Relative reactivity of hydroxyl groups in inositol derivatives: role of metal ion chelation

Article abstract of DOI:10.1016/j.carres.2009.04.007

O-Alkylation of myo-inositol derivatives containing more than one hydroxyl group via their alkali metal alkoxides (sodium or lithium) preferentially occurs at a hydroxyl group having a vicinal cis-oxygen atom. In general the observed selectivity is relatively higher for lithium alkoxides than for the corresponding sodium alkoxide. The observed regioselectivity is also dependent on other factors such as the solvent and reaction temperature. A perusal of the results presented in this article as well as those available in the literature suggests that chelation of metal ions by inositol derivatives plays a significant role in the observed regioselectivity. Steric factors associated with the axial or equatorial disposition of the reacting hydroxyl groups do not contribute much to the outcome of these O-alkylation reactions. These results could serve as guidelines in planning synthetic strategies involving other carbohydrates and their derivatives.

Full text of DOI:10.1016/j.carres.2009.04.007

Carbohydrate Research 344 (2009) 1159–1166
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Relative reactivity of hydroxyl groups in inositol derivatives: role of metal
ion chelation
*
Subramanian Devaraj, Rajendra C. Jagdhane, Mysore S. Shashidhar
Division of Organic Chemistry, National Chemical Laboratory, Pashan Road, Pune, Maharashatra 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
O-Alkylation of myo-inositol derivatives containing more than one hydroxyl group via their alkali metal
alkoxides (sodium or lithium) preferentially occurs at a hydroxyl group having a vicinal cis-oxygen atom.
In general the observed selectivity is relatively higher for lithium alkoxides than for the corresponding
sodium alkoxide. The observed regioselectivity is also dependent on other factors such as the solvent
and reaction temperature. A perusal of the results presented in this article as well as those available in
the literature suggests that chelation of metal ions by inositol derivatives plays a significant role in the
observed regioselectivity. Steric factors associated with the axial or equatorial disposition of the reacting
hydroxyl groups do not contribute much to the outcome of these O-alkylation reactions. These results
could serve as guidelines in planning synthetic strategies involving other carbohydrates and their
derivatives.
Received 4 February 2009
Received in revised form 4 April 2009
Accepted 9 April 2009
Available online 12 April 2009
Keywords:
Carbohydrate
Chelation
Cyclitol
Inositol
Ó 2009 Elsevier Ltd. All rights reserved.
Protecting group
1. Introduction
ylated derivatives and potential medicinal and pharmacological
applications of inositol derivatives as enzyme inhibitors and leads
Achieving selective reaction at one hydroxyl group in polyhy-
droxy compounds such as carbohydrates and cyclitols or their par-
tially protected derivatives is a challenge and is a topic of current
research interest.1–5 This has implications for the synthesis of sev-
eral classes of biologically or medicinally important compounds as
exemplified by antibiotics, oligosaccharides, inositols and their
derivatives as well as natural products that can be synthesized
from these polyols.6–14 Classical methods for the discrimination
of hydroxyl groups in polyols include (a) selective reaction of pri-
mary alcohols (with electrophiles), in the presence of secondary
and tertiary alcohols; (b) preferential O-substitution of an equato-
rial hydroxyl group over that of an axial hydroxyl group in cyclo-
hexane-derived alcohols; (c) preferential formation of cis-acetals
over trans-acetals in vicinal cyclic diols; (d) preferential hydrolysis
of trans acetals over cis acetals of vicinal cyclic diols;15–18 and (e)
preferential formation of trans-acetals over cis-acetals in vicinal
diols.19–22 Hydrolysis and reduction of orthoesters23–28 and ke-
tals29–31 of diols and triols are also reported to be specific although
their use in synthesis is limited. However, when all the non-equiv-
alent hydroxyl groups in a molecule are secondary or tertiary in
nature (as in cyclitols), obtaining selectively derivatized products
is a formidable task, due to subtle differences in their reactivity
and/ or difficulty in separation of isomeric products.
for drug discovery.10,32–37 Inositols and their derivatives have also
shown promise as viable starting materials for the synthesis of nat-
ural products,9,11,12,14 as scaffolds for the construction of specific
metal ion complexing agents,38–42 and as synthons for supramolec-
ular assemblies with unusual physical and chemical proper-
ties.43–49 The selective functionalization of myo-inositol,
a
cyclohexane hexol having six secondary hydroxyl groups with
more or less similar chemical environment, is one of the main chal-
lenges in synthetic inositol chemistry. Often, partially protected
ketals or orthoesters of inositol are used for further selective func-
tionalization during phosphoinositol synthesis. Such a modifica-
tion usually perturbs the chemical environment of different
hydroxyl groups unevenly making them prone to better discrimi-
nation during synthetic manipulations.
We had observed earlier that the specificity and the facility of
complexation of alkali metal ions with inositol derivatives strongly
depend on the relative orientation of the oxygen atoms involved in
binding of the metal ions.42,50 This prompted us to examine the
regioselectivity of O-substitution reactions in myo-inositol ortho-
esters in the presence of strong bases derived from sodium and
lithium.51 These experiments revealed that the use of lithium alk-
oxides allows better discrimination (as compared to the corre-
sponding sodium alkoxide) of myo-inositol orthoester hydroxyl
groups during their reaction with electrophiles (Scheme 1). For in-
stance, the sequential reaction of myo-inositol orthoformate (1) with
Chemistry of inositols has been the subject of intense investiga-
tion by chemists due to the biological significance of its phosphor-
* Corresponding author. Tel.: +91 20 25902055; fax: +91 20 25902624.
E-mail address: ms.shashidhar@ncl.res.in (M.S. Shashidhar).
All the asymmetrically substituted inositol derivatives shown in schemes are
racemic, however only one of the enantiomers is shown for simplicity.
0008-6215/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2009.04.007

1160
S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
H
BnO
HO
H
H
OH
a
OBn
OH
10
BnO
O
O
O
O
O
O
O 6
O
O
OBn
9
a,b
a,b
HO
HO
HO
HO
or c,b
BnO
4
2
O
HO
OH
HO
BnO
c,d
b
OH
OBn
OBn
O
OH
OBn
OBn
1
2
3
11
HO
HO
OBn
OBn
18
c,b
17
H
H
H
+
MeOMe
MeOMe
MeO
AllO
MeO
HO
M
O
O
O
O
Me
Me
O
O
AllO
3
BnO
O
+
O
OBn
O
O
O
O
O
O
OBn
OAll
h
f,g
e
O
13
O
BnO
OAll
OH
BnO
BnO
OH
M
O
HO
OBn
O
BnO
O
+
M
MeO
Me
4
MeO
Me
M
5 Li
7 Li
21
MeOMe
MeOMe
6
8
Na
Na
20
19
H
H
Scheme 1. Reagents and conditions: (a) BuLi/THF, 0 sC; (b) BnBr / DMF, 0 sC–rt;
and (c) NaH, DMF.
O
O
O
O
AllO
OBn
O
O
i
j, k
h
OBn
HO
HO
AllO
14
15
BnO
OBn
BnO
sodium hydride followed by benzyl bromide gives a mixture of two
dibenzyl ethers 3 and 4, while the use of lithium hydride (or butyl-
lithium) instead of sodium hydride for the same reaction, provides
the symmetrical dibenzyl ether 3 exclusively.51 This difference in
reactivity between lithium and sodium alkoxides could be exploited
to sequentially react the three hydroxyl groups in myo-inositol
orthoesters in the order C4–C6–C2. The improvement in the regiose-
lectivity on going from sodium to lithium alkoxides was attributed
to the differences in the relative stability of the corresponding che-
lates 5–8.
Hence we postulated that if such effects due to chelation of me-
tal ions prevail during the reaction of partially protected inositol
derivatives (without the orthoester cage) they would help discrim-
inate between hydroxyl groups with different relative orientations,
toward O-substitution. A comparison of the results of the sequen-
tial reaction of myo-inositol derivatives (Scheme 2) with butyllith-
ium or sodium hydride followed by an electrophile showed that
relatively higher selectivity at a hydroxyl group cis to a vicinal oxy-
gen could be achieved using butyllithium as the base to generate
the alkoxide. The results presented here also support that chelation
of metal ions by inositol derivatives plays a major role in deciding
the outcome of these O-substitution reactions in terms of the ob-
served regioselectivity.
BnO
OAll
AllO
OH
O
2
H
22
H
23
O
O
O
BnO
OMe
O
O
l, m
o
j, n
OMe
OMe
BnO
MeO
HO
OH
MeO
BnO
OBn
1
24
25
Scheme 3. Reagents and conditions: (a) BuLi, THF, AllBr, DMF, 28 h, 71%; (b) 2,2-
dimethoxypropane, camphorsulfonic acid, dichloromethane, reflux, 3 h, 75%; (c)
DMF, NaH, BnBr, 1 h; (d) dichloromethane, concd HCl, MeOH, 3 h, 74% (for two
steps); (e) DMF, NaH, AllBr, rt, 3 h., 71%; (f) aq trifluoroacetic acid, rt, 2 h; (g) DMF,
NaH, BnBr, rt, 24 h, 87% (for two steps); (h) MeOH/H2O, 10% Pd–C, TsOH, reflux, 24 h
(39% for 13), (35% for 14); (i) DMF, NaH, AllBr, rt, 12 h, 86%; (j) MeOH, TsOH
(3 equiv), rt, 14 h; (k) DMF, NaH, BnBr, rt, 24 h, 80% (two steps); (l) DMF, NaH
(1.1 equiv), MeI (1.1 equiv); (m) NaH, BnBr, 70% (two steps); (n) DMF, NaH, MeI, rt,
24 h, 74% (two steps); and (o) MeOH, 10% Pd–C, H2, rt, 24 h, 85%.
with alkyl halides were maintained to allow comparison of the
results.
A comparison of the results on O-substitution of the triol 9 and
the diols 10, 11, and 16 (see below) clearly shows that the observed
regioselectivity for O-substitution at a hydroxyl group that has a
neighboring (vicinal) cis-oxygen atom is better in reactions involv-
ing lithium alkoxide than in reactions involving the corresponding
sodium alkoxide. The highly selective reaction at the C1-hydroxyl
group in the triol 9 and the diol 10 in the presence of lithium ions
allows the sequential substitution of both C-1 and C-3 hydroxyl
groups (in 9) that are cis to the C-2 oxygen leaving the C-5 hydroxyl
group undisturbed. It is pertinent to note that the reaction of lith-
ium alkoxide of the diol 16 (entry 15), in which there is no adjacent
cis-oxygen to either of the hydroxyl groups resulted in a mixture of
productsà consisting of equal amounts of the mono-allylethers 52
and 53.59 Alkylation of the racemic 1,2-diol 12 in DMF at different
temperatures, using butyllithium to generate the alkoxide revealed
that the proportion of the axial C2-ether can be increased at lower
temperature. At a given temperature (0 °C) the proportion of the
equatorial C1-benzyl ether formed was higher when sodium alkox-
ide (64:36) was used instead of the lithium alkoxide (52:48). Hence
opposite regio-selectivities can be obtained by using judicious com-
bination of the reaction temperature and the base used to generate
the alkoxide of 12.
2. Results and discussion
Sequence of reactions for the preparation of the diols 10, 11,52,53
13,54 14,55 and 15 are shown in Scheme 3. The triol 9,56 the diols
1257 and 1658 were prepared by known methods. Results of the
O-alkylation reaction of myo-inositol-derived diols and triol are
summarized in Scheme 4 and Table 1. Same experimental condi-
tions for the reaction of sodium alkoxides and lithium alkoxides
BnO
BnO
HO
BnO
OH
BnO
OH
OAll
OBn
OH
OBn
OH
OH
OBn
OBn
HO
OBn
OBn
9
10
11
HO
HO
HO
OR1
OH
OBn
OR1
OR1
OBn
OBn
BnO
BnO
OBn
OBn
OH R1O
OBn
12
OH
13
R1
14
Bn
15 Me
O
OBn
à
We did not carry out the alkylation of the diol 16 using the corresponding sodium
OH
OH
OBn
O
alkoxide since the reaction of its lithium alkoxide yielded a mixture of products.
However, alkylation of a 5,6-diol (1-deoxy-1-fluoro-2,3-isopropylidene-4-O-benzyl-
myo-inositol) which is structurally similar to 16, using sodium hydride is reported59
to give a mixture of both the possible isomeric ethers (C5-ether:C6-ether = 1:2).
16
Scheme 2.

S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
1161
R7O
OR6
OBn BnO
BnO
BnO
BnO
OBn
BnO
OR1
OR4
OR5
OBn
OR3
OBn
OR8
R2O
OBn
BnO
OBn
BnO
BnO
BnO
BnO
R8
H
45 Ac
R1
H
H
Ts
Ac All
Ts All
R2
All
H
R3
H
All
H
Ac
Ac
All
Ac
R6 R7
Bn
R4
32 All
33
34
35
R5
44
10
36
H
H
All
Ac
All
26
27
28
29
37
38
H
All
Bn
H
All
H
All
Ac
All
39 H
40 Bn Ac
30 Ac Ac
31 Ac Ac
41
42
43
Ac
All
Ac
Bn
Ac
All
BnO
OBn
BnO
R10
O
O
OMe
OBn
OR12
OR13
OBn
OMe
OMe
MeO
O
OBn
R9O
R11
O
BnO
R9
H
Ac
R10 R11
R12 R13
52 H
53 All
46
47
48 Bn
49
50
H
Bn
All
H
H
Bn Ac
54
55
Ac All
All Ac
51 Ac Bn
Scheme 4.
Table 1
Results on O-alkylation of partially protected myo-inositol derivativesa
come of several benzyl groups present in the tetrabenzyl ethers 13
and 14 and hence we carried out the benzylation of the correspond-
ing tetramethyl ether 15. However, major O-substitution at the C2-
axial hydroxyl group was observed again showing that the observed
regioselectivity was not dependent on the inositol hydroxyl protect-
ing groups. X-ray crystal structure (see Supplementary data) of these
diols did not show any unusual feature in the molecular structures of
13, 14, and 15 that could provide clues for the unexpected observed
regioselectivity. Preferential substitution at an axial hydroxyl group
over an equatorial hydroxyl group has earlier been reported.55 Since
high regioselectivity was observed for these diols on using sodium
hydride as the base, there was no need to carryout the corresponding
reactions with butyllithium.
The results presented in Table 1 can be explained based on the
relative stability of the alkoxides generated by the reaction of the
diols with butyllithium or sodium hydride. Some of the experi-
ments which suggested the involvement of alkali metal chelates
(Scheme 5) in the reactions described so far are given below. Use
of THF alone as a solvent for the reaction resulted in a reduction
in the rate of the reaction and the yield of the products did not ap-
pear to be of practical utility. Increase in the temperature of the
reaction (to decrease the reaction time), resulted in poorer regiose-
lectivity. Since alkali metal alkoxides of the diols under study ap-
peared to be less soluble in dry THF than in dry DMF, a mixture
of these two solvents was essential to achieve good regioselectivity
and conversion. Use of DMF as a co-solvent drove the reaction to
completion at lower temperatures with higher regioselectivity.
Hence it appears that DMF helps to solubilize the alkoxide and
facilitates the reaction with electrophiles. The factors that could
contribute to the stability of the alkoxides 56–61 are (a) the metal
ion involved; (b) relative orientation of the vicinal oxygen atom
which could chelate with the metal ion; (c) the solvent in which
the alkoxide exists, and (d) the temperature of the reaction med-
ium. In reactions involving lithium alkoxides, it is conceivable that
Entry
Diol/triol
Reaction conditions
Products (ratio;% yield)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
9
9
9
a, b
c, b
10 (71)
10:26 (1:1, 95)
10 (61)
NaH, b,4
a, d
10
11
11
12
12
12
12
12
13
14
15
16
27 (53)
a, b
c, b
32:33 (4:1; 67)
32:33 (2:1; 75)
36:37 (45:55; 69)
36:37 (52:48; 70)
36:37 (71:29; 74)
36:37 (64:36; 76)
38:39 (67:33; 66)
44:36 (19:1, 59)
46:36 (19:1, 47)
48:49 (18:1, 60)
52:53 (1:1; 76)
a, e, À78 °C
a, e, 0 °C
a, e, 76 °C
c, e, 0 °C
a, b, 0 °C
c, e
c, e
c, e
a, b
(a) THF, n-BuLi; previous experience51 on the O-alkylation of myo-inositol ortho-
esters had shown that although other bases such as lithium hydride could be used
for the O-substitution reactions, butyllithium worked best. Hence in the present
work butyllithium was used to generate lithium alkoxides from diols and triols.
Reactions carried out with lithium hydride were much slower than the corre-
sponding reactions with butyllithium.
(b) DMF, AllBr.
(c) THF, NaH.
(d) DMF, TsCl.
(e) DMF, BnBr.
a
See Schemes 2 and 4 for the structure of reactants and products. The molar ratio
of the diol/triol:base:alkyl halide in all the experiments was 1:1:1.
b
Isolated yields. The ratio of the products for entries 2 and 5–15 was estimated
from the 1H NMR spectra of acetates obtained after acetylation of the mixture of
isomeric products.
Benzylation of the 2,5- and 2,4-diols 13, 14, and 15 gave the cor-
responding C2-benzyl ether as the major product. This was unex-
pected based on the fact that equatorial hydroxyl groups
normally undergo O-substitution with better facility than the axial
hydroxyl groups in cyclohexanols. However, such reasoning may
not be accurate60 in reactions under discussion since inositols have
many (protected) hydroxyl groups which could influence the reac-
tivity of each other.§ We wondered whether this could be an out-
M
M
R1O
R1O
M
O
O
O
R1O
M
M
56 Na
57 Li
§
M
This is similar to the fact that while cyclohexane rings carrying a few substituents
a chair conformation with minimum number of axial substituents (or
60
Na
58 Na
59 Li
61 Li
adopt
maximum number of equatorial substituents), inositol derivatives carrying bulky
substituents are known to adopt chair conformation with maximum number of axial
substituents.
Scheme 5. Structure of possible alkali metal chelates involved in the O-alkylation
reactions (R1 = alkyl). All the hydroxyl groups of inositol are not shown for clarity.

1162
S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
the chelation from a vicinal cis-oxygen atom is better than the che-
lation from a vicinal trans-oxygen atom. This is analogous to the
relative strength of intramolecular hydrogen bonding in polyhy-
droxy cyclohexanes which is known to decrease in the order 1,3-
diaxial diols > 1,2-cis diols > 1,2-trans diols.61,62 Intramolecular
hydrogen bonds in cis-1,3 (diaxial) diols have been observed in
their crystals.61,63,64 Hence the relative stability of alkali metal che-
lates is expected to decrease in the order 56,57 > 58,59 > 60,61.65
For a given diol, the lithium chelate would be expected to be more
stable than the corresponding sodium chelate due to the ability of
lithium to form chelates better. This difference in the facility of
chelation would translate in the preferential O-substitution at a
hydroxyl group having a vicinal cis-oxygen atom. In reactions
involving sodium alkoxides, although chelates 56, 58, and 60 are
formed, their relative stability may not be very different since so-
dium ion is not a chelator as good as lithium ion. Hence the reac-
tions using sodium alkoxides show poorer selectivity (as
compared to lithium alkoxides) under similar experimental condi-
tions. However, when one of the two hydroxyl groups in a diol has
two adjacent cis-oxygen atoms while the other has two trans-oxy-
gen atoms (as in 13–15), O-substitution preferentially takes place
at the former, since the corresponding alkoxide is stabilized by
two neighboring cis-oxygen atoms while the equatorial hydroxyl
group is stabilized by two trans-oxygen atoms. Similarly during
the reaction of the alkoxides of the 1,2 cis diol 12 the alkoxide de-
rived from the C2-axial hydroxyl group is stabilized by two cis-oxy-
gen atoms while the alkoxide derived from the C1-equatorial
hydroxyl group is stabilized by one cis and one trans-oxygen atom.
This implies relatively greater stabilization of the C2-lithium alkox-
ide and hence higher yield of the C2-ether (especially as the temper-
ature decreases). Chelation-assisted regioselective O-substitution of
vicinal diols (using heavier metals)66,67 and myo-inositol orthoes-
ters (using lithium alkoxides)51 has been reported earlier.
We have reported a method for the preferential O-substitution
of hydroxyl groups that have an adjacent cis oxygen atom in myo-
inositol-derived diols and triols. A comparison of the O-alkylation
of partially protected inositol derivatives via their lithium and so-
dium alkoxides presented here (also see Supplementary data),
clearly shows that the use of lithium alkoxides generally leads to
better discrimination between the hydroxyl groups in diols and tri-
ols (Scheme 3 and 4) and minimizes the formation of diethers.
These results could serve as guidelines in planning synthetic strat-
egies with other polyols and their derivatives as well as molecules
containing polyol moieties. We did not carry out acylation in the
present study due to the potential of hydroxyl esters to undergo in-
ter or intra molecular acyl migration,3,68,69 which would hamper
conclusions on the observed regioselectivity. Also, since esterifica-
tion of alcohols proceeds by addition elimination (at a carbonyl
group) mechanism whereas ether formation proceeds by direct
nucleophilic substitution at a tetrahedral carbon atom, outcome
of the two reactions may not be a fair measure to conclude
whether chelates are involved in these two reactions which pro-
ceed by different mechanisms.55
with concd H2SO4 or chromic acid. Column chromatographic sepa-
rations (silica gel, 100–200 mesh) and flash column chromato-
graphic separations (silica gel, 230–400 mesh) were carried out
with light petroleum–ethyl acetate mixtures as eluent. ‘Usual
work-up’ implies washing of the organic layer with water followed
by brine, drying over anhydrous sodium sulfate, and removal of the
solvent under reduced pressure using a rotary evaporator. IR spec-
tra were recorded (in CHCl3 solution or as Nujol mull or as neat
film) on a Shimadzu FTIR-8400 or Perkin Elmer 16 spectrophotom-
eter. NMR spectra were recorded on Bruker ACF 200 spectrometer
(200 MHz for 1H and 50.3 MHz for 13C) unless otherwise
mentioned. Chemical shifts (d) reported are referred to internal
tetramethylsilane. Microanalytical data were obtained using a
Carlo-Erba CHNS-0 EA 1108 elemental analyzer. All the melting
points reported are uncorrected and were recorded using a Büchi
B-540 electro-thermal melting point apparatus. Compounds previ-
ously reported in the literature were characterized by comparison
of their meltingpoints and/or 1H NMR spectrawith the reported data.
3.2. Racemic 1,6-O-isopropylidene-2,4,5-tri-O-benzyl-myo-
inositol (18)
The racemic triol 1758 (2.00 g, 4.44 mmol), 2,2-dimethoxypro-
pane (1.101 g, 10.57 mmol), and camphorsulfonic acid (0.516 g,
2.22 mmol) were refluxed in dichloromethane (60 mL) for 3 h.
The resulting solution was cooled to room temperature and neu-
tralized with triethylamine. Solvents were evaporated and the so-
lid obtained was purified by column chromatography to obtain the
racemic acetal 18 (1.784 g, 82%) as a colorless solid. Mp 78–80 °C;
IR (nujol, cmÀ1) 3115–3489; 1H NMR (CDCl3) d 7.20–7.45 (m, 15H),
4.60–5.10 (m, 6H), 4.15–4.30 (m, 2H), 3.56–3.74 (m, 3H), 3.49 (dd,
J = 2, 10 Hz, 1H), 2.40–2.50 (br s, 1H, D2O exchangeable), 1.49 (s,
3H), 1.47 (s, 3H); 13C NMR (CDCl3) d 138.6, 138.5, 138.0, 128.4,
128.3, 128.2, 128.0, 127.8, 127.6, 127.4, 111.8, 84.0, 80.2, 77.8,
76.9, 75.9, 74.4, 74.2, 73.5, 72.9, 27.1, 26.7; Anal. Calcd for
C30H34O6.1.2 H2O; C, 70.34; H, 7.16. Found: C, 70.03; H, 7.33.
3.3. Racemic 2,3,4,5-tetra-O-benzyl-myo-inositol (11)
To a solution of the racemic ketal 18 (1.500 g, 3.06 mmol) in
DMF (15 mL) sodium hydride (0.184 g, 4.59 mmol) was added
and stirred for 20 min. The reaction mixture was cooled to 0 °C
and benzyl bromide (1.047 g, 6.12 mmol) was added drop-wise
and the mixture was stirred for 1 h. The reaction was quenched
by the addition of ice and worked up as usual with ethyl acetate.
The residue obtained (1.020 g) after evaporation of ethyl acetate
was dissolved in dichloromethane (16 mL) and methanol (8 mL)
and stirred with concd HCl (0.25 mL) for 4 h. Triethylamine was
added to the reaction mixture and the solvents were evaporated
under reduced pressure. The solid residue was purified by column
chromatography to get the racemic 1,6-diol 11 (0.761 g, 80%) as a
colorless solid. Mp 167–169 °C, Lit.53 mp 162–164 °C; 1H NMR
(CDCl3) d 7.20–7.40 (m, 20H), 4.63–5.10 (m, 8H), 3.96–4.10 (m,
2H), 3.76–3.91 (m, 1H), 3.48 (dd, J = 2, 10 Hz, 1H), 3.25–3.39 (m,
2H), 2.47 (br s, 1H, D2O exchangeable), 2.30 (d, 1H, J = 8 Hz, D2O
exchangeable). Anal. Calcd for C34H36O6; C, 75.53; H, 6.71. Found:
C, 75.55; H, 6.59.
3. Experimental
3.1. General methods
All the reactions were carried out in an atmosphere of argon.
Dry DMF and dry THF were used as solvents in all the experiments
involving metal hydrides or n-butyllithium. Sodium hydride used
in experiments was 60% suspension in mineral oil. A stock solution
of n-butyllithium (0.6–1.62 M) in dry hexanes was prepared and
used in all the experiments. Thin layer chromatography was per-
formed on E. Merck pre-coated 60 F254 plates and the spots were
rendered visible either by shining UV light or by charring the plates
3.4. 1,6:3,4-Bis-[O-(2,3-dimethoxybutane-2,3-diyl)]-2,5-di-O-
allyl-myo-inositol (20)
To an ice-cooled solution of 1970 (2.478 g, 6.07 mmol) in dry
DMF (40 mL), sodium hydride (2.50 g, 62.5 mmol) was added fol-
lowed by allyl bromide (7.34 g, 60.6 mmol) and the mixture was
stirred at room temperature for 24 h. Excess of sodium hydride
was quenched by the addition of ice and the solvents were

S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
1163
removed under reduced pressure. The residue was worked up ‘as
usual’ with dichloromethane; the crude product was purified by
flash column chromatography to afford 20 (2.10 g, 71%) as a
gum. 1H NMR (CDCl3) d 6.08–5.84 (m, 2H), 5.36 (q, J = 1.7 Hz,
1H), 5.27 (q, J = 1.63, 2.05 Hz, 1H), 5.2–5.0 (m, 2H), 4.36–4.26 (m,
4H), 4.06 (t, J = 9.4 Hz, 2H), 3.74 (t, J = 2.3 Hz, 1H), 3.50 (dd,
J = 2.4, 9.4 Hz, 2H), 3.38 (t, J = 9.3 Hz, 1H), 3.27 (s, 6H), 3.23 (s,
6H), 1.28 (s, 12H); 13C NMR (CDCl3) d 136.0, 135.7, 115.7, 115.2,
99.4, 98.9, 78.3, 75.4, 73.4, 72.4, 69.7, 69.2, 47.8, 47.6, 17.8, 17.5.
Anal. Calcd for C24H40O10: C, 58.99; H, 8.24. Found C, 58.65; H, 8.46.
A mixture of 22 (1.125 g, 3.12 mmol), p-toluenesulfonic acid
monohydrate (1.781 g, 9.36 mmol), and methanol (15 mL) was
stirred at room temperature overnight. Solvents were removed un-
der reduced pressure; the residue was taken in ethyl acetate,
washed with saturated sodium bicarbonate solution, and worked
up ‘as usual’ to afford crude racemic 2,4-di-O-allyl-6-O-benzyl-
myo-inositol (1.050 g) as a pale yellow gum.
To an ice-cooled solution of the crude triol (1.050 g) obtained
above in dry DMF (20 mL), sodium hydride (0.980 g, 24.5 mmol)
was added followed by a solution of benzyl bromide (4.190 g,
24.5 mmol) in dry DMF (5 mL). The reaction mixture was stirred
at room temperature for 40 h. Excess of sodium hydride was
quenched with ice, solvents were removed under reduced pres-
sure, and worked up ‘as usual’ with ethyl acetate to afford the
crude product, which was purified by flash column chromatogra-
phy to obtain the tetrabenzyl ether 2355 as a colorless solid
(1.549 g, 80%); mp 62–64 °C (crystals from methanol).
3.5. Preparation of 2,5-di-O-allyl-1,3,4,6-tetra-O-benzyl-myo-
inositol (21)
A solution of 20 (2.10 g, 4.30 mmol) in TFA–H2O (9:1, 40 mL),
was stirred at room temperature for 2 h. The solvent was removed
under reduced pressure and the residue co-evaporated with tolu-
ene to get crude 2,5-di-O-allyl-myo-inositol (1.25 g) as a white so-
lid. The tetrol so obtained was suspended in dry DMF (30 mL),
cooled with ice, sodium hydride (2.80 g, 70 mmol) was added, fol-
lowed by benzyl bromide (7.97 g, 46.6 mmol); the mixture was
stirred at room temperature for 48 h. Excess of sodium hydride
was quenched by the addition of ice, the solvents were removed
under reduced pressure and the residue was worked up ‘as usual’
with ethyl acetate. The crude product was purified by flash column
chromatography to obtain the tetrabenzyl ether 21 (2.319 g, 87%)
as a white solid. Mp 83–84 °C; 1H NMR (CDCl3) d 7.40–7.27 (m,
20H), 6.10–5.86 (m, 2H), 5.34–5.12 (m, 4H), 4.84 (AB q,
J = 10.4 Hz, 4H), 4.66 (s, 4H), 4.36–4.32 (m, 4H), 4.01–3.92 (m,
3H), 3.34–3.24 (m, 3H);. 13C NMR (CDCl3) d 138.8, 138.3, 135.7,
135.3, 128.2, 128.0, 127.5, 116.7, 116.5, 83.3, 81.6, 80.5, 75.8,
74.6, 73.8, 73.3, 72.7. Anal. Calcd. For C40H44O6: C, 77.39; H, 7.14.
Found C, 76.98; H, 6.91.
3.8. Racemic 1,3,4,5-tetra-O-benzyl-myo-inositol (14)
A mixture of 23 (0.420 g, 0.68 mmol), 10% Pd/C (0.126 g), p-tol-
uenesulfonic acid (0.126 g, 0.732 mmol), methanol (12 mL), and
water (2.5 mL) was heated (70–80 °C) for 30 h. The reaction mix-
ture was diluted with methanol and passed through Celite to re-
move Pd/C. The filtrate was concentrated under reduced pressure
and the residue was taken in ethyl acetate, washed with saturated
sodium bicarbonate solution, and worked up ‘as usual’. The crude
product was purified by flash column chromatography to obtain
14 (0.130 g, 35%) as a colorless solid. In several trials the yield of
14 varied; maximum yield obtained was 35%; mp 116–118 °C
(from ethyl acetate–light petroleum), lit.71 mp 111–113 °C (crys-
tals obtained by slow evaporation of methanol solution, at ambient
temperature).
3.6. 1,3,4,6-Tetra-O-benzyl-myo-inositol (13)
3.9. Racemic 2,4-di-O-benzyl-6-O-methyl-myo-inositol 1,3,5
orthoformate (24)
A mixture of the diallyl ether 21 (0.500 g, 0.806 mmol), 10% Pd/
C (0.051 g), p-toluenesulfonic acid (0.023 g, 0.13 mmol), methanol
(13 mL), and water (1.6 mL) was heated (75–80 °C) for 24 h. Excess
of 10% Pd/C (0.010 g) was added and the mixture was stirred at
room temperature for 2 days. The reaction mixture was then di-
luted with methanol and passed through Celite to remove Pd/C.
The filtrate was concentrated under reduced pressure; the residue
was diluted with ethyl acetate, washed with saturated sodium
bicarbonate solution, and then worked up ‘as usual’. The crude
product was purified by flash column chromatography to obtain
13 (0.170 g, 39%) as a white solid. In several trials the yield of 13
varied; the best yield obtained was 39%. Mp 129–131 °C (crystals
from warm light petroleum–dichloromethane), lit54 mp 125 °C.
To an ice-cooled solution of 1 (0.380 g, 2.00 mmol) in dry DMF
(5 mL), sodium hydride (0.088 g, 2.20 mmol) was added followed
by a solution of methyl iodide (0.312 g, 2.20 mmol) in dry DMF
(1 mL) and the mixture was stirred at room temperature for 2 h.
The reaction mixture was cooled with ice, sodium hydride
(0.500 g, 12.5 mmol) was added followed by benzyl bromide
(1.725 g, 10.0 mmol). The resulting mixture was stirred at room
temperature overnight. Excess sodium hydride was quenched by
adding ice, the solvents were removed under reduced pressure
and the residue was worked up with ethyl acetate ‘as usual’. The
crude product obtained was purified by flash column chromatogra-
phy to obtain the dibenzyl ether 24 (0.540 g, 70%) as a gum. 1H
NMR (CDCl3) d 7.43–7.28 (m, 10H), 5.52 (d, J = 1.3 Hz, 1H), 4.67
(s, 2H), 4.55 (AB q, 2H), 4.44–4.39 (m, 1H), 4.36–4.27 (m, 2H),
4.24–4.19 (m, 1H), 4.16–4.11 (m, 1H), 3.97–3.92 (m, 1H), 3.38 (s,
3H); 13C NMR (CDCl3) d 137.7, 137.5, 128.18, 128.21, 127.7,
127.56, 127.64, 127.2, 102.9, 75.7, 73.6, 71.3, 70.2, 70.0, 67.4,
67.2, 57.0. Anal. Calcd for C22H24O6: C, 68.73; H, 6.29. Found: C,
69.11; H, 6.24.
3.7. Racemic 1,3,4,5-tetra-O-benzyl-2,6-di-O-allyl-myo-inositol
(23)
To an ice-cooled solution of the benzyl ether 256 (1.085 g,
3.88 mmol) in dry DMF (10 mL), sodium hydride (0.465 g,
11.6 mmol) was added, followed by the addition of a solution of al-
lyl bromide (1.641 g, 13.6 mmol) in dry DMF (5 mL). The reaction
mixture was stirred at room temperature for 90 min. The reaction
was quenched by the addition of ice to the reaction mixture, sol-
vents were removed under reduced pressure and then worked up
‘as usual’ with ethyl acetate to afford the crude product, which
was purified by flash column chromatography to obtain 22 as a
gum (1.203 g, 86%). 1H NMR (CDCl3) d 7.33 (m, 5H), 6.09–5.77
(m, 2H), 5.52 (d, J = 1.3 Hz, 1H), 5.37–5.17 (m, 4H), 4.63 (AB q,
J = 12 Hz, 4H), 4.45–4.40 (m, 1H), 4.35–4.28 (m, 4H), 4.16–4.06
(m, 4H), 3.93–3.98 (m, 1H).
3.10. Racemic 1,3,4,5-tetra-O-methyl-2,6-di-O-benzyl-myo-
inositol (25)
A mixture of 24 (0.500 g, 1.30 mmol), p-toluenesulfonic acid
monohydrate (0.740 g, 3.89 mmol), and methanol (10 mL) was
stirred at room temperature for 10 h, the solvent was removed
under reduced pressure. The residue was taken in ethyl acetate,
washed with a saturated solution of sodium carbonate, and

1164
S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
then worked up ‘as usual’ to obtain the crude triol as a gum
(0.540 g).
124.3, 124.2, 123.9, 123.6, 123.5, 112.8, 73.5, 72.9, 72.3, 71.3,
70.8, 68.0, 67.3. Anal. Calcd for C30H34O6 C: 73.45; H, 6.99. Found:
C, 73.07; H, 6.89.
To an ice-cooled solution of the triol (0.540 g) obtained above,
in dry DMF (8 mL), sodium hydride (0.577 g, 14.4 mmol) was
added followed by a solution of methyl iodide (2.0 g, 14.1 mmol)
in dry DMF (2 mL) and the mixture was stirred at room tempera-
ture for 24 h. The reaction was quenched by the addition of ice
to the reaction mixture, solvents were removed under reduced
pressure, and the residue was worked up ‘as usual’ using ethyl ace-
tate. The product was subjected to flash column chromatography
to isolate 25 (0.400 g, 74%) as gum which turned into a solid on
storing at room temperature. Mp 66–67 °C; 1H NMR (CDCl3) d
7.44–7.27 (m, 10H), 4.84 (s, 2H), 4.81 (AB q, J = 10.7 Hz, 2H) 4.08
(t, J = 2.3 Hz, 1H), 3.83 (t, J = 9.4 Hz), 3.65–3.53 (m, 1H), 3.64 (s,
3H), 3.62 (s, 3H), 3.44 (s, 3H), 3.42 (s, 3H), 3.11–3.02 (m, 2H),
2.96 (dd, J = 2.2, 9.8 Hz, 1H); 13C NMR (CDCl3) d 138.88, 138.78,
128.17, 127.93, 127.50, 127.38, 127.16, 85.37, 83.04, 82.72, 82.38,
81.46, 75.48, 73.79, 72.41, 61.04, 60.78, 58.34, 58.17. Anal. Calcd
for C24H32O6: C, 69.21; H, 7.74. Found: C, 69.07; H, 7.76.
3.12.3. Allylation of 2,4,6-tri-O-benzyl-myo-inositol (9) with
sodium hydride/allyl bromide
The 1,3,5-triol 9 (0.100 g, 0.22 mmol) was allylated as in the
general procedure (reaction time 2 h), using sodium hydride
(0.011 g, 0.27 mmol) and allyl bromide (0.040 g, 0.33 mmol) to ob-
tain a mixture of allyl ethers. This mixture was acetylated using
acetic anhydride (0.3 mL) and pyridine (0.6 mL) overnight at room
temperature. Usual work-up with ethyl acetate gave mixture
(0.121 g) of acetates 28 and 30. 1H NMR spectrum of the mixture
of acetates showed that 28 and 30 were present in the ratio 1:1.
The acetate 28 was prepared from 10 for comparison with NMR
spectra of the mixture of acetates 28 and 30.
3.12.4. Racemic 1-O-allyl-2,4,6-tri-O-benzyl-3-O-(p-
toluenesulfonyl)-myo-inositol (27)
The racemic allyl ether 10 (0.254 g, 0.52 mmol) was sulfonylat-
ed as in the general procedure (reaction time 15 h), using butyllith-
ium (0.76 mL, 0.62 mmol) and p-toluenesulfonyl chloride (0.148 g,
0.78 mmol) to obtain the racemic 3-tosylate 27 (0.179 g, 53%) as a
gum, after column chromatography. IR (neat, cmÀ1) 3216–3630; 1H
NMR (CDCl3) d 7.73 (d, 2H, J = 8 Hz), 7.05–7.48 (m, 17H), 5.75–6.01
(m, 1H), 5.24–5.37 (m, 1H), 5.13–5.23 (m, 1H), 4.66–4.96 (m, 4H),
4.55 (AB q, J = 11.4 Hz, 2H), 4.37 (dd, J = 2.3, 10.2 Hz, 1H), 4.25 (t,
J = 2.4 Hz, 1H), 4.08 (dt, J = 1.5, 5.5 Hz, 2H), 3.84 (AB q, J = 9.3 Hz,
2H), 3.44 (t, J = 9.4 Hz, 1H), 3.32 (dd, J = 2.3, 9.8 Hz, 1H), 2.43 (s,
1H, D2O exchangeable), 2.34 (s, 3H); 13C NMR (CDCl3) d 141.3,
136.3, 135.1, 131.1, 130.4, 126.3, 125.0, 124.8, 124.4, 124.2,
124.1, 113.5, 75.3, 74.0, 73.6, 73.3, 73.2, 71.9, 71.8, 71.6, 71.3,
68.1, 18.1. The racemic tosylate 27 was characterized as its acetate
29: The racemic tosylate 27 (0.020 g, 0.03 mmol) was acetylated
using acetic anhydride (0.04 mL, 0.46 mmol) and pyridine
(0.7 mL) overnight at room temperature. Usual work-up of the
reaction mixture with ethyl acetate gave the acetate 29 (0.021 g,
99%) as a gum. IR (neat, cmÀ1) 3193–3520, 1747. 1H NMR (CDCl3)
d 7.74 (d, 2H, J = 8.4 Hz), 7.02–7.54 (m, 17H), 5.82–6.01 (m, 1H),
5.29–5.41 (m, 1H), 5.19–5.28 (m, 1H), 4.80–5.06 (m, 4H), 4.56–
4.65 (m, 1H), 4.32–4.46 (m, 4H), 4.14 (dt, J = 1.5, 5.5 Hz, 2H), 3.93
(AB q, J = 9.9 Hz, 2H), 3.44 (dd, J = 2.2, 9.6 Hz, 1H), 2.34 (s, 3H),
1.75 (s, 3H). Anal. Calcd for C39H42O9S.H2O; C, 66.46; H, 6.29.
Found: C, 66.78; H, 6.04.
3.11. Racemic 1,3,4,5-tetra-O-methyl-myo-inositol (15)
A mixture of 25 (1.15 g, 2.76 mmol), 10% Pd/C (0.064 g), and
methanol (15 mL) was stirred at room temperature under H2 atmo-
sphere for 24 h. The catalyst was removed by passing the reaction
mixture through Celite. The filtrate was evaporated under reduced
pressure to obtain the diol 15 (0.550 g, 85%) as a colorless solid. Mp
137–138 °C (crystals obtained by cooling a warm solution of ethyl
acetate to room temperature), Lit.72 mp 130–132 °C. IR (CHCl3,
cmÀ1) 3300–3550 (OH); 1H NMR (CDCl3) d 4.36 (t, J = 2.7 Hz, 1H),
3.86 (t, J = 9.6, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 3.55–3.45 (2s and m,
7H), 3.09–2.93 (m, 3H), 2.69 (br s, OH), 2.41 (br s, OH); 13C NMR
(CDCl3) d 84.4, 82.5, 82.0, 81.3, 71.6, 65.2, 60.8, 58.3, 57.8. Anal.
Calcd for C10H20O6: C, 50.83; H, 8.53. Found: C, 50.98; H, 8.89.
3.12. O-Alkylation of myo-inositol-derived triol and diols
3.12.1. General procedure
The required myo-inositol-derived triol or diol (0.5–1 mmol)
was dissolved in dry THF (3–6 mL) and cooled to 0 °C. n-Butyllith-
ium (1.0–1.2 mmol) was added drop-wise using a syringe followed
by a solution of the required alkyl halide or sulfonyl halide (1.2–
1.5 mmol) in DMF (0.5–1 mL) at 0 °C. The reaction mixture was
stirred for 20–56 h at room temperature and worked up as usual
with ethyl acetate. The products were separated by column chro-
matography using 10–20% ethyl acetate–light petroleum (80% for
mixture of monobenzyl ethers 48 and 49) or light petroleum–
dichloromethane mixtures as eluent. In some experiments, the ra-
tio of the mixture of ethers formed was estimated by 1H NMR spec-
troscopy of their acetate derivatives. The same procedure was
followed in the case of reactions where sodium hydride was used
to generate the alkoxides.
3.12.5. Allylation of racemic 2,3,4,5-tetra-O-benzyl-myo-
inositol (11)
3.12.5.1. Procedure A (with butyllithium/allyl bromide). The
racemic diol 11 (0.280 g, 0.52 mmol) in THF (3 mL) was allylated
at 0 °C using butyllithium (0.41 mL, 0.57 mmol) and allyl bromide
(0.082 g, 0.68 mmol) in DMF (0.8 mL) over 56 h as in the general
procedure. The mixture of monoethers 32 and 33 (0.194 g, 65%)
was separated by column chromatography using 10% ethyl acetate
– light petroleum as eluent. This mixture (0.194 g) was acetylated
using acetic anhydride (0.6 mL) in pyridine (2 mL) overnight at
room temperature. Usual work-up of the reaction mixture with
ethyl acetate gave a mixture of acetates 34 and 35 (0.203 g). The
1H NMR spectrum of the mixture showed that 34 and 35 were
present in the ratio 4:1.
3.12.2. Racemic 1-O-allyl-2,4,6-tri-O-benzyl-myo-inositol (10)
The 1,3,5-triol 9 (0.450 g, 1 mmol) was allylated as in the gen-
eral procedure (reaction time 28 h), using butyllithium (1.46 mL,
1.20 mmol) and allyl bromide (0.182 g, 1.50 mmol) to obtain the
racemic 1-allyl ether 10 (0.351 g, 71%) as a gum after column chro-
matography. A small amount of the symmetric diallyl ether
(0.089 g, 17%) was also obtained as a solid. IR (neat, cmÀ1) 3196–
3641. 1H NMR (CDCl3) d 7.20–7.45 (m, 15H), 5.80–6.05 (m, 1H),
5.26–5.39 (m, 1H), 5.14–5.24 (m, 1H), 4.68–5.04 (m, 6H), 4.10–
4.18 (m, 2H), 4.04 (t, J = 2.4 Hz, 1H), 3.85 (t, J = 9.4 Hz, 1H), 3.68
(t, J = 9.4 Hz, 1H), 3.51 (t, J = 9.0 Hz, 2H), 3.35 (dd, J = 2.4 and
9.8 Hz, 1H), 2.52 (s, 1H, D2O exchangeable), 3.33 (d, 1H,
J = 5.9 Hz, D2O exchangeable); 13C NMR (CDCl3) d 134.6, 130.5,
3.12.5.2. Procedure B (with sodiumhydride/allyl bromide). The
racemic diol 11 (0.100 g, 0.19 mmol) in THF (1 mL) was allylated at
0 °C, using sodium hydride (0.008 g, 0.21 mmol) and a solution of
allyl bromide (0.030 g, 0.25 mmol) in DMF (0.3 mL) as mentioned
above. The reaction mixture was worked up with ethyl acetate
and the mixture of monoethers (32 and 33, 0.083 g, 77%) was

S. Devaraj et al. / Carbohydrate Research 344 (2009) 1159–1166
1165
separated by column chromatography using 10% ethyl acetate–
light petroleum as eluent. The mixture of monoethers (0.083 g)
was acetylated using acetic anhydride (0.2 mL) and pyridine
(1 mL) at room temperature overnight. Usual work-up of the reac-
tion mixture with ethyl acetate gave the mixture of acetates (34
and 35, 0.086 g). The 1H NMR spectrum of the mixture of acetates
showed that 34 and 35 were present in the ratio 2:1.
1H NMR spectrum of the mixture showed that 42 and 43 were
present in the ratio 67:33.
3.12.7. Benzylation of 1,3,4,6-tetra-O-benzyl-myo-inositol (13)
The racemic diol 13 (0.075 g, 0.138 mmol) was benzylated as in
the general procedure (reaction time 18 h, rt) using sodium hy-
dride (0.006 g, 0.165 mmol) and benzyl bromide (0.0258 g,
0.151 mmol) to obtain a mixture of penta-O-benzyl myo-inositols
44 and 36 (0.051 g, 59%) as a colorless solid, the starting diol 13
(0.016 g, 22%), and hexa-O-benzyl-myo-inositol (0.011 g, 11%).
The mixture of benzyl ethers (0.025 g) was acetylated using acetic
anhydride (0.05 mL) and pyridine (1 mL) overnight at room tem-
perature. Usual work-up of the reaction mixture with ethyl acetate
gave a mixture of acetates 45 and 4057 (0.024 g). The 1H NMR spec-
trum of the mixture showed that major product is 45 (ꢀ95%).
3.12.6. Alkylation of racemic 3,4,5,6-tetra-O-benzyl-myo-
inositol (12)
3.12.6.1. Procedure A. The racemic diol 12 (0.200 g, 0.37 mmol)
was benzylated as in the general procedure (reaction time 26 h,
À78 °C), using butyllithium (0.23 mL, 0.37 mmol) and benzyl bro-
mide (0.076 g, 0.44 mmol) to obtain a mixture of pentabenzyl
ethers 3657 and 37 (0.161 g, 69%) and hexa-O-benzyl-myo-inosi-
tol57 (0.048 g, 18%). The mixture of pentaethers (0.040 g) was acet-
ylated using acetic anhydride (0.03 mL) and pyridine (1 mL)
overnight at room temperature. Usual work-up of the reaction
mixture with ethyl acetate gave a mixture of acetates 4057 and
41 (0.041 g). The 1H NMR spectrum of the mixture showed that
40 and 41 were present in the ratio 45:55.
3.12.8. Benzylation of racemic 1,3,4,5 tetra-O-benzyl-myo-
inositol (14) with sodium hydride and benzyl bromide
The racemic diol 14 (0.100 g, 0.19 mmol) was benzylated as in
the general procedure (reaction time 16 h, rt) using sodium hy-
dride (0.008 g, 0.20 mmol) and benzyl bromide (0.035 g,
0.20 mmol) to obtain a mixture of penta-O-benzyl myo-inositols
4655 and 36 (0.054 g, 47%) and the starting diol 14 (0.047 g, 47%).
The mixture of benzyl ethers (0.020 g) was acetylated using acetic
anhydride (0.04 mL) and pyridine (1 mL) overnight at room tem-
perature. Usual work-up of the reaction mixture with ethyl acetate
gave a mixture of acetates 47 and 4057 (0.021 g). The 1H NMR spec-
trum of the mixture showed that major product is 47 (ꢀ95%).
3.12.6.2. Procedure B. The racemic diol 12 (0.100 g, 0.19 mmol)
was benzylated as in the general procedure (reaction time 26 h,
0 °C–rt), using butyllithium (0.12 mL, 0.20 mmol) and benzyl bro-
mide (0.076 g, 0.44 mmol) to obtain the mixture of pentabenzyl
ethers 36 and 37 (0.084 g, 72%) and hexa-O-benzyl-myo-inositol
(0.020 g, 15%). The mixture of pentaethers (0.050 g) was acetylated
using acetic anhydride (0.04 mL) and pyridine (1 mL) overnight at
room temperature. Usual work-up of the reaction mixture with
ethyl acetate gave a mixture of acetates 40 and 41 (0.053 g). The
1H NMR spectrum of the mixture showed that 40 and 41 were
present in the ratio 52:48.
3.12.9. Benzylation of racemic 1,3,4,5-tetra-O-methyl-myo-
inositol (15) using sodium hydride and benzyl bromide
The racemic diol 15 (0.100 g, 0.42 mmol) was benzylated as in
the general procedure (reaction time 24 h, rt) using sodium hy-
dride (0.021 g, 0.50 mmol) and benzyl bromide (0.079 g,
0.46 mmol) to obtain a mixture of monobenzyl ethers 48 and 49
(0.083 g, 60%), the dibenzyl ether 25 (0.040 g, 23%), and the start-
ing diol 15 (0.010 g, 10%). The mixture of benzyl ethers (0.035 g)
was acetylated using acetic anhydride (0.05 mL) and pyridine
(1 mL) overnight at room temperature. Usual work-up of the reac-
tion mixture with ethyl acetate gave a mixture of acetates 50 and
51 (0.034 g). The 1H NMR spectrum of the mixture showed that 50
and 51 were present in the ratio 18:1. The acetate 50 was made
from 48 (see below) for comparison with the NMR spectrum of
the mixture of 50 and 51.
3.12.6.3. Procedure C. The racemic diol 12 (0.200 g, 0.37 mmol)
was benzylated as in the general procedure (reaction time 26 h at re-
flux ꢀ76 °C), using butyllithium (0.45 mL, 0.37 mmol, added at 0 °C)
and benzyl bromide (0.076 g, 0.44 mmol, added at reflux tempera-
ture) to obtain a mixture of pentabenzyl ethers 36 and 37 (0.172 g,
74%) and hexa-O-benzyl-myo-inositol (0.051 g, 19%). The mixture
of pentaethers (0.100 g) was acetylated using acetic anhydride
(0.15 mL) and pyridine (2 mL) overnight at room temperature. Usual
work-up of the reaction mixture with ethyl acetate gave a mixture of
acetates 40 and 41 (0.103 g). The 1H NMR spectrum of the mixture
showed that 40 and 41 were present in the ratio 71:29.
3.12.10. Racemic 2-O-benzyl-1,3,4,5-tetra-O-methyl-myo-
inositol (48)
3.12.6.4. Procedure D. The racemic diol 12 (0.200 g, 0.37 mmol)
was benzylated as in the general procedure (reaction time 26 h,
0 °C), using sodium hydride (0.015 g, 0.37 mmol) and benzyl bro-
mide (0.076 g, 0.44 mmol) to obtain the mixture of pentabenzyl
ethers 36 and 37 (0.177 g, 76%) and hexa-O-benzyl-myo-inositol
(0.058 g, 22%). The mixture of pentaethers (0.100 g) was acetylated
using acetic anhydride (0.15 mL) and pyridine (2 mL) overnight at
room temperature. Usual work-up of the reaction mixture with
ethyl acetate gave the mixture of acetates 40 and 41 (0.105 g).
The 1H NMR spectrum of the mixture showed that 4057 and 41
were present in the ratio 64:36.
A mixture of 25 (0.344 g, 0.82 mmol), 10% Pd/C (0.026 g), and
ethyl acetate (5 mL), was stirred under hydrogen atmosphere at
room temperature for 48 h. Analysis of the reaction mixture by
TLC showed the presence of the starting material 25. Excess of
10% Pd/C (0.050 g) and methanol (3 mL) were added and the mix-
ture was stirred under hydrogen atmosphere at room temperature
for another 3 h. The catalyst was removed by passing the reaction
mixture through a bed of Celite. The filtrate was evaporated under
reduced pressure and the residue was flash chromatographed on a
column of silica gel to afford the monobenzyl ether 48 (0.130 g,
48%) as a gum (which turned into a solid on storing at room tem-
perature) and the diol 15 (0.096 g, 49%) as a colorless solid. Data for
48; mp 55–57 °C. IR (CHCl3, cmÀ1) 3250–3550 (OH). 1H NMR
(CDCl3) d 7.42–7.27 (m, 5H), 4.81 (AB q, J = 12 Hz, 2H), 4.12 (t, J =
2.2 Hz, 1H), 3.95 (t, J = 9.5 Hz, 1H), 3.64 (s, 3H), 3.62–3.54 (m, 4H,
Ins H), 3.46 (s, 3H), 3.37 (s, 3H), 3.04–2.90 (m, 3H), 2.59 (bs, OH);
13C NMR (CDCl3) d 138.8, 128.2, 127.7, 127.4, 84.84, 83.1, 83.0,
82.1, 74.0, 72.1, 71.5, 60.8, 60.7, 58.4, 57.7. Anal. Calcd for
C17H26O6: C, 62.56; H, 8.03. Found: C, 62.86; H, 8.34.
3.12.6.5. Procedure E. The racemic diol 12 (0.150 g, 0.28 mmol)
was allylated as in the general procedure (reaction time 20 h,
0 °C), using butyllithium (0.19 mL, 0.28 mmol) and allyl bromide
(0.044 g, 0.36 mmol) to obtain a mixture of allyl ethers 38 and 39
(0.107 g, 66%). The mixture of allyl ethers (0.032 g) was acetylated
using acetic anhydride (0.03 mL) and pyridine (1 mL) overnight at
room temperature. Usual work-up of the reaction mixture with
ethyl acetate gave a mixture of acetates 42 and 43 (0.034 g). The

1166
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3.12.11. Allylation of racemic 1,2-O-isopropylidene-3,6-di-O-
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The racemic diol 16 (0.200 g, 0.50 mmol) was allylated as in the
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Acknowledgments
S.D. and R.J. thank the Council of Scientific and Industrial Re-
search, New Delhi, for Senior Research Fellowships. We thank Dr.
Rajesh Gonnade and Dr. Mohan M. Bhadbhade (center for materials
characterization, NCL, Pune-08) for collecting the single crystal X-
ray data. Financial assistance for this work was provided by the
Department of Science and Technology, New Delhi.
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