Lithium hydride as an efficient reagent for the preparation of 1,2-anhydro inositols: Does the reaction proceed through ‘axial rich’ conformation?

Article abstract of DOI:10.1016/j.carres.2018.04.014

scyllo-Inositol derived 1,2-trans-diequatorial halohydrins can be efficiently converted to the corresponding epoxides in the presence of lithium hydride. The structure of one of the epoxides was determined by single crystal X-ray diffraction analysis. Thi

Full text of DOI:10.1016/j.carres.2018.04.014

Accepted Manuscript
Lithium hydride as an efficient reagent for the preparation of 1,2-anhydro inositols:
Does the reaction proceed through ‘axial rich’ conformation?
Nitai Sarkar, Richa S. Sardessai, Mysore S. Shashidhar, Majid I. Tamboli, Rajesh G.
Gonnade
PII:
S0008-6215(18)30177-0
10.1016/j.carres.2018.04.014
CAR 7559
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 23 March 2018
Revised Date: 20 April 2018
Accepted Date: 25 April 2018
Please cite this article as: N. Sarkar, R.S. Sardessai, M.S. Shashidhar, M.I. Tamboli, R.G. Gonnade,
Lithium hydride as an efficient reagent for the preparation of 1,2-anhydro inositols: Does the
reaction proceed through ‘axial rich’ conformation?, Carbohydrate Research (2018), doi: 10.1016/
j.carres.2018.04.014.
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Graphical Abstract
RO
RO
OR
OR
HO
OR
OR
O
I
LiH
OH
OR
OR
OR
OR
R = Me, All, Bn
RO
I
OR
Inositol derived trans-diequatorial halohydrins cyclize to yield the corresponding epoxides in the
presence of lithium hydride.

ACCEPTED MANUSCRIPT
Lithium hydride as an efficient reagent for the preparation of 1,2-
anhydro inositols: Does the reaction proceed through ‘axial rich’
conformation?
Nitai Sarkar,a,b Richa S. Sardessai,b Mysore S. Shashidhar,*a,b Majid I.
Tamboli,b Rajesh G. Gonnadea,c
aAcademy of Scientific and Innovative Research (AcSIR),
bThe Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pashan Road,
Pune - 411 008, India. Fax: 91-20-25902629; Tel: 91-20-25902055.
cCenter for Materials Characterization, CSIR- National Chemical Laboratory, Pashan Road,
Pune – 411008.
Emails: nn.sarkar@ncl.res.in;
rs.sardessai@gmail.com; ms.shashidhar@ncl.res.in;
tambolimi@gmail.com; rg.gonnade@ncl.res.in.
Abstract
scyllo-Inositol derived 1,2-trans-diequatorial halohydrins can be efficiently converted to the
corresponding epoxides in the presence of lithium hydride. The structure of one of the
epoxides was determined by single crystal X-ray diffraction analysis. This provides a
potential route for the preparation of ring modified inositol derivatives. DFT calculations
suggest that this epoxide formation could be proceeding through the intermediacy of the
cyclohexane ring-inverted axial-rich conformer (1,2-trans-diaxial halohydrin). This is
supported by the results of DFT calculations on the formation of inositol orthoformate, where
the product is locked in the axial-rich conformation, while the starting inositol has the
equatorial-rich conformation.
Keywords: Cyclitol; Epoxide; Halohydrin; Inositol; Lithium hydride.
1. Introduction
Inositol derivatives have gained importance as potential agents for the
pharmacological intervention of certain diseases related to cellular signal transduction
pathways (the myo-inositol cycle) and anchoring of proteins to cell membranes [1-3].
Impairment of the myo-inositol cycle could lead to certain diseases including cancer and
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diabetes
[4-6].
Synthetic
inositol
derivatives,
especially
phosphoinositols,
glycosylphosphoinositols and their analogs are useful for the study of the myo-inositol cycle.
There are several reports on the use of myo-inositol as a starting material for the synthesis of
certain natural products and their analogs [7]. 1,2-Anhydro inositols are useful precursors for
the synthesis of ring-modified inositol derivatives [8]. Synthesis of 1,2-anhydro inositols
have been accomplished from benzene derivatives, sugars and O-protected inositol
derivatives [9-12]. As a part of an ongoing program on the chemistry of inositol derivatives,
we required several 1,2-anhydro inositol derivatives. We were able to obtain these in good
yields from their trans-diequatorial diol precursors, using lithium hydride as the base. A
perusal of the literature revealed that lithium hydride is seldom used as a reagent in organic
synthetic transformations due to its low bascity and consequent increase in its ability to
function as a reducing agent [13]. The results presented here show that lithium hydride can
indeed be an efficient reagent for the formation of epoxides due to its ease of handling and
lower susceptibility to reaction with moisture.
2. Results and discussion.
The inositol derived racemic cis-diols 6-10 (Scheme 1) were prepared using methods
previously reported in the literature [14-17]. These diols on reaction with iodine,
triphenylphosphine and imidazole gave the corresponding racemic trans-iodo-alcohols 11-15
[18]. Treatment of 11-15 with lithium hydride in THF resulted in the formation of the
corresponding racemic epoxide 16-20 in good yields.
2

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O
OR1
HO
OR1
(a)
OR2
OR2
OR1
OR2
O
OR2
HO
OR1
1 R1 = R2 = Bn
6 R1 = R2 = Bn
7 R1 = R2 = Me
2 R1 = R2 = Me
3 R1 = R2 = All
8 R1 = R2 = All
4 R1 = Bn, R2 = Me
5 R1 = Bn, R2 = All
9 R1 = Bn, R2 = Me
10 R1 = Bn, R2 = All
(b)
OR1
OR1
OR2
OR2
OR2
OR1
(c)
I
OR2
HO
O
OR1
16 R1 = R2 = Bn
17 R1 = R2 = Me
18 R1 = R2 = All
19 R1 = Bn, R2 = Me
20 R1 = Bn, R2 = All
11 R1 = R2 = Bn
12 R1 = R2 = Me
13 R1 = R2 = All
14 R1 = Bn, R2 = Me
15 R1 = Bn, R2 = All
Scheme 1. (a) Methanol, 1M HCL, 30 min, 66-92%; (b) triphenylphosphine, imidazole,
iodine, toluene, 90-100 ⁰C, 2.5 h, 56-70%; (c) lithium hydride, THF, 60-70 ⁰C, 2-2.5 h, 62-
85%.
Good crystals of the epoxide 19 could be obtained and its structure was solved (Figure
1) by single crystal X-ray diffraction analysis. In the crystal of the epoxide 19 the six
membered carbocyclic ring adopts a half chair conformation; the respective values of
φ were 50.1(4)° and 222.6(5)° and the puckering amplitude (q), which provides a measure of
the magnitude of the puckering was 0.477(3) Å. The ideal values of and for a half-chair
θ and
θ
φ
conformation are 50.8° and 210° respectively.[19] Hence these values imply that the C5 atom
deviates from the plane defined by the other five atoms of the carbocyclic ring, resulting in its
half-chair conformation.
Figure 1. An ORTEP view of the racemic epoxide 19 with 50% probability displacement
ellipsoids; H atoms are shown as small spheres of arbitrary radii. The epoxide moiety of the
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molecules in the crystal showed statistical disorder over two orientations (conformational)
with occupancies 87% and 13% respectively, see ESI for details.
Formation of 1,2-anhydro inositol (Scheme 1) was interesting since epoxide
formation from cyclohexane derived trans-diequatorial-diols (or their derivatives such as the
corresponding halohydrins) is generally not as facile as epoxide formation from the
corresponding trans-diaxial diols (or their derivatives) [20]. Hence we believe the ‘equatorial
rich’ inositol ring (21) flips to an ‘axial rich’conformation (22) in which the epoxide (23)
formation is facile. Subsequently, the inositol ring reverts back to the corresponding
‘equatorial rich’ conformation (24, Scheme 2).
I
OR
OR
OR
OR
OR
I
HO
RO
OR
HO
OR
21
22
OR
OR
OR
RO
OR
OR
O
O
OR
24
OR
23
Scheme 2. Plausible mechanism for the formation of 1,2-anhydro inositols.
From synthetic point of view, facile formation of 1,2-anhydro inositols from the
corresponding trans-diequatorial-diols allows the preparation of a variety of 1,2-anhydro
inositols, since relative stereochemistry of most vicinal diol moieties in inositols are trans-
diequatorial. trans-Diaxial diol moieties only occur in chiro- and muco-inositols. Use of
chiro- and muco-inositols would render 1,2-anhydride formation impractical due to their
scanty availability [11].
4

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HO
OBn
OBn
OBn
OBn
OBn
I
4.4
4.8
HO
BnO
I
OBn
OBn
OBn
11
25
OBn
OBn
O
OBn
OBn
O
BnO
26
OBn
OH
OBn
16
HO
OH
OH
7.5
OH
OH
HO
HO
HO
OH
27
HO
OH
28
Scheme 3. Summary of the DFT calculations for the inversion of scyllo-inositol and its
derivatives. Numbers (Kcal / mol) on the arrows depict calculated differences in energies
between the two conformers, which indicate higher relative stability of ‘equatorial rich’
conformers 11, 16 and 27 in each pair (see ESI for details).
DFT calculations revealed that the relative difference in energy between the
‘equatorial rich’ and the ‘axial rich’ conformers (Scheme 3) is relatively less for the
halohydrins (4.4 k cals/mol) and the corresponding epoxide (4.8 k cals/mol) as compared to
the corresponding inositol (7.5 k cals/mol) under standard conditions. Hence it is likely that
the inositol ring in halohydrins undergoes a conformational change at the higher reaction
temperature (60-70 °C) to the axial-rich conformation which facilitates epoxide formation. It
is also likely that the lithium ions facilitate the change in conformation of the inositol ring.
Previous reports on the reactions of inositol derivatives in the presence of lithium containing
reagents support the involvement of chelates with lithium especially the 1,3-diaxial oxygen
atoms of inositol [1, 21-22]. These results support the conformational change of halohydrins
from ‘equatorial rich’ to ‘axial rich’ conformation prior to the formation of the corresponding
epoxide. In order to ascertain the validity of this line of reasoning, we also looked at reactions
which definitely involve inversion of the inositol ring (Scheme 4).
H
HO
OH
O
O
(a)
O
OH
OH
HO
HO
OH
HO
OH
29
30
5

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Scheme 4. Formation of myo-inositol orthoformate; (a) DMF, triethyl orthoformate, p-
toluene sulfonic acid, 100-110 ⁰C.
Instances of inversion of the inositol ring in their reactions are recorded in the
literature, for example, formation of inositol orthoesters [23]. In this reaction the inositol ring
is frozen in its axial-rich conformation in the product formed, confirming a conformational
change in the myo-inositol ring, during the reaction. Although inositol orthoesters have often
been used as key intermediates during the synthesis of cyclitol derivatives [24-26],
mechanism of formation of inositol orthoesters has not been discussed explicitly. Delineation
of the mechanism of inositol orthoester formation would also shed light on the formation of
1,2-anhydro inositols (Schemes 1 and 2). Hence we carried out DFT calculations (see below)
on a few myo-inositol systems to gain insight into the ease of inversion of the ‘equatorial-
rich’ inositol ring to the corresponding ‘axial-rich’ ring. Since formation of an inositol
orthoformate involves the displacement of three ethoxyl groups in succession, we calculated
the energy differences between some plausible intermediates (which are not stable enough to
be isolated) as well as free myo-inositol, as a reference (Schemes 5).
HO
HO
OH
OH
OH
5.2
OH
OH
HO
HO
HO
29 OH
31
OH
OH
HO
HO
OH
OR1
6.3
OH
OH
HO
R1O
HO
32 OH
OH
33
R1 = HC(OEt)2
HO
OR1
HO
OH
OH
3.7
OH
OH
R1O
HO
34 OR1
HO
OR1
35
R1 = HC(OEt)2
R1O
HO
OH
OR1
HO
OH
9.4
OH
OH
R1O
R1O
36 OH
37
OH
Scheme 5. Summary of the DFT calculations for the inversion of myo-inositol and its
derivatives. Numbers (Kcal/mol) on the arrows depict calculated differences in energies
between the two conformers, which indicate higher relative stability of ‘equatorial rich’
conformers 29, 32, 34 and 36 in each pair (see ESI for details).
6

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The results reveal that the inversion of ‘equatorial-rich’ inositol to the corresponding
‘axial-rich’ inositol becomes increasingly facile depending on the bulk and relative position
of the O-substituent (diethoxymethyl group). This has also been observed experimentally in
the case of certain O-silylated inositol derivatives, which crystallize in the axial-rich
conformation [27]. The reaction of inositol with triethylorthoformate leads to the formation
of an intermediate (such as 32 and 34). To relieve the strain caused by the O-substituents, the
inositol ring (in 34) flips to an axial rich conformation 35, wherein the proximity of the
reacting groups facilitates the formation of the corresponding orthoester 30. Among the O-
substituted inositol derivatives shown in Scheme 5, difference in energy between the two
conformers is minimum for the di-O-substituted derivative 34. The all axial conformer 35 is
also well suited for the subsequent cyclization reactions, which results in the formation of the
orthoformate. As observed in the case of halohydrins, the difference in energy between the
‘equatorial rich’ and the ‘axial rich’ conformers of the O-substituted inositols is much less
than that for the analogous conformers of free myo-inositol. The smaller difference in the
energies of the two conformers (such as 34 and 35) allows the required change in
conformation at the reaction temperature (100-110 °C). Other isomeric di-O-substituted
derivatives would also (in principle) lead to the formation of the orthoformate. However,
involvement of 37, as an intermediate during the formation of the orthoformate is unlikely,
since the difference in energy between the two conformers is more than that for free myo-
inositol, (29, 31) as well as its mono-O-substituted derivative (32, 33). Hence a plausible
mechanism for the formation of the orthoformate 30 can be summarized as in scheme 6. The
uncyclized orthoesters (such as 32 and 36) revert back to 34 (for eg., via steps 29 ↔ 32 ↔ 34
↔ 36) or hydrolyze during work-up and/or isolation of the product 30, and hence leave no
trace of their existence during the inositol orthoester formation.
7

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HO
DMF, H+
HC(OEt)3
OH
32 + C2H5OH
OH
OH
HO
DMF, H+
HC(OEt)3
29
35
OH
34 + C2H5OH
H
H
OEt
OH
and/or
EtO
HO
O
O
O
O
HO
HO
+ C2H5OH
HO
OH
HO
OR1
39
38
R1 = HC(OEt)2
H
O
O
Aqueous
work-up
O
HO
30
HO
40
OR1
Scheme 6. Plausible mechanism for the formation of the orthoformate 30 from myo-inositol.
We also computed and estimated the difference in energies for a few tri-O-substituted
myo- and scyllo-inositol derivatives (as control) to see how facile the inversion of the inositol
ring is, as compared to the di-O-substituted derivatives. This was because, in principle,
certain tri-O-substituted intermediates (such as 42, 46, 48,) could also lead to the formation of
inositol orthoformate 30. The results are shown in Scheme 7.
8

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HO
HO
OH
OR1
OH
OR1
6.7
R1O
HO
OH
R1O
41 OR1
OR1
OR1
42
HO
R1 = HC(OEt)2
HO
OH
OR1
-3.4
OH
OR1
R1O
HO
HO
OR1
43 OR1
44
R1O
HO
OR1
OH
OH
8.4
OH
OH
R1O
R1O
45 OR1
HO
OR1
46
R1 = HC(OEt)2
2
OR1
HO
OR1
OH
OH
HO
R1O
OR1
HO
47 OR1
OR1
HO
48
Scheme 7. Summary of the DFT calculations for the inversion of tri-O-substituted inositol
derivatives. Numbers (Kcal/mol) on the arrows depict calculated differences in energies
between the two conformers, which indicate higher relative stability of ‘equatorial rich’
conformers 41, 45, 47 and the ‘axial rich’ conformer 44 in each pair (see ESI for details).
These results reveal that the difference in energy between the equatorial rich- and the
corresponding axial rich conformer (as expected) depends on the relative position of the O-
substitutent as well as relative disposition (cis- or trans-) of the vicinal substituents. The myo-
1,5,6-derivative is an outlier since the axial-rich isomer 44, is more stable than the
corresponding equatorial-rich isomer 43, while for all other derivatives the opposite is true.
However, in spite of this, 44, cannot form the orthoformate 30 directly, since two of the three
hydroxyl groups that are required to form the orthoformate 30 are already substituted.
3. Conclusions.
All in all, We have presented a facile method for the preparation of 1,2-anhydro-inositols
from the corresponding vicinal trans-diequatorial diols using lithium hydride as a reagent.
The results of the DFT calculations presented support a conformational change leading to the
inversion of the inositol ring during the formation of 1,2-anhydro inositols. This mechanism
is supported by the results of DFT calculations pertaining to the formation of myo-inositol
orthoformate, where in the myo-inositol ring is locked in the ‘axial rich’ confirmation.
9

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4. Experimental Section.
4.1 General
Inositol derivatives 1-8 and 11 were prepared with the help of reported procedures
[14, 16-18, 28, 29]. ‘Usual work-up’ implies, decomposition of the reaction mixture, removal
of the volatiles under reduced pressure, suspension or dissolution of the residue in water and
extraction with a suitable solvent (ethyl acetate, dichloromethane, ether etc.), washing of the
solvent extract sequentially with dil. HCl, (if necessary), water, brine, drying of the organic
extract over anhydrous sodium sulfate and evaporation of the solvent under reduced pressure.
All the column chromatographic separations were carried out on silica gel (60-120 mesh).
All the density functional theory calculations were carried out using the Turbomole suite of
programs [30-32]. The DFT Geometry optimizations were performed using the B-P 86
functional [33-34]. The electronic configuration of the atoms was described by a triple-zeta
basis set augmented by a polarization function (TURBOMOLE basis set TZVP) [35]. The
resolution of identity (RI), along with the multipole accelerated resolution of identity (marij)
[36,37] approximations were employed for an accurate and efficient treatment of the
electronic Coulomb term in the density functional calculations. Solvent effects have been
incorporated using the COSMO model, 44 with toluene (epsilon = 2.38) [38] as the solvent.
4.2 Preparation of Racemic 1-deoxy-1-iodo-2,3,4,5-tetra-O-alkyl-scyllo-inositols. General
procedure A.
The racemic diol, dry toluene, triphenylphosphine, imidazole and iodine were mixed
o
and heated at 100 C for 2.5 h. The reaction mixture was cooled to room temperature and
filtered. The solid was washed 2-3 times with ethyl acetate. The combined filtrate was
concentrated under reduced pressure. The residue obtained was purified by column
chromatography to get the corresponding racemic iodo alcohol.
4.2.1 Racemic 1-deoxy-1-iodo-2,3,4,5-tetra-O-methyl-scyllo-inositol (12).
The diol 7 (1.000 g, 4.1 mmol), dry toluene (15 mL), triphenylphosphine (1.700 g,
6.5 mmol), imidazole (0.420 g, 6.5 mmol) and iodine (1.200 g, 4.2 mmol) were used as in
the general procedure A to obtain the racemic iodo alcohol 12 (0.800 g, 55%) after column
⁰
chromatography (eluent 3:7 ethyl acetate and light petroleum). mp 88 C, IR (Nujol):
ν
3300-3500 cm-1; 1H NMR (400 MHz, Chloroform-D) δ 3.79 (t, J =10.9 Hz, 1 H), 3.69 - 3.59
10

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(4s, 12 H), 3.56 (t, J = 9.2 Hz, 1 H), 3.26 - 3.16 (m, 1 H), 3.12 - 2.97 (m, 2 H), 2.97 - 2.85 (m,
1 H), 2.76 (br. s, 1 H, D2O exchangeable); 13C NMR (101 MHz, Chloroform-D) δ 86.3, 84.5,
84.2, 74.6, 61.2, 61.1, 61.0, 35.9; HRMS calcd for C10H20O5I,347.0350, found 347.0335.
4.2.2 Racemic 1-deoxy-1-iodo-2,3,4,5-tetra-O-allyl-scyllo-inositol (13).
The diol 8 (3.300 g, 9.7 mmol), dry toluene (100 mL), triphenylphosphine (4.600 g,
17.2 mmol), imidazole (1.190 g, 17.6 mmol) and iodine (3.260 g, 12.9 mmol) were used as
in the general procedure A to obtain the racemic iodo alcohol 13 as a gum (1.900 g, 47%)
after column chromatography (eluent 1:3 ethyl acetate and light petroleum). IR (neat):
ν
3300-3500 cm-1; 1H NMR (500 MHz, Chloroform-D) δ 6.02 - 5.78 (m, 4 H), 5.30 - 5.0 (m, 8
H), 4.34 - 4.14 (m, 8 H), 3.79 (t, J = 11.1 Hz, 1 H), 3.63 - 3.48 (m, 1 H), 3.40- 3.25 (m, 2H,
13
1H D2O exchangeable), 3.25 - 3.12 (m, 2 H), 3.07 (t, J = 9.1, 1 H); C NMR (126 MHz,
Chloroform-D) δ 134.8, 134.7, 134.6, 134.3, 116.9(CH2), 116.8(CH2), 116.5(CH2),
116.4(CH2), 83.2, 82.2, 81.7, 81.3, 74.4(CH2), 74.3(CH2), 74.0(CH2), 74.0(CH2), 36.6;
HRMS calcd for C18H28O5I, 451.0976, found 451.0970.
4.2.3 Racemic 1-deoxy-1-iodo-3,6-di-O-benzyl-4,5-di-O-methyl-scyllo-inositol (14)
The diol 9 (0.420 g, 1.1 mmol), dry toluene (35 mL), triphenylphosphine (0.709 g,
2.7 mmol), imidazole (0.185 g, 2.7 mmol) and iodine (0.546 g, 2.2 mmol) were used as in
the general procedure A to obtain the racemic iodo alcohol 14 (0.380 g, 70%) after column
⁰
chromatography (eluent 3:7 ethyl acetate and light petroleum). mp 108-110 C; IR (Nujol):
ν
1
3200 – 3400 cm-1; H NMR (400 MHz, Chloroform-D) δ 7.49 (d, J = 7.3 Hz, 2 H), 7.43 -
7.13 (m, 9 H), 4.96 - 4.81 (m, 3 H), 4.77 (d, J = 11.0 Hz, 1 H), 3.87 (t, J = 11.2 Hz, 1 H),
3.66 (s, 3 H),3.67 (s, 3H), 5.2 (t, J = 9.4 Hz, 1 H), 3.25 - 3.07 (m, 3 H), 2.67 (s, 1H, D2O
exchangeable); 13C NMR (101 MHz, Chloroform-D) δ 138.2, 137.8, 128.6, 128.4, 128.0,
86.4, 84.5, 82.6, 82.5, 77.3, 77.0, 76.7, 75.8(CH2), 75.5(CH2), 74.8, 61.2, 35.9; HRMS calcd
for C22H28O5I, 499.0976, found 499.0979.
4.2.4 Racemic 1-deoxy-1-iodo-3,6-di-O-benzyl-4,5-di-O-allyl-scyllo-inositol (15).
The diol 10 (0.520 g, 1.2 mmol), dry toluene (20 mL), triphenylphosphine (0.738 g,
1.8 mmol), imidazole (0.305 g, 1.8 mmol) and iodine (0.336 g, 1.2 mmol) were used as in
the general procedure A to obtain the racemic iodo alcohol 15 (0.350 g, 53%) after column
⁰
chromatography (eluent 1:9 ethyl acetate and light petroleum). mp 81-82 C; IR (Nujol):
ν
11

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3200-3400 cm-1; 1H-NMR (500 MHz, Chloroform-D) δ 7.47 (d, J = 7.2 Hz, 2 H), 7.42 - 7.18
(m, 8 H), 6.05 - 5.89 (m, 2 H), 5.30 (d, J = 17.2 Hz, 2 H), 5.18 (d, J = 10.3 Hz, 2 H), 4.94 -
4.84 (m, 3 H), 4.76 (d, J = 11.4 Hz, 1 H), 4.38 - 4.27 (m, 4 H), 3.92 - 3.81 (m, 1 H), 3.68 (t, J
= 9.9 Hz, 1 H), 3.57 (m, 1 H), 3.39 (t, J = 9.5 Hz, 1 H), 3.32 (t, J = 9.3 Hz, 1 H), 3.28 - 3.18
13
(m, 1 H), 2.65 (br. s., 1 H, D2O exchangeable); C NMR (101 MHz, Chloroform-D) δ 36,
74.44(CH2) 74.53(CH2), 74.91, 75.63(CH2), 75.81(CH2), 81.82, 82.50, 83.79, 117(CH2),
117.1(CH2), 128.04, 128.42, 128.38, 128.62, 128.62, 134.76, 134.87,137.71, 138.19; HRMS
calcd for C26H32O5I, 551.1289, found 551.1287.
4.3 Preparation of 1,2-anhydro-scyllo-inositol derivatives. General procedure B.
The racemic iodo-inositol derivative was dissolved in dry THF. Lithium hydride was
added to the above solution and stirred for 15 min. The reaction mixture was then heated at
o
66 C till the TLC analysis showed absence of the starting iodo-alcohol (about 2h 30 min).
The reaction mixture was decomposed by the addition of few pieces of ice and THF was
evaporated under reduced pressure. The residue was worked up with ethyl acetate. The
product was purified by column chromatography (60-120 mesh silica gel) to isolate the
racemic epoxide.
4.3.1 Racemic 1,2-anhydro-3,4,5,6-tetra-O-benzyl-scyllo-inositol (16)
The racemic iodo-inositol derivative 11 (5.000 g, 7.7 mmol), THF (130 mL), lithium
hydride (0.184 g, 23.1 mmol) were used as in the general procedure B to obtain the racemic
epoxide 16 as a solid (3.600 g, 89%, eluent for column chromatography, 1:9 ethyl acetate and
⁰
⁰
light petroleum). mp 109 C; lit. [11] mp 106-107 C.
4.3.2 Racemic 1,2-anhydro-3,4,5,6-tetra-O-methyl-scyllo-inositol (17).
The iodo derivative 12 (0.400 g, 1.1mmol) dry THF (15 mL) and lithium hydride (0.026 g,
3.3 mmol) were used as in general procedure B to obtain the racemic epoxide 17 (0.210 g,
1
84%) after column chromatography (eluent 1:5 ethyl acetate and light petroleum). H NMR
(400 MHz, Chloroform-D) δ 3.62 - 3.51 (m, 13 H), 3.47 (d, J = 7.9 Hz, 1 H), 3.40 (br. s, 1
H), 3.19 - 3.12 (m, 2 H), 3.05 - 2.98 (m, 1 H);13C NMR (101MHz, Chloroform-D) δ 85.0,
80.8, 80.7, 80.2, 61.0, 60.6, 58.6, 58.3, 54.4, 53.3; HRMS calcd for C10H18O5Na 241.1046,
found 241.1045.
4.3.3 Racemic 1,2-anhydro-3,4,5,6-tetra-O-allyl-scyllo-inositol (18).
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The iodo-inositol 13 (1.500 g, 3.3 mmol), lithium hydride (0.08 g, 10 mmol) and dry THF
were used as in the general procedure B to obtain the racemic epoxide 18 (0.800 g, 74%)
1
after column chromatography (eluent 1:9 ethyl acetate and light petroleum). H NMR (500
MHz, Chloroform-D) δ 6.07 - 5.85 (m, 4 H), 5.35 - 5.1 (m, 8 H), 4.31 - 4.10 (m, 8 H), 3.72 -
3.67 (m, 1 H), 3.65 (d, J = 8.0 Hz, 1 H), 3.37 - 3.28 (m, 2 H), 3.21 (dd, J = 8.0, 10.3 Hz, 1 H),
3.12 (d, J = 3.4 Hz, 1 H); 13C NMR (126 MHz, Chloroform-D) δ 135.0, 134.7, 134.1,
117.1(CH2), 116.8(CH2), 116.3(CH2), 116.2(CH2), 82.7, 78.7, 78.3, 78.2, 74.1(CH2),
73.9(CH2), 71.8(CH2), 71.8(CH2), 55.0, 53.6; HRMS calcd for C18H26O5Na 345.1672, found
345.1670.
4.3.4 Racemic 1,2-anhydro-3,6-di-O-benzyl-4,5-di-O-methyl-scyllo-inositol (19).
The iodo derivative 14 (0.380 g, 0.8 mmol), dry THF (30 mL) and lithium hydride (0.018 g,
2.3 mmol) were used as in general procedure B to obtain the racemic epoxide 19 (0.239 g,
⁰
84%). mp 67-68 C; 1H NMR (400 MHz, Chloroform-D) δ 7.53 - 7.23 (m, 10 H), 4.90 - 4.80
(m, 1 H), 4.79 - 4.67 (m, 3 H), 3.75 (t, J = 8.2 Hz, 2 H), 3.61 (s, 3 H), 3.60 (s, 3H) 3.31 - 3.19
13
(m, 2 H), 3.19 - 3.05 (m, 2 H); C NMR (101 MHz, Chloroform-D) δ 138.3, 137.8, 128.5,
128.4, 127.9, 127.8, 85.4, 80.8, 79.0, 78.9, 77.3, 76.7, 73.2(CH2), 73.0(CH2), 61.2, 60.9, 55.3,
53.9; HRMS calcd for C22H27O5, 371.1853, found 371.1852.
4.3.5 Racemic 1,2-anhydro-3,6-di-O-benzyl-4,5-di-O-allyl-scyllo-inositol (20).
The iodo derivative 15 (0.300 g, 0.5 mmol), THF (15 mL) and lithium hydride (0.013 g, 1.6
mmol) were used as in the general procedure B to obtain the racemic epoxide 20 as a solid
(0.160 g, 71%) after column chromatography (eluent 2:23 ethyl acetate and light petroleum).
⁰
mp 53-54 C; 1H NMR (500 MHz, Chloroform-D) δ 7.48 - 7.24 (m, 10 H), 6.04 - 5.85 (m, 2
H), 5.36 - 5.21 (m, 2 H), 5.15 (d, J = 10.3 Hz, 2 H), 4.96 - 4.79 (m, 1 H), 4.78 - 4.69 (m, 3
H), 4.34 - 4.17 (m, 4 H), 3.85 - 3.68 (m, 2 H), 3.49 - 3.33 (m, 1 H), 3.31 - 3.23 (m, 2 H), 3.15
(d, J = 3.8 Hz, 1 H); 13C NMR (126 MHz, Chloroform-D) δ 138.3, 137.7, 135.2, 135.2,
128.5, 128.4, 127.9, 127.8, 127.8, 127.7, 116.7(CH2), 116.6(CH2), 83.1, 79.0, 78.9, 78.5,
74.5(CH2), 74.3(CH2), 73.3(CH2), 73.1(CH2), 55.3, 53.9; HRMS calcd for C26H30O5Na,
445.1985, found 445.1983.
Supporting Information: NMR spectra for all the new compounds; geometry optimized
colored diagrams and Cartesian co-ordinates (DFT data) for structures 11, 16, 25–29, 31–37,
41–48 associated with this article. Complete crystallographic data for the structural analysis
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have been deposited with the Cambridge Crystallographic Data Centre, CCDC number
1585249. Copies of this information may be obtained free of charge from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB21EZ, UK. (fax:
+44-1223-336033, e-mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
Conflicts of interest: There are no conflicts to declare.
Acknowledgements. NS and RSS thank the UGC, New Delhi, and MIT thanks the CSIR,
New Delhi, for fellowships. Discussions with Dr. Kumar Vanka regarding DFT calculations
are highly appreciated. This work was supported by the Science and Engineering Research
Board (grant No. SB/S1/OC-23/2013), New Delhi.
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Highlights.
Lithium hydride converts halohydrins to epoxides efficiently.
Inositol derived halohydrin flips to axial-rich conformation prior to reaction.
DFT calculations support 1,2-anhydro inositol formation via axial-rich conformation.