A novel and stereoselective synthesis of 2-bromo-6-chloro-5-methylcyclohex-4-ene-1,3-diyl diacetate: conduritol-A derivative

Article abstract of DOI:10.1007/s13738-019-01810-3

The stereoselective synthesis of 2-bromo-6-chloro-5-methylcyclohex-4-ene-1,3-diyl diacetate, methyl-substituted dihaloconduritol-A is reported. Bromination of 2-methylbenzo-1,4-quinone followed by the reduction in the carbonyl groups with NaBH₄ to give a dioldibromo compound. The diol was converted to diacetates by acetylation with Ac₂O-pyridine. Reaction of methyl-dioldibromodiacetate with LiOH gave stereoselectively the monoepoxide compound. Controlled reaction of the epoxide with AcCl in methylene chloride furnished the desired new dihaloconduritol-A derivative which was characterized by spectroscopic methods. All the synthesized compounds were characterized by FT-IR, ¹H-NMR, ¹³C-NMR, COSY (2D-NMR), and HRMS analyses.

Full text of DOI:10.1007/s13738-019-01810-3

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01810-3
ORIGINAL PAPER
A novel and stereoselective synthesis
of 2‑bromo‑6‑chloro‑5‑methylcyclohex‑4‑ene‑1,3‑diyl diacetate:
conduritol‑A derivative
Latif Kelebekli1 · Dilek Kaplan1
Received: 22 June 2018 / Accepted: 11 November 2019
© Iranian Chemical Society 2019
Abstract
The stereoselective synthesis of 2-bromo-6-chloro-5-methylcyclohex-4-ene-1,3-diyl diacetate, methyl-substituted dihalo-
conduritol-A is reported. Bromination of 2-methylbenzo-1,4-quinone followed by the reduction in the carbonyl groups with
NaBH4 to give a dioldibromo compound. The diol was converted to diacetates by acetylation with Ac2O-pyridine. Reaction
of methyl-dioldibromodiacetate with LiOH gave stereoselectively the monoepoxide compound. Controlled reaction of the
epoxide with AcCl in methylene chloride furnished the desired new dihaloconduritol-A derivative which was characterized
by spectroscopic methods. All the synthesized compounds were characterized by FT-IR, 1H-NMR, 13C-NMR, COSY (2D-
NMR), and HRMS analyses.
Keywords Dihalogen cyclitol · Dihaloconduritol · Cyclitol · Dihaloconduritol-A derivative
is an active-site-directed irreversible inhibitor of glucosi-
dases [3, 4]. Notably, bromoconduritol has been known as
an inhibitor of glucosidase II, which plays pivotal roles in
glycoprotein processing and folding in the endoplasmic retic-
ulum [5]. In connection with the conduritols, haloconduritols
(with halo-substituents such as –Br, –Cl, and –F), particu-
larly mono- and dihaloconduritols have also gained increas-
ing importance over the last decade [6–11]. All of them have
been carried out using an acid or Lewis acid-catalyzed reac-
tions (HX, H2SO4, BX3, Li2CuCl4, etc.).
Introduction
Conduritols and carbasugars are a class of polyhydroxylated
cyclohexanoids that have continued to attract the attention of
chemists and biologists due to their involvement in various
biological processes [1]. Conduritols which are precursors for
the synthesis of cyclitols and their derivatives have interesting
biological activities. Their biological activities, particularly
glycosidase inhibition, have extensively been evaluated [2].
Bromoconduritol (6-bromo-3,4,5-trihydroxycyclohex-1-ene)
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01810-3) contains
supplementary material, which is available to authorized users.
1
* Latif Kelebekli
Department of Chemistry, Faculty of Science and Arts, Ordu
lkelebekli@odu.edu.tr
University, 52200 Ordu, Turkey
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
On the other hand, pericosines are a class of highly
oxygenated cyclohexenoid natural products and have been
targets of many synthetic studies. C7-cyclitols, such as
gabosines (gabosine A, N, and H) [12–14] with a methyl
substituent and pericosines (pericosine A, D, and E) [15–18]
with chloride group which include a cyclohexenoid moiety,
represent an important category of highly oxygenated natu-
ral products and may be classifed as pseudo- or carbasugars.
Conduritols A–F are useful intermediates in organic syn-
thesis. In connection with the conduritols, haloconduritols
and double bond-substituted conduritols (such as methy-,
phenyl-, bromo-substituted conduritols) have also gained
importance in the last decade [19–23]. For instance, bromo-
conduritols are interesting molecules in AIDS research
because they are active-site-directed covalent inhibitors of
α-glucosidases [22]. Moreover, since these compounds show
structural similarities to carbohydrates, they exhibit interest-
ing biological activities such as antibiotic, anticancer, and
DNA binding properties [24–26].
by stereoselective reduction in the carbonyl groups with
the NaBH4 in ether [19]. The stereochemical course of the
reduction was mainly determined as the trans confguration
to bromide groups. After successful isolation and charac-
terization of the result of reduction, the acetylation of 3 with
Ac2O/pyridine system at room temperature gave dibromo-
diacetoxy compound 4 [19, 20] as a sole product in 86%
yield. Thus, stereochemistry of compound 4 was protected
such as in 3 as conduritol B (Scheme 1).
Epoxide 5 was regioselectively prepared from dibromide
4 by treatment with lithium hydroxide as a base [19, 20].
Although epoxide 5 was known, the observed regio- and
stereoselectivity for this reaction was remarkable. Thus, we
focused on the detailed spectroscopic studies to provide the
best approach by checking related structure. In the 1H-NMR
spectrum of 5, the irradiation of H-4 at 5.62 ppm (CH=C)
resulted in the signal of H-6 at 3.36 ppm changing from a
double doublet to a doublet (J=4.0 Hz). Upon irradiation of
H-3 at 4.49–4.43 ppm, both the signal of H-2 at 4.02 ppm and
the signal of –OH proton at 2.47 ppm changed from a double
doublet to a broad singlet and from a doublet to a singlet,
respectively. When H-6 at 3.36 ppm was irradiated, both the
signal of H-4 at 5.62 ppm and the signal of H-1 at 3.74 ppm
changed from a double doublet to a triplet (J=1.6 Hz) and
from a double doublet to a singlet, respectively. These results
clearly indicate that H-6 with H-1 and the H-4 with H-3 are
the neighboring protons with each other.
There is considerable interest in the stereocontrolled synthe-
sis of these compounds as they have proved to be useful inter-
mediates for the preparation of cyclitols. Recently, we have
reported the stereospecifc synthesis of some polyhydroxylated
compounds [27–30]. Consequently, based on these results, we
aimed to synthesize a dihaloconduritol derivative. Herein, we
report the synthesis of a dihaloconduritol derivative including
a methyl substituent having the conduritol-A construction.
Additionally, for this interesting epoxide formation,
geometry optimization calculations (DFT) were carried out
on the epoxide 5 without any simplifcation using the ORCA
program package with the RI-BP86 [31]. The epoxide 5 is
5.60 kcal/mol more stable than epoxide in other allylic posi-
tion, which was not obtained.
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 required allylic trans-diol 3 for synthesis
of the target compound was obtained as the sole product
The products of the ring opening of epoxides by various
carbon, nitrogen, oxygen, halogen, and sulfur-containing
Scheme 1 Synthesis of com-
pound 4
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Journal of the Iranian Chemical Society
nucleophiles are versatile intermediates in the synthesis of
various biologically active compounds [32]. The chlorohy-
drins are very important intermediates in the production
of epoxides and chlorohydrin esters and in the preparation
of many natural products [33–35]. As well as halohydrin
derivatives, a convenient pathway to halohydrin esters from
epoxides is the direct reaction with acyl halides. The halohy-
drin-ester synthesis from acyl halides and epoxides has been
versatilely investigated. Previous reports have described the
acylative cleavage of cyclic ethers using metal-reagent sys-
tems in conjunction with acid chlorides [33–39].
13C-NMR spectra reveal the formation of only one isomer.
The eleven-line 13C-NMR spectrum is in agreement with
structure 7 having the asymmetry element.
In the 1H-NMR spectrum of 7, the irradiation of H-3 at
5.58 ppm resulted in the signal of H-2 at 4.49 ppm chang-
ing from a double doublet to a broad singlet. When H-2 at
4.49 ppm was irradiated, H-3 showed a singlet and H-1 also
showed a doublet (J=3.6 Hz) but H-6 remained unchanged.
These results clearly indicate that H-2 with H-1 and H-3 are
the neighboring protons with each other. Upon irradiation of
H-1 at 5.39 ppm, both the signal of H-2 at 4.49 ppm and the
signal of H-6 at 4.34 ppm changed from a double doublet to
a doublet (J=7.6 Hz) and from a doublet to a singlet, respec-
tively. When H-6 at 4.34 ppm was irradiated, H-1 showed
a broad singlet but for H-2 no change was observed. These
results clearly indicate that connectivity of 7 is as shown
(Scheme 2).
We frstly aimed the acetylation of hydroxyl group in the
molecule. However, after the treatment with CH3COCl in
methylene chloride at room temperature for acetylation of
–OH, the expected acetoxy compound 6 was not obtained
as deduced from the 1H-NMR data. Contrary to expectation,
regio- and stereoselective ring opening of epoxide 5 with
CH3COCl resulted in ( )-(1RS,2SR,3RS,6SR)-2-bromo-6-
chloro-5-methylcyclohex-4-ene-1,3-diyl diacetate 7 which
possess a conduritol-A-type confguration as the only reac-
tion product (Scheme 2). All analytical methods showed the
formation of a single isomer with high selectivity. Espe-
cially, the NMR spectral studies showed the formation of
two acetate groups. Additionally, the most conspicuous fea-
tures in the 13C-NMR spectrum of 7 are only the resonances
of the two carbonyl groups. These results clearly indicate
that epoxide ring has been opened under these conditions.
The observed regio- and stereoselectivity for this reaction
was remarkable since stereochemistry is transformed into
conduritol-A-type confguration in the compound 7 from
conduritol-B-type confguration in the compound 4. The
exact confguration of compound 7 was determined on the
basis of the 1H-NMR and 13C-NMR spectra in conjunction
Notably, analysis of the COSY (2D-NMR) spectrum
shows that the H-6 (–CHCl) at 4.34 ppm is coupled to H-1 at
5.39 ppm. The proton for H-2 (–CHBr) at 4.49 ppm is cou-
pled to the H-3 at 5.58 ppm as well as the H-1 at 6.39 ppm.
The proton for H-3 (–CHOAc) at 5.58 ppm is coupled to
the H-2 at 4.49 ppm and H-4 at 5.49–5.52 ppm. The proton
for H-1 (–CHOAc) at 5.39 ppm is coupled to the H-2 at
4.49 ppm and H-6 at 4.34 ppm (Fig. 1). These results also
clearly illustrate that these protons are the neighboring pro-
tons with each other.
We suggest the following mechanism for the formation
of stereospecifc synthesis of methyl-substituted dihalocon-
duritol-A 7 from epoxide 5 (Scheme 3). At frst, compound
5 is acetylated under CH3COCl in methylene chloride. One
mole of HCl comes out under these reaction conditions. The
formed HCl during the reaction leads to contribute the stere-
oselective epoxide ring opening as a subtle diference. That
1
with 2D-NMR (COSY) experiments. The H-NMR and
Scheme 2 Synthesis of com-
pound 7
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Journal of the Iranian Chemical Society
Fig. 1 The COSY spectrum for compound 7 in CDCl3 at room temperature (400 MHz)
is, it can be easily understood here that the opening of the
epoxide ring is catalyzed by acid (HCl). The formed cyclic
oxonium ion 9 undergoes ring opening through attack by
chloride ion, most likely at the allylic C-atom to produce
compound 10. In the fnal step, compound 7 can be obtained
by the acetylation of –OH group. Thus, the observed cis-
relation of the Br-atom and –OAc C(1) in compound 7 can
be explained by this mechanism.
Experimental section
Melting points were determined on a capillary melting appa-
ratus (Electrothermal) and are uncorrected. IR spectra were
obtained from KBr (solution in 0.1 mm cells) or flm with a
Shimadzu spectrophotometer. The 1H NMR, 13C NMR, and
2D NMR (COSY) spectra were recorded on 400 (100)-MHz
Varian spectrometer 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).
Conclusion
In conclusion, we have reported stereospecific synthe-
sis of novel methyl-substituted dihaloconduritol (includ-
ing Br- and Cl atoms) via an allylic epoxide starting from
2-methylbenzo-1,4-quinone. We underline that AcCl can
serve to forming halocyclitols without any catalyst. All the
synthesized compounds were thoroughly characterized by
IR, 1H-NMR, 13C-NMR, COSY (2D-NMR), HRMS, melt-
ing point, etc. With continuous research of novel halogened
conduritols, new approaches to this type of products can be
anticipated to appear in the future and be applied extensively
in practical synthesis. This compound has potential to be
used as a precursor for the synthesis of metoxy-, azido-, and
aminocyclitol derivatives.
( )‑(1RS,2SR,3RS,6RS)‑2‑bromo‑5‑methyl‑7‑oxabi‑
cyclo[4.1.0]hept‑4‑en‑3‑ol (5) A solution of dibromo-
diacetoxy 4 (4.20 g, 11.30 mmol) in 80 mL diethyl ether
and 60 mL MeOH is cooled to 0 °C, and then 0.61 g
(24.41 mmol) anhydrous LiOH to stirring solution under
N2 atmosphere is added. The reaction mixture is stirred for
2 h at this temperature. The reaction mixture was monitored
by TLC, and after the reaction is completed, H2O (100 mL)
to the residue was added, and the reaction mixture was
quenched by the addition of water. Then, Et2O (100 mL)
was added, the layers were separated, and the aqueous layer
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Journal of the Iranian Chemical Society
Scheme 3 Mechanism of for-
mation of compound 7
extracted with diethyl ether (2× 100 mL). The combined
organic layers were washed with water, brine, dried over
Na2SO4, and fltered. The solvent was evaporated under
reduced pressure to afford ( )-(1RS,2SR,3RS,6RS)-
2-Bromo-5-methyl-7-oxabicyclo[4.1.0]hept-4-en-3-ol
5 (1.76 g, 76%). The product 5 was recrystallized from
( )‑(1RS,2SR,3RS,6SR)‑2‑bromo‑6‑chloro‑5‑methyl‑
cyclohex‑4‑ene‑1,3‑diyl diacetate (7) To a solution of
epoxide 5, (0.85 g, 4.14 mmol) in CH2Cl2 (15 mL) was
added AcCl (8 mL) and the resulting solution was stirred
overnight at room temperature. The excess of unreacted
AcCl and solvent was evaporated (60 °C, 20 mmHg). The
residue was dissolved in CH2Cl2. Further purifcation was
carried out by short column chromatography on silica gel.
Evaporation of solvent gave (1R,2S,3R,6S)-2-bromo-6-
chloro-5-methylcyclohex-4-ene-1,3-diyl diacetate 7 as color-
less oil (0.66 g, 56%); 1H-NMR (400 MHz CDCl3, ppm): δ
5.58 (br d, 1H, J=7.6 Hz, H3), 5.49–5.52 (m, 1H, H4), 5.39
(dd, 1H, J=3.6, 2.4 Hz, H1), 4.49 (dd, 1H, J=7.6, 2.4 Hz,
H2), 4.34 (d, 1H, J=3.6 Hz, H6), 2.11 (s, 3H, –OAc), 2.09
(s, 3H, –OAc), 1.82 (s, 3H, –CH3); 13C-NMR (100 MHz
CDCl3, ppm): δ 170.1 (C=O), 169.7 (C=O), 135.3 (C qua-
ternary), 123.6 (C=C), 74.8 (–O–C), 71.7 (–O–C), 57.3
(–C–Br), 46.2 (–C–Cl), 20.9 (–CH3), 20.7 (–CH3), 20.6 (–
CH3); IR (KBr, cm−1): 2359, 2324, 1746, 1373, 1223, 1085,
1035, 862, 788; HRMS: m/z calculated for C11H14BrClNaO4
1
AcOEt/hexane as colorless crystals, mp 128–130 °C; H-
NMR (400 MHz, CDCl3, ppm): δ 5.62 (dd, 1H, J = 3.8,
1.8 Hz, HC=C), 4.49–4.43 (m, 1H, –CHO), 4.02 (dd, 1H,
J = 8.4, 1.2 Hz, –CHBr), 3.74 (dd, 1H, J = 4.0, 0.8 Hz, –
CHO), 3.36 (dd, 1H, J =4.0, 2.4 Hz, –CHO), 2.47 (d, 1H,
J = 4.3 Hz, –OH), 1.96 (dd, 3H, J = 2.6, 1.7 Hz, –CH3);
13C-NMR (100 MHz, CDCl3, ppm): 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 cal-
culated for C7H9BrKO2 [M+K]+ (Br79), 242.9418; found:
243.0123 and C7H9BrKO2 [M + K]+ (Br81), 244.9397;
found: 245.0002.
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Journal of the Iranian Chemical Society
[M + Na]+ (Br79, Cl35), 346.9656; found: 346.9692 and
C11H14BrClNaO4 [M + Na]+ (Br81, Cl35 or Br79, Cl37),
348.9636; found: 348.9670.
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