Inositol to aromatics –benzene free synthesis of poly oxygenated aromatics

Article abstract of DOI:10.1016/j.carres.2018.03.007

A method for the preparation of benzene derivatives from myo-inositol, an abundantly available phyto chemical is described. 1,3-Bridged acetals of inososes undergo step-wise elimination leading to the formation of polyoxygenated benzene derivatives. This aromatization reaction proceeds through the intermediacy of a β-alkoxyenone, which could be isolated. This sequence of reactions starting from myo-inositol, provides a novel route for the preparation of polyoxygenated benzene derivatives including polyoxygenated biphenyl. This scheme of synthesis demonstrates the potential of myo-inositol as a sustainable non-petrochemical resource for aromatic compounds.

Full text of DOI:10.1016/j.carres.2018.03.007

Carbohydrate Research 461 (2018) 38e44
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Inositol to aromatics ebenzene free synthesis of poly oxygenated
aromatics
,
Bharat P. Gurale a, Mysore S. Shashidhar a *, Richa S. Sardessai a, Rajesh G. Gonnade b
a The Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pashan Road, Pune, 411 008, India
b Center for Materials Characterization, CSIR- National Chemical Laboratory, Pashan Road, Pune, 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the preparation of benzene derivatives from myo-inositol, an abundantly available phyto
chemical is described. 1,3-Bridged acetals of inososes undergo step-wise elimination leading to the
formation of polyoxygenated benzene derivatives. This aromatization reaction proceeds through the
Received 6 February 2018
Received in revised form
13 March 2018
Accepted 13 March 2018
Available online 14 March 2018
intermediacy of a b-alkoxyenone, which could be isolated. This sequence of reactions starting from myo-
inositol, provides a novel route for the preparation of polyoxygenated benzene derivatives including
polyoxygenated biphenyl. This scheme of synthesis demonstrates the potential of myo-inositol as a
sustainable non-petrochemical resource for aromatic compounds.
Keywords:
Biomass
© 2018 Elsevier Ltd. All rights reserved.
Cyclitol
Inositol
Sustainable
Polyhydroxybenzene
1. Introduction
derived sources [18e21]. There are few reports on the synthesis
of benzene derivatives starting from sugars such as glucose. Some
Functionalized benzene moieties occur in a variety of useful
chemicals such as drugs, agrochemicals, and natural products
isolable from plant and marine sources. Polyhydroxy-benzene
moieties, such as 1,2,3,5-tetrahydroxy benzene, are present in a
variety of organic molecules and natural products (e.g. baicalein,
khellin, oroxylin, liphagal), which possess interesting chemical and
biological properties [1e5]. Some of these polyphenolic com-
pounds (flavonoids) [6,7] are known to have anti-carcinogenic,
anti-viral, anti-xiolytic, anti-protozoal and anti-inflammatory ac-
tivities [8e15]. Phosphorylated derivatives of polyhydroxy ben-
zenes have been tested as substitutes for inositol polyphosphates in
the context of cellular signal transduction in eukaryotic systems
[16]. Synthesis of several polyhydroxy benzene derivatives have
been reported via the classical chemistry [17]. However, use of
classical aromatic chemistry is associated with certain limitations
such as dependence on petrochemicals and health hazards asso-
ciated with handling of aromatic compounds in every step of the
synthetic sequence. Hence there has been a recent upsurge in in-
terest in the preparation of benzene derivatives from bio-mass
of these conversions are mediated by enzymes which convert
sugars (e.g. glucose) to a carbocycle (e.g. shikimic acid) which is the
precursor for the benzene derivative [22e26].
myo-Inositol (1, Scheme 1, a hexahydroxy cyclohexane e a car-
bocycle) can be obtained in reasonably large quantities from plant
sources, where it is predominantly present as phytic acid (2, myo-
inositol hexakisphosphate). Chemistry of inositols has been well
investigated due to the involvement of phosphoinositols in cellular
signal transduction pathways [27e30] and aromatization of myo-
inositol derivatives during synthetic transformations have been
encountered [31e35]. Hence use of myo-inositol as a sustainable
source for >4 carbon building blocks is not unrealistic. As proof of
this concept, we report herein a preparative method for the con-
version of myo-inositol to tetrahydroxy benzene derivatives via 1,3-
bridged acetals.
2. Results and discussion
As a part of an ongoing program on the synthetic utility of myo-
inositol we were investigating the potential of myo-inositol derived
1,3-bridged acetals as key intermediates for the synthesis of natural
products containing the cyclitol moiety [29,36,37]. We observed
that 5 was converted (within 5 min) to the benzene derivative 6 in
* Corresponding author.
E-mail addresses: bharatg@ashstevens.com (B.P. Gurale), ms.shashidhar@ncl.res.
in (M.S. Shashidhar), rg.gonnade@ncl.res.in (R.G. Gonnade).
https://doi.org/10.1016/j.carres.2018.03.007
0008-6215/© 2018 Elsevier Ltd. All rights reserved.

B.P. Gurale et al. / Carbohydrate Research 461 (2018) 38e44
39
Scheme 1. Structure of myo-inositol (1), phytic acid (2), glucose (3) and tetrahydroxy
benzene (4).
Scheme 3. (a) Ethyl acetate, IBX, reflux, 3 h; (b) THF, NaH, 15 min.
the presence of sodium hydride in THF, at 0 ꢀC (Scheme 2). The
inosose 7 also aromatized under similar conditions to form tetra-
hydroxyl benzene (THB) derivative 6.
synthesis of polyhydroxybiaryls from myo-5-inosose. myo-5-
Inosose 5 was converted to the 5-C-phenyl triol 19 (Scheme 4);
one of the secondary hydroxyl groups in 19 was tosylated to afford
20. Oxidation of the secondary hydroxyl group in 20 with IBX and
exposure of the resulting ketone 21 to sodium hydride in THF gave
the biaryl 22. This reaction can also be adopted for the preparation
of C-alkylated tetra-hydroxy benzenes, by using different Grignard
reagents. This sequence of reactions provides an alternative to
other methods that depend on benzene derivatives as starting
materials for obtaining biphenyls [38e43]. On the basis of the
experimental findings described so far, we believe, mechanism for
the aromatization reaction involves several enolizations (of the
inosose derivatives) followed by elimination of benzaldehyde or p-
toluenesulfonic acid (see ESI for mechanistic schemes).
As evident from Scheme 4, Grignard reaction of the ketone 5
was highly selective to yield only the neo-inositol derivative 19. We
had also observed similar high selectivity during the hydride
reduction of 1,3-bridged inositol-derived ketones earlier [37]. Since
these bridged ketones can in principle exist in three conformations
(23e25 Scheme 5), it was not obvious to conclude that the observed
selectivity (formation of the neo-inositol derivative 19) in product
formation was due to the presence of the 1,3-acetal bridge in 5.
Hence in order to ascertain the role of the 1,3-acetal bridge, a
C5-ketone 26 without the 1,3-acetal bridge was prepared (Scheme
We could establish the intermediacy of the
a,b-unsaturated
ketone 9 in this process by exposing the inosose 5 (and 7) to a
milder base, triethylamine, at or below ꢁ10 ꢀC (to isolate 9) and
subsequent treatment of 9 with sodium hydride in THF to obtain 6.
The observed conversion of the acetals 5 (and 8) to 6 and 9 was
seemingly unusual, since these conversions involved cleavage of
acetals under basic conditions (to which acetals are normally sta-
ble). The 1,3-bridged acetals 5 and 8 when exposed to acid under-
went solvolysis (as expected) to provide the corresponding diol 7
and no aromatization was observed. The diol 7 on exposure to
triethylamine or sodium hydride (behaved similar to the acetals 5
and 8) gave the unsaturated ketone 9 and the benzene derivative 6
respectively. The structure of 6 was established by single crystal X-
ray diffraction analysis.
On the samelines, orthogonally protected inosose derivatives
13e15 could be converted to the corresponding tetrahydrox-
ybenzene derivatives 16e18 (Scheme 3). The ketone 14 was pre-
pared in two steps from 4,6-di-O-allyl-myo-inositol-1,3,5-
orthoformate (via the alcohol 11 which was not isolated; see
experimental section for details).
We were also able to develop a completely new route for the
Scheme 4. (a) Diethyl ether, C6H5MgBr, ꢁ10 ꢀC, 1 h; (b) aq. HCl, THF, reflux 2 h, 65%; (c)
pyridine, tosyl chloride, 2 h, 72%; (d) ethyl acetate, IBX, reflux, 3 h; (e) THF, sodium
hydride, 15 min, 94% (for 2 steps).
Scheme 2. (a) THF, NaH, 0 ꢀC, 5 min, 96e98%; (b) THF:MeOH, concd HCl, reflux, 1 h,
91%; (c) THF, Et3N, ꢁ10 ꢀC, 1 h, 89%.

40
B.P. Gurale et al. / Carbohydrate Research 461 (2018) 38e44
presented here provide access to aromatic compounds without
using benzene (a known carcinogen) or its derivatives as precursors
[45,46]. Some of the polyoxygenated benzene derivatives reported
here can be used as intermediates for the synthesis of flavanoids
[47].
4. Experimental procedures
4.1. Aromatization of inososes: general procedure A
To a cooled (0 ꢀC) solution of the inosose (1.00e3.00 mmol) in
dry THF (5e15 mL) was added sodium hydride (1.00e3.00 mmol)
and stirred for 5 min. The solvent was removed under reduced
pressure and the crude reaction mixture was dissolved in ethyl
acetate, washed successively with water, 2% aq. hydrochloric acid,
saturated sodium bicarbonate solution followed by brine and dried
over anhd sodium sulfate. The solvent was removed under reduced
pressure and the crude product obtained was purified by column
chromatography (eluent: ethyl acetate in light petroleum) to afford
the corresponding tetrahydroxy benzene derivative.
4.2. 2,4,6-tris(benzyloxy)phenol 6
Scheme 5. (a) Toluene, CH3MgI, 1 h, 27:28 ¼ 2.4:1; (b) methanol, NaBH4, reflux, 24 h;
(c) pyridine, Ac2O, DMAP, 48 h, 32:31 ¼1:3.8.
The myo-inosose 5 [37] (1.61 g, 3 mmol), dry THF (15 mL) and
sodium hydride (0.12 g, 3 mmol) were used (Procedure A) to obtain
6 as a colorless solid (1.21 g, 98%) after column chromatography
(eluent: 3:17 ethyl acetate-light petroleum). TLC Rf ¼ 0.3 (3:17 ethyl
acetate-light petroleum); mp 103e105 ꢀC; IR (CHCl3):
n
3340e3620,
1630 cmꢁ1 1H NMR (CDCl3, 200 MHz):
; d 7.26e7.50 (m, 15H), 6.30
(s, 2H), 5.21 (s, 1H, D2O exchangeable), 5.09 (s, 4H), 4.90 (s, 2H)
ppm; 13C NMR (CDCl3, 50.3 MHz): 151.8, 146.4, 136.9, 136.6, 130.4,
128.54, 128.48, 128.0, 127.9, 127.53, 127.48, 95.4, 71.4 (CH2), 70.7
(CH2) ppm; Anal. calcd for C27H24O4 (412.48): C 78.62, H 5.86;
found: C 78.40, H 5.62.
4.3. 2,4,6-Tris(benzyloxy)-5-hydroxycyclohex-2-enone 9
To a cooled (ꢁ10 ꢀC) solution of the myo-inosose 5 (1.60 g,
3 mmol) in dry THF (15 mL) was added triethyl amine (0.50 mL,
3.5 mmol) and stirred for 1 h. The reaction mixture was diluted
with ethyl acetate, washed with water, followed by brine and dried
over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the brown solid obtained was purified by
column chromatography (eluent: 30% ethyl acetate-light petro-
leum) to afford 9 as a colorless solid (1.15 g, 89%). TLC Rf ¼ 0.3 (3:7
Scheme 6. (a) DMF, NaH, allyl bromide, 3 h, 92%; (b) HCl, methanol, 12 h; (c) DMF,
NaH, benzyl bromide, 3 h, 82% over 2 steps; (d) ethanol, K2CO3, Pd(PPh3)4, reflux, 48 h,
86%; (e) ethyl acetate, IBX, 6 h, 96%.
ethyl acetate-light petroleum); mp 86e88 ꢀC; IR (CHCl3):
n
3497,
1705, 1626 cmꢁ1; 1H NMR (CDCl3, 200 MHz):
d 7.27e7.50 (m, 15H),
6) and subjected to sodium borohydride reduction as well as
Grignard reaction. Both the reactions (Scheme 5) on the myo-ino-
sose derivative 26 resulted in the formation of a mixture of myo-
and neo-inositol derivatives. The ratio of isomeric C-methylated
inositols 27 and 28 obtained was 2.4:1 and the ratio of isomeric
inositols 29:30 was 1:3.8 (estimated as the corresponding acetates
31 and 32) as revealed by 1H NMR spectroscopy. These results
conclusively establish the role of the 1,3-acetal bridge in directing
selective nucleophilic addition to the carbonyl group in inososes.
5.70 (d, 1H, J ¼ 5.6 Hz), 5.00 (d, 1H, J ¼ 11.2 Hz), 4.82 (s, 2H),
4.55e4.75 (m, 3H), 4.40e4.47 (m, 1H), 4.35 (d, 1H, J ¼ 8.7 Hz),
4.05e4.17 (m, 1H), 2.72 (d, 1H, J ¼ 4.5 Hz, D2O exchangeable) ppm;
13C NMR (CDCl3, 50.3 MHz):
d 191.4, 150.3, 137.8, 137.4, 135.4, 128.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.85, 127.81, 127.2, 112.2, 80.4,
73.6 (CH2), 72.4, 72.1 (CH2), 71.1, 69.8 (CH2) ppm; Anal. calcd for
C27H26O5 (430.49): C 75.33, H 6.09; found: C 75.52, H 6.42%.
4.4. 2,4,6-Tri-O-benzyl-myo-5-inosose 7
3. Conclusions
A mixture of myo-5-inosose 8 [48] (2.3 g, 5 mmol), conc. HCl
(4 mL) and THF-water mixture (25 mL þ 2.5 mL) was refluxed for
12 h. The solvents were removed under reduced pressure to obtain
gummy residue which was dissolved in dichloromethane
(100e200 mL). The organic extract was washed with saturated
sodium bicarbonate solution followed by brine and dried over anhd
sodium sulfate. The solvent was removed under reduced pressure
and the solid obtained was purified by column chromatography
We have herein demonstrated the potential of myo-inositol to
be used as a biomass derived source [44] for the preparation of
polyoxygenated aromatic compounds including biphenyls, which
are not easily accessible. This sequence of reactions can also be
adopted for the preparation of C-alkylated tetrahydroxy benzenes
(Scheme 4), by using different Grignard reagents. The results

B.P. Gurale et al. / Carbohydrate Research 461 (2018) 38e44
41
(eluent: 3:7 ethyl acetate in light petroleum) to obtain the diol 7 as
a colorless solid (2.04 g, 91%). TLC Rf ¼ 0.3 (7:13 ethyl acetate-light
500 MHz):
d
5.30 (d, 1H, J ¼ 4.9 Hz), 4.51 (d, 1H, J ¼ 4.8 Hz),
4.37e4.40 (m, 2H), 4.15 (t, 1H, J ¼ 1.2 Hz), 3.59 (d, 2H, J ¼ 3.6 Hz),
petroleum); mp 124e127 ꢀC; IR (CHCl3):
n
3325e3550, 1733 cmꢁ1
;
3.44 (s, 3H), 3.35 (s, 6H) ppm; 13C NMR (CDCl3, 125.76 MHz):
1H NMR (CDCl3, 200 MHz):
d
7.24e7.50 (m, 15H), 4.92 (s, 2H),4.72
d 202.9, 85.7, 84.5, 72.0, 71.9, 58.9, 56.7; Anal. calcd for C10H16O6
(q, 4H, J ¼ 11.1 Hz), 4.42 (d, 2H, J ¼ 10.0 Hz), 4.22 (t, 1H, J ¼ 2.6 Hz),
(232.23): C 51.72, H 6.94; found: C 51.69, H 7.14%.
3.72 (dd, 2H, J1 ¼ 2.6, J2 ¼ 10.1 Hz), 2.38e2.85 (br s, 2H, D2O
exchangeable) ppm; 13C NMR (CDCl3, 50.3 MHz):
d
203.0, 138.3,
4.10. 1,3-O-Methylidene-2-O-methyl-4,6-di-O-allyl-myo-5-inosose
137.2, 128.45, 128.37, 128.2, 128.0, 127.9, 127.8, 82.7, 78.1, 75.6, 73.3,
72.2 ppm; Anal. calcd for C27H28O6 (448.50): C 72.30, H 6.29; found:
C 72.52, H 6.02%.
14
The 4,6-di-O-allyl-1,3,5-orthoformate [50] (5.00 g, 18.5 mmol)
dry DMF (100 mL), sodium hydride (0.96 g, 24 mmol) and methyl
iodide (1.30 mL, 20.3 mmol) were used to obtain the corresponding
methyl ether (5.30 g); TLC Rf ¼ 0.4 (in 1:4 ethyl acetate-light pe-
troleum) which was used in the next reaction without purification.
The crude methyl ether (5.30 g), 1 M solution of DIBAL-H in toluene
(46 mL, 46 mmol), dry dichloromethane (150 mL), Na/K tartrate
(110 g in 180 mL water) and saturated ammonium chloride solution
(180 mL) were used (as in the preparation of 10) to obtain crude 11
(5.31 g); TLC Rf ¼ 0.4 (1:3 ethyl acetate-light petroleum) as a
gummy liquid, which was used without purification.
4.5. Reaction of inosose 8 and 9 with sodium hydride
The inosose 8 or 9 (2 mmol), dry THF (10 mL) and sodium hy-
dride (1.0e1.5 mmol) were used (Procedure A) to obtain 2,4,6-
tris(benzyloxy)phenol 6 as a colorless solid (94e96%) after col-
umn chromatography.
4.6. Reaction of inosose 7 and 8 with triethyl amine
To
a
cooled (ꢁ10 ꢀC) solution of the inosose
7
or
8
The crude 11 (2.7 g), ethyl acetate (50 mL) and IBX (5.18 g,
18.5 mmol) were used (procedure B) to obtain the ketone 14 (2.45 g,
93%, over 3 steps) as a colorless gum, after column chromatography
(eluent: 1:9 ethyl acetate-light petroleum). TLC Rf ¼ 0.45 (3:17 ethyl
(1.0e1.5 mmol) in dry THF (10 mL), dry triethyl amine
(1.0e1.5 mmol) was added and stirred for 1 h. The reaction mixture
was worked up with ethyl acetate and the brown solid obtained
was purified by column chromatography to obtain 9 as a colorless
solid (88e90%).
acetate-light petroleum); IR (CHCl3):
200 MHz):
n ;
1726 cmꢁ1 1H NMR (CDCl3,
5.75e596 (m, 2H), 5.32e5.40 (m, 2H), 5.16e5.27 (m,
d
3H), 4.60 (d, 1H, J ¼ 5.2 Hz), 4.42e4.50 (m, 2H), 4.32e4.35 (m, 1H),
4.7. 1,3-O-Methylidene-2,4,6-tri-O-methyl-myo-inositol 10
3.93e4.16 (m, 4H), 3.86 (d, 2H, J ¼ 3.2 Hz), 3.52 (s, 3H, CH3) ppm;
13C NMR (CDCl3, 125.76 MHz):
d 202.9, 133.2, 118.0, 85.3(CH2), 81.2,
1 M solution of DIBAL-H in toluene (12.50 mL, 12.5 mmol) was
added drop-wise over a period of 15 min to a solution of 2,4,6-tri-O-
methyl-myo-inositol-1,3,5-orthoformate [49] (1.16 g, 5 mmol) in
dry dichloromethane (50 mL) at 0 ꢀC and then stirred at room
temperature for 2.5 h. The reaction mixture was poured into a
stirred solution of sodium potassium tartarate (30 g in 50 mL water)
and saturated solution of ammonium chloride (50 mL) and stirred
for 12 h. The mixture was extracted with dichloromethane
(2 ꢂ 75 mL), washed with brine and dried over anhd sodium sul-
fate. The solvent was removed under reduced pressure to obtain
the crude alcohol. The acetal 10 (1.17 g, 98%) was isolated as a
colorless solid by column chromatography (eluent: 1:3 ethylacetate
- light petroleum). TLC Rf ¼ 0.3 (1:3 ethyl acetate-light petroleum);
71.7, 71.6, 71.2, 56.4; Anal. calcd for C14H20O6 (227.23): C 59.14, H
7.09; found: C 59.03, H 6.47%.
4.11. 1,3-O-Methylidene-2-O-(4-methoxybenzyl)-4,6-di-O-benzyl-
myo-5-inosose 15
The alcohol 12 [35] (1.48 g, 3 mmol), IBX (1.68 g, 6 mmol) and
ethyl acetate (20 mL) were used (Procedure B) to obtain the ketone
15 as a colorless gum (1.41 g, 95%) after column chromatography
(eluent: 1:9 ethyl acetate-light petroleum). TLC Rf ¼ 0.35 in 1:9
ethyl acetate-light petroleum; IR (CHCl3):
(CDCl3, 200 MHz):
n ;
1719 cmꢁ1 1H NMR
7.15e7.40 (m, 12H), 6.80e6.91 (m, 2H), 5.46 (d,
d
1H, J ¼ 4.7 Hz), 4.71 (t, 1H, J ¼ 1.4 Hz), 4.57e4.67 (m, 5H), 4.42e4.51
mp 70e71 ꢀC; IR (CHCl3):
200 MHz):
n ;
3250e3620 cmꢁ1 1H NMR (CDCl3,
(m, 4H), 3.91 (d, 2H, J ¼ 3.6 Hz), 3.79 (s, 3H) ppm; 13C NMR (CDCl3,
d
5.41 (d, 1H, J ¼ 5.1 Hz), 4.70 (d, 1H, J ¼ 5.1 Hz),
50.3 MHz): d 202.8, 159.4, 136.9, 129.7, 128.3, 127.8, 113.9, 85.5, 81.7,
4.30e4.45 (m, 2H), 3.75e3.90 (m, 4H), 3.48 (s, 6H), 3.46 (s, 3H), 3.00
72.32, 72.28, 70.7 (CH2), 69.2, 55.2 ppm; Anal. calcd for C29H30O7
(490.54): C 71.00, H 6.16; found: C 70.93, H 5.93%.
(d, 1H, J ¼ 9.2 Hz, D2O exchangeable) ppm; 13C NMR (CDCl3,
50.3 MHz): d 85.3 (CH2), 83.4, 71.8, 71.2, 69.6, 58.3, 56.1; Anal. calcd
for C10H18O6 (234.25): C 51.27, H 7.75; found: C 51.13, H 7.68%.
4.12. 2,4,6-Tri-methoxyphenol 16
4.8. Preparation of inososes: general procedure B
The myo-inosose 13 (0.23 g,1 mmol), dry THF (5 mL) and sodium
hydride (0.04 g, 1 mmol) were used (Procedure A) to obtain 16
(0.175 g, 95%) as a yellow crystalline solid after column chroma-
tography (eluent: 1:9 ethyl acetate-light petroleum). TLC Rf ¼ 0.3
To a solution of the alcohol (2e4 mmol) in ethyl acetate
(20e40 mL) was added IBX (4e8 mmol) and refluxed for 3 h. Then
the reaction mixture was filtered through sintered glass funnel and
washed with ethyl acetate. The combined filtrate and washings
were evaporated under reduced pressure to obtain the corre-
sponding inosose.
(3:7 ethyl acetate-light petroleum); mp 58e61.2 ꢀC; IR (CHCl3):
n
3440e3450, 1622 cmꢁ1 1H NMR (CDCl3, 200 MHz):
; d 6.19 (s, 2H),
5.12 (s, 1H, D2O exchangeable), 3.87 (s, 3H), 3.77 (s, 6H) ppm; 13C
NMR (CDCl3, 50.3 MHz): 153.0, 147.3, 129.0, 91.7, 56.2, 55.7 ppm;
Anal. calcd for C9H12O4 (184.19): C 58.69, H 6.57; found: C 58.30, H
6.78%.
4.9. 1,3-O-Methylidene-2,4,6-tri-O-methyl-myo-5-inosose 13
The alcohol 10 (0.80 g, 3.4 mmol), ethyl acetate (15 mL) and IBX
(0.56 g, 6 mmol) were used (Procedure B) to obtain the ketone 13
(0.74 g, 94%) as a crystalline solid (crystals from hot 3:17 ethyl ac-
etate e light petroleum). TLC Rf ¼ 0.5 (1:3 ethyl acetate-light pe-
4.13. 2,6-Bis(allyloxy)-4-methoxyphenol 17
The myo-inosose 14 (0.85 g, 3 mmol), dry THF (15 mL) and so-
dium hydride (0.12 g, 3 mmol) were used (Procedure A) to obtain 17
(0.67 g, 95%) as a colorless solid, after column chromatography
troleum); mp 45.8e47 ꢀC; IR (CHCl3): 1725 cmꢁ1; 1H NMR (CD2Cl2,
n

42
B.P. Gurale et al. / Carbohydrate Research 461 (2018) 38e44
(eluent: 1:9 ethyl acetate-light petroleum). TLC Rf ¼ 0.5 (1:4 ethyl
acetate-light petroleum); mp 63.5e65 ꢀC; IR (CHCl3):
3100e3400,
1622 cmꢁ1; 1H NMR (CDCl3, 200 MHz):
6.19 (s, 2H), 5.98e6.17 (m,
2H), 5.43e5.47 (m, 1H), 5.30e5.40 (m, 2H), 5.24e5.30 (m, 1H), 5.17
(s, 1H, D2O exchangeable), 4.55e4.59 (m, 4H), 3.73 (s, 3H) ppm; 13
NMR (CDCl3, 50.3 MHz): 152.6, 146.3, 133.1, 129.9, 118.0, 93.7, 70.2,
55.6, ppm; Anal. calcd for C13H16O4 (236.26): C 66.09, H 6.83;
found: C 66.28, H 7.00%.
6.55e6.70 (m, 2H), 4.74e5.01 (m, 3H), 3.88e4.15 (m, 7H), 3.72 (d,
1H, J ¼ 10.4 Hz), 2.96 (s, 1H, D2O exchangeable), 2.35 (m, 3H), 2.05
(s, 1H, D2O exchangeable) ppm; 13C NMR (CDCl3, 125.76 MHz):
n
d
d
144.8, 142.4, 138.5, 137.5, 137.0, 133.7, 129.8, 128.5, 128.3, 128.1,
C
127.9, 127.82, 127.77, 127.6, 127.5, 82.5, 82.1, 80.2, 78.6, 78.1, 75.7
(CH2), 75.6, 75.3 (CH2), 21.6; Anal. calcd for C40H40O8S (680.81): C
70.57, H 5.92, S4.71; found: C 70.88, H 5.80, S 4.92%.
4.17. 2,4,6-Tris(benzyloxy)-[1,10-biphenyl]-3-ol 22
4.14. 2,6-Bis(benzyloxy)-4-(4-methoxybenzyloxy)phenol 18
The alcohol 20 (0.068 g, 0.1 mmol), ethyl acetate (10 mL) and IBX
(0.056 g, 0.2 mmol) were used (procedure B) to obtain the ketone
21 as a gummy liquid (0.066 g, TLC Rf ¼ 0.3 in 1:4 ethyl acetate-light
petroleum) which was used for the next reaction without
purification.
The myo-inosose 15 (0.98 g, 2 mmol), dry THF (10 mL) and so-
dium hydride (0.80 g, 2 mmol) were used (procedure A) to obtain
18 as a colorless solid (0.85 g, 96%) after column chromatography
(eluent: 1:9 ethyl acetate-light petroleum). TLC Rf ¼ 0.3 in 1:9 ethyl
acetate-light petroleum; mp 94.6e95.7 ꢀC; IR (CHCl3):
n
3514 cmꢁ1
;
The ketone 21 (0.066 g), dry THF (5 mL) and sodium hydride
(0.01 g, 0.25 mmol) were used (procedure A) to obtain 22 (0.046 g,
94%) as a gummy liquid after column chromatography (eluent: 1:9
ethyl acetate-light petroleum). TLC Rf ¼ 0.6 in 1:9 ethyl acetate-
1H NMR (CDCl3, 200 MHz):
2H), 6.29 (s, 2H), 5.21 (s,1H, D2O exchangeable), 5.09 (s, 4H), 4.82 (s,
2H), 3.81 (s, 3H) ppm; 13C NMR (CDCl3, 50.3 MHz):
159.3, 151.8,
d 7.27e7.49 (m, 12H), 6.80e6.95 (m,
d
ꢁ1
;
1H NMR (CDCl3,
146.4, 136.7, 130.3, 129.2, 128.9, 128.5, 128.0, 127.5, 113.9, 95.4, 71.3
(CH2), 70.4 (CH2), 55.2 ppm; Anal. calcd for C28H26O5 (442.50): C
76.00, H5.92; found: C 75.60, H 6.05%.
light petroleum; IR (CHCl3):
200 MHz):
exchangeable), 5.10 (s, 2H, 4.79 (s, 2H), 4.57 (s, 2H) ppm; 13C NMR
(CDCl3, 125.76 MHz): 148.8, 145.6, 144.3, 137.2, 136.9, 136.6, 134.5,
n
3525 cm
d
7.0e7.50 (m, 20H), 6.50 (s, 1H), 5.37 (s, 1H, D2O
d
4.15. 2,4,6-Tri-O-benzyl-5-C-phenyl-neo-inositol 19
133.8, 131.1, 128.7, 128.4, 128.3, 128.27, 128.2, 128.0, 127.8, 127.7,
127.6, 127.1, 126.9, 119.9, 98.8, 74.9 (CH2), 72.3 (CH2), 71.6 (CH2)
ppm; Anal. calcd for C33H28O4 (488.57): C 81.12, H 5.78, found: C
79.85, H 6.12%.
To a cooled (ꢁ10 ꢀC) solution of the inosose 5 (2.15 g, 4 mmol) in
dry diethyl ether (40 mL) was added a 1M solution of phenyl-
magnesium bromide in diethyl ether (6.00 mL, 6 mmol) and stirred
for 1 h. The reaction mixture was diluted with diethyl ether, washed
with saturated solution of ammonium chloride, water, followed by
brine and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the crude product obtained
was used for the next reaction without purification.
4.18. 1,3-O-Methylidene-2,4,6-tri-O-benzyl-5-O-allyl-myo-inositol
34
To an ice cooled solution of 33 [51] (4.835 g, 10.4 mmol) in DMF
(6 mL), sodium hydride (1.123 g, 46.8 mmol) and allyl bromide
(4 mL, 46.8 mmol) were added and stirred subsequently for 3 h at
ambient temperature. Ice was added to the reaction mixture and
solvents were removed under reduced pressure and the residue
worked up with ethyl acetate, dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure to obtain crude
34. The crude product was purified by column chromatography
(eluent: 3:17 ethyl acetate-light petroleum, silica 100e120 mesh) to
afford 34 (4.793 g, 92% yield) as a gum. TLC Rf ¼ 0.5 (in 1:4 ethyl
The crude product obtained above, concd HCl (2 mL) and THF-
water mixture (20 mL þ 2 mL) was refluxed for 2 h. The solvents
were removed under reduced pressure to obtain gummy residue
which was dissolved in dichloromethane. The organic extract was
washed with saturated NaHCO3 solution followed by brine and
dried over anhd sodium sulfate. The solvent was removed under
reduced pressure and the gummy residue was purified by column
chromatography (eluent: 1:1 ethyl acetate-light petroleum) to
afford the triol 19 as a colorless solid (1.35 g, 65%). TLC Rf ¼ 0.3 (2:3
acetate-light petroleum). IR (Chloroform):
NMR (200 MHz, CDCl3) 7.44e7.25 (m, 15 H), 6.04e5.74 (m, 1 H),
n ;
3100e2900 cmꢁ1 1H
ethyl acetate-light petroleum); mp 125e129 ꢀC; IR (CHCl3):
n
3542-
d
3567 cmꢁ1
;
1H NMR (CDCl3,200 MHz):
d
7.33e7.70 (m, 10H),
5.33e5.05 (m, 3 H), 4.82 (d, 1 H, J ¼ 5.6 Hz), 4.74e4.51 (m, 6 H), 4.26
7.15e7.25 (m, 6H), 7.85e7.04 (m), 4.88 (s, 2H), 4.01e4.13 (m, 5H),
4.07 (q, 4H, J ¼ 11.0 Hz), 2.99 (s, 1H, D2O exchangeable), 2.24 (br s,
(s, 2 H), 4.13 (m, 2 H), 3.91 (d, 2 H, J ¼ 5.6 Hz), 3.84 (t, 1 H, J ¼ 2.0 Hz),
3.55 (t, 1H, J ¼ 5.6 Hz) ppm; 13C NMR (50.3 MHz, CDCl3)
d 137.8,
2H, D2O exchangeable) ppm; 13C NMR (CDCl3, 50.3 MHz):
d
143.3,
135.0, 128.5, 127.9, 127.9, 117.1(CH2), 85.5 (CH2), 82.1, 80.0, 72.6,
138.8, 137.6, 128.5, 128.4, 128.2, 127.8, 127.7, 127.4, 125.8, 83.6, 79.2,
78.0, 75.4 (CH2), 75.1 (CH2), 71.9 ppm; Anal. calcd for C33H34O6
(526.62): C 75.26, H 6.51; found: C 74.88; H 6.60%.
72.1(CH2), 71.9 (CH2), 71.0(CH2), 70.3 ppm; HRMS: m/z calcd for
C
31H35O6 503.2434 [M þ Hþ]; found: 503.2433.
4.19. 1,2,3,4,6-Penta-O-benzyl-5-O-allyl-myo-inositol 36
4.16. Racemic 2,4,6-tri-O-benzyl-5-C-phenyl-1-O-(p-
toluenesulfonyl)-neo-inositol 20
The acetal 34 (1.964 g, 3.8 mmol) was dissolved in methanol
(12 mL) and conc. HCL (7 mL) and refluxed for 12 h. The acid was
neutralized with solid sodium bicarbonate, the solvent was
removed under reduced pressure to yield a solid (crude 35). This
solid was suspended in dry DMF (15 mL) and sodium hydride
(0.38 g, 9.4 mmol) was added and cooled to 0 ꢀC. Benzyl bromide
(1.1 mL, 9.4 mmol) was added and stirred at ambient temperature
for 2 h. Ice was added to the reaction mixture and solvents were
removed under reduced pressure and the residue worked up with
ethyl acetate and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure to obtain crude 36 which was
purified by column chromatography (eluent 3:17 ethyl acetate:
light petroleum, 100e200 mesh silica gel) to afford 36 (1.864 g,
To a cooled (0 ꢀC) solution of the triol 19 (0.30 g, 0.6 mmol) in
pyridine (3 mL), tosyl chloride (0.11 g, 0.6 mmol) was added and
stirred for 12 h. The reaction mixture was concentrated under
reduced pressure to get a gum which was worked up with ethyl
acetate; the organic extract was dried over anhd sodium sulfate.
The solvent was removed under reduced pressure and the gummy
compound obtained was purified by column chromatography
(eluent: 1:4 ethyl acetate-light petroleum) to afford 20 as a gummy
liquid (0.29 g, 72%). TLC Rf ¼ 0.5 (3:7 ethyl acetate-light petroleum);
IR (CHCl3):
n
3510-3550 cmꢁ1
;
1H NMR (CDCl3, 200 MHz):
d
7.70e7.87 (m, 2H), 7.05e7.60 (m, 18H), 6.85e7.00 (m, 2H),

B.P. Gurale et al. / Carbohydrate Research 461 (2018) 38e44
43
82%) as a solid. TLC Rf ¼ 0.3 (in 1:3 ethyl acetate-light petroleum.).
mp 87e89 ꢀC (crystallized from chloroform and benzene); IR
(Chloroform):
was quenched by adding aqueous ammonium chloride solution.
The resulting mixture was concentrated under reduced pressure
and the residue was worked up with ethyl acetate. The solid ob-
tained was acetylated using pyridine (1 mL), acetic anhydride
(0.5 mL) and DMAP (0.010 g) at room temperature for 48 h. The
reaction mixture was quenched by adding few pieces of ice, solvent
was removed under reduced pressure and the residue obtained was
worked up with ethyl acetate to obtain a mixture of acetates 31 and
32 (0.041 g, 93%) which was analyzed by 1H-NMR spectroscopy.
n d 7.46e7.19
3350 cm-1; 1H NMR (200 MHz, CDCl3)
(m, 26 H), 6.12e5.81 (m, 1 H), 5.35e5.06 (m, 2 H), 4.94e4.75 (m,
6 H), 4.72e4.50 (m, 4 H), 4.35 (d, 2 H, J ¼ 5.6 Hz), 4.10e3.92 (m, 3 H),
3.40e3.22 (m, 3 H) ppm; 13C NMR (50.3 MHz, CDCl3)
d 138.9, 138.4,
135.3, 128.3, 128.1, 127.7, 127.5, 127.3, 116.5 (CH2), 83.5, 81.6, 80.8,
75.9 (CH2), 74.6 (CH2), 74.4, 74.1 (CH2), 72.8 (CH2) ppm. HRMS: m/z
calcd for C44H47Oþ6 : 671.3367 [M þ Hþ]; found: 671.3371.
4.20. 1,2,3,4,6-Penta-O-benzyl-myo-inositol 37
Supporting information
To a solution of 36 (0.112 g, 0.17 mmol) in degassed ethanol
(3 mL), anhydrous potassium carbonate (0.276 g, 2 mmol) and tet-
rakistriphenylphosphine palladium (0.045 g) were added and
refluxed for 8 h. Additional quantity of tetrakistriphenylphosphine
palladium (0.045 g) was added and refluxing was continued for
40 h. Solvents were removed under reduced pressure and the res-
idue was diluted in ethyl acetate, washed with 2N HCl followed by
water and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure to obtain crude 37. The crude
product was purified by column chromatography (eluent 3:97 ethyl
acetate-light petroleum, silica 100e120 mesh) to afford 37 (0.092 g,
86%) as a colorless solid. TLC Rf ¼ 0.3 (in 3:17 ethyl acetate-light
petroleum). mp 182e185 ꢀC (crystallized from benzene and
Schemes for plausible mechanism of aromatization of inositol
derivatives; NMR spectra of all the new compounds; single crystal
X-ray diffraction data for 6, 36, 37. Complete crystallographic data
for the structural analysis have been deposited with the Cambridge
Crystallographic Data Centre, CCDC no. 1566522, 1566523,
1566524. Copies of this information may be obtained free of charge
from the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB21EZ, UK. (fax: þ44-1223-336033, e-
mail: deposit@ccdc.cam.ac.uk or via: www.ccdc.cam.ac.uk).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
dichloromethane); IR (Chloroform):
(200 MHz, CDCl3) 7.48e7.27 (m, 25 H), 5.01e4.55 (m, 10 H),
4.17e3.83 (m, 3 H), 3.62e3.28 (m, 3 H), 1.97 (s, 1H, D2O exchange-
able) ppm; 13C NMR (50.3 MHz, CDCl3)
138.9, 138.8, 138.3, 128.3,
n ;
3360 cmꢁ1 1H NMR
d
d
BPG and RSS thank CSIR, and UGC India respectively for research
fellowships. This work was supported by the Science and Engi-
neering Research Board (grant number SB/S1/OC-23/2013), New
Delhi.
128.0, 127.7, 127.6, 127.4, 81.1, 80.7, 75.4 (CH2), 75.1, 74.5, 74.2(CH2),
72.6 (CH2) ppm; HRMS: m/z calcd for C41H43Oþ6 : 631.3054 [M þ Hþ];
found: 631.3054.
4.21. 1,2,3,4,6-Penta-O-benzyl-myo-inosose 26
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column chromatography (eluent 1:9 ethyl acetate-light petroleum,
silica gel 100e200 mesh) to afford 26 (0.34 g, 96%) as a colorless
solid. TLC Rf ¼ 0.3 (in 1:4 ethyl acetate - light petroleum). mp.
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