Stereoselective synthesis of several azido/amino- and diazido/diamino-myo-inositols and their phosphates from p-benzoquinone

Article abstract of DOI:10.1039/b302622a

A practical route is described for the preparation of azido-myo-inositols, amino-myo-inositols and azido-conduritol B derivatives. Starting from p-benzoquinone, optically pure compounds in both forms can be prepared via enzymatic resolution of a derived diacetoxy conduritol B derivative. Selective introduction of nitrogen-containing functional groups in four of the six possible positions in the cyclitol moiety is followed by further functionalization to yield the target compounds.

Full text of DOI:10.1039/b302622a

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Stereoselective synthesis of several azido/amino- and
diazido/diamino-myo-inositols and their phosphates from
p-benzoquinone
Michael A. L. Podeschwa, Oliver Plettenburg and Hans-Josef Altenbach*
Institut für Organische Chemie, Bergische Universität Wuppertal, Gaussstrasse 20,
42097 Wuppertal, Germany. E-mail: orgchem@uni-wuppertal.de; Fax: ϩ49 (0)202 439 2648
Received 10th March 2003, Accepted 10th April 2003
First published as an Advance Article on the web 30th April 2003
A practical route is described for the preparation of azido-myo-inositols, amino-myo-inositols and azido-conduritol B
derivatives. Starting from p-benzoquinone, optically pure compounds in both forms can be prepared via enzymatic
resolution of a derived diacetoxy conduritol B derivative. Selective introduction of nitrogen-containing functional
groups in four of the six possible positions in the cyclitol moiety is followed by further functionalization to yield the
target compounds.
toward enzymatic cleavage and competitively inhibit β--
Introduction
galactosidase from Escherichia coli (the NH2 group competing
The myo-inositol pathway is an attractive target for intervention
for the activating proton).12 Furthermore, azido-conduritol
in the control of cellular growth and proliferation.1,2 After the
derivatives are potential precursors for the synthesis of com-
discovery in 19833,4 that -myo-inositol 1,4,5-trisphosphate is
pounds which may be useful to elucidate the biosynthesis of
involved in the signal transduction as a Ca2ϩ-mobilizing second
aminoglycosides like butirosin,13,14 minosaminomycin15 and
messenger, there has been an increased interest in the synthesis
streptomycin.16
of analogues. Legler showed that free and conjugated amino-
In this report we show that in addition to the above men-
derivatives of myo-inositol are capable of inhibiting glyco-
tioned monoazido-route the synthesis of enantiopure diazido-
sidases and play an active role in antibiotic action.5 Azido
conduritol B can be carried out in a one-pot reaction starting
myo-inositols have direct antiproliferative activity on tumor
from diacetate 1.
cells (derived from fibroblasts).6 It was shown that 3-substituted
Finally, amino- and azido-myo-inositol phosphates were syn-
azido- and amino-myo-inositol derivatives were taken up by
thesized. We were attracted to the synthesis of derivatives of
cells and in the absence of myo-inositol selectively inhibited the
myo-inositol phosphates as part of our ongoing study of the
cell growth.7 These effects were attributed to interference of
regiospecificity of phosphohydrolases.17 Such compounds
the examined azido- and amino-inositols with phosphatidyl-
inositol 3Ј-kinase and interaction with the signalling cascade.
Kozikowski showed that tritiated 3-azido-myo-inositol was
should prove valuable tools to explain substrate–structure
relationships for dephosphorylation by phytases and other
phosphohydrolases and can also serve as affinity-material
incorporated into cellular phosphatidylinositols of v-sis NIH
ligands for the isolation of inositol pentakis- and hexakis-
3T3 cells.6a This suggests that certain azido- and amino-
phosphate binding enzymes.
myo-inositol derivatives might be useful as therapeutic agents
for cancer and other diseases in which cellular-growth
regulation is disturbed.7
Results and discussion
However, there are only a few syntheses of amino- or azido-
myo-inositols reported in the literature to date. This might be
attributed in part to the fact that starting from chiral materials
like -quebrachitol8 offers access to only a very limited number
of stereoisomers. The use of myo-inositol as the most inexpen-
sive starting material requires introduction of the nitrogen-
containing moiety either under retention or double-inversion of
a specific stereocenter.9 Alternatively, two separate inversions of
a cis diol unit have been used to reconstitute the myo-conform-
ation.10 Furthermore, the non-chiral starting material has
to be converted to an enantiomerically differentiated form. This
problem, which can cause synthetic difficulties, can be circum-
vented by a de-novo approach.
The known diacetoxy-dibromocyclohex-5-ene (ϩ)-1 and (Ϫ)-1
(or the corresponding diols (Ϫ)- and (ϩ)-2) are used as enan-
tiomeric building blocks18,19 for the synthesis of all the azido-/
amino-myo-inositol derivatives. They can easily be prepared
from p-benzoquinone in three steps and 70% overall yield.
Enantiopure compounds are obtained by hydrolysis of racemic
diacetate 1 with PPL in Et2O–phosphate buffer at pH 7.0. The
hydrolysis stopped after 50% conversion and proceeded with
excellent enantioselectivity (>99% ee) for both the remaining
diacetate (ϩ)-1 and the resulting diol (ϩ)-2.18,19 The prod-
ucts can easily be separated on a 100 g scale by their different
solubility in dichloromethane.
A synthesis of 5-azido- and 6-azido-derivatives was previ-
ously reported by Sanfilippo and co-workers in a synthetic
scheme requiring six steps from racemic conduritol E.11
Here we describe a novel route to azido-myo-inositols
starting from p-benzoquinone and subsequent enzymatic
resolution of the derived diacetate 1. As intermediates in our
synthesis of azido-myo-inositol derivatives the enantiopure
azido-conduritol B derivatives were synthesized. These inter-
mediates have themselves pharmacological potential. Lehmann
and co-workers have shown that racemic diamino-conduritols,
after β--galactosylation to pseudo-disaccharides, are stable
Preparation of mono-azido/amino-myo-inositols
Epoxide (Ϫ)-3 can be prepared in high yield (>90%) from diol
(ϩ)-2 by use of lithium hydroxide as base. The diacetate (ϩ)-1
could be converted in the same way to give the enantiomer
(ϩ)-3. The azido moiety is introduced by selective opening of
the epoxide in the allylic position.20,18
Reaction of the azide (ϩ)-4 under the above-mentioned
mildly basic conditions resulted in the formation of an epoxide
intermediate 5. The direct hydrolysis of the intermediate in
water with catalytic amounts of p-toluenesulfonic acid yielded a
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Scheme 1 Reagents and conditions: (a) LiOH, Et2O–MeOH (99%). (b) NaN3, DME, H2O, EtOH, NH4Cl (90%). (c) LiOH, Et2O–MeOH.
(d) p-TsOH, H2O [overall yield (a–d): 41%]. (e) Ac2O, pyridine (96%).
mixture which contained, besides the desired (ϩ)-6, byproducts
resulting from SNЈ-reactions. However, simple recrystallization
from ethyl acetate gave pure azido-conduritol B (ϩ)-6 (41%
over four steps, starting from diol (ϩ)-2). The details of this
efficient reaction sequence are summarized in Scheme 1. The
conduritol B derivative (ϩ)-6 was synthesized from diol (ϩ)-2
without need for purification of the intermediates. Only in the
last step of this sequence is a recrystallization necessary.
Because of this simple reaction sequence it is easy to scale up
the synthesis of azido-conduritol B (ϩ)-6.
Acetylation, followed by cis-dihydroxylation of the conduri-
tol B derivative (ϩ)-7 with ruthenium trichloride and sodium
metaperiodate, gave (ϩ)-9 and (Ϫ)-8 in high yields. To minimize
protection group migration, acetonitrile as a solvent proved to
be superior to ethyl acetate. cis-Dihydroxylation of conduritol-
B-derivatives led only to the myo-configuration of the resulting
inositol, but in the case of non-symmetrical starting materials
attack of the hydroxylating agent leads to two diastereomers in
a 6 : 4 ratio (Scheme 2). The two products, however, show
remarkably different solubility in chloroform; while 4,5,6-tri-O-
acetyl-3-azido-myo-inositol (ϩ)-9 remained insoluble as a white
solid (purity >99%), 3,4,5-tri-O-acetyl-6-azido-myo-inositol
(Ϫ)-8 (purity >90–95%) dissolves readily. If a higher purity of
the 6-azido/6-amino-myo-inositol derivative is desired, the
pentaacetate (ϩ)-10 can be recrystallised from EtOH. From tri-
acetate 7, 3-azido-pentaacetate 11 and 6-azido-pentaacetate 10
can be obtained in two steps in 50% and 35% yield, respectively.
Deprotection of the 6-azido-tri- or pentaacetate and
3-azido-tri- or pentaacetate with sodium methoxide in
anhydrous methanol gave 6-azido-myo-inositol (Ϫ)-12 or
3-azido-myo-inositol (ϩ)-13, respectively, in quantitative yield.
Pd/C-catalyzed reduction of the azide with hydrogen led to
6-amino-myo-inositol (ϩ)-14 and 3-amino-myo-inositol (ϩ)-15
in quantitative yield. 3-Amino-myo-inositol (ϩ)-15 and
6-amino-myo-inositol (ϩ)-14 can be obtained in an overall yield
of about 19% and 14%, respectively, from 2 in eight steps.
Since this route can start from either of two building blocks,
as depicted in Scheme 3, azido and amino groups can easily be
introduced in the 1-, 3-, 4- and 6-position of the cyclitol ring,
depending on choice of starting material. For a deeper insight
into myo-inositol nomenclature see refs. 1 and 2.
Starting from the diol (ϩ)-2 leads to the diastereomeric pair
(ϩ)-13 and (Ϫ)-12, bearing nitrogen substituents in the 3- and
6-position. On the other hand, starting from the corresponding
diacetate (ϩ)-1 leads to the diastereomeric pair (Ϫ)-13 and
(ϩ)-12, containing an azido group in the 1- and 4-position,
respectively (Scheme 3).
The derived inositol derivatives were used to synthesize
inositol phosphate analogues.
The introduction of five phosphate functionalities was
achieved by treatment of 6-azido-myo-inositol (Ϫ)-12 or
3-azido-myo-inositol (ϩ)-13 with (1,5-dihydro-2,4,3-benzo-
dioxaphosphepin-3-yl)diethylamine in the presence of 1H-
tetrazole in acetonitrile (Scheme 4). After 4 h the resulting
pentaphosphite was oxidized with m-CPBA and purified by
flash chromatography to give the protected pentakisphosphate
in 50% yield. The phosphorylation requires carefully chosen
reaction conditions. An excess of the phosphorylation reagent
or prolonged reaction times can lead to by-products probably
by Staudinger reduction of the azido moiety. Since solubility of
the free azido-inositol is low and the problems mentioned above
interfere, a complete conversion can be difficult to achieve.
However, bearing in mind the problems described above and
considering that this reaction is a functionalization of five
hydroxy groups, the yield of 51% seems acceptable, equalling an
average yield of 87% per OH group. It proved to be possible to
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phosphorylate diastereomeric mixtures of 3-azido-myo-inositol
(ϩ)-13 and 6-azido-myo-inositol (Ϫ)-12, alternatively. Both
phosphorylated products can easily be separated by flash
chromatography.
The subsequent Pd/C-catalyzed deprotection–hydrogenolysis
gave 3-amino-myo-Ins(1,2,4,5,6)P5 (Ϫ)-16 or 6-amino-myo-
Ins(1,2,3,4,5)P5 (Ϫ)-17, respectively, already pure as detected by
NMR (Fig. 1). Purification of the resulting amino-inositol
pentakisphosphates by HPLC ensures isomeric purity suitable
for biological experiments. Under the chosen chromatographic
purification conditions, the two isomers differ in retention time
by 5 min.
The two amino-substituted CH groups can be recognized
easily as they do not change multiplicity upon phosphorus
decoupling. They show characteristic coupling patterns, the
3-amino-isomer showing up as a doublet (with the small
3J(H2,H3)-cis-coupling not being resolved), while the 6-isomer
is characterized by a triplet signal, resulting from two almost
3
equivalent J(H,H)-trans-couplings. Further positional assign-
ment of hydrogen, phosphorus and carbon signals was carried
out with two-dimensional NMR spectra.
The N-acetyl moiety was introduced by hydrogenolysis of
(Ϫ)-11 and (ϩ)-10 and further acetylation in pyridine–acetic
anhydride. The acetamides obtained by this procedure were
phosphorylated in an analogous manner to 17 to yield
(Ϫ)-18 and (ϩ)-19, respectively.
Although chromatographic separation of phosphorylated
derivatives is feasible and useful for the synthesis of pentakis-
phosphates, recrystallization at an earlier stage should prove
to be extremely useful for preparation of more highly differen-
tiated inositol analogues. This will enable the synthesis of more
differentiated, orthogonally protected derivatives, which in turn
should allow access to several analogues of biologically relevant
molecules. It should be noted that this concept is not limited to
the differentiation of the hydroxy groups introduced by di-
hydroxylation and the acetylated ones from the conduritol. We
were delighted to see that isopropylidene protection of the triol
6 leads to exclusive formation of 21 (Scheme 5).
The course of this reaction can be rationalized by molecular
modelling. The derivative protected in the 3- and 4-position
is clearly energetically disfavoured. A similar outcome was
Scheme 2 Reagents and conditions: (a) RuCl3, NaIO4, CH3CN (91%).
(b) Ac2O, pyridine (98%). (c) NaOMe, MeOH (99%). (d) Pd/C, H2,
ethanol–water (99%).
Scheme 3 Retrosynthetic scheme.
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Fig. 1 1H{31P}- and 1H-NMR of 4-/6-amino-myo-inositolpentakisphosphate 17 and 1-/3-amino-myo-inositolpentakisphosphate 16.
Scheme 4 Reagents and conditions: (a) 1, (1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine, 1H-tetrazole, CH3CN, then m-CPBA (51%).
2, Pd/C, H2 ethanol–water (90%). (b) 1, Pd/C, H2, methanol (80%). 2, Ac2O, pyridine (99%). 3, NaOMe, MeOH (80%). 4, (1,5-dihydro-2,4,3-benz-
odioxaphosphepin-3-yl)diethylamine, 1H-tetrazole, CH3CN, then m-CPBA (43%). 5, Pd/C, H2 ethanol–water (80%).
observed by Trost21 and coworkers for a different conduritol
derivative.
Preparation of diazido/diamino-myo-inositols
Substituted 3,6-diazido-myo-inositol was prepared from the
same precursor (ϩ)-diol 2. Synthesis of racemic diazido-
conduritol B 22 has been reported from ( )-diol 2 in a
two-step approach, via anti-benzene dioxide.12 By use of
enantiomerically pure anti-benzene dioxide, prepared accord-
Scheme 5 Reagents and conditions: 1, 2,2-DMP, acetone, cat. PPTSA.
2, acetone, PTSA (73%).
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ing to a procedure reported previously by our group,19 the
diazido-conduritol B derivative (ϩ)-22 should be available
enantiomerically pure. However, we were able to facilitate the
synthesis by a one-pot approach, starting from 2. We chose
the same conditions as reported for the conversion of 3,
but instead of workup, we added sodium azide to the reac-
tion. The epoxides generated in situ are directly opened in
allylic position, delivering the desired product in 50% yield
(Scheme 6).
zole followed by oxidation with m-CPBA gave the protected
diazido-tetrakisphosphate (Ϫ)-26. To maintain the azido
moiety of the required product, complete deprotection was
achieved in one step with trimethylsilyl bromide to yield 3,6-
diazido-myo-inositol tetrakisphosphate (Ϫ)-27 in quantitative
yield.
This molecule may serve as a tool in elucidating further
aspects in intracellular signalling. It has been shown that myo-
Ins(1,2,4,5)P4, a non-physiological inositol phosphate, binds
to the 1,4,5-IP3 receptor and promotes calcium release with
potencies nearly comparable to that of myo-Ins(1,4,5)P3.22–24
Furthermore it has been demonstrated that racemic myo-
Ins(1,2,4,5)P4 competitively inhibits the dephosphorylation of
tritiated myo-Ins(1,4,5)P3 by a human erythrocyte membrane
associated Ins(1,4,5)P3 5-phosphatase with a Ki-value of 15.9
µM.25
Conclusion
The present work further emphasizes the potential of (ϩ)- and
(Ϫ)-1 as a versatile building block in the construction of non-
racemic inositol phosphate derivatives. The azido-conduritols
obtained were transformed into several azido-inositols on a
multigram scale without the need for chromatographic separ-
ation. The described efficient, high-yielding routes allowed
the introduction of nitrogen-containing functional groups in
the 1-, 3-, 4- and 6-position of the cyclitol ring system to give
several pure azido- and amino-myo-inositols in both enantio-
meric forms. The synthesis comprises ten steps, starting from
p-benzoquinone.
Scheme 6 Reagents and conditions: (a) Et2O–MeOH (2 : 1), LiOH,
NaN3, 40 ЊC for 1 day and then 2 days at room temperature (51%).
(b) Ac2O, pyridine (99%).
Experimental
After acetylation, cis-dihydroxylation with ruthenium tri-
chloride and sodium metaperiodate gave the protected diazido
myo-inositol (Ϫ)-24. Because of the inherent C2-symmetry of
the acetylated diazido-conduritol B (ϩ)-23, cis-dihydroxylation
gives only one product. Cleavage of the acetate groups under
basic conditions leads to free diazido-inositol (Ϫ)-25. Hydro-
genation of (Ϫ)-25 gives diamino-inositol (ϩ)-28 (structure not
shown).
To test the potential of this approach, diazido-myo-Ins-
(1,2,4,5)P4 27 was synthesized (Scheme 7). Phosphorylation of
the diazido-tetrol 25 by reaction with (1,5-dihydro-2,4,3-benzo-
dioxaphosphepin-3-yl)diethylamine in the presence of 1H-tetra-
General
All NMR spectra were recorded on a Bruker ARX 400 (400
MHz) spectrometer. Besides 1H, 13C and 31P experiments,
2D COSY (1H–1H, 1H–13C as well as 1H–31P) and DEPT spectra
for the unequivocal correlation of the hydrogen-, carbon-
and phosphorus atoms were recorded. The chemical shifts
are given in ppm downfield of TMS, although the solvents
actually served as internal standard. The multiplicity is given
by the following symbols: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), ψt (pseudotriplet for unresolved dd)
and br (broad). The coupling constant J is given in Hz. Melting
points are uncorrected. IR spectra were obtained in KBr and
only noteworthy absorptions (cmϪ1) are listed. Flash-column
chromatography was performed on Merck silica gel (40–63 µm).
All organic extracts were dried over MgSO4, filtered and con-
centrated with a rotary evaporator under reduced pressure.
Only distilled solvents were used. [α]D Values are given in units
of 10Ϫ1 deg cm2 gϪ1
.
Purification and analysis of inositol phosphates
Inositol phosphates were purified and analyzed by the HPLC-
MDD method described previously.26 The compounds were
separated by anion-exchange chromatography on a Mono Q
HR 10/10 column (Pharmacia). A linear gradient was applied
to elute the inositol phosphates (0 min, 0.2 mM HCl; 70 min,
0.5 M HCl; flow rate 1.5 mL minϪ1). In analytical runs, photo-
metric detection at 546 nm was achieved with a modified metal–
dye-reagent (2 M Tris/HCl (pH 9.1), 200 µM 4-(2-pyridyl-
azo)resorcinol (PAR), 30 µM YCl3, 10% (v/v) MeOH; flow
rate 0.75 mL minϪ1). Purification steps, where on-line detec-
tion was impossible, an analogous experiment could be
carried out on microplate. In brief, a 0.2–10 µL portion
of a sample (depending on the InsPx concentration) was mixed
with 100 µL of metal–dye reagent, and the absorbance was
measured at 540 nm.
Scheme 7 Reagents and conditions: (a) RuCl3, NaIO4, CH3CN (99%).
(b) NaOMe, MeOH (99%). (c) (1,5-dihydro-2,4,3-benzodioxa-
phosphepin-3-yl)diethylamine, 1H-tetrazole, CH3CN, then m-CPBA
(45%). (d) CH2Cl2, TMSBr (90%).
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(1R,2S,3R,6R)-2-Bromo-7-oxabicyclo[4.1.0]hept-4-en-3-ol
(؊)-3
solution was washed twice with brine and concentrated under
reduced pressure. To remove all LiOH, the residue was taken up
in EtOAc and the organic solution washed again two times with
brine. Evaporation of the solvent yielded 12.1 g of a yellow oil.
The resulting monoepoxide (11 g, 85 mmol) was dissolved in
water (130 mL); a trace of p-toluenesulfonic acid was added,
and the solution was stirred for 2 d at room temperature. The
water was removed by lyophilisation. Recrystallization from
EtOAc (30 mL) yielded (ϩ)-6 (7 g, 47%) as a colourless solid.
Rf: 0.51 (CH2Cl2–MeOH 80 : 20). [α]2D0 = ϩ239 (c = 0.85, H2O).
2,3-Dibromocyclohex-5-ene-1,4-diol (ϩ)-2 (27.2 g, 0.1 mol) was
dissolved in Et2O (600 mL) and MeOH (300 mL). At 0 ЊC
LiOH (5.4 g, 0.225 mol, 98%) was added and the mixture was
stirred at this temperature for 2 h. After the reaction was com-
pleted, water (400 mL) and Et2O were added, and the aqueous
layer was extracted with Et2O (4 × 250 mL). The combined
organic layer was washed twice with brine and concentrated
under reduced pressure to yield a colourless solid (19.2 g, 99%).
For an analytical sample recrystallization from CHCl3–hexane
1 : 1 yielded pure (Ϫ)-3 as white needles. Rf: 0.37 (cyclohexane–
1
mp 128 ЊC. H-NMR (D2O): δ 3.49 (Ψt, 1H, J 9.4 Hz, H-3),
3.58 (Ψt, 1H, J 9.4 Hz, H-2), 4.06 (Ψd, 1H, J 8.2 Hz, H-1), 4.16
(m, 1 H, H-4), 4.66 (s, 3 H, OH), 5.61 (d, 1H, J 10.2 Hz, H-5),
5.71 (d, J 10.7 Hz, H-6). 13C-NMR (D2O): δ 66.3 (C-1),
73.9 (C-4), 76.1 (C-2), 77.7 (C-3), 127.1 (C-5), 133.4 (C-6).
IR (KBr): 3383 (s, br), 2890 (w), 2103 (s), 1358 (w), 1286 (w),
1245 (m), 1119 (w), 1021 (m). Anal. Calcd. for C6H9O3N3: C,
42.11; H, 5.30; N, 24.55. Found: C, 41.91; H, 5.24; N, 24.47%.
HR-MS (ESI-pos., TOF): m/z: 194.0553 [M ϩ Na]ϩ calcd. for
C6H9O3N3Na: 194.050416.
EtOAc 1 : 1). [α]2D0 = Ϫ170 (c = 0.4, CHCl3); Lit:18 [α]2D0
=
1
Ϫ172 (c = 0.36, CHCl3). H-NMR (CDCl3): δ 2.65 (d, 1 H,
J 4.6 Hz, OH), 3.51 (dψt, 1 H, J 3–4 and 2 Hz, H-6), 3.75 (dd,
1 H, J 0.7 and 4.1 Hz, H-1), 4.05 (dd, 1 H, J 1.0 and 8.7 Hz,
H-2), 4.49 (m, 1 H, H-3), 5.92 (dψt, 1 H, J 9.7 and 2.0–1.5 Hz,
H-5), 6.06 (dψt, 1 H, J 9.7 and 3.1–3.6 Hz, H-4). 13C-NMR
(CDCl3): δ 51.5 (C-6), 55.3 (C-1), 55.5 (C-2), 71.2 (C-3), 123.5
(C-4), 134.8 (C-5); MS (EI, 70 eV, m/z (%)): 163 (3), 161 (3), 111
(95), 81 (100). IR (KBr): 3300 (s), 3070 (w), 3040 (w), 2920 (m),
1650 (w), 1080 (s), 845 (s), 650 (s). Anal. Calcd. for C6H7BrO2:
C, 37.73; H, 3.69. Found: C, 38.00; H, 3.71%.
(1R,2S,3S,4R)-1-Azidoconduritol B (؊)-6
A solution of (Ϫ)-4 was allowed to react under the same condi-
tions as described for the preparation of (ϩ)-6 to give (Ϫ)-6.
[α]2D0 = Ϫ238 (c = 0.36, H2O). Analytical data were identical to
the data obtained for (ϩ)-6.
(1S,2R,3S,6S )-2-Bromo-7-oxabicyclo[4.1.0]hept-4-en-3-ol
(؉)-3
(ϩ)-1 was converted under the same conditions as described for
the preparation of (Ϫ)-3 to give (ϩ)-3. [α]2D0 = ϩ171 (c = 0.7,
CHCl3). Analytical data were identical to data obtained for
(Ϫ)-3.
(1S,2R,3R,4S )-2,3,4-Tri-O-acetyl-1-azidoconduritol B (؉)-7
(ϩ)-6 (4 g, 23 mmol) was dissolved in a cooled mixture of pyrid-
ine (20 mL) and acetic anhydride (12 mL). The mixture was
stirred for 12 h at room temperature. Evaporation of the solvent
and recrystallization from EtOH yielded pure 7 (6.7 g, 96 %) as
a white solid. [α]2D0 = ϩ240 (c = 0.72, CHCl3). 1H-NMR (CDCl3):
δ 2.03, 2.04, 2.09 (s, 9 H, CH3), 4.20 (dd, 1H, J 7.7 and 2.5 Hz,
H-1), 5.25 (Ψt, 1 H, J 10.7 Hz, H-2), 5.29 (Ψt, 1 H, J 10.8 Hz,
H-3), 5.55 (dd, 1H, J 7.1 and 2.6 Hz, H-4), 5.72 (s, 2 H, H-5,
H-6). 13C-NMR (CDCl3): δ 20.5 (2 × CH3), 20.7 (CH3), 61.1
(C-1), 71.3 (C-2), 71.4 (C-4), 71.8 (C-3), 126.7, 127.9 (C-5, C-6),
(1R,2S,3R,6S )-6-Azido-2-bromocyclohex-4-ene-1,3-diol (؉)-4
To a vigorously stirred ice-cooled solution of (Ϫ)-3 (18.8 g,
98 mmol) in 1,2-dimethoxyethane (200 mL), water (130 mL)
and ethanol (130 mL) was added NaN3 (26 g, 0.4 mol) and
NH4Cl (21.1 g, 0.4 mol) and the mixture was stirred for 3 h at
0 ЊC. The solution was concentrated under reduced pressure,
and the resulting aqueous layer was washed four times with
EtOAc. The combined organic layer was evaporated to yield
21 g (90%) of a yellow oil. For an analytical sample, the oil was
purified by flash-chromatography (cyclohexane–EtOAc 3 : 2) to
yield pure (ϩ)-4 as a colourless solid. Rf: 0.37 (cyclohexane–
EtOAc 1:1). [α]2D0 = ϩ220 (c = 0.66, CHCl3); [α]2D0 = ϩ144 (c = 1.4,
acetone); Lit:18 [α]2D0 = Ϫ146 (c = 1.1, acetone, for other
169.5, 169.9, 170.0 (C᎐O). MS (EI, 70 ev, m/z (%)): 297 [Mϩ],
᎐
255 (4), 226 (2), 195 (2), 138 (83), 43 (100), IR (KBr): 2850 (w),
2097 (s), 1755 (s), 1375 (w), 1224 (s), 1057 (w), 1002 (m). Anal.
Calcd. for C12H15O6N3: C, 48.49; H, 5.09; N, 14.14. Found: C,
48.46; H, 4.80; N, 13.96%.
(1R,2S,3S,4R)-2,3,4-Tri-O-acetyl-1-azidoconduritol B (؊)-7
1
enantiomer). H-NMR (CDCl3): δ 3.97 (m, 1 H, H-1), 4.07
(Ϫ)-6 was converted under the same conditions as described for
the preparation of (ϩ)-7 to give (Ϫ)-7. [α]2D0 = Ϫ233 (c = 1.25,
CHCl3). Analytical data were identical to the data obtained for
(ϩ)-7.
(m, 1 H, J 7.1 Hz, H-6), 4.24 (ψt, 1H, J 3.1 Hz, H-2), 4.44 (m,
1 H, J 4.1 and 9.1 Hz, H-3), 5.03 (d, 1 H, J 6.1 Hz, OH-3), 5.07
(d, 1 H, J 5.6 Hz, OH-1), 5.67 (dd, 1 H, J 2.5 and 10.2 Hz, H-5),
5.85 (dddd, 1 H, J 10.2, 3.9, 1.7, and 1.0 Hz, H-4). 13C-NMR
(CDCl3): δ 60.1 (C-2), 63.8 (C-6), 71.0 (C-1), 71.5 (C-3), 127.4
(C-5), 131.3 (C-4). IR (KBr): 3311 (s), 2886 (m), 2108 (s), 1393
(m), 1358 (m), 1282 (m), 1258 (m), 1094 (m), 1008 (m). Anal.
Calcd. for C6H8BrN3O2: C, 30.79; H, 3.45; N, 17.95. Found: C,
30.75; H, 3.53; N, 18.10%.
3,4,5-Tri-O-acetyl-6-azido-myo-inositol (؊)-8 and
4,5,6-tri-O-acetyl-3-azido-myo-inositol (؉)-9
To a vigorously stirred ice cooled solution of (ϩ)-7 (4.5 g,
15.2 mmol) in acetonitrile (220 mL, HPLC grade) was added a
solution of sodium metaperiodate (4.7 g, 22 mmol, 1.5 eq.) and
ruthenium trichloride trihydrate (290 mg, 1.1 mmol) in 33 mL
water. The stirring was continued until TLC showed absence of
starting material (approx. 8 min). The reaction was quenched
by addition of aqueous Na2S2O3 (300 mL, 20%). The aqueous
layer was separated and extracted four times with EtOAc
(4 × 200 mL). The combined organic layer, washed twice
with brine and concentrated under reduced pressure, yielded
the diastereomeric mixture as a colourless foam (4.6 g, 91%).
The diastereomeric ratio of the two isomers (Ϫ)-8 and (ϩ)-9 in
the crude mixture was estimated by NMR to be 4 : 6.
(1S,2R,3S,6R)-6-Azido-2-bromocyclohex-4-ene-1,3-diol (؊)-4
(ϩ)-3 was converted under the same conditions as described for
the preparation of (ϩ)-4 to give (Ϫ)-4. [α]2D0 = Ϫ212 (c = 0.5,
CHCl3). Analytical data were identical to those of obtained for
(ϩ)-4.
(1S,2R,3R,4S )-1-Azidoconduritol B (؉)-6
To a vigorously stirred solution of (ϩ)-4 (20 g, 85 mmol) in
Et2O (430 mL) and MeOH (210 mL) was added at 0 ЊC LiOH
(4.3 g, 180 mmol). The solution was stirred for 2 h at 10 ЊC.
After the reaction was completed, water (250 mL) was added
and the aqueous layer was extracted with Et2O. The organic
The crude product was suspended in 25 mL CHCl3. 4,5,6-tri-
O-acetyl-3-azido-myo-inositol (ϩ)-9 remained insoluble as
white solid (2.0 g, 40%) and was filtered off. The solvent was
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
1924

View Article Online
evaporated to give 3,4,5-tri-O-acetyl-6-azido-myo-inositol
(Ϫ)-8 (2.5 g, 50%) as a colourless foam. Repeating the pro-
cedure with a smaller volume of CHCl3 gave (Ϫ)-8 (purity
>90%).
Analytical data for 3,4,5-tri-O-acetyl-6-azido-myo-inositol
(Ϫ)-8: Rf: 0.11 (EtOAc–cyclohexane 1 : 1). [α]2D0 = Ϫ20.1
(c = 1.27, CHCl3). 1H-NMR (CDCl3): δ 2.00, 2.09, 2.10 (s, 9 H,
CH3), 3.14 (s, br, 2 H, OH), 3.65 (dd, 1 H, J 9.9 and 2.8 Hz,
H-1), 3.91 (Ψt, 1 H, J 10.2 Hz, H-6), 4.27 (Ψt, 1 H, J 2.8 Hz,
H-2), 4.90 (dd, 1 H, J 10.2 and 2.6 Hz, H-3), 5.00 (Ψt, 1 H, J 9.9
Hz, H-5), 5.50 (Ψt, 1 H, J 9.9 Hz, H-4). 13C-NMR (CDCl3):
δ 20.51, 20.55, 20.67 (CH3), 63.4 (C-6), 69.8 (C-4), 69.9 (C-2),
was dissolved in a cooled mixture of 10 mL pyridine and 10 mL
of acetic anhydride. The mixture was stirred for 12 h. Evapor-
ation of the solvent and recrystallization from EtOH yielded
pure 11 (1.24 g, 99%) as a white solid. Rf: 0.42 (EtOAc–cyclo-
hexane 1 : 1). [α]2D0 = Ϫ2.0 (c = 1.09, CHCl3). Lit.27 [α]2D0 = Ϫ3.5
1
(c = 2.9, CHCl3). H-NMR (CDCl3): δ 1.99, 2.00, 2.01, 2.09,
2.19 (s, 15 H, CH3), 3.68 (dd, 1 H, J 10.7 and 2.5 Hz, H-3), 4.97
(dd, 1 H, J 10.7 and 2.8 Hz, H-1), 5.16 (Ψt, 1 H, J 9.9 Hz, H-5),
5.44 (Ψt, 1 H, J 10.4 Hz, H-4), 5.45 (Ψt, 1 H, J 10.2 Hz, H-6),
5.64 (Ψt, 1 H, J 2.6 Hz, H-2); 13C-NMR (CDCl3): δ 20.37
(2 × CH3), 20.47, 20.50, 20.60 (CH3), 59.2 (C-3), 68.5 (C-2),
69.0 (C-6), 69.4 (C-1), 70.5 (C-4), 71.5 (C-5), 169.4, 169.46,
70.4 (C-1), 71.0 (C-3), 71.4 (C-5), 169.88, 170.02, 170.08 (C᎐O).
169.51 (C᎐O), 169.7 (2 × C᎐O). MS (EI, 70 ev, m/z (%)): 310 (1),
᎐
᎐ ᎐
IR (KBr): 3476 (s, br), 2925 (w), 2113 (s, v[N3]), 1754 (s), 1371
(m), 1228 (s), 1062 (m), 1036 (m). Anal. Calcd. for C12H17O8N3:
C, 43.51; H, 5.17; N, 12.68. Found: C, 43.20; H, 4.87; N,
12.01%. HR-MS (ESI): m/z: 330.0917 [M Ϫ H]ϩ calcd. for
C12H16N3O8: 330.0937.
226 (15), 184 (25), 157 (15), 142 (44), 115 (27), 43 (100). IR
(KBr): 2920 ϩ 2850 (m), 2100 (m), 1750 (s). Anal. Calcd. for
C16H21O10N3: C, 46.27; H, 5.10; N, 10.12. Found: C, 46.43; H,
5.75; N, 9.34. HR-MS (ESI): m/z: 416.1365 [M ϩ H]ϩ calcd. for
C16H22N3O10: 416.1305.
Analytical data for 4,5,6-tri-O-acetyl-3-azido-myo-inositol
(ϩ)-9: Rf: 0.11 (EtOAc–cyclohexane 1 : 1). [α]2D0 = ϩ21.8
(c = 0.83, acetone). H-NMR (d6-DMSO): δ 1.88, 1.92, 1.98
2,3,4,5,6-Penta-O-acetyl-1-deoxy-1-azido-myo-inositol (؉)-11
1
The (Ϫ)-enantiomer 9 was acetylated as described for (Ϫ)-11 to
yield (ϩ)-11. [α]2D0 = ϩ1.2 (c = 2.81, CHCl3). Analytical data
were identical to the data obtained for (Ϫ)-11.
(s, 9 H, CH3), 3.62 (ddd, 1 H, J 10, 5.5 and 2.5 Hz, H-1), 3.64
(dd, 1 H, J 10.9 and 2.3 Hz, H-3), 3.95 (dΨt, 1 H, J 4.6 and 2.3
Hz, H-2), 5.01 (Ψt, 1 H, J 10.0 Hz, H-5), 5.11 (Ψt, 1 H, J 9.7
Hz, H-6), 5.25 (d, 1 H, J 5.2 Hz, C-1-OH), 5.27 (Ψt, 1 H,
J 9.9 Hz, H-4), 5.77 (d, 1 H, J 4.8 Hz, C-2-OH). 13C-NMR
(d6-DMSO): δ 20.2, 20.3, 20.6 (CH3), 60.1 (C-3), 69.0 (C-1),
70.0 (C-4), 71.3 (C-2), 71.6 (C-5), 72.0 (C-6), 169.42, 169.45,
6-Deoxy-6-azido-myo-inositol (؊)-12
3,4,5-Tri-O-acetyl-6-azido-myo-inositol (Ϫ)-8 (760 mg, 2.3
mmol) was suspended in anhydrous methanol (15 mL) under
argon and cooled to 4 ЊC. A 5.5 M sodium methanolate solu-
tion (80 µL, 0.4 mmol) was added. The solution was allowed to
warm to room temperature and stirred for 12 h. The solution
was neutralized by addition of ion exchanger (Hϩ-form, Dowex
50-X), filtered and the resin was washed with water. The filtrate
was first reduced in volume under high vacuum and then lyo-
philized to yield (Ϫ)-12 (470 mg, 100%) as a colourless foam.
[α]2D0 = Ϫ14.8 (c = 0.25, H2O). 1H-NMR (D2O): δ 3.27 (Ψt, 1 H,
J 9.4 Hz, H-5), 3.45 (dd, 1 H, J 10.2 and 3.0 Hz, H-3), 3.52–3.56
(m, 2 H, H-6, H-1), 3.62 (Ψt, 1 H, J 9.7 Hz, H-4), 4.02 (Ψt, 1 H,
J 2.3 Hz, H-2). 13C-NMR (D2O): δ 65.9 (C-6), 70.3 (C-1), 71.0
(C-3), 72.3 (C-2), 72.7 (C-4), 73.4 (C-5). IR (KBr): 3350 (s, br),
2920 (w), 2110 (s). HR-MS (ESI): m/z: 204.0574 [M Ϫ H]ϩ
calcd. for C6H10N3O5: 204.062.
169.62 (C᎐O). IR (KBr): 3433 (s, br), 2971, 2958, 2938, 2914
᎐
(w), 2117 (s), 1749, 1725 (s), 1367 (m), 1232 (s), 1039 (s). Anal.
Calcd. for C12H17O8N3: C, 43.51; H, 5.17; N, 12.68. Found C,
43.69; H, 5.53; N, 11.75%. HR-MS: m/z: 332.114 [M ϩ H]ϩ
calcd. for C12H18O8N3: 332.1094.
1,5,6-Tri-O-acetyl-4-azido-myo-inositol (؉)-8 and
4,5,6-tri-O-acetyl-1-azido-myo-inositol (؊)-9
The (Ϫ)-enantiomer 7 was cis-dihydroxylated as described for
(ϩ)-7 to yield 1,5,6-tri-O-acetyl-4-azido-myo-inositol (ϩ)-8
([α]2D0 = ϩ22.3 (c = 0.81, CHCl3)) and 4,5,6-tri-O-acetyl-1-azido-
myo-inositol (Ϫ)-9 ([α]2D0 = Ϫ22.2 (c = 0.77, acetone)). Analytical
data were identical to the data obtained for (Ϫ)-8 and (ϩ)-9,
respectively.
1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-azido-myo-inositol (؉)-10
4-Deoxy-4-azido-myo-inositol (؉)-12
3,4,5-Tri-O-acetyl-6-azido-myo-inositol (Ϫ)-8 (1 g, 3.0 mmol)
was dissolved in a cooled mixture of pyridine (10 mL) and
acetic anhydride (10 mL). The mixture was stirred for 12 h.
Evaporation of the solvent and recrystallization from EtOH
yielded pure 10 (1.22 g, 98%) as a white solid. Rf: 0.42 (EtOAc–
The (ϩ)-enantiomer 8 was deacetylated as described for (Ϫ)-12
to yield (ϩ)-12. [α]2D0 = ϩ17.2 (c = 0.33, H2O). Analytical data
were identical to the data obtained for (Ϫ)-12.
cyclohexane 1 : 1). [α]2D0 = ϩ16.5 (c = 0.47, CHCl3). Lit.11 [α]2D0
=
3-Deoxy-3-azido-myo-inositol (؉)-13
1
ϩ14.3 (c = 0.4, CHCl3). H-NMR (CDCl3): δ 1.97, 2.00, 2.07,
2.10, 2.19 (CH3), 3.97 (Ψt, 1 H, J 10.7 Hz, H-6), 4.95 (dd, 1 H,
J 10.9 and 2.8 Hz, H-1), 5.04 (Ψt, 1 H, J 9.9 Hz, H-5), 5.07 (dd,
1 H, J 10.4 and 2.8 Hz, H-3), 5.41 (Ψt, 1 H, J 10.2 Hz, H-4),
5.58 (Ψt, 1 H, J 2.8 Hz, H-2). 13C-NMR (CDCl3): δ 20.33,
20.41, 20.43, 20.45, 20.60 (CH3), 60.9 (C-6), 68.25 (C-3), 68.32
(C-2), 69.1 (C-1), 69.7 (C-4), 71.0 (C-5), 169.06, 169.21, 169.30,
The deprotection of 4,5,6-tri-O-acetyl-3-azido-myo-inositol
(ϩ)-9 was carried out as described for (Ϫ)-8, yielding 3-deoxy-
3-azido-myo-inositol (ϩ)-13 as a colourless solid. [α]2D0 = ϩ9.2
1
(c = 0.71, H2O). H-NMR (D2O): δ 3.29 (Ψt, 1 H, J 9.2 Hz,
H-5), 3.38 (dd, 1 H, J 10.4 and 2.3 Hz, H-3), 3.49 (dd, 1 H,
J 10.2 and 2.5 Hz, H-1), 3.56 (Ψt, 1 H, J 9.7 Hz, H-6), 3.70 (Ψt,
1 H, J 9.9 Hz, H-4), 4.11 (Ψt, 1 H, J 2.4 Hz, H-2). 13C-NMR
(D2O): δ 63.50 (C-3), 71.1 (C-2), 71.52 (C-4), 71.62 (C-1), 72.33
(C-6), 75.00 (C-5); IR (KBr): 3405 (s, br), 2969, 2917 (m), 2111
(s), 1376 (m), 1247 (m), 1091 (m), 1030 (m). Anal. Calcd. for
C6H11N3O5: C, 35.12; H, 5.40; N, 20.48. Found: C, 34.71; H,
5.49; N, 19.99%. HR-MS (ESI): m/z: 204.0587 [M Ϫ H]ϩ calcd.
for C6H10N3O5: 204.062.
169.49, 169.86 (C᎐O). Anal. Calcd. for C H O N : C, 46.27;
᎐
16 21 10
3
H, 5.10; N, 10.12. Found: C, 46.22; H, 5.64; N, 9.22%. HR-MS
(ESI): m/z: 416.1355 [M ϩ H]ϩ calcd. for C16H22N3O10:
416.1305.
1,2,3,5,6-Penta-O-acetyl-4-deoxy-4-azido-myo-inositol (؊)-10
The (ϩ)-enantiomer 8 was acetylated as described for (ϩ)-10 to
yield (Ϫ)-10. [α]2D0 = Ϫ16 (c = 0.45, CHCl3). Analytical data were
identical to the data obtained for (ϩ)-10.
1-Deoxy-1-azido-myo-inositol (؊)-13
The (Ϫ)-enantiomer 9 was deacetylated as described for (ϩ)-13
to yield (Ϫ)-13. [α]2D0 = Ϫ8.0 (c = 0.5, H2O). Analytical data were
identical to the data obtained for (ϩ)-13.
1,2,4,5,6-Penta-O-acetyl-3-deoxy-3-azido-myo-inositol (؊)-11
4,5,6-Tri-O-acetyl-3-azido-myo-inositol (ϩ)-9 (1 g, 3.0 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
1925

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6-Deoxy-6-amino-myo-inositol (؉)-14
ethanol–water (1 : 1) was added Pd/C (170 mg). The mixture
was stirred at room temperature under H2 overnight. The
catalyst was filtered off, and the filtrate was reduced in volume
and lyophilized to give (Ϫ)-16 as a colourless, hygroscopic foam
Pd/C (12 mg) was added to a suspension of 6-deoxy (Ϫ)-12
(50 mg, 0.24 mmol) in methanol (30 mL). The mixture was
stirred at room temperature under H2 overnight. The catalyst
was filtered off and washed with water, and the filtrate was
reduced in volume and lyophilized to give a colourless foam
(149 mg, 99%). Preparative HPLC assured purity >99%. [α]2D0
=
Ϫ10.8 (c = 6.3, H2O). 1H-NMR (D2O, pH adjusted to 6
(ND4OD)): δ 3.48 (d, 1 H, J 10.2 Hz, H-3), 4.11 (Ψt, 1 H, J 7.9
Hz, H-1), 4.14 (Ψq, 1 H, J 8.1 Hz, H-5), 4.34 (Ψq, 1 H, J 9.2
Hz, H-4), 4.39 (Ψq, 1 H, J 8.8 Hz, H-6), 4.76 (d, 1H, J 8.1 Hz,
H-2). 13C-NMR (D2O, pH adjusted to 6 (ND4OD)): δ 55.7 (s,
C-3), 73.1 (d, J 5.1 Hz, C-2), 74.9 (m, C-4), 75.8 (m, C-1), 78.0
(m, C-6), 79.9 (m, C-5). 31P-NMR{1H} (D2O, pH adjusted to
6 (ND4OD)): δ 1.91 (PC-6), 2.14, 2.26 (PC-1, PC-5), 4.43
(PC-4), 4.67 (PC-2); HR-MS (MALDI-FTMS): m/z: 577.9013
[M Ϫ H]ϩ calcd. for C6H17NO20P5: 577.9038.
(42 mg, 99%). [α]2D0 = ϩ7.1 (c = 0.17, H2O). H-NMR (D2O):
1
δ 2.94 (Ψt, 1 H, J 10.2 Hz, H-6), 3.15 (Ψt, 1 H, J 9.5 Hz, H-5),
3.41 (dd, 1 H, J 10.1 and 2.1 Hz, H-1), 3.47 (dd, 1 H, J 10.1 and
2.1 Hz, H-3), 3.56 (Ψt, 1 H, J 9.4 Hz, H-4), 3.99 (Ψt, 1 H, J 2.2
Hz, H-2). 13C-NMR (D2O): δ 55.7 (C-6), 73.1 (C-1), 73.4 (C-3),
74.6 (C-2), 75.1 (C-4), 76.1 (C-5). IR (KBr): 3339 (s, br), 2920,
2881 (w), 1596 (m), 1384 (m), 1091 (m), 1048 (s); HR-MS (ESI):
m/z: 180.0853 [M ϩ H]ϩ calcd. for C6H14NO5: 180.0872.
4-Deoxy-4-amino-myo-inositol (؊)-14
1-Deoxy-1-amino-myo-inositol-2,3,4,5,6-pentakisphosphate
(؉)-16
The (ϩ)-enantiomer 12 was hydrogenated as described for
(ϩ)-14 to yield (Ϫ)-14. [α]2D0 = Ϫ9.4 (c = 0.14, H2O). Analytical
data were identical to the data obtained for (ϩ)-14.
The (Ϫ)-enantiomer 13 was phosphitylated as described for
(Ϫ)-16. Oxidation, deprotection and purification as before gave
(ϩ)-16. [α]2D0 = ϩ9 (c = 8.0, H2O). Analytical data were identical
to the data obtained for (Ϫ)-16.
3-Deoxy-3-amino-myo-inositol (؉)-15
The diastereomer (ϩ)-13 was deprotected as described for
(Ϫ)-12. Work-up as before gave (ϩ)-15 as a colourless foam
(99%). [α]2D0 = ϩ9.4 (c = 0.35, H2O). Lit.28 [α]2D0 = ϩ9.2 (H2O).
1H-NMR (D2O): δ 2.49 (dd, 1 H, J 10.2 and 2.1 Hz, H-3), 3.11
(Ψt, 1 H, J 9.4 Hz, H-5), 3.26 (Ψt, 1 H, J 9.9 Hz, H-4), 3.36 (dd,
1 H, J 9.9 and 2.8 Hz, H-1), 3.43 (Ψt, 1 H, J 9.4 Hz, H-6), 3.82
(Ψt, 1 H, J 2.4 Hz, H-2). 13C-NMR (D2O): δ 55.4 (C-3), 73.9
(C-2), 74.3 (C-1), 74.6 (C-6), 75.3 (C-4), 77.3 (C-5). IR (KBr):
3363 (s, br), 2917 (w), 1591 (m), 1384 (m), 1115 (m), 1049 (m),
1002 (m). HR-MS (ESI): m/z: 180.0884 [M ϩ H]ϩ calcd. for
C6H14 NO5: 180.0872.
6-Deoxy-6-amino-myo-inositol-1,2,3,4,5-pentakisphosphate
(؊)-17
Phosphorylation of 6-deoxy-6-azido-myo-inositol (Ϫ)-12 and
further deprotection were carried out as described for (ϩ)-13
(see synthesis of 3-deoxy-3-azido-myo-inositol-1,2,4,5,6-
pentakisphosphate (Ϫ)-16), yielding 6-deoxy-6-amino-myo-
inositol-1,2,3,4,5-pentakisphosphate (Ϫ)-17 in 50% yield.
[α]2D0 = Ϫ1.7 (c = 8.67, H2O). H-NMR (D2O, pH adjusted to 6
1
(ND4OD)): δ 3.62 (Ψt, 1 H, J 10.7 Hz, H-6), 4.11 (Ψt, 1 H,
J 8.9 Hz, H-3), 4.16 (Ψq, 1 H, J 9.3 Hz, H-5), 4.25 (Ψt, 1 H,
J 9.4 Hz, H-1), 4.37 (Ψq, 1 H, J 9.3 Hz, H-4), 4.88 (d, 1 H,
J 9.7 Hz, H-2). 13C-NMR (D2O, pH adjusted to 6 (ND4OD)):
δ 56.3 (d, J 5.1 Hz, C-6), 72.6 (m, C-1), 75.5 (C-3, C-5), 76.3 (d,
J 5.1 Hz, C-2), 78.6 (m, C-4). 31P-NMR{1H} (D2O, pH adjusted
to 6 (ND4OD)): δ 1.82 (PC-2), 1.92 (PC-3), 2.33 (PC-4), 2.91
(PC-1), 4.15 (PC-5). HR-MS (MALDI-FTMS): m/z: 577.9031
[M Ϫ H]ϩ calcd. for C6H17NO20P5: 577.9038.
1-Deoxy-1-amino-myo-inositol (؊)-15
The (Ϫ)-enantiomer 13 was hydrogenated as described for
(ϩ)-15 to yield (Ϫ)-15. [α]2D0 = Ϫ10 (c = 0.4, H2O); Lit.29 [α]2D0
=
Ϫ4.2 (c = 2.7, H2O). Analytical data were identical to the data
obtained for (ϩ)-15.
3-Deoxy-3-amino-myo-inositol 1,2,4,5,6-pentakisphosphate
(؊)-16
4-Deoxy-4-amino-myo-inositol-1,2,3,5,6-pentakisphosphate
(؉)-17
To a solution of 3-deoxy-3-azido-myo-inositol (ϩ)-13 (215 mg,
1.05 mmol) and 1H-tetrazole (700 mg, 10 mmol) in anhydrous
acetonitrile (30 mL) under argon was added (1,5-dihydro-2,4,3-
benzodioxaphosphepin-3-yl)diethylamine (1.4 g, 6 mmol), and
the solution was stirred at room temperature for 4 h. The mix-
ture was cooled to Ϫ20 ЊC, and an anhydrous solution of
m-CPBA (4.3 g, 17.5 mmol) in dichloromethane (20 mL) [dried
over NaSO4] was added. The solution was allowed to warm to
room temperature, and stirring was continued for another
hour. The reaction mixture was diluted with dichloromethane
(150 mL) and washed consecutively with aqueous sodium
bisulfite (20%, 2 × 100 mL), saturated NaHCO3 and brine.
After evaporation of dichloromethane the product was purified
by flash chromatography (Rf = 0.20 (CH2Cl2–MeOH 95 : 5)) to
yield the protected pentakisphosphate (570 mg, 51%) as a
colourless foam.
Diastereomeric mixtures of 3-deoxy-3-azido-myo-inositol
(ϩ)-13 and 6-deoxy-6-azido-myo-inositol (Ϫ)-12 were also
phosphorylated as mentioned above. The two protected prod-
ucts were easily separated by flash chromatography [Rf: 0.12
(CH2Cl2–MeOH 95 : 5) for 6-deoxy-6-azido-1,2,3,4,5-penta-O-
(3-oxo-1,5-dihydro-3λ5-2,4,3-benzodioxaphosphepin-3-yl)-
myo-inositol].
The (ϩ)-enantiomer 12 was phosphitylated as described for
(Ϫ)-17. Oxidation, deprotection and purification as before
gave (ϩ)-17. [α]2D0 = ϩ1.6 (c = 7.7, H2O). Analytical data were
identical to the data obtained for (Ϫ)-17.
6-Deoxy-6-acetamido-myo-inositol-1,2,3,4,5-pentakisphosphate
(؊)-18
Pd/C (40 mg Degussa RW 10, preactivated in 10 mL MeOH)
was added to a solution of (ϩ)-10 (500 mg, 1.2 mmol) in
MeOH (10 mL). The mixture was stirred under H2 at room
temperature until TLC showed absence of starting material
(approx. 2 h). The catalyst was filtered off, and the residue was
washed with EtOAc. The solvent was removed under reduced
pressure, and the residue was dried under high vacuum.
The residue was dissolved in pyridine (5 mL) and acetic
anhydride (3 mL). The mixture was stirred for 12 h, and the
solvent was removed under high vacuum to yield 1,2,3,4,5-
penta-O-acetyl-6-deoxy-6-acetamido-myo-inositol (400 mg,
0.95 mmol, 80%) as a colourless foam.
This crude product (350 mg, 0.8 mmol) was suspended in
anhydrous MeOH (5 mL) under argon, and cooled to 4 ЊC. A
5.5 M sodium methanolate solution (80 µL, 0.4 mmol) was
added dropwise. The solution was allowed to warm to room
temperature and stirred for 4 h. The solution was neutralized by
ion exchanger (Hϩ, Dowex 50-X), filtered off and washed with
Deprotection: to a suspension of 300 mg (0.27 mmol)
3-deoxy-3-azido-1,2,4,5,6-penta-O-(3-oxo-1,5-dihydro-3λ5-
2,4,3-benzodioxaphosphepin-3-yl)-myo-inositol in 30 mL
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
1926

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water. The filtrate was reduced in volume and then lyophilized
to give the pentol (140 mg, 80%) as a colourless solid.
acetone (10 mL). Pyridinium p-toluenesulfonic acid [PPTSA]
(40 mg) was added, and the solution was stirred for 24 h. 10%
aqueous NaOH (2 mL), brine (1 mL) and EtOAc (20 mL) were
added, and the solution stirred for a further 5 min. The layers
were separated, and the organic layer, washed with brine, was
concentrated under reduced pressure.
The crude product contained mainly 1-azido-2,3-O-iso-
propylconduritol B and as by-product 1-azido-2,3-O-isopropyl-
4-mono-O-(2-methoxy)isopropylconduritol B.
This crude product was dissolved in anhydrous acetone
(15 mL), and a trace of p-toluenesulfonic acid (PTSA) was
added. The solution was stirred until TLC showed absence of
the by-product (30 minutes). The organic layer was washed with
aqueous NaHCO3 and with brine. Evaporation of the solvent
gave 21 (900 mg, 73%) as an oil. Rf: 0.35 (EtOAc–cyclohexane
1 : 1). [α]2D0 = ϩ97 (c = 1.7, acetone). 1H-NMR (CDCl3): δ 1.47 (s,
6 H, 2 × CH3), 2.95 (s, br, 1 H, OH), 3.55 (m, 2 H, H-2, H-3),
4.17 (dd, 1H, J 4.8 and 2.3 Hz, H-1), 4.47 (d, 1 H, J 4.5 Hz,
H-4), 5.61 (dΨt, 1 H, J 10.2 and 2.0 Hz, H-5), 5.77 (dΨt, 1 H,
J 10.2 and 2.0 Hz, H-6).13C-NMR (CDCl3): δ 26.8 (CH3), 26.9
(CH3), 61.4 (C-1), 70.4 (C-4), 78.0, 81.0 (C-2, C-3), 111.7
(C(CH3)2), 125.8 (C-5), 132.7 (C-6). MS (EI, 70 ev, m/z (%)):
196 (15) [Mϩ Ϫ CH3], 168 (3) [Mϩ Ϫ N3], 111 (29), 59 (88)
[C3H7Oϩ], 43 (100) [C3H7ϩ]. IR (KBr): 3430 (s, br), 3030 (w),
2970 ϩ 2860 (m), 2090 (s), 1630 (w). Anal. Calcd. for
C9H13O3N3: C, 51.18; H, 6.20; N, 19.89. Found C, 51.30; H,
6.00; N, 20.10%.
The solid (140 mg, 0.63 mmol) and 1H-tetrazole (440 mg, 6.3
mmol) were suspended in anhydrous dichloromethane (30 mL)
under argon, and (1,5-dihydro-2,4,3-benzodioxaphosphepin-3-
yl)diethylamine (860 mg, 3.8 mmol) was added. The mixture
was stirred at room temperature for 4 h. The product was
worked up as described [2.7 g m-CPBA (70%), 11 mmol in
15 mL CH2Cl2; dried over NaSO4] for 16. Purification by flash
chromatography yielded a colourless solid (300 mg, 43%,
Rf = 0.13 (CH2Cl2–MeOH 95 : 5)).
To a suspension of 6-deoxy-6-acetamido-1,2,3,4,5-penta-O-
(3-oxo-1,5-dihydro-3λ5-2,4,3-benzodioxaphosphepin-3-yl)-
myo-inositol (140 mg, 0.13 mmol) in ethanol–water (1 : 1,
30 mL) was added Pd/C (100 mg). The mixture was stirred at
room temperature under H2 overnight. The catalyst was filtered
off, and the filtrate was reduced in volume under high vacuum
and then lyophilized to give a colourless, hygroscopic foam
(76 mg, 99%). Further purification by HPLC assured purity
>99%. [α]2D0 = Ϫ4.4 (c = 5.2, H2O). 1H-NMR (D2O, pH adjusted
to 6 (ND4OD)): δ 2.01 (s, CH3), 4.01 (Ψq, 1 H, J 9.7 Hz, H-5),
4.04 (Ψt, 1 H, J 8.4 Hz, H-3), 4.06 (Ψt, 1 H, J 7.9 Hz, H-1), 4.24
(Ψt, 1 H, J 10.4 Hz, H-6), 4.38 (Ψq, 1 H, J 9.5 Hz, H-4), 4.85 (d,
1 H, J 10.2 Hz, H-2). 13C-NMR (D2O, pH adjusted to 6
(ND4OD)): δ 24.85 (CH3), 54.1 (m, C-6), 74.5 (m, C-3), 75.7 (m,
C-1), 76.8 (d, J 6.1 Hz, C-2), 77.8 (m, C-5), 78.6 (m, C-4), 177.5
(C᎐O). 31P-NMR{1H} (D2O, pH adjusted to 6 (ND4OD)):
᎐
δ 1.30 (PC-3), 1.38 (PC-5), 2.16 (PC-2, PC-1), 3.13 (PC-4).).
HR-MS (ESI-neg, phosphoric acid 0.002%, H2O–acetonitrile
1 : 1, Q-TOF): m/z: 619.9150 [M Ϫ H]Ϫ calcd. for C8H19NO21P5:
619.9138.
(1S,2R,3R,4S )-1,4-Diazidoconduritol B (؉)-22
A solution of diol (ϩ)-2 (6.8 g, 25 mmol), Et2O–MeOH (2 : 1,
225 mL) and LiOH (3.0 g, 0.13 mol) was stirred for 2 h at 10 ЊC,
and then a solution of NaN3 (16.1 g, 0.25 mol) in water (30 mL)
was added. The mixture was stirred at 40 ЊC for 1 day and
then 2 days at room temperature. The solvent was removed
under vacuum, and the residue was taken up with water
(50 mL) and Et2O. The aqueous layer was extracted four
times with Et2O, and the combined organic layer was washed
with brine. Drying and evaporation of the solvent gave 4 g of a
crude product. Purifying by flash chromatography (CH2Cl2–
methanol 95 : 5) yielded (ϩ)-22 in 51% (2.5 g) as a colourless
solid. Rf: 0.22 (CH2Cl2–MeOH 95 : 5). [α]2D0 = ϩ 341 (c = 0.55,
CHCl3). 1H-NMR (CDCl3): δ 3.70 (dd, 2 H, J 2.3 and 5.85 Hz,
H-2, H-3), 3.84 (s, 2 H, OH ), 4.06 (dd, 2 H, J 2.3 and 5.85 Hz,
H-1, H-4), 5.71 (s, H-5, H-6). 13C-NMR (CDCl3): δ 63.3
(C-1, C-4), 74.4 (C-2, C-3), 127.1 (C-5, C-6); MS (EI, 70 eV,
m/z (%)): 153 (8), 136 (18), 124 (7), 96 (17), 81 (29), 53 (100).
IR (KBr): 3300 (m), 2850 (m), 2080 (m, br), 1632 (m), 1347
(m), 1247 (s), 1106 (s), 1049 (m). Anal. Calcd. for C6H8O2N6:
C, 36.74; H, 4.11; N, 42.84. Found C, 36.80; H, 4.12; N,
43.10%.
4-Deoxy-4-acetamido-myo-inositol-1,2,3,5,6-pentakisphosphate
(؉)-18
A solution of (Ϫ)-10 was allowed to react under the same con-
ditions as described for the preparation of (Ϫ)-18 to give
(ϩ)-18. [α]2D0 = ϩ4.6 (c = 6.0, H2O). Analytical data were identi-
cal to those obtained for (Ϫ)-18.
3-Deoxy-3-acetamido-myo-inositol-1,2,4,5,6-pentakisphosphate
(؉)-19
The diastereomer was synthesized as described for 6-deoxy-6-
acetamido-myo-inositol-1,2,4,5,6-pentakisphosphate
(Ϫ)-18
(1,2,4,5,6-penta-O-acetyl-3-deoxy-3-azido-myo-inositol (Ϫ)-11
was taken as starting material). Workup as before gave (ϩ)-19
as a colourless foam. [α]2D0 = ϩ4.9 (c = 1.6, H2O). H-NMR
1
(D2O, pH adjusted to 6 (ND4OD)): δ 2.01 (s, CH3), 3.99 (d, 1 H,
J 10.7 Hz, H-3), 4.16 (Ψt, 1 H, J 8.9 Hz, H-1), 4.17 (Ψq, 1 H,
J 8.8 Hz, H-5), 4.28 (Ψq, 1 H, J 9.7 Hz, H-4), 4.37 (Ψq, 1 H,
J 9.3 Hz, H-6), 4.66 (d, under HDO, H-2). 13C-NMR (D2O, pH
adjusted to 6 (ND4OD)): δ 24.7 (CH3), 53.8 (m, C-3), 76.4
(m, C-1, C-2), 76.8 (m, C-4), 78.5 (m, C-6), 80.4 (m, C-5), 176.5
(1R,2S,3S,4R)-1,4-Diazidoconduritol B (؊)-22
(C᎐O). 31P-NMR{1H} (D2O, pH adjusted to 6 (ND4OD)):
᎐
A solution of (ϩ)-1 was allowed to react under the same condi-
tions as described for the preparation of (ϩ)-22 to give (Ϫ)-22.
[α]2D0 = Ϫ320 (c = 0.6, CHCl3). Analytical data were identical to
the data obtained for (ϩ)-22.
δ 1.72 (PC-4), 1.80 (PC-1), 2.16 (PC-2), 2.33 (PC-6), 3.10
(PC-5). HR-MS (ESI-neg, phosphoric acid 0.002%, H2O–
acetonitrile 1 : 1, Q-TOF): m/z: 619.9121 [M Ϫ H]Ϫ calcd. for
C8H19NO21P5: 619.9138.
(1S,2R,3R,4S )-2,3-Di-O-acetyl-1,4-diazidoconduritol B (؉)-23
1-Deoxy-1-acetamido-myo-inositol-2,3,4,5,6-pentakisphosphate
(؊)-19
(ϩ)-22 (1 g, 5.1 mmol) was dissolved in a cooled mixture of
pyridine (10 mL) and acetic anhydride (5 mL). The mixture was
stirred for 12 h. Evaporation of the solvent under high vacuum
gave (ϩ)-23 (1.4 g, 100%) as a colourless solid. Rf: 0.63 (EtOAc–
A solution of (ϩ)-11 was allowed to react under the same
conditions as described for the preparation of (ϩ)-19 to
give (Ϫ)-19. [α]2D0 = Ϫ5.6 (c = 2.1, H2O). Analytical data were
identical to the data obtained for (ϩ)-19.
cyclohexane 1 : 1). [α]2D0 = ϩ324 (c = 0.29, CHCl3). H-NMR
1
(CDCl3): δ 2.10 (s, 6 H, CH3), 4.20 (dd, 2 H, J 2.5 and 5.6 Hz,
H-1, H-4), 5.21 (dd, 2 H, J 2.5 and 5.6 Hz, H-2, H-3), 5.78 (s,
2 H, H-5, H-6). 13C-NMR (CDCl3): δ 20.5 (CH3), 60.9 (C-1,
(1S,2R,3R,4S )-1-Azido-2,3-O-isopropylconduritol B (؉)-21
(1S,2R,3R,4S)-1-Azidoconduritol B (ϩ)-6 (1 g, 5.8 mmol) was
dissolved in 2,2-dimethoxypropane (20 mL) and anhydrous
C-4), 71.8 (C-2, C-3), 127.2 (C-5, C-6), 169.7 (C᎐O). MS (EI,
70 eV, m/z (%)): 238 (2), 153 (4), 136 (5), 122 (8), 111 (8), 95 (14),
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
1927

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81 (76), 43 (100). Anal. Calcd. for C10H12O4N6: C, 42.86; H,
4.32; N, 29.99. Found: C, 42.77; H, 4.34; N, 29.90%.
water (1 : 3, 40 mL) was added Pd/C (20 mg). The mixture was
stirred at room temperature under H2 for 5 h. The catalyst was
filtered off, and the filtrate was reduced in volume and lyo-
philized to give a colourless, hygroscopic foam (40 mg, 100%).
(1R,2S,3S,4R)-2,3-Di-O-acetyl-1,4-diazidoconduritol B (؊)-23
[α]2D0 = ϩ5.9 (c = 0.34, H2O). H-NMR (D2O): δ 2.72 (dd, 1 H,
1
A solution of (Ϫ)-22 was allowed to react under the same
conditions as described for the preparation of (ϩ)-23 to give
(Ϫ)-23. [α]2D0 = Ϫ323 (c = 0.53, CHCl3). Analytical data were
identical to the data obtained for (ϩ)-23.
J 1.8 and 10.4 Hz, H-3), 2.97 (Ψt, 1 H, J 10.2 Hz, H-6), 3.20
(Ψt, 1 H, J 9.7 Hz, H-5), 3.44 (Ψt, 1 H, J 9.9 Hz, H-4), 3.48 (dd,
1 H, J 2.0 and 9.7 Hz, H-1), 3.97 (Ψs, 1 H, H-2). 13C-NMR
(D2O): δ 55.6 (C-3), 55.9 (C-6), 73.59 (C-2), 73.65 (C-1), 75.1
(C-4), 76.4 (C-5). HR-MS (ESI-pos., TOF): m/z: 179.1024
[M ϩ H]ϩ calcd. for C6H15N2O4: 179.1032.
4,5-Di-O-acetyl-3,6-dideoxy-3,6-diazido-myo-inositol (؊)-24
To a vigorously stirred ice-cooled solution of (ϩ)-23 (1.0 g, 3.6
mmol) in acetonitrile (55 mL) was added a solution of sodium
metaperiodate (1.1 g, 5.2 mmol, 1.5 eq.) and ruthenium tri-
chloride trihydrate (70 mg, 0.23 mmol) in water (7 mL). The
stirring was continued until TLC showed absence of starting
material (approx. 8 min). The reaction was quenched by addi-
tion of aqueous Na2S2O3 (20%, 50 mL). The aqueous layer was
separated and extracted four times with EtOAc (4 × 100 mL).
The combined organic layer was washed twice with brine and
concentrated under reduced pressure to yield pure (Ϫ)-24 as a
colourless foam (1.1 g, 100%). Rf: 0.31 (EtOAc–cyclohexane
1 : 1). [α]2D0 = Ϫ48.3 (c = 0.4, CHCl3). 1H-NMR (CDCl3): δ 2.09,
2.11 (s, 2 × 3 H, CH3), 3.05 (s, br, 2 H, OH), 3.50 (dd, 1 H, J 2.5
and 10.2 Hz, H-3), 3.56 (dd, 1 H, J 2.5 and 10.2 Hz, H-1), 3.90
(Ψt, 1 H, J 10.2 Hz, H-6), 4.25 (Ψt, 1 H, J 2.5 Hz, H-2), 4.97
(Ψt, 1 H, J 9.9 Hz, H-5), 5.47 (Ψt, 1 H, J 10.2 Hz, H-4). 13C-
NMR (CDCl3): δ 20.54, 20.57 (CH3), 61.4 (C-3), 63.4 (C-6),
1,4-Dideoxy-1,4-diamino-myo-inositol (؊)-28
A solution of (ϩ)-25 was allowed to react under the same
conditions as described for the preparation of (ϩ)-28 to give
(Ϫ)-28. [α]2D0 = Ϫ5.1 (c = 0.3, H2O); Analytical data were
identical to the data obtained for (ϩ)-28.
3,6-Dideoxy-3,6-diazido-1,2,4,5-tetra-O-(3-oxo-1,5-dihydro-
3ꢀ5–2,4,3-benzodioxaphosphepin-3-yl)-myo-inositol (؊)-26
To a solution of (Ϫ)-25 (200 mg, 0.86 mmol) and 1H-tetra-
zole (480 mg, 6.8 mmol) in anhydrous dichloromethane
(20 mL) under argon was added (1,5-dihydro-2,4,3-benzo-
dioxaphosphepin-3-yl)diethylamine (980 mg, 4.1 mmol), and
the mixture was stirred at room temperature for at most 4 h.
The mixture was cooled to Ϫ40 ЊC, and an anhydrous solution
of m-CPBA (3.5 g, 14.4 mmol) in dichloromethane (20 mL,
dried over Na2SO4) was added. The solution was allowed to
warm to room temperature, and the stirring was continued for
another hour. The reaction mixture was diluted with dichloro-
methane (150 mL) and washed consecutively with aqueous
sodium bisulfite (20%) (2 × 100 mL), saturated NaHCO3 and
brine. After evaporation of dichloromethane the crude product
was purified by flash chromatography (CH2Cl2–MeOH 95 : 5)
to yield (Ϫ)-26 (350 mg, 45%) as a colourless foam. Rf: 0.22
(CH2Cl2–MeOH 95 : 5). [α]2D0 = Ϫ34.4 (c = 0.215, CHCl3).
1H-NMR (CDCl3): δ 3.80 (Ψt, 1 H, J 9.9 Hz, H-6), 4.23
(dd, 1 H, J 2.0 and 8.1 Hz, H-3), 4.95–5.70 (m, 20 H,
4 × (CH2)2C6H4, H-1, H-2, H-4, H-5), 7.18–7.38 (m, 16 H,
Ph-H). 13C-NMR (CDCl3): δ = 60.9 (C-3), 63.5 (C-6), 68.71–
69.43 (m, 4 × (CH2)2C6H4), 74.2 (m), 77.0 (m), 77.4 (m), 77.7
(Ψt, J 4.8 Hz) (C-1, C-2, C-4, C-5), 128–129.5 (Carom.), 134.65,
134.74, 134.99, 135.15, 135.33, 135.49, 135.55 (Cipso).
31P{1H}-NMR (CDCl3): δ Ϫ1.90, Ϫ1.85, Ϫ1.20, Ϫ1.12 (PC-1,
PC-2, PC-4, PC-5). HR-MS (ESI-pos., TOF): m/z: 959.1376
[M ϩ H]ϩ calcd. for C38H39N6O16P4: 959.1373.
70.9 (C-2), 71.0 (C-4), 71.0 (C-1), 72.0 (C-5), 170.0 (2 × C᎐O).
᎐
Anal. Calcd. for C10H14O6N6: H 4.49, C 38.22, N 26.74; found:
H 4.73, C 38.01, N 27.00%.
5,6-Di-O-acetyl-1,4-dideoxy-1,4-diazido-myo-inositol (؉)-24
(Ϫ)-23 was allowed to react under the same conditions as
described for the preparation of (Ϫ)-24 to give (ϩ)-24. [α]2D0
=
ϩ52 (c = 0.4, CHCl3). Analytical data were identical to the data
obtained for (Ϫ)-24.
3,6-Dideoxy-3,6-diazido-myo-inositol (؊)-25
(Ϫ)-24 (500 mg, 1.6 mmol) was suspended in anhydrous meth-
anol (10 mL) under argon and cooled to 4 ЊC. A 5.5 M sodium
methanolate solution (100 µL, 0.55 mmol) was added dropwise
over 10 min. The solution was allowed to warm to room tem-
perature and stirred for 12 h. The solution was neutralized by
ion exchanger (Hϩ, Dowex 50-X), activated carbon was added,
then filtered off, and the residue was washed with MeOH. The
filtrate was reduced in volume under high vacuum. recrystalliz-
ation from methanol yielded (Ϫ)-25 (400 mg, 99%) as colour-
less solid. [α]2D0 = Ϫ48.8 (c = 0.24, MeOH). 1H-NMR (d4-
MeOH): δ 3.12 (dd, 1 H, J 2.5 and 10.2 Hz, H-3), 3.18 (Ψt, 1 H,
J 9.4 Hz, H-5), 3.36 (dd, 1 H, J 2.5 and 10.2 Hz, H-1), 3.50 (Ψt,
1 H, J 10.2 Hz, H-6), 3.78 (dd, 1 H, J 9.2 and 10.7 Hz, H-4),
3.97 (Ψt, 1 H, J 2.5 Hz, H-2). 13C-NMR (d4-MeOH): δ 64.9 (C-
3), 67.7 (C-6), 72.5 (C-1), 72.9 (C-4), 73.0 (C-2), 75.8 (C-5); MS
(70 eV, m/z (%)): 230 (2) [Mϩ], 173 (1), 98 (16), 88 (16), 73 (47),
60 (100), 42 (64). IR (KBr): 3384 (s, br), 2921 (w), 2110 (s), 1632
(w), 1259 (m), 1136 (m), 1104 (m), 1010 (m). Anal. Calcd. for
C6H10O4N6: C, 31.31; H, 4.38; N, 36.51. Found: C, 31.12; H,
4.60; N, 36.82%.
3,6-Dideoxy-3,6-diazido-1,2,4,5-myo-inositol tetrakisphosphate
(؊)-27
(Ϫ)-26 (130 mg, 0.13 mmol) was dissolved in anhydrous
CH2Cl2 (15 mL) under argon. At 0 ЊC trimethylsilyl bromide
(530 µL, 4 mmol) was slowly added, and the solution was
stirred for 3 h at 0 ЊC. The reaction was quenched by addition
of 0.4 mL water, and the solvent was removed under vacuum.
The residue was diluted with water and extracted with Et2O.
The aqueous layer was lyophilized to yield (Ϫ)-27 (63 mg, 90%)
as a colourless, hygroscopic foam. [α]2D0 = Ϫ13.0 (c = 1.0, H2O);
1H-NMR (D2O, pH 1): δ 3.76 (d, 1 H, J 10.2 Hz, H-3), 3.88
(Ψt, 1 H, J 10.2 Hz, H-6), 4.08 (Ψq, 1 H, J 9.5 Hz, H-5), 4.14
(Ψt, 1 H, J 10.9 Hz, H-1), 4.35 (Ψq, 1 H, J 9.8 Hz, H-4), 4.83 (d,
1 H, J 9.7 Hz, H-2). 13C-NMR (D2O, pH 1): δ 61.1 (Ψt, J 2.9
Hz, C-3), 63.1 (m, C-6), 73.7 (m, C-1), 75.3 (d, J 6.4 Hz, C-2),
76.1 (m, C-4), 77.0 (m, C-5). 31P{1H}-NMR (D2O, pH 1):
δ Ϫ0.25 (PC-2), ϩ0.11 (PC-1), ϩ0.58 (PC-5), ϩ0.82 (PC-4).
IR (KBr): 3423 (s, br), 2921 (m), 2121 (m), 1718, 1012 (s). HR-
MS (ESI-neg, phosphoric acid 0.002%, H2O–acetonitrile 1 : 1,
Q-TOF): m/z: 548.9365 [M Ϫ H]Ϫ calcd. for C6H13N6O16P6:
548.9339.
1,4-Dideoxy-1,4-diazido-myo-inositol (؉)-25
(ϩ)-24 was allowed to react under the same conditions as
described for the preparation of (Ϫ)-25 to give (ϩ)-25. [α]2D0
=
ϩ44 (c = 0.31, MeOH). Analytical data were identical to the
data obtained for (Ϫ)-25.
3,6-Dideoxy-3,6-diamino-myo-inositol (؉)-28
To a suspension of (Ϫ)-25 (40 mg, 0.17 mmol) in methanol–
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
1928

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11 C. Sanfilippo, A. Patti and G. Nicolosi, Tetrahedron: Asymmetry,
Acknowledgements
1998, 9, 2809–2817.
12 J. Lehmann and B. Rob, Carbohydr. Res., 1995, 276, 199–208 and
references cited therein.
13 T. Furumai, K. Takeda, A. Kinumaki, Y. Ito and T. Okuda,
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We thank Dr. W. V. Turner for critical reading of the
manuscript. We are grateful to the Bayer AG Company for
supporting this project in many aspects, especially for pre-
paring the HR-MS spectra. We also thank in particular
Dr. W. Schrader and Mrs. Blumenthal (Max-Planck Institut
für Kohlenforschung) for mass spectra analysis. We thank
Dr S. Adelt and G. Dallmann for purification of the inositol
phosphates.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 9 1 9 – 1 9 2 9
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