Stereospecific synthesis of novel methyl-substituted mono- and di-methoxy conduritols

Article abstract of DOI:10.1016/j.tet.2016.11.042

Methyl-monomethoxy conduritol-B and methyl-dimethoxy conduritol-B were synthesized starting from 2-methylbenzo-1,4-quinone. Bromination of 2-methylbenzo-1,4-quinone was followed by the reduction of the carbonyl groups with NaBH₄to give a dioldibromo compound. Methyl-dimethoxy conduritol-B was synthesized from the reaction of the dioldibromo compound with CH₃ONa, followed by acetylation with Ac₂O-pyridine to obtain methyl-dimethoxy diacetate. On the other hand, acetylation of the methyl-dioldibromo compound followed by reaction with LiOH gave a monoepoxide compound stereoselectively. The reaction of the epoxide with H⁺/Ac₂O afforded the monobromo triacetate. Controlled reaction of monobromo-triacetate with CH₃ONa in MeOH furnished the desired new methyl-monomethoxy conduritol-B. The structures of all synthesized compounds were characterized by spectroscopic methods.

Full text of DOI:10.1016/j.tet.2016.11.042

Accepted Manuscript
Stereospecific synthesis of novel methyl-substituted mono- and di-methoxy
conduritols
Latif Kelebekli, Dilek Kaplan
PII:
S0040-4020(16)31197-8
10.1016/j.tet.2016.11.042
TET 28256
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 August 2016
Revised Date: 31 October 2016
Accepted Date: 14 November 2016
Please cite this article as: Kelebekli L, Kaplan D, Stereospecific synthesis of novel methyl-substituted
mono- and di-methoxy conduritols, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.042.
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ACCEPTED MANUSCRIPT
GRAPHICAL ABSTRACT
-----------------------------------------------------------------------------------------------------------------
Stereospecific synthesis of novel methyl-substituted mono- and di-methoxy conduritols
Latif Kelebekli*, Dilek Kaplan

ACCEPTED MANUSCRIPT
Stereospecific synthesis of novel methyl-substituted mono-
and di-methoxy conduritols
Latif Kelebekli*, Dilek Kaplan
Department of Chemistry, Ordu University, 52200 Ordu, Turkey
Abstract
Methyl-monomethoxy conduritol-B and methyl-dimethoxy conduritol-B were synthesized
starting from 2-methylbenzo-1,4-quinone. Bromination of 2-methylbenzo-1,4-quinone was
followed by the reduction of the carbonyl groups with NaBH4 to give a dioldibromo
compound. Methyl-dimethoxy conduritol-B was synthesized from the reaction of the
dioldibromo compound with CH3ONa, followed by acetylation with Ac2O-pyridine to obtain
methyl-dimethoxy diacetate. On the other hand, acetylation of the methyl-dioldibromo
compound followed by reaction with LiOH gave a monoepoxide compound stereoselectively.
The reaction of the epoxide with H+/Ac2O afforded the monobromo triacetate. Controlled
reaction of monobromo-triacetate with CH3ONa in MeOH furnished the desired new methyl-
monomethoxy conduritol-B. The structures of all synthesized compounds were characterized
by spectroscopic methods.
Keywords: Conduritol, Methyl-methoxy conduritol-B, Methyl-conduritol

ACCEPTED MANUSCRIPT
1. Introduction
Cyclitols, their derivatives and analogs have continued to attract the attention of chemists
and biologists due to their involvement in various biological processes.1 Conduritols and their
epoxide derivatives possess interesting biological properties, epoxyconduritols and
aminoconduritols act as inhibitors of glycosidases.2 Recently, dimethoxy conduritols have
been synthesized from some natural compounds.3-5 Among these compounds, (+)-1,4-
dimethoxy conduritol-B and –F were enantioselectively synthesized starting from D-sorbitol.4
In connection with the conduritols, vinylic-substituted conduritols (with -CH3, -Ph, and halo-
substituents) have also gained importance over the last decade.6-11
OH
OCH3
OH
OH
OH
OH
H3C
OH
OCH3
1,4-Dimethoxy conduritol
Methyl-substituted conduritol
OCH3
O
OH
OH
H3COOC
OH
OH
H3C
OH
OH
Gabosine
Pericosine
C7-cyclitols, such as gabosines12 with a methyl substituent (gabosine A, N, and H) and
pericosines13 with a methoxy group (pericosine B and C) which include a cyclohexenoid
moity, represent an important category of highly oxygenated natural products and may be
classified as pseudo- or carbasugars. Since these compounds show structural similarities to
carbohydrates, they exhibit interesting biological activities because of their antibiotic,
anticancer, and DNA binding properties.14 Among these base-sensitive ketocarbasugars,
gabosine features a trihydroxylated cyclohexanone or cyclohexenone core with a methyl or
2

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hydroxymethyl substituent.12a The preparation of cyclitols and their analogues are challenging
due to the dense stereochemistry of the hydroxylated carbon centers. Recently, we have
reported the stereospecific synthesis of some polyhydroxylated compounds.15 Consequently,
based on these results, we aimed to synthesize polyoxygenated cyclohexenes (cyclitols or
carbasugars). Herein, we report the synthesis of two new mono- and dimethoxy conduritol-B
analogues including methyl substituent.
2. Results and discussion
Methyl-substituted para-benzoquinone 1 was brominated at low temperature to give only the
trans-dibromo compound 2 in high yield. The allylic trans-diol 3 is a key intermediate for the
synthesis of target compounds which are methyl-monomethoxy conduritol and methyl-
dimethoxy conduritol. The required allylic trans-diol 3 was obtained as the sole product by
stereoselective reduction of the carbonyl groups with NaBH4 in ether.6 The stereochemical
course of the reduction was mainly determined as the trans configuration to bromide groups.
Scheme 1. Dimethoxy conduritol-B 4
3

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Treatment of dibromodiol 3 with a metallic sodium-methanol system (MeONa/MeOH)16
under N2(g) leads to a stereocontrolled transformation to conduritol-B derivative 4 in 76%
1
13
yield (Scheme 1). The structure of 4 was unambiguously deduced from its H and C NMR
spectra in CDCl3. Compound 4 showed the presence of two –OCH3 groups at 3.37 and 3.32
ppm in 1H NMR spectrum. Furthermore, the 13C NMR spectrum of 4 consisted of nine carbon
resonances. In the 13C NMR spectrum of 4, in particular, two olefinic and methoxy carbons (-
OCH3) were observed at 135.8, 124.1, 58.3 and 57.1 ppm, respectively. Thus, by arranging
from a conduritol-B derivative having full trans-structure to a different methyl-substituted
conduritol-B derivative including two methoxy function, all substituents are in a mutual
trans-arrangement (Scheme 1). The formation depends on nucleophilic ring opening from the
allylic position of the trans-diepoxide which occurred as an intermediate product.16 For
further structural proof, diol 4 was converted into the corresponding diacetate 5. After
purification, 5 was obtained in 89% yield as the only isomer detected by NMR spectroscopy.
The coupling constant between H-1 and H-2 in 5 are measured as J = 11.0 Hz because they
are in trans configuration. The 13C NMR spectrum of 5 consisted of thirteen carbon
resonances. The carboxyl carbons were particularly observed at 170.2 and 170.1 ppm (C=O).
These results also clearly show that compound 5 has a methyl-substituted conduritol-B
diacetate structure protected stereochemistry in 4.
OAc
OAc
OH
Br
Br
OAc
Br
H3C
H3C
Br
Br
H3C
Ac2O/pyridine
0 oC, N2(g), 86%
OAc
OAc
OH
7
6
3
AcOK, AcOH
Ac2O, reflux, 80%
OAc
H3C
Br
OAc
8
Scheme 2. Reaction of 6 under basic conditions
4

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After successful isolation and characterization of the methyl-dimethoxy conduritol-B 4, we
turned our attention to the synthesis of its monomethoxy derivative. For this purpose, the
acetylation of 3 with Ac2O/pyridine system gave compound 6 as a sole product in 86% yield.
We firstly aimed for the synthesis of compound 7 via a short way known in literature.6 When
compound 6 was treated with AcOK and Ac2O in AcOH in order to substitute the Br-atom by
an AcO group, contrary to our expectations, acetylation of 6 resulted in the formation of 2-
bromo-5-methyl-1,4-phenylene diacetate 817 having an aromatic structure in 80% yield
(Scheme 2). In the literature, only the melting point (mp) of aromatic compound 8 has been
reported until now.
1
The structure of 8 was assigned on the basis of H and 13C NMR spectra. Compound 8
showed the presence of two -OAc and a -CH3 as well as a signal belonging to two aromatic
1
protons in the H NMR spectrum. Furthermore, the 13C NMR spectrum of 8 consisted of
eleven carbon resonances. In the 13C NMR spectrum of compound 8, the carbonyl and
aromatic carbons were observed at 168.7 and 168.6 ppm (C=O) and 147.2, 145.8, 131.1,
126.5, 125.4 and 112.9 ppm (arom.) as well as the three methyl signals at 20.8, 20.7 and 16.1
ppm. respectively. These results also clearly show that compound 8 has an aromatic structure.
Epoxide 9 was regioselectively prepared from dibromide 6 by treatment with lithium
hydroxide (Scheme 3).6 The observed regio- and stereoselectivity for this reaction was
remarkable since the stereochemistry is transformed into a conduritol-A type-configuration.
The position of the epoxide-ring protons were determined by means of a COSY experiment.
1
In the H NMR spectrum of 9, irradiation of H-4 at 5.62 ppm (CH=C), the signal of H-6 at
3.36 ppm turned from a double doublet to a doublet (J = 4.0 Hz). The irradiation of H-6 at
3.36 ppm, the signal of H-4 at 5.62 ppm turned from a double doublet to a triplet (J = 1.6 Hz)
and the signal of H-1 at 3.74 also turned from a double doublet to a doublet to a singlet. These
results clearly indicate that H-6 with H-1 and H-4 with H-3 are the neighboring protons with
each other.
For the synthesis of our target compound, 7 is a key compound because of a conduritol-A
type-configuration in the structure that may be stereoselectively prepared from epoxide 9.
However, treatment with CH3COCl in methylene chloride at room temperature for the
acetylation of the -OH group in 9, it did not afford the expected acetoxy compound 10 as
1
deduced from the H NMR data. In order to overcome this potential challenge, we explored
alternative acetylation methods. Treatment of the epoxide in hand with Ac2O in a catalytic
amount of H2SO4 at 0 oC (then at room temperature) for 12 h afforded the bromotriacetate 7 in
5

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1
77% yield. The structure of 7 was elucidated on the basis of H and 13C NMR data. We
assume that the epoxide first undergoes a ring-opening followed by acetylation to give the
bromotriacetate 7. Since the ring-opening takes place at the allylic position under acidic
conditions, the configuration of the free hydroxyl group will be preserved. Additionally, to
test the potential of this approach, bromotriacetate 7 was obtained in two steps from epoxide 9
following a reported procedure in the literature.6
OH
OH
Br
H3C
OH
11
Ac2O/Pyr.,
rt, 78%
CBr4, H2O
35 oC, 51%
OAc
OAc
O
H3C
OAc
Br
Br
Br
H3C
H3C
6
3
1
2
LiOH
H+/Ac2O
0 oC to rt, 12 h, 77%
1
5
4
6
5
2
3
4
Et2O/MeOH (2:1),
0 oC, 70%
Br
OH
OAc
OAc
9
6
7
CH3ONa, N2(g)
5 oC, 14 h, 93%
OH
O
OH
OH
H3C
H3C
3
2
4
1
6
5
Br
OCH3
OAc
12
10
Scheme 3. Monomethoxy conduritol-B 12
After we obtained the dimethoxy conduritol-B 4 successfully, we tried to synthesize
monomethoxy conduritol-B 12 using the same procedure as described above. For this
purpose, treatment of bromotriacetate 7 with a metallic sodium-methanol system
(MeONa/MeOH) under N2(g) atmosphere led to a stereocontrolled transformation to a new
6

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conduritol-B derivative 12 in 93% yield (Scheme 3). Thus, methyl-monomethoxy conduritol-
B 12 was stereoselectively synthesized in high yield. The structure of 12 was unambiguously
1
13
deduced from its H and C NMR spectra in CDCl3. Compound 12 showed the presence of
1
only one -OCH3 at 3.46 ppm in particular in H NMR spectra. Furthermore, the 13C NMR
spectrum of 12 consisted of eight carbon resonances owing to asymmetry in the molecule. In
13
the C NMR spectrum of 12, in particular, two olefinic and one methoxy carbon (-OCH3)
signals were observed at 137.2, 121.2 and 56.8 ppm, respectively.
Scheme 4. Mechanism of formation of monomethoxy conduritol-B 12
We suggest the following mechanism for the stereospecific synthesis of 12 from 7 (Scheme
4). At first, compound 7 is deacetylated under Zemplén conditions18 (NaOMe in MeOH).
Reaction of the 11 under the above-mentioned mildly basic conditions resulted in the
formation of an epoxide intermediate 13. The formed diol epoxide 13 undergoes a
regioselective ring-opening from the allylic position through attack by methoxide ion to
produce the monomethoxy derivative 12 as described above. Thus, in the final step,
transformation from a conduritol-A to a conduritol-B type-configuration is provided.
3. Conclusion
7

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In conclusion, we have reported a stereospecific synthesis of novel methyl-substituted mono-
and di-methoxy conduritols starting from commercially available 2-methylbenzo-1,4-quinone.
For the stereoselective reduction of the keto function in 2, employing sodium borohydride in
ethanol gave the allyl dioldibromo compound. The reactions of allylic trans-diol and epoxide
compounds with CH3ONa/MeOH resulted in the related methoxy-conduritols, respectively.
We assume that these types of compound may have important biological activities and may be
used as a precursor for the synthesis of other cyclitol derivatives such as conduritol and
inositol.
4. Experimental section
4.1. General
Melting points were determined on a capillary melting apparatus (Electrothermal) and are
uncorrected. IR spectra were obtained from KBr (solution in 0.1 mm cells) or film with a
Shimadzu spectrophotometer. The 1H and 13C NMR spectra were recorded on 400 (100) MHz
Bruker spectrometer (Avance III) and are reported in δ units with SiMe4 as internal standard.
TLC was performed on E. Merck Silica Gel 60 F254 plate (0.2 mm). All column
chromatography was performed on silica gel (60 mesh, Merck). HRMS were recorded by LC-
MS TOF electrospray ionization technique (6230, Agilent).
4.2. (±)-(1R*,4R*,5S*,6S*)-5,6-Dibromo-2-methylcyclohex-2-ene-1,4-diol (3):
Prepared according to the procedure described in the literature.6 (19 g, 85%) (recrystallized
from AcOEt/hexane), mp 111-112 oC; 1H-NMR (400 MHz, CD3OD) δ 5.48 (dd, 1H, J = 1.7,
3.3 Hz, -CH=C), 4.20-4.39 (m, 2H, -OH), 4.06-4.18 (m, 2H, -CHBr), 1.79-1.81 (m, 3H, -
13
CH3); C-NMR (100 MHz, CD3OD) δ 137.4 (C=C), 125.9 (C=C), 75.4 (C-O), 72.7 (C-O),
60.3 (C-Br), 60.2 (C-Br), 17.9 (-CH3); IR (KBr, cm-1): 3390, 3352, 2974, 2908, 1678, 1400,
1284, 1161, 1060, 1041, 991, 956, 840, 694, 547.
4.3. (±)-(1S*,2S*,3S*,6S*)-3,6-Dimethoxy-4-methylcyclohex-4-ene-1,2-diol (4):
o
In a 250 mL round-bottomed flask fitted with a stirring bar at 0 C, sodium metal (ca. 2.6 g,
113.0 mmol) was added to dry methanol (100 mL) and the resulting suspension was stirred
until all the sodium had disappeared and hydrogen liberation ceased. Dibromo-1,4-diol 3 (1.9
8

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o
g, 6.64 mmol) was added slowly and the mixture was stirred under N2 for 1 h at 0 C and
stirring was continued for 24 h at room temperature to provide complete conversion. The
reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with
AcOEt (3 × 300 mL). The organic extracts were combined, dried (Na2SO4), and the solvent
removed in vacuo to give 3,6-dimethoxy-4-methylcyclohex-4-ene-1,2-diol 4 as colorless
o
1
crystals (0.96 g, 76%); mp 159-161 C (recrystallized from CH2Cl2/Et2O); H-NMR (400
MHz, CDCl3) δ 5.37 (d, 1H, J = 1.3 Hz, -CH=C), 5.01 (d, 1H, J = 4.8 Hz, -COH), 4.96 (d,
1H, J = 4.8 Hz, -COH), 3.58-3.56 (m, 1H, -CHOC), 3.26-3.20 (m, 1H, CHOC), 3.37 (s, 3H, -
OCH3), 3.32 (s, 1H, -OCH3), 3.36 (s, 1H, -OH), 2.51-2.50 (m, 3H, -OH), 1.65 (s, 3H, -CH3);
13C-NMR (100 MHz, CD3OD) δ 135.8 (C=C), 124.1 (C=C), 83.8 (C-OCH3), 81.2 (C-OCH3),
74.8 (C-O), 74.5 (C-O), 58.3 (-OCH3), 57.1 (-OCH3), 19.1 (CH3); IR (KBr, cm-1): 3390, 3352,
2974, 2908, 1678, 1400, 1284, 1161, 1060, 1041, 991, 956, 840, 694, 547; HRMS: m/z
calculated for C9H16NaO4 [M+Na]+, 211.0941; found: 211.0970.
4.4. (±)-(1R*,2R*,3S*,6S*)-3,6-Dimethoxy-4-methylcyclohex-4-ene-1,2-diyl diacetate (5):
3,6-Dimethoxy-4-methylcyclohex-4-ene-1,2-diol 4 (5.6 g, 29.75 mmol) was dissolved in
pyridine (12 mL). To the magnetically stirred solution was added Ac2O (13 mL) and stirred at
room temperature for 12 h. The mixture was poured into ice-water (30 mL) and 4 M HCl
solution (20 mL) was added and the mixture extracted with ether (3×100 mL). The combined
organic extracts were washed with saturated aqueous NaHCO3 solution (100 mL) and water
(50 mL) and then dried over Na2SO4 and concentrated in vacuo. The crude material was
purified by column chromatography on silica gel by using AcOEt/hexane (3:2) to give 3,6-
dimethoxy-4-methylcyclohex-4-ene-1,2-diyl diacetate 5 (7.2 g, 89%); Compound 5 was
o
1
recrystallized from CH2Cl2/hexane to give colorless crystals, mp 66-68 C; H-NMR (400
MHz, CDCl3): δ 5.50-5.46 (m, 1H, -CH=C), 5.22 (dd, 1H, A part of AB system, J = 7.8, 11.0
Hz, -CHOAc), 5.11 (dd, 1H, B part of AB system, J = 7.8, 11.0 Hz, -CHOAc), 4.02-3.92 (m,
2H, -CH-O), 3.31 (s, 3H, -OCH3), 3.30 (s, 3H, -OCH3), 2.03 (s, 3H, -OAc), 2.02 (s, 3H, -
13
OAc), 1.74 (s, 3H, -CH3); C-NMR (100 MHz, CDCl3): δ 170.2 (C=O), 170.1 (C=O), 136.2
(C=C), 123.8 (C=C), 80.9 (C-O), 78.2 (C-O), 72.3 (C-O), 71.9 (C-O), 56.9 (-OCH3), 56.4 (-
OCH3), 29.7 (-CH3), 20.9 (-CH3), 18.6 (-CH3); IR (KBr, cm-1): 2951, 1748, 1435, 1366, 1238,
1215, 1096, 1033, 957, 880, 736, 698, 651, 601, 571; HRMS: m/z calculated for C13H20NaO6
[M+Na]+, 295.1152; found: 295.1211.
9

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4.5. (±)-(1R*,4R*,5S*,6S*)-5,6-Dibromo-2-methylcyclohex-2-ene-1,4-diyl diacetate (6):
5,6-Dibromo-2-methylcyclohex-2-ene-1,4-diol 3 (10.0 g, 34.97 mmol) was dissolved in
pyridine (13 mL). To the magnetically stirred solution was added Ac2O (13 mL) and stirred at
room temperature for 12 h. The mixture was poured into ice-water (30 mL) and 4 M HCl
solution (20 mL) was added and the mixture extracted with CH2Cl2 (3×100 mL). The
combined organic extracts were washed with a saturated solution of NaHCO3 (100 mL) and
water (50 mL) and then dried over Na2SO4 and concentrated in vacuo. The crude material was
purified by column chromatography on silica gel by using EtOAc/hexane (4:1) to give 5,6-
dibromo-2-methylcyclohex-2-ene-1,4-diyl diacetate 6 (11.15 g, 86%); Compound 6 was
recrystallized from EtOH as colorless crystals, mp 94-96 oC (Lit.19 enantipure (-)-6, mp:102-
103 oC); 1H-NMR (400 MHz, CDCl3): δ 5.84-5.79 (m, 1H, H4), 5.70-5.64 (m, 1H, H1), 5.53-
5.49 (m, 1H, H3), 4.32-4.24 (m, 2H, -CHBr), 2.19 (s, 3H, -COCH3), 2.14 (s, 3H, -COCH3),
1.67 (s, 3H, -CH3); 13C-NMR (100 MHz, CDCl3): δ 170.0 (C=O), 169.9 (C=O), 136.2 (C=C),
123.8 (C=C), 74.8 (C-O), 73.6 (C-O), 53.4 (C-Br), 52.6 (C-Br), 20.9 (-CH3), 20.7 (-CH3),
18.8 (-CH3); IR (KBr, cm-1): 2978, 1724, 1435, 1369, 1228, 1169, 1123, 1088, 1053, 1022,
995, 910, 883, 772, 702;
4.6. 2-Bromo-5-methyl-1,4-phenylene diacetate (8):
A vigorously stirred mixture of 6 (1.0 g, 2.70 mmol) in AcOH (15 mL), Ac2O (3 mL), and
anhydrous AcOK (1.55 g, 15.8 mmol) was heated at reflux for 3 days under N2. The solvent
was evaporated, MeOH (10 mL) and H2O (5 mL) to the residue were added, and the mixture
was stirred for 10 min. The mixture was extracted with Et2O (3×50 mL). The combined
organic extracts were washed with a saturated solution of NaHCO3 (50 mL) and water (50
mL) and then dried over Na2SO4 and concentrated in vacuo. The product 8 was recrystallized
o
o
1
from EtOH (0.62 g, 80%) as colorless crystals, mp 123-125 C (lit:17 125.0-125.4 C); H-
NMR (400 MHz, CDCl3): δ 7.31 (br s, 1H, H3 or H6), 7.03 (br s, 1H, H3 or H6), 2.36 (s, 3H, -
13
OAc), 2.33 (s, 3H, -OAc), 2.16 (s, 3H, -CH3); C-NMR (100 MHz, CDCl3): δ 168.7 (C=O),
168.6 (C=O), 147.2 (arom-quaternary), 145.8 (arom-quaternary), 131.1 (arom-CH3), 126.5
(arom.), 125.4 (arom.), 112.9 (arom-Br), 20.8 (-CH3), 20.7 (-CH3), 16.1 (-CH3); IR (KBr, cm-
1): 2939, 1744, 1485, 2369, 1204, 1142, 1007, 918, 867, 810, 652, 586; HRMS: m/z
calculated for C13H20O6 [M+H]+, 286.9914; found: 286.9882.
10

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4.7. (±)-(1R*,2S*,3R*,6R*)-2-Bromo-5-methyl-7-oxabicyclo[4.1.0]hept-4-en-3-ol (9):
A solution of 6 11.15 g (30.13 mmol) in 200 mL diethyl ether and MeOH (100 mL) was
o
cooled to 0 C and then 1.67 g (69.75 mmol) anhydrous LiOH was added to stirring solution
under N2 atmosphere. The reaction mixture was stirred for 2 h at this temperature. After the
reaction mixture was monitored by TLC, H2O (250 mL) was added to the reaction mixture.
The phases were separated and the aqueous phase was extracted with diethyl ether (3×200
mL). The combined organic phases were dried over Na2SO4, filtered and the solvent was
evaporated to epoxide 9 (4.30 g, 70%). The product 9 was recrystallized from AcOEt/hexane
o
1
as colorless crystals, mp 128-130 C; H-NMR (400 MHz, CDCl3): δ 5.62 (dd, 1H, J = 1.8,
3.8 Hz, CH=C), 4.49-4.43 (m, 1H, -CHO-), 4.02 (dd, 1H, J = 1.2, 8.4 Hz, -CHBr), 3.74 (dd,
1H, J = 0.8, 4.0 Hz, -CHO-), 3.36 (dd, 1H, J = 2.4, 4.0 Hz, -CHO-), 2.47 (d, 1H, J = 4.3 Hz, -
OH), 1.96 (dd, 1H, J = 1.7, 2.6 Hz, -CH3); 13C-NMR (100 MHz, CDCl3): δ 132.2 (C=C),
127.5 (C=C), 70.9 (C-O), 56.0 (C-Br), 55.6 (C-O), 55.5 (C-O), 21.1 (-CH3); IR (KBr, cm-1):
3318, 3252, 3024, 2978, 2916, 1663, 1450, 1381, 1339, 1273, 1234, 1180, 1185, 1034, 1011,
944, 899, 800, 822, 756, 656, 611; HRMS: m/z calculated for C7H9KO2 [M+K]+, 242.9418;
found: 243.0123.
4.8. (±)-(1S*,2R*,3S*,4R*)-3-Bromo-6-methylcyclohex-5-ene-1,2,4-triyl triacetate (7):
To a stirred solution of epoxide 9 (1.4 g, 6.83 mmol) in Ac2O (10 mL) was added dropwise
H2SO4 (four drops) and stirred for 12 h at 0oC. The solution was neutralized with NaHCO3
and extracted with AcOEt (3 × 300 mL). The organic extracts were combined, dried
(Na2SO4), and the solvent removed in vacuo. The crude material was purified by column
chromatography on silica gel by using AcOEt/hexane (3:7) to give 3-bromo-6-
methylcyclohex-5-ene-1,2,4-triyl triacetate 7 (1.74 g, 77%). Compound 7 was recrystallized
from AcOEt/hexane as colorless crystals, mp 86-88 oC; 1H-NMR (400 MHz, CDCl3): δ 5.65-
5.62 (m, 1H, CH=C), 5.55 (dd, 2H, J = 2.8, 6.0 Hz, -CHOAc), 5.30 (dd, 1H, J = 2.8, 6.0 Hz, -
CHOAc), 4.36 (dd, 1H, J = 2.8, 5.6 Hz, -CHBr-), 2.14 (s, 3H, -COCH3), 2.13 (s, 6H, -
COCH3), 1.74 (s, 3H, -CH3); 13C-NMR (100 MHz, CDCl3): δ 170 (C=O), 169.9 (C=O),169.8
(C=O), 136.3 (C=C), 122,6 (C=C), 71.4 (C-O), 71.1(C-O), 70.8 (C-O), 47.7 (C-Br), 20.9 (-
CH3), 20.8 (-CH3), 20.7 (-CH3), 19.4 (-CH3); IR (KBr, cm-1): 2322, 1736, 1520, 1435, 1369,
1219, 1157, 1096, 1022, 976, 910, 860, 775, 663, 509, 451;
11

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4.9. (±)-(1S*,2R*,3S*,4R*)-3-Bromo-6-methylcyclohex-5-ene-1,2,4-triol (11):
4.14 g (20.19 mmol) 9 was are suspended in 40 mL H2O, 0.72 g (2.17 mmol) CBr4 was added
o
and the suspension was heated to 35 C under N2 for 14 h. The aqueous layer was extracted
with AcOEt (3×50 mL). The combined organic phases were dried over Na2SO4, filtered and
the solvent was evaporated to give bromotriol 11 (2.3 g, 51%). The product 11 was
o
1
recrystallized from EtOH as colorless crystals, mp 132 C; H-NMR (400 MHz, CD3OD): δ
5.55 (dd, 1H, J = 1.6, 4.0 Hz, CH=C), 4.26 (dt, 1H, J = 2.2, 8.4 Hz, H4), 4.01 (dd, 1H, J = 1.2,
8.4 Hz, H1), 3.72 (dd, 1H, J = 0.8, 4.0 Hz, H2), 3.39 (dd, 1H, J = 2.4, 4.0 Hz, H3), 1.96 (dd,
3H, J = 1.6, 2.6 Hz, -CH3); 13C-NMR (100 MHz, CD3OD): δ 132.1 (C=C), 128.6 (C=C), 70.3
(C-O), 55.7 (C-O), 55.2 (C-O), 54.6 (C-Br), 19.6 (-CH3); IR (KBr, cm-1): 3317, 3240, 1450,
1338, 1273, 1234, 1180, 1010, 948, 898, 860, 821, 756, 655, 601, 547; HRMS: m/z calculated
for C13H20NaO6 [M+Na]+, 244.9784; found: 244.9766.
4.10. Synthesis of 7 from 11:
Bromotriol 11 (1.2 g, 5.38 mmol) was dissolved in pyridine (10 mL). To the magnetically
stirred solution Ac2O (10 mL) was added and stirred at room temperature for 12 h. The
mixture was poured into ice-water (30 mL) and was added 4 M HCl solution (50 mL) and
extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with
saturated solution NaHCO3 (100 mL) and water (40 mL) and then dried over Na2SO4 and
concentrated in vacuo. The crude material was purified by column chromatography on silica
gel by using EtOAc/hexane (15:85) to give triacetate 7 (1.46 g, 78 %);
4.11. (±)-(1S*,2R*,3S*,6S*)-6-Methoxy-4-methylcyclohex-4-ene-1,2,3-triol (12):
In a 250 mL round-bottomed flask fitted with a stirring bar at 0 oC, sodium metal (ca. 0.74 g,
32.18 mmol) was added to dry methanol (100 mL) and the resulting suspension was stirred
until all the sodium has disappeared and hydrogen liberation ceased. Compound 7 (2.5 g, 7.15
o
mmol) was added slowly and the mixture which was stirred in N2 atmosphere for 1 h at 0 C
o
and stirring was continued for 24 h at +5 C to provide complete conversion. The reaction
mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (3 ×
12

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300 mL). The organic extracts were combined, dried (Na2SO4), and the solvent removed in
vacuo. The crude material was purified by column chromatography on silica gel using
AcOEt/MeOH (1:0.1) to give 6-methoxy-4-methylcyclohex-4-ene-1,2,3-triol 12 as a colorless
crystals (1.16 g, 93%); mp 63-65 oC (recrystallized from EtOH); 1H-NMR (400 MHz, CDCl3)
δ 5.4-5.42 (m, 1H, CH=C), 5.15-5.09 (m, 1H, -CHO-), 4.66-5.61 (m, 1H, -CHO-), 4.45-4.44
(m, 1H, -CHO-), 4.05 (s, 1H, -OH), 3.82 (s, 1H, -OH), 3.65-3.56 (m, 1H, -CHOMe), 3.46 (s,
3H, -OCH3), 2.71 (s, 1H, -OH), 1.79 (s, 3H, -CH3); 13C-NMR (100 MHz, CDCl3) δ 137.2
(C=C), 121.2 (C=C), 81.2 (C-O), 75.9 (C-O), 74.2 (C-O), 73.9 (C-O), 56.8 (-OCH3), 18.7 (-
CH3); IR (KBr, cm-1): 3316, 2974, 2903, 2877, 1454, 1371, 1321, 1283, 1194, 1088, 1051,
995, 966, 891, 825, 611, 521; HRMS: m/z calculated for C8H14NaO4 [M+Na]+, 197.0785;
found: 197.0874.
Acknowledgements
The authors are indebted to Ordu University Scientific Research Projects Coordination Unit
(ODU/BAP, Grant No: TF-1451) for financial support of this work.
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GRAPHICAL ABSTRACT
-----------------------------------------------------------------------------------------------------------------
Stereospecific synthesis of novel methyl-substituted mono- and di-methoxy conduritols
Latif Kelebekli*, Dilek Kaplan
15