Flexible stereo- and regioselective synthesis of myo-inositol phosphates (Part 2): Via nonsymmetrical conduritol B derivatives

Article abstract of DOI:10.1002/ejoc.200400918

A practical route is described for the preparation of myo-inositol phosphates. Optically pure compounds can be prepared, in both forms, from p-benzoquinone by enzymatic resolution of a diacetoxyconduritol key intermediate. Monosubstituted inositol derivat

Full text of DOI:10.1002/ejoc.200400918

FULL PAPER
Flexible Stereo- and Regioselective Synthesis of myo-Inositol Phosphates
(Part 2): Via Nonsymmetrical Conduritol B Derivatives
Michael A. L. Podeschwa,[a] Oliver Plettenburg,[a] and Hans-Josef Altenbach*[a]
Keywords: Asymmetric synthesis / Biocatalytic resolution / Inositol phosphates / Natural products / Phosphorylation /
Protecting groups
A practical route is described for the preparation of myo-ino-
sitol phosphates can be synthesized by combining the pre-
sitol phosphates. Optically pure compounds can be prepared, viously reported symmetrical approach with this new non-
in both forms, from p-benzoquinone by enzymatic resolution
of a diacetoxyconduritol key intermediate. Monosubstituted
inositol derivatives can be obtained by breaking the C2 sym-
metry of conduritol B derivatives. A wide variety of myo-ino-
symmetrical approach.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
tected derivatives with free hydroxy group(s) at the desired
position for phosphorylation.[17] Our group has pioneered
a concept for the synthesis of inositol phosphates that is
based on C2-symmetric conduritol B derivatives. We have
also been able to demonstrate that regioselective enzymatic
dephosphorylation expands the number of accessible deriv-
atives,[11,18] but up until now this has been the only way to
overcome the substitution pattern dictated by the choice of
C2-symmetric starting materials. In this paper, we present
an extension to this concept that leads to even greater flexi-
bility. As reported previously,[19] the syntheses of myo-inosi-
tol phosphates via C2-symmetric conduritol B derivatives
leads to pairwise protected (differentiated) myo-inositol in-
termediates, and this limits the number of possible myo-
inositol phosphates. Breaking the C2 symmetry of the con-
duritol B precursors makes additional substitution patterns
available; we used this approach already to synthesize azi-
do- and amino-myo-inositols.[20] In the work reported here,
we describe its application to the synthesis of a number of
inositol phosphates, substantially extending the scope of
our approach. This new concept abolishes the C2 symmetry
of conduritol B derivatives by using a route analogous to
the synthesis of monoazidoconduritol B. This route also
starts from the enantiomeric building blocks 1 or 2 (see
Scheme 1) and converts them, by monoepoxide formation
and monoepoxide ring-opening (see Scheme 2), into mono-
benzylated conduritol B derivatives 3 or ent-3, respectively.
cis-Dihydroxylation leads only to the myo configuration
of the resulting inositol derivatives; in contrast to the sym-
metrical route, however, in the case of nonsymmetric start-
ing materials the attack of the hydroxylating agent leads to
an isomeric mixture of 4 and 5. Although at first glance this
seems to be disadvantageous, it turns out to be a powerful
alternative if an effective method for separating the two iso-
mers is at hand.
Introduction
myo-Inositol phosphates are members of a large family
of naturally occurring compounds that have been inten-
sively studied in the last two decades because of their com-
plex role in cell signaling and homoeostasis.[1–4] In particu-
lar, d-myo-inositol 1,4,5-trisphosphate, which is generated
from the phospholipase C catalyzed cleavage of membrane-
bound phosphatidylinositol bisphosphate (PIP2), plays an
essential role as a second messenger by inducing Ca2+ re-
lease from intracellular storage.[5,6]
Since myo-inositol phosphates are so important, a large
number of chemical syntheses have been reported in the
literature to date. Many of these start from achiral myo-
inositol, use selective protection of the alcohol groups, and
also involve enzymatic or chemical resolution for the prepa-
ration of enantiomerically pure compounds.[7,8] Recently,
peptide-based asymmetric phosphorylation has been
achieved.[9] Some de novo concepts have also been de-
scribed, for instance based on microbial oxidation of ben-
zene,[10] or starting from p-benzoquinone followed by enzy-
matic resolution,[11] or by dynamic kinetic asymmetric
transformation of the conduritol B derivatives (all-trans-5-
cyclohexene-1,2,3,4-tetraol).[12]. Several chiral pool ap-
proaches start with carbohydrates[13–15] or (–)-quinic
acid,[16] and have been used to prepare conduritols that are
suitable as intermediates for the syntheses of inositols.
Key intermediates for the synthesis of specific myo-inosi-
tol phosphates are the corresponding hydroxy group(s) pro-
[a] Institut für Organische Chemie, Bergische Universität Wupper-
tal,
Gaussstrasse 20, 42097 Wuppertal, Germany
Fax: +49-202-439-2648
E-mail: orgchem@uni-wuppertal.de
3116
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DOI: 10.1002/ejoc.200400918
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myo-Inositol Phosphates via Nonsymmetrical Conduritol B Derivatives
FULL PAPER
meric building blocks[11,21] for the synthesis of myo-inositol
derivatives. As we have described previously, they can easily
be prepared from p-benzoquinone in four steps on a 100-g
scale.
Preparation of Monobenzylconduritol B Derivatives
The monoepoxide (–)-6 can be prepared in quantitative
yield from diol (+)-1 by treatment with lithium hydroxide
as base in diethyl ether/methanol. Under the same condi-
tions the diacetate (+)-2 could be converted into the enanti-
omer (+)-6 (see Scheme 2).[20] Treatment of the monoepox-
ide (–)-6 with benzyl alcohol and a catalytic amount of con-
centrated sulfuric acid leads to (+)-7 by ring-opening of the
epoxide in the allylic position. No ring opening at the other
position takes place; however, careful examination of the
crude product shows that up to 10% of the SNЈ by-product
is formed. For analytical purposes the products can be sep-
arated by chromatography, but it turned out to be easier to
continue with the crude product as separation later, at the
triol stage 8, is very effective and opens up a fast, straight-
forward approach.
Scheme 1.
Reaction of the benzyl-protected (+)-7 under the above-
mentioned basic conditions transformed the bromohydrin
into an epoxide intermediate which, on direct hydrolysis in
water/tetrahydrofuran with catalytic amounts of p-tolu-
enesulfonic acid, yielded a mixture of triols formed by SN2
and SNЈ reactions. One by-product, for example, was deter-
mined to be 2-benzylconduritol B. Crystallization from
ethyl acetate gave pure triol (+)-8 in low yield (less than
30%), therefore this reaction is less effective than the route
for the preparation of monoazidoconduritols.[20] The low
tendency of (+)-8 and (+)-9 to crystallize forced us to se-
arch for alternatives. It should be mentioned that this route
can be pursued more effectively for the synthesis of racemic
compounds (8 or 9), since the racemic intermediates show
an increased tendency to crystallize, so that purification is
easy at the stage of the triol.
In view of the newly developed synthetic route to condu-
ritol E and B derivatives,[22] it is possible to transform the
bromohydrin derivative (+)-7 into diacetates via acetoxon-
ium intermediates. This avoids epoxide formation and epox-
ide opening and thus prevents formation of the by-products
mentioned above (see Scheme 3). Therefore, diol (+)-7 was
first acetylated and then further converted under the condi-
tions leading to either the trans- or the cis-diacetate pro-
duct.
In the absence of water the acetoxonium intermediate
undergoes ring opening by attack of acetate anions exclu-
sively at the allylic centers to form the Prévost[23] product
(+)-9, thus establishing the conduritol B stereochemistry, in
55% yield. In the presence of a sufficient amount of water
the acetoxonium intermediate is transformed into the
Woodward product (–)-10, with the conduritol F configura-
tion, in 60% yield.[24,25] We performed this reaction by heat-
Scheme 2. Reagents and conditions: (a) LiOH, Et2O/MeOH (92%).
(b) BnOH, CH2Cl2, H2SO4 (cat.) (99%). (c) 1. LiOH, Et2O/MeOH
(99%); 2. p-TSA, H2O (after crystallization Ͻ30%). (d) Ac2O, pyri-
dine (99%). (e) 1. Ac2O, pyridine (100%); 2. KOAc, glacial AcOH/
Ac2O, 5 d, 125 °C (55%).
Results and Discussion
Diacetoxydibromocyclohex-5-ene (+)-2 and (–)-2 [or the ing acetylated (+)-7 in anhydrous or aqueous acetic acid
corresponding diols (–)- and (+)-1] are again the enantio- with powdered KOAc. In the case of the Woodward pro-
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An isomeric mixture of the pentaols (–)-13 and (+)-14
was phosphorylated by treatment with (1,5-dihydro-2,4,3-
benzodioxaphosphepin-3-yl)diethylamine in the presence of
1H-tetrazole. Oxidation of the resulting phosphite with m-
CPBA gave an isomeric mixture of the protected pentakis-
phosphates. To remove the excess of phosphorylating rea-
gent, the crude product was purified by flash chromatog-
raphy (CH2Cl2/MeOH, 95:5). The isomers can be separated
easily by this method, and an earlier separation of the iso-
mers is thus not needed. Pd/C-catalyzed hydrogenolysis led
to the target compounds myo-Ins(1,2,3,4,5)P5 [(–)-15] and
myo-Ins(1,2,4,5,6)P5 [(–)-16] in quantitative yield.
Since this route can start from either of two building
blocks, as depicted in Scheme 1, both the d- and the l-series
of myo-inositol polyphosphates are obtainable. In the case
of myo-inositol derivatives this leads to different regioiso-
mers, where the benzyl protecting group can easily be intro-
duced in the 1-, 3-, 4-, and 6-position of the cyclitol ring,
depending on the choice of starting material (see Scheme 5).
For a deeper insight into myo-inositol nomenclature see
refs.[1,2] Consequently, starting from the diacetate (+)-2, the
enantiomers myo-Ins(1,2,3,5,6)P5 [(+)-15] and myo-
Ins(2,3,4,5,6)P5 [(+)-16] are available.
Scheme 3. Reagents and conditions: Preparation of the Prévost
product (+)-9: (a) Ac2O, pyridine (100%). (b) KOAc, glacial
AcOH/Ac2O, 5 d, 125 °C (55%). Preparation of the Woodward
product (+)-10: (a) Ac2O, pyridine (100%). (b) 1. KOAc, AcOH
(95%), 5 d, 125 °C; 2. Ac2O, CH2Cl2, DMAP (cat.) (60%).
duct, the crude reaction product had first to be acetylated.
The triacetate (+)-9 was purified by flash chromatography
followed by recrystallization from diethyl ether/cyclohex-
ane.
Synthesis of myo-Inositol Pentakisphosphates
cis-Dihydroxylation (see Scheme 4) of the conduritol B
derivative (+)-9 with ruthenium trichloride and sodium me-
taperiodate, followed by acetylation, gave a mixture of the
myo-configured products (+)-11 and (+)-12 in high yields
in a ratio of 6:4. The two products can be separated by
fractional recrystallization, although it is more convenient
to separate the two isomers at the stage of the protected
myo-inositol phosphates.
Scheme 5. Reagents and conditions: (a) 1. RuCl3, NaIO4, acetoni-
trile; 2. Ac2O, pyridine (99%). (b) NaOMe, MeOH (99%). (c) 1.
(1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine, 1H-
tetrazole, CH2Cl2, then m-CPBA (50%); 2. Pd/C, H2, ethanol/water
(99%).
Separation of the resulting myo-inositol pentakisphos-
phates by HPLC ensures isomeric purity suitable for bio-
logical experiments. Under the chosen chromatographic pu-
rification conditions, the two isomers (–)-15 and (–)-16 or
(+)-15 and (+)-16 differ in retention time by 6 min and can
therefore also be separated easily at this stage.
The identity of (–)-15 and (–)-16 was confirmed by one-
and two-dimensional NMR spectroscopy (see Figures 1 and
2), as it was possible to assign all the 1H, 13C, and 31P reso-
nances. The NMR spectra show no traces of the other ino-
sitol pentakisphosphate isomer. The chemical shifts of the
Scheme 4. Reagents and conditions: (a) 1. RuCl3, NaIO4, acetoni-
trile; 2. Ac2O, pyridine (99%). (b) NaOMe, MeOH (99%). (c) 1.
(1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine, 1H-
tetrazole, CH2Cl2, then m-CPBA (50%); 2. Pd/C, H2, ethanol/water
(99%).
Deprotection of the 6-benzyl-pentaacetate (+)-11 and 3- inositol ring protons are highly dependent on the pH, and
benzyl-pentaacetate (+)-12 with sodium methoxide in anhy- good resolution was achieved after adjustment of the pH
drous methanol gave 6-benzyl-myo-inositol [(–)-13] and 3- to 6 with ND4OD. The two nonphosphorylated CH groups
benzyl-myo-inositol [(+)-14], respectively, in quantitative in myo-Ins(1,2,3,4,5)P5 [(–)-15] and myo-Ins(1,2,4,5,6)P5
1
yield.
[(–)-16] can easily be recognized in the H NMR spectra as
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myo-Inositol Phosphates via Nonsymmetrical Conduritol B Derivatives
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1
Figure 1. H-1H COSY spectrum of myo-Ins(1,2,3,4,5)P5 (–)-15.
1
Figure 2. H-1H COSY spectrum of myo-Ins(1,2,4,5,6)P5 [(–)-16].
they do not change multiplicity upon phosphorus decoup- 15 is characterized by a triplet signal resulting from two
3
ling and are the signals at highest field (15: δ = 3.87 ppm; almost equivalent JH,H couplings. In the 1H-1H COSY
16: δ = 3.64 ppm). They also show characteristic coupling spectrum of (–)-16 the 2-H signal is hidden under that of
patterns: 3-H in (–)-16 exhibits a doublet (with the small HDO at δ = 4.70 ppm, but can be found by its cross-peaks
3J2-H,3-H cis coupling not being resolved), while 6-H in (–)- to 1-H and 3-H.
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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach
FULL PAPER
myo-Ins(1,2,3,4,5)P5 [(–)-15], myo-Ins(1,2,4,5,6)P5 [(–)-
16], and their enantiomers, were used as standards to assign
the absolute configuration of enzymatic (phytases) degrada-
tion products of myo-InsP6 by HPLC-MDD.[26]
Synthesis of myo-Inositol Tetrakisphosphates
Selective protection of one of the free equatorial or axial
hydroxy groups after cis-dihydroxylation of the unsymmet-
rical conduritol B derivative (+)-9 allows access to different
myo-inositol tetrakisphosphates.
Synthesis of myo-Ins(1,3,4,5)P4 [(–)-20]
One of the most interesting targets that can be synthe-
sized by this asymmetric route is myo-Ins(1,3,4,5)P4 [(–)-20].
As mentioned above, cis-dihydroxylation of the conduri-
tol B derivative (+)-9 with ruthenium trichloride and so-
dium metaperiodate gave a mixture of the isomeric diols 17
(for a clearer view only the main isomer is shown in
Scheme 6). Separation of the isomers was rendered counter-
productive by protecting-group migration. This isomeric
mixture was therefore further converted directly. For the
synthesis of (–)-20 there is the need for a suitable protected
precursor with free hydroxy groups in the 1-, 3-, 4-, and 5-
positions. Protection of the axial hydroxy group is therefore
essential. The two hydroxy groups were differentiated by
monofunctionalization of the axial hydroxy group of 17 by
a previously reported method.[22] Treatment of 17 with tri-
ethyl orthoacetate in anhydrous tetrahydrofuran under
acidic conditions (p-toluenesulfonic acid) resulted in the
formation of an intermediate orthoester that can be con-
verted directly, with acetic acid, into the axial acetate.[27]
Regioselectivity in this reaction can be traced to stereoelec-
tronic effects.[28] In this case the acetate groups in positions
3, 4, and 5 cannot be removed without removing the acetate
group in the 2-position. The problem is thus that an orthog-
onal set of protecting groups is needed. Because we were
searching for a fast and efficient route, a tedious multistep
protection and deprotection route, for example via silylated
8, was undesirable. One way to solve this problem is to use
the intermediate orthoester as a protecting group for the
diol. This orthoester 18 is stable towards base, therefore,
after its formation, the acetate groups were removed with
NaOMe in methanol. The orthoester was then directly con-
verted with acetic acid into the axial acetate (see Scheme 6).
This new method significantly shortens the route to the de-
sired precursor 19.
Scheme 6. Reagents and conditions: (a) RuCl3, NaIO4, acetonitrile.
(b) 1. MeC(OEt)3, p-TSA; 2. NaOMe, MeOH; 3. 80% HOAc
(99%). (c) 1. (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-
ylamine, 1H-tetrazole, CH2Cl2, then m-CPBA; 2. Pd/C, H2, etha-
nol/water; 3. 0.25 n NaOH (over all steps 20%).
the presence of 1H-tetrazole, followed by oxidation with m-
CPBA, gave the protected tetrakisphosphate, which, on de-
protection by Pd/C-catalyzed hydrogenolysis and then
cleavage of the acetate groups in aqueous NaOH, gave the
target compound myo-Ins(1,3,4,5)P4 [(–)-20] in 20% yield
over all steps. Separation by preparative HPLC ensured a
purity suitable for biological experiments.
As an interesting alternative we tried opening epoxide 21
with dibenzyl phosphate (see Scheme 7). The racemic inter-
mediate 22 was easy to purify by recrystallization. cis-Dihy-
droxylation and selective acetylation of the axial OH group
gave 23, the direct precursor for the synthesis of myo-
Ins(1,3,4,5)P4 (20). However, enantiomerically pure 22
turned out to be difficult to purify because of its drastically
diminished tendency to crystallize. Therefore it is relatively
tedious to synthesize larger amounts of starting material.
Interestingly, cis-dihydroxylation proceeds preferably from
the upper face, thus leading to a 2:1 ratio of the diols (for
a better view only the main isomer is shown in Scheme 7).
The success of this approach can be seen by monitoring
1
the H NMR spectra. The chemical shifts of the ring pro-
tons of the product are significantly different from those of
the starting material. The resonances of all groups, except
for the group in the 2-position, are strongly shifted upfield,
indicating that the acetate groups in positions 3, 4, and 5
1
Scheme 7. Reagents and conditions: (a) LiOH, Et2O/MeOH. (b)
CH2Cl2, dibenzyl phosphate (40%). (c) RuCl3, NaIO4, CH2Cl2,
acetonitrile. (99%). (d) 1. MeC(OEt)3, p-TSA; 2. 80% HOAc
(92%). (e) 1. (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-
ylamine, 1H-tetrazole, CH2Cl2, then m-CPBA.; 2. Pd/C, H2, etha-
have been removed. In the H NMR spectrum 2-H appears
as a pseudotriplet (3J Ϸ 3 Hz) with δ Ͼ 5 ppm, demonstrat-
ing that an acetate group is at the 2-position.
Phosphorylation of the tetraol 19 by reaction with (1,5-
dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine in nol/water; 3. 0.25 n NaOH (40%).
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myo-Inositol Phosphates via Nonsymmetrical Conduritol B Derivatives
FULL PAPER
This is thus a less useful route to enantiomerically pure but these isomers are prepared more effectively by the sym-
myo-Ins(1,3,4,5)P4 [(–)-20].
metric concept, as reported earlier.[19]
Synthesis of myo-Inositol Trisphosphates
Outlook
As an alternative to the previously described chemoen-
zymatic synthesis[11] of myo-Ins(3,4,5)P3 [(–)-25] and myo-
Ins(4,5,6)P3 (26), these myo-inositol trisphosphates can be
synthesized in a few steps from (+)-9, as depicted in
Scheme 8.
It should be noted that this concept is not limited to the
protecting pattern described above. It is possible to differen-
tiate within the triol unit in monobenzylconduritol B (8) by
isopropylidene protection: only the 2,3-O-isopropylidene-
conduritol B derivative 30 is obtained, in 80% yield
(Scheme 10). This opens the synthesis of further myo-inosi-
tol polyphosphates. The course of this reaction can be ra-
tionalized by the fact that the 3- and 4-positions are clearly
disfavored. A similar result was previously reported by
Trost[29] and by us[20] for other conduritol derivatives.
Scheme 8. Reagents and conditions: (a) 1. NaOMe, MeOH; 2. (1,5-
dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine, 1H-tetra-
zole, CH2Cl2, then m-CPBA. (b) 1. RuCl3, NaIO4, acetonitrile; 2.
Pd/C, H2, ethanol/water.
Scheme 10. Reagents and conditions: (a) 2,2-dimethoxypropane,
anhydrous acetone, PPTSA, 3 d (80%).
As previously mentioned, all the products are available in
both enantiomeric forms, which in the case of myo-inositol
derivatives lead to different regioisomers in the d- or l-
series. The concept of desymmetrization described in this
paper greatly enhances the accessibility of regioisomers of
myo-inositol phosphates.
Synthesis of myo-Inositol Monophosphates
myo-Ins(6)P [(–)-28]
Because of the orthogonal set of protecting groups used
in the synthesis of myo-inositol pentakisphosphates, it
should be easy to synthesize myo-inositol monophosphates.
Indeed, penta-O-acetyl-6-O-benzyl-d-myo-inositol [(+)-11]
is a perfect precursor for the synthesis of myo-Ins(6)P [(–)-
28]. The preparation started with Pd/C-catalyzed hydro-
genolysis of (+)-11 to deliver the free hydroxy group in the
6-position (see Scheme 9). Phosphorylation with (1,5-dihy-
dro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine in the
presence of 1H-tetrazole, followed by oxidation with m-
CPBA, gave (+)-27 in good yield. Pd/C-catalyzed hydro-
genolysis followed by cleavage of the acetate groups in
aqueous NaOH yielded (–)-28 in quantitative yield.
Conclusions
In this part of the work, several myo-inositol phosphates
have been synthesized by a nonsymmetrical approach. The
new, very short and efficient, high-yielding routes described
have allowed the synthesis of myo-Ins(1,2,3,4,5)P5 [(–)-15],
myo-Ins(1,2,4,5,6)P5 [(–)-16], myo-Ins(2,3,4,5,6)P5 [(+)-16],
myo-Ins(1,2,3,5,6)P5 [(+)-15], myo-Ins(6)P [(–)-28], myo-
Ins(4)P [(+)-28], myo-Ins(3,4,5)P3 [(–)-25], myo-Ins(4,5,6)P3
(26), and myo-Ins(1,3,4,5)P4 [(–)-20].
Experimental Section
General Remarks: All NMR spectra were recorded with a Bruker
ARX 400 (400 MHz) spectrometer. Besides 1H, 13C, and 31P experi-
ments, 2D COSY (1H-1H, 1H-13C as well as 1H-31P) and DEPT
spectra were recorded for the unequivocal correlation of the hydro-
gen, carbon, and phosphorus atoms. The chemical shifts are given
in ppm relative to TMS, although in practice the solvents were
taken as internal standard. The multiplicity is inidcated by the fol-
lowing symbols: s (singlet), d (doublet), t (triplet), q (quadruplet),
m (multiplet), ψt (pseudotriplet for unresolved dd), ur (unresolved)
and br (broad). Melting points (not corrected) were recorded with
a Büchi 510 heating block. IR spectra were obtained in pressed
KBr, and only noteworthy absorptions (cm–1) are listed. All optical
rotations of the myo-inositol phosphates are given after adjusting
to pH = 6 with NH4OH or as free acids. TLC analyses were carried
Scheme 9. Reagents and conditions: (a) 1. Pd/C, H2, EtOAc (99%);
2.
(1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine,
1H-tetrazole, CH2Cl2, then m-CPBA (51%). (b) 1. Pd/C, H2, etha-
nol/water; 2. 0.25 n NaOH (99%).
The synthesis of myo-Ins(3)P (+)-29 and its enantiomer
myo-Ins(1)P (–)-29 can also be accomplished by this route, out on Merck (Darmstadt, Germany) aluminum-backed silica gel
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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach
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60 F254 0.25 mm plates and were visualized by UV illumination at
254 nm before being sprayed with phosphomolybdic acid (10% in
MeOH) and heated. For column chromatography, Merck silica gels
60 (40–63 μm, flash) and 60H (dry) were used. All organic extracts
were dried with MgSO4, filtered, and concentrated in a rotary evap-
orator. Only distilled solvents were used. The building blocks (+)-
reduced pressure. To remove all LiOH, the residue was taken up in
CH2Cl2 (200 mL) and the organic solution washed again twice with
brine. Evaporation of the solvent yielded enantiopure 21 (17 g) as
an oil. The resulting enantiopure monoepoxide 21 (16 g, 73 mmol)
was dissolved in tetrahydrofuran (80 mL) and then water (200 mL);
a trace of p-toluenesulfonic acid was added, and the solution was
1, (–)-1, (–)-2, (+)-2,[11,21,22] (+)-6, (–)-6,[20,21] and their precursors, stirred at room temperature for 3 d. The filtrate was first reduced
were prepared according to literature methods.
in volume under high vacuum and then lyophilized to yield a brown
oil. Crystallization from EtOAc yielded (+)-8 (6 g, 30%) as a color-
less solid. Rf = 0.06 (cyclohexane/ethyl acetate, 1:1). [α]2D0 = +134
Purification and Analysis of Inositol Phosphates (HPLC-MDD):
Inositol phosphates were purified and analyzed by the HPLC-
MDD method described previously.[11,30] The compounds were sep-
arated by anion-exchange chromatography on a MonoQ HR10/10
column (Pharmacia). A linear gradient of HCl was applied (0 min
0.2 mm HCl; 70 min 0.5 m HCl; flow rate 1.5 mLmin–1). In analyti-
cal runs, photometric detection at 546 nm was achieved with a me-
tal-dye reagent [2 m Tris/HCl (pH = 9.1), 200 μm 4-(2-pyridylazo)
resorcinol (PAR), 30 μm YCl3, 10% (v/v) MeOH; flow rate
0.75 mLmin–1]. In purification steps, where on-line detection was
impossible, an analogous experiment was carried out on a micro-
plate. In brief, a 0.2–2-μL portion of the collected fraction was
mixed with 100 μL of metal-dye reagent, and the absorbance at
540 nm was measured.
1
(c = 0.8, MeOH). H NMR ([D6]DMSO): δ = 3.20 (dψt, J = 4.5,
J = 9.4 Hz, 1 H, 2-H or 3-H), 3.39 (m, 1 H, 2-H or 3-H), 3.90 (m,
2 H, 1-H, 4-H), 4.60, 4.65 (AB, J = 12 Hz, 2×1 H, Ph–CH2), 4.86
(d, J = 4.1 Hz, 1 H, OH), 4.91 (d, J = 4.6 Hz, 1 H, OH), 4.93 (d,
J = 5.6 Hz, 1 H, OH), 5.49 (d, J = 10.2 Hz, 1 H, Holef.), 5.54 (d, J
= 10.2 Hz, 1 H, Holef.), 7.22–7.36 (m, 5 H, Ph-H) ppm. 13C NMR
(CDCl3/MeOD, 6:1): δ = 70.9 (PhCH2), 71.3, 79.81 (C-1, C-4),
74.8, 76.2 (C-2, C-3), 126.3, 131.6 (C-5, C-6), 127.2, 127.45, 128.1
(Carom.), 139.1 (Cipso) ppm. MS (EI, 70 eV): m/z (%) = 236 (56)
[M+], 107 (57), 91 (100), 41 (27). IR (KBr): ν = 3460 (m, br), 3020
˜
(w), 1500 (w), 1450, 1370 (m), 1050 (s), 735 and 695 (m) cm–1.
C13H16O4 (236.3): calcd. C 66.09, H 6.83; found C 65.88, H 6.43.
HR-MS (ESI-neg., TOF): calcd. for C13H15O4 [M – H]– 235.0981;
found 235.0970.
(1R,2S,3R,6S)-6-Benzyloxy-2-bromocyclohex-4-ene-1,3-diol [(+)-7]:
To remove all LiOH, the crude (1R,2S,3R,6R)-2-bromo-7-oxabicy-
clo[4.1.0]hept-4-en-3-ol [(–)-6] (18 g, 94 mmol; for the synthesis see
refs.[20,21]) was taken up in CH2Cl2 (500 mL) and the organic solu-
tion washed twice with brine and dried with MgSO4. The MgSO4
was filtered off, and the filtrate was put in a 1-L round-bottomed
flask. Benzyl alcohol (50 mL, 0.46 mol) and a catalytic amount of
concentrated sulfuric acid (0.1 mL) were added to this solution and
stirred at room temperature for 3 d. Saturated NaHCO3 (20 mL)
was added, and the aqueous solution was extracted twice with
CH2Cl2. The combined organic layers were concentrated under re-
duced pressure to yield a brown oil (23 g), which, besides (+)-7,
contained the SNЈ by-product (approx. 10–15%). For an analytical
sample the crude product was purified by flash chromatography
(cyclohexane/ethyl acetate, 2:1) to yield pure (+)-7. Rf = 0.14 (cyclo-
hexane/ethyl acetate, 2:1). [α]2D0 = +64.9 (c = 1.8, CHCl3). 1H NMR
(CDCl3,): δ = 2.55, 2.65 (br. s, 1 H, OH), 4.06 (dd, J = 4.6, J =
2.0 Hz, 1 H, 6-H), 4.16 (dd, J = 4.3, J = 2.3 Hz, 1 H, 1-H), 4.39
(dd, J = 6.6, J = 2.0 Hz, 1 H, 2-H), 4.51 (d, J = 6.6 Hz, 1 H, 3-H),
4.66 (s, 2 H, CH2), 5.88 (s, 2 H, 4-H, 5-H), 7.28–7.41 (m, 5 H, Ph-
H) ppm. 13C NMR (CDCl3): δ = 59.3 (C-2), 70.3 (C-3), 71.3 (C-
1), 72.0 (CH2Ph), 76.3 (C-6), 126.9 (C-4 or C-5), 127.8, 128.0, 128.5
(3×CH, Carom), 129.8 (C-4 or C-5), 137.8 (Cipso) ppm. MS (EI,
70 eV): m/z (%) = 298 (2) [M+], 219 (8), 201 (61), 109 (4), 91 (100),
(1R,2S,3S,4R)-1-O-Benzylconduritol B [(–)-8]: A solution of (–)-7
was allowed to react to give (–)-8 under the conditions described
for the preparation of (+)-8. [α]2D0 = –130 (c = 1.0, MeOH). The Rf
1
value and H and 13C NMR spectroscopic data are identical with
those obtained for (+)-8.
(1S,2R,3R,4R)-2,3,4-Tri-O-acetyl-1-O-benzylconduritol F [(–)-10]:
The diol (+)-7 (4.6 g, 15 mmol) was dissolved in a cooled mixture
of pyridine (15 mL) and acetic anhydride (10 mL) and stirred over-
night. Evaporation of the solvent yielded the diacetate (5.7 g, 99%)
as a colorless oil. This residue was added to a hot solution of potas-
sium acetate or sodium acetate (12 g) in acetic acid (100 mL) and
water (5 mL). The mixture was stirred at 125 °C for 3 d. The sol-
vent was then removed under reduced pressure, and the residue was
dried under high vacuum. The residue was suspended in anhydrous
dichloromethane, then acetic anhydride (25 mL) and 4-dimeth-
ylaminopyridine (DMAP, 100 mg) were added and the mixture was
stirred overnight. For workup the mixture was added slowly to a
vigorously stirred saturated solution of NaHCO3 (200 mL water).
The aqueous phase was extracted three times with ethyl acetate
(3×100 mL). The combined organic phase was filtered through a
small glass frit with silica gel, and the silica gel was washed with
ethyl acetate. After evaporation of the solvent, the raw product was
crystallized from ethanol to yield (–)-10 (3.1 g, 54%) as a colorless
81, 79 (13, 34), 65 (76), 51 (19), 41 (22). IR (KBr): ν = 3390 (s, br),
˜
3010 (w), 2860 (w), 1650 (w), 1490 (m,), 1470, 1380 (m), 1060 (s),
690 (s), 735 u. 695 (m) cm–1. C13H15BrO3 (299.2): calcd. C 52.19,
H 5.05; found C 52.13, H, 5.07.
1
solid. [α]2D0 = –10.2 (c = 1.3, CHCl3). H NMR (CDCl3): δ = 2.01,
2.05, 2.11 (3×s, 3×3 H, 3×CH3), 4.18 (dψt, J = 2.3, J = 7.6 Hz,
1 H, 1-H), 4.56, 4.68 (2×d, AB, J = 11.7 Hz, 2×1 H, PhCH2),
5.05 (dd, J = 4.1, J = 10.7 Hz, 1 H, 3-H), 5.57–5.67 (m, 2 H, 4-H,
2-H), 5.85 (ddd, J = 2.0, J = 5.1, J = 10.2 Hz, 1 H, 5-H), 6.01 (dd,
J = 2.5, J = 10.2 Hz, 1 H, 6-H), 7.26–7.40 (m, 5 H, Ph-H) ppm.
13C NMR (CDCl3): δ = 20.6, 20.83, 20.85 (3×CH3), 66.2 (C-4),
68.9 (C-3), 69.7 (C-2), 71.1 (CH2Ph), 77.1 (C-1), 124.2 (C-5), 127.9,
128.4 (Carom.), 132.5 (C-6), 137.7 (Cipso), 169.8, 170.0, 170.3 (C=O)
ppm. C19H22O7 (362.4): calcd. C 62.98, H 6.12; found C 62.90, H
6.00.
(1S,2R,3S,6R)-6-Benzyloxy-2-bromocyclohex-4-ene-1,3-diol [(–)-7]:
A solution of (+)-6 was allowed to react under the conditions de-
scribed for the preparation of (+)-7 to yield (–)-7. [α]2D0 = –55 (c =
2.0, CHCl3). The Rf value and 1H and 13C NMR spectroscopic
data are identical with those obtained for (+)-7.
(1S,2R,3R,4S)-1-O-Benzylconduritol B [(+)-8]: Powdered LiOH
(4.0 g, 168 mmol) was added to a vigorously stirred solution of (+)-
7 (22 g, 74 mmol) in Et2O (450 mL) and MeOH (220 mL) at 0 °C
and the solution was stirred at 10 °C for 3 h. After the reaction was
complete, water (300 mL) was added, and the aqueous layer was
extracted with Et2O (3×200 mL) and EtOAc (1×100 mL). The or-
ganic solution was washed twice with brine and concentrated under
(1S,2R,3R,4S)-2,3,4-Tri-O-acetyl-1-O-benzylconduritol B [(+)-9].
Route 1 [via (+)-8]: (1S,2R,3R,4S)-1-O-Benzylconduritol B [(+)-8,
1 g, 4.2 mmol] was dissolved in an ice-cooled mixture of pyridine
(15 mL) and acetic anhydride (10 mL) and the mixture was stirred
3122
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 3116–3127

myo-Inositol Phosphates via Nonsymmetrical Conduritol B Derivatives
FULL PAPER
overnight. Evaporation of the solvent gave pure (+)-9 (1.5 g, 99%)
as a colorless solid. Route 2 [via (+)-7]: (+)-7 (10 g, 34 mmol) was
dissolved in an ice-cooled mixture of pyridine (30 mL) and acetic
anhydride (20 mL) and the mixture was stirred for 12 h. Evapora-
tion of the solvent yielded a brown oil, which was taken up in ethyl
acetate. The solution was then filtered through a small glass frit
with silica gel, and the silica gel was washed with ethyl acetate.
The filtrate was concentrated under reduced pressure to give the
diacetate (13 g, 100%) as a brown oil. This diacetate was added to
a hot solution of potassium acetate or sodium acetate (10 g) in
anhydrous acetic acid (40 mL) and acetic anhydride (3 mL). The
5.06 (dd, J = 9.9, J = 2.8 Hz, 1 H, 1-H), 5.09 (dd, J = 10.2, J =
3.0 Hz, 1 H, 3-H), 5.19 (ψt, J = 9.9 Hz, 1 H, 5-H), 5.41 (ψt, J =
10.2 Hz, 1 H, 4-H), 5.58 (ψt, J = 2.8 Hz, 1 H, 2-H), 7.20–7.36 (m,
5 H, Ph-H) ppm. 13C NMR (CDCl3): δ = 20.4 (CH3), 20.5
(2×CH3), 20.6, 20.7 (CH3), 68.5, 68.6 (C-2, C-3), 70.0 (C-4), 70.5
(C-1), 72.4 (C-5), 75.1 (CH2Ph), 77.1 (C-6), 127.5, 127.8, 128.4
(Carom.), 137.8 (Cipso), 169.3(2×C=O), 169.5, 169.6, 170.0 (C=O)
ppm. HR-MS (ESI-pos., TOF): calcd. for C23H29O11 [M + H]+
481.1709; found 481.1710. (+)-12: Rf = 0.30 (ethyl acetate/cyclohex-
1
ane, 3:2). [α]2D0 = +13.8 (c = 0.24, CHCl3). H NMR (CDCl3): δ =
1.99, 2.00, 2.01, 2.02, 2.20 (s, 5×3 H, CH3), 3.61 (dd, J = 10.2, J
mixture was stirred at 130 °C for 5 d. The solvent was removed = 3.1 Hz, 1 H, 3-H), 4.41, 4.67 (2×d, AB, J = 12.2 Hz, 2×1 H,
under high vacuum, and the residue was taken up in ethyl acetate.
The solution was then filtered through a small glass frit with silica
gel, and the silica gel was washed with ethyl acetate. After evapora-
tion of the solvent, the raw product was purified by flash
chromatography (cyclohexane/ethyl acetate, 3:2) to give a colorless
oil (8.2 g). Crystallization from Et2O/cyclohexane yielded (+)-9
(6.5 g, 55%) as a colorless solid. Rf = 0.40 (cyclohexane/ethyl ace-
tate, 1:1). [α]2D0 = +243 (c = 1.9, CHCl3). 1H NMR (CDCl3): δ =
2.01 (s, 6 H, 2×CH3), 2.03 (s, 3 H, CH3), 4.28 (ddd, J = 7.8, J =
5.2, J = 2.4 Hz, 1 H, 1-H), 4.52, 4.66 (2×d, AB, J = 11.7 Hz, 2×1
H, CH2), 5.24 (dd, J = 11.2, J = 8.1 Hz, 1 H, 3-H), 5.35 (dd, J =
11.3, J = 8.1 Hz, 1 H, 2-H), 5.57 (ddd, J = 7.6, J = 4.8, J = 2.5 Hz,
1 H, 4-H), 5.62 (dt, J = 10.3, J = 2.3 Hz, 1 H, Holef.), 5.84 (dt, J
= 10.7, J = 1.8 Hz, 1 H, Holef.), 7.25–7.36 (m, 5 H, Ph-H) ppm.
13C NMR (CDCl3): δ = 20.5; 20.6; 20.7 (CH3), 71.2 (CH2Ph), 71.7
(C-3), 71.8 (C-4), 72.1 (C-2), 76.5 (C-1), 126.1, 129.2 (C-5, C-6),
127.7, 127.8, 128.4 (Carom.), 137.6 (Cipso), 169.6, 170.0, 170.1 (C=O)
ppm. C19H22O7 (362.4): calcd. C 62.98, H 6.12; found C 62.63, H
5.60. HR-MS (ESI-pos., TOF): calcd. for C19H22O7Na [M – H]+
385.1299; found 385.1263.
CH2), 4.95 (dd, J = 2.8, J = 10.4 Hz, 1 H, 1-H), 5.09 (ψt, J =
9.9 Hz, 1 H, 5-H), 5.43 (ψt, J = 9.9 Hz, 1 H, 4-H), 5.49 (ψt, J =
10.4 Hz, 1 H, 6-H), 5.76 (ψt, J = 2.8 Hz, 1 H, 2-H), 7.21–7.37 (m,
5 H, Ph-H) ppm. 13C NMR (CDCl3): δ = 20.5 (CH3), 20.5
(2×CH3), 20.6, 20.8 (CH3), 66.7 (C-2), 69.2 (C-1), 69.5 (C-6), 70.9
(C-4), 71.2 (C-5), 71.8 (CH2Ph), 74.5 (C-3), 127.8, 128.0, 128.5
(Carom.), 136.9 (Cipso), 169.56, 169.62, 169.8, 169.9, 170.0 (C=O)
ppm. HR-MS (ESI-pos., TOF): calcd. for C23H29O11 [M + H]+
481.1709; found 481.1710.
1,2,3,5,6-Penta-O-acetyl-4-O-benzyl-D-myo-inositol [(–)-11] and
2,3,4,5,6-Penta-O-acetyl-1-O-benzyl-myo-inositol [(–)-12]: The (–)-
enantiomer 9 was cis-dihydroxylated and acetylated, as described
for the conversion of (+)-9, to yield (–)-11 {[α]2D0 = –9.8 (c = 0.30,
CHCl3)} and (–)-12 {[α]2D0 = –15.1 (c = 0.29, CHCl3)}. The Rf val-
ues and 1H and 13C NMR spectroscopic data are identical with
those obtained for (+)-11 and (+)-12.
3-O-Benzyl-D-myo-inositol [(+)-14]: 1,2,4,5,6-Penta-O-acetyl-3-O-
benzyl-myo-inositol [(+)-12; 30 mg, 0.06 mmol] was suspended in
anhydrous methanol (5 mL) under argon and cooled to 4 °C. A
5.5 m sodium methoxide solution (10 μL, 0.05 mmol) was then
added. The solution was allowed to warm to room temperature
and stirred for 12 h. The solution was neutralized by addition of
an ion exchanger (H+ form, Dowex 50-X), then filtered; the resin
was washed with water/methanol. The filtrate was first reduced in
volume under high vacuum and then lyophilized to yield (+)-14
(16 mg, 100%) as a colorless solid. [α]2D0 = +29 (c = 0.3, MeOH).
(1R,2S,3S,4R)-2,3,4-Tri-O-acetyl-1-O-benzylconduritol B [(–)-9]: A
solution of (–)-8 was allowed to react under the conditions used
for the preparation of (+)-9 to give (–)-9. [α]2D0 = –229 (c = 1.5,
CHCl3). The Rf value and 1H and 13C NMR spectroscopic data
are identical with those obtained for (+)-9.
1,2,3,4,5-Penta-O-acetyl-6-O-benzyl-D-myo-inositol [(+)-11] and
1
Ref.[31] [α]2D0 = +25 (c = 0.5, MeOH). H NMR ([D4]MeOH): δ =
1,2,4,5,6-Penta-O-acetyl-3-O-benzyl-myo-inositol [(+)-12]: A solu-
tion of sodium metaperiodate (2.1 g, 9.8 mmol, 1.5 equiv.) and ru-
thenium trichloride trihydrate (200 mg, 0.8 mmol) in water (24 mL)
was added to a vigorously stirred ice-cooled solution of (+)-9 (2.4 g,
6.6 mmol) in acetonitrile (120 mL). The stirring was continued un-
til TLC showed the complete absence of starting material (approx.
10 min). The reaction was then quenched by addition of aqueous
Na2S2O3 (20%, 100 mL). The aqueous layer was separated and ex-
tracted three times with EtOAc (3×100 mL). The combined or-
ganic layer was washed twice with brine and concentrated under
reduced pressure to yield 2.4 g of an isomeric mixture of 3,4,5-tri-
O-acetyl-6-O-benzyl-myo-inositol and 4,5,6-tri-O-acetyl-3-O-ben-
zyl-myo-inositol as a colorless foam. Separation of the isomers was
rendered counterproductive by protecting-group migration. The
crude product was therefore dissolved in a cooled mixture of pyri-
dine (15 mL) and acetic anhydride (15 mL) and stirred overnight.
Evaporation of the solvent gave a colorless solid. The isomeric ratio
of the two isomers (+)-11 and (+)-12 in the crude mixture was
estimated by NMR spectroscopy to be 6:4. Recrystallization from
ethanol yielded a pure isomeric mixture (1.9 g, 3.9 mmol, 60%).
For analytical samples the isomers were separated by fractional
crystallization from ethanol. (+)-11: Rf = 0.30 (ethyl acetate/cyclo-
3.15 (ψt, J = 9.2 Hz, 1 H, 5-H), 3.22 (dd, J = 9.9, J = 2.8 Hz, 1 H,
3-H), 3.25 (dd, J = 8.1, J = 2.5 Hz, 1 H, 1-H), 3.60 (ψt, J = 9.7 Hz,
1 H, 6-H), 3.75 (ψt, J = 9.7 Hz, 1 H, 4-H), 4.11 (ψt, J = 2.8 Hz, 1
H, 2-H), 4.64, 4.71 (2×d, AB, J = 12.2 Hz, 2×1 H, CH2), 7.20–
7.45 (m, 5 H, Ph-H) ppm. 13C NMR ([D4]MeOH): δ = 70.9 (C-2),
73.0 (CH2Ph),73.3 (C-1), 73.7 (C-4), 74.1 (C-6), 76.5 (C-5), 81.1
(C-3), 128.6, 129.1, 129.3 (Carom.), 139.9 (Cipso) ppm. HR-MS (ESI-
neg., TOF): calcd. for C13H17O6 [M – H]– 269.1033; found
269.1025.
1-O-Benzyl-D-myo-inositol [(–)-14]: A solution of (–)-12 was al-
lowed to react to give (–)-14 under the conditions described for the
preparation of (+)-14. [α]2D0 = –28 (c = 0.21, MeOH). The Rf value
1
and H and 13C NMR spectroscopic data are identical with those
obtained for (+)-14.
6-O-Benzyl-D-myo-inositol [(–)-13]: The deprotection of 1,2,3,4,5-
penta-O-acetyl-6-O-benzyl-myo-inositol
[(+)-11; 120 mg,
0.25 mmol] was carried out as described for the preparation of (+)-
14 to yield 6-O-benzyl-myo-inositol (–)-13 (70 mg, 100%) as a col-
orless solid. [α]2D0 = –8 (c = 0.25, MeOH). Ref.[8h] [α]2D0 = –5.9 (c =
1.1, MeOH). 1H NMR ([D4]MeOH): δ = 3.29 (ψt, J = 9.0 Hz, 1
H, 5-H), 3.33 (dd, J = 9.4, J = 2.3 Hz, 1 H, 1-H or 3-H), 3.49 (dd,
J = 9.7, J = 3.1 Hz, 1 H, 1-H or 3-H), 3.61 (ψt, J = 10.2 Hz, 1 H,
4-H or 6-H), 3.63 (ψt, J = 9.7 Hz, 1 H, 4-H or 6-H), 3.94 (ψt, J =
1
hexane, 3:2). [α]2D0 = +10.7 (c = 0.28, CHCl3). H NMR (CDCl3):
δ = 1.95, 1.96, 1.99, 2.01, 2.18 (s, 5×3 H, CH3), 3.99 (ψt, J =
9.9 Hz, 1 H, 6-H), 4.62, 4.68 (2×d, AB, J = 11.7 Hz, 2×1 H, CH2),
Eur. J. Org. Chem. 2005, 3116–3127
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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach
FULL PAPER
2.8 Hz, 1 H, 2-H), 4.84 (s, 2 H, CH2), 7.20–7.45 (m, 5 H, Ph-H) [c = 1.29, H2O, pH adjusted to 6 (NH4OH)]. Ref.[8h] [α]2D0 = –4.0 (c
1
ppm. 13C NMR ([D4]MeOH): δ = 73.2, 73.3 (C-1, C-3), 74.4, 74.5
(C-2, C-6 or C-4), 76.0 (CH2Ph), 76.4 (C-5), 83.2 (C-4 or C-6),
128.4, 129.1, 129.2 (Carom.), 140.5 (Cipso) ppm. HR-MS (ESI-neg.,
TOF): calcd. for C13H17O6 [M – H]– 269.1033; found 269.1025.
= 0.23, H2O, free acid, pH = 1.6) H NMR [D2O, pH adjusted to
6 (ND4OD)]: δ = 3.87 (ψt, J = 9.7 Hz, 1 H, H-6), 4.00 (ψq, J =
9.0 Hz, 1 H, 5-H), 4.03 (dψt, J = 2.5, J = 9.7 Hz, 1 H, 1-H), 4.08
(dψt, J = 2.5, J = 9.7 Hz, 1 H, 3-H), 4.34 (ψq, J = 9.4 Hz, 1 H, 4-
H), 4.83 (dψt, J = 2.3, J = 9.7 Hz, 1 H, 2-H) ppm. 13C NMR [D2O,
pH adjusted to 6 (ND4OD)]: δ = 71.3 (dd, J = 2.2, J = 6.7 Hz, C-
6), 73.7 (m, C-3), 74.3 (dd, J = 2.3, J = 5.4 Hz, C-1), 74.8 (d, J =
6.4 Hz, C-2), 76.1 (m, C-4), 78.16 (m, C-5) ppm. 31P{1H} NMR
[D2O, pH adjusted to 6 (ND4OD)]: δ = 1.96 (PC-1, PC-2), 2.21
(PC-3), 2.74 (PC-4), 2.87 (PC-5) ppm. HR-MS (ESI-neg., phospho-
ric acid, Q-TOF): calcd. for C6H16O21P5 [M – H]– 578.8844; found
578.8873. (–)-16: [α]2D0 = –7.8 [c = 1.3, H2O, pH adjusted to 6
(NH4OH)]. Ref.[8h] [α]2D0 = –7.1 (c = 0.86, H2O, free acid, pH =
4-O-Benzyl-D-myo-inositol [(+)-13]: A solution of (–)-11 was al-
lowed to react under the same conditions as those used for the
preparation of (–)-13 to give (+)-13. [α]2D0 = +9 (c = 0.25, MeOH).
The Rf value and 1H and 13C NMR spectroscopic data are identical
with those obtained for (–)-13.
D-myo-Inositol 1,2,3,4,5-Pentakisphosphate [(–)-15] and D-myo-Ino-
sitol 1,2,4,5,6-Pentakisphosphate [(–)-16]: (1,5-Dihydro-2,4,3-
benzodioxaphosphepin-3-yl)diethylamine (1.25 g, 5.2 mmol) was
added to a suspension of a isomeric mixture of 6-O-benzyl-myo-
inositol [(–)-13] and 3-O-benzyl-myo-inositol [(+)-14] (235 mg,
0.87 mmol), obtained by saponification of a pure isomeric mixture
of (+)-11 and (+)-12, and 1H-tetrazole (610 mg, 8.7 mmol) in anhy-
drous dichloromethane (50 mL), and the solution was stirred at
room temperature for 4 h. It was then cooled to –20 °C, and an
anhydrous solution of m-CPBA (3.8 g, 15 mmol) in dichlorometh-
ane (30 mL, dried with Na2SO4) was added. The solution was al-
lowed to warm to room temperature, and the stirring was continued
for 1 h. The reaction mixture was diluted with dichloromethane
(200 mL) and washed consecutively with aqueous sodium sulfite
(20%, 2×100 mL), saturated NaHCO3 (3×150 mL), and then
brine. After evaporation of the solvent, the resulting colorless foam
was purified by flash chromatography (CH2Cl2/MeOH, 95:5),
whereby the isomeric products were separated to yield 3-O-benzyl-
1,2,4,5,6-penta-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzodioxaphos-
1
1.6). H NMR [D2O, pH adjusted to 6 (ND4OD)]: δ = 3.64 (dd, J
= 2.3, J = 9.9 Hz, 1 H, 3-H), 4.06 (ψq, J = 9.5 Hz, 51 H, 5-H),
4.08 (dψt, J = 2.5, J = 9.6 Hz, 1 H, 1-H), 4.27 (ψq, J = 9.8 Hz, 1
H, 4-H), 4.35 (ψq, J = 9.8 Hz, 1 H, 6-H), 4.76 (under HDO, 2-H)
ppm. 13C NMR [D2O, pH adjusted to 6 (ND4OD)]: δ = 72.6 (s, C-
3), 75.8 (m, C-1), 77.4 (d, J = 5.1 Hz, C-2), 78.6 (ψt, C-6), 79.5
(dd, J = 2.5, J = 6.6 Hz, C-4), 79.8 (m, C-5) ppm. 31P{1H} NMR
[D2O, pH adjusted to 6 (ND4OD)]: δ = 1.96 (PC-1), 2.37 (PC-
4), 2.61 (PC-6), 3.16 (PC-5), 3.78 (PC-2) ppm. HR-MS (ESI-neg.,
phosphoric acid, Q-TOF): calcd. for C6H16O21P5 [M – H]–
578.8845; found 578.8873.
D
-myo-Inositol 2,3,4,5,6-Pentakisphosphate [(+)-16] and D-myo-Ino-
sitol 1,2,3,5,6-Pentakisphosphate [(+)-15]: A solution of an isomeric
mixture of 1-O-benzyl-myo-inositol [(–)-14] and 4-O-benzyl-myo-
inositol [(+)-13] was allowed to react under the conditions de-
scribed for the preparation of (–)-15 and (–)-16 to give (+)-15 and
(+)-16. (+)-15: [α]2D0 = +6.0 (c = 1.0, H2O). (+)-16: [α]2D0 = +8.2 (c
phepin-3-yl)-myo-inositol [200 mg, 20%, Rf
= 0.34 (CH2Cl2/
MeOH, 95:5)] and 6-O-benzyl-1,2,3,4,5-penta-O-(3-oxo-1,5-dihy-
dro-3λ5-2,4,3-benzodioxaphosphepin-3-yl)-myo-inositol [350 mg,
35%, Rf = 0.27 (CH2Cl2/MeOH, 95:5)] as a colorless foam.
= 1.5, H2O). The H NMR and 13C NMR spectroscopic data are
identical with those obtained for (–)-15 and (–)-16, respectively.
1
D
-myo-Inositol 1,3,4,5-Tetrakisphosphate [(–)-20]: (1S,2R,3R,4S)-
6-O-Benzyl-1,2,3,4,5-penta-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzo-
dioxaphosphepin-3-yl)-myo-inositol: 1H NMR (CDCl3): δ = 4.00
(ψt, J = 9.4 Hz, 1 H, 6-H), 4.76–5.76 [m, 27 H, Ph-CH2, 1-H, 2-
H, 3-H, 4-H, 5-H, 5×(CH2)2C6H4], 7.06–7.50 (m, 25 H, Ph-H)
ppm. 13C NMR (CDCl3): δ = 67.8–69.6 [m, 5×(CH2)2C6H4], 73.6
(m, CH), 74.3 (Ph-CH2), 74.8 (m, CH), 76.6 (m, CH), 77.3 (m,
CH), 77.4 (m, CH), 77.8 (m, CH), 127.2–129.5 (Carom.), 134.5–
137.5 (Cipso) ppm. 31P{1H} NMR (CDCl3): δ = +1.37, +0.12,–
0.83, –1.65,–2.63 (PC-1, PC-2, PC-3, PC-4, PC-5) ppm.
3-O-Benzyl-1,2,4,5,6-penta-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzo-
dioxaphosphepin-3-yl)-myo-inositol: 1H NMR (CDCl3): δ = 3.85 (d,
J = 9.2 Hz, 1 H, 3-H), 4.53–5.80 [m, 27 H, Ph-CH2, 1-H to 5-
H, 5×(CH2)2C6H4], 7.06–7.57 (m, 25 H, Ph-H) ppm. 13C NMR
(CDCl3): δ = 68.0–69.7 [m, 5×(CH2)2C6H4], 72.5 (Ph-CH2), 74.2
(m, CH), 75.9 (CH), 76.7 (m, CH), 77.3 (m, CH), 77.6 (m, CH),
127.6–129.6 (Carom.), 134.4–137.0 (Cipso) ppm. 31P{1H} NMR
(CDCl3): δ = +0.10, –1.03, –2.51, –3.05, –3.23 (PC-1, PC-2, PC-4,
PC-5, PC-6) ppm.
2,3,4-Tri-O-acetyl-1-O-benzyl-conduritol B [(+)-9] was cis-dihy-
droxylated as described for the preparation of (+)-11 and (+)-12. p-
Toluenesulfonic acid monohydrate (6 mg) and triethyl orthoacetate
(60 mg, 0.37 mmol) were added to a solution of the mixture of diols
3,4,5-tri-O-acetyl-6-O-benzyl-myo-inositol and 4,5,6-tri-O-acetyl-3-
O-benzyl-myo-inositol (50 mg, 0.11 mmol) in anhydrous tetra-
hydrofuran (50 mL) under argon. The mixture was stirred vigor-
ously for 24 h. The solvent was then removed under reduced pres-
sure and the residue was dried under high vacuum. The residue
was dissolved in anhydrous methanol (15 mL) under argon and
cooled to 4 °C. A 5.5 m sodium methoxide solution (18 μL,
0.1 mmol) was added. When the solution had come to room tem-
perature and had been stirred for 2 h, it was neutralized by addition
of an ion exchanger (H+ form, Dowex 50-X), then filtered; the resin
was washed with methanol. The filtrate was concentrated under
reduced pressure, and the residue was dissolved in aqueous acetic
acid (30 mL, 80%) and stirred at room temperature for 1 h. The
organic phase was concentrated to yield a brown oil (30 mg), which
contained only a mixture of 2-O-acetyl-6-O-benzyl-myo-inositol
(19) and 2-O-acetyl-3-O-benzyl-myo-inositol. 1H NMR (CDCl3/
[D4]MeOH, 6:1): δ = 1.93, 2.04 (2×s, 0.65×3 H, 0.35×3 H, CH3),
3.17-3.65 (m, 5 H, CH), 4.37, 4.64 (2×d, AB, J = 11.2 Hz, 2×0.35
H, Ph–CH2), 4.74, 4.80 (2×d, AB, J = 11.2 Hz, 2×0.65 H, Ph-
CH2), 5.32 (ψt, J = 3.1 Hz, 0.65 H, 2-H), 5.55 (ψt, J = 2.8 Hz, 0.35
H, 2-H), 7.13–7.35 (m, 5 H, Ph-H) ppm. 13C NMR (CDCl3/[D4]-
MeOH, 6:1): δ = 20.7, 20.8 (2×CH3), 70.1, 70.2, 72.3, 73.00, 73.4,
74.2, 74.4, 74.7, 77.9, 81.7 (C-ring), 72.0, 75.2 (Ph-CH2), 127.6,
Deprotection/Hydrogenolysis: Preactivated Pd/C (150 mg, Degussa
RW 10) in ethanol/water, (1:2, 30 mL) was added to a suspension
of
6-O-benzyl-1,2,4,5,6-penta-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-
benzodioxaphosphepin-3-yl)-myo-inositol or 3-O-benzyl-1,2,4,5,6-
penta-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzodioxaphosphepin-3-
yl)-myo-inositol (350 mg, 0.27 mmol) in ethanol (10 mL) and the
mixture was stirred at room temperature under H2 overnight. After
the catalyst had been filtered off, the filtrate was concentrated un-
der high vacuum and then lyophilized to give (–)-15 or (–)-16,
respectively, (150 mg, 96%) as a colorless, very hygroscopic foam. 127.79, 127.81, 127.9, 128.16, 128.22, 128.3, 128.4, 129.9 (Carom.),
Separation by HPLC assured a purity Ͼ99%. (–)-15: [α]2D0 = –6.2
134.6, 134.7 (Cipso), 170.2, 171.9 (C=O) ppm. (1,5-Ddihydro-2,4,3-
3124
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3116–3127

myo-Inositol Phosphates via Nonsymmetrical Conduritol B Derivatives
FULL PAPER
benzodioxaphosphepin-3-yl)diethylamine (174 mg, 0.8 mmol) was
added to a solution of 2-O-acetyl-6-O-benzyl-myo-inositol and 2-
O-acetyl-3-O-benzyl-myo-inositol (30 mg, 0.11 mmol) and 1H-
tetrazole (96 mg, 1.28 mmol) in dichloromethane (20 mL), and the
solution was stirred at room temperature for 5 h. The solution was
then cooled to –40 °C, and an anhydrous solution of m-CPBA
(730 mg, 3 mmol) in dichloromethane (15 mL, dried with Na2SO4)
was added. The solution was allowed to warm to room tempera-
ture, and the stirring was continued for 1 h. The reaction mixture
was diluted with dichloromethane (30 mL) and washed consecu-
tively with aqueous sodium sulfite (20%, 2×50 mL), saturated
NaHCO3 (3×50 mL), and brine. After evaporation of the solvent,
the resulting colorless foam was purified by flash chromatography
(CH2Cl2/MeOH, 95:5, Rf = 0.1) to yield a colorless foam (30 mg,
0.03 mmol, 30%), which contained 2-O-acetyl-6-O-benzyl-1,3,4,5-
tetra-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzodioxaphosphepin-3-yl)-
myo-inositol (purity Ͼ80%). This protected inositol (30 mg,
30 μmol) was deprotected, as described for the preparation of (–)-
28, to give (–)-20 as a colorless, very hygroscopic foam. Separation
by preparative HPLC provided a sample (10 mg, 0.02 mmol) suita-
bly pure for biological experiments. [α]2D0 = –4.7 [c = 0.67, H2O, pH
adjusted to 6 (NH4OH)]. Ref.[8e] [α]2D0 = –4.08 (c = 2.02, H2O, so-
(40 mL), and the solution was stirred at room temperature for 4 h.
It was then cooled to –20 °C, and an anhydrous solution of m-
CPBA (3.3 g, 13 mmol) in dichloromethane (30 mL, dried with
Na2SO4) was added. The solution was allowed to warm to room
temperature, and the stirring was continued for 1 h. The reaction
mixture was diluted with dichloromethane (100 mL) and washed
consecutively with aqueous sodium sulfite (20%, 2×100 mL), satu-
rated NaHCO3 (3×150 mL), and brine. After evaporation of the
solvent, the resulting colorless foam was purified by flash
chromatography (cyclohexane/ethyl acetate, 1:3) to yield (+)-24
(500 mg 58%) as a colorless foam. Rf = 0.38 (ethyl acetate/cyclo-
hexane, 3:1). [α]2D0 = +28.5 (c = 0.4, CHCl3). 1H NMR (CDCl3):
δ = 4.42 (m, 1 H, 1-H), 4.67–5.64 [m, 15 H, 2-H, 3-H, 4-H,
3×(CH2)2C6H4], 5.89 (dψt, J = 10.7, J = 1.8 Hz, 1 H, 5-H or 6-
H), 6.03 (dψt, J = 10.2, J = 2.0 Hz, 1 H, 5-H or 6-H), 7.16–7.46
(m, 17 H, Ph-H) ppm. 13C NMR (CDCl3): δ = 67.1 (d, J = 6.3 Hz),
68.6 (d, J = 7.0 Hz), 68.9 (d, J = 7.0 Hz), 69.1–69.4 (m), 69.5 (d, J
= 8.3 Hz) (CH2)2C6H4], 71.5 (PhCH2), 77.5 (m), 77.9 (m), 78.7 (m)
(C-1, C-2, C-3, C-4), 126.25 (C-5 or C-6), 128.1–129.5 (C-5 or C-
6, Carom.), 134.9, 135.0, 135.2, 135.3, 135.4, 135.5, 137.0, 137.5
(Cipso) ppm. 31P{1H} NMR (CDCl3): δ = –2.03, –1.20, 0.04 (PC-2,
PC-3, PC-4) ppm. C37H37O13P3 (782.6): calcd. C 56.78, H 4.77;
dium salt, pH = 9.7). 1H NMR [D2O, pH adjusted to 6 (ND4OD)]: found C 56.51, H 5.01.
δ = 3.86 (ψt, J = 10.2 Hz, 1 H, 6-H), 3.99 (ψq, J = 9.2 Hz, 1 H, 5-
(1R,2S,3S,4R)-1-O-Benzyl-2,3,4-tri-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-
H), 4.00 (ψt, J = 9.7 Hz, 1 H, 1-H), 4.06 (dψt, J = 1.5, J = 9.7 Hz,
1 H, 3-H), 4.33 (ψs, 1 H, 2-H), 4.35 (ψq, J = 9.0 Hz, 1 H, 4-H)
ppm. 13C NMR [D2O, pH adjusted to 6 (ND4OD)]: δ = 72.9 (s),
73.4 (m), 76.6 (m, 2×C), 78.3 (m), 80.5 (m) ppm. 31P{1H} NMR
[D2O, pH adjusted to 6 (ND4OD)]: δ = 2.11, 2.26, 2.65 (PC-1, PC-
3, PC-5), 2.95 (PC-4) ppm. HR-MS (ESI-neg., phosphoric acid, Q-
TOF): calcd. for C6H15O18P4 [M – H]– 498.9159; found 498.9209.
benzodioxaphosphepin-3-yl)conduritol B [(–)-24]: A solution of (–)-
9 was allowed to react under the conditions described for the prep-
aration of (+)-24 to give (–)-24. [α]2D0 = –31.6 (c = 0.5, CHCl3). The
Rf value and 1H and 13C NMR spectroscopic data are identical
with those obtained for (+)-24.
D-myo-Inositol 3,4,5-Trisphosphate [(–)-25] and myo-Inositol 4,5,6-
Trisphosphate (26): A solution of sodium metaperiodate (140 mg,
0.65 mmol, 1.5 equiv.) and ruthenium trichloride trihydrate (13 mg,
0.04 mmol) in water (2 mL) was added to a vigorously stirred ice-
cooled solution of (+)-24 (350 mg, 0.44 mmol) in acetonitrile
(120 mL). The stirring was continued until TLC showed the com-
plete absence of starting material (approx. 10 min). The reaction
was then quenched by addition of aqueous Na2S2O3 (20%, 20 mL)
and the aqueous layer was separated and extracted with EtOAc
(3×500 mL). The combined organic layers were washed with brine
and concentrated under reduced pressure to yield an isomeric mix-
ture of diols (290 mg, 80%) as a colorless solid. Preactivated Pd/C
(100 mg, Degussa RW 10) in ethanol/water (1:2, 30 mL) was added
to a suspension of the crude product (200 mg, 0.24 mmol) in etha-
nol (10 mL), and the mixture was stirred at room temperature un-
der H2 overnight. The catalyst was filtered off, and the filtrate was
concentrated under high vacuum and then lyophilized. At this stage
the isomers were separated by preparative HPLC to give (–)-25
(50 mg, 12 μmol, 50%) and 26 (30 mg, 7 μmol, 30%) with purity
Ͼ99% as colorless, very hygroscopic foam. The analytical data for
myo-inositol 3,4,5-trisphosphate [(–)-25] are in agreement with pre-
viously published results.[11] 26: 1H NMR [D2O, pH adjusted to 8.5
(ND4OD)]: δ = 3.64 (dd, J = 2.0, J = 9.7 Hz, 2 H, 1-H and 3-H),
3.98 (ψs, 1 H, 2-H), 4.00 (ψq, J = 9.2 Hz, 1 H, 5-H), 4.19 (ψq, J =
9.0 Hz, 2 H, 4-H and 6-H) ppm. 13C NMR [D2O, pH adjusted to
8.5 (ND4OD)]: δ = 71.3 (s, C-2), 71.7 (s, C-1 and C-3), 75.9 (m, C-
4 and C-6), 78.0 (m, C-5) ppm. 31P{1H} NMR [D2O, pH adjusted
to 8.5 (ND4OD)]: δ = 2.07 (PC-5), 5.67 (PC-4 and PC-6) ppm. 31P
NMR [D2O, pH adjusted to 8.5 (ND4OD)]: δ = 2.07 (d, J = 9.4 Hz,
1 P, PC-5), 5.67 (d, J = 8.3 Hz, 2 P, PC-4 and PC-6) ppm. For
further analytical data see ref.[32]
1-O-Benzyl-4-O-(di-O-benzylphospho)conduritol B (22): Dibenzyl
phosphate (4.7 g, 16.9 mmol) was added to a solution of racemic
monoepoxide 21 (3.1 g, 14.1 mmol) [for the preparation see the syn-
thesis of (+)-8] in anhydrous dichloromethane (100 mL) and the
solution was stirred at room temperature overnight. The solvent
was then removed under reduced pressure. Recrystallization from
ethyl acetate yielded 22 (2.8 g, 40%) as a voluminous, colorless so-
1
lid. H NMR (CDCl3): δ = 3.71 (m, 2 H, 2-H, 3-H), 4.05 (m, 1 H,
1-H), 4.39 (br. s, 2 H, OH), 4.69 and 4.79 (2×d, AB, J = 11.7 Hz,
2 H, PhCH2), 4.78 (m, 1 H, 4-H), 4.97–5.11 (m, 4 H, CH2-OP),
5.47 (dt, J = 10.7, J = 2.0 Hz, 1 H, 6-H), 5.72 (dt, J = 10.7, J =
2.0 Hz, 1 H, 5-H), 7.23 (m, 15 H, Ph-H) ppm. 13C NMR (CDCl3):
δ = 69.9 (ψt, J = 5.6 Hz, CH2C6H4), 72.5 (PhCH2), 74.5 (d, J =
3.0 Hz, C-3), 74.9 (s, C-2), 78.4 (s, C-1), 79.7 (d, CH, J = 5.1 Hz,
C-4), 127.8 (d, J = 7.1 Hz, C-5), 127.7, 127.77, 127.83, 128.0, 128.1,
128.3, 128.4, 128.45, 128.56, 128.65, 128.73 (Carom.), 130.3 (s, C-
6), 135.4, 135.5 (Cipso-CH2P), 138.3 (Cipso) ppm. 31P{1H} NMR
(CDCl3): δ = 0.95 ppm. 31P NMR (CDCl3): δ = 0.95 (ψsext, JP,H
= 8.0 Hz) ppm.
(1S,2R,3R,4S)-1-O-Benzyl-2,3,4-tris-O-(3-oxo-1,5-dihydro-3λ5-
2,4,3-benzodioxaphosphepin-3-yl)conduritol B [(+)-24]: Triacetate
(+)-9 (0.55 g, 1.3 mmol) was suspended in anhydrous methanol
(10 mL) under argon and cooled to 4 °C. A 5.5 m sodium methox-
ide solution (0.1 mL, 0.55 mmol) was then added, the solution was
allowed to warm to room temperature, and stirred for 12 h. The
solution was neutralized by addition of an ion exchanger (H+ form,
Dowex 50-X) and filtered; the resin was washed with methanol.
The filtrate was first reduced in volume under high vacuum to yield
(+)-8 (350 mg, 100%) as a colorless solid. (1,5-Dihydro-2,4,3-
benzodioxaphosphepin-3-yl)diethylamine (1.1 g, 4.7 mmol) was
added to a suspension of this triol (+)-8 (260 mg, 1.1 mmol) and
1H-tetrazole (550 mg, 7.8 mmol) in anhydrous dichloromethane
D-myo-Inositol 1,5,6-Trisphosphate [(+)-25] and myo-Inositol-4,5,6-
Trisphosphate (26): A solution of (–)-24 was allowed to react under
Eur. J. Org. Chem. 2005, 3116–3127
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3125

M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach
FULL PAPER
the conditions used for the preparation of (–)-25 and 26 to give
(+)-25 and 26. [α]2D0 = +2.2 (c = 2.3, H2O, free acid). The Rf value
31P{1H} NMR [D2O, pH adjusted to 6 (ND4OD)]: δ = 4.55 (PC-
6) ppm. HR-MS (ESI-neg., phosphoric acid, Q-TOF): calcd. for
C6H12O9P [M – H]– 259.0246; found 259.0219.
1
and H and 13C NMR spectroscopic data are identical with those
obtained for (–)-25 and 26.
D-myo-Inositol 4-Phosphate [(+)-28]: A solution of (–)-27 was al-
1,2,3,4,5-Penta-O-acetyl-6-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzo-
dioxaphosphepin-3-yl)-D-myo-inositol [(+)-27]: Pd/C (20 mg) was
lowed to react under the conditions used for the preparation of
(–)-28 to give (+)-28. [α]2D0 = +3.3 [c = 0.4, H2O, pH adjusted to 6
(NH4OH)]. The 1H NMR and 13C NMR spectroscopic data are
identical with those obtained for (–)-28.
added to a suspension of (+)-11 (80 mg, 0.17 mmol) in ethyl acetate
(20 mL). After the mixture had been stirred at room temperature
for 4 h, the catalyst was filtered off and washed with ethyl acetate.
The filtrate was concentrated under reduced pressure to give the
monoalcohol (66 mg, 100%) as a colorless foam. (1,5-Dihydro-
2,4,3-benzodioxaphosphepin-3-yl)diethylamine (50 mg, 0.21 mmol)
was added to a suspension of the 1,2,3,4,5-penta-O-acetyl-d-myo-
inositol (66 mg, 0.17 mmol) and 1H-tetrazole (36 mg, 0.5 mmol) in
anhydrous dichloromethane (10 mL), and the solution was stirred
at room temperature for 12 h. The solution was then cooled to
–40 °C, and an anhydrous solution of m-CPBA (190 mg, 0.8 mmol)
in dichloromethane (10 mL, dried with Na2SO4) was added. The
solution was allowed to warm to room temperature, and the stir-
ring was continued for 1 h. The reaction mixture was diluted with
dichloromethane (40 mL) and washed consecutively with aqueous
sodium sulfite (20%, 2×30 mL), saturated NaHCO3 (3×50 mL),
and brine. After evaporation of the solvent, the resulting colorless
foam was purified by flash chromatography (ethyl acetate) to yield
(+)-27 (50 mg, 51%) as a colorless foam. Rf = 0.45 (ethyl acetate).
[α]2D0 = +16.4 (c = 0.24, CHCl3). 1H NMR (CDCl3): δ = 2.00, 2.02,
2.12, 2.14, 2.21 (5×s, 5×3 H, CH3), 4.95-5.22 [m, 5 H, (CH2)2-
C6H4, 6-H], 5.11 (dd, J = 3.1, J = 10.7 Hz, 1 H, 3-H), 5.27 (dd, J
= 2.8, J = 10.4 Hz, 1 H, 1-H), 5.31 (ψt, J = 9.7 Hz, 1 H, 5-H), 5.49
(ψt, J = 10.2 Hz, 1 H, 4-H), 5.60 (ψt, J = 2.8 Hz, 1 H, 2-H), 7.21–
7.38 (m, 4 H, Ph-H) ppm. 13C NMR (CDCl3): δ = 20.4, 20.5, 20.57,
20.60, 20.7 (5×CH3), 68.2 (C-2), 68.4 (t, J = 3.8 Hz), 67.8 (s) (C-
1, C-3), 68.6-68.9 [(CH2)2C6H4], 69.1 (C-4), 71.0 (d, J = 2.9 Hz, C-
5), 76.3 (d, J = 5.7 Hz, C-6), 128.6, 128.7, 129.1 (Carom.), 134.6,
134.7 (Cipso), 169.5, 169.7, 169.8, 170.1 (C=O) ppm. 31P{1H} NMR
(CDCl3): δ = –0.63 (PC-6) ppm. HR-MS (ESI-pos.): calcd. for
C24H29O14PNa [M + Na]+ 595.119; found 595.1193.
1-O-Benzyl-2,3-O-isopropylideneconduritol B (30): 1-O-Benzyl-con-
duritol B (8; 0.97 g, 4.2 mmol) was dissolved in 2,2-dimethoxypro-
pane (20 mL) and anhydrous acetone (20 mL). Pyridinium p-tolu-
enesulfonic acid (PPTSA; 40 mg) was then added, and the solution
was stirred for 3 d. The solution was then diluted with diethyl ether
(30 mL), and 2 n aqueous NaOH (20 mL) and brine (20 mL) were
added. The aqueous layer was separated and extracted with diethyl
ether (3×30 mL). The combined organic layers were concentrated
under reduced pressure to yield 30 (1.0 g, 81%) as a yellowish oil.
Rf = 0.30 (cyclohexane/ethyl acetate, 1:1). 1H NMR (CDCl3,
400 MHz): δ = 1.48 (s, 6 H, CH3), 3.08 (br. s, 1 H, OH), 3.51 (dd,
J = 9.9, J = 8.4 Hz, 1 H, 2-H or 3-H), 3.66 (dd, J = 9.7, J = 8.1 Hz,
1 H, 2-H or 3-H), 4.26 (ddd, J = 3.1, J = 8.1, J = 1.5 Hz, 1 H, 1-
H or 4-H), 4.45 (dψt, J = 8.0, J = 1.4 Hz, 1 H, 1-H or 4-H), 4.67
and 4.84 (2×d, AB system, J = 12.2 Hz, 2×1 H, Ph-CH2), 5.65
and 5.69 (2×d, J = 10.2 Hz, 2×1 H, 5-H and 6-H), 7.27–7.40 (m,
5 H, PhH) ppm. 13C NMR (CDCl3): δ = 27.0 (2×CH3), 70.6 (C-
4), 77.3 (C-1), 80.1, 80.9 (C-2 and C-3), 111.03 [C(CH3)2], 126.8
(C-5 or C-6), 127.7, 128.3, 128.7 (C6H5), 130.8 (C-5 or C-6), 138.2
(Cipso) ppm. MS (EI, 70 eV): m/z (%) = 276 (3) [M+], 170 (2) [M+
+ H – OBn], 107 (19), 91 (100), 43 (54), 41 (35). IR (KBr): ν =
˜
3400 (br. m), 3040 (w), 2900, 2860 (w), 1500 (w), 1450, 1370, 1050
(m), 735 (m), 695 (m) cm–1. HR-MS (ESI-pos.): calcd. for
C16H20O4 [M+] 276.1346; found 276.1362.
Acknowledgments
We thank Dr. W. V. Turner for critical reading of the manuscript.
We are grateful to Bayer AG for supporting many aspects of this
report, especially for recording the HR-MS spectra. We thank Dr.
S. Adelt and G. Dallmann for help with the HPLC purification of
the inositol tris-, tetrakis-, and pentakisphosphates.
1,2,3,5,6-Penta-O-acetyl-4-O-(3-oxo-1,5-dihydro-3λ5-2,4,3-benzo-
dioxaphosphepin-3-yl)-D-myo-inositol [(–)-27]: A solution of (–)-11
was allowed to react under the conditions described for the prepa-
ration of (+)-27 to give (–)-27. [α]2D0 = –15.9 (c = 0.40, CHCl3). The
Rf value and 1H and 13C NMR spectroscopic data are identical
with those obtained for (+)-27.
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Received: December 29, 2004
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