Chemoselective alcoholysis/acetolysis of trans-ketals over cis-ketals and its application in the total synthesis of the cellular second messenger, d-myo-inositol-1,4,5-trisphosphate

Article abstract of DOI:10.1039/c3ob40789f

The involvement of natural phosphoinositols in various cellular signalling processes and the use of synthetic inositol derivatives in catalysis, supramolecular chemistry, natural product synthesis etc. gave momentum to myo-inositol chemistry. The presence of six secondary hydroxyl groups necessitates efficient protection-deprotection strategies for the synthesis of inositol derivatives. An important strategy for the initial protection of myo-inositol is the di-ketalization, which gives a mixture of three diketals, each having both cis-fused and trans-fused ketals. It is important to have methodologies either to selectively hydrolyze one of the two ketals or to convert one of the two acid labile ketals to an orthogonal base labile protecting group. By exploiting the difference in strain between trans-ketals and cis-ketals, we developed two operationally simple, high yielding methodologies for the chemoselective hydrolysis/acetolysis of trans-ketals (both isopropylidene and cyclohexylidene) of inositols, leaving the cis-ketal undisturbed, using cheap and easily preparable H₂SO ₄-silica as the catalyst. Also, terminal ketal moieties of carbohydrates and acyclic polyols could be selectively hydrolyzed/acetolyzed leaving the internal ketals intact. The use of methanol as the solvent leads to chemoselective alcoholysis but the use of DCM and acetic anhydride leads to chemoselective acetolysis. Applying this methodology, a short synthesis of d-myo-inositol-1,4,5-trisphosphate has been achieved. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob40789f

Organic &
Biomolecular Chemistry
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PAPER
Chemoselective alcoholysis/acetolysis of trans-ketals
over cis-ketals and its application in the total synthesis
of the cellular second messenger, D-myo-inositol-
1,4,5-trisphosphate†
Cite this: Org. Biomol. Chem., 2013, 11,
5443
Adiyala Vidyasagar,‡ Atchutarao Pathigoolla‡ and Kana M. Sureshan*
The involvement of natural phosphoinositols in various cellular signalling processes and the use of syn-
thetic inositol derivatives in catalysis, supramolecular chemistry, natural product synthesis etc. gave
momentum to myo-inositol chemistry. The presence of six secondary hydroxyl groups necessitates
efficient protection–deprotection strategies for the synthesis of inositol derivatives. An important strategy
for the initial protection of myo-inositol is the di-ketalization, which gives a mixture of three diketals,
each having both cis-fused and trans-fused ketals. It is important to have methodologies either to selec-
tively hydrolyze one of the two ketals or to convert one of the two acid labile ketals to an orthogonal
base labile protecting group. By exploiting the difference in strain between trans-ketals and cis-ketals, we
developed two operationally simple, high yielding methodologies for the chemoselective hydrolysis/
acetolysis of trans-ketals (both isopropylidene and cyclohexylidene) of inositols, leaving the cis-ketal
undisturbed, using cheap and easily preparable H2SO4-silica as the catalyst. Also, terminal ketal moieties
of carbohydrates and acyclic polyols could be selectively hydrolyzed/acetolyzed leaving the internal
ketals intact. The use of methanol as the solvent leads to chemoselective alcoholysis but the use of DCM
and acetic anhydride leads to chemoselective acetolysis. Applying this methodology, a short synthesis of
D-myo-inositol-1,4,5-trisphosphate has been achieved.
Received 19th April 2013,
Accepted 20th June 2013
DOI: 10.1039/c3ob40789f
www.rsc.org/obc
calcium influx4 and cell regulation.5 Also, pyrophosphorylated
inositols are thought to be involved in several biological pro-
Introduction
Myo-inositol has attracted considerable scientific attention pri- cesses.6 At least 26 IPns, 8 PIPns and several glycosylated ino-
marily due to the involvement of phosphoinositols in various sitols are known to occur naturally (Fig. 1).7 Though the
cellular signallings.1 Phospholipase C mediated hydrolysis of involvement of some of these phosphoinositols in various bio-
the lipid, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], logical processes has been established,3–6 a clear picture of the
produces D-myo-inositol-1,4,5-trisphosphate (IP3), which medi-
ates calcium release from the endoplasmic reticulum through
the activation of IP3 receptor.1e,2 IP3 will then be metabolized
and finally recycled by the sequential action of several kinases
and phosphatases resulting in the formation of several inositol
phosphates (IPn), pyrophosphates (PPIPn) and phosphatidyl
inositol phosphates (PIPns). The lipid phosphatidylinositol
3,4,5-trisphosphate is involved in Akt signalling,3 capacitative
School of Chemistry, Indian Institute of Science Education and Research,
Thiruvananthapuram 695016, India. E-mail: kms@iisertvm.ac.in
†Electronic supplementary information (ESI) available: 1H NMR, COSY, 13C
NMR, DEPT and HMQC spectra of all new compounds, 1H NMR and 31P NMR
spectra of 35, 36 and 5 and crystal structure of 24a. CCDC 925397, 925398 and
925399. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ob40789f
‡These authors contributed equally.
Fig. 1 Representative members of various phosphoinositols.
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cellular role played by many phosphoinositols is lacking.1d,f
It has been known that the ketals of anti-diols are more
The scarcity of these natural products and the necessity of sterically strained than ketals of the syn-diols.19 This difference
large quantities of these substances and their unnatural ana- in energy has been exploited in the selective cleavage of the
logues for biological studies demand the chemical synthesis of trans-acetonides of 1,3-diols.20 Also selective cleavage of trans-
phosphoinositols8 and their analogues.9 Furthermore, the use acetonides in the presence of cis acetonides has been reported
of synthetic inositol derivatives in catalysis,10 supramolecular in myo-inositol derivatives using PTSA,21 acetyl chloride in
chemistry,11 natural product synthesis12 etc. gives additional methanol.16d However, these methods are low yielding and
impetus to the inositol chemistry.
less selective.21b This is often due to the use of homogeneous
Owing to the presence of six secondary hydroxyl groups of catalysts which warrants workup to remove these acidic impu-
similar reactivities, synthesis of inositol derivatives necessi- rities. At times, lengthy workup leads to complete non-selective
tates efficient strategies for the protection and deprotection of deprotection also. This limitation can be circumvented by the
specific hydroxyl groups. Hence, developing methodologies for use of a solid supported catalyst which can be removed rapidly
selective protection and deprotection13 of inositol hydroxyl after the reaction by just a simple filtration.
groups is an important area of research. Also, for the efficient
synthesis of target products from polyols such as carbo-
hydrates, inositol etc., specific hydroxyl groups need to be
selectively functionalized in a specific order in the synthetic
Results and discussion
sequence. For such regiotemporal control, it is important to Recently, H2SO4-silica has gained attention as a mildly acidic
use orthogonal protecting groups, so that any of these protect- heterogeneous catalyst for various transformations.22 We have
ing groups (PGs) can be selectively removed without disturbing recently demonstrated the utility of H2SO4-silica as an efficient
the others and hence the required hydroxyl group can be catalyst for the ketalization and orthoesterification of myo-
exposed. Acid labile ketals and base labile acetates constitute a inositol.23 This prompted us to use this catalyst for selective
pair of orthogonal protecting groups for hydroxyl groups.
deprotection of trans ketals. In order to test the efficiency of
One of the important strategies for the initial protection of H2SO4-silica in ketal cleavage, ( )-1,2:5,6-di-O-isopropylidene-
myo-inositol is acid catalyzed di-ketalization,14 which gives a myo-inositol (9) was treated with a catalytic amount of H2SO4-
mixture of three diketals, each of which has a cis fused and a silica in MeOH at rt. To our satisfaction, the tetrol 15 was
trans fused ketal moiety (Scheme 1).15 Both isopropylidene obtained in very good yield as a result of the selective deprotec-
and cyclohexylidene ketals are used frequently. These diketals tion of the trans-ketal (Table 1). Similarly, the trans-isopropyli-
have been used in phosphoinositol synthesis,16 natural dene group of ( )-1,2:4,5-di-O-isopropylidene-myo-inositol (10)
product synthesis12,16d and the synthesis of myo-inositol based and ( )-1,2:3,4-di-O-isopropylidene-myo-inositol (11) could be
supramolecular entities.17 Though di-ketalization is an impor- selectively cleaved to get the tetrol 15 in good yields under
tant early protection of inositol, protection of four hydroxyl these conditions. No appreciable amount of cis-ketal deprotec-
groups with an acid labile ketal moiety is often disadvanta- tion was observed in any of these diketals. A change of the
geous (non-orthogonal) for further synthetic manipulations. solvent from methanol to ethanol slowed down the reaction
Thus, it is important to have methodologies either to selec- and it took a longer time for complete reaction. On the other
tively hydrolyze one of the two ketals or to convert one of the hand, the reaction was not facile in aprotic solvents like DCM
two acid labile ketals to an orthogonal base labile PG (e.g. as anticipated.
ester). Usually such transformations are done in two steps, the
Our next target was to check the tolerability of different pro-
acid catalyzed cleavage of ketal to the diol followed by its base tecting groups under the reaction conditions. Thus various
catalyzed esterification.12d,18 We herein report two operation- derivatives of diketals 9 and 10 were treated with H2SO4-silica
ally simple methodologies for the chemoselective alcoholysis/ in methanol (Table 1). It was found that various common pro-
acetolysis (one step conversion of ketal to diacetate) of trans- tecting groups such as benzyl ethers, PMB ethers, methyl
ketals without disturbing the cis-ketals, using cheap and easily ethers, esters and sulfonates tolerate the deprotection con-
preparable H2SO4-silica as the catalyst under ambient con- ditions.
A remarkable selectivity for the trans-ketal was
ditions. Also, we illustrate the efficiency of this methodology observed in the case of benzyl ethers, PMB ethers, esters and
by a short synthesis of the cellular second messenger, D-myo- sulfonates. However, in the case of methyl ether derivatives of
inositol-1,4,5-trisphosphate (IP3).
9 and 10, there was no selectivity and this resulted in complete
deprotection of both cis- and trans-ketals. In general, the
benzyl and PMB ether derivatives gave better yields than ester
derivatives. Also, derivatives of 10 gave better yields than
derivatives of 9, presumably due to the difference in the strain.
Interestingly, treatment of 1,2:3,4:5,6-tri-O-isopropylidene-
D-chiro-inositol (17) with H2SO4-silica in MeOH resulted in
selective cleavage of only the trans-ketal giving the diketal 18
in 90% yield. Compound 18 was characterized by solving its
crystal structure using single crystal XRD. Fig. 2 shows the
Scheme 1 Di-ketalization of myo-inositol.
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Table 1 Selective deprotection of trans-ketals over cis-ketals of inositol derivativesa
Reactant
R1
R2
Product
R1
R2
Yield
941
H
Bn
Bz
H
Bn
Bz
1543
H
Bn
Bz
H
Bn
Bz
76
78
72
9a29
9b29
15a30
15b16d
1041
H
H
1543
H
H
Bn
PMB
H
74
81
86
70
10a29
10b29
10c31
Bn
PMB
Ts
Bn
PMB
H
16a25
16b32
16c
Bn
PMB
Ts
1145
—
—
—
—
1543
—
—
—
—
75
90
1733
1833
1934
—
—
2034
—
—
92
1242
12a
H
Bz
H
Bz
2144
21a
H
Bz
H
Bz
93
73
1342
H
Bn
Me
PMB
H
Bn
Me
PMB
2144
22a36
22b
H
Bn
Me
PMB
H
Bn
Me
PMB
91
89
92
94
13a12a
13b35
13c
22c
1442
—
—
2144
—
—
90
a RR = –(CH2)5–. aH2SO4-silica, MeOH, rt.
ORTEP diagram of compound 18. Also, the acyclic derivative cyclohexylidene ketals, the methyl derivatives also underwent
1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol (19) underwent selective hydrolysis of the trans-ketal in excellent yields. Also, it
selective hydrolysis of one of the terminal isopropylidene is noteworthy that the trans-cyclohexylidene cleavage is regio-
groups to give diol 20 in good yield. Diol 20 has been exploited specific and higher yielding than the isopropylidene cleavage.
for the total synthesis of several natural products.24 These Even with prolonged reaction time, we could not observe any
examples suggest that H2SO4-silica is applicable not only for trace of product formed from cis-ketal cleavage in the case of
the deprotection of trans-ketal of myo-inositol but also that of cyclohexylidene ketals. Hence, it is advisable to use cyclohexyli-
other cyclitols and acyclic derivatives.
dene derivatives for better selectivity and better yields.
In order to check the generality of this trans-ketal deprotec-
Having succeeded in the chemoselective hydrolysis of the
tion, we have applied this methodology to various derivatives trans-ketal without disturbing the cis-ketal, we were curious to
of cyclohexylidene ketals 12, 13 and 14 (Scheme 1). In all these know whether H2SO4-silica can affect chemoselective acetolysis
cases, the trans-cyclohexylidene group underwent cleavage of the trans-ketal, the one step conversion of the trans-ketal to
selectively in excellent yields. Remarkably, in the case of diacetates. Such a direct and one pot conversion of an acid
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labile protecting group to a base labile protecting group will be
advantageous. In order to check this, the model diketal 9a was
treated with H2SO4-silica in the presence of acetic anhydride
in dry DCM. Gratifyingly, the trans-isopropylidene very selec-
tively underwent acetolysis under this condition giving the di-
acetate 23a in very good yield (Table 2). Similar selectivity and
reactivity was observed when dry CHCl3 was used as the
solvent. However, the use of wet DCM (not dried) resulted in
the formation of a mixture of the expected diacetate 23a and
diol 16a in poor yields.
In order to understand whether the observed acetolysis is a
two-step reaction involving the initial acid catalyzed cleavage
of the ketal followed by acid catalyzed acetylation, diketal 9a
was treated with H2SO4-silica alone (in the absence of Ac2O) in
dry DCM. Interestingly, no ketal cleavage was observed and the
starting material could be recovered almost quantitatively
suggesting that the reaction is not a stepwise process and the
acetic anhydride has a role in the cleavage step itself. Similarly,
Fig. 2 ORTEP diagram of compound 18.
Table 2 Selective acetolysis of trans-ketals over cis-ketals of inositol derivativesa
Reactant
R1
Product
R1
Yield
941
H
Bn
Bz
2331
23a30
23b
Ac
Bn
Bz
80
84
92
9a29
9b29
1041
H
Bn
PMB
2331
Ac
Bn
PMB
84
78
80
10a29
10b29
24a18b
24b
1733
2537
86
1242
12a
H
Bz
2638
26a
Ac
Bz
82
95
1342
H
Bn
Me
2638
27a
27b
Ac
Bn
Me
88
98
87
13a12a
13b35
1442
H
2638
Ac
79
a RR = –(CH2)5–. aH2SO4-silica, Ac2O, dry DCM, Ar, rt.
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Fig. 3 ORTEP diagram of compound 26.
Scheme 2 Plausible mechanism for acetolysis.
when the diketal 9a was treated with Ac2O alone (absence of
H2SO4-silica), there was no reaction. Also the reaction was not
facile when normal silica was used in the place of H2SO4-silica.
A plausible mechanism is given in Scheme 2. The catalyst
H2SO4-silica might activate the ketal A by protonation. The
oxonium ion (I) on C–O bond cleavage would give oxocarbe-
nium ion (II). The hydroxyl group would then undergo acid
catalyzed acetylation and the nucleophilic attack by the liber-
ated acetate ion on the oxocarbenium ion (III) would lead to
Scheme 3 Acetolysis of terminal ketals of sugars and acyclic polyols. a: H2SO4-
silica, Ac2O, dry DCM, Ar, rt.
acetylated hemiacetal (IV). The relatively more nucleophilic derivatives. Notably, the dimethyl derivative 13b also under-
oxygen of this acetylated hemiacetal could attack another went smooth selective acetolysis at rt.
molecule of protonated acetic anhydride leading to the inter-
Having established the generality of the trans-ketal acetoly-
mediate (V). Finally, the attack of the released acetic acid on sis in inositol derivatives, we have explored the utility of this
the intermediate (VI) will generate a molecule of Ac2O, acetone method in other ketal protected polyols (Scheme 3). In these
and the diacetate B. However, the possible hydrolysis of acetic cases also, we could find selectivity between different ketal
anhydride by acidic silica to acetic acid and subsequent cataly- groups. For instance, 1,2:3,4:5,6-tri-O-isopropyledene-D-manni-
sis by this acid can also not be ruled out.
tol (19) underwent acetolysis of both the terminal ketal selec-
Next, we have studied the generality of this highly chemo- tively giving the tetra-acetate (30)40 in very good yield.
selective acetolysis. Interestingly, the trans-ketal of several Similarly, di-isopropylidene-D-glucose (28)39 underwent selec-
derivatives of both 1,2:5,6-di-O-isopropylidene-myo-inositol tive acetolysis of the terminal ketal giving the triacetate 29 in
(9–9b) and 1,2:4,5-di-O-isopropylidene-myo-inositol (10–10b) very good yield. When only one cis-ketal was present (31), its
underwent acetolysis in very good yields (Table 2). In general, acetolysis took a very long time. Though cis-ketal underwent
benzoates and benzyl ether derivatives gave very good yields of acetolysis after prolonged reaction, interestingly the acid labile
the products. Interestingly, chiro-inositol triketal (17) having BDA group (33) was stable to acetolysis even at reflux
two cis-ketal and one trans-ketal also underwent selective conditions.
acetolysis of the trans-ketal at 0 °C.
Having established two simple, efficient and reliable metho-
In order to investigate the utility of this methodology in dologies for chemoselective discrimination of trans-ketals from
selective acetolysis of other ketals, we have attempted the cis-ketals, we decided to illustrate the applicability of these
acetolysis of various di-O-cyclohexylidene derivatives of myo- methodologies. We have used chemoselective hydrolysis for
inositol prepared from different parent diketals (12–14). In all the total synthesis of the cellular second messenger D-myo-ino-
these cases (Table 2, six examples), the trans-cyclohexylidene sitol 1,4,5-trisphosphate. Optically pure diketal (+)-108c was
motif underwent acetolysis very selectively in high yields benzylated using NaH/BnBr to get the dibenzyl ether (+)-10a.
(Fig. 3). In general, the yields of acetolysis of cyclohexylidene The trans-isopropylidene group was selectively hydrolyzed
derivatives were better than that of the isopropylidene using H2SO4-silica to get the diol (+)-16a. This intermediate
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could be selectively acetolyzed leaving the internal ketals
untouched. We believe that these two methodologies will find
applications in natural product synthesis, carbohydrate chem-
istry and phosphoinositol synthesis. The importance of the
chemoselective hydrolysis has been demonstrated by the total
synthesis of a representative phosphoinositol, D-myo-inositol
1,4,5-trisphosphate (5).
Experimental section
Materials and methods
Scheme 4 Synthesis of myo-inositol 1,4,5-trisphosphate: (i) NaH, BnBr, DMF,
0 °C, 95%, (ii) H2SO4 silica, MeOH, 84%, (iii) dibenzyl-N,N-diisopropylphosphora-
midate, DCM, rt and then m-CPBA at −78 °C, 79%, (iv) aq. HCl, 95%, (v) POCl3
in DCM, (vi) Pd(OH)2/C, cyclohexene, MeOH–H2O, 60% for two steps.
Thin layer chromatography was carried out using pre-coated
silica gel plates. Chromatograms were visualized under UV
light and by dipping plates into either phosphomolybdic acid
in MeOH or anisaldehyde in ethanol, followed by heating with
a hot air gun. IR spectra were recorded by preparing KBr
has been used in the synthesis of many phosphoinositols.25
The diol (+)-16a was phosphorylated to get the bis-phosphate
(+)-35 in 79% yield. Deprotection of the remaining isopropyli-
dene group using aqueous HCl in MeOH gave the diol (+)-36.
Phosphorylation of the diol (+)-36 using POCl3 as the phos-
phorylating agent gave an inseparable mixture of two com-
pounds, whose 31P NMR revealed that one of the products is a
cyclic phosphate (ESI). This mixture on debenzylation using
transfer hydrogenolysis (Pd(OH)2/C in cyclohexene) yielded
D-myo-inositol 1,4,5-trisphosphate [(+)-5] as the only product
(Scheme 4).26 This result suggests that the cyclic phosphate
undergoes regioselective opening to form (+)-5 during the
hydrogenolysis. To the best of our knowledge, this is the first
example of the use of POCl3 for the regioselective phosphory-
lation of inositol hydroxyl groups. The fact that the intermedi-
ate (+)-29 has been used for the synthesis of D-myo-inositol
2,4,5-trisphosphate and D-myo-inositol 1,2-cyclic-4,5-trisphos-
phate27 shows the utility of our method for the synthesis of
other inositol phosphates too.
1
pellets, using an IR spectrometer. The H NMR, COSY, DEPT,
13C NMR and HMQC spectra were recorded on a 500 MHz
NMR spectrometer. Proton chemical shifts are reported in
ppm (δ) relative to internal tetramethylsilane (TMS, δ 0.0 ppm)
or with the solvent reference relative to TMS employed as the
internal standard (CDCl3, δ 7.26 ppm). Data are reported as
follows: chemical shift (multiplicity [singlet (s), doublet (d),
triplet (t), quartet (q), and multiplet (m)], coupling constants
[Hz], integration). All NMR signals were assigned on the basis
of 1H NMR, 13C NMR, COSY and HMQC experiments. 13C
spectra were recorded with complete proton decoupling.
Carbon chemical shifts are reported in ppm (δ) relative to TMS
with the respective solvent resonance as the internal standard.
All NMR data were collected at 25 °C. Melting points were
determined using a Stuart SMP30 melting point apparatus and
are uncorrected. Elemental analyses were performed using an
elemental analyzer. Flash column chromatography was per-
formed using silica gel (200–400 mesh). H2SO4-silica was pre-
pared as reported.22g X-ray intensity data measurements of
freshly grown crystals of 18 and 26 were carried out at 298 K
on a single crystal X-ray diffractometer with graphite-mono-
chromatized (MoK = 0.71073 Å) radiation. The X-ray generator
was operated at 50 kV and 30 mA. Data were collected with a
Conclusions
In conclusion, we report two simple methodologies for chemo- scan width of 0.3° at different settings of φ (0°, 90° and 180°)
selective hydrolysis/acetolysis of trans-ketals in the presence of keeping the sample to detector distance fixed at 40 mm and
cis-ketals of cyclitols in good yields using the cheaply available the detector position (2θ) fixed at 24°. The X-ray data collection
and easily preparable H2SO4-silica as the catalyst. The use of a was monitored by SMART program (Bruker, 2003). All the data
cheap and easy-to-prepare catalyst, milder reaction conditions, were corrected for Lorentzian, polarization and absorption
a simple work-up procedure, excellent chemoselectivity, high effects using SAINT and SADABS programs (Bruker, 2003).
yield and wide applicability make these methods practically SHELX-97 was used for structure solution and full matrix least-
usable. Our one step conversion of a trans-ketal to diacetate is squares refinement on F2. All the hydrogen atoms were placed
synthetically very important and economical, as such trans- in a geometrically idealized position (C–H = 0.95 Å for the
formations are traditionally done in a two step process. Most phenyl and the acetylene H atoms, C–H = 0.99 Å for the
of the common protecting groups tolerate the acetolysis con- methylene H-atoms and C–H = 1.0 Å for the central sugar ring
dition. To the best of our knowledge, this is the first report on H-atoms) and constrained to ride on their parent atoms
selective acetolysis between cis- and trans-ketals. We have illus- [Uiso (H) = 1.2Ueq. (C)]. Molecular and packing diagrams were
trated the utility of this selective acetolysis not only in inositol generated using ORTEP-3 and Mercury-3.0. Geometrical calcu-
chemistry but also in sugars and other acyclic polyols. In the lations were performed using SHELXTL (Bruker, 2003) and
case of sugars and acyclic polyols, the terminal ketal groups PLATON.
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Crystal data of 18. CCDC 925397. C12H20O6, M = 260.28, col- completion of the reaction (1 h), pyridine was removed under
orless hexagonal blocks, 0.2 × 0.15 × 0.1 mm3, orthorhombic, reduced pressure. The crude material was dissolved in ethyl-
space group P2(1)2(1)2(1), a = 5.6971(2), b = 11.5145(3), c = acetate and washed with 1 M aq. citric acid. The organic layer
19.4201(5) Å, V = 1273.94(6) Å3, Z = 4, T = 293(2) K, 2θmax
=
was dried over Na2SO4 and concentrated. The crude was puri-
50.00°, Dcalc (g cm−3) = 1.355, F(000) = 560.0, μ (mm−1) = 0.108, fied by column chromatography using 1 : 19 (v/v) ethylacetate
5497 reflections collected, 2187 unique reflections (Rint and petroleum ether as an eluent to yield the colourless solid
=
0.0292), multi-scan absorption correction, Tmin = 0.9786, Tmax 12a (765 mg, 95%). MP: 187–189 °C. IR (KBr) 3057, 2977, 2909,
1
= 0.9892, the number of parameters = 163, the number of 1728, 1454, 1328, 1236 cm−1. H NMR (500 MHz, DMSO-d6) δ:
restraints = 0, GoF = 1.059, R1 = 0.0285, wR2 = 0.0823, R indices 8.01(d, J = 7.6 Hz, 2H), 7.97 (d, J = 7.5 Hz, 2H), 7.67–7.71 (m,
based on 2133 reflections with I > 2σ(I) (refinement on F2). 2H), 7.56 (t, J = 7.3 Hz, 4H), 5.54 (dd, J = 3.5, 3.8 Hz, 1H), 5.45
Δρmax = 0.195, Δρmin = −0.173 (e Å−3).
(dd, J = 3.5, 9 Hz, 1H), 4.79 (dd, J = 3.8, 6.3 Hz, 1H), 4.58 (dd,
Crystal data of 24a. CCDC 925399. C27H32O8, M = 484.54, J = 6.3, 7.3 Hz, 1H), 4.16 (dd, J = 7.3, 10.3 Hz, 1H), 4.08 (dd, J =
colorless needle, 0.25 × 0.2 × 0.15 mm3, orthorhombic, space 9, 10.3 Hz, 1H), 1.7–1.3 (m, 20H). 13C NMR (125 MHz, Acetone-
group Pca 21, a = 10.298(4), b = 11.735(5), c = 22.178(9) Å, V = d6) δ: 164.8, 164.3, 133.5, 133.4, 129.7, 129.6, 129.5, 128.6,
2680.2(18) Å3, Z = 4, T = 110(2) K, 2θmax = 46.00°, Dcalc (g cm−3
)
128.5, 112.9, 111.1, 78, 76.2, 75.5, 73.9, 73.8, 73.0, 36.4, 36.3,
= 1.193, F(000) = 1020.0, μ (mm−1) = 0.088, 3318 reflections col- 36.2, 34.0, 24.8, 24.7. Anal. Calcd for C32H36O8: C, 70.06; H,
lected, 2798 unique reflections (Rint = 0.1305), multi-scan 6.61. Found: C, 69.95; H, 6.72.
absorption correction, Tmin = 0.9801, Tmax = 0.9965, the
( )-1,2:4,5-Di-O-cyclohexylidene-3,6-di-O-para-methoxybenzyl-
number of parameters = 284, the number of restraints = 1, GoF myo-inositol (13c). Compound 12 (500 mg, 1.47 mmol) in dry
= 1.196, R1 = 0.1150, wR2 = 0.1117, R indices based on 2798 DMF (10 mL) was cooled to 0 °C. To this cooled solution,
reflections with I > 2σ(I) (refinement on F2). Δρmax = 0.384, sodium hydride (60% in paraffin oil) (176 mg, 4.41 mmol), fol-
Δρmin = −0.237 (e Å−3).
lowed by p-methoxybenzylchloride (600 μL, 4.41 mmol) were
Crystal data of 26. CCDC 925398. C20H28O10, M = 428.42, added. The reaction mixture was allowed to warm to room
colorless needle, 0.2 × 0.15 × 0.1 mm3, monoclinic, space temperature. The reaction was monitored using TLC. After
group Cc, a = 12.681(4), b = 18.138(5), c = 9.663(3) Å, V = 2208.1(11) completion of the reaction (4 h), the reaction mixture was
Å3, Z = 4, T = 296(2) K, 2θmax = 50.00°, Dcalc (g cm−3) = 1.284, quenched with ice cold water and evaporated under reduced
F(000) = 912.0, μ (mm−1) = 0.104, 3430 reflections collected, pressure. The crude material was dissolved in ethylacetate and
2729 unique reflections (Rint = 0.0246), multi-scan absorption washed with water. The organic layer was dried over Na2SO4
correction, Tmin = 0.9796, Tmax = 0.9897, the number of and concentrated. The crude was purified by column chrom-
parameters = 271, the number of restraints = 2, GoF = 1.031, R1 = atography using 1 : 9 (v/v) ethylacetate and petroleum ether as
0.0411, wR2 = 0.1117, R indices based on 2744 reflections with I > an eluent to yield the colourless solid 13c (758 mg, 89%). MP:
2σ(I) (refinement on F2). Δρmax = 0.211, Δρmin = −0.141 (e Å−3).
General procedure for selective
96–98 °C. IR (KBr): 3045, 2920, 2877, 1478, 1369, 1250 cm−1
.
trans-ketal 1H NMR (500 MHz, DMSO-d6) δ: 7.22–7.18 (m, 4H), 6.84–6.81
hydrolysis. 1 mmol of diketal in MeOH (8 mL) treated with (m, 4H), 4.58 (q, J = 11.9, 17.1 Hz, 2H), 4.51 (s, 2H), 4.36 (t, J =
H2SO4-silica (8 mg) at rt. When the TLC showed almost com- 4.4 Hz, 1H), 3.99 (dd, J = 4.1, 10.2 Hz, 1H), 3.72 (t, J = 9.4 Hz,
pletion of the starting material, the reaction mixture was 1H), 3.67 (s, 3H), 3.66 (s, 3H) 1.55–1.27 (m, 20H). 13C NMR
quenched with solid NaHCO3, filtered, concentrated and puri- (125 MHz, DMSO-d6) δ: 158.7, 158.6, 130.2, 129.39, 129.37,
fied by column chromatography.
129.2, 113.59, 113.50, 111.4, 109.0, 79.9, 77.7, 76.3, 75.1, 74.6,
General procedure for acetolysis of ketals. To a solution of 70.7, 69.8, 55.0, 37.1, 36.0, 34.6, 24.4, 23.6, 23.5, 23.4. Anal.
diketal (1 mmol) and Ac2O (3 mmol; if hydroxyl groups were in Calcd for C34H44O8: C, 70.32; H, 7.64. Found: C, 70.41; H, 7.69.
the starting material, an additional equivalent of Ac2O per
( )-1,2-O-Isopropylidene-3-O-tosyl-myo-inositol (16c). Yield:
hydroxyl group was added) in dry DCM (5 mL), 25 mg of (262 mg, 70%). MP: 155–158 °C, IR (KBr): 3404, 3050, 2988,
1
freshly prepared H2SO4-silica was added. The reaction mixture 2846, 1350, 1224 cm−1. H NMR (500 MHz, DMSO-d6) δ: 7.80
was stirred at room temperature under an inert atmosphere (d, J = 8.25 Hz, 2H), 7.44 (d, J = 8.05, 2H), 5.27 (d, J = 5.0 Hz,
and the reaction was monitored using TLC. When the starting 1H), 5.04 (d, J = 4.7 Hz, 1H), 4.98 (d, J = 4.7 Hz, 1H), 4.08 (t, J =
material disappeared (2–6 h), the reaction mixture was 5.15 Hz, 1H), 3.87 (t, J = 6.9 Hz, 1H), 3.50–3.45 (m, 1H),
quenched by the addition of solid NaHCO3. Solid material was 3.02–2.97 (m, 1H), 2.41 (s, 3H), 1.34 (s, 3H), 1.05 (s, 3H); 13C
filtered off and the organic layer was washed with a saturated NMR (125 MHz, DMSO-d6) δ: 145.0, 134.3, 130.2, 128.1, 109.0,
aq. NaHCO3 solution. The organic layer was dried over Na2SO4 81.0, 80.9, 79.2, 74.0, 73.8, 73.7, 70.4, 46.1, 28.1, 26.0, 21.5.
and evaporated on a rotary evaporator. The crude product thus Anal. Calcd for C16H22O8S: C, 51.33; H, 5.92; S, 8.56. Found: C,
obtained was purified using flash column chromatography.
51.11; H, 6.09; S, 8.38.
( )-1,2:5,6-Di-O-cyclohexylidene-3,4-di-O-benzoyl-myo-inositol
( )-1,2-O-Cyclohexylidene-3,4-di-O-benzoyl-myo-inositol (21a).
(12a). To a solution of compound 12 (500 mg, 1.47 mmol) in Yield: (342 mg, 73%). MP: 164–166 °C, IR (KBr): 3479, 3035,
1
dry pyridine (10 mL), benzoylchloride (520 μL, 4.42 mmol) and 2960, 2870, 1737, 1462, 1344, 1225 cm−1. H NMR (500 MHz,
dimethylaminopyridine (9 mg, 0.07 mmol) (DMAP) were DMSO-d6) δ: 8.13 (d, J = 7.35 Hz, 2H), 8.10 (d, J = 7.35 Hz, 2H),
added at 0 °C. The reaction was monitored using TLC. After 7.75 (t, J = 7.25 Hz, 1H), 7.67–7.61 (m, 4H), 5.78 (m, 1H),
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5.54–5.52 (m, 2H), 5.34 (t, J = 9.75 Hz, 1H), 4.25 (t, J = 10 Hz,
( )-1,2-O-Cyclohexylidene-3,4-di-O-benzoyl-5,6-di-O-acetyl-myo-
1H), 4.09–4.07 (m, 1H), 3.91–3.85 (m, 2H), 1.66–1.33 (m, 10H). inositol (26a). Yield: (524 mg, 95%). MP: 180–181 °C. IR (KBr):
1
13C NMR (125 MHz, DMSO-d6) δ: 165.09, 165.06, 133.3, 129.8, 3066, 2979, 2916, 1754, 1730, 1480, 1357, 1240 cm−1. H NMR
129.5, 129.2, 128.8, 128.6, 111.7, 74.4, 73.9, 73.7, 73.1, 70.9, (500 MHz, DMSO-d6) δ: 7.98–7.95 (m, 2H), 7.74–7.71 (m, 1H),
69.4, 35.8, 35.5, 24.2, 23.0. Anal. Calcd for C26H28O8: C, 66.66; 7.61–7.57 (m, 2H), 5.75–5.73 (m, 1H), 5.57–5.50 (m, 3H), 4.69
H, 6.02. Found: C, 66.49; H, 6.27.
(t, J = 4.1 Hz, 1H), 4.66–4.63 (m, 1H), 1.94 (s, 3H), 1.84 (s, 3H),
( )-1,2-O-Cyclohexylidene-3,6-di-O-methyl-myo-inositol (22b). 1.81 (br, 2H), 1.59–1.5 (m, 6H), 1.42 (br, 2H). 13C NMR
Yield: (264 mg, 92%). MP: 147–149 °C. IR (KBr): 3470, 2970, (125 MHz, DMSO-d6) δ: 169.50, 169.20, 164.83, 164.77, 133.88,
1
2841, 1340, 1219 cm−1. H NMR (500 MHz, DMSO-d6) δ: 4.89 133.80, 129.26, 129.24, 128.97, 128.90, 128.85, 128.80, 110.63,
(d, J = 4.5 Hz, 1H –OH), 4.82 (d, J = 4.3 Hz, –OH), 4.36 (t, J = 4.9 75.26, 73.70, 73.04, 69.66, 69.57, 69.33, 36.82, 34.59, 24.24,
Hz, 1H), 3.92 (t, J = 6.4, 1H), 3.47–3.44 (m, 1H), 3.43 (s, 3H), 23.55, 23.15, 20.22, 20.07. Anal. Calcd for C30H32O10: C, 65.21;
3.37 (s, 3H), 3.23 (dd, J = 3.8, 9.0 Hz, 1H), 3.10–3.06 (m, 1H), H, 5.84. Found: C, 65.38; H, 5.82.
1.65–1.35 (m, 10H); 13C NMR (125 MHz, DMSO-d6) δ: 108.7,
( )-1,2-O-Cyclohexylidene-3,6-di-O-benzyl-4,5-di-O-acetyl-myo-
84.8, 78.9, 77.9, 73.0, 72.8, 71.4, 59.2, 57.2, 37.4, 34.8, 24.5, inositol (27a). Yield: (513 mg, 98%) Semi-solid. IR (KBr): 3018,
23.5, 23.3. Anal. Calcd for C14H24O6: C, 58.32; H, 8.39. Found: 2987, 2851, 1748, 1457, 1222 cm−1. 1H NMR (500 MHz, DMSO-
C; 58.02; H, 8.61.
d6) δ: 7.39–7.27 (m, 10H), 5.19 (t, J = 9.5 Hz, 1H), 4.99 (t, J = 9.5
( )-1,2-O-Cyclohexylidene-3,6-di-O-para-methoxybenzyl-myo- Hz, 1H), 4.66 (ABq, J = 12 Hz, 86 Hz, 2H), 4.64 (t, J = 13 Hz,
inositol (22c). Yield: (470 mg, 94%). MP: 146–148 °C, IR (KBr): 2H), 4.52 (t, J = 5 Hz, 1H), 4.27–4.24 (m, 1H), 3.99 (dd, J =
3420, 3021, 2927, 2869, 1511, 1457, 1238 cm−1 1H NMR 3.5 Hz, 9.5 Hz, 1H), 3.65 (dd, J = 7 Hz, 9.5 Hz, 1H), 1.99 (s, 3H),
.
(500 MHz, DMSO-d6) δ: 7.31–7.30 (m, 4H), 6.89 (t, J = 6.6 Hz, 1.96 (s, 3H), 1.71–1.69 (m, 2H), 1.61–1.54 (m, 6H), 1.39 (br,
4H), 4.98 (d, J = 4.3 Hz, 1H –OH), 4.90 (d, J = 4.7 Hz, 1H, –OH), 2H). 13C NMR (125 MHz, DMSO-d6) δ: 169.40, 169.24, 138.29,
4.7–4.65 (m, 2H), 4.59 (q, J = 11.6, 17.3 Hz, 2H), 4.33 (t, J = 138.24, 128.18, 128.15, 127.49, 127.45, 127.40, 109.67, 79.92,
3.9 Hz, 1H), 3.99 (t, J = 5.4 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 77.58, 74.41, 72.89, 72.58, 71.39, 71.10, 70.65, 37.17, 34.53,
3.53–3.52 (m, 1H), 3.47 (dd, J = 3.5, 8.9 Hz, 1H), 3.17–3.14 (m, 24.46, 23.65, 23.33, 20.46, 20.44. Anal. Calcd for C30H36O8: C,
1H), 1.57–1.35 (m, 10H). 13C NMR (125 MHz, DMSO-d6) δ: 68.68; H, 6.92. Found: C, 68.71; H, 6.80.
158.5, 158.4, 131.0, 130.9, 129.1, 129.0, 113.4, 113.3, 108.7,
( )-1,2-O-Cyclohexylidene-3,6-di-O-methyl-4,5-di-O-acetyl-myo-
82.3, 78.0, 77.1, 73.4, 72.2, 71.6, 70.8, 55.02, 55.01, 37.3, 34.7, inositol (27b). Yield: (323 mg, 87%). MP: 92–93 °C. IR (KBr):
1
24.5, 23.6, 23.3. Anal. Calcd for C28H36O8: C, 67.18; H, 7.25. 2927, 2841, 1366, 1228 cm−1. H NMR (500 MHz, DMSO-d6) δ:
Found: C, 67.10; H, 7.229.
5.13 (t, J = 9.55 Hz, 1H), 4.90 (t, J = 9.55 Hz, 1H), 4.51–4.49 (m,
( )-1,2-O-Isopropylidene-3,4-di-O-benzoyl-5,6-di-O-acetyl-myo- 1H), 4.16–4.14 (m, 1H), 3.73 (dd, J = 3.85 Hz, 9.45, 1H), 3.41 (s,
inositol (23b). Yield: (471 mg, 92%). MP: 221–222 °C, IR (KBr): 3H), 3.41–3.37 (m, 1H), 3.42 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H),
3075, 2987, 2920, 1749, 1727, 1450, 1373, 1275, 1238 cm−1
.
1.75–1.71 (m, 2H), 1.62–1.50 (m, 6H), 1.38 (br, 2H). 13C NMR
1H NMR (500 MHz, DMSO-d6) δ: 7.87–7.81 (m, 4H), 7.66–7.61 (125 MHz, DMSO-d6) δ: 169.41, 169.28, 109.57, 81.85, 77.10,
(m, 2H), 7.52–7.47 (m, 4H), 5.89 (dd, J = 3.95 Hz, 9.8 Hz, 1H), 75.81, 72.30, 71.54, 70.74, 59.19, 57.24, 37.16, 34.54, 24.44,
5.71 (t, J = 9.55 Hz, 1H), 5.53 (t, J = 9.95 Hz, 1 H), 5.34 (dd, J = 23.57, 23.30, 20.52, 20.46. Anal. Calcd for C18H28O8: C, 58.05;
7.55 Hz, 10.1 Hz, 1H), 4.68 (t, J = 4.65 Hz, 1H), 4.53 (dd, J = H, 7.58. Found: C, 58.22; H, 7.75.
5.05 Hz, 7.4 Hz, 1H), 2.09 (s, 3H), 1.87 (s, 3H), 1.54 (s, 3H),
(+)-1,2-O-Isopropylidene-3,6-di-O-benzyl-myo-inositol (16a). To
1.31 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ: 169.40, 169.26, a solution of (+)-10 (800 mg, 3.076 mmol) in dry DMF was
164.96, 164.73, 133.85, 133.82, 129.21, 129.03, 128.85, 128.54, added NaH (184 mg, 7.69 mmol) and BnBr (1.3 g, 7.69 mmol)
128.50, 110.14, 75.61, 73.50, 72.24, 70.37, 69.62, 69.38, 27.43, at 0 °C. The reaction mixture was stirred at the same temp-
25.82, 20.46, 20.10. Anal. Calcd for C27H28O10: C, 63.28; H, erature for 2 h. The reaction mixture was diluted with ethylace-
5.51. Found: C, 63.51; H, 5.75.
tate, washed with water and brine. The organic layer was dried
( )-1,2-O-Isopropylidene-3,6-di-O-para-methoxybenzyl-4,5-di- over Na2SO4 and concentrated to get the corresponding diben-
O-acetyl-myo-inositol (24b). Yield: (435 mg, 80%) gum. IR zyl ether (+)-10a (1.285 g, 95%) as a syrupy liquid. A solution of
1
(KBr) 3050, 2980, 2854, 1745, 1490, 1383, 1265 cm−1. H NMR (+)-10a (800 mg, 1.818 mmol) in methanol (20 mL) was stirred
(500 MHz, DMSO-d6) δ: 7.15–7.09 (m, 4H), 6.85–6.82 (m, 4H), with H2SO4-silica (25 mg) at room temperature for 2 h. The
5.07 (t, J = 9.5 Hz, 1H), 4.87 (t, J = 9.5 Hz, 1H), 4.50 (ABq, J = mixture was quenched by adding solid sodium bicarbonate, fil-
12 Hz, 52.5 Hz, 2H), 4.44 (ABq, J = 11.5 Hz, 46.5 Hz, 2H), tered through a filter paper, concentrated and purified by
4.43–4.42 (m, 1H), 4.15 (m, 1H), 3.85 (dd, J = 4 Hz, 10 Hz, 1H), column chromatography to yield known (+)-16a25 (610 mg,
3.673 (s, 3H), 3.67 (s, 3H), 3.52 (dd, J = 7 Hz, 9.5 Hz, 1H), 1.89 84%) as a white solid.
(s, 3H), 1.88 (s, 3H), 1.38 (s, 3H), 1.24 (s, 3H). 13C NMR
(+)-1,2-O-Isopropylidene-3,6-di-O-benzyl-4,5-bis-O-(di-O-benzyl-
(125 MHz, DMSO-d6) δ: 169.37, 169.24, 158.79, 158.76, 130.11, phospho)-myo-inositol (35). To a solution of (+)-16a (500 mg,
129.13, 129.05, 113.62, 113.58, 109.06, 79.06, 77.88, 73.89, 1.25 mmol) in dry DCM, tetrazole (193 mg, 2.75 mmol) and
73.20, 72.04, 71.53, 70.83, 70.65, 55.07, 55.04, 27.64, 26.33, bis(benzyloxy)(N,N-diisopropylamino)phosphine (948 mg,
25.69, 20.48, 20.47. Anal. Calcd for C29H36O10: C, 63.96; H, 2.75 mmol) were added. The resulting reaction mixture was
6.66. Found: C, 64.10; H, 6.81.
stirred at rt for 1 h and cooled to −78 °C, and then m-CPBA
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(429 mg, 2.75 mmol) was added and stirred for another hour.
The mixture was warmed to room temperature and then
diluted with EtOAc. The solution was washed with a Na2SO3
solution, saturated NaHCO3, and brine. The organic layer was
dried over MgSO4, and concentrated to give an oily residue.
This was further purified by column chromatography using
ethyl acetate–petroleum ether (2 : 3 v/v) to yield known
(+)-3521b (910 mg, 79%) as an oil. 1H NMR (500 MHz, CDCl3) δ:
7.38–7.19 (m, 30H), 5.09–4.97 (m, 8H), 4.92–4.88 (m, 1H),
4.76–4.68 (m, 5H), 4.37 (dd, J = 3.4, 6.8 Hz, 1H), 4.28 (t, J =
6 Hz, 1H), 4.08 (t, J = 6.1 Hz, 1H), 3.97 (dd, J = 3.3, 7.6 Hz, 1H),
1.50 (s, 3H), 1.33 (s, 3H).
(+)-3,6-Di-O-benzyl-4,5-bis-O-(di-O-benzylphospho)-myo-inositol
(36). To a solution of ketal (+)-35 (800 mg, 0.869 mmol) in
methanol (10 mL), 1 N aq. HCl (1 mL) was added and the
mixture was stirred at room temperature for 1 h. The solvents
were evaporated and the residue was chromatographed using
ethylacetate–petroleum ether (4 : 1 v/v) as an eluent to get the
known diol (+)-3626 (725 mg, 95%) as a white solid. MP:
91–93 °C, 1H NMR (500 MHz, CDCl3) δ: 7.25–7.02 (m, 30H),
5.00–4.96 (m, 2H), 4.89–4.73 (m, 8H), 4.60 (t, J = 11 Hz, 2H),
4.46–4.41 (m, 2H), 3.98 (br, 1H), 3.80 (t, J = 9 Hz, 1H), 3.47
(d, J = 7.3 Hz, 1H), 3.41 (d, J = 8.5 Hz, 1H).
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myo-Inositol-1,4,5-trisphosphate (+)-5. To
a solution of
(+)-36 (125 mg, 0.142 mmol) in pyridine (3 mL) at 0 °C, POCl3
(20 μL, 0.1562 mmol) was added and the reaction mixture was
stirred at the same temperature. The consumption of starting
material was confirmed by TLC analysis after 30 min. Pyridine
was evaporated, the residue was diluted with ethylacetate,
washed with dil. HCl and the organic layer was dried over
sodium sulphate and concentrated. To the crude product
(120 mg) thus obtained, Pd(OH)2/C (150 mg), cyclohexene
(4 mL), H2O (0.75 mL) and MeOH (10 mL) were added and
heated at 80 °C for 8 hours. The reaction mixture was filtered
through a filter paper, and the crude debenzylated product
was purified by ion exchange chromatography in Bio-Rad
FPLC using triethylammonium bicarbonate as the eluent
buffer (gradient elution) to get pure phosphate (+)-528
(35.8 mg, 60% for two steps). [α]2D5 = −25°(C = 0.11, H2O, pH
8.5), 1H NMR (500 MHz, D2O) δ: 4.16–4.13 (m, 2H), 3.88 (br,
2H), 3.78 (d, J = 8.4 Hz, 1H), 3.58 (d, J = 9.2 Hz, 1H). 31P NMR
(200 MHz, D2O, a drop of TEA) δ: 4.57, 4.46, 2.68.
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