cl /n-hexane. H-NMR
2
2
(
400 MHz, CDCl ) δ 4.20-3.60 (m, 2H, H-3 and OH), 3.53-3.51 (m, 1H, H-2), 3.50-
3
3
8
.28 (m, 1H, OH), 3.19 (dd, J= 8.8, 4.7 Hz, 1H, H-1), 3.05 (dt, J= 10.2, 4.7 Hz, 1H, H-
1
3
); 2.25 (dm, J= 14.3 Hz, 1H), 1.97-1.08 (series of m, 7H); C-NMR (100 MHz,
-1
CDCl ) δ 73.2, 72.6, 57.2, 55.8, 32.2, 28.5, 25.4, 21.0; IR (KBr, cm ) 3386, 2931, 2868,
3
+
2
336, 1636, 1460, 1239, 1053, 979, 836, 752. HRMS (ESI): calcd for C H O Na (M
8 14 3
+Na): 181.0841, found: 181.0847.
4
.11.
Acetolysis
and
hydrolysis
of
(1R(S),2S(R),3S(R),8S(R))-9-
oxabicyclo[6.1.0]nonane-2,3-diol (13). To a stirred solution of 13 (1.67 g, 10.57 mmol)
in dioxane (4 mL) and water (1 mL) was added a catalytic amount of concentrated
H SO (ca. 300 mg). The reaction mixture was stirred for 5 h at 110 °C. The mixture
2
4
was cooled to at room temperature and was neutralized to pH 7 with BaCO (0.7 g). The
3
residue was filtrated and after removal of the organic layer in vacuo, the aqueous layer
was frozen and lyophilized to give the product mixture (1.28 g, total yield 69%). The
mixture (1.28 g, 7.27 mmol) was dissolved in anhydrous pyridine (8 mL) and the
solution was cooled to 0 °C. Ac O (5.93 g, 58.16 mmol) and 4-
2
(Dimethylamino)pyridine (DMAP) (10 mg) were added and the solution was stirred at
1
7

ACCEPTED MANUSCRIPT
room temperature for 24 h. The mixture was cooled to 0 °C and 2 N HCl (150 mL)
solution was added. The mixture was extracted with ether (4x50 mL). The combined
organic extracts were washed with NaHCO solution (2x20 mL) and water (15 mL) and
3
then dried (Na SO ). Removal of the solvent under reduced pressure gave the product
2
4
mixture (1.65 g, total yield 66 %). Chromatography of the mixture on a silica gel
column (100 g) eluting with EtOAc/n-hexane (30:70) gave the first fraction as diacetate
1
3e
1
4 (0.81 g, 49%), the second as tetraacetate 16 (0.200 g, 12%). and the third as
1
3e
tetraacetate 15 (0.64 g, 39%). Diacetate 14 was recrystallized from absolute ethanol at
°C as a colorless solid; mp 47-48 °C.
0
Data for (1R(S),6S(R),7S(R),8S(R))-9-Oxabicyclo[4.2.1]nonane-7,8-diyl diacetate
1
(
14). H-NMR (400 MHz, CDCl ) δ 5.27 (dd, J = 7.8, J = 4.7 Hz, 1H, H-7), 5.10 (dd,
3
6,7
7,8
J = 4.6, J = 2.6 Hz, 1H, H-8), 4.69 (t, J= 6.7 Hz, 1H, H-6), 4.18-4.11 (m, 1H, H-1),
7
,8
1,8
1
3
2
.09 (s, 3H, CH ), 2.08 (s, 3H, CH ), 1.99-1.90 (m, 2H), 1.80-1.40 (m, 6H); C-NMR
3 3
(
100 MHz, CDCl ) δ 171.3, 170.4, 84.5, 82.9, 79.0, 78.1, 33.2, 29.5, 24.5, 24.4, 21.2,
3
-1
2
1.0; IR (KBr, cm ) 2936, 2857, 1741, 1444, 1372, 1228, 1064, 1029, 973. Anal. Calcd
for C H O : C, 59.49; H, 7.49. Found: C, 59.38; H, 7.52.
1
2
18
5
4
.12. (1R(S),6S(R),7R(S),8R(S))-9-Oxabicyclo[4.2.1]nonane-7,8-diol (17). The
diacetate 14 was submitted to ammonolysis with NH3(g) MeOH following the method
described above for the ammonolysis of 10b to give 12: 0.12 g, 92 %; colorless solid;
1
mp 83-85 °C, from CH Cl /n-hexane. H-NMR (400 MHz, CDCl ) δ 4.61-4.56 (m, 1H,
2
2
3
OH), 4.44-4.34 (m, 2H, OCH and OH), 4.30-4.23 (m, 1H), 4.16-4.10 (m, 1H), 4.07-4.02
13
(
m, 1H), 1.98-1.42 (series of m, 8H); C-NMR (100 MHz, CDCl ) δ 84.6, 83.7, 80.6,
3
-1
7
9.6, 33.0, 28.8, 24.9, 24.4; IR (KBr, cm ) 3366, 2929, 1443, 1261, 1079, 1014, 752.
Anal. Calcd for C H O : C, 60.74; H, 8.92. Found: C, 60.89; H, 9.09.
8
14
3
4
.13. (1R(S),2R(S),3R(S),4S(R))-3-Chlorocyclooctane-1,2,4-triyl triacetate (30). To
endoperoxide 23 (1.0 g, 7.14 mmol) in CH Cl (150 mL) was added m-
2
2
chloroperbenzoic acid (4.81 g, 27.81 mmol, 77%). The resulting mixture was stirred for
5 h at room temperature, the solvent was removed in vacuo. A solution of the residue
1
in absolute ethanol (40 mL) was hydrogenated at 1 atm pressure in the presence of 10%
palladium on charcoal (40 mg) at room temperature. After 5 h, the catalyst was filtered
1
8

ACCEPTED MANUSCRIPT
and the subsequent solvent was removed in vacuo. The residue was acetylated with
pyridine-acetic anhydride and DMAP as described above to give 30. The crude product
3
0 was dissolved in ethyl acetate (100 mL) and cooled to 0 °C, and then 0.5% NaOH
(100 mL) solution was added. The mixture was stirred for 5 min and then the mixture
was extracted with ethyl acetate (3x20 mL). The combined organic extracts were
washed with water (15 mL) and then dried (Na SO ). Removing of the solvent under
2
4
reduced pressure gave pure 30 (1.50 g, total yield 66 %) as a colorless solid,
1
recrystallized from methylene chloride/n-hexane, mp 94-94.5 °C. H-NMR (400 MHz,
CDCl ) δ 5.35-5.26 (m, 2H), 5.22 (ddd, J = 8.8, 5.9 and 2.7 Hz, 1H), 4.34 (dd, J = 8.8
3
and 7.7 Hz, 1H), 2.11 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 2.00-1.50 (series of m, 8H);
1
3
C-NMR (100 MHz, CDCl ) δ 170.0, 169.9, 169.8, 74.6, 73.1, 71.9, 61.0, 29.3, 28.9,
3
-1
2
2.9, 22.4, 21.2, 20.9; IR (KBr, cm ) 2941, 1744, 1443, 1370, 1231, 1025. Anal. Calcd
for C H ClO : C, 52.42; H, 6.60. Found: C, 52.56; H, 6.76.
1
4
21
6
4
.14.
(1R(S),2R(S),3R(S),4S(R))-3-Chlorocyclooctane-1,2,4-triol
(29).
(1R(S),2R(S),3R(S),4S(R))-3-Chlorocyclooctane-1,2,4-triyl triacetate (30) (0.50 g, 1.56
mmol) was dissolved in absolute methanol (9 ml) and cooled to 0 °C. AcCl (3 mL) was
added and the mixture was stirred at 0 °C for 10 min and then at room temperature for
2
4 h. Removal of the solvents under reduced pressure gave 29 colorless oil (0.28 g, 92
%).
1
H-NMR (400 MHz, D O) δ 4.13-4.06 (m, 1H, H-3), 3.99-3.94 (m, 1H, H-1), 3.81-3.73
2
1
3
(
m, 2H, H-2 and H-4), 1.80-1.30 (series of m, 8H); C-NMR (100 MHz, D O) δ 73.8,
2
-1
7
2.5, 71.2, 68.8, 32.2, 30.2, 23.3, 20.7; IR (KBr, cm ) 3292, 2934, 2875, 1459, 1402,
322, 1295, 1256, 1234, 1215, 1144, 1040, 975. Anal. Calcd for C H ClO : C, 49.36;
1
8
15
3
H, 7.77. Found: C, C, 49.41; H, 7.74.
4
.15. Epoxidation of Endoperoxide 23 with dimethyldioxirane (DMDO).
Dimethyldioxirane was prepared from acetone using potassium monoperoxysulfate as
2
3
described by Adam. To a magnetically stirred solution of dimethyldioxirane (ca.3.7
mmol) in 200 mL of acetone was added 50 mg (0.35 mmol) of endoperoxide 23 in 3 mL
of CH Cl and stirred for 2h at -5 °C, then for 24 h at room temperature. After filtering
2
2
of the precipitate, evaporation of the solvent afforded the mixture of epoxides 24 and 25
1
9

ACCEPTED MANUSCRIPT
1
in a ratio of 1:1 determined by H-NMR integration (54 mg, combined yield: 97%).
Purification of the residue on silica gel column (50 g) eluting with ethyl acetate and
hexane (10:90) afforded epoxide 25 (52 mg, 93%).
7
,9
4
.16. (1R(S),6S(R),7S(R),9S(R))-8,10-Dioxatricyclo[4.3.1.0 ]decane-1-ol (25). A.
From (23). To endoperoxide 23 (1.0 g, 7.14 mmol) in CH Cl (100 mL) was added m-
2
2
chloroperbenzoic acid (1.76 g, 10.2 mmol, 77%) and NaHCO (0.60 g, 7.14 mmol). The
3
resulting mixture was stirred 5 days at room temperature, then cooled to 0 °C. To the
mixture, 1% NaOH (100 mL) solution was added and stirred for 15 min until it reached
-
5 °C. The mixture was extracted with CH Cl (4x25 mL). The combined organic
2 2
extracts were washed with saturated aqueous NaCl and then dried (Na SO ).
2
4
Evaporation of solvent gave 25 (0.58 g, 53%) as pure white crystals from CH Cl /n-
2
2
1
hexane, mp 86.5-88 °C. H-NMR (400 MHz, CDCl ) δ 4.38 (dd, J = 7.1 and J6,5’
=
3
6,5
1
.3 Hz, 1H, H-6), 3.51 (d, A-part of AB-system, JAB = 2.9 Hz, 1H, H-7 or H-9), 3.49 (d,
B-part of AB-system, JAB = 2.9 Hz, 1H, H-7 or H-9), 3.47 (bs, -OH, 1H), 2.03-1.32
1
3
(
series of m, 8H); C-NMR (100 MHz, CDCl ) δ 104.3, 74.8, 59.0, 58.5, 37.0, 31.8,
3
-1
2
3.6, 23.3; IR (KBr, cm ) 3416, 2930, 2860, 1448, 1407, 1338, 1211, 1144, 1115,
+
1
076, 946, 879, 794, 636. HRMS (ESI): calcd for C H O Na (M +Na): 179.0684,
8
12
3
found: 179.0689.
B. From (27). with m-CPBA. Unsaturated oxabicycle 27 (1.10 g, 7.90 mmol) was
dissolved in 13 ml of CH Cl , m-CPBA (1.80 g, 10.30 mmol, 77%) and NaHCO (0.66
2
2
3
g, 7.90 mmol) were added, and then the reaction was stirred at reflux temperature for 16
days. The reaction mixture was cooled to -5 °C and 1% NaOH (30 mL) solution was
added, and then stirred for 15 min. The mixture was extracted with CH Cl (4x25 mL).
2
2
The combined organic extracts were washed with saturated NaCl solution (20 mL) and
water (20 mL) and then dried (Na SO ). Evaporation of solvent gave 25 (0.80 g, 66%).
2
4
23
with DMDO. Unsaturated oxabicycle 27 (50 mg, 0.35 mmol) was submitted to
epoxidation with DMDO as in the method described above for the epoxidation of 23 to
give 25: 54 mg, 97%.
4
.17. Crystal structure determination
For the crystal structure determination, the single-crystal of compound 30 was used for
data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with
2
0

ACCEPTED MANUSCRIPT
a two-dimensional area IP detector). The graphite-monochromatized Mo K radiation
α
(λ=0.71073 Å) and oscillation scans technique with ꢀω=5˚ for one image were used for
data collection. The lattice parameters were determined by the least-squares methods on
2
2
the basis of all reflections with F >2σ(F ). Integration of the intensities, correction for
Lorentz and polarization effects and cell refinement was performed using CrystalClear
2
5b
(
Rigaku/MSC Inc., 2005) software. The structures were solved by direct methods
2
5c
using SHELXS-97 and refined by a full-matrix least-squares procedure using the
2
5c
program SHELXL-97. H atoms were positioned geometrically and refined using a
riding model. The final difference Fourier maps showed no peaks of chemical
significance. Crystal data for 30: C H O Cl, crystal system, space group: triclinic, P-
14
21
6
1
α
1
; (no:2); unit cell dimensions: a= 7.5308(2), b= 10.5140(3), c= 11.0554(4) Å,
3
=79.43(2) β=70.50(2),
γ
=74.87(2)˚; volume: 792.08(5)Å ; Z=2; calculated density:
3
−1
.34 mg/m ; absorption coefficient: 0.264 mm ; F(000): 340; θ-range for data
2
collection 2.7–26.4˚; refinement method: full-matrix least-square on F ;
2
data/parameters: 2165/193; goodness-of-fit on F : 1.028; final R indices [I>2σ(I)]: R =
1
0
.055, wR =0.115; R indices (all data): R =0.087, wR =0.131; largest diff. peak and
2 1 2
−
3
hole: 0.170 and -0.237 e Å .
Crystallographic data (excluding structure factors) for the structures reported in this
article have been deposited with the Cambridge Crystallographic Data Centre with
supplementary publication number CCDC 787346. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk)
Acknowledgments
The authors are indebted to the Department of Chemistry (Atatürk University)
and the Scientific and Technological Research Council of Turkey (TUBITAK, Grant
No. TBAG-106T647) for their financial support of this work. We would also like to
thank Professor Hasan Seçen for helpful discussions during the preparation of the
manuscript. Furthermore, we would like to thank researcher Mine Bilsel (TUBITAK,
National Metrology Institute) for the HRMS spectra, Dr. Ertan Sahin for performing the
X-ray analyses.
2
1

ACCEPTED MANUSCRIPT
Supplementary data
1
13
H and C NMR spectra for all new compounds, as well as selected 2D NMR spectra
and crystallographic data for compound 30 are provided. Supplementary data associated
with this article can be found in the online version, at http://......tet.......
References and notes
1
. (a) Posternak, T. The Cyclitols, French Ed., Hermann: Paris, 1965. (b) Ogawa, S. In
Carbohydrate Mimics: Concept and Methods; Chapleur, Y., Ed.; Wiley-VCH:
Weinheim, Germany, 1998; p 87. (c) Sable, H. Z.; Powell, K. A.; Katchian, H.;
Niewoehner, C. B.; Kadlec, S. B. Tetrahedron, 1970, 26(6), 1509-24.
2
. Last review for cyclitols, see: (a) Kilbas, B.; Balci, M. Tetrahedron, 2011, 67(13),
2
355-2389. (b) Diaz, L.; Delgado, A. Curr. Med. Chem., 2010, 17(22), 2393-2418.
(c) Delgado, A. Eur. J. Org. Chem., 2008, 23, 3893-3906. (d) Gultekin, M. S.;
Celik, M.; Balci, M. Curr. Org. Chem. 2004, 8, 1159-1186.
3
4
. (a) Wang, W.; Zhang, Y.; Zhou, H.; Blériot, Y.; Sinaÿ, P. Eur. J. Org. Chem. 2001,
1
053-1059. (b) Blériot, Y.; Giroult, A.; Mallet, J. M.; Rodriguez, E.; Vogel, P.;
Sinaÿ, P. Tetrahedron: Asymmetry, 2002, 13, 2553-2565 and refs cited therein.
. (a) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605-611. (b) Suami, T.; Ogawa,
S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 21-90. (c) Suami, T. Top. Curr.
Chem. 1990, 154, 257-283. (d) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
Ed. Engl. 1999, 38, 750-770.
5
. (a) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K; Thorpe, A. J. Chem. Rev. 1996, 96,
1
195-1220. (b) Suami, T. Pure Appl. Chem. 1987, 59, 1509-1520. (c) Balci, M.
Pure Appl. Chem. 1997, 69, 97-104. (d) Werschkun, B.; Thiem, J. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2793-2794. (e) Hanna, I.; Ricard, L. Org. Lett. 2000, 2,
2
651-2654. (f) Mehta, G.; Ramesh, S. S. Tetrahedron Lett. 2001, 42, 1987-1990.
g) Mehta, G.; Reddy, D. S.; Ramesh, S. S.; Tatu, U. Tetrahedron Lett. 1999, 40,
141-9144.
. (a) Andriuzzi, O.; Gravier-Pelletier, C.; Le Merrer, Y.; Tetrahedron Lett. 2004, 45,
043-8046. (b) Andriuzzi, O.; Gravier-Pelletier, C.; Bertho, G.; Prangé, T.; Le
Merrer, Y. Beil. J. Org. Chem. 2005, 1, 1-7. (c) Marco-Contelles, J.; de Opazo, E.;
(
9
6
8
2
2

ACCEPTED MANUSCRIPT
Tetrahedron Lett. 2000, 41, 5341-5345. (d) Mehta, G.; Pallavi, K. Chem. Commun.
2
002, 2828-2829. (e) Mehta, G.; Sen, S.; Pallavi, K. Acta Cryst. C 2007, 63, o726-
o728. (f) Paquette, L.A.; Zhang, Y. J. Org. Chem. 2006, 71, 4353-4363.
. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645-1680. (b) Berecibar, A.; Grandjean, C.; Siriwardena, A.
Chem. Rev. 1999, 99, 779-844. (c) Lillelund, V. H.; Jensen, H. H.; Liang, X. F.;
Bols, M. Chem. Rev. 2002, 102, 515-553. (d) VonItzstein, M.; Thomson, R. J.
Curr. Med. Chem. 1997, 4, 185-210. (e) Yuasa, H.; Saotome, C.; Kanie, O. Trends
Glycosci. Glycotechnol. 2002, 14, 231-251.
7
8
. (a) Mehta, G.; Ramesh, S. S. Chem. Commun. 2000, 24, 2429-2430. (b)
Ritthiwigroma, T.; Nash, R. J.; Pyne, S. G. Tetrahedron 2010, 66, 9340-9347. (c)
Li, Y.Q.; Zhou, F.C.; Gao, F.; Bian, J. S.; Shan, F. J. Agric. Food Chem. 2009, 57,
1
1463-11468.
9
. Tanabe, G.; Otani, T.; Cong, W.; Minematsu, T.; Ninomiya, K.; Yoshikawa, M.;
Muraoka, O. Bioorg. Med. Chem. Lett. 2011, 21, 3159-3162.
1
0. (a) Mehta, G.; Pallavi, K.; Katukojvala, S. Tetrahedron Lett. 2009, 50, 4519-4522.
(b) Mehta, G.; Mohanrao, R.; Katukojvala, S.; Landais, Y.; Sen, S. Tetrahedron
Lett. 2011, 52, 2893-2897.
1
1. (a) Seçen, H.; Salamci, E.; Sütbeyaz, Y.; Balci, M. Synlett 1993, 8, 609-10. (b)
Salamci, E.; Seçen, H.; Sütbeyaz, Y.; Balci, M. Synth. Commun. 1997, 27, 2223-
2234. (c) Salamci, E.; Seçen, H.; Sütbeyaz, Y.; Balci, M. J. Org. Chem. 1997, 62,
2453-2457. (d) Gültekin, M. S.; Salamci, E.; Balci, M. Carbohyd. Res. 2003, 338,
1615-1619.(e) Baran, A.; Bekarlar, M.; Aydin, G.; Nebioglu, M.; Sahin, E.; Balci,
M. J. Org. Chem. 2012, 77, 1244-1250. (f) Baran, A.; Aydin, G.; Savran, T.; Sahin,
E.; Balci, M. Org. Lett. 2013, 15, 4350-4353. (g) Aydin, G.; Savran, T.; Aktaş, F.;
Baran, A.; Balci, M. Org. Biomol. Chem. 2013, 11, 1511-1524. (h) Palframan, M.
J.; Kociok-Köhn, G.; Lewis, S. E. Chem. Eur. J. 2012, 18, 4766-4774. (i) Pilgrim,
S.; Kociok-Köhn, G.; Lloyd, M. D.; Lewis, S. E. Chem. Commun. 2011, 4799-
4
801. (j) Griffen, J. A.; White, J. C.; Kociok-Köhn, G.; Lloyd, M. D.; Wells, A.;
Arnot T. C.; Lewis, S. E. Tetrahedron, 2013, 69, 5989-5997.
1
2. (a) Blériot, Y.; Giroult, A.; Mallet, J.-M.; Rodriguez, E.; Vogel, P.; Sinaÿ, P.
2
3

ACCEPTED MANUSCRIPT
Tetrahedron: Asymmetry 2002, 13, 2553–2565. (b) Sisu, E.; Sollogoub, M.; Mallet,
J.-M.; Sinaÿ, P. Tetrahedron 2002, 58, 10189–10196. (c) Sengul, M. E.; Menzek,
A.; Saracoglu, N. J. Chem. Res. 2005, 6, 382–384.
1
3. (a) Wang, W.; Zhang, Y.; Sollogoub, M.; Sinaÿ, P. Angew. Chem., Int. Ed. 2000, 39,
2
466–2467. (b) Paquette, L. A.; Zhang, Y. Org. Lett. 2005, 7, 511–513. (c)
Andriuzzi, O.; Gravier-Pelletier, C.; Vogel, P.; Le Merrer, Y. Tetrahedron 2005,
6
1, 7094–7104. (d) Paquette, L. A.; Moura-Letts, G.; Wang, G. P. J. Org. Chem.
2
009, 74, 2099–2107. (e) Salamci, E. Tetrahedron 2010, 66, 4010–4015. (f)
Gypser, A.; Michel, D.; Nirschl, D. S.; Sharpless, K. B. J. Org. Chem. 1998, 63,
322-7327.
4. Grabowski, S.; Armbruster, J.; Prinzbach, H. Tetrahedron Lett. 1997, 38, 5485-
488.
7
1
1
1
1
5
5. Crandall, J. K.; Banks, D. B.; Colyer, R. A.; Watkins, R. J.; Arrington, J. P. J. Org.
Chem. 1968, 33, 423-425.
6. (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297-368. (b) The Chemistry
of the Azido Group; Patai, S., Ed.; Wiley: New York, 1971.
7. Goksu, S.; Ozalp, C.; Secen, H.; Sutbeyaz, Y.; Saripinar, E. Synthesis 2004, 17,
2
849-2854.
1
1
2
8. VanRheenen, R.; Kelly, R.C.; Cha, D. Y., Tetrahedron Lett. 1976, 17, 1973-1976.
1
13
9. Balci, M. Basic H and C NMR Spectroscopy; Elsevier: New York, 2005.
0. (a) Mete, E.; Altundaş, R.; Seçen, H.; Balci, M. Turk. J. Chem., 2003, 145-153. (b)
Trabanco, A. A.; Montalban, A. G.; Rumbles, G.; Barrett, A. G. M.; Hoffman, B.
M. Synlett 2000, 7, 1010-1012. (c) Horinaka, A.; Nakashima, R.; Yoshikawa, M.;
Matsuura, T. Bull. Chem. Soc. Jpn. 1975, 48, 2095-2098. (d) Kayama, Y.; Oda, M.;
Kitahara, Y. Chem. Lett. 1974, 345-348.
2
1. (a) Kornblum, N.; DeLaMare, H. E. J. Am. Chem. Soc., 1951, 73, 880–881. (b)
Kelly, D. R.; Bansal, H.; Morgan, J. J. G. Tetrahedron Lett., 2002, 43, 9331-9333.
(c) Kato, S.; Ellison, G. B.; Bierbaum, V. M.; Blanksby, S. J. J. Phys. Chem. A
2
008, 112, 9516-9525. (d) Schalley, C. A.; Wesendrup, R.; Schrçder, D.; Schwarz,
H; Organometallics 1996, 15, 678-683.
2
2. Turner, J. A.; Herz, W. J. Org. Chem. 1977, 42, 2006-2008.
3. Adam, W.; Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164, 45-62.
2
2
4

ACCEPTED MANUSCRIPT
2
4. (a) Smith, C. R.; Justice, D. E.; Malpass, J. R. Tetrahedron 1994, 50, 11039-11056.
(b) Mehta, G.; Padma, S. Tetrahedron 1991, 47, 7783-7806.
2
5. (a) Price, S. L.; Stone, A. J.; Lucas, J.; Rowland, R. S.; Thornley, A. E. J. Am.
Chem. Soc., 1994, 116, 4910-4918. (b) Rigaku (2005), CrystalClear, Version 1.3.6.
Rigaku American Corporation, 9009 New Trails Drive, The woodlands, TX 77381-
5
209, USA. (c) Sheldrick, G. M. SHELXS97 and SHELXL97; University of
Göttingen: Göttingen, Germany, 1997.
2
6. Baran, A.; Balci, M. J. Org. Chem. 2009, 74, 88-95.
2
5

ACCEPTED MANUSCRIPT
Graphical Abstract
Efficient and shortcut syntheses of some novel eight-membered ring
cyclitols starting from cycloocta-1,3-diene
†
Kadriye Ecer, and Emine Salamci
Department of Chemistry, Faculty of Sciences, Atatürk University, 25240 Erzurum, Turkey
HO
2
H N
HO
HO
HO
HO
HO
Cl
O
O
HO
HO
HO
HO
HO
HO
HO
HO
HO
O
+
+
HO
HO
†
Corresponding author. Tel: +90 442 231 4429; fax: +90 442 2314109 (E.S.).
E-mail address: esalamci@atauni.edu.tr (E. Salamci).
2
6

ACCEPTED MANUSCRIPT
Supplementary Material
Efficient and shortcut syntheses of some novel
eight-membered ring cyclitols starting from
cycloocta-1,3-diene
*
Kadriye Ecer, and Emine Salamci
Department of Chemistry, Faculty of Sciences, Atatürk University, 25240
Erzurum, Turkey
*
Corresponding author. Tel: +90 442 231 4429; fax: +90 442 2314109 (E.S.).
E-mail address: esalamci@atauni.edu.tr (E. Salamci).

ACCEPTED MANUSCRIPT
Table of contents
1
13
H NMR, C NMR and 2D Spectra ..............................................................1
(
(
(
(
(
1R(S),2S(R),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraacetate (meso-16): CDCl .............................. 1
3
1R(S),2S(R),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraol (meso-19): D O ......................................... 2
2
1R(S),2R(S),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraacetate (rac-15): CDCl .................................. 3
3
1R(S),2R(S),3R(S),4S(R))-Cyclooctane-1,2,3,4-tetraol (rac-18): D O ............................................. 4
2
1R(S),2S(R),3S(R),8S(R))-9-oxabicyclo[6.1.0]nonane-2,3-diol (13): CDCl ..................................... 5
3
NOESY spectrum for 13.................................................................................................................. 6
COSY spectrum for 13 .................................................................................................................... 7
(
1R(S),6S(R),7S(R),8S(R))-9-oxabicyclo[4.2.1]nonane-7,8-diyl diacetate (14): CDCl ..................... 8
3
NOESY and COSY spectra for 14..................................................................................................... 9
(
(
(
(
1R(S),6S(R),7R(S),8R(S))-9-oxabicyclo[4.2.1]nonane-7,8-diol (17): CDCl ................................... 10
3
1S(R),2S(R),Z)-2-azidocyclooct-3-enol (9a): CDCl ...................................................................... 11
3
1S(R),2S(R),Z)-2-azidocyclooct-3-enyl acetate (9b): CDCl .......................................................... 12
3
1R(S),2(S)R,3R(S),4S(R))-3-azidocyclooctane-1,2,4-triyl triacetate (10b): CDCl ........................ 13
3
NOESY and COSY spectra for 10b................................................................................................. 14
1
H-NMR double resonance spectrum for 10b.............................................................................. 15
7
,9
(
1R(S),6S(R),7S(R),9S(R))-8,10-dioxatricyclo[4.3.1.0 ]decane-1-ol (25): CDCl .......................... 16
3
NOESY and COSY spectra for 25................................................................................................... 17
HMQC spectrum for 25 ................................................................................................................ 18
(
(
(
1R(S),2R(S),3R(S),4S(R))-3-chlorocyclooctane-1,2,4-triyl triacetate (30): CDCl ......................... 19
3
1R(S),2R(S),3R(S),4S(R))-3-chlorocyclooctane-1,2,4-triol (29): D O............................................ 20
2
1R(S),2S(R),3R(S),4S(R))-3-aminocyclooctane-1,2,4-triol (12): CD OD ....................................... 21
3
X-Ray Crystal Structure Analysis of Chlorotriacetate 30 ........................22
Table 1.......................................................................................................................................... 23
1

ACCEPTED MANUSCRIPT
Table 2.......................................................................................................................................... 25
Table 3.......................................................................................................................................... 27
Table 4.......................................................................................................................................... 28
Table 5.......................................................................................................................................... 31
Table 6.......................................................................................................................................... 32
2