Regio- and stereospecific synthesis of DL-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol

Article abstract of DOI:10.1016/j.tetlet.2018.02.050

The regio- and stereospecific synthesis of DL-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol is reported. Bromination of p-benzoquinone followed by reduction of the carbonyl groups with NaBH₄ gave the corresponding trans-dibromodiol compou

Full text of DOI:10.1016/j.tetlet.2018.02.050

Accepted Manuscript
Regio- and stereospecific synthesis of DL-4,5-dibromo-4,5-dideoxy-3,6-O-
methyl-chiro-inositol
Latif Kelebekli, Kadir Aksu, Ertan Şahin
PII:
S0040-4039(18)30240-5
https://doi.org/10.1016/j.tetlet.2018.02.050
TETL 49735
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 December 2017
6 February 2018
19 February 2018
Please cite this article as: Kelebekli, L., Aksu, K., Şahin, E., Regio- and stereospecific synthesis of DL-4,5-
dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.02.050
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Regio- and stereospecific synthesis of DL-4,5-dibromo-4,5-
dideoxy-3,6-O-methyl-chiro-inositol
Latif Kelebeklia,*, Kadir Aksua, Ertan Şahinb
aDepartment of Chemistry, Ordu University, 52200 Ordu, Turkey
bDepartment of Chemistry, Ataturk University, 25240 Erzurum, Turkey
Abstract:
The regio- and stereospecific synthesis of DL-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-
chiro-inositol is reported. Bromination of p-benzoquinone followed by reduction of the
carbonyl groups with NaBH4 gave the corresponding trans-dibromodiol compound, which
was reacted with sodium methoxide to produce dimethoxy conduritol-B. Regiospecific
bromination of the alkene moiety furnished the desired chiro-inositol derivative.
Keywords: chiro-inositol, methoxy conduritol-B, methoxy inositol, regio- and stereospecific
synthesis
Correspondence Author:
Prof. Dr. Latif Kelebekli
Ordu University, Faculty of Science and Arts,
Department of Chemistry
52200-Ordu/ Turkey
Tel: (90) 452 234 50 10
Fax: (90) 452 233 91 49
E-mail: lkelebekli@odu.edu.tr

1. Introduction
Inositol 1 and its derivatives are an important class of biologically active natural
products. Among the nine theoretically possible inositols, six are known to occur in Nature.1
Interestingly, inositols containing one or more methyl ethers have been isolated from plants,
and these methyl inositols are presumed to have important functions in plant biology.1b,1c D-
chiro-Inositol 2, a naturally occurring inositol, is clinically used for the treatment of
polycystic ovary syndrome.2 Additionally, myo-inositol and D-chiro-inositol have been shown
to possess insulin-mimetic properties, acting as secondary messengers in the insulin
intracellular pathway.3 Recently, their methyl-inositol or methoxy-inositol derivatives
(pinitol,4a,4b 1,4-di-O-methyl-chiro-inositol 3,4c 1,2-di-O-methyl-chiro-inositol4d) have also
been synthesized. Moreover, halo-substituted inositols (dimethoxydichloro 4,5
methoxydibromo 5,6 methoxyfluoro 67) have also gained importance over the last decade
(Fig. 1).
Figure 1. Selected inositol derivatives
The preparation of cyclitols and their analogues is challenging due to the numerous
hydroxy bearing stereocenters. Recently, we reported the stereospecific synthesis of
polyhydroxylated compounds.8 Consequently, based on these results, we aimed to synthesize
2

novel halogenated deoxyinositols containing methyl groups. Due to the important biological
activity of methoxyinositols and the interesting structural features of halogenated
deoxyinositols, we focused on the synthesis of a dimethoxydibromo deoxyinositol, namely
DL-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol 11.
2. Results and Discussion
p-Benzoquinone 7 was brominated at low temperature to give only the trans-dibromo
compound 8 in high yield. The required key intermediate, allylic trans-diol 9, was obtained as
the sole product by the stereoselective reduction of the carbonyl groups with NaBH4 in diethyl
ether.9 The stereochemical course of the reduction was as shown and was proven by NMR
and X-ray analysis of a later intermediate. Treatment of dibromodiol 9 with a metallic
sodium-methanol system (MeONa/MeOH)10 under a N2 atmosphere led to the
stereocontrolled transformation to conduritol-B derivative 10 in 76% yield (Scheme 1). The
structure of compound 10, which possesses C2-symmetry, was unambiguously deduced by 1H
and 13C NMR spectroscopy.
Scheme 1. Synthesis of dimethoxy conduritol-B 10
3

Treatment of dimethoxydiol 10 with bromine in CH2Cl2 at low temperature for 2 days
afforded DL-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol 11 as the sole product in
68% yield. Regio- and stereoselective addition of bromine to compound 10 resulted in
product 11, a chiro-inositol derivative. The structure of compound 11 was unambiguously
13
deduced by 1H and C NMR spectroscopy. The 13C NMR spectrum consisted of four carbon
resonances owing to the C2-symmetry. Furthermore, selective decoupling experiments
1
allowed the connectivity of 11 to be determined. In the H NMR spectrum, irradiation of -
CHOH (4.83 ppm) caused the H-6 signal (3.36 ppm) to change. The irradiation of -CHBr
(3.95 ppm) resulted in the -CHOMe signal (3.73 ppm) changing from a triplet doublet into a
doublet. Upon irradiation of -CHOMe (3.73 ppm), both the -CHOH signal (4.83 ppm) and the
-CHBr signal (3.95 ppm) changed from a doublet into a singlet and from a doublet of doublet
into a singlet, respectively. These results clearly indicate that the connectivity of 11 is as
shown.
Scheme 2. Synthesis of dimethoxydibromo inositol 11
Next, we focused on the bromination reaction of compound 12, including the larger
acetate groups. For this purpose, acetylation of 10 with the Ac2O/pyridine system gave
4

compound 1210a as the sole product in 89% yield. The reaction of 12 with bromine in CH2Cl2
under the same conditions produced the desired chiro-inositol dibromodiacetoxy 13 as the
13
sole product in 76% yield. A six-line pattern in the C NMR spectrum of 13 confirmed the
proposed structure due to the C2-symmetry in the molecule. However, NMR spectroscopic
studies did not allow configurational assignment of the bromine groups. Therefore, single
crystal X-ray analysis of chiro-inositol derivative 13 (Fig. 2) was required to confirm the
structural assignment. Compound 13 crystallizes in the monoclinic P21/c space group with
four molecules in the unit cell. C-C bond lengths of the cyclohexene unit are in the range of
1.516(3)-1.534(3) Å. In this cyclic unit, the bromine and acetate groups are trans to each
other. The structure contains six asymmetric carbon atoms and all have (R)-stereogenic
centers.
Figure 2. Molecular structure of the chiro-inositol derivative 13. Thermal ellipsoids are
drawn at the 30% probability level.
5

Scheme 3. Acetylation of dibromodiol 11
Additionally, to test the potential of this approach, dibromodiacetate 13 was obtained
in one-step from dibromodiol 11 by treatment with CH3COCl in CH2Cl2 at room temperature.
After crystallization from AcOEt/hexane, compound 13 was obtained in 92% yield, as the
only isomer detected by NMR spectroscopy.
We suggest the following mechanism for the regio- and stereospecific synthesis of 11
(Scheme 4). In general, the electrophilic bromination reaction of olefins is stereoselective and
leads to trans-1,2-dibromides via a three-membered bromonium ion intermediate. Since the
diequatorial arrangement predominates as the favoured conformation of 10, the bromination
reaction progresses from this conformation. Here the bromonium ion may form on both faces
of the ring (e.g. 14 and 15), but in both cases the same diaxial product occurs due to ring-
opening progressing according to the Fürst-Plattner rule.11 In the light of these findings, the
electrophilic bromine can attack the double bond in 10 at both sides of the double bond to
form cyclic bromonium ions 14 and 15, respectively (Scheme 4). The formation of
intermediate 15 is important not only in terms of the synthetic aspect, but also in view of the
mechanism of compound 11 which was regioselectively obtained as the sole product. It is
evident from the configuration of the bromine atoms in 11 that attack of the bromide through
the trans-diaxial chair conformation is preferred at C-1, which gave DL-4,5-dibromo-4,5-
dideoxy-3,6-O-methyl-chiro-inositol.
6

Scheme 4. Proposed mechanism for the formation of dibromdimethoxy deoxyinositol 11
3. Conclusion
The regio- and stereospecific synthesis of a novel dimethoxy-dibromo-deoxyinositol
possessing chiro-inositol stereochemistry is reported. As shown by the efficient preparation of
11 and 13, these compounds have potential to be used as precursors for the synthesis of
methoxy-, azido- and aminoinositol derivatives.
7

Acknowledgements
The authors are indebted to Ordu University Scientific Research Projects Coordination Unit
(ODU/BAP, Grant No: AR-1324) for financial support of this work.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at…
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9

Latif Kelebekli
The regio- and stereospecific synthesis of (DL)-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-
chiro-inositol.
Concise route to a chiro-inositol derivative ingluding bromine groups was developed.
Precursors of methoxy-, azido-, and aminoinostols were efficiently synthesized.
10

GRAPHICAL ABSTRACT
-----------------------------------------------------------------------------------------------------------------
Regio- and stereospecific synthesis of (DL)-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-
inositol
Latif Kelebeklia*, Kadir Aksua, Ertan Şahinb
11