Concise syntheses and some biological activities of dl-2,5-di-O-methyl-chiro-inositol, dl-1,4-di-O-methyl-scyllo-inositol, and dl-1,6-dibromo-1,6-dideoxy-2,5-di-O-methyl-chiro-inositol

Article abstract of DOI:10.1002/ardp.202000254

The regio- and stereospecific synthesis of O-methyl-chiro-inositols and O-methyl-scyllo-inositol was achieved, starting from p-benzoquinone. After preparing dimethoxy conduritol-B as a key compound, regiospecific bromination of the alkene moiety of dimeth

Full text of DOI:10.1002/ardp.202000254

Received: 24 July 2020
Revised: 7 September 2020
Accepted: 10 September 2020
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DOI: 10.1002/ardp.202000254
F U L L P A P E R
Concise syntheses and some biological activities of DL‐2,5‐di‐
O‐methyl‐chiro‐inositol, DL‐1,4‐di‐O‐methyl‐scyllo‐inositol,
and DL‐1,6‐dibromo‐1,6‐dideoxy‐2,5‐di‐O‐methyl‐chiro‐
inositol
Kadir Aksu1
| Hulya Akincioglu2
| Ilhami Gulcin3
| Latif Kelebekli1
1Department of Chemistry, Faculty of Sciences
and Arts, Ordu University, Ordu, Turkey
Abstract
2Department of Chemistry, Faculty of Sciences
and Arts, Agri Ibrahim Cecen University, Agri,
Turkey
The regio‐ and stereospecific synthesis of O‐methyl‐chiro‐inositols and O‐methyl‐scyllo‐
inositol was achieved, starting from p‐benzoquinone. After preparing dimethoxy
conduritol‐B as a key compound, regiospecific bromination of the alkene moiety of
dimethoxy conduritol‐B and acid‐catalyzed ring opening of dimethoxydiacetate
conduritol‐B epoxide with Ac2O afforded the desired new chiro‐inositol derivatives and
scyllo‐inositol derivative, respectively. Spectroscopic methods were employed for the
characterization of all synthesized compounds. The novel inositols (11–17) had effective
inhibition profiles against human carbonic anhydrase isoenzymes I and II (hCA I and II)
and acetylcholinesterase (AChE). The novel inositols 11–17 were found to be effective
inhibitors against AChE, hCA I, and hCA II enzymes. Ki values were calculated in the
range of 87.59 7.011 to 237.95 17.75 μM for hCA I, 65.08 12.39 to
538.98 61.26 μM for hCA II, and 193.28 43.13 to 765.08 209.77 μM for AChE,
respectively. Also, due to the inhibitory effects of the novel inositols 11–17 against the
tested enzymes, these novel inositols are potential drug candidates to treat some
diseases such as glaucoma, epilepsy, leukemia, and Alzheimer's disease.
3Department of Chemistry, Faculty of
Sciences, Ataturk University, Erzurum, Turkey
Correspondence
Latif Kelebekli, Department of Chemistry,
Faculty of Sciences and Arts, Ordu University,
52200 Ordu, Turkey.
Email: lkelebekli@odu.edu.tr and
lkelebekli@yahoo.com
K E Y W O R D S
acetylcholinesterase, carbonic anhydrase, chiro‐inositol, methoxyinositol, stereospecific
synthesis
ovary syndrome (PCOS).[5–8] Moreover, myo‐inositol and D‐chiro‐
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1
INTRODUCTION
inositol, which are inositol isomers, have been shown to possess
Inositol 1 and its derivatives (Figure 1) are an important class of bio-
logically active natural products. In theory, there are nine possible
inositols, of which six (myo‐, D‐chiro‐, L‐chiro‐, scyllo‐, neo‐, and muco‐
inositols) are known to occur in nature.[1–3] Recently, biological ac-
tivities of chiro‐inositol, scyllo‐inositol, and their derivatives have been
extensively studied. Isolation of one or more methyl esters of these
compounds from plants has been reported, and these methyl inositols
are presumed to have important functions in plant biology.[4] chiro‐
Inositol is a naturally occurring inositol isomer in which D‐chiro‐inositol
2 has been effectively employed in the management of polycystic
insulin‐mimetic properties and found to act as second messengers in
the insulin intracellular pathway.[9,10] Recently, accumulating evidence
has suggested that one of the most important mechanisms of PCOS
pathogenesis is insulin resistance.[11] It is known that some physiolo-
gical activities of myo‐inositol and D‐chiro‐inositol determine the do-
sages and timing of inositol supplementation in the treatment of
PCOS.[12] In addition, the combined administration of myo‐inositol and
D‐chiro‐inositol allows treatment for PCOS. For this reason, the use of
such inositol isoforms as insulin sensitizers has gained increasing at-
tention due to their safety profile and effectiveness.[12–14]
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Arch Pharm. 2020;e2000254.
wileyonlinelibrary.com/journal/ardp
© 2020 Deutsche Pharmazeutische Gesellschaft
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FIGURE 1 Selected inositol derivatives
d
p
However, both scyllo‐ and D‐chiro‐inositols have potential roles in
medicine. scyllo‐Inositol 3 has shown promise as a potential ther-
apeutic for Alzheimer's disease (AD), by directly interacting with the
(CO2) to bicarbonate (HCO3−) and proton (H+). This important re-
−
action affects pH values and provides HCO3 ions in several meta-
bolic, physiological, and biosynthetic pathways.[31–33] The CAs are an
active research area for medicinal chemists, as effective CA inhibitors
(CAIs) need to be designed, which play a main role in the treatment
of glaucoma, epilepsy, altitude sickness, and idiopathic intracranial
hypertension.[34–36] CAIs can constitute new therapeutics against
cancer or can have capacity as antiviral and antifungal drugs.
Nowadays, the inhibition act of CAs by sulfonamide molecules has
also been reported to inhibit the growth and development of pa-
thogenic microorganisms.[37,38] Indeed, selective inhibition of CA II
establishes an effective approach to fight against the disturbances
caused by the detrimental effects of the CA II isoenzyme.[39–41]
Acetylcholinesterase (AChE) is typically synthesized in muscle,
nerve, and some hematopoietic cells. In inducible tissues, AChE is lo-
calized on the extracellular surface of both muscle and nerve and is
arranged by tissue. The prime effect of AChE is the termination of
nerve impulse conduction by the rapid hydrolysis of acetylcholine
(ACh) in cholinergic synapses.[42–44] Recently, a large spectrum of
AChE inhibitors has been developed and approved to treat myasthenia
gravis, Parkinson's disease (PD), senile dementia, AD, and ataxia. There
are diverse drugs, for example, tacrine, donepezil, and rivastigmine,
based on the duration of memory loss and cognitive dysfunction re-
lated to AD.[45–47] Indeed, these molecules have been recorded to
have some effects like gastrointestinal disturbances.[48–50] These
clinical medications can prevent ACh disruption and enhance its level
in cholinergic synapses, which can increase cognitive deficits. How-
ever, the adverse and undesired effects including nausea, weight loss,
and vomiting have restrained their clinical usage and efficacy. So, it is
essential to develop novel AChE inhibitors with less toxic side effects
and better therapeutic effects.[51–53]
amyloid
β
(Aβ) peptide to inhibit Ab42 fiber formation.[15–17]
1H nuclear magnetic resonance (NMR) spectroscopy has been used
to detect scyllo‐inositol in the brain and in cancers. D‐chiro‐Inositol
can also be used for reducing hyperglycemia due to its insulin‐
mimetic property by restoring insulin sensitivity.[10] Recently, their
methyl inositols or methoxyinositols (pinitol),[18,19] 1,4‐di‐O‐methyl‐
chiro‐inositol 4 (pinpollitol),[20] 1,2‐di‐O‐methyl‐chiro‐inositol,[21] and
1,4‐di‐O‐methyl‐scyllo‐inositol 5[16] have been synthesized from
some natural compounds. Moreover, halo‐substituted inositols
(dimethoxydichloro compound,[22] methoxyfluoro compound,[23] such
as methoxydibromo 6)[24] have also gained importance over the last
decade. (+)‐Pinpollitol, a dimethyl ether of chiro‐inositol was isolated
from the pollen and needles of Pinus radiata by Gallagher,[25] and its
structure has been proven as 1D‐1,4‐di‐O‐methyl‐chiro‐inositol 4.[26]
Another dimethyl ether of chiro‐inositol, 1D‐1,3‐di‐O‐methyl‐chiro‐
inositol, was synthesized by Sureshan et al.[26]
The preparation of cyclitols and their analogs is challenging due
to the dense stereochemistry of the hydroxylated carbon centers.
Thus, every step in the progress of the synthesis of inositols is very
important. Recently, we have reported the stereospecific synthesis of
some polyhydroxylated compounds.[27–30] Consequently, regarding
the previous results, we aimed to synthesize novel halogenated
deoxyinositols containing methyl groups. Due to the improvements in
the biological activity of various cyclitols on methoxyinositol and
interesting structural features of halogenated deoxyinositols, we
focused on the synthesis of dimethoxydibromo deoxyinositol.
Carbonic anhydrases (CAs) are structurally several distinct en-
zyme families that catalyze the transformation of carbon dioxide

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In this study, we synthesized some novel inositol derivatives
Epoxide 12 was obtained from the treatment of dimethoxydiacetate
11 with m‐chloroperoxybenzoic acid (m‐CPBA) in methylene chloride at
0°C. Thus, epoxide 12 was smoothly accomplished as a single isomer in a
70% yield (Scheme 1). A twelve‐line pattern in the 13C NMR spectrum of
12 confirms the proposed structure. These carbon atoms resonated at
170.0 ppm (–CO2CH3), 169.8 ppm (–CO2CH3), 78.4 ppm (–CHOMe),
78.0 ppm (–CHOMe), 72.7 ppm (–CHOAc), 68.5 ppm (–CHOAc),
58.5 ppm (–OCH3), 57.3 ppm (–OCH3), 54.10 ppm (–CHOCH), 52.6 ppm
(–CHOCH), and 20.7 ppm (–CO2CH3 × 2).
(11–17) and determined their inhibition properties against the CA I,
CA II isoenzymes, and AChE enzymes linked to some global diseases
including epilepsy, glaucoma, AD, PD, and leukemia.
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2
RESULTS AND DISCUSSION
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2.1
Chemistry
Treatment of dimethoxydiol 10 with bromine in CH2Cl2 at low
temperature for 2 days led to the formation of DL‐1,6‐dibromo‐1,
6‐dideoxy‐2,5‐di‐O‐methyl‐chiro‐inositol 13[59] (naming by ChemDraw,
DL‐4,5‐dibromo‐4,5‐dideoxy‐3,6‐O‐methyl‐chiro‐inositol[59]) as the sole
product in 68% yield (Scheme 2). The stereochemical course of the
bromination may be syn or anti with respect to the cyclohexane ring.
The structure of compound 13 was unambiguously deduced from its
1H and 13C NMR spectra. Especially, the 13C NMR spectrum of
13 consisted of four carbon resonances owing to the C2 symmetry.
These carbon atoms resonated at 77.7 ppm (C–OMe × 2), 73.2 ppm
(C–OH × 2), 57.5 ppm (–OCH3 × 2), and 50.0 ppm (C–Br × 2). However,
the NMR spectroscopic studies did not allow the assignment of the
exact configuration of the bromine groups. The absolute configuration
of chiro‐inositol derivative 13[59] was unambiguously established by
X‐ray crystallography.
p‐Benzoquinone 7 was brominated at low temperature to give only
the trans‐dibromo compound 8 in a high yield. The required key in-
termediate, allylic trans‐diol 9, for the synthesis of the target com-
pounds was obtained as the sole product by stereoselective
reduction of the carbonyl groups with NaBH4 in ether.[54–56] Di-
methoxydiol 10, which is a conduritol‐B derivative, was obtained
from the reaction of dibromodiol 9 with sodium methoxide prepared
by dissolving sodium metal in methanol under nitrogen atmosphere
in high yields (87%).[57,58] The stereochemical course of the trans-
formation was mainly determined as the trans configuration to
methoxy groups. Dimethoxydiacetate 11 was smoothly prepared
from the dimethoxydiol 10, as described previously (Scheme 1).[57]
The structures of both 10 and 11, which possess C2 symmetry, were
unambiguously deduced from their 1H and 13C NMR spectra. Thus,
according to the NMR data of dimethoxydiacetate 11, it was clear
that the conduritol‐B configuration was retained after the methox-
ylation and acetylation reactions of 9, respectively.
However, to investigate the introduction of bromine into the
double bond, bromination of dimethoxydiacetate 11 under the
same condition led to the desired dibromodiacetoxy 14, which is a
–5
–15
m-CPBA
SCHEME 1 The synthesis of dimethoxy conduritol‐B epoxide 12. m‐CPBA, m‐chloroperoxybenzoic acid

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SCHEME 2 Bromination of compounds
10 and 11
–5
–5
chiro‐inositol derivative, as the sole product in a 76% yield. A six‐line
pattern in the 13C NMR spectrum of 14 confirms the proposed
structure due to C2 symmetry in the molecule. These carbon atoms
resonated at 169.9 ppm (C═O × 2), 76.3 ppm (–C–OAc × 2), 72.3 ppm
(–C–OMe × 2), 58.1 ppm (–OCH3 × 2), 49.9 ppm (–C–Br × 2), and
20.7 ppm (–CH3 × 2). Moreover, the potential of this approach was
controlled via acetylation of the –OH groups in 13 with CH3COCl
in methylene chloride at room temperature, resulting in di-
bromodiacetoxy 14. After crystallization from AcOEt/hexane, com-
pound 14 was obtained in 92% yield as the only isomer confirmed by
SCHEME 3 Regio‐ and stereocontrolled opening of cyclitol epoxide 12

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NMR spectroscopy. Thus, the addition of excellent regio‐ and stereo-
selective bromine to compounds 10 and 11 resulted in products 13 and
14, a chiro‐inositol derivative. Bromine may be added stereospecifically
to form trans‐adducts, which have served as valuable precursors in
synthetic organic chemistry. The regiochemistry of the bromonium ion
ring opening under these conditions was fully not corroborated by the
simplification of the NMR pattern observed for this adduct due to the
symmetry considerations. The formation mechanism of compounds 13
and 14 was examined in detail in our previous study.[59]
(HRMS) data as spectroscopic evidence. In addition, hydrolysis of the
mixture of 15 and 16 using K2CO3 in MeOH under basic conditions gave
DL‐2,5‐di‐O‐methyl‐chiro‐inositol 17 and DL‐1,4‐di‐O‐methyl‐scyllo‐inositol
18, and their ratio (9:1) was determined on the basis of 1H and 13C NMR
data. In accordance with the Fürst–Plattner rule[60,61] the epoxide ring
under acidic conditions opens selectively to form the trans‐diaxial product
(major product), the chiro‐isomer 15, and bromination of 10 (its acetate
11) provides selectivity to form the trans‐diaxial product, the chiro‐isomer
13 (its acetate 14).
Treatment of epoxide 12 with Ac2O under acidic conditions yielded
the desired regioisomers 15, chiro‐inositol derivative, and 16, scyllo‐
inositol derivative, in 78% yield (Scheme 3). Ring opening of epoxide 12
led to the corresponding C2 regioadduct 15 as the major product and
the corresponding C1 regioadduct 16 as the minor product. However, an
eight‐line pattern in the 13C NMR spectrum of 15 confirms the proposed
structure due to C2 symmetry in the molecule. These carbon atoms
resonated at 170.2 ppm (–CO2CH3 × 2), 169.1 ppm (–CO2CH3 × 2),
77.4 ppm (–CHOMe), 71.4 ppm (–CHOAc × 2), 65.8 ppm (–CHOAc × 2),
58.5 ppm (–OCH3 × 2), 20.83 ppm (–CO2CH3 × 2), and 20.77 ppm
(–CO2CH3 × 2). Regioadduct 16, found in the lowest amount, has C2v
symmetry in contrast to 15 with C2 symmetry and shows as a five‐line
pattern in the 13C NMR spectrum, which resonated at 169.8 ppm
(–CO2CH3 × 4), 79.3 ppm (–CHOMe × 2), 71.9 ppm (–CHOAc × 4),
60.6 ppm (–OCH3 × 2), and 20.7 ppm (–CO2CH3 × 4), respectively. Thus,
its NMR spectra support the proposed structure 16. Therefore, adduct
16 should be the adduct C1 of epoxide.
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2.2
Enzyme inhibition results
The enzyme inhibition results of hCA I and hCA II isoenzymes and
AChE enzymes (IC50 and Ki values) are presented in Table 1. AD is a
deadly neurodegenerative discomfort that increases gradually, and it
has become a significant health difficulty, especially in industrialized
countries with high living controls. The AD pathogenesis is not fully
clarified; therefore, there is no therapy for the disease, except for
symptomatic curation against mild‐to‐moderate AD kinds. As AD is
recognized with acetylcholine (ACh) deficit in the brain of patients
with AD, AChE inhibitors have become the most prescribed medi-
cation class in the curation of AD.[62, 63] Indeed, it is recorded that
AD is related to metal agglomeration in senile plaques formed in
oxidative stress and patients. Then, it is fundamental that any po-
tential medication that can be used for the duration of AD has both
cholinesterases inhibitory as well as antioxidant effects. Inhibition of
AChEIs can give rise to the recovery of cognitive impairment and
they are the most extensively utilized effective clinical drugs for
AD.[64] Several pieces of evidence over the years have recorded that
interplay could exist among AD and epilepsy. Patients with AD have a
remarkably higher risk of developing epilepsy than AD and non‐AD
patients are associated with an increment occurrence of possessions
To conclude the synthesis of our target compound 17, approaches
to convert the acetate groups into free alcohols using NH3(g) in me-
thanol were unsuccessful. Hydrolysis of tetraacetate groups in 15 was
performed with K2CO3 in MeOH under very mild conditions to give
DL‐2,5‐di‐O‐methyl‐chiro‐inositol 17 in 61% yield. The structure of 17 was
established on the basis of 1H and 13C NMR data, which was further
verified by the infrared (IR) and high‐resolution mass spectroscopy
TABLE 1 The summarized inhibition parameters of novel inositol derivatives (11–17) against enzymes including carbonic anhydrases I and II
isoenzymes and acetylcholinesterase
hCA I
IC50 (µM)
440.1
585.3
333.0
325.2
380.8
371.6
261.8
0.89
hCA II
IC50 (µM)
379.3
431.0
440.0
309.1
263.6
265.2
321.7
1.0
AChE
IC50 (µM)
423.6
425.9
423.9
203.1
344.8
215.3
738.8
–
Compounds
R2
Ki (µM)
R2
Ki (µM)
R2
Ki (µM)
11
.9378
.9781
.8677
.9470
.9654
.9892
.9385
.9672
238 18
226 49
169 19
160 58
152 10
171 31
.9727
.9081
.9503
.9258
.9967
.9754
.9446
.9822
539 61
226 78
143 53
142 35
65 13
.8731
.9018
.8698
.8686
.9230
.9743
.8376
–
553 181
682 47
619 190
193 43
221 20
244 43
765 210
–
12
13
14
15
16
169 54
17
88
7
122 1
AZAa
TACa
0.21
1
0.27 1
0.54
.9618
0.21 1
aAcetazolamide (AZA) and tacrine (TAC) were used as standard inhibitors for all carbonic anhydrases (CAs) and acetylcholinesterases (AChEs),
respectively.

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in patients with early‐onset forms of the disease. Recently, AChEI has
also been considered as a promising approach for pharmacological
intervention in epilepsy.[65,66]
hCA II isoenzymes and AChE enzyme were evaluated together. The
novel inositol derivatives (11–17) showed inhibition effects against
the hCA I and II isoenzymes and AChE enzyme activities at micro-
molar concentration. The results may be beneficial for designing and
synthesizing new metabolic enzyme inhibitors and in the develop-
ment of drugs to treat some metabolic and common diseases
including epilepsy, leukemia, glaucoma, and AD in the future.
It is clear from the results presented in Table 1 that these com-
pounds effectively inhibited AChE, with Ki values in the range of 193 43
to 765 210 μM. However, all of these compounds had micromolar in-
hibition profiles. The most active ( )‐(1SR,2SR,3RS,4RS,5RS,6RS)‐4,
5‐dibromo‐3,6‐dimethoxycyclohexane‐1,2‐diyl diacetate (14) showed a
Ki value of 193 43 μM. However, tacrine showed a Ki value of
0.214 0.02 μM against the cholinergic enzyme of AChE. The results
recorded that all these derivatives demonstrated efficient AChE in-
hibitory effects; however, these inhibition abilities were lower than that
of tacrine (Ki: 0.21 1 μM) as the standard cholinergic enzyme inhibitor.
All novel inositol derivatives (11–17) demonstrated a competitive in-
hibition type against the cholinergic AChE enzyme which is the primary
cholinesterase in the body and serves to terminate synaptic
transmission.[67]
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4
EXPERIMENTAL
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4.1
Chemistry
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4.1.1
General
A capillary melting apparatus (Electrothermal) was used for de-
termining melting points without further correction. IR spectra (see
Supporting Information) were obtained from KBr (solution in 0.1‐mm
cells) or film with a Shimadzu spectrophotometer. The 1H NMR, 13C
NMR, and 13C attached proton test (APT) NMR spectra (see Sup-
porting Information) were recorded on a 400 (100) MHz Bruker
spectrometer (Avance III) and are reported in δ units with SiMe4 as
the internal standard. The structures were assigned, whenever ne-
cessary, with the help of 2D correlation experiments (correlation
spectroscopy [COSY] and nuclear Overhauser effect spectroscopy
[NOESY]). TLC was performed on E. Merck Silica Gel 60 F254 plate
(0.2 mm). Flash‐column chromatography was performed on Merck
silica gel (60 mesh). MgSO4 was used for drying all organic extracts
before filtration and the extracts were concentrated on a rotary
evaporator. The solvents were distilled for all synthetic procedures.
HRMS were recorded by liquid chromatography–mass spectrometry
(LC–MS) time‐of‐flight (TOF) electrospray ionization technique
(6230; Agilent).
It is worth mentioning that the synthesized inositol derivatives
(11–17) had an effective inhibition profile against the slow hCA I
isoform, as seen in Table 1. The hCA I isoform was inhibited by these
compounds in micromolar levels, with the Ki values varying between
88 7 and 238 18 μM. However, acetazolamide (AZA), which is
considered a broad‐specificity CA inhibitor owing to its widespread
inhibition of CAs, showed a Ki value of 0.21 0 μM against hCA I
isoenzyme. Among the inhibitors, DL‐2,5‐di‐O‐methyl‐chiro‐inositol
(17) was obtained to be the excellent hCA I inhibitor with a Ki value
of 88 7 μM, respectively. All novel inositol derivatives, 11–17, de-
monstrated a competitive inhibition type against the slow hCA I
isoform that maintains acid–base balance and helps CO2 transport in
the human body.[68,69]
The hCA I inhibition effects of all novel inositol derivatives
(11–17) were found to be weaker than that of AZA, which was a
clinically strong and standard CA inhibitor. Against the physiologically
dominant isoform hCA II, novel inositol derivatives (11–17) demon-
strated Ki values varying from 65 13 to 539 61 μM (Table 1). These
compounds had effective inhibition effects toward hCA II, whereas
standard compound AZA showed a Ki value of 0.27 1 μM against
hCA II. Thus, (1SR,2SR,3SR,4SR,5SR,6SR)‐3,6‐dimethoxycyclohexane‐
1,2,4,5‐tetrayl tetraacetate (15) is shown as the most effective hCA II
inhibition, with a Ki value of 65 13 μM. All novel inositol derivatives
(11–17) demonstrated a competitive inhibition type against the phy-
siologically dominant hCA II isoform, which is one of 16 isoforms of the
human α‐CA family.[70,71]
The InChI codes of the investigated compounds, together with
some biological activity data, are provided as Supporting Information.
( )‐(1SR,2SR,3SR,6SR)‐3,6‐Dimethoxycyclohex‐4‐ene‐1,2‐diol (10)
The title compound was prepared in 87% yield (recrystallized from
AcOEt/hexane), as described in the literature.[54–57]
( )‐(1RS,2RS,3SR,6SR)‐3,6‐Dimethoxycyclohex‐4‐ene‐1,2‐diyl
diacetate (11)
3,6‐Dimethoxycyclohex‐4‐ene‐1,2‐diol 10 (1.2 g, 6.89 mmol) was dis-
solved in pyridine (8 ml). To the magnetically stirred solution, Ac2O
(11 ml) was added, which was stirred at room temperature overnight.
The mixture was poured into ice water (20 ml) and 4 M HCl solution
(20 ml) was added, and the mixture was extracted with ether
(3 × 100 ml). The combined organic extracts were washed with the
saturated aqueous NaHCO3 solution (100 ml) and water (50 ml), then
dried over Na2SO4, and concentrated in vacuo. The crude material was
recrystallized from CH2Cl2/Et2O to give ( )‐(1RS,2RS,3SR,6SR)‐3,
6‐dimethoxycyclohex‐4‐ene‐1,2‐diyl diacetate 11[30] (1.58 g, 89%) as
colorless crystals.
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3
CONCLUSION
We report the regio‐ and stereospecific synthesis of dimethoxy chiro‐
and scyllo‐inositol derivatives having a chiro‐ and scyllo‐inositol ste-
reochemistry. Bromination of dimethoxydiol 10 and acid‐catalyzed
ring opening of dimethoxydiacetate conduritol‐B epoxide 12 syn-
thesized the target compounds as stereocontrolled. Also, the inhibi-
tion effects of all novel inositol derivatives (11–17) against hCA I and

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(1RS,2RS,3SR,4SR,5RS,6SR)‐2,5‐Dimethoxy‐7‐oxabicyclo[4.1.0]-
heptane‐3,4‐diyl diacetate (12)
removed under pressure. The crude material was recrystallized from
AcOEt/hexane to give ( )‐(1SR,2SR,3RS,4RS,5RS,6RS)‐4,5‐dibromo‐3,6‐
dimethoxycyclohexane‐1,2‐diyl diacetate 14 (1.23 g, 76%) as colorless
crystals. Mp, 185–187°C; 1H NMR (400 MHz, CDCl3) δ 5.42 (dd, 2H,
J = 2.8, 6.9 Hz, –CHOAc), 4.83 (d, 2H, J = 2.7 Hz, –CHBr), 3.95 (td, 2H,
( )‐(1RS,2RS,3SR,6SR)‐3,6‐Dimethoxycyclohex‐4‐ene‐1,2‐diyl diacetate
11 (4.25 g, 16.46 mmol) was dissolved in CH2Cl2 (50 ml) and this so-
lution was cooled to 0°C. To the solution, m‐CPBA (2.98 g, 17.28 mmol)
was added in small portions. Then the reaction mixture was warmed to
room temperature. To this solution, which was stirred at room tem-
perature for 24 hr, m‐CPBA (2.98 g, 17.28 mmol) was added and then
refluxed for 48 hr. The reaction mixture was evaporated under reduced
pressure, dissolved in ethyl acetate (100 ml), and washed with 2 M
NaOH (3 × 50 ml) and brine (50 ml). The organic layer was dried over
Na2SO4 and evaporated. The residue was recrystallized from ethyl
acetate/hexane (1:3) to give (1RS,2RS,3SR,4SR,5RS,6SR)‐2,5‐dimethoxy‐
7‐oxabicyclo[4.1.0]heptane‐3,4‐diyl diacetate 12 (3.16 g, 70%) as a
white solid. Mp, 78–80°C; 1H NMR (400 MHz CDCl3): δ 5.13 (dd, 1H, A
part of AB system, J = 10.9, 8.9 Hz, –CHOAc), 4.99 (dd, 1H, B part of AB
system, J = 10.9, 8.2 Hz, –CHOAc), 3.86 (dd, 1H, J = 8.9, 1.7 Hz,
–CHOMe), 3.68 (d, 1H, J = 8.1 Hz, –CHOMe), 3.52 (m, 1H, –CHOCH),
3.51 (s, 3H, –OCH3), 3.50 (s, 3H, –OCH3), 3.28 (d, 1H, J = 3.8 Hz,
–CHOCH), 2.07 (s, 3H, –CO2CH3), 2.06 (s, 3H, –CO2CH3); 13C NMR
J = 2.7, 6.8 Hz, –CHOMe), 3.44 (s, 6H, –OCH3), 2.08 (s, 6H, –CH3); 13
C
NMR (100 MHz, CDCl3) δ 169.9 (C═O × 2), 76.3 (–C–OAc × 2), 72.3
(–C–OMe × 2), 58.1 (–OCH3 × 2), 49.9 (–C–Br × 2), 20.7 (–CH3 × 2); IR
(KBr, cm−1): 3,001, 2,964, 2,939, 2,833, 1,747, 1,366, 1,250, 1,221,
1,209, 1,132, 1,109, 1,051, 1,042, 912, 826; HRMS: m/z calculated for
C12H18Br2NaO6 [M+Na]+, 441.064; found: 440.924.
Acetylation of 13
To a solution of 4,5‐dibromo‐3,6‐dimethoxycyclohexane‐1,2‐diol 13
(0.31 g, 0.92 mmol) in CH2Cl2 (5 ml), acetyl chloride (10 ml) was ad-
ded and the mixture was stirred at room temperature for 6 hr. The
solvent of the mixture was removed under pressure. The crude ma-
terial was recrystallized from AcOEt/hexane to give dibromide 14
(0.35 g, 92%).
(100 MHz CDCl3):
δ
170.0 (–CO2CH3), 169.8 (–CO2CH3), 78.4
(1SR,2SR,3SR,4SR,5SR,6SR)‐3,6‐Dimethoxycyclohexane‐1,2,4,5‐
tetrayl tetraacetate (15) and (1RS,2RS,3SR,4SR,5SR,6SR)‐3,6‐
dimethoxycyclohexane‐1,2,4,5‐tetrayl tetraacetate (16)
(–CHOMe), 78.0 (–CHOMe), 72.7 (–CHOAc), 68.5 (–CHOAc), 58.5
(–OCH3), 57.3 (–OCH3), 54.10 (–CHOCH), 52.6 (–CHOCH), 20.7
(–CO2CH3 × 2); IR (KBr, cm−1): 2,994, 2,932, 2,820, 1,740, 1,458, 1,436,
1,370, 1,219, 1,157, 1,092, 1,042, 1,022, 949, 841, 806, 718, 613;
HRMS: m/z calculated for C12H18NaO7 [M+Na]+, 297.094; found:
297.085.
(1RS,2RS,3SR,4SR,5RS,6SR)‐2,5‐Dimethoxy‐7‐oxabicyclo[4.1.0]heptane‐
3,4‐diyl diacetate 12 (1.03 g, 3.76 mmol) and acetic anhydride (20 ml)
were placed in a 50‐ml flask. To this solution, a catalytic amount (five
drops) of conc. H2SO4 was added at 0°C. The reaction mixture was
stirred at room temperature for 12 hr. This mixture was acidified with
1 N HCl and stirred in an ice bath for 1 hr. The reaction mixture was
extracted with chloroform (3 × 50 ml). Organic layers were combined
and washed with saturated NaHCO3 (3 × 50 ml) and brine (50 ml). The
organic layer was dried over Na2SO4 and evaporated. The ratio of the
two isomers to each other (15:16, 9:1) was determined by NMR
spectroscopy. The overall yield was 78% (1.1 g, 2.92 mmol) and the
isolated yields were as follows: (1SR,2SR,3SR,4SR,5SR,6SR)‐3,6‐
dimethoxycyclohexane‐1,2,4,5‐tetrayl tetraacetate 15: 35% (0.49 g,
1.30 mmol) and (1RS,2RS,3SR,4SR,5SR,6SR)‐3,6‐dimethoxycyclohexane‐
1,2,4,5‐tetrayl tetraacetate 16: 6% (85.00 mg, 0.23 mmol).
Tetraacetate 15: mp, 136–138°C; IR (KBr, cm−1): 2,940, 2,828,
1,740, 1,505, 1,485, 1,435, 1,370, 1,211, 1,161, 1,107, 1,045, 1,011,
934, 725, 675, 614; 1H NMR (400 MHz CDCl3): δ 5.47 (d, 2H,
J = 2.3 Hz, –CHOAc × 2), 5.25 (dd, 2H, J = 7.2, 2.8 Hz, –CHOAc × 2),
3.58 (dt, 2H, J = 6.8, 2.5 Hz, –CHOMe × 2), 3.38 (s, 6H, –OCH3 × 2),
2.17 (s, 6H, CO2CH3 × 2), 2.08 (s, 6H, CO2CH3 × 2); 13C NMR
(100 MHz CDCl3): δ 170.2 (–CO2CH3 × 2), 169.1 (–CO2CH3 × 2), 77.4
(–CHOMe), 71.4 (–CHOAc × 2), 65.8 (–CHOAc × 2), 58.5
(–OCH3 × 2), 20.83 (–CO2CH3 × 2), 20.77 (–CO2CH3 × 2); HRMS: m/z
calculated for C16H24NaO10 [M+Na]+, 399.126; found: 399.115.
Tetraacetate 16: mp, 204–207°C; IR (KBr, cm−1): 1,732, 1,377,
1,223, 1,165, 1,123, 1,030, 968, 934, 698, 606, 579, 417; 1H NMR
(400 MHz CDCl3): δ 5.08 (dd, 4H, J = 6.9, 2.8 Hz, –CHOAc × 4), 3.43
(m, 8H, –CHOMe × 2, –OCH3 × 2), 2.08 (s, 12H, CO2CH3 × 4); 13C
NMR (100 MHz CDCl3): δ 169.8 (–CO2CH3 × 4), 79.3 (–CHOMe × 2),
( )‐(1SR,2SR,3RS,4RS,5RS,6RS)‐4,5‐Dibromo‐3,6‐
dimethoxycyclohexane‐1,2‐diol: DL‐1,6‐dibromo‐1,6‐dideoxy‐2,5‐di‐
O‐methyl‐chiro‐inositol (13)
A solution of Br2 (1.11 g, 6.95 mmol) in CH2Cl2 (10 ml) was added
dropwise to a solution of 10 (1.21 g, 6.95 mmol) in CH2Cl2 (40 ml) at
−5°C and the mixture were stirred for 2 days. The reaction mixture
was warmed to room temperature and the solvent of the mixture was
removed under pressure. The crude material was recrystallized from
AcOEt/hexane to give DL‐1,6‐dibromo‐1,6‐dideoxy‐2,5‐di‐O‐methyl‐
chiro‐inositol 13 (1.57 g, 68%) as colorless crystals. Mp, 147–150°C;
1H NMR (400 MHz, CDCl3) δ 4.83 (d, 2H, J = 2.5 Hz, –CHOH), 3.94
(dd, 2H, J = 2.4, 6.7 Hz, –CHBr), 3.73 (td, 2H, J = 2.5, 6.6 Hz,
–CHOMe), 3.50 (s, 6H, –OCH3), 3.33 (bs, 2H, –OH); 13C NMR
(100 MHz, CDCl3),
δ 77.7 (C–OMe × 2), 73.2 (C–OH × 2), 57.5
(–OCH3 × 2), 50.0 (C‐Br × 2); IR (KBr, cm−1): 3,410, 3,368, 2,994,
2,924, 2,839, 1,377, 1,346, 1,265, 1,188, 1,126, 1,107, 1,053, 980,
964, 625; HRMS: m/z calculated for C8H14Br2NaO4 [M+Na]+,
356.991; found: 356.910.
( )‐(1SR,2SR,3RS,4RS,5RS,6RS)‐4,5‐Dibromo‐3,6‐
dimethoxycyclohexane‐1,2‐diyl diacetate (14)
A solution of Br2 (0.62 g, 3.87 mmol) in CH2Cl2 (10 ml) was added
dropwise to a solution of 11 (1.0 g, 3.87 mmol) in CH2Cl2 (40 ml) at
−5°C and the mixture were stirred for 2 days. The reaction mixture
was warmed to room temperature and the solvent of the mixture was

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AKSU ET AL.
|
71.9 (–CHOAc × 4), 60.6 (–OCH3 × 2), 20.7 (–CO2CH3 × 4); HRMS:
m/z calculated for C16H24NaO10 [M+Na]+, 399.126; found: 399.124.
CONFLICTS OF INTERESTS
The authors declare that there are no conflicts of interests.
DL‐2,5‐Di‐O‐methyl‐chiro‐inositol (17)
ORCID
(1SR,2SR,3SR,4SR,5SR,6SR)‐3,6‐Dimethoxycyclohexane‐1,2,4,5‐tetrayl
tetraacetate 15 (0.20 g, 0,53 mmol) was dissolved in absolute MeOH
(10 ml). To the magnetically stirred solution, K2CO3 (0.29 g,
2.13 mmol) was added, and the mixture was stirred at room tem-
perature for 12 hr. The reaction mixture was filtered and the solvent
was removed in the evaporator. The crude material was purified by
column chromatography on silica gel by using EtOAc/petroleum ether
(1:1) to give DL‐2,5‐di‐O‐methyl‐chiro‐inositol 17 (61%, 67.00 mg,
0.32 mmol). Mp, 162–164°C; IR (KBr, cm−1): 3,360, 2,990, 2,920,
2,824, 2,496, 1,458, 1,400, 1,334, 1,192, 1,142, 1,103, 1,049, 976, 910,
853, 799, 764, 625; 1H NMR (400 MHz D2O): δ 4.23 (bs, 2H,
–CHOH × 2), 3.55 (m, 2H, –CHOH × 2), 3.38 (bs, 6H, –OCH3 × 2), 3.33
(m, 2H, –CHOMe); 13C NMR (100 MHz, D2O): δ 80.0 (–CHOH × 2),
72.0 (–CHOH × 2), 66.8 (–CHOMe × 2), 56.9 (–OCH3 × 2); HRMS: m/z
calculated for C8H16NaO6 [M+Na]+, 231.083; found: 231.083.
Kadir Aksu
https://orcid.org/0000-0002-2729-2168
Hulya Akincioglu
Ilhami Gulcin
https://orcid.org/0000-0001-5453-0953
https://orcid.org/0000-0001-5993-1668
http://orcid.org/0000-0002-6242-2589
Latif Kelebekli
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