Efficient syntheses of optically pure chiro- and allo-inositol derivatives, azidocyclitols and aminocyclitols from myo-inositol

Article abstract of DOI:10.1016/j.tet.2008.02.032

Efficient routes for the syntheses of optically pure and hitherto unknown l-chiro- and d-allo-inositol derivatives, azido- and aminocyclitols of l-chiro-configuration, diazido- and diaminocyclitols of d-allo-configuration from economically viable myo-inositol are described. These routes provide access to synthetically flexible 1,2:4,5-di-O-isopropylidene-chiro-inositol and 1,6:3,4-di-O-isopropylidene-allo-inositol, which are otherwise difficult to synthesize directly from their parent inositols. A one pot methodology that allows rapid access to both chiro- and allo-inositol derivatives has also been developed. Investigations on the glycosidase inhibitory properties of these novel azido- and amino-inositols unraveled the potentials of these classes of compounds as novel class of glycosidase inhibitors. Both d and l forms of these cyclitols could be synthesized from myo-inositol in gram scales and hence by exploiting the difference in reactivities of cis- and trans-ketals, a variety of protected derivatives, which are useful for the synthesis of unnatural phosphoinositols and natural products, can be synthesized.

Full text of DOI:10.1016/j.tet.2008.02.032

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4072e4080
www.elsevier.com/locate/tet
Efficient syntheses of optically pure chiro- and allo-inositol
derivatives, azidocyclitols and aminocyclitols from myo-inositol
b
b
a,
Kana M. Sureshan a, , Kyoko Ikeda , Naoki Asano , Yutaka Watanabe
*
*
a Department of Material Science and Biotechnology, Graduate School of Science and Engineering, Ehime University, Matsuyama, Japan
b Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
Received 22 January 2008; received in revised form 7 February 2008; accepted 12 February 2008
Available online 15 February 2008
Abstract
Efficient routes for the syntheses of optically pure and hitherto unknown L-chiro- and D-allo-inositol derivatives, azido- and aminocyclitols of
L-chiro-configuration, diazido- and diaminocyclitols of D-allo-configuration from economically viable myo-inositol are described. These routes
provide access to synthetically flexible 1,2:4,5-di-O-isopropylidene-chiro-inositol and 1,6:3,4-di-O-isopropylidene-allo-inositol, which are oth-
erwise difficult to synthesize directly from their parent inositols. A one pot methodology that allows rapid access to both chiro- and allo-inositol
derivatives has also been developed. Investigations on the glycosidase inhibitory properties of these novel azido- and amino-inositols unraveled
the potentials of these classes of compounds as novel class of glycosidase inhibitors. Both D and L forms of these cyclitols could be synthesized
from myo-inositol in gram scales and hence by exploiting the difference in reactivities of cis- and trans-ketals, a variety of protected derivatives,
which are useful for the synthesis of unnatural phosphoinositols and natural products, can be synthesized.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclitol; Inositol; Carbohydrate; Glycosidase inhibitor; Aminocyclitol
1. Introduction
receptors involved in these processes are necessary to unravel
the finer details of cellular events. Thus one of the major foci
of the synthetic inositol chemistry is the judicious design,
synthesis and structureeactivity relationship (SAR) studies
of different structurally modified analogs of natural substrates
of different metabolic enzymes and receptors. Inositols being
cyclohexane hexols, there are nine isomeric possibilities dif-
fering in the relative orientation of hydroxyl groups. Naturally,
ligands derived from these isomeric inositols became the tar-
get candidates for these studies. However, the facts that only
four isomeric inositols occur naturally and the paucity of nat-
urally occurring ones are major hurdles to such investigations.
As a consequence, there have been several attempts to synthe-
size these inositols from different starting materials. In
addition, inositols are increasingly being used as synthons
for many natural products,4 scaffolds for metal complexing
agents,5 gelators,6 catalysts,7 supramolecular assemblies,8
etc. These novel applications of inositols also give further
impact for developing efficient methodologies for their
syntheses.
A great deal of attention has been paid to the synthetic ino-
sitol chemistry due to the involvement of phosphorylated or
glycosylated inositols in various biological processes. Several
inositol phosphates and phospholipids occur in Nature. Apart
from the well established roles of Ins(1,4,5)P3 in cellular
signal transduction1,2 and glycosylphosphatidylinositols in
protein anchoring,3 the biological roles of majority of
phosphoinositols and glycoinositols are yet to be unraveled.
Many of the phosphoinositols are metabolized by different
specific kinases and phosphatases resulting in site selective
phosphorylation and/or dephosphorylation of these phosphoi-
nositols. However, the biological significances of these phos-
phorylationedephosphorylation cascades are unknown. The
design and syntheses of novel ligands of the enzymes/
* Corresponding authors.
E-mail addresses: sureshankm@yahoo.co.in (K.M. Sureshan), wyutaka@
dpc.ehime-u.ac.jp (Y. Watanabe).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.032

K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
4073
chromatography.24a Acylation of (ꢀ)-6 with (S)-O-acetyl-
mandeloyl chloride provided diastereomeric di-(S)-O-acetyl-
mandelate derivatives 7 and 8 (Scheme 1) from which 8
was crystallized from a mixture of ethyl acetateehexane (3:7
v/v) solution and 7 was crystallized from chloroform solution
of the concentrated mother liquor.26a Removal of the chiral
auxiliaries by aminolysis with isobutylamine provided enan-
tiomers of 6 in quantitative yields. The amides could be
washed off with hexane and pure diols L-6 and D-6 could be
obtained by crystallization from a mixture of dichloromethane
and hexane. The use of cheaply available O-acetylmandelic
acid as the chiral auxiliary and avoidance of chromatography
for purification render inexpensive access to optically active
derivatives D-6 and L-6.
OH
NH2
NH2
OR1
NH2
HO
HO
HO
HO
HO
HO
HO
HO
NH2
OH
OH
OH
OH
OH
OR2
OMe
OH
4
OMe
1
NHMe
5
2: R1 = Me; R2 = H
3: R1R2 = CH2
Chart 1. Aminocyclitol moieties of aminoglycoside antibiotics.
On the other hand, aminocyclitols have gained importance
because of their glycosidase inhibitory properties9 and antibac-
terial properties. Aminocyclitols forms the aglycons in many
aminoglycoside antibiotics10 and SAR studies11,12 have estab-
lished the importance of the aminocyclitol part for antibacterial
activities. For instance, amino-inositols 1e5 (Chart 1) are the
aminocyclitol part of antibiotics KA-3093, methoxyhygromy-
cin, hygromycin A, minosaminomycin, and fortimicin, respec-
tively. To control the bacterial resistance toward antibiotics,
developing novel antibiotics using analogs of natural amino-
cyclitols forms an important area of medicinal chemistry
research.13 Also aminocyclitols are potential synthons for nat-
ural products like Amarylladaceae alkaloids (e.g., pancratista-
tin, narciclasine, lycoricidine, etc.). In addition, some of the
synthetic azidocyclitols, the synthetic precursors for aminocy-
clitols, have been shown to possess potent anticancer
properties.14
O
O
O
O
O
RO
O
O
HO
O
O
O
OR
O
_
+
a
b
+
OR
OH
RO
O
8. R = (S)-O-acetylmandeloyl
D-6. R = H
6
7. R = (S)-O-acetylmandeloyl
L-6. R = H
b
Scheme 1. (S)-O-Acetylmandeloyl chloride, Py, 0 ꢁC; (b) isobutylamine,
MeOH, reflux.
During the synthesis of neo-inositol, Potter et al. have
observed an enhancement in yield and regioselectivity for
trifluoromethanesulfonylation compared to other sulfonyla-
tions.20 This report has prompted us to use trifluoromethane-
sulfonic (triflic) anhydride for sulfonylation. Regioselective
sulfonylation of diol D-6 with 1.1 equiv of triflic anhydride
in the presence of pyridine provided 3-triflate D-9 (Scheme
2) in excellent yield (90%). Although trace of ditriflate D-10
(6%) was formed, monotriflate resulting from the sulfonyla-
tion of C6eOH was not observed. In agreement with previous
observation,20 a comparison of yields of previously reported
tosylation18 with our triflylation reveals that the yield and re-
gioselectivity for triflylation is superior to those for other sul-
fonylations. It is worthy to note that such a high degree of
2. Results and discussions
Due to the aforementioned importance of cyclitols and ami-
nocyclitols, various elegant syntheses of isomeric inositols,15
monoaminocyclitols,16 and diaminocyclitols17 from different
starting materials have been reported. However, use of cheaply
available myo-inositol as starting material for the synthesis of
such cyclitols and aminocyclitols is advantageous. Since the
regioselective protectionedeprotection of myo-inositol hy-
droxyl groups with a wider range of protecting groups18 and
methods for optical resolution of protected myo-inositol deriv-
atives2c are known, by choosing an appropriate optically pure
myo-inositol derivative as the starting material, desirably pro-
tected isomeric inositol derivatives and aminocyclitols in opti-
cally pure form can be made. Although scyllo,19 neo,20 cis,21
D-chiro22 and L-chiro23 inositols (or their derivatives) have
been synthesized from myo-inositol, only a few of these re-
ports19b,22,23 deal with the syntheses of optically homogeneous
derivatives. We herein report the full details of our synthesis of
enantiomerically pure chiro- and allo-inositol derivatives and
aminocyclitols.24
O
O
OH
1
O
1
3
HO
O
O
TfO
O
O
HO
HO
OH
OH
1
AcO
O
O
d
c
1
b
5
a
5
5
3
OH
3
OH
5
O
OH
3
O
L-12
OH
L-13
O
L-11
D-9
D-6
Racemic 1,2:4,5-di-O-isopropylidene-myo-inositol (6),25
due to its ease of preparation, difference in reactivity between
two hydroxyl groups and the possibility for the selective de-
protection of trans ketal in presence of the cis-ketal, has
been chosen as the starting material for the synthesis of iso-
meric inositol derivatives and aminocyclitols via SN2 substitu-
tion of mono and di-sulfonate derivatives of 6. We have
recently developed26 an efficient method for the diastereo-
meric resolution of (ꢀ)-6 without involving column
OH
O
O
O
HO
HO
OH
OH
1
HO
O
O
5
3
AcO
O
O
TfO
O
O
d
f
OAc
b
3
1
5
e
3
OH
OTf
1
O
5
OH
O
O
D-10
16
L-15
D-14
Scheme 2. (a) Tf2O (1.1 equiv), Py, CH2Cl2, ꢂ20 ꢁC; (b) KOAc, DMA, 70 ꢁC;
(c) MeOH, Et3N, reflux; (d) TFAeH2O (4:1), rt; (e) Tf2O (2.2 equiv), Py,
CH2Cl2, ꢂ20 ꢁC; (f) NaOMe, MeOH, reflux.

4074
K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
regioselectivity during acylation, silylation, alkylation, and
sulfonylation has not been observed for this diol previously.18
Ditriflate D-10 can be washed away with hexane. Ultra-pure
crystalline D-9 could be obtained by crystallization from
CH2Cl2ehexane. However, D-9 is very unstable at rt and hence
a perfect combustion analysis was not possible. Also D-9 al-
ways decomposed in solution during the acquisition of 13C
NMR. Also this compound did not melt on heating but charred
in the temperature range 110e130 ꢁC probably due to the de-
composition before melting point. For this reason crude D-9,
obtained by simply washing off the ditriflate D-10, was con-
verted to the next product as soon as it was prepared.
At first we attempted to substitute the triflyl group with ace-
tate in SN2 fashion to synthesize chiro-inositol derivatives.
However, treatment of D-9 with potassium acetate (KOAc) in
DMF resulted in the formation of an inseparable mixture of
formate and acetate. The use of DMF as formate anion equiv-
alent in substitution of sulfonates has been documented in lit-
erature.20,27 Potter et al.20 used aq dimethylacetamide (DMA)
as acetate anion equivalent to substitute the triflate group. An
analogous approach using aq DMA to substitute the triflyl
group in D-9 was sluggish to be of practical use. However,
a clean SN2 substitution of triflate with acetate could be
achieved by the use of KOAc in DMA. Evaporation of
DMA under reduced pressure followed by aqueous work-up
of the residue provided pure 1-O-acetyl-2,3:5,6-di-O-isopro-
pylidene-L-chiro-inositol (L-11) in quantitative yield without
the need of chromatography. Products arising from elimination
or substitution (SN1) with retention of configuration were not
detected. The acetate moiety in L-11 was removed by metha-
nolysis and pure 1,2:4,5-di-O-isopropylidene-L-chiro-inositol
(L-12) could be obtained quantitatively by simple evaporation
of the solvents. Finally, acid hydrolysis of the ketal moieties
and evaporation of the solvents provided pure L-chiro-inositol
(L-13), which could be crystallized from a mixture of water
and ethanol.
Sulfonylation of diol D-6 with 2.2 equiv of triflic anhydride in
the presence of pyridine provided the ditriflate D-10 (Scheme 2).
Treatment of D-10 with KOAc in DMA provided D-2,5-di-
O-acetyl-1,6:3,4-di-O-isopropylidene-allo-inositol (D-14) in
quantitative yield. The acetate moieties were removed by meth-
anolysis using catalytic amount of NaOMe in methanol. Neu-
tralization of the reaction mixture with dry ice followed by
evaporation to dryness and trituration with dichloromethane
provided the D-1,6:3,4-di-O-isopropylidene-allo-inositol D-15
in quantitative yield. allo-Inositol 16 being a meso-cyclitol, it
was prepared from the racemic 15. Thus (ꢀ)-15, prepared
from (ꢀ)-6 in a similar sequence as above, on acid hydrolysis
afforded allo-inositol (16).
In light of the demand for various inositols for ligand syn-
thesis in short time, we investigated the syntheses of allo- and
chiro-inositol derivatives in one pot. A co-spotted TLC (Thin
Layer Chromatography) analysis of individually synthesized
chiro-acetate L-11 and allo-diacetate D-14 revealed that they
are chromatographically separable. Hence we decided to syn-
thesize L-11 and D-14 in one pot. Thus a mixture of monotri-
flate D-9 and ditriflate D-10 were synthesized by reacting the
diol D-6 with 1.5 equiv of triflic anhydride in pyridine. Treat-
ment of the crude mixture of D-9 and D-10 thus obtained with
KOAc in DMA, followed by work-up and chromatography
provided acetate L-11 (41%) and diacetate D-14 (54%). Thus
this procedure gives access to two important inositol deriva-
tives essentially in two steps from diol D-6.
It is noteworthy that protected derivatives 11 and 12 cannot
be obtained from chiro-inositol directly, as isopropylidenation
is reported18 to give C2 symmetric 1,2;5,6-di-O-isopropyl-
idene-chiro-inositol (both cis), which is not expected to show
any selectivity for cleavage. Although protection of allo-inosi-
tol is not known, 1,6:3,4-di-O-isopropylidene-allo-inositol
(15), is not expected to be a product of di-isopropylidenation
of allo-inositol (16) as other two diketals (with two cis-ketals)
are expected to be more stable than 15. Hence our routes pro-
vide access to protected derivatives (11,12,14, and 15), which
cannot be obtained directly from respective inositols. The rel-
ative lability of trans-isopropylidene over cis-isopropylidene18
on mild acid hydrolysis or transketalization can be exploited to
synthesize further set of partially protected inositol derivatives
(cis-mono ketals) from these diketals. Such partially protected
inositol derivatives are essential for the syntheses of phospho-
inositols and natural products.
We then turned our attention to the synthesis of novel ami-
nocyclitols. Nucleophilic substitution of the triflate D-9 with
sodium azide in DMF provided 1L-1-azido-1-deoxy-2,3:5,6-
di-O-isopropylidene-chiro-inositol (L-17, Scheme 3). As in
the case of substitution with acetate, compounds arising
from elimination or SN1 reaction were not observed. Contrary
to the reaction of D-9 with KOAc in DMF, competing substi-
tution with formate anion was not observed in this case.
This could be due to the large difference in nucleophilicities
of azide and O-acyl anion. The formate being less nucleophilic
may not be able to compete with highly nucleophilic azide an-
ion for the SN2 substitution of triflate. But since the difference
in nucleophilicities of two O-acyl anions (formate and acetate)
being small, formate anion competes with acetate during the
substitution with KOAc in DMF. The ketal protecting
groups in L-17 were removed by acid hydrolysis and pure
OH
OH
O
O
3
1
OH
H2N
HO
OH
OH
TfO
O
O
N3
HO
N3
O
1
O
c
d
b
a
1
5
5
OH
OH
5
O
3
OH
OH
3
OH
O
D-9
L-17
L-18
L-19
D-6
OH
OH
O
O
H2N
HO
OH
NH2
N3
OH
N3
O
O
3
5
TfO
O
d
c
b
3
1
e
HO
N3
N3
O
OTf
1
O
5
O
OH
OH
D-10
D-20
D-21
D-22
Scheme 3. (a) Tf2O (1.1 equiv), Py, CH2Cl2, ꢂ20 ꢁC; (b) NaN3, DMF, 70 ꢁC;
(c) TFAeH2O (4:1), rt; (d) H2, PdeC, MeOH, rt; (e) Tf2O (2.2 equiv), Py,
CH2Cl2, ꢂ20 ꢁC.

K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
4075
OH
OH
isomaltase, respectively. Interestingly, the inhibition of some
of the enzymes by (ꢀ)-22 is better than that by D-22.
OH
4
OH
3
OH
3
N3
2
5
6
5
6
6
5
1
1
NH2
4
N3
OH
HO
HO
OH
OH
H2N
N3
Although there are a few reports on the synthesis of various
mono-amino16 and dimaino-inositols,17aeh the glycosidase in-
hibitory activities of these derivatives have not been investi-
gated. In general, the enzyme inhibitions by our azido- or
amino-inositol are comparable with that by other cyclitol28
or aminocyclitol29 derivatives and more potent than amino-
di-inositols17i and some of the aminocyclitols30 but much
less potent than conformationally restricted bicyclic aminocy-
clitol31 or valienamine analogs.32 Our results suggest that
there is enough scope for investigation of various amino and
azido-inositols as novel class of glycosidase inhibitors.
2
2
4
1
3
OH
OH
N3
1C4 conformer
4C1 conformer
D-22
D-21 1C4 conformer
D-21
Chart 2. Conformational preferences of D-21 and D-22.
1L-1-azido-1-deoxy-chiro-inositol (L-18) could be obtained as
a gum in quantitative yield by simple evaporation of the sol-
vents. Hydrogenolysis of the azide L-18 provided 1L-1-
amino-1-deoxy-chiro-inositol (L-19).
Similarly, treatment of the ditriflate D-10 with NaN3 in
DMF provided 1D-2,5-di-azido-2,5-di-deoxy-1,6:3,4-di-O-iso-
propylidene-allo-inositol (D-20, Scheme 3) in 93% yield. Re-
moval of the isopropylidene groups by acid hydrolysis
provided 1D-2,5-diazido-2,5-di-deoxy-allo-inositol (D-21).
Owing to the allo (3a/3e) configuration and hence the plausi-
ble dynamic interchange between two different chair confor-
mations (Chart 2), the signals in both 1H NMR and 13C
NMR of D-21 were very broad. However, the signals were re-
solved at high temperature as expected. Finally, hydrogenoly-
sis of D-21 provided 1D-2,5-diamino-2,5-di-deoxy-allo-inositol
(D-22). Surprisingly, D-22 showed sharp peaks in the NMR
3. Conclusions
In conclusion, we have reported efficient routes for the
syntheses of different protected chiro- and allo-inositol deri-
vatives, monoazido- and monoamino-inositol of chiro
configuration and diazido- and diamino-inositols of allo con-
figuration in optically active form from myo-inositol. Since
the trans-isopropylidene can be cleaved leaving the cis-ketal
unaffected, by exploiting this selectivity, different derivatives
for cyclitol and aminocyclitol based natural product and phos-
phoinositol syntheses can be made easily. A one pot method
for the simultaneous preparation of both chiro- and allo-inosi-
tol derivative provides easy access to derivatives of two differ-
ent inositols. Also another advantage is that the derivatives,
which cannot be obtained directly from the respective inosi-
tols, can be obtained via our method through sulfonate inver-
sion of the respective myo-inositol derivative. Preliminary
investigation on the glycosidase inhibitory activity of the novel
azido and aminocyclitols suggests that these classes of com-
pounds have potential to be novel class of glycosidase
inhibitors.
3
spectra. Analysis of the JHH coupling constants suggested
that D-22 takes the chair conformation where both amino
groups and C-4eOH are in equatorial orientation (1C4 confor-
mation). Coupling constants of 10.5 Hz for H-4/H-5 coupling
and 3.5 Hz for H-1/H-6 coupling are indicative of diaxial ori-
entation of H-4 and H-5 and diequatorial orientation of H-1
1
and H-6. This is in agreement with the C4 conformation of
the cyclohexyl ring. Further evidence for such a conformation
came from the observed cross-peaks between H-1 and H-3 in
the COSY spectra due to the W-coupling.
The abilities of these azido-inositols and amino-inositols to
inhibit various glycosidases were investigated. All of these
compounds showed weak to moderate inhibition toward the
enzymes tested. Inhibition of various glycosidases and glyco-
gen phosphorylase by compounds L-18, L-19, D-21, D-22, and
(ꢀ)-22 is shown in Table 1. However, it is worthy to note that
the azido-inositol L-18 showed relatively good inhibition to-
ward rat intestinal sucrase and isomaltase with the IC50 values
of 0.66 and 0.54 mM, respectively. Also, the compounds L-18,
D-21, and D-22 showed about 50% inhibition at 1 mM toward
rice a-glucosidase, rat intestinal sucrase, and rat intestinal
4. Experimental
4.1. General
All experiments were conducted under nitrogen atmo-
sphere. Melting points were determined with a Yanaco Micro
Melting Point Apparatus and are uncorrected. Flash column
chromatography was performed using silica gel (Fuji Silysia,
Table 1
Enzyme inhibition rate (%) of amino- and azido-inositols at 1 mM
Enzyme
(ꢀ)-22
D-21
D-22
L-18
L-19
a-Glucosidase (rice, pH 5.0)
25.4
18.8
20.0
29.1
11.1
21.7a
0.4
17.4
0.0
29.9
3.8
49.3
26.2
31.3
0.0
Rat intestinal maltase (pH 5.8)
Rat intestinal sucrase (pH 5.8)
Rat intestinal isomaltase (pH 5.8)
b-Glucosidase (almonds, pH 5.0)
Glycogen phosphorylase b (rabbit muscle)
a-Fucosidase (human placenta)
b-Xylosidase (Aspergillus niger)
47.9
28.1
21.7
7.6b
12.9
8.3
34.4
49.1
7.6
11.4b
9.5
61.5 (IC50¼0.66 mM)
32.8
19.3
0.0
3.2b
19.9
23.8
68.7 (IC50¼0.54 mM)
0.0
3.5b
20.1
18.1
8.3
21.5
a
Inhibition at 1 mg/mL.
Inhibition at 0.4 mM.
b

4076
K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
Silica gel BW-300). H and 13C NMR spectra were recorded
on a Bruker-DPX-400 instrument. Chemical shifts (dH values
relative to tetramethylsilane and dC values relative to CDCl3)
and coupling constants (J values) are given in parts per million
and hertz, respectively. Optical rotations were recorded in
a JASCO P-1010 Polarimeter. Elemental analyses were carried
out on a YANACO MT-5 elemental analyzer. Usual work-up
refers to evaporation of the reaction solvent followed by disso-
lution of the residue in ethyl acetate and washing successively
with water, dil HCl, satd NaHCO3 solution, and brine followed
by drying over anhyd MgSO4 and concentration under reduced
pressure.
(563 mg, 46%, mp 215e217 ꢁC; [a]D þ64.4 (c 1, CH2Cl2))26b
could be obtained by crystallization from a mixture of ethyl
acetate and hexane (1:3 v/v). The concentrated mother liquor
was re-dissolved in a mixture of CHCl3 (10 mL) and hexane
(20 mL) to get crystals of 7 (514 mg, 42%, mp 177 ꢁC; [a]D
þ53.2 (c 1, CH2Cl2)).26b
1
4.5. D-1,2:4,5-Di-O-isopropylidene-myo-inositol (D-6)
4.5.1. Method A
A suspension of 8 (800 mg, 1.3 mmol) and isobutylamine
(2 mL) in methanol (10 mL) was refluxed for 1 h, when
TLC showed complete disappearance of the starting material.
The solvent and excess isobutylamine were evaporated off un-
der reduced pressure and the residue thus obtained was chro-
matographed with ethyl acetateehexane (8:2 v/v) as eluent
to get pure D-6 (334 mg, 99%). Mp 159e161 ꢁC; [a]D
ꢂ21.8 (c 1, MeCN); lit.35 values for enantiomer of D-6 mp
159e161 ꢁC; [a]D 22 (c 1, MeCN).
4.2. Enzyme assay
The enzymes a-glucosidase (from rice, assayed at pH 5.0),
b-glucosidase (from almonds, assayed at pH 5.0), a-fucosidase
(from human placenta, assayed at pH 6.8), b-xylosidase (from
Aspergillus niger, assayed at pH 5.0), p-nitrophenyl glyco-
sides, and disaccharides were purchased from Sigma-Aldrich
Chemical Co. (St. Louis, MO, USA). Brush border membranes
prepared from rat small intestine according to the method of
Kessler et al.33 were assayed at pH 5.8 for rat intestinal malt-
ase, isomaltase, and sucrase using maltose, isomaltose, and su-
crose. The released D-glucose was determined colorimetrically
using the Glucose CII-test Wako (Wako Pure Chemical Indus-
tries, Osaka, Japan). Other glycosidase activities were deter-
mined using an appropriate p-nitrophenyl glycoside as
substrate. The reaction was stopped by adding 400 mM
Na2CO3. The released p-nitrophenol was measured spectro-
metrically at 400 nm. Glycogen phosphorylase activity was as-
sayed in the direction of glycogen breakdown from the rate of
NADPH formation in an assay coupled to phosphoglucomu-
tase and glucose 6-phosphate dehydrogenase.34
4.5.2. Method B
To a suspension of 8 (1.84 g, 3 mmol) in dry methanol
(50 mL) was added triethylamine (9 mL) and the mixture
was stirred at rt overnight. The solvents were evaporated and
the residue was washed with hexane to get pure diol D-6
(0.781 g, 100%).
4.6. (ꢀ)-3-O-Trifluoromethanesulfonyl-1,2:4,5-di-
O-isopropylidene-myo-inositol [(ꢀ)-9]
To a solution of diol (ꢀ)-6 (2.6 g, 10 mmol) in a mixture of
pyridine (20 mL) and dichloromethane (100 mL) at ꢂ20 ꢁC
was added triflic anhydride (1.93 mL) dropwise and the mix-
ture was stirred overnight gradually warming it to rt. The sol-
vents were evaporated off, the residue was dissolved in ethyl
acetate and washed successively with water, dil HCl, satd
NaHCO3 solution, and brine, dried over anhyd MgSO4, and
evaporated under reduced pressure. The residue was chroma-
tographed using 1:9 ethyl acetateehexane to get ditriflate
(712 mg, 13.6%) and further elution with 3:7 ethyl acetatee
hexane provided the monotriflate (3.29 g, 84%).
In an easy method the ditriflate can effectively be removed
by washing the residue with hexane (5ꢃ10 mL) and the re-
maining solid was very pure monotriflate. Note: it has been
observed that the monotriflate, after work-up, is prone to
decomposition via ketal cleavage and hence the next reaction
has to be done immediately.
4.3. Preparation of S-O-acetyl-mandeloyl chloride
A solution of (S)-O-acetyl mandelic acid (194 mg, 1 mmol)
in dichloromethane (5 mL) was cooled to 0 ꢁC. To this solu-
tion added oxalyl chloride (105 mL, 1.1 mmol) and then a cat-
alytic amount (10 mL) of DMF and the resulting mixture was
stirred at 0 ꢁC till the effervescence ceases (about 2 h). This
solution was directly used for esterification. Pure S-O-acetyl-
mandeloyl chloride can also be obtained by evaporating off
the dichloromethane and extracting the residue with dry hex-
ane followed by evaporation of the hexane extract.
4.4. Separation of 7 and 8
4.7. D-3-O-Trifluoromethanesulfonyl-1,2:4,5-di-
To a solution of diol (ꢀ)-6 (520 mg, 2 mmol) in pyridine
(10 mL), a solution of (S)-O-acetylmandeloyl chloride (893 mg,
4.2 mmol) in CH2Cl2 (5 mL) was added dropwise at 0 ꢁC and
stirred for 3 h gradually allowing the reaction mixture to attain
rt. After 3 h, ethyl acetate was added and washed successively
with water, dil HCl, satd solution of NaHCO3, and brine. The
organic layer was dried over anhyd Na2SO4 and evaporated un-
der reduced pressure to obtain a solid (1.23 g). Compound 8
O-isopropylidene-myo-inositol (D-9)
To a solution of diol D-6 (1.3 g, 5 mmol) in a mixture of
pyridine (10 mL) and dichloromethane (50 mL) at ꢂ20 ꢁC,
was added trifluoromethanesulfonic anhydride (985 mL,
5.1 mmol) dropwise and the solution was stirred at that tem-
perature for 2 h. The mixture was then diluted with ethyl ace-
tate (150 mL), washed with water, dil HCl, aq NaHCO3, and

K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
4077
brine, dried over anhyd MgSO4, and evaporated. The residue
was washed with hexane (5ꢃ10 mL) and concentration of
the combined hexane washings provided ditriflate D-10
(131 mg, 6%). The residue remained after washing with hex-
ane was pure monotriflate D-9 (1.765 g, 90%). [a]D 13 (c 1,
(CMe2), 111.95 (CMe2). Anal. Calcd for C12H20O6: C,
55.37; H, 7.74. Found: C, 55.21; H, 7.69.
4.10. L-chiro-Inositol (L-13)
1
MeOH); H NMR (CDCl3, 400 MHz): 1.38 (s, 3H, Me), 1.46
Diketal L-12 (100 mg, 0.38 mmol) was stirred in a mixture
of TFA and H2O (4:1 v/v, 3 mL) at rt for 3 h. Evaporation to
dryness provided L-chiro-inositol (L-13, 69 mg) as a white
solid. [a]D ꢂ59.0 (c 1.2, H2O); lit.23 [a]D ꢂ58.2 (c 1.3, H2O).
(s, 3H, Me), 1.48 (s, 3H, Me), 1.56 (s, 3H, Me), 2.45 (br,
OH), 3.40 (dd, 10.25, 9.77 Hz, H-5), 3.94 (dd, 10.74, 6.38 Hz,
H-6), 4.08e4.16 (m, 2H, H-1 and H-4), 4.57 (t, 4.40 Hz,
H-2), 5.07 (dd, 10.24, 4.40 Hz, H-3).
4.11. (ꢀ)-3,6-Di-O-trifluoromethanesulfonyl-1,2:4,5-di-O-
isopropylidene-myo-inositol [(ꢀ)-10]
4.8. 1-O-Acetyl-2,3:5,6-di-O-isopropylidene-L-chiro-inositol
(L-11)
To a solution of diol (ꢀ)-6 (1.17 g, 4.5 mmol) in a mixture
of pyridine (15 mL) and dichloromethane (75 mL) at ꢂ20 ꢁC
was added triflic anhydride (1.93 mL, 10 mmol) dropwise
and the mixture was stirred overnight gradually warming the
mixture to rt. The solvents were evaporated off and the residue
was dissolved in ethyl acetate and washed successively with
water, dil HCl, satd NaHCO3 solution, and brine, dried over
anhyd MgSO4, and evaporated under reduced pressure. The
crude residue thus obtained was chromatographed with 1:9
(v/v) ethyl acetateehexane to get the ditriflate (ꢀ)-10 (2.2 g,
93%) as a white solid. This solid did not show a sharp melting
point. At 92 ꢁC, the crystals shrinked, further heating resulted
in browning of the crystals at 112e116 ꢁC and finally
the crystals got charred at 120 ꢁC. 1H NMR (CDCl3,
400 MHz): 1.41 (s, 3H, Me), 1.47 (s, 3H, Me), 1.50 (s, 3H,
Me), 1.59 (s, 3H, Me), 3.60 (dd, 10.8, 10.25 Hz, H-5), 4.19
(t, 10.8 Hz, H-4), 4.36 (dd, 6.35, 4.40 Hz, H-1), 4.62 (t,
4.40 Hz, H-2), 4.87 (dd, 10.8, 6.5 Hz, H-6), 5.08 (dd, 10.25,
4.40 Hz, H-3); 13C NMR (CDCl3): 25.51 (CH3), 26.51 (CH3),
26.54 (CH3), 27.39 (CH3), 74.02 (Ins C), 74.72 (Ins C), 75.79
(Ins C), 78.58 (Ins C), 81.40 (Ins C), 87.11 (Ins C), 112.28
(CMe2), 114.74 (CMe2), 118.38 (q, CF3), 118.42 (q, CF3).
Anal. Calcd for C14H18F6O10S2: C, 32.06; H, 3.46. Found: C,
31.91; H, 3.54.
The triflate D-9 (392 mg, 1 mmol) was stirred with potassium
acetate (491 mg, 5 mmol) in dimethylacetamide (9 mL) at
70 ꢁC for overnight. The solvent was evaporated under reduced
pressure and the residue on usual work-up provided pure L-11
(299 mg, 99%). Mp 126e128 ꢁC; [a]D ꢂ65.0 (c 1, CHCl3);
1H NMR (Me2SO-d6, 400 MHz): 1.24 (s, 3H), 1.29 (s, 3H),
1.35 (s, 3H), 1.39 (s, 3H), 2.05 (s, 3H), 3.58 (m, H-4), 3.64e
3.68 (overlapped, H-2 and H-3), 3.96 (dd, 5.9, 5.7 Hz, H-5),
4.22 (dd, 5.7, 1.8 Hz, H-6), 5.38 (t, 1.8 Hz, H-1), 5.62 (d,
5.5 Hz, OH); 1H NMR (CD3OD, 400 MHz): 1.33 (s, 3H),
1.37 (s, 3H), 1.42 (s, 3H), 1.47 (s, 3H), 2.10 (s, 3H), 3.73e
3.81 (overlapped, H-2, H-3 and H-4), 4.06 (dd, 5.7, 5.6 Hz,
1
H-5), 4.28 (dd, 5.6, 1.8 Hz, H-6), 5.55 (t, 1.8 Hz, H-1); H
NMR (Me2CO-d6, 400 MHz): 1.28 (s, 3H), 1.32 (s, 3H), 1.36
(s, 3H), 1.41 (s, 3H), 2.08 (s, 3H), 3.74e3.81 (overlapped, H-
2, H-3 and H-4), 4.07 (t, 5.4 Hz, H-5), 4.28 (dd, 5.4, 1.8 Hz,
1
H-6), 4.74 (d, 3.7 Hz, OH), 5.53 (t, 1.8 Hz, H-1); H NMR
(CDCl3, 400 MHz): 1.34 (s, 3H), 1.40 (s, 3H), 1.46 (s, 3H),
1.49 (s, 3H), 2.11 (s, 3H), 2.73 (br, OH), 3.83e3.90 (overlap-
ped, H-2, H-3 and H-4), 4.13 (dd, 6.4, 5.6 Hz, H-5), 4.23 (dd,
5.6, 2.4 Hz, H-6), 5.68 (t, 2.4 Hz, H-1); 13C NMR (CDCl3,
100 MHz): 20.55 (COCH3), 25.54 (CH3), 26.24 (CH3), 26.86
(CH3), 27.69 (CH3), 66.17 (Ins C), 74.89 (Ins C), 75.21 (Ins
C), 76.58 (Ins C), 77.22 (Ins C), 81.02 (Ins C), 109.81
(CMe2), 111.91 (CMe2), 169.20 (OCOMe). Anal. Calcd for
C14H22O7: C, 55.62; H, 7.33. Found: C, 55.96; H, 7.27.
4.12. D-3,6-Di-O-trifluoromethanesulfonyl-1,2:4,5-di-
O-isopropylidene-myo-inositol (D-10)
4.9. 1,2:4,5-Di-O-isopropylidene-L-chiro-inositol (L-12)
To a solution of diol D-6 (1.3 g, 5 mmol) in a mixture of
pyridine (17 mL) and dichloromethane (83 mL) at ꢂ20 ꢁC,
was added trifluoromethanesulfonic anhydride (2.123 mL,
11 mmol) dropwise and the solution was stirred at that temper-
ature for 2 h. The solvent was evaporated and the residue thus
obtained was dissolved in ethyl acetate and washed succes-
sively with water, cold dil HCl, aq NaHCO3, and brine, dried
over anhyd MgSO4, and the solvent was evaporated to get D-10
The acetate L-11 (200 mg, 0.66 mmol) was refluxed in
a mixture of methanol (4 mL) and triethylamine (1 mL) for
2 h. The reaction mixture was cooled and the solvents were
evaporated under reduced pressure to obtain pure L-12
(171 mg, 99.3%) as a white solid. A small fraction of this solid
was crystallized from a mixture of CHCl3 and hexane. [a]D
1
1
ꢂ61.0 (c 1.1, CHCl3); H NMR (CDCl3, 400 MHz): 1.34 (s,
(2.543 g, 97%) as a white powder. Since H NMR showed no
impurity, this was not purified further.
3H, CH3), 1.45 (s, 3H, CH3), 1.47 (s, 6H, 2ꢃCH3), 2.67 (br
s, 6-OH), 3.06 (br s, 3-OH), 3.75 (dd, 9.2, 2.8 Hz, H-5),
3.80e3.95 (2H overlapped, H-3 and H-4), 4.15 (t, 5.6 Hz,
H-2), 4.33 (dd, 5.6, 2.0 Hz, H-1), 4.48 (m, 1H, H-6); 13C
NMR (CDCl3, 100 MHz): 25.64 (CH3), 26.58 (CH3), 27.13
(CH3), 27.88 (CH3), 65.63 (Ins C), 74.72 (Ins C), 75.78 (Ins
C), 77.26 (Ins C), 79.06 (Ins C), 81.2 (Ins C), 109.43
4.13. D-2,5-Di-O-acetyl-1,6:3,4-di-O-isopropylidene-allo-
inositol (D-14)
The triflate D-10 (1.049 g, 2 mmol) was stirred with potas-
sium acetate (981 mg, 10 mmol) in dimethylacetamide

4078
K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
(16 mL) at 70 ꢁC for overnight. The solvent was evaporated
under reduced pressure and the residue on usual work-up
provided pure D-14 (688 mg, quant) as white solid. A small
fraction of this solid was crystallized from a mixture of chlo-
C), 78.56 (Ins C), 109.38 (CMe2), 110.92 (CMe2). Anal. Calcd
for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.19; H, 7.81.
4.16. (ꢀ)-1,2:4,5-Di-O-isopropylidene-allo-inositol [(ꢀ)-15]
1
roform and hexane. Mp 140 ꢁC; [a]D ꢂ55.0 (c 1, CHCl3); H
NMR (CDCl3, 400 MHz): 1.33 (s, 3H, Me), 1.42 (s, 3H, Me),
1.44 (s, 3H, Me), 1.49 (s, 3H, Me), 2.11 (s, 3H, COCH3), 2.13
(s, 3H, COCH3), 3.93 (dd, 10.2, 2.57 Hz, H-1), 4.24 (dd, 5.66,
1.60 Hz, H-4), 4.27 (dd, 10.20, 3.37 Hz, H-6), 4.37 (t, 5.67 Hz,
H-3), 5.64 (dd, 5.65, 2.58 Hz, H-2), 5.74 (dd, 3.37, 1.60 Hz, H-
5); 13C NMR (CDCl3, 100 MHz): 20.70 (COCH3), 21.13
(COCH3), 25.01 (CH3), 25.88 (CH3), 26.61 (CH3), 26.64
(CH3), 66.14 (Ins C), 66.75 (Ins C), 70.83 (Ins C), 72.24
(Ins C), 72.84 (Ins C), 77.02 (Ins C), 110.10 (CMe2), 111.45
(CMe2), 169.26 (OCOMe), 169.71 (OCOMe). Anal. Calcd
for C16H24O8$0.3H2O: C, 54.94; H, 7.09. Found: C, 54.86;
H, 6.92.
Diacetate (ꢀ)-14 (200 mg, 0.58 mmol) and sodium meth-
oxide (10 mg) were reacted in methanol (6 mL) for 2 h as
above to get (ꢀ)-15 (131 mg, 87%).
4.17. allo-Inositol (16)
Compound (ꢀ)-15 (100 mg, 0.38 mmol) was stirred with
a mixture of TFA and water (4:1 v/v, 3 mL) for 3 h. Evapora-
tion to dryness provided allo-inositol (16, 69 mg) as a white
solid.
4.18. Synthesis of 1-O-acetyl-2,3:5,6-di-O-isopropylidene-L-
chiro-inositol and D-2,5-di-O-acetyl-1,6:3,4-di-O-
isopropylidene-allo-inositol in one pot
4.14. (ꢀ)-2,5-Di-O-acetyl-1,6:3,4-di-O-isopropylidene-allo-
inositol [(ꢀ)-14]
To a solution of diol D-6 (260 mg, 1 mmol) and pyridine
(2 mL) in CH2Cl2 (10 mL) was added Tf2O (255 mL,
1.5 mmol) dropwise at ꢂ20 ꢁC. The reaction mixture was
stirred overnight at rt. The solvents were evaporated and the
residue was dissolved in ethyl acetate, washed successively
with water, cold dil HCl, satd aq NaHCO3, and brine, dried
(Na2SO4), and evaporated. The crude mixture of D-9 and D-10
thus obtained was dissolved in DMA (7 mL) and reacted with
KOAc (500 mg, 5.1 mmol) at 70e80 ꢁC for 5 h. DMA was
evaporated and usual work-up of the residue followed by col-
umn chromatography yielded L-11 (124 mg, 41%) and D-14
(186 mg, 54%).
To a solution of ditriflate (ꢀ)-10 (524 mg, 1 mmol) in
DMA (10 mL), KOAc (491 mg, 5 mmol) was added and the
mixture was stirred at 80 ꢁC for 8 h. DMA was evaporated un-
der reduced pressure and the residue was dissolved in ethyl ace-
tate and washed successively with water and brine, dried over
anhyd MgSO4, and the solvent was evaporated. The residue
thus obtained was chromatographed using ethyl acetatee
hexane as eluent to get the diacetate (ꢀ)-14 (300 mg, 87%).
Mp 161 ꢁC (sublimed).
4.15. L-1,2:4,5-Di-O-isopropylidene-allo-inositol (L-15)
The diacetate D-14 (344 mg, 1 mmol) and catalytic amount
of sodium methoxide (10 mg) were refluxed in methanol
(10 mL) for 2 h. The reaction mixture was cooled, neutralized
by the addition of solid CO2, and then the solvents were evap-
orated under reduced pressure. Trituration of the residue with
dichloromethane provided pure L-15 (260 mg, 100%) as
a white solid. A small fraction of this solid was crystallized
from a mixture of ethyl acetate and hexane. Mp 136 ꢁC;
4.19. (ꢀ)-1-Azido-1-deoxy-2,3:5,6-di-O-isopropylidene-
chiro-inositol [(ꢀ)-17]
To a solution of (ꢀ)-9 (3.295 g, 8.4 mmol) in DMF (50 mL)
was added NaN3 (1.3 g, 20 mmol) and the mixture was stirred
at 70 ꢁC for 5 h. DMF was then evaporated under diminished
pressure and the residue was dissolved in ethyl acetate and
washed successively with water and brine, dried over
MgSO4, and the solvent was evaporated under reduced pres-
sure. The crude azide thus obtained was crystallized from
a mixture of dichloromethane and hexane to get pure (ꢀ)-17
(2.17 g, 90.8%) as a colorless solid. Mp 128 ꢁC.
1
[a]D ꢂ85.0 (c 1, CHCl3); H NMR (Me2SO-d6, 400 MHz):
1.26 (s, 3H, Me), 1.33 (s, 3H, Me), 1.34 (s, 3H, Me), 1.44 (s,
3H, Me), 3.80 (dd, 9.8, 1.5 Hz, H-4), 4.05e4.11 (overlapped,
H-3 and H-5), 4.22 (dd, 4.4, 3.4 Hz, H-2), 4.82 (dd, 4.4,
1
0.5 Hz, H-6), 5.30 (dd, 4.4, 0.5 Hz, H-1); H NMR (C6D6,
400 MHz): 1.15 (s, 3H, Me), 1.39 (s, 6H, 2ꢃMe), 1.49 (s,
3H, Me), 3.86e3.90 (overlapped, H-2 and H-4), 4.16 (dd,
4.4, 2.4 Hz, H-3), 4.33 (dd, 5.9, 1.5 Hz, H-1), 4.53 (dd, 3.4,
4.20. L-1-Azido-1-deoxy-2,3:5,6-di-O-isopropylidene-
chiro-inositol (L-17)
1
1.5 Hz, H-6), 4.62 (dd, 9.8, 3.4 Hz, H-5); H NMR (CDCl3,
Using D-9 (392 mg, 1 mmol) and NaN3 (130 mg, 2 mmol)
optically pure L-17 (240 mg, 84%) could be obtained. Mp sub-
400 MHz): 1.40 (s, 3H, Me), 1.47 (s, 3H, Me), 1.52 (s,
3H, Me), 1.55 (s, 3H, Me), 2.42 (s, OH), 2.47 (s, OH), 3.95
(dd, 10.0, 2.4 Hz, H-4), 4.29 (dd, 6.0, 4.4 Hz, H-2), 4.33e
4.38 (overlapped, H-3 and H-5), 4.41 (dd, 6.0, 1.6 Hz, H-1),
4.51 (dd, 3.2, 1.6 Hz, H-6); 13C NMR (CDCl3, 100 MHz):
24.44 (CH3), 25.73 (CH3), 26.67 (CH3), 26.75 (CH3), 65.59
(Ins C), 65.95 (Ins C), 71.68 (Ins C), 73.32 (Ins C), 74.18 (Ins
1
limed in the range 100e125 ꢁC; [a]D ꢂ10.1 (c 1, CHCl3); H
NMR (CDCl3, 400 MHz): 1.34 (s, 3H, Me), 1.48 (s, 3H, Me),
1.49 (s, 3H, Me), 1.50 (s, 3H, Me), 3.84 (m, H-4), 3.88e3.94
(m, H-2 and H-3), 4.06 (t, 5.9 Hz, H-5), 4.18 (dd, 5.40,
1.95 Hz, H-6), 4.44 (t, 2.0 Hz, H-1); 13C NMR (CDCl3,
100 MHz): 25.5, 26.0, 26.9, 27.6, 56.9, 75.3, 75.5, 76.2,

K.M. Sureshan et al. / Tetrahedron 64 (2008) 4072e4080
4079
77.6, 80.8, 109.7, 112.3; FABMS (Mþ1): 286. Anal. Calcd for
4.25. (ꢀ)-2,5-Di-azido-2,5-di-deoxy-allo-inositol [(ꢀ)-21]
C12H19N3O5: C, 50.52; H, 6.71; N, 14.73. Found: C, 50.31; H,
6.62; N, 14.68.
Diazide (ꢀ)-20 (202 mg, 0.65 mmol) was dissolved in 50%
aq TFA (4 mL) and the solution was stirred at rt overnight.
Then the solvents were evaporated to give pure diazide (ꢀ)-
4.21. L-1-Azido-1-deoxy-chiro-inositol (L-18)
1
21 (150 mg, 100%) as a white gummy solid. H NMR (D2O,
1
400 MHz, rt): 3.70e4.05 (br, 4H), 4.05e4.25 (br, 2H); H
Compound L-17 (143 mg, 0.5 mmol) was stirred in a mix-
ture of TFA and H2O (4:1 v/v, 2 mL) at rt for 4 h. Evaporation
of the solvents provided L-18 (102 mg, 99.4%) as a gum. [a]D
NMR (D2O, 400 MHz, 80 ꢁC): 3.80e3.86 (br, 1H), 3.88e
3.98 (m, 2H), 4.03 (t, 1H), 4.12 (dd, 1H), 4.14e4.18 (m,
1H); 1H NMR (CD3OD, 400 MHz): 3.45e3.60 (br, 1H),
3.70e3.80 (m, 1H), 3.86 (dd, 9.70, 3.08 Hz, 1H), 3.95e4.00
(br, 1H), 4.00e4.05 (dd, 4.6, 3.0 Hz, 1H), 4.05e4.20 (br,
1
ꢂ11 (c 1, H2O); H NMR (D2O, 400 MHz): 3.26e3.33 (m,
2H, H-3 and H-4), 3.38 (ddd, 8.8, 3.5, 1.0 Hz, H-5), 3.69
(dd, 8.8, 3.8 Hz, H-2), 3.81 (t, 3.8 Hz, H-1), 3.86 (t, 3.5 Hz,
H-6); 13C NMR (D2O, 100 MHz): 64.5, 70.0, 70.1, 70.2,
72.6, 72.8. Anal. Calcd for C6H11N3O5: C, 35.12; H, 5.40;
N, 20.48. Found: C, 34.99; H, 5.56; N, 20.41.
13
1H); C NMR (D2O, 100 MHz, 80 ꢁC): 61.1, 62.2, 70.4,
70.7, 71.4, 72.0. Anal. Calcd for C6H10N6O4: C, 31.31; H,
4.38; N, 36.51. Found: C, 31.27; H, 4.44; N, 36.36.
4.26. D-2,5-Di-azido-2,5-di-deoxy-allo-inositol (D-21)
4.22. L-1-Amino-1-deoxy-chiro-inositol (L-19)
Use of D-20 (100 mg, 0.32 mmol) in place of (ꢀ)-20 and
80% aq TFA (2 mL) in the above reaction provided D-21
(74 mg, quant). [a]D 32.0 (c 1, H2O).
Compound L-18 (51 mg, 0.25 mmol) was dissolved in wet
methanol (2 mL) and stirred with 10% PdeC (10 mg) under
an atmosphere of hydrogen (hydrogen balloon) for 24 h. Fil-
tered through a small pad of Celite, washed well with water
and methanol. The combined filtrate was evaporated to dry-
ness to get L-19 (38 mg, 84%). [a]D ꢂ85.2 (c 1.15, H2O);
1H NMR (D2O, 400 MHz): 3.36 (br, H-1), 3.55e3.65 (m,
2H, H-3 and H-4), 3.75e3.85 (br, H-5), 3.85e3.90 (br, H-2),
4.05 (br, H-6); 13C NMR (D2O, 100 MHz): 54.4, 70.0, 70.2,
71.9, 72.4, 72.8. Anal. Calcd for C6H13NO5: C, 40.22; H,
7.31; N, 7.82. Found: C, 40.01; H, 7.42; N, 7.67.
4.27. (ꢀ)-2,5-Diamino-2,5-di-deoxy-allo-inositol [(ꢀ)-22]
To a solution of (ꢀ)-21 (100 mg, 0.43 mmol) in methanol
(3 mL) was added 10% Pd on carbon (20 mg) and suspension
was stirred under an atmosphere of hydrogen (1 atm, H2 bal-
loon) at rt overnight. The mixture was filtered through a mem-
brane filter washing the filter with methanol and water. The
combined filtrates were evaporated to give diamino-inositol
(ꢀ)-22 (60 mg, 77%) as a semi-solid. 1H NMR (D2O,
400 MHz): 2.90 (br s, H-2), 2.98 (dd, 10.5, 2.75 Hz, H-5),
3.47 (dd, 10.5, 1.3 Hz, H-4), 3.74 (dd, 3.5, 1.6 Hz, H-1),
3.83 (dd, 1.3, 2.5 Hz, H-3), 3.89 (t, 3.50 Hz, H-6); 13C NMR
(D2O, 100 MHz): 47.6, 47.7, 71.1, 72.0, 74.2, 74.3; FABMS
(Mþ1): 179. Anal. Calcd for C6H14N2O4: C, 40.44; H, 7.92;
N, 15.72. Found: C, 40.27; H, 8.06; N, 15.54.
4.23. (ꢀ)-2,5-Di-azido-2,5-dideoxy-1,6:3,4-di-O-
isopropylidene-allo-inositol [(ꢀ)-20]
To a solution of ditriflate (ꢀ)-10 (967 mg, 1.84 mmol) in
DMF (5 mL), NaN3 (260 mg, 4 mmol) was added and the mix-
ture was stirred at 70 ꢁC for 5 h. DMF was evaporated under
reduced pressure, the residue was dissolved in ethyl acetate
and washed successively with water and brine, dried over an-
hyd MgSO4, and the solvent was evaporated. The residue thus
obtained was chromatographed using ethyl acetateehexane as
eluent to get the diazide (ꢀ)-20 (548 mg, 96%) as a crystalline
4.28. D-2,5-Diamino-2,5-di-deoxy-allo-inositol (D-22)
Reaction of D-21 (60 mg, 0.26 mmol) and PdeC (12 mg) in
methanol (3 mL) under hydrogen atmosphere as above pro-
vided D-22 (38 mg, 82%). [a]D 43.0 (c 1.5, H2O).
1
solid. Mp 132e135 ꢁC; H NMR (CDCl3, 400 MHz): 1.37 (s,
3H, Me), 1.50 (s, 6H, 2ꢃMe), 1.61 (s, 3H, Me), 3.95 (dd, 10.0,
2.8 Hz, H-1), 4.15 (dd, 5.4, 1.6 Hz, H-4), 4.25 (dd, 5.4, 2.8 Hz,
H-2), 4.29 (dd, 10.0, 3.6 Hz, H-6), 4.32 (t, 5.4 Hz, H-3), 4.46
(dd, 3.6, 1.6 Hz, H-5); 13C NMR (CDCl3, 100 MHz): 25.1,
25.2, 26.5, 26.7, 57.1, 60.5, 72.3, 72.5, 74.2, 77.3, 110.7,
112.2. Anal. Calcd for C12H18N6O4: C, 46.45; H, 5.85; N,
27.08. Found: C, 46.38; H, 5.81; N, 27.02.
Acknowledgements
We thank JSPS for a postdoctoral fellowship (K.M.S.) and
Grant-in-aid (No. 02170). Also we thank Venture Business
Laboratory and Advanced Instrumentation Center for Chemi-
cal Analysis, Ehime University for NMR and elemental anal-
ysis, respectively.
4.24. D-2,5-Di-azido-2,5-di-deoxy-1,6:3,4-di-O-
isopropylidene-allo-inositol (D-20)
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