The synthesis of monocyclic and bicyclic molecules and their antioxidant properties

Article abstract of DOI:10.1016/j.molstruc.2019.04.034

The synthesis and antioxidant activity of novel cyclitol, lactone and epoxide derivatives starting from appropriate 1.4-cyclohexadiene are reported in this study. All structures of these products were characterized by ¹H NMR, ¹³C NMR, MS and IR spectroscopy. The antioxidant capacities of some synthesized compounds were studied by using the methods of the scavenging effect on DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals. It is seen that the antioxidant properties of two of the five synthesized molecules were close to α-tocopherol.

Full text of DOI:10.1016/j.molstruc.2019.04.034

Accepted Manuscript
The synthesis of monocyclic and bicyclic molecules and their antioxidant properties
Esen Yıldız Bekfelavi, Nermin Şimşek Kuş
PII:
S0022-2860(19)30429-6
DOI:
https://doi.org/10.1016/j.molstruc.2019.04.034
MOLSTR 26406
Reference:
To appear in: Journal of Molecular Structure
Received Date: 26 December 2018
Revised Date: 7 March 2019
Accepted Date: 6 April 2019
Please cite this article as: Esen.Yıı. Bekfelavi, Nermin.Şş. Kuş, The synthesis of monocyclic and
bicyclic molecules and their antioxidant properties, Journal of Molecular Structure (2019), doi: https://
doi.org/10.1016/j.molstruc.2019.04.034.
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ACCEPTED MANUSCRIPT
1
The synthesis of monocyclic and bicyclic molecules and their antioxidant properties
Esen Yıldız Bekfelavi, Nermin Şimşek Kuş*
Mersin University Department of Chemistry, 33343 Mersin, Turkey
Mobile phone: +905325485084 phone: +9032436100017, fax: +903243610046, simner@mersin.edu.tr
ABSTRACT
The synthesis and antioxidant activity of novel cyclitol, lactone and epoxide derivatives starting from
appropriate 1.4-cyclohexadiene are reported in this study. All structures of these products were
characterized by 1H-NMR, 13C-NMR, MS and IR spectroscopy. The antioxidant capacities of some
synthesized compounds were studied by using the methods of the scavenging effect on DPPH (2,2-
diphenyl-1-picrylhydrazyl) radicals. It is seen that the antioxidant properties of two of the five synthesized
molecules were close to α-tocopherol.
Graphical abstract
Keywords
Cyclitols, bicyclic molecules, lactones, epoxide, antioxidant properties, DPPH.
Highlights
1. Hydroxyl and epoxide group containing molecules were synthesized and characterized
2. The antimicrobial activity of the synthesized compounds was evaluated.
3. A new mechanism was proposed in the synthesis of triol.

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1. Introduction
Fig. 1. A few examples showing biological activity
Cyclitols are sugar alcohol with one hydroxyl group on each of three or more ring atoms, which attract
attention since they have many biological properties such as anticancer, antibacterial, antifungal, HIV
inhibitory, enzyme inhibitory activities, etc [1-6]. Therefore, the synthesis of cyclitol derivatives also gain
interest [7-14]. Some of the methyl ether inositol derivatives are plant secondary metabolites, molecules
that are not directly involved in normal growth but play an important role in defense against adverse
environmental conditions [15-18]. Mondal and coworkers synthesize (±)-cyclophellitol, (±)-valienamine,
(±)-gabosine I, (±)-gabosine G, (±)-gabosine K, (±)-streptol, (±)-1-epi-streptol, (±)-uvamalol A, lincitol A,
lincitol B, uvacalol I, uvacalol J, and uvacalol K starting from myo-inositol [19, 20]. Another example,
Pennicillide derivative 1, which is a lactone ring and methyl ether, has been shown to be an antagonist of
the peptide hormone oxytocin as an inhibitor of the cholesterol ester transfer protein [20-24]. Lactones
which are one of the biologically important molecules can also be used as antitumor agents [20].
Pancratistatin (2) is a cyclitols derivative, a phenanthridone-type natural product, which is isolated from
several plants of the Amaryllidaceae family and has antiproliferative, antivascular, antiviral and
antiparasitic properties [25]. Epoxy-cyclitols are also molecules with biological properties. Conduritol
epoxides, and more specifically, the fungal metabolite cyclophellitol (3), are potent glycosidase inhibitors
and are under investigation as inhibitors of HIV infection and cancer metastasis [26-28]. Numerous studies
on the importance and synthesis of cyclitols are available in literature [1-31]. Due to the biological
importance of cyclitols, studies on their synthesis are still popular. So in this paper, we describe a new
synthetic methodology leading to the synthesis of various cyclitol derivatives having lactone, metoxy,
epoxy groups and their antioxidant properties, which have been measured by the DPPH method.
2. Experimental section
2.1. General
1
Infrared spectra were recorded on the Perkin Elmer Win First® Satellite. The H and 13C NMR
spectra were recorded on the Bruker Ultrashield Plus Biospin GmbH 400 MHz spectrometer. Column
chromatography was performed on silica gel (60-mesh, Merck), TLC was carried out on Merck 0.2 mm
silica gel 60 F254 analytical aluminum plates. All the chemicals and reagents were of analytical grade and
obtained from either Sigma or Merck.
2.2. trans-5,6-Dibromohexahydrobenzofuran-2(3H)-one (9) with H2O2 (Method 1)[32]
A solution of H2O2 (177 mg, 30%) in acetic acid (0.88 mL) was added to a solution of trans-3,4-
dibromobicyclo[4.2.0]octan-7-one (7) (500 mg, 1.77 mmol) in CH2Cl2 (5 mL) and the resulting mixture was

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stirred for 20 h at room temperature. After the completion of the reaction, the mixture was washed with
water and saturated NaHCO3. The organic phase was dried over MgSO4. The residue was
chromatographed on a silica gel (5 g) column eluting with ethyl acetate/hexane (1:1). At the end of the
reaction only one product was obtained, identified as trans-5,6-dibromohexahydrobenzofuran-2(3H)-one
(9) (449 mg, 85%) [18].
2.3. cis-5,6-Dibromohexahydrobenzofuran-2(3H)-one(10)
The experiment was performed according to method 1. As a result of the experiment cis-5,6-
dibromohexahydrobenzofuran-2(3H)-one (10) was obtained with the yield of 80% (423 mg, colorless
liquid).
2.4. Reaction of cis- and trans-dibromo-lactones (9 and 10) with NaOMe
463 mg Na metal (20.1 mmol) was dissolved in 30 mL methanol. 5.98 g of dibromide 9 and 10 were
dissolved in 10 mL of methanol and added to the NaOMe solution, which was stirred for 24 hours. After
the reaction was completed, it was purified by column chromatography via silica gel (1:4 ethyl
acetate/hexane). rac-Methyl 6-hydroxy-4-methoxycyclohex-2-en-1-yl)acetate (11) with an yield of 35%
(1.42 g), rac-methyl 4,5-dibromo-2-hydroxycyclohexyl)acetate (12) with an yield of 30% (1.98 g) and rac-6-
methoxy-3,3a,7,7a-tetrahydrobenzofuran-2(6H)-one (13) with an yield of 20% (674 mg) were obtained.
2.5. Typical procedure for the formation of rac-methyl 2-(6-hydroxy-4-methoxycyclohex-2-en-1-
yl)acetate(11) with OsO4/NMO oxidation (Method 2)[32]
rac-Methyl2-(6-hydroxy-4-methoxycyclohex-2-en-1-yl)acetate (11) (500 mg, 2.5 mmol) was dissolved
in a mixture of H2O–acetone (10 mL, 1:1) solution and NMO (500 mg, 5.18 mmol) and then, OsO4 (5
mg,0.02 mmol) in acetone (5 mL) was added to the stirring solution of molecule 11. The mixture was
stirred at room temperature for 24 h. The reaction was monitored by TLC. The solution was evaporated,
and then the crude residue was directly purified by column chromatography on silica gel using EtOAc-
hexane as eluent to give rac-methyl 2-(2,3,4,6-tetrahydroxycyclohexyl)acetate (16) (385 mg, 70%).
4.6 rac-4,5,6-Trihydroxyhexahydrobenzofuran-2(3H)-one (17)
The experiment was performed according to method 2. As a result of the rac-4,5,6-
trihydroxyhexahydrobenzofuran-2(3H)-one (17) was obtained with the yield of 80% (448 mg, colorless
liquid).
4.7 rac-2-(2-hydroxyethyl)cyclohex-3-enol(18) [32]
To a magnetically stirred slurry of 2 eq. LiAlH4 (127 mg, 3.35 mmol) in 100 mL of ether was added a
solution of methoxy lactone 13 (500 mg, 2.97 mmol) in ether (50 mL) dropwise at 0 °C for over 2 h. The
mixture was stirred at room temperature for 5 h. Then the reaction mixture was cooled to 0 °C and cold
water was added and it was filtered through silica gel (20 g). The organic layer was dried over MgSO4 and
the solvent was removed. The residue was chromatographed on a silica gel (30 g) column eluting with
diethyl ether/hexane (3:1). rac-2-(2-hydroxyethyl)cyclohex-3-enol (18) was obtained at the end of the
reaction (296 mg, 70%, colorless liquid)
4.8 rac-Tetrahydrobenzofuran-2(3H)-one (19)
The experiment was performed according to method 1. As a result of the experiment
tetrahydrobenzofuran-2(3H)-one (19) was obtained with the yield of 60% (339 mg, colorless liquid).

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4.9 rac-Hexahydrooxireno[2,3-f]benzofuran-4(1aH)-one (20) [33]
Tetrahydrobenzofuran-2(3H)-one (19) (500 mg, 3.62 mmol) was dissolved in 150 mL of chloroform, 1
eq. (624.7 mg, 3.62 mmol) 70% m-CPBA was added, and then the reaction was stirred at room
temperature for 24 h. The reaction mixture was added to 15 mL of 50% NaHSO3 solution and the mixture
was stirred for 15 min. The organic layer was separated and then washed with saturated aqueous
NaHCO3 (100 mL), dried with MgSO4 and concentrated to give rac-hexahydrooxireno[2,3-f]benzofuran-
4(1aH)-one (20) (385 mg, 69%).
4.10 rac-5,6-Dihydroxyhexahydrobenzofuran-2(3H)-one(21)
The experiment was performed according to method 2. As
a result of the rac-5,6-
dihydroxyhexahydrobenzofuran-2(3H)-one (21) was obtained with the yield of 75% (467.4 mg, colorless
liquid).
4.11 Bicyclo[4.2.0]oct-3-en-7-ol (22)
2 g (16.4 mmol) of starting material 6 is dissolved in 100 mL methanol solution and NaBH4 (620 mg,
10.8 mmol) is slowly added (2 min) by stirring. The mixture is allowed to react for 24 h. The residue was
chromatographed on a silica gel (30 g) column eluting with diethyl ether/hexane (1:1). Bicyclo[4.2.0]oct-3-
en-7-ol (22) was obtained with the yield of 60% (1.22 g, colorless liquid) at the end of the experiment.
4.12 Bicyclo[4.2.0]octane-3,4,7-triol (23)
The experiment was performed according to method 2. As a result of the bicyclo[4.2.0]octane-3,4,7-
triol (23) was obtained with the yield of 75% (448 mg, colorless liquid).
4.13 Antioxidant activities, Scavenging effect on DPPH radicals [34]
1 mL of the methanol extract in arrange of concentrations (0.03–0.5 mg/mL) was added to 1mL of
DPPH radical solution in methanol (the final concentration of DPPH was 0.2 mM). The mixture was
shaken vigorously and kept to stand for 30 min in the dark, and the absorbance was measured at 517 nm
against a blank using the Elisa Reader. Ascorbic acid, Gallic acid, BHT and α-tocopherol were used as
standard controls. The inhibition of DPPH free radicals was calculated in percentages via the following
equation.
I% = (Ablank-Asample) / Ablank x 100
Where Ablank is the absorbance of the control reaction, and Asample is the absorbance of the test
compound. The extract concentration providing 50 % inhibition (IC50) was calculated from a graph plotting
inhibition percentage against extract concentration. Tests were performed in triplicate.
4. Result and discussion
Bicyclic ketone 6, the key compound of the synthesis, can be easily synthesized via ketene addition
to 1,4-cylohexadiene (4) described by Kishalı [10]. Later, trans- and cis-dibromide (7, 8) were obtained at
0 °C as a result of the bromination of bicyclic ket one 6 which were separated by column chromatography
(Fig. 2) [35]. trans-Isomer 7 (Rf=0.95) has a larger Rf value than cis-isomer 8 (Rf=0.83) [hexane/ ethyl

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acetate mixture (9:1)]. trans-Dibromide 7 was formed as the major product with 60% yield. The absorption
bands at 1774 cm-1 (8) and 1779 (7) in the FT-IR spectra confirmed the cyclobutanone ring in the
structure. In molecule 7, H4 and cyclobutanone rings are in a different space. Because there is no w-
interaction as a Cosy spectrum; but H3 and cyclobutanone rings are in the same space since there is a w-
interaction as a Cosy spectrum. In molecule 8, H3 did not give a w-interaction with H1 and H4 did not give a
w-interaction with the H6 proton. This shows that the bromines are in cis-position relative to each other
and in the trans-position relative to the cyclobutanone ring. In the next step, the oxidation of trans- and cis-
dibromide 7 and 8 with H2O2 were made and trans-dibromolactone 9 with 85% yield and cis-dibromo
lactone 11 were obtained with 80% yield (Fig. 2). There is the signal of carbonyl carbonof trans-dibromo
lactone 9 in 175.4 ppm and the signal of carbonyl carbon of cis-dibromo lactone 10 175.0 ppm in the 13C
NMR spectrum of lactone.
Fig 2. Reagents and conditions: (i) Cl3CCOCl, Zn, POCl3, ether, 25 οC, 87%; (ii) Zn, CH3COOH, 92%; (iii)
Br2, CHCl3, 0 οC, 60% trans, 30% cis; (iv) H2O2, CH2Cl2, 85%, (v) H2O2, CH2Cl2, r.t., 80% [17].
The reaction of trans- and cis-dibromo lactone 9 and 10 with excess of NaOMe gave three products
(11-13) (Fig. 3). All NMR data of the synthesized molecules (11-13) were in agreement with the proposed
structure. The w-interaction between H4 and H6 is clearly seen in the Cosy spectrum molecule 11. This
proves that the position of the groups relative to each other is cis. The H5 and the H1 are in trans-position
relative to each other, since there is no w-interaction between H1 and H5 in molecule 12 according to the
Cosy spectrum. They are in the cis-position of each other in H4 and H2 because there is w-interaction
between H2 and H4 in molecule 12 according to the Cosy spectrum. In molecule 13, the H6 and H8 are are
in cis-position relative to each other, because of w-interaction between H6 and H8.
Fig 3. The reaction of trans- and cis-dibromo lactone 9 and 10 with NaOMe [18].
After the successful purification and characterization of the cyclitol derivatives 11-13, molecule 11
reacted with a catalytic amount of OsO4 in the presence of 2 eq. NMO as co-oxidant (Fig. 4) and

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unexpected product tetrol 16 was obtained. We assume that molecule 16 was obtained via well-known SNi
reaction. First, the OsO4 addition reaction occurred, and then the five-atom ring was opened via SNi
reaction. Molecule 16 was consistent over intermediate 15. As a result, the direction of the hydroxyl
groups is also in the transposition relative to the other groups. As protons H4’ and H6’ overlap, we cannot
comment on these protons for compound 16. But, the absence of w-interaction between H1’ and H3’
indicates that these protons are trans. The absence of w-interaction between H2’ and H4’ again indicates
that these protons are trans. As a result, we can say that H3’ and H1’ (again H4’ and H2’) are in trans
position.
Fig. 4. The synthesis of tetrol16 and the reaction of molecule11 with OsO4/NMO
The cis-hydroxylation reaction of the methoxy lactone 13 was carried out. As in molecule 11, SNi
reaction was observed in this reaction and triol-lactone 17 was obtained (Fig. 5). As a result, the direction
of the hydroxyl groups (C4-OH and C5-OH) is also in the trans position relative to the other group (C6-OH
and lactone ring). Furthermore, H5 does not interact with H9, based on the Cosy spectrum of molecule 17.
In addition, H4 does not interact with H8.
HO
HO
H3CO
O
O
OsO4
NMO
80%
O
O
17
OH
13
.
Fig. 5. The synthesis of triol-lactone 17
The reaction of the methoxylactone 13 with LiAlH4 resulted in a surprising product (Fig. 6). As a result
of the reaction, the lactone reaction was followed by a substitution reaction with hydride. In the end, diol
18 was obtained from methoxylactone 13.
Fig. 6. The synthesis of diol 18

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On the other hand, bicyclic ketone 6 was converted to bicyliclactone 19 in 60% yield with H2O2 (Fig.
7). Bicyclic lactone 19 reacted with m-CPBA, epoxy lactone 20 was obtained with 69% yield (Fig. 7). If the
epoxide and lactone rings are in the trans position, the hydrogen of the epoxide ring gives the triplet
signal. When we look at the 1H NMR spectrum, we see that one of the hydrogens of the epoxide ring gives
triplet and the other gives a close signal to triplet. In addition, the absence of the w-interaction between the
H5-H9 and H6-H8 in the Cosy spectrum also confirms the structure. The same is applied to molecule 21.
Fig. 7. The synthesis of molecules20 and 21
Finally, the reaction of bicyclic ketone 6 with NaBH4 and bicyclic alcohol 22 was obtained with 60%
yield (Fig. 8). The reaction of bicyclic ketone with OsO4/NMO gave bicyclic triol 23 with 75% yield (Fig. 8).
In triol 23, hydroxyl groups are in different space with cyclobutanone, because there is no w-interaction
between H3 and H1, and at the same time H4-H6. This is also applied to H4 and H6. The absence of the w-
interaction between H5a and H5b with H7 proves to be in the same space as the hydroxyl groups.
Fig. 8. The synthesis of bicyclic triol 23
Table 1. Spectral data of synthesized molecules
FTIR
2961, 2919
(-C-H),
1HNMR
13C NMR
GCMS
ELEMENTEL
C8H10Br2O2,
C, 32.25, H,
3.38%, found:
C, 32.23, H,
3.40%
4.68 (m, H8, 1H), 4.64 (m, 175.4,
75.4, 297.8, (M+, -Br),
H6, 1H), 4.5 (m, H5, 1H), 50.1, 44.3, 36.7, 217, (M+, -Br),
1761 (-C=O)
2.87 (m, H9, H7a, H4a and 30.9, 29.9, 29.1
H7b, 4H), 2.46 (m, H3a,
1H), 2.36 (d, H4b, 1H, J=
137, (M+, -COO)
17.01 Hz), 2.09 (dt, H3b,
1H, J= 15.25, 4.43 Hz)
2923 (-CH)
1764 (-C=O)
4.62 (m, H8, 1H), 4.31 (m, 175.0,
77.8, 302.9, (M+, -OH),
C8H14Br2O2,
C, 31.82, H,
4.67%, found:
C, 31.84, H,
4.65%
H6, 1H), 4.17 (m, H5, 1H), 51.5, 49.9, 37.2, 284, 283, 282 (M+, -
2.98 (dt, H7a, 1H, J=15.3 36.6, 36.4, 35.3
and 34.1), 2.67 (m, H3a,
H4a, H9, 3H), 2.52 (d, H3b,
1H, J= 14.74 Hz), 2.32 (m,
H7b, 1H), 2.01 (m, H4b, 1H)
CH2CH2),
258, 257, 256, 255,
254, (M+, -Br)
176, 175, 174, 173,
(M+, -OH)

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160, 159, 158, 157,
(M+, -Br)
80, 79, 78, 77
3435 (-OH)
2955, 2926 (-
C-H),
5.88 (m, H2’, 1H), 5.79 (m, 173.7,
H3’, 1H), 3.92 (m, H6’, 1H), 123.6,
129.9, 200.9, (M+, -CO2CH3),
78.1, 146 (M+, -CH3),
C10H16O4, C,
59.98,
H,
3.70 (s, -OCH3), 3.64 (m, 70.2, 56.6, 51.6, 132.8 (M+, -O, -OH)
H4’, 1H), 3.46 (s, -OCH3), 34.8, 32.3, 27.9
2.63 (dd, H2a, 1H, J= 15.3,
8.05%, found:
C, 59.87, H,
8.09%
1730 (-C=O)
5.1 Hz), 2.47 (m, H1’, 1H),
2.34 (dd, H2b, 1H, J= 15.3
2 Hz), 2.21 (bd, H5a’, 1H),
2.04 (bd, H5b’, 1H)
4.33 (m, H4’, 1H), 4.02 (m, 172.8,
3458 (-OH)
2921 (-C-H),
1719 (-C=O)
68.6, 330 (M+, -OCH3),
C9H14Br2O3,
C, 32.76, H,
4.28%, found:
C, 32.72, H,
4.25%
H3’, 1H), 3.91 (m, H6’, 1H), 55.8, 52.7, 51.9, 300
3.62 (s, -OCH3), 2.55 (dt, 44.8, 38.9, 37.7, (M+, -C=O, -Br),
H5’a, 1H, J= 14.2, 4.3 Hz), 36.3
2.39 (dd, H2’a, 1H, J= 15.7,
7.7 Hz), 2.25 (dd, H2’b, 1H,
J= 15.7, 6.0 Hz), 2.16 (m,
H1’ and H2a, 2H), 2.02 (m,
H5’b and H2b)
196 (M+, -Br)
2929 (-CH),
1774 (-C=O)
5.93 (m, H5, 1H), 5.84 (dt, 176.2,
H4, 1H, J= 10.1, 2.5 Hz), 126.8,
128.2, 168 (M+, -CH3),
82.7, 153 (M+, -O),
C9H12O3,
C, 64.27, H,
7.19%, found:
C, 64.19, H,
7.21%
4.58 (dd, H8, 1H, J= 6.7, 75.9, 57.2, 35.5, 153 (M+, -CO2),
3.59 Hz), 3.83 (m, H6, 1H), 31.4, 26.6
3.47 (s, -OCH3, 3H), 2.72
(dd, H3a, 1H, J= 16.8, 8.6
Hz), 2.64 (m, H9, 1H), 2.36
(m, H3b, 1H), 2.25 (dd, H7a,
1H, J= 12.6, 4.1 Hz), 1.87
(m, H7b, 1H)
109
3344 (-OH),
2923, 2852 (-
CH), 1765 (-
C=O)
4.63 (t, H2, 1H, J= 5.79 175.6,
80.5, 220.2 (M+, -OH), 205.2 C9H16O6:
C,
H,
Hz), 3.94 (t, H4, 1H, J= 80.2, 68.7, 68.1, (M+, -OCH3, -3OH), 49.09,
2.91 Hz), 3.9 (m, H6, 1H), 59.1, 35.1, 30.5, 126.1 (M+, -CO), 112.1 7.32%. Found:
3.55 (s, -OCH3, 3H), 3.53 30.2, 29.9
(m, H3, 1H), 2.84 (m, H1,
C, 49.07, H,
7.30%
1H), 2.6 (dd, H2a’, 1H, J=
17.19, 7.7 Hz), 2.3 (dd,
H2b’, 1H, J= 17.19, 6.62
Hz), 2.08 (m, H5a, 1H),
1.65 (ddd, H5b, 1H, J=
14.36, 7.61, 3.85 Hz)
3393 (-OH),
2925 (-CH),
1723 (-C=O)
4.08 (m, H9, 1H), 3.87 (m, 173.4,
79.6, 185.1 (M+, -CO), 157.1 C8H12O5:
C,
H,
H5 and H6, 2H), 3.66 (t, H4, 71.2, 69.6, 68.1, (M+, -CH2, -O), 111.1 51.06,
1H, J= 3.18 Hz), 2.55 (dd, 36.5, 32.9, 28.8
H1a, 1H, J= 15.6, 7.2 Hz),
2.36 (dd, H1b, 1H, J= 15.6,
6.8 Hz), 2.26 (m, H8, 1H),
1.61 (m, H7ab, 2H)
(M+, -OH), 95.1, (M+, - 6.43%. Found:
OH), 79.1
C, 51.07, H,
6.45%
2929, 2847 (-
CH), 1715 (-
C=O)
5.86 (m, H5, 1H), 5.76 (m, 179.8,
H6, 1H), 4.83 (td, H3a’, 1H, 125.1,
127.2, 138.1 (M+, -C=O), C8H10O2:
C,
H,
79.8, 110.1 (M+, -OH), 96.1,
69.54,
J= 9.34, 3.3 Hz), 2.8 (dd, 37.9, 33.4, 28.3,
H1a, 1H, J= 17.1, 7.9 Hz), 27.2
2.71 (m, H7a’, 1H), 2.51 (m,
7.30%. Found:
C, 69.59, H,
7.34%
H7a, 1H), 2.41 (m, H4a’
1H), 2.3 (dd, H1b, J= 17.0,
3.81 Hz), 1.92 (m, H4b’
,
,
1H), 1.33 (d, H7b, J= 14.9
Hz)
2929, 2847 (-
CH), 1715 (-
C=O)
5.86 (m, H5, 1H), 5.76 (m, 179.8,
H6, 1H), 4.83 (td, H3a’, 1H, 125.1,
127.2, 138.1 (M+, -O), 124.1, C8H10O2:
79.8, (M+, -C), 112, (M+, -O), 69.54,
C,
H,
C
J= 9.3, 3.3 Hz), 2.8 (dd, 37.9, 33.4, 28.3, 96.0
H1a, 1H, J= 17.1, 7.9 Hz), 27.2
2.71 (m, H7a’, 1H), 2.41 (m,
H4a, 1H), 2.3 (dd, H1b, 1H,
J= 17.0, 3.8 Hz), 1.92 (m,
H4b, 1H), 2.51 (m, H7a,
1H), 1.33 (d, H7b, 1H, J=
14.9 Hz)
7.30%.,
69.55,
7.37%
H,

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3005, 2942 (-
CH),1763 (-
C=O),
4.57 (t, H8, 1H), 3.27 (t, H6, 176.0,
75.7, 154.0 (M+, -C=O), C8H10O3:
C,
H,
1H, J= 3.6 Hz), 3.21 (m, 51.0, 49.3, 36.5, 126.0 (M+, -O), 114 62.33,
H5, 1H), 2.72 (m, H9, 1H), 30.0, 26.2, 25.7
2.68 (m, H3a, 1H), 2.6
(ddd, H7a, 1H, J= 16.7, 7.8,
(M+, -CH2) 84,
6.54%. Found:
C, 62.35, H,
6.57%
1.8 Hz), 2.3 (m, H3b, H4a
and H7b, 3H), 1.79 (dd,
H4b, 1H, J= 15.1, 9.9 Hz)
3376, 3257 (-
OH), 2963,
4.73 (m, H5, 1H), 3.92 (m, 179.7,
69.1, 172.0 (M+, -OH), 154.0 C8H12O4:
C,
H,
H6, 1H), 3.72 (m, H8, 1H), 67.8, 81.9, 31.6, (M+, -C=O), 112 (M+, - 55.81,
2899 (-CH),
1766 (-C=O),
3.34 (m, H9, 1H), 2.81 (dd, 48.8, 33.2, 30.7
H3a, 1H, J= 16.4, 1.9 Hz),
2.66 (m, H7a, 1H), 2.23
(dd, H3b, 1H, J= 16.9, 1.2
Hz), 2.1 (m, H7b, 1H), 2 (dt,
H4a, 1H, J= 14.5, 5.4 Hz),
1.38 (m, H4b, 1H)
6.01 (m, H3, 1H), 5.74 (m, 127.7,
H4, 1H), 4.22 (m, H7, 1H), 65.8, 37.4, 23.5,
2.67 (m, H6, 1H), 2.43 (m, 37.2, 26.4, 18.5
CH2) 95
7.02%. Found:
C, 55.79, H,
7.04%
3322 (-OH),
2966, 2926,
2830 (-CH),
126.6, 122 (M+, -OH), 108
C8H12O:
77.38,
C,
H,
9.74%. Found:
C, 77.37, H,
9.72%
H8a, 2H), 2.26 (m, H5ab
,
2H), 2.03 (m, H2ab, 2H),
1.85 (m, H1, 1H), 1.62 (m,
H8b, 2H
3337 (-OH),
2907, 2868,
2804 (-CH),
4.15 (m, H7, 1H), 3.9 (m, 70.3, 70.2, 65.3, 158.1 (M+, 3-OH), C8H14O3:
C,
H,
H4, 1H), 3.73 (ddd, H3, 1H, 36.3, 34.7, 29.0, 110.1
J= 11.4, 5.2, 2.0 Hz), 2.52 27.0, 25.7, 20.8
(m, H6, 1H), 2.17 (m, H8a,
1H), 2.09 (m, H1, 1H), 2.02
(s, H5a, 1H), 1.96 (m, H5b,
1H), 1.88 (m, H8a, 1H),
1.77 (m, H2a, 1H), 1.54
60.74,
8.92%. Found:
C, 60.70, H,
8.89%
(dd, H2b, 1H, J= 13.3, 5.2
Hz)
Antioxidant potential
The DPPH radical scavenging effects of five synthesized molecules (16, 17, 18, 20, and 23), along
with those of ascorbic acid, gallic acid, BHT, α−tocopherol controls, rose with the increased concentration
from 0.1 mL to 1 mL (Table 2) [35].If we look at the% SCV of 16 and 23, we will see that the antioxidant
property of molecules 16 and 23 at 45 minutes is close to α-tocopherol. There are studies in literature that
some cyclitol derivatives have antioxidant properties. Our study supports these studies [36,37].

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Table 2. % SCV graphic against concentration of molecules 16 and 20
30. mn
100
45. mn
90
ascorbic acid 30.mn
80
ascorbic acid 45.mn
70
60
50
40
30
20
10
0
64.83
62.85
62.76
tocoferol 30.mn
tocoferol 45.mn
gallic acid 30.mn
gallic acid 45.mn
BHT 30.mn
59.94
55.58
56.51
51.02
60.93
58.34
53.87
44.30
39.24
53.46
48.58
38.69
34.22
41.92
37.41
36.69
31.22
BHT 45.mn
0
0.5
Concentration
1
30. mn
100
45. mn
90
80
70
60
50
40
30
20
10
0
ascorbic acid 30.mn
ascorbic acid 45.mn
tocoferol 30.mn
tocoferol 45.mn
gallic acid 30.mn
gallic acid 45.mn
BHT 30.mn
60.03
56.55
58.43
51.68
49.74
43.57
55,73
52,95
52,02
39.28
39.62
35.94
32.43
47,97
45,53
39,76
36,26
36,20
32,28
30,20
BHT 45.mn
0
0.5
1
1.5
2
Concentration
The scavenging values are 0.59 mg/mL for tetrol 16, 5.46 mg/mL for triol 17, 4.94 mg/ml for diol 18, 1.4
mg/mL for epoxide 20, 1.57 mg/mL for triol 23, 6.6 mg/mL for ascorbic acid, 3.2 for gallic acid, 8,8. 10-2
mg/mL for BHT and 4,4.10-3 mg/mL for α-tocoferol for 30 min. (Table 2). Antioxidant results of several of
the synthesized compounds with respect to ascorbic acid, gallic acid, BHT, and α-tocopherol were
reported in Table 3.

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Table 3. IC50 values of some synthesized molecules in the DPPH
IC50 (mg/mL)
30 min.
0.59
45 min.
0.53
5.46
4.9
4.94
1.4
4.14
1.36
1.57
1.3
Ascorbic Acid
6.6
10.62
5.2
Gallic Acid
3.2
BHT (Butylated hydroxytoluene)
α-tocopherol
8,8.10-2
4,4.10-3
0.9
0.4
5. Conclusion
In the study, we developed a route for the synthesis of cyclitol, lactone and epoxide derivatives
starting from appropriate 1,4-cyclohexadiene.The synthesis was carried out by a series of reactions such
as the addition of dichloroketene to one of the double bonds in 1,4-cyclohexadiene, the reduction of a
ketene addition product and the epoxidation and cis-hydroxylation of double bond. Consequently,
monocyclic, bicyclic diol, triol, tetrol, bicyclic lactones and bicyclic epoxide were obtained, which were
likely to show biological activity. In addition, the antioxidant properties of five molecules (16, 17, 18, 19,
and 22) were measured and compared with standards (Ascorbic acid, Gallic acid, BHT, α-tocopherol).In
conclusion, it was observed that the antioxidant properties of the two cyclitols (16 and 20) were close to α-
tocopherol.
Acknowledgement
This study was supported by the Research Fund of Mersin University in Turkey with Project Number:
2015-TP3-1236”. This academic work was linguistically supported by the Mersin Technology Transfer
Office Academic Writing Center of Mersin University.

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