Stereoselective synthesis of new rac-quercitols containing hydroxymethyl groups as glucosidase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2018.05.034

Stereoselective and efficient synthesis of hydroxymethyl-substituted rac-quercitols (13–15) was achieved, starting from cis-furan (Kobayashi, 2008) with photooxygenation reaction, which is readily available by the reduction of cis-phtalic anhydride. α- and β-Glucosidase enzyme activity of the target molecules was evaluated and good inhibitor activity was seen. One- and two-dimensional NMR spectroscopy, IR spectroscopy and X-ray crystallography were utilized in the structure characterization of products.

Full text of DOI:10.1016/j.bmcl.2018.05.034

Accepted Manuscript
Stereoselective synthesis of new rac-quercitols containing hydroxymethyl
groups as glucosidase inhibitors
Gokay Aydin, Tahir Savran, Şule Baran, Arif Baran
PII:
S0960-894X(18)30435-9
https://doi.org/10.1016/j.bmcl.2018.05.034
BMCL 25851
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 February 2018
14 May 2018
16 May 2018
Please cite this article as: Aydin, G., Savran, T., Baran, S., Baran, A., Stereoselective synthesis of new rac-quercitols
containing hydroxymethyl groups as glucosidase inhibitors, Bioorganic & Medicinal Chemistry Letters (2018), doi:
https://doi.org/10.1016/j.bmcl.2018.05.034
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MANUSCRIPT
Stereoselective synthesis of new rac-quercitols containing
hydroxymethyl groups as glucosidase inhibitors
Gokay Aydin, Tahir Savran, Şule Baran, Arif Baran*
Department of Chemistry, Sakarya University, 54187, Sakarya, Turkey.
ABSTRACT
+
Stereoselective and efficient synthesis of hydroxymethyl-substituted rac-quercitols (13-15)
was achieved, starting from cis-furan3 with photooxygenation reaction, which is readily
available by the reduction of cis-phtalic anhydride. α- and β-Glucosidase enzyme activity of
the target molecules was evaluated and good inhibitor activity was seen. One- and two-
dimensional NMR spectroscopy, IR spectroscopy and X-ray crystallography were utilized in
the structure characterization of products.
Keywords: Quercitol, Carbasugar, Synthetic Method, Biological Activity
1

Polyhydroxylated cyclic compounds are numerous in nature. These moieties, also known as
cyclitols, have three or more hydroxyl groups on a ring.1 They are not only isolated from
natural sources2 but also synthesized by several types of synthetic strategies. These
compounds have many potential biological activities such as anti-obesity, anti-diabetic, anti-
fungal and anti-human immunodeficiency virus (HIV).3 Quercitols (fundamentally
deoxyinositols), used as a generic term for cyclohexanepentols,4 are a subclass of cyclitols as
well as inositols, conduritols and carbasugars along with other varieties5 (Figure 1).
Figure 1. Subclasses of cyclitols.
The quercitol family contains 16 stereoisomers, all of these stereoisomers can be recognized
easily but only three optically active quercitols, the (+)-proto-, (-)-proto-quercitol and (-)-
vibo-quercitol, have hitherto been found in nature and only exist in plants.5b, 6 Meanwhile, the
carbocyclic polyols have been of interest to those concerned with carbohydrates.6
Carbohydrates, the most widespread biomolecules, are represented as free monosaccharides,
oligosaccharides, polysaccharides and essential fragments of glycoconjugates, In many
biologically active natural products, the sugar units not only increase water solubility, but also
decrease toxicity. In addition, some aglycones are also required components for the
bioactivity of natural products.7 Highly oxygenated cyclohexanes are often referred to as
pseudosugars (or carbasugars) due to the similarity of their structure to that of real sugars.2a
Carbasugars (analogues of monosaccharides)8 are glycomimics or sugar-mimetics9 in which
the pyranose ring oxygen is replaced with a methylene group like quercitols,8,10 but
carbasugars contain a hydroxymethyl substituent additionally (Figure 2).
Figure 2. Structures of true sugar and carbasugar.
2

These compounds take part in the regulation and function of biological processes like in
cellular recognition, inhibition effects of carbohydrate-based enzymes (amylases,
glucosidases) and signal transmitters.5a The lack of a glucosidic linkage in these entities,
which moreover resemble monosaccharides in shape, size and functionalization, makes them
hydrolytically stable towards acidic as well as enzymatic hydrolysis.11 These compounds are
regarded as potential drug candidates rather than natural sugars and are generally evaluated in
glucosidase inhibition applications.2a,12a
Many enzymes perform function in the synthesis and degradation reactions of
carbohydrates and contribute to completing digestion such as glucosidase (α, β), maltase and
sucrase. α- and β-Glucosidases break down α-, β- 14 glucosidic2g,2h bond between
carbohydrate or sugar molecules in the brush border of intestine and form monosaccharide
units such as glucose and fructose. Glucosidase inhibitors (α, β) are commonly used as agents
to retard carbohydrate digestion and thus decelerate the blood glucose level,12b,12c,12d,12e so the
development of inhibitors for glucosidases is an important challenge for the treatment of a
range of carbohydrate-mediated diseases. 11,13,14,15,16
we herein report a stereoselective synthesis of some quercitols from a commercially available
and cheap starting material, and their inhibitor activities toward α- and β-glucosidase enzyme
were also investigated.
3

In the present strategy based on retrosynthetic analysis (Scheme 1), we initially
synthesized the key molecule cis-furan 3 via reduction of readily available cis-phthalic
anhydride 117 with LiAlH4 in THF to afford cis-diol 2 (95%), followed by the ring-closing
procedure of 2 utilized with tosyl chloride (TsCl) in pyridine under reflux conditions, which
resulted18 in 85% yield.
Scheme 1. Retrosynthetic analysis of the target quercitols.
A tetraphenylporphyrin-catalyzed photooxygenation reaction19a of cis-furan 3 in
dichloromethane at rt under a 500-W projection lamp gave two hydroperoxides 3a and 4a
(2:3) according to the NMR spectra over a singlet oxygen ene-reaction19b-e as expected.
Reagents and conditions: i. LiAlH4, THF, 95%; ii. TsCl, pyridine, reflux, 85%; iii. (a) TPP, 1O2, hv, DCM, rt,
(b) Ti(OiPr)4, (CH3)2S, DCM, 0 °C, 42% for 3b, 41% for 4b.
Scheme 2. ‟ene”-Reaction of singlet oxygen of hydrofurane 3.
The diastereoisomeric 3a and 4a were prepared,19b-e and without any additional purification
were determined in 39% yield for 3a and 51% yield for 4a by 1H-NMR spectra. Reduction of
peroxide 3a and 4a with (CH3)2S using titanium tetraisopropoxide as a catalyst in methylene
chloride20 as a solvent at 0°C furnished a mixture of residue. The residue was separated via
column chromatography by eluting with CH2Cl2, which afforded two isomers, 3b (42%) and
4b (41%) (Scheme 2).
In the 1H- and 13C-NMR analysis, the double bond of 3b resonates as an AB system that
appears at 5.76 ppm and 5.64 ppm with coupling constants J34 = 10.0 Hz, J33a = 1.5 Hz, J45 =
4

2.0 Hz for H3 and H4, respectively. Likewise the double bond of 4b resonates as an AB system
that appears at 5.83 ppm and at 5.68 ppm with coupling constants J43 = 10.0 Hz, J45 = 1.5 Hz,
J33a = 1.1 Hz for H4 and H3. H5 in both diastereomeric 3b and 4b appear as multiplets at 4.21
ppm and 4.13 ppm with H6. The eight line carbon signal for each construction confirmed the
structure but the coupling constants between H5 and H6 in both 3b and 4b appear as multiplets
consequently. The configurations of 3b and 4b did not match each other exactly. Therefore,
the relative stereochemistry of 3b and 4b is not known obviously for the synthesis of the
target molecule. In the ongoing stage, for not affording undesired side reactions and for
correction of the configuration readily, the hydroxy group in diastereoisomeric 3b and 4b was
treated with pyridine and Ac2O at rt (Scheme 3) to afford the corresponding monoacetates 5
and 6 in 84% and 87% yield, respectively.18
For the synthesis and design of new scaffolds of cyclitol derivatives, our main attempts were
to establish their relative stereochemistry. Thus, it was difficult for proving diastereomeric
compounds to make a decision about configuration separately and to decide on the
configuration of compounds for which H5 gave a multiplet at 5.20 ppm with H6 and H4 or H3
in compound 5 and H5 gave a multiplet at 5.34-5.28 ppm with H6 and H4 or H3 in compound
6. Roughly ten lines of the carbon signals for each construction confirmed monoacetate 5 and
6 as scaffolds. For further characterization we tried to crystalize structures 5 and 6, but there
were no single crystals using different solution ratios in all cases for X-ray crystal analysis.
Therefore, the double bond in monoacetates 5 and 6 was exposed to a cis-hydroxylation
reaction8,21 separately with a catalytic amount of OsO4 in the presence of N-methyl-
morpholine N-oxide (NMO) in a solution of acetone:water (1:1) at 0 °C to afford cis-diols as
racemic mixtures. Without any purification the mixture was followed by acetylation using
Ac2O/pyr. and after separations chromatographically afforded triacetate stereoisomers 7, 8
and 9. While compound 7 (in 73% yield) was obtained from 5, compounds 8 (in 54% yield)
and 9 (in 31% yield) were obtained from 6 (Scheme 3).
5

Reagents and conditions: (a) Ac2O, pyridine, rt, 84% for 5, 87% for 6, (b) i. OsO4, NMO, (CH3)2CO:H2O (1:1)
0 °C, ii. Ac2O, pyr., rt, 73% for 7, 54% for 8, 31% for 9.
Scheme 3. Synthesis of furane-triacetate 7, 8 and 9.
The configurations of 7, 8 and 9 were verified by 1D- and 2D-NMR spectrums and also 7 was
verified by X-ray crystallographic analysis (Figure 3).
Figure 3. Crystal structure of 7.
The analysis of the NMR spectra of 7, 8 and 9 exhibited different configurations as expected.
The result of cis-hydroxylation and acetylation reactions gave trans-cis-cis configuration of 7
where the coupling constants appear as J45 = 8.5 Hz as a doublet of doublets at 5.12 ppm, J56
= 2.8 Hz as a doublet of doublets at 5.14 ppm, and J65 = 2.8 Hz as a doublet of doublets at
5.35 ppm for H-4, H-5, and H-6. The cis-cis-cis configuration for 8 showed coupling
constants of J45 = 2.3 Hz as a doublet of quartets at 5.05 ppm, J56 = 2.3 Hz as a triplet at 5.51
ppm, and J65 = 2.3 Hz as a doublet of doublets at 4.86 ppm for H-4, H-5, and H-6. On the
other hand, compound 9 showed a trans-cis-cis configuration with coupling constants of J45
=4.1 Hz as a doublet of triplets at 5.18 ppm, J56 = 3.3 Hz as a doublet of doublets at 5.47
ppm, and J65 = 3.3 Hz as a doublet of doublets at 5.08 ppm for H-4, H-5, and H-6. It was easy
to confirm the exact position of vicinal protons of H4 and H5 for the structures 7, 8 and 9.
Comparison of the coupling constant between H4 and H5 for all compounds indicated the
highest values for 7 (J45 = 8.5 Hz) and 9 (J45 = 4.1 Hz) in trans configuration while for
compound 8 (J45 = 2.3 Hz) indicated a low value in cis configuration obviously. After the
occurrence of cis-hydroxylation reactions and assessment of configurational assignments of 7,
8 and 9 the results were summarized in Table 1.
Table 1. 1H−1H coupling constants in 7, 8 and 9.
6

Compounds
J45 = 8.5 Hz dd
J56 = 2.8 Hz dd
J45 = 2.3 Hz dq
J56 = 2.3 Hz t
J45 = 4.1 Hz dt
J56 = 3.3 Hz dd
Coupling Constants
Thus the relative stereochemistry of furanes for H4, H5, and H6 was elucidated easily but the
most difficult other problem was to measure the coupling constant of H-6 and H-7a or H-3
and H-3a exactly for 7, 8 and 9. Single crystal analysis of 7 was performed (Figure 3) and its
structure was determined to be in trans-cis-cis-trans configuration. Similarly, we wanted to
conduct single crystal analysis of 8 and 9, but the structures were not formed as expected, and
we were not able to attain the final relative chemistry of 8 and 9 constructions. Therefore,
triacetates were separately submitted to the acetolysis reaction18,22a,22b to open the
tetrahydrofuran ring in the structures with sulfamic acid catalyzed in a mixture of acetic acid
and acetic anhydride (1:1) at reflux temperature to provide pentaacetates 10, 11 and 12 as
colorless liquids in yields of 76%, 82% and 78%, respectively (Scheme 4). After isolation and
purification, the configuration of 10 was not changed as in 7 but pentaacetate isomers 11 and
12 were not determined clearly enough during the tetrahydrofuran ring opening reaction,
which was deduced from detailed analysis of the NMR spectrum taking the coupling constant.
Reagents and conditions: (a) H2NSO3H, Ac2O/AcOH (1:1), reflux, 76% for 10, 82% for 11, 78% for 12; (b)
NH3(g), MeOH, rt, 81% for 13, 85% for 14, 94% for 15.
7

Scheme 4. Synthesis of pentaacetates 10, 11, and 12 and the target quercitol analogues 13, 14, and 15.
According to the NMR analysis results given the numbering system in 10 as shown in Table
2, pentaacetate 10 has a trans-cis-cis-trans configuration as in 7 in which ring opening
resulted in 10 with the same configuration without any neighboring group effect or
rearrangement. The resonance signals for H1, H2 and H3 appear at 5.03, 5.48 and 2.50 ppm,
respectively, as J12 = 10 Hz as a doublet of doublets, J23 = 3.1 Hz as a doublet of doublets and
J34 = 4.1 Hz as a doublet of doublets of doublets of doublets with coupling constant,
respectively. In brief, even though the NMR analysis results indicate J12 has trans, J23 has cis
and J34 has trans configuration for 10, X-ray crystallographic analysis was performed to
determine the exact configuration.
Using the same numbering system for the other two stereoisomers 11 and 12 according to the
relative stereochemistry, the resonance signal for H1, H2 and H3 of 11 indicated that J12 =
broad singlet at 5.45 ppm, J23 = broad singlet at 5.17 ppm and J34 = multiplet in the range of
2.56-2.43 ppm, and the resonance signal for H1, H2 and H3 of 12 indicated that J12 = 8.6 Hz as
a doublet of triplets at 5.14 ppm, J23 = 2.9 Hz as a doublet of doublets at 4.95 ppm and J34 =
multiplet at 5.42 ppm in Table 2, respectively.
Table 2. 1H−1H Coupling constants in 10, 11 and 12.
Compounds
J12 = 10 Hz dd, J23 = 3.1 J12 = bs, J23 = bs, J34
Hz dd J34 = 4.1 Hz dddd m
=
Coupling Constants
J12 = 8.6 Hz dt J23 = 2.9 Hz
dd, J34 = m
The results for scaffolds were supported by COSY, HETCOR and DEPT tecnique. The
coupling constants of 10, 11 and 12 were examined and the collected results given in Table 2
showed that the relative stereochemistry of J34 for 11 and 12 is very difficult to determine
using only NMR techniques. For this reason X-ray crystallographic analysis of 11 and 12 was
conducted for elimination of these uncertain configurations and confirmed the expected
construction.
8

Figure 4. Crystal structure of 11 and 12.
After determining the structures of 10, 11 and 12, the acetyl groups in the structure were
hydrolyzed with ammonia18,22a,22b in absolute MeOH after evaporation of solution and
forming acetamide to give the relevant pentols 13, 14 and 15 in roughly quantitative yields
(Scheme 4). It was deduced that the asymmetry of compounds 13, 14 and 15 was exactly in
agreement with the NMR spectroscopic data and X-ray crystallographic analysis results.
β-Glucosidase inhibition for the target molecules 13, 14 and 15 was evaluated using acarbose
as a positive control. All compounds showed β-glucosidase inhibitory activity (10-180 µM).
The best inhibitory activity was observed for compound 14. While the inhibition of compound
14 at 51.80 ± 11.36 for 180 µM concentration (IC50 = 197.77 µM) was sufficiently strong, the
inhibition of acarbose at 66 ± 0.7 for 180 µM concentration (IC50 = 57.78. µM) showed good
inhibitory activity. However, at low concentration (20 µM), it can be said that β-glucosidase
inhibitory activity for compound 13 is stronger than that of acarbose. The test assay and the
results are summarized in Table 3.
Table 3. Inhibition of β-glucosidase by racemic compounds 13, 14 and 15.
β-Glucosidase inhibition ( %) a
Compo-
unds
IC50
10 µM
20 µM
25 µM
45 µM
80 µM
120 µM
180 µM
(µM)c
Acarbosed
17±0.6
3.4±2.1
25±2.8
29±1.0
39±1.9
52±0.9
60±0.6
66±0.7
57.78
27.76±1
28.36±1.1
30.4±0.9 31.78±2.4 32.12±7.1
34.3±4.2 37.5±5.3 42.66±4.1
33.3±0.8 ND b
13
14
15
18±5.95 20.41±16 28.96±4.4
2.2±1.9 4.98±3.8 12.66±2.7
51.80±11 197.77
13.7±2.2 19.1±2.84 20.16±7.85 30.8±7.2 ND b
a Concentration required for 50% inhibition of the enzyme activity under the assay conditions. b Not determined.
c Four experiments were performed for all compounds in each experiment triplicated. d Positive control.
9

Consequently, compounds 13, 14 and 15 appear to have increasing inhibition activity rates
compared to acarbose as exhibited by the β-glucosidase inhibition (%)-concentration plot in
(Figure 5).
Figure 5. β-Glucosidase inhibition % for (10-180 µM) test compounds and acarbose (12) control. Control of β-
glucosidase inhibition % compared to acarbose (12) concentration of 13, 14 and 15 compounds. Mean values ±
S.D. are shown for triplicate experiments.
On the other hand, the inhibitory effects of the target molecules 13, 14 and 15 were evaluated
for α-glucosidase using acarbose as a positive control. All compounds showed α-glucosidase
inhibitory activity more or less, but did not exhibit IC50 values. The results and test assay are
summarized in Table 4.
Table 4. Inhibition of α-glucosidase by racemic compounds 13, 14 and 15.
α-Glucosidase inhibition (%) a
Compo-
unds
IC50
10 µM
20 µM
25 µM
45 µM
80 µM
1120 µM 1180 µM
(µM)c
Acarbosed
22±0.82
30±3.1
33±1.5
46±3.2 60±0.71
63±0.5
74±1.3
52.47
13
14
15
15.8±0.6 18.75±1.1 19.36±1
19.86±1
19±5.1
21±2.6
21.4±0.48 37.6±2.4 42.2±1.1 NDb
2±1
6±1.9
14±2.3
19±1.7
20±6.1
31±3.6
22±1.8
40±2.6
25±1.3
42±2.4
ND b
ND b
10±2.1
13±1.6
a Concentration required for 50% inhibition of the enzyme activity under the assay conditions. b Not determined.
c Four experiments were performed for all compounds in each experiment triplicated. d Positive control.
10

Acarbose exhibited better α-glucosidase inhibition activity compared to test compounds 13,
14 and 15. While in the α-glucosidase inhibition (%)-concentrations (µM) plot an increase
was seen for compounds 14 and 15 proportionally with acarbose, compound 13 showed a
weak inhibition in the concentration range 10-80 µM, but showed an increase in inhibition
after 120 µM concentration (Figure 7).
Figure 6. α-Glucosidase inhibition % for (10-180 µM) test compounds and acarbose (12) control. Control of α-
glucosidase inhibition % compared to acarbose (12) concentration of 13, 14 and 15 compounds. Mean values ±
SD are shown for triplicate experiments.
As a result, the inhibitory effect of target molecules 13, 14 and 15 against both α-glucosidase
and β-glucosidase was evaluated as described in the experimental section. Acarbose was used
as a positive control for this evaluation. The results are presented in Tables 3 and 4. The
concentration range was 10-180 µM. Inhibition behaviors of the compounds to the aforesaid
enzymes are presented in Figures 5 and 7. Moreover, the inhibition power of the compounds
for both enzymes was compared and the results are shown in Figure 9. Synthesized molecules
exhibited both α- and β-glucosidase inhibition but an IC50 value could not be obtained for all
compounds. The only IC50 value calculated was 197.77 µM for compound 14 against β-
glucosidase.
11

Figure 7. α-Glucosidase and β-glucosidase % inhibition of compound 14 fractions by different concentrations.
The compound was tested with concentrations ranging from 10 µM to 180 µM. Results are the means ± S.D. of
three replicates of each group.
We have described the stereoselective synthesis of some rac-carbasugar-based quercitols
from commercially available anhydride, as result of a series of stereospecific reactions and
evaluation of their inhibitory effects toward α- and β-glucosidases. Initially, cis-furan 3, a key
compound obtained from 1, was subjected to TPP-catalyzed photooxygenation in the presence
of oxygen atmosphere and afforded two hydroperoxides. Following the reduction of
hydroperoxides, cis-dihydroxylation of alkene units, ring-opening of the furan reaction and
finally hydrolysis of the pentaacetates afforded the desired pentols 13, 14 and 15,
respectively. These polyhydroxy compounds were investigated for glucosidase inhibitory
activities. All of them exhibited moderate inhibitions against α- and β-glucosidases in
comparison to acarbose. Finally, these quercitol moieties are considered carbasugar-mimetics
due to hydroxymethylene substituents and they may serve as novel drug candidates.
12

Acknowledgments
The authors are grateful to the Scientific and Technological Research Council of Turkey
(TUBITAK, Grand No. TBAG-113Z699 and KBAG-115Z644) and the Unit of Scientific
Research Projects of Sakarya University (SAU-BAP, Grand No. 2014-02-03-003) for
financial support of this work and Scientific and Technological Research Application and
Research Center, Sinop University, Turkey, for the use of the Bruker D8 QUEST
diffractometer. This work conducted at Organic Chemistry Research Laboratory at Sakarya
University.
Supplementary Material
Crystallographic data for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre, CCDC No. 1566930 for 7, 1566924 for 11 and 1566929 for 12.
Copies of this information may be obtained free of charge from the Director, CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
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Highlights
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Short, selective and efficient synthesis for some carbasugar derivatives was performed.
It is very important to synthesize these compounds by known methods using cheap starting materials.
Our knowledge it is the first report where dihydroisobenzofuran system generate “ene reaction”.
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