Regioselective opening of myo-inositol orthoesters: Mechanism and synthetic utility

Article abstract of DOI:10.1021/jo3027774

Acid hydrolysis of myo-inositol 1,3,5-orthoesters, apart from orthoformates, exclusively affords the corresponding 2-O-acyl myo-inositol products via a 1,2-bridged five-membered ring dioxolanylium ion intermediate observed by NMR spectroscopy. These C-2-substituted inositol derivatives provide valuable precursors for rapid and highly efficient routes to 2-O-acyl inositol 1,3,4,5,6-pentakisphosphates and myo-inositol 1,3,4,5,6-pentakisphosphate with biologically interesting and anticancer properties. Deuterium incorporation into the α-methylene group of such alkyl ester products (2-O-C(O)CD ₂R), when the analogous alkyl orthoester is treated with deuterated acid, is established utilizing the novel orthoester myo-inositol 1,3,5-orthobutyrate as an example. Such deuterated ester products provide intermediates for deuterium-labeled synthetic analogues. Investigation into this selective formation of 2-O-ester products and the deuterium incorporation is presented with proposed mechanisms from NMR experiments.

Full text of DOI:10.1021/jo3027774

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Regioselective Opening of myo-Inositol Orthoesters: Mechanism and
Synthetic Utility
Himali Y. Godage,† Andrew M. Riley,† Timothy J. Woodman,† Mark P. Thomas,† Mary F. Mahon,‡
and Barry V. L. Potter*,†
‡
†Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, X-ray Crystallographic Suite,
Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.
S
* Supporting Information
ABSTRACT: Acid hydrolysis of myo-inositol 1,3,5-orthoesters, apart
from orthoformates, exclusively affords the corresponding 2-O-acyl myo-
inositol products via a 1,2-bridged five-membered ring dioxolanylium ion
intermediate observed by NMR spectroscopy. These C-2-substituted
inositol derivatives provide valuable precursors for rapid and highly
efficient routes to 2-O-acyl inositol 1,3,4,5,6-pentakisphosphates and myo-
inositol 1,3,4,5,6-pentakisphosphate with biologically interesting and
anticancer properties. Deuterium incorporation into the α-methylene
group of such alkyl ester products (2-O-C(O)CD2R), when the
analogous alkyl orthoester is treated with deuterated acid, is established
utilizing the novel orthoester myo-inositol 1,3,5-orthobutyrate as an
example. Such deuterated ester products provide intermediates for
deuterium-labeled synthetic analogues. Investigation into this selective
formation of 2-O-ester products and the deuterium incorporation is
presented with proposed mechanisms from NMR experiments.
acyl ester at various positions on the inositol ring.18,19 myo-
Inositol orthoformate (1) has been extensively investigated
INTRODUCTION
■
Inositol phosphates are important intracellular messengers that
over the years.11−17 Acid hydrolysis partially or completely
play a vital role in many cellular functions including cell growth,
removes the orthoformate ester, since any intermediate formate
migration, differentiation, apoptosis, and endocytosis.1,2 To
ester produced is easily further cleaved under acidic conditions.
facilitate biochemical investigations, it is vital that efficient
myo-Inositol orthoacetate (2), which we18 and others19,20 have
routes to these naturally occurring inositol phosphates are
also explored, has the advantage that acid hydrolysis leaves an
established.3−7 As the demand for key synthetic intermediates
acetate ester on one of the oxygen atoms of the inositol ring,
increases, so does the need for differentially protected entities
and this can be retained as a protecting group for further
having free hydroxyl groups at specific positions. myo-Inositol
manipulation. However, such acetate esters are prone to
1,3,5-orthoesters have been extensively utilized as synthetic
migration under acid conditions, and therefore, we have
precursors for such inositol derivatives,8−21 since the O-1, O-3,
recently investigated derivatives of myo-inositol orthobenzoate
and O-5 atoms can be protected in a single step leaving O-2, O-
(3) as synthetic precursors.21,22 Acid hydrolysis of the
4, and O-6 for further manipulation (Scheme 1). Also, varied
orthobenzoate 3 gives a much more stable benzoate ester,
patterns of hydroxyl group protection can be obtained by the
which can be directed to different positions on the ring, e.g., C-
cleavage of orthoesters with reducing agents,11−15 and in the
1 and C-3 by choosing suitable conditions and protection of
case of the alkyl orthoesters, acid hydrolysis can introduce an
other OH groups21 and in concert with chiral desymmetrization
can lead to optically active targets.
In contrast, apart from orthoformate 1, acid hydrolysis of C-2
Scheme 1
unprotected myo-inositol orthoesters 2, 3, and 4 unexpectedly
affords the 2-O-acyl myo-inositol derivatives 5, 6, and 7,
respectively (Scheme 2). In a preliminary communication,22 we
reported the surprising regioselective conversion of orthoben-
zoate 3 to the 2-O-benzoyl derivative 6 and demonstrated that
this proceeds via the intermediacy of a 1,2-bridged 2′-phenyl-
Received: December 27, 2012
Published: February 25, 2013
© 2013 American Chemical Society
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Scheme 2
1′,3′-dioxolan-2′-ylium ion. We now report full details and
extension of this work including mechanistic NMR and labeling
experiments and show that the resulting protected inositol can
be used to provide a highly efficient route to two emerging
anticancer agents.23−25
When acidic hydrolysis of orthoacetate 2 was carried out in
other solvents such as ethanol, methanol, or acetonitrile, or
with use of mineral acids such as HCl, the observed selectivity
for 5 was reduced and longer reaction times were also needed.
Furthermore, under the selective reaction conditions using 10:1
TFA/water (50%) but in the presence of another solvent such
as methanol (50%), small amounts of 1/3-O-acetate were also
obtained.
In order to further investigate this high regioselectivity and
also to further understand the observed deuterium incorpo-
ration, both the C-2 hydroxyl-free and protected orthoacetates
4,6-di-O-benzyl orthoacetate (12) and 2,4,6-tri-O-benzyl
orthoacetate (13) were synthesized (Scheme 3).
RESULTS AND DISCUSSION
■
Regioselective Synthesis of myo-Inositol 2-O-Acetate
and Mechanistic Investigations. Orthoacetate 2 was
prepared by treating myo-inositol with triethyl orthoacetate
and PTSA in DMF under reflux as previously reported.18
Treatment of 2 with aqueous TFA (10:1) gives 2-O-acetate 5
with complete selectivity in quantitative yield. This reaction is
extremely fast and clean with no starting material observed by
TLC even after 5 min of commencing the reaction.
Scheme 3. Orthoacetates in Deuterated TFA
Our finding that acid hydrolysis of 2 leads to the selective
formation of ester 5 was unexpected. Previous studies21 on the
hydrolysis of myo-inositol orthoesters have shown that the ester
group is directed to the C-1 or C-3 position, although in these
studies, the 2-OH group was protected. Interestingly, it was
previously reported that acid hydrolysis of ( )-4-deoxy-myo-
inositol 1,3,5-orthopentanoate gave the 2-O-pentanoate,
although the authors attributed this to acyl migration.26 We
reasoned, however, that acyl migration could not explain the
high regioselectivity in the formation of 5 from 2 and a series of
NMR experiments was therefore undertaken in an attempt to
observe intermediates in this hydrolysis reaction.
Metal alkoxide chelation-controlled regioselective protection
of C-4 and C-6 hydroxyl groups was achieved in excellent yield
when orthoacetate triol 2 was treated with lithium hydride and
benzyl bromide in dry DMF. A higher yield was obtained when
lithium hydride was used in comparison to that using n-
butyllithium.27 Observation of 12 in deuterated TFA and
CDCl3 by NMR spectroscopy (1H, 2H, and 13C) again showed
the disappearance of the signal corresponding to the methyl
group of the orthoacetate at 1.56 ppm (1H NMR) and an
increase in the height of the deuterated methyl peaks over time
by 2H NMR spectra, once more confirming that the protons of
the methyl group were exchanging with solvent deuterium.
Although the major peaks seen were of the starting material
which was being deuterated, there was a very small amount of
hydrolyzed product, myo-inositol 4,6-di-O-benzyl 2-O-acetate,
as well as a minute amount of some other broad peaks, perhaps
corresponding to an intermediate species. This other species
showed downfield broad signals at 5.91 and 5.72 ppm
corresponding to one proton each and a multiplet around
4.21−4.27 ppm corresponding to four protons, along with a
broad singlet at 2.67 ppm corresponding to three protons,
perhaps representing a methyl group. However, since this
A 1H NMR spectrum taken immediately after treatment of 2
with deuterated TFA and CDCl3 showed only the starting
material and some 2-O-acetate product 5, the latter presumably
arising from adventitious water. A small amount of CDCl3 was
used due to difficulty in attaining a lock signal in neat
CF3CO2D. Although we were unable to observe any
intermediates at this initial stage, a small change in the methyl
peak of 5 was seen. Over time, the disappearance of the methyl
singlet at 1.52 ppm and the appearance of new peaks next to it
and their disappearance was observed by 1H NMR (Supporting
Information, Figure 1), leading us to believe that the methyl
group was being deuterated giving a mixture of −CH3, −CH2D,
and −CHD2 peaks. The reaction was therefore repeated, and
further 2H and 13C NMR spectra were taken at different times.
Deuterium NMR spectra showed an increase in the deuterated
methyl peaks (−CH2D, −CHD2, and −CD3) at 1.52 ppm over
1
time, complementary to the H NMR decrease in the methyl
singlet (−CH3) proving that methyl group protons were
exchanging (Supporting Information, Figure 2). This was
further proven by 13C NMR spectra taken on a different time
scale. Splitting patterns were seen progressively in the 13C
NMR spectrum with initially a singlet (−CH3) at δ 23 ppm, a
mixture of the singlet and a triplet (indicating −CH2D), a
mixture along with a quintet showing some −CHD2, and a
septet showing −CD3.
1
species was observed only in trace amounts by H NMR and
not by 13C NMR, identification of this potential intermediate
was impossible.
Tribenzyl orthoacetate 13, synthesized by conventional
benzylation of 2,28 was treated with deuterated TFA, and
after 15 min, only starting material was seen by NMR
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spectroscopy, and no intermediates or changes to the methyl
singlet were observed. Additionally, H NMR spectra taken up
to 5 days showed no peaks due to deuterium incorporation into
the methyl group of starting material 13.
Role of a 1,2-bridged Dioxolanylium Ion Intermediate
in Orthoester Opening. After establishing that 2-O-benzoate
6 is not a migratory product of acid hydrolysis of orthobenzoate
3, further NMR experiments were undertaken in an attempt to
observe the intermediates involved in the hydrolysis reaction.
To our surprise, the 1H NMR spectrum taken immediately after
the treatment of 3 with deuterated TFA showed a new species
along with product 6, the latter presumably arising from
adventitious water. (See Figure 3 in the Supporting Information
for a full spectrum. Expansions are shown in Figure 1.)
No residual starting material was observed, indicating
complete conversion to this novel intermediate, later identified
as the 1,2-bridged 2′-phenyl-1′,3′-dioxolan-2′-ylium ion (diox-
olenium ion) ( )-15 (Scheme 5) possessing characteristic
downfield signals at 6.12 and 6.29 ppm, corresponding to H-1
and H-2 of the inositol ring protons. H-1 and H-2 are strongly
deshielded relative to the other inositol ring protons, and the
coupling constant between them is unusually large (J1−2 9.0 Hz,
while J1−2 1.9 Hz for orthobenzoate 3) owing to the
incorporation of C-1 and C-2 into the five-membered
dioxolanylium ring. The signals corresponding to the phenyl
ring protons of the dioxolanylium ion are clearly distinguishable
from those in the starting material or product, being more
deshielded [δH 8.40−8.37 (2H/Ar-ortho), 8.19−8.15 (1H/Ar-
para) and 7.82−7.78 (2H/Ar-meta)] compared to those in 3
[δH 7.68−7.66 (2H) and 7.40−7.38 (3H)] and product 6 [δH
8.03−8.01 (2H/Ar-ortho), 7.74−7.70 (1H/Ar-para) and 7.54−
7.50 (2H/Ar-meta)]. In addition, fully in line with the values
reported for similar dioxolanylium ions and α,α-dialkoxybenzyl
cations,30−32 the 13C NMR spectrum of ( )-15 also showed a
signal attributable to C-2′ of the dioxolanylium ion at 183.3
ppm (Supporting Information, Figure 4).
2
Regioselective Synthesis of myo-Inositol 2-O-Ben-
zoate (6). Orthobenzoate 3 was synthesized by trans-
esterification of myo-inositol using DMSO as the solvent.21,22
Distilling off the formed methanol (for example, by carrying out
the reaction in a rotary evaporator) shortened the reaction
time. Initial attempts to carry out the reaction in DMF at the
usual temperatures for orthoformate 1 and orthoacetate 2
synthesis (100 °C) gave very low yields, and higher
temperatures (>140 °C) were required.21,22,29 When DMF
was used a large excess of both the acid catalyst (p-
toluenesulfonic acid) and trimethyl orthobenzoate was needed,
perhaps due to thermal decomposition. Use of DMSO as the
reaction solvent also gives a much cleaner reaction, making the
purification easier.
Acid hydrolysis of 3 with aqueous TFA gave 2-O-benzoate 6,
once more with complete selectivity and in quantitative yield.
Again, this reaction was extremely fast. However, when alcohols
such as ethanol or methanol were used as the solvent, along
with longer reaction times, selectivity was reduced and 1- or 3-
O-benzoyl-myo-inositol ( 14) was also obtained as a minor
product (Scheme 4).
Scheme 4. Acid Hydrolysis of 3 under Various Conditions
It is likely that the dioxolanylium ion intermediate ( )-15
formed from myo-inositol orthobenzoate (3) is more stable
than the corresponding intermediate for opening of myo-
inositol orthoacetate (2). This would account for our finding
1
that ( )-15 can readily be observed by H and 13C NMR.
Therefore, we went on to synthesize the 4,6-di-O-methyl (16)
and 4,6-di-O-benzyl (19) derivatives of 3, keeping the C-2
hydroxyl group free to allow formation of 1,2-bridged
intermediate for further studies.
Thus, protection of the C-2 hydroxyl group of 3 as its
TBDMS ether followed by C-4 and C-6 methylation afforded
the compound 23 in good yield (Scheme 6). Finally, removal of
the TBDMS group gave the required 4,6-di-O-Me orthoben-
zoate 16.
Investigation into the Possibility of Acyl Migration.
While we believed that acyl migration could not be a result of
the high regioselectivity in the formation of 2-O-ester products,
further studies were undertaken to establish that 5 and 6 are
not products of acyl migration of their 1- or 3-O-acyl myo-
inositol regioisomers. We therefore tested the migratory
abilities of the benzoyl group in both 6 and ( )-14 under a
variety of reaction conditions.
Treatment of 16 with deuterated TFA showed a similar
1
dioxolanylium ion intermediate by H NMR for a second time
with immediate consumption of starting material to give the
1,2-bridged dioxolanylium ion 17 (Scheme 5) comprising
downfield signals at 5.92 and 6.16 ppm, representing strongly
deshielded inositol ring protons H-1 and H-2 with a large J1−2
value of 8.9 Hz (Supporting Information, Figure 5). 13C NMR
spectra further confirmed the structure of the intermediate ion
( )-17 with a signal at 182.9 ppm corresponding to the
carbocation (Supporting Information, Figure 6). A trace
amount of 4,6-di-O-methyl 2-O-benzoate product 18 was also
observed along with the dioxolanylium ion 17.
Chelation-controlled regioselective protection of C-4 and C-
6 hydroxyl groups of 3 was achieved using benzyl bromide to
afford 4,6-di-O-benzyl orthobenzoate 19 in high yield. When 19
was treated with deuterated TFA, along with hydrolyzed
product di-O-benzyl 2-O-benzoate 21, a 1,2-bridged dioxola-
Both the ( )-14 and 6 regioisomers were tested individually
for the migratory ability of their benzoyl group under the same
reaction conditions used for the acid hydrolysis of orthoesters 2
and 3 (i.e., TFA/H2O 10:1). However, no products due to
migration were obtained even after extended reaction times,
proving that 6 is not a migratory product from ( )-14. Partial
migration was observed only at elevated temperatures and with
much longer reaction times. For example, when ( )-14 was
treated in 1 M HCl and ethanol at 80 °C for 10 h, a 6.5:1
mixture of ( )-14 and 6 was obtained, while treatment of 6
under the same reaction conditions gave a 4:1 mixture of 6 and
( )-14, respectively. Therefore, since more of the ester 6 is
converted to ( )-14, the equatorial benzoyl ester ( )-14 may
be the thermodynamically more stable product while the axial
regioisomer 6 is the kinetic product.
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Figure 1. Proton NMR of the 1,2-bridged intermediate ( )-15 (labeled as I) and product 6 (labeled as P): (A) expansion of 3.90−6.45 ppm; (B)
expansion of 7.40−8.50 ppm.
Scheme 5. Acid Hydrolysis of Orthobenzoate Derivatives Proceeds Regioselectively via a 1,2-Bridged Intermediate
Scheme 6. Synthesis of myo-Inositol 4,6-Di-O-methyl 1,3,5-Orthobenzoate 16
nylium ion intermediate 20 was also observed. Dioxolanylium
ion 20 exhibited spectroscopic data analogous to 15 and 17
a 1,3-bridged dioxanylium (dioxenium) ion intermediate, when
the 2-hydroxyl group in the starting material is free for instant
rearrangement. Once the 2-hydroxyl group is protected, and
there is therefore no possibility of rearrangement, only 1- or 3-
O-subsituted product is obtained,21 providing further evidence
of the involvement of a 1,3-bridged dioxanylium intermediate in
the initial stages of the acid hydrolysis. Therefore, 2,4,6-tri-O-
methylated, 2,4,6-tri-O-benzylated, and 2,6-di-O-benzylated
orthobenzoates were synthesized to facilitate NMR experi-
ments, with the anticipation that the initial opening of the
orthobenzoate cage might be observed due to the absence of a
2-hydroxyl, thus preventing the formation of any 1,2-bridged
intermediates or even a potential transient 1,2,3-cage structure.
1
with H NMR signals at 6.02 and 6.25 ppm and 13C NMR
signal at 182.3 ppm. The aromatic protons of the dioxolanylium
ion were also clearly noticeable since they were more
deshielded in comparison to those in the starting material or
product. Vicinal proton proton coupling constants (3JH,H) are
compatible with slightly twisted boat conformation (see the SI
for a computational molecular dynamics study of dioxolanylium
ion 20).
Although it was not possible to observe the initial acid-
catalyzed opening of the orthobenzoate cage owing to the
rapidity of the reaction, it is most likely that the more stable
1,2-bridged dioxolanylium ion is produced by rearrangement of
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Scheme 7. Reversible Opening of C-2 Hydroxyl-Protected Orthobenzoates
Conventional methylation of 3 afforded the 2,4,6-tri-O-
methyl orthobenzoate 24. However, when 24 was treated with
deuterated TFA, signals in the 1H NMR spectrum were
broadened suggesting a rapid equilibration. Inositol ring signals
[δH 5.47 (2H), 4.55−4.52 (2H), 4.37−4.36 (2H)] were more
deshielded in comparison to those in the starting material [δH
4.58−4.56 (3H), 4.28−4.26 (2H), 3.67 (1H)] in just CDCl3
(Supporting Information, Figure 7). The signals corresponding
to the phenyl ring protons [δH 8.09 (2H/Ar-ortho), 7.87 (1H/
Ar-para) and 7.63−7.59 (2H/Ar-meta)] were also more
deshielded, with broadened peaks for ortho and para protons
from those in the starting material 24 [δH 7.65−7.63 (2H) and
7.34−7.31 (3H)]. Broadening of the signals in the 13C NMR
spectrum was also significant, along with the disappearance of
some signals corresponding to inositol ring carbons and
aromatic ortho and para carbons as well as the orthoester
carbon (O3CPh), again consistent with a dynamic equilibrium
(Supporting Information, Figure 8).
principal, the orthobenzoate cage could also be opened to give
dioxanylium ions bridged between O-5 and O-1/3 of the
inositol ring in the initial stage of acid hydrolysis, only 1/3-O-
benzoate ester products were obtained from acid hydrolysis of
all 2,6-di and 2,4,6-tri-O-benzylated and 2,4,6-tri-O-methylated
orthobenzoates 26, 25, and 24, respectively. However, on one
occasion acid hydrolysis of 25 in TFA and DCM, gave a minor
product 31 in 8% yield where a trifluoro acetyl group was
substituted at the C-5 position along with the 1- or 3-O-benzoyl
major product 30 (Scheme 8). This unexpected acylation at the
Scheme 8. Acid Hydrolysis of 2,4,6-Tri-O-benzyl
Orthobenzoate 25 in TFA/DCM; 1:1
2,4,6-Tri-O-benzyl 1,3,5-orthobenzoate 25 was also obtained
from 3, and treatment of 25 with deuterated TFA again showed
broad signals in the 1H NMR spectrum with deshielded inositol
and aromatic protons, especially H-1 and H-3 at 5.26 ppm
instead of 4.52 ppm and ortho and para protons of
orthobenzoate at 8.15 ppm and 8.00 ppm respectively instead
of 7.23−7.69 ppm in the starting material 25, indicative of a
rapid equilibration (Supporting Information, Figure 9).
Significant broadening and disappearance/reduction of some
signals corresponding to inositol ring carbons and the aromatic
region of the orthobenzoate were also clearly distinguishable in
the 13C NMR spectrum from those in 25, again demonstrating
a dynamic equilibrium (Supporting Information, Figure 10).
Treatment of 2621 with deuterated TFA yet again showed
broad signals in the 1H NMR spectrum, with deshielded
inositol and aromatic protons along with broadened or lost
signals in the 13C NMR spectrum, once more suggesting a rapid
equilibration. This may be due to reversible opening of the
orthobenzoate cage33 giving a rapidly interconverting mixture
of starting material (24, 25, and 26) and the respective 1,3-
dioxan-2-ylium ion (27, 28, and 29) (Scheme 7). Nonetheless,
addition of water to this equilibrium mixture did not give rise to
the expected hydrolysis product, but instead resulted in ring
closure to reform the starting material. This presumably results
from destabilization of the dioxanylium intermediate due to
dilution of the acid concentration, and demonstrates that
hydrolysis is the rate limiting step of this reaction. Since the
departing hydroxyl group remains in close proximity to the
cationic center after ring-opening, the intramolecular ring
closure will be much faster for a such 1,3-bridged dioxanylium
ion intermediate than addition of water.34,35 Although in
C-5 position and not on the C-1 or C-3 positions also implies
that the orthobenzoate cage may only be opened to give a
bridge between O-1 and O-3, leaving the 5-hydroxyl group free
for esterification by solvent. It could be that O-5 may perhaps
be more easily protonated since O-1 and O-3 are more
hindered due to the equatorial C-2 substituent.
This may, in addition, be due to the fact that symmetrical
1,3-bridged 2′-phenyl-1′,3′-dioxan-2′-ylium ions 27, 28, and 29
are thermodynamically more stable, since conformationally all
four hydroxyl groups of the twisted boat could attain a less-
hindered equatorial orientation in comparison to an alternative
1,5- or 3,5-bridged dioxanylium ion intermediate that would
possess two equatorial and two axial hydroxyl groups.
Therefore, from the above observations we can postulate that
the mechanism of acid hydrolysis of orthobenzoate 3 takes
place via initial reversible ring-opening giving the 1,3-bridged
2′-phenyl-1′,3′-dioxan-2′-ylium ion 32 (indirectly observed as
1
broad signals in the H and 13C NMR spectra of compounds
with the 2-OH protected). This symmetrical, six-membered
intermediate then rearranges immediately to the more stable
1,2-bridged 2′-phenyl-1′,3′-dioxolan-2′-ylium ion ( )-15,
which is then followed by the rate-determining attack by
water, presumably from the less hindered face, to provide the
hemiorthoester ( )-33 (Scheme 9). Subsequent decomposi-
tion of ( )-33, under stereoelectronic control,36−38 affords the
product with an axial benzoate ester and equatorial hydroxyl
groups (6). However, for substrates in which the 2-hydroxyl
group is protected, rearrangement to the presumed five
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Scheme 9. Proposed Mechanism for the Acid Hydrolysis of Orthobenzoate 3
membered dioxolanylium intermediate is not possible and thus
slow hydrolysis gives product ( )-35 with the benzoate ester at
O-1 or O-3, via a 1,3-bridged hemiorthoester intermediate 34.
Acid Hydrolysis of myo-Inositol 1,3,5-Orthoformate
(1). Orthoformate 1 was also explored under the selective
conditions used in opening orthoesters 2 and 3 onto the C-2
position. Orthoformate 1 was prepared using literature
procedures.39 It should be noted that in the 1H NMR spectrum
of the orthoformate, the signal that corresponds to the
methylidyne proton is a small doublet of 1.1 Hz due to a 5
bond long-range spin coupling with C-2-H.
evaluated by NMR after evaporation to establish product ratios.
The 1H NMR spectrum showed the presence of inositol
(arising due to hydrolysis of the formate ester group under the
acidic conditions), 2-O-formate product and 1/3-O-formate
product in a ratio of 1:1.7:1.2.
Regioselective Synthesis of myo-Inositol 2-O-Buta-
noate 9 and Mechanistic Investigations. Having studied
orthoacetate 2, orthobenzoate 3, and orthoformate 1 opening
under acid hydrolysis and seeing their similarities and
differences, we synthesized another orthoester, this time with
a longer alkyl chain to investigate further deuterium
incorporation and intermediate cation formation. The novel
orthoester, myo-inositol orthobutanoate (4), was prepared in
high yield using analogous conditions for the synthesis of
orthoacetate 1 by treatment of myo-inositol with trimethyl
orthobutyrate and a catalytic amount of PTSA in DMF at 140
°C (this time due to shorter reaction time than for
orthobenzoate synthesis under the same reaction conditions).
4 Was then treated with aqueous TFA to obtain myo-inositol
2-O-butanoate (7) in quantitative yield. Recrystallization of 7 in
water and methanol afforded long thin crystals for which an X-
ray crystal structure was obtained (Figures 2 and 3).
Therefore, from the above results, we can conclude that any
1,3,5-orthoester apart from orthoformate 1 should selectively
open to give the axial 2-O-ester product under the above acidic
hydrolysis conditions as already established for orthoacetate 2
and orthobenzoate 3. This ties in well with the rationalization
offered by King and Allbutt36 based on the differences in steric
strain among the possible transition states that fulfill the
stereoelectronic requirements of dialkoxycarbonium ion for-
mation.
1
An H NMR spectrum taken immediately after treatment of
1 with deuterated TFA and CDCl3 showed only the starting
material and no intermediate species or hydrolyzed products.
When the same NMR sample was analyzed after being at room
temperature for 15 h mainly the starting material was seen,
along with very small amounts of products. Also, no deuterated
starting material or products were seen even after 3 days.
However, when the reactions were carried out in deuterated
TFA and CDCl3 with a drop of D2O, the spectrum taken 5 min
after the addition of D2O showed a 50:50 mixture of starting
material and products, though no other intermediates were
seen. Among the products, both the 2-O-formate and 1/3-O-
formate products were present at a ratio of 2.8:1, the 2-O-
formate product still being predominant. Analysis of the same
NMR sample after 30 min showed a starting material to
products ratio of 1: 9.3, with 2-O-formate product to 1/3-O-
formate product corresponding to a ratio of 2.5:1.
Acid hydrolysis of 1 was carried out using 10:1 mixture of
TFA:water at room temperature for 15 min until all starting
material had been consumed and the resulting mixture was
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92%) with trace amounts of 2-O-butanoate 7 and 2-O-
C(O)CHDCH2CH3 myo-inositol, perhaps arising due to
adventitious water. Therefore, any such alkyl orthoesters 36
could be treated in deuterated acid under anhydrous conditions
for the deuterium exchange to take place before hydrolysis to
yield 2-O-C(O)D2R ester products 44 with deuterated
methylene group at the α-position (Scheme 11). These
deuterium incorporated products could provide valuable
intermediates to many deuterium labeled synthetic analogues
that could be used to study biologically important metabolic
pathways or chemical reactions.
We have also proven that this deuterium incorporation only
takes place before the hydrolysis step and thus before the
formation of the hemiorthoester intermediate ( )-46 (Scheme
12). Therefore, once the products are formed deuterium
incorporation at the α-methylene position is not possible in
deuterated acid. To confirm this, 2-O-acetate and butanoate
products 5 and 7 were treated in both deuterated TFA and
CDCl3 and deuterated TFA and D2O for 9 days and monitored
by NMR spectroscopy for deuterium exchange. No deuterium
Figure 2. X-ray crystal structure of 7. Ellipsoids are represented at 30%
probability.
Mechanistic investigations of orthobutanoate 4 in deuterated
TFA again showed deuterium incorporation at the α-position.
However, unlike for orthobenzoate, only a minor species was
seen by 1H NMR, perhaps attributed to a 1,2-bridged 2′-butyl-
1′,3′-dioxolan-2′-ylium ion intermediate akin to ( )-15 which
could not be fully identified due to the small amount present.
Hence, having observed α-methylene protons exchange for
deuterium in orthobutanoate 4, orthoacetate 2 and 12 using
deuterated acid, we can postulate that the mechanism of
exchange proceeds via a ketene acetal 38 or ( )-40 or both
(Scheme 10). Although, having observed only a small amount
of deuterium exchanged product and no such exchange in the
starting material when tri-O-Bn orthoacetate 13 was treated
with deuterated acid, this suggests that when the C-2 hydroxyl
group is protected, the equilibrium may lie quite far on the side
of the 1,3-dioxan-2-ylium ion 37 due to the rapid
interconvertion between the starting material 13 and the ion
37. Thus, when the C-2 hydroxyl group is free, the equilibrium
being rapidly established may lie greatly toward the side of the
ketene acetal ( )-40 due to the immediate rearrangement of
1,3-dioxan-2-ylium ion 37 to the1,2-bridged ion ( )-39.
Treatment of 4 in deuterated TFA for 24 h followed by the
addition of water in the subsequent hydrolysis gave the 2-O-
C(O)CD2CH2CH3 myo-inositol as the major product (over
2
exchange was observed by H NMR spectroscopy over 9 days;
1
only decomposition and migration products were seen by H
NMR spectroscopy, further proving that deuterium incorpo-
ration only takes place via the ketene acetal ( )-40 and that no
exchange takes place once products are formed through a
mechanism similar to that occupy in migration of products
involving a hemiorthoester intermediate ( )-46.
Synthesis of 2-O-Benzoyl myo-Inositol 1,3,4,5,6-
Pentakisphosphate 9 and myo-Inositol 1,3,4,5,6-
Pentakisphosphate 11. The efficient regioselective trans-
formation observed also facilitates exploitation in the synthesis
of inositol polyphosphates with 2-position substitutions that are
of biological interest23 as well as providing a proficient route to
the anticancer agent inositol pentakisphosphate 11.24,25 Thus,
2-O-benzoyl myo-inositol 6 was phosphitylated using N,N-
diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine in the
presence of 5-phenyltetrazole. The commonly used 1H-
tetrazole, which has potential explosive properties at room
temperature, has recently become difficult to obtain due to
shipping restrictions and we found that 5-phenyltetrazole is
equally effective as an activator in such phosphitylation
reactions. The intermediate pentakisphosphite was subse-
Figure 3. Crystal packing diagram for compound 7 showing the extensive H-bonding network.
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Scheme 10. Proposed Mechanism for the Deuterium Exchange
Scheme 11. Proposed Mechanism for the Formation of α-Methyl Deuterated Ester Products
Scheme 12. No Deuterium Incorporation after Formation of Product
Scheme 13. Synthesis of 2-O-Benzoyl myo-Inositol 1,3,4,5,6-Pentakisphosphate 9 and myo-Inositol 1,3,4,5,6-Pentakisphosphate
11
quently oxidized in situ by m-CPBA to afford the symmetrical
pentakisphosphate 47 in 96% yield (Scheme 13). 6 could also
be phosphorylated with the phosphitylating agent bis-
(benzyloxy)diisopropylaminophosphine in good yield (94%)
using 5-phenyltetrazole followed by oxidation. After purification
of the product, the phosphate protection was removed by
hydrogenolysis to afford pure 2-O-benzoyl pentakisphosphate
9. Finally, the cleavage of benzoate ester in concentrated
aqueous ammonia followed by simple removal of benzamide
byproduct after aqueous work up with dichloromethane
provided the Ins(1,3,4,5,6)P5 11 as the ammonium salt in
86% isolated overall yield from myo-inositol. Pentakisphosphate
11 could also be synthesized from 2-O-acetyl myo-inositol 5 or
2-O-butanoyl myo-inositol 7 in a similar method in high yield.
This sequence greatly benefits from involving only a single
chromatographic purification step thus, eliminating the need for
the usual ion-exchange chromatography and also allows easy
access to multigram scale quantities for in vivo studies. We
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and brine (100 mL), dried (MgSO4), and evaporated in vacuo. The
resulting compound was purified by column chromatography (pet.
ether/ethyl acetate, 3:1) to afford 12 (1.37 g, 89%) as a white solid:
mp 87.0−88.5 °C (ethyl acetate/hexane); 1H NMR (400 MHz,
CDCl3) δ 1.50 (3H, s, CH3), 3.41 (1H, d, J = 11.6 Hz, C-2-OH), 4.21
(1H, app br d, C-2-H), 4.30 (2H, m, J1,2 = J2,3 = J1,5 = J3,5 = 1.8 Hz, J1,6
= J3,4 = 3.6 Hz, C-1-H and C-3-H), 4.36 (2H, t, J4,5 = J5,6 = 3.6 Hz, C-4-
H and C-6-H), 4.43−4.45 (1H, m, C-5-H), 4.63 (4H, AB, JAB = 11.6
Hz, CH2Ph), 7.29−7.33 (10H, m, Ar-H); 13C NMR (100.6 MHz,
(CDCl3) δC 24.2 (q, CH3), 60.2 (d, C-2), 67.6 (d, C-5), 71.4 (t,
CH2Ph), 73.3 (d, C-1 and C-3), 73.4 (d, C-4 and C-6), 109.0 (s,
O3CCH3), 127.5, 128.2 (2 × d, Ar-Cortho and Ar-Cmeta), 127.6 (d, Ar-
Cpara), 137.4 (s, Ar-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H25O6 385.1651, found 385.1646. Anal. Calcd for C22H24O6
(384.42): C, 68.74; H, 6.29. Found: C, 68.7; H, 6.31.
2,4,6-Tri-O-benzyl myo-Inositol 1,3,5-Orthoacetate (13).
Compound 13 was prepared as reported earlier:28 mp 77.5−78.5
°C; 1H NMR (400 MHz, CF3CO2D and CDCl3) δ 1.54 (3H, s, CH3),
4.28 (1H, t, J1,2 = J2,3 = 1.6 Hz, C-2-H), 4.41 (2H, br s, Ins-H), 4.46−
4.47 (3H, m, Ins-H), 4.64 (4H, AB, JAB = 11.7 Hz, C-4 and C-6
CH2Ph), 4.76 (2H, s, C-2 CH2Ph), 7.29−7.32 (4H, m, Ar-H), 7.40−
7.46 (11H, m, Ar-H); 13C NMR (100.6 MHz, CF3CO2D and CDCl3)
δC 23.2 (q, CH3), 67.6, 69.6, 72.1, 73.5 (2 × d, 2 × t, C-2, C-5,
CH2Ph), 74.0, 74.4 (2 × d, C-1 and C-3, C-4 and C-6), 105.7 (s,
O3CCH3), 129.3, 129.6 (2 × d, C-4 and C-6 Ar-Cortho and Ar-Cmeta),
129.7, 129.7, 129.8, 130.1 (4 × d, Ar-C), 135.6 (s, C-2 Ar-Cipso), 136.9
(s, C-4 and C-6 Ar-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C29H31O6 475.2121, found 475.2115.
anticipate that this route can give efficient synthetic access to a
range of 2-substituted inositol phosphate derivatives of
potential biological interest and such work is in progress.23
CONCLUSIONS
■
In summary, we show that acid hydrolysis of C-2 unprotected
inositol-based orthoesters, apart from the orthoformate, can
lead to exclusive formation of 2-O-acyl myo-inositol products.
This interesting regioselectivity is rationalized through the
intermediacy of a 1,2-bridged 2′-substituted-1′,3′-dioxolan-2′-
ylium ion that is observed by NMR spectroscopy and preceded
by a 1,3-bridged dioxanylium ion intermediate. Deuterium
incorporation into the α-methylene group at inositol C-2 of an
alkyl ester (2-O-C(O)D2R) is possible when the corresponding
alkyl orthoester is treated in deuterated acid under anhydrous
conditions, with deuterium exchange taking place before
hydrolysis. Furthermore, using these observations, we describe
a most efficient route for gram-scale synthesis of Ins(1,3,4,5,6)-
P5 11 and 2-O-Benzoyl Ins(1,3,4,5,6)P5 9 via myo-inositol 1,3,5-
orthobenzoate 3.
EXPERIMENTAL SECTION
■
All reagents and solvents either were of commercial quality or were
synthesized and purified in the laboratory using standard procedures.
Some solvents were redistilled and dried where necessary using
standard procedures or purchased in anhydrous form. Petroleum ether
40−60 °C is abbreviated as pet. ether. 1H NMR and 13C NMR
chemical shifts were measured in ppm (δ) relative to internal
tetramethylsilane (TMS), and 31P NMR chemical shifts are measured
in ppm (δ) relative to phosphoric acid as an external standard. Signals
are expressed and abbreviated as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), br (broad), and app (apparent). All 1H NMR
and 13C NMR assignments are based on gCOSY, gHMQC, gHMBC,
and DEPT experiments. Coupling constants (J) are given in hertz.
TLC was performed on precoated plates (aluminum sheets, silica gel
60 F254) with detection by UV light or with phosphomolybdic acid in
ethanol followed by heating. Flash chromatography was performed on
silica gel (particle size 40−63 μm).
myo-Inositol 1,3,5-Orthobenzoate (3). Trimethyl orthoben-
zoate (10 mL, 55 mmol) was added to a suspension of oven-dried
myo-inositol (9.0 g, 50 mmol) and camphorsulfonic acid (232 mg, 1.00
mmol) in anhydrous DMSO (30 mL). The resulting mixture was then
heated at 60−80 °C under a pressure of 260−280 mbar for 3 h on a
rotary evaporator, after which time TLC (ethyl acetate) indicated the
complete consumption of starting material (Rf 0.0) and the formation
of a major product (Rf 0.4). The resulting clear solution was allowed to
cool, and the catalyst was neutralized by addition of triethylamine (1.0
mL). The reaction mixture was concentrated under reduced pressure,
redissolved in hot ethyl acetate (500 mL), filtered through a pad of
silica gel, and washed further with hot ethyl acetate (2 × 250 mL). The
resulting filtrate was concentrated under reduced pressure to about a
volume of approximately 100 mL, and the solution was left in the
refrigerator overnight. Concentration of the mother liquor and cooling
gave a further crops of crystals to give a total yield of 12.2g (92%) of
2-O-Acetyl myo-Inositol (5). A mixture of TFA (10 mL) and
water (1 mL) was added to 2 (1.5 g, 7.3 mmol) prepared as
described,18 and the solution was stirred for 5 min after which time
TLC (ethyl acetate) indicated the complete conversion of starting
material (Rf 0.5) to a product (Rf 0.0). The reaction mixture was then
coevaporated with water followed by DCM in vacuo to obtain 5 (1.63
1
colorless crystals of 3: mp 213-214 °C (ethyl acetate); H NMR (400
MHz, (CD3)2SO) δ 4.11 (1H, dt, J1,2 = J2,3 = 1.9 Hz and JH,OH = 6.3
Hz, C-2-H), 4.18−4.20 (2H, m, C-1-H and C-3-H), 4.23−4.25 (IH, m,
C-5-H), 4.42−4.45 (2H, m, C-4-H and C-6-H), 5.38 (1H, d, C-2-
OH), 5.57 (2H, d, JH,OH = 6.2 Hz, C-4-OH and C-6-OH), 7.34−7.41
(3H, m, Ar-H), 7.56−7.61 (2H, m, Ar-H); 13C NMR (100.6 MHz,
(CD3)2SO) δC 58.2 (d, C-2), 67.7 (d, C-4 and C-6), 70.6 (d, C-5),
76.3 (d, C-1 and C-3), 106.9 (s, O3C-Ar), 126.0 (d, Ar-C), 128.0 (d,
Ar-C), 129.5 (d, Ar-C), 138.3 (s, Ar-C); HRMS (ESI-TOF) m/z [M +
H]+ calcd for C13H15O6 267.0869, found 267.0863. Anal. Calcd for
C13H14O6 (266.25): C, 58.64; H, 5.30. Found: C, 58.80 H, 5.33.
2-O-Benzoyl myo-Inositol (6). A mixture of TFA (10 mL) and
water (1 mL) was added to 3 (1.5 g, 5.6 mmol), and the solution was
stirred for 3 min after which time TLC (ethyl acetate) indicated the
complete conversion of starting material (Rf 0.4) to a product (Rf 0.0).
The reaction mixture was then coevaporated with water in vacuo to
obtain 6 (1.6 g, quantitative) as a white solid: mp 240−242 °C
(ethanol/water); 1H NMR (400 MHz, D2O) δ 3.26−3.30 (1H, m, C-
5-H), 3.64−3.71 (4H, m, C-1-H, C-3-H, C-4-H and C-6-H), 5.57 (1H,
t, J1,2 = J2,3 = 2.7 Hz, C-2-H), 7.39−7.43 (2H, m, Ar-Hmeta), 7.54−7.58
(1H, m, Ar-Hpara), 7.92 (2H, m, Jortho,meta = 8.2 Hz, Jortho,para = 1.2 Hz,
Ar-Hortho); 13C NMR (100.6 MHz, D2O) δC 70.0, 73.0 (2 × d, C-1 and
C-3, C-4 and C-6), 74.4 (d, C-5), 75.2 (d, C-2), 128.9 (d, Ar-Cmeta),
128.9 (s, Ar-Cipso), 129.8 (d, Ar-Cortho), 134.2 (d, Ar-Cpara), 168.1 (s,
CO2Ph); HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H17O7
1
g, quantitative) as a white solid: H NMR (400 MHz, D2O) δ 2.12
(3H, s, CH3), 3.25 (1H, t, J4,5 = J5,6 = 9.2 Hz, C-5-H), 3.57 (2H, t, J1,6
= J3,4 = 10.2 Hz, C-4-H and C-6-H), 3.65 (2H, dd, J1,2 = J2,3 = 2.7 Hz,
C-1-H and C-3-H), 5.38 (1H, t, C-2-H); 13C NMR (100.6 MHz,
D2O) δC 20.4 (q, CH3), 69.6 (d, C-1 and C-3), 72.5 (d, C-4 and C-6),
74.1 (d, C-5), 74.3 (d, C-2), 173.8 (s, CO2CH3); HRMS (ESI-TOF)
m/z [M + H]+ calcd for C8H15O7 223.0818, found 223.0812; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C8H14O7Na 245.0637, found
245.0632; 1H NMR (400 MHz, CF3CO2D and CDCl3) δ 2.25 (3H, s,
CH3), 3.85 (1H, m, J = 7.4 Hz, C-5-H), 4.06−4.13 (4H, m, C-1-H and
C-3-H, C-4-H and C-6-H), 5.74 (1H, t, J1,2 = J2,3 = 2.4 Hz, C-2-H),
13C NMR (100.6 MHz, CF3CO2D and CDCl3) δC 20.2 (q, CH3),
70.4, 73.0 (2 × d, C-1 and C-3, C-4 and C-6), 73.8, 73.9 (2 × d, C-2
and C-5), 175.9 (s, CO2CH3).
4,6-Di-O-benzyl myo-Inositol 1,3,5-Orthoacetate (12). Lith-
ium hydride (133.9 mg of 95%, 16 mmol) was added portionwise to a
solution of 2 (816.7 mg, 4 mmol) in dry DMF (12 mL) under argon.
The resulting mixture was stirred for 10 min, and benzyl bromide
(1.05 mL, 8.8 mmol) in dry DMF (4 mL) was then added dropwise.
Stirring was continued for a further 16 h, after which time TLC (2:1,
pet. ether/ethyl acetate) showed the complete conversion of starting
material (Rf 0.05) to a product (Rf 0.46). The reaction mixture was
then diluted with ethyl acetate (80 mL), washed with water (100 mL)
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285.0974, found 285.0969. Anal. Calcd for C13H16O7 (284.26): C,
54.93; H, 5.67. Found: C, 54.90; H, 5.75.
C21H33O6Si 409.2046, found 409.2041. Anal. Calcd for C21H32O6Si
(408.20): C, 61.73; H, 7.89. Found: C, 61.80; H, 7.93.
4,6-Di-O-methyl myo-Inositol 1,3,5-Orthobenzoate (16).
TBAF (1.3 mL of a 1 M solution in THF, 1.3 mmol) was added
dropwise to a stirred solution of 23 (350 mg, 0.86 mmol) in dry THF
(2.5 mL) under argon. Stirring was continued for a further 15 h, after
which time TLC (2:1, pet. ether/ethyl acetate) showed the complete
conversion of starting material (Rf 0.70) to a product (Rf 0.16). The
reaction mixture was then diluted with ethyl acetate (50 mL), washed
with water (50 mL) and brine (50 mL), dried (MgSO4), and
evaporated in vacuo. The resulting compound was purified by column
chromatography (pet. ether/ethyl acetate, 1.5:1) to afford 16 (236 mg,
Data for 1,2-bridged 2′-phenyl-1′,3′-dioxolan-2′-ylium ion inter-
1
mediate ( )-15 observed by H and 13C NMR spectroscopy soon
after the addition of deuterated trifluoroacetic acid (0.5 mL) into a
NMR sample tube containing the dry myo-inositol 1,3,5-orthobenzoate
3 (50 mg, 0.19 mmol) and anhydrous deuterated chloroform (0.2
mL). A small amount of CDCl3 was used due to the difficulty in
attaining a lock signal in neat CF3CO2D: 1H NMR (400 MHz,
CF3CO2D and CDCl3) δ 4.18 (1H, dd, J4,5 = 5.9 Hz, J5,6 = 10.2 Hz, C-
5-H), 4.48 (1H, app t, J3,4 = 5.1 Hz, C-4-H), 4.76 (1H, dd, J2,3 = 3.5
Hz, C-3-H), 4.95 (1H, dd, J1,6 = 6.7 Hz, C-6-H), 6.12 (1H, dd, J1,2
=
1
94%) as a white solid: mp 121.0−122.5 °C (ethyl acetate); H NMR
9.0 Hz, C-1-H), 6.29 (1H, dd, C-2-H), 7.80 (2H, dd, Jmeta,para = 7.8 Hz,
Jortho,meta = 8.6 Hz, Ar-Hmeta), 8.17 (1H, t, Ar-Hpara), 8.38 (2H, dd,
Jortho,para = 1.2 Hz, Ar-Hortho); 13C NMR (100.6 MHz, CF3CO2D and
CDCl3) δC 69.6 (d, C-3), 71.5 (d, C-6), 73.9 (d, C-5), 74.9 (d, C-4),
87.1 (d, C-2), 90.2 (d, C-1), 115.9 (s, Ar-Cipso), 131.2 (d, Ar-Cmeta),
134.8 (d, Ar-Cortho), 143.5 (d, Ar-Cpara), 183.3 (s, C-2′).
(400 MHz, CDCl3) δ 3.13 (1H, JH,OH = 12.0 Hz, C-2-OH), 3.49 (6H,
s, 2 × OCH3), 4.06 (1H, dt, J1,2 = J2,3 = 1.9 Hz, C-2-H), 4.28 (2H, t,
J1,6 = J3,4 = J4,5 = J5,6 = 3.7 Hz, C-4-H and C-6-H), 4.45 (2H, quintet,
J1,5 = J3,5 = 1.9 Hz, C-1-H and C-3-H), 4.56 (1H, septet, C-5-H),
7.37−7.39 (3H, m, Ar-H), 7.63−7.65 (2H, m, Ar-H); 13C NMR
(100.6 MHz, CDCl3) δC 57.9 (q, 2 × OCH3), 60.5 (d, C-2), 68.4 (d,
C-5), 73.8 (d, C-1 and C-3), 75.9 (d, C-4 and C-6), 108.0 (s, O3CPh),
125.2, 128.1 (2 × d, Ar-Cortho and Cmeta), 129.7 (d, Ar-Cpara), 136.9 (s,
Ar-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H19O6
295.1182, found 295.1176. Anal. Calcd for C15H18O6 (294.30): C,
61.22; H, 6.16. Found: C, 61.20; H, 6.17.
1
2-O-Benzoyl myo-inositol (6) in CF3CO2D and CDCl3: H NMR
(400 MHz) δ 4.08 (1H, t, J4,5 = J5,6 = 9.8 Hz, C-5-H), 4.33 (2H, dd, J1,2
= J2,3 = 2.7 Hz, J1,6 = J3,4 = 10.2 Hz, C-1-H and C-3-H), 4.46 (2H, t, C-
4-H and C-6-H), 6.12 (1H, t, C-2-H), 7.52 (2H, dd, Jortho,meta = 8.2 Hz,
Jmeta,para = 7.8 Hz, Ar-Hmeta), 7.70−7.74 (1H, m, Ar-Hpara), 8.02 (2H,
dd, Jortho,para = 1.2 Hz, Ar-Hortho); 13C NMR (100.6 MHz) δC 71.0 (d,
C-1 and C-3), 73.4 (d, C-4 and C-6), 74.3 (d, C-2 and C-5), 127.4 (s,
Ar-Cipso), 129.5 (d, Ar-Cmeta), 130.3 (d, Ar-Cortho), 136.0 (d, Ar-Cpara),
170.0 (s, CO2Ph).
Data for 1,2-bridged 2′-phenyl-1′,3′-dioxolan-2′-ylium ion ( )-17
from 4,6-di-O-methyl orthobenzoate 16: 1H NMR (400 MHz,
CF3CO2D) δH 3.61 (3H, s, CH3), 3.78 (3H, s, CH3), 3.95 (1H, br
t, H-4), 4.15 (1H, dd, J4,5 = 3.6 Hz, J5,6 = 9.0 Hz, H-5), 4.53 (1H, dd,
J1,6 = 6.1 Hz, H-6), 4.76 (1H, br t, H-3), 5.92 (1H, dd, J1,2 = 8.9 Hz, H-
1), 6.16 (1H, dd, J2,3 = 2.7 Hz, H-2), 7.78 (2H, t, Ar-Hmeta), 8.14 (1H,
t, Ar-Hpara), 8.34 (2H, d, Ar-Hortho); 13C NMR (400 MHz, CF3CO2D)
δC 58.4, 59.7 (2 × q, 2 × CH3), 66.7 (d, C-3), 72.3 (d, C-5), 79.1 (d,
C-6), 84.0 (d, C-4), 87.0 (d, C-2), 89.6 (d, C-1), 115.6 (s, Ar-Cipso),
131.0 (d, Ar-Cmeta), 134.5 (d, Ar-Cortho) 143.3 (d, Ar-Cpara), 182.9 (s,
C-2′).
2-O-tert-Butyldimethylsilyl myo-Inositol 1,3,5-Orthoben-
zoate (22). TBDMSCl (317 mg, 2.1 mmol) was added portionwise
to a solution of 3 (532.5 mg, 2 mmol) in dry DMF (5 mL) and 2,6-
lutidine (0.5 mL, 5 mmol) under argon and stirred for 2 days. The
resulting mixture was evaporated in vacuo and purified by column
chromatography (pet. ether/ethyl acetate, 8:1) to afford 22 (555 mg,
1
73%) as a white solid: mp 148.5−149.5 °C (Et2O, hexane); H NMR
(400 MHz, CDCl3) δ 0.15 (6H, s, 2 × CH3), 0.96 (9H, s, 3 × CH3),
3.84 (2H, br s, C-4-OH and C-6-OH), 4.11−4.12 (1H, m, J = 1.6 and
3.7 Hz, C-5-H), 4.19−4.20 (2H, m, J = 1.6 and 2.9 Hz, C-1-H and C-
3-H), 4.23 (1H, t, J1,2 = J2,3 = 1.6 Hz, C-2-H), 4.45−4.47 (2H, m, J =
3.7 Hz, C-4-H and C-6-H), 7.36−7.39 (3H, m, Ar-H), 7.62−7.64 (2H,
m, Ar-H); 13C NMR (100.6 MHz, CDCl3) δC −4.6 (q, 2 × CH3), 18.3
(s, C(CH3)3), 25.8 (q, 3 × CH3), 59.6 (d, C-2), 68.1 (d, C-4 and C-6),
69.3 (d, C-5), 75.9 (d, C-1 and C-3), 106.9 (s, O3CPh), 125.3, 128.1
(2 × d, Ar-Cortho and Cmeta), 129.6 (d, Ar-Cpara), 136.9 (s, Ar-Cipso);
HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H29O6Si 381.1733,
found 381.1728. Anal. Calcd for C19H28O6Si (380.51): C, 59.97; H,
7.42. Found: C, 59.80; H, 7.50.
4,6-Di-O-benzyl myo-Inositol 1,3,5-Orthobenzoate (19).
Lithium hydride (133.9 mg of 95%, 16 mmol) was added portionwise
to a solution of 3 (1.07 g, 4 mmol) in dry DMF (12 mL) under argon.
The resulting mixture was stirred for 10 min, and benzyl bromide
(1.05 mL, 8.8 mmol) in dry DMF (4 mL) was then added dropwise.
Stirring was continued for a further 18 h, after which time TLC (2:1,
pet. ether/ethyl acetate) showed the complete conversion of starting
material (Rf 0.07) to a product (Rf 0.52). The reaction mixture was
then diluted with ethyl acetate (80 mL), washed with water (100 mL)
and brine (100 mL), dried (MgSO4), and evaporated in vacuo. The
resulting compound was purified by column chromatography (pet.
ether/ethyl acetate, 4:1) to afford 19 (1.57 g, 88%) as a white solid:
1
2-O-tert-Butyldimethylsilyl 4,6-Di-O-methyl myo-Inositol
1,3,5-Orthobenzoate (23). Sodium hydride (240 mg of a 60%
dispersion in oil, 6 mmol) was added portionwise to a solution of 22
(570.8 mg, 4 mmol) in dry THF (6 mL) at 0 °C. The resulting
mixture was stirred for 10 min, and methyl iodide (0.37 mL, 6 mmol)
was then added dropwise. Stirring was continued for a further 15 h,
after which time TLC (2:1, pet. ether/ethyl acetate) showed the
complete conversion of starting material (Rf 0.48) to a product (Rf
0.78). The reaction mixture was then diluted with ethyl acetate (50
mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4),
and evaporated in vacuo. The resulting compound was purified by
column chromatography (pet. ether/ethyl acetate, 8:1) to afford 23
(491 mg, 80%) as a white solid: mp 122.5−123.5 °C (ethyl acetate/
mp 84.5−85.5 °C (ethyl acetate/pet. ether); H NMR (400 MHz,
CDCl3) δ 3.06 (1H, d, J = 11.4 Hz, C-2-OH), 4.29 (1H, app br d, C-2-
H), 4.45 (2H, quintet, J1,2 = J2,3 = J1,5 = J3,5 = 1.8 Hz, J1,6 = J3,4 = 3.8 Hz,
C-1-H and C-3-H), 4.51 (2H, t, J4,5 = J5,6 = 3.8 Hz, C-4-H and C-6-H),
4.59 (1H, septet, C-5-H), 4.68 (4H, AB, JAB = 11.5 Hz, CH2Ph), 7.30−
7.31 (10H, m, Bn-Ar-H), 7.37−7.38 (3H, m, Bz-Ar-H), 7.63−7.65
(2H, m, Bz-Ar-H); 13C NMR (100.6 MHz, (CDCl3) δC 60.7 (d, C-2),
68.7 (d, C-5), 71.8 (t, 2 × CH2Ph), 73.7 (d, C-4 and C-6), 74.4 (d, C-
1 and C-3), 108.0 (s, O3CPh), 125.3, 127.9, 128.1 (3 × d, Bn-Ar-Cpara
,
Bz-Ar-Cortho and Bz-Ar-Cmeta), 127.7, 128.5 (2 × d, Bn-Ar-Cortho and
Bn-Ar-Cmeta), 129.7 (d, Bz-Ar-Cpara), 137.0 (s, Bz-Ar-Cipso), 137.6 (s,
Bn-Ar-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H27O6
447.1808, found 447.1802. Anal. Calcd for C27H26O6 (446.49): C,
72.63; H, 5.87. Found: C, 72.80; H, 5.93.
1
pet. ether); H NMR (400 MHz, CDCl3) δ 0.15 (6H, s, 2 × CH3),
0.95 (9H, s, 3 × CH3), 3.48 (6H, s, 2 × OCH3), 4.16 (1H, t, J1,2 = J2,3
= 1.8 Hz, C-2-H), 4.22 (2H, t, J1,6 = J3,4 = J4,5 = J5,6 = 3.6 Hz, C-4-H
and C-6-H), 4.32−4.34 (2H, m, C-1-H and C-3-H), 4.55 (1H, septet,
J1,5 = J3,5 = 1.8 Hz, C-5-H), 7.33−7.37 (3H, m, Ar-H), 7.64−7.66 (2H,
m, Ar-H); 13C NMR (100.6 MHz, CDCl3) δC −4.6 (q, 2 × CH3), 18.2
(s, C(CH3)3), 25.8 (q, 3 × CH3), 57.9 (q, 2 × OCH3), 60.3 (d, C-2),
68.3 (d, C-5), 74.0 (d, C-1 and C-3), 76.5 (d, C-4 and C-6), 107.7 (s,
O3CPh), 125.3, 128.0 (2 × d, Ar-Cortho and Cmeta), 129.3 (d, Ar-Cpara),
137.5 (s, Ar-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for
Data for 1,2-bridged 2′-phenyl-1′,3′-dioxolan-2′-ylium ion 20 from
1
4,6-di-O-benzyl orthobenzoate 19: H NMR (400 MHz, CF3CO2D)
δH 4.25 (1H, t, J3,4 = J4,5 = 3.7 Hz, H-4), 4.33 (1H, dd, J5,6 = 8.9 Hz, H-
5), 4.79 (1H, dd, J1,6 = 6.0 Hz, H-6), 4.84 (1H, br t, H-3), 4.89 (2H, s,
CH2Ph), 5.02 (2H, AB, JAB = 12.1 Hz, CH2Ph), 6.02 (1H, dd, J1,2 = 9.0
Hz, H-1), 6.25 (1H, dd, J2,3 2.9 Hz, H-2), 7.38−7.46 (10H, m, Bn-Ar-
H), 7.81 (2H, t, Jortho,meta = Jmeta,para = 7.9 Hz, Bz-Ar-Hmeta), 8.18 (1H, t,
Bz-Ar-Hpara), 8.24 (2H, d, Bz-Ar-Hortho); 13C NMR (400 MHz,
CF3CO2D) δC 67.0 (d, C-3), 73.0 (d, C-5), 76.2 (d, C-6), 80.1 (d, C-
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4), 86.7 (d, C-2), 89.0 (d, C-1), 115.1 (s, Ar-Cipso), (Bn-Ar-C) (*see
below), 130.4 (d, Ar-Cmeta), 133.9 (d, Ar-Cortho) 142.7 (d, Ar-Cpara),
182.3 (s, C-2′); *13C NMR (400 MHz, CF3CO2D) 128.4, 128.7,
128.7, 128.8, 128.8, 129.0, 129.1, 129.1, 129.3, 134.6, 134.8 (11 × d,
Bn-Ar-C of both intermediate 20 and product 21 and Bz-Ar-Cmeta of
Product 21).
O3CAr-Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for C34H33O6
537.2277, found 537.2272.
2,4,6-Tri-O-benzyl 1-O-benzoyl 5-O-trifluoroacetyl myo-
Inositol 1,3,5-Orthobenzoate (31): mp 138−139 °C (ethyl
1
acetate/pet. ether); H NMR (400 MHz, CDCl3) δ 2.26 (1H, br s,
C-3-OH), 3.81 (1H, br d, J3,4 = 9.7 Hz, C-3-H), 4.00 (1H, t, J4,5 = 9.7
4,6-Di-O-benzyl 2-O-benzoyl myo-Inositol (21): 1H NMR (400
MHz, CF3CO2D and CDCl3) δ 4.28 (1H, t, J4,5 = J5,6 = 9.2 Hz, C-5-
H), 4.42 (2H, dd, J1,2 = J2,3 = 2.7 Hz, J1,6 = J3,4 = 10.1 Hz, C-1-H and
C-3-H), 4.48 (2H, t, C-4-H and C-6-H), 5.10 (4H, AB, JA,B = 11.0 Hz,
CH2Ph), 6.16 (1H, t, C-2-H), 7.38−7.46 (10H, m, Bn-Ar-H), 7.63
(2H, t, Jortho,meta = Jmeta,para = 7.9 Hz, Bz-Ar-Hmeta), 7.81 (1H, t, Bz-Ar-
Hpara), 8.14 (2H, dd, Jortho,para = 1.2 Hz, Bz-Ar-Hortho); 13C NMR (100.6
MHz, CF3CO2D and CDCl3) δC 70.3 (d, C-1 and C-3), 73.8 (d, C-2),
74.2 (d, C-5), 76.2 (t, 2 × CH2Ph), 80.0 (d, C-4 and C-6), 127.1 (s,
Bz-Ar-Cipso), (Bn-Ar-C and Bz-Ar-Cmeta) *(see above), 129.9 (d, Bz-
Ar-Cortho), 135.2 (d, Bz-Ar-Cpara), 169.4 (s, CO2Ph).
Hz, C-4-H), 4.22 (1H, t, J1,2 = J2,3 = 2.6 Hz, C-2-H), 4.33 (1H, t, J1,6
=
J5,6 = 10.0 Hz, C-6-H), 4.66 (2H, AB, J = 10.8 Hz, CH2Ph), 4.73 (2H,
s, CH2Ph), 4.74 (2H, AB, J = 11.8 Hz, CH2Ph), 5.18 (1H, dd, C-1-H),
5.29 (1H, t, C-5-H), 7.07−7.10 (2H, m, Ar-H), 7.16−7.20 (3H, m, Ar-
H), 7.21−7.39 (10H, m, Ar-H), 7.47 (2H, t, J = 7.9 Hz, Bz-Hortho),
7.60−7.64 (1H, m, Bz-Hpara), 8.00−8.02 (2H, m, Bz-Hmeta); 13C NMR
(100.6 MHz, CDCl3) δC 72.1 (d, C-3), 74.0 (d, C-1), 75.2, 75.4, 75.6
(3 × t, CH2Ph), 76.9 (d, C-6), 77.5 (d, C-2), 78.6 (d, C-5), 79.0 (d, C-
2
4), 114.7 (quartet, JC,F = 286.0 Hz, CO2CF3), 127.8, 127.9, 128.0,
128.0, 128.2, 128.3, 128.5, 128.6, 128.6 (9 × d, Bz-Cortho, Ar-C), 129.2
(s, Bz-Cipso), 129.7 (d, Bz-Cmeta), 133.5 (d, Bz-Cpara), 137.0, 137.4,
137.8 (3 × s, Ar-Cipso), 156.5 (quartet, 3JC,F = 42.9 Hz, CO2CF3), 165.4
(s, CO2Ph); 19F NMR (376.4 MHz, CDCl3) δF −74.9 (3F, s,
CO2CF3). Anal. Calcd for C36H33F3O8 (650.64): C, 66.46; H, 5.11.
Found: C, 66.45; H, 5.00.
2,4,6-Tri-O-methyl 1,3,5-Orthobenzoate 24. Sodium hydride
(451 mg of a 60% dispersion in oil, 11.3 mmol) was added portionwise
to a solution of 3 (500 mg, 1.9 mmol) in dry THF (6 mL) at 0 °C.
The resulting mixture was stirred for 10 min, and methyl iodide (0.70
mL, 11.3 mmol) was then added dropwise. Stirring was continued for
a further 16 h, after which time TLC (1:1, pet. ether/ethyl acetate)
showed the complete conversion of starting material (Rf 0.10) to a
product (Rf 0.45). The reaction mixture was then diluted with ethyl
acetate (50 mL), washed with water (50 mL) and brine (50 mL), dried
(MgSO4), and evaporated in vacuo. The resulting compound was
purified by column chromatography (pet. ether/ethyl acetate, 2:1) to
afford 24 (562 mg, 97%) as a white solid: mp 121.5−122.8 °C (ethyl
myo-Inositol 1,3,5-Orthoformate (1): 1H NMR (270 MHz,
CF3CO2D and CDCl3) δ 4.47−4.49 (3H, m, C-1-H, C-3-H and C-5-
H), 4.51−4.54 (1H, m, C-2-H), 4.80 (2H, dd, J = 3.8 and 4.2 Hz, C-4-
H and C-6-H), 5.64 (1H, d, J = 1.1 Hz, O3CH); 13C NMR (100.6
MHz, CF3CO2D and CDCl3; peaks referenced to CDCl3) δC 61.4,
67.7 (2 × d, C-2 and C-5) 67.7, 73.6 (2 × d, C-1 and C-3, C-4 and C-
6), 102.7 (d, O3CH); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C7H11O6 191.0556, found 191.0550; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C7H10O6Na 213.0375, found 213.0370.
1
acetate/hexane); H NMR (400 MHz, CDCl3) δH 3.48 (6H, s, C-4-
Acid Hydrolysis of myo-Inositol 1,3,5-Orthoformate (1). A
mixture of TFA (2 mL) and water (0.2 mL) was added to 1 (100 mg,
0.53 mmol), and the solution was stirred for 15 min after which time
TLC (ethyl acetate) indicated the complete conversion of starting
material (Rf 0.5) to products (Rf 0.0). The reaction mixture was then
coevaporated with water in vacuo to obtain a white solid containing a
mixture of 2-O-formyl myo-inositol, 1/3-O-formyl myo-inositol, and
OCH3 and C-6-OCH3), 3.53 (3H, s, C-2-OCH3), 3.67 (1H, br s, C-2-
H), 4.26−4.28 (2H, m, C-4-H and C-6-H), 4.56−4.58 (3H, m, C-1-H,
C-3-H and C-5-H), 7.31−7.34 (3H, m, Ar-H), 7.63−7.65 (2H, m, Ar-
H); 13C NMR (100.6 MHz, CDCl3) δC 56.8 (q, C-2-OCH3), 57.8 (q,
C-4-OCH3 and C-6-OCH3), 68.3, 68.3 (2 × d, C-2 and C-5), 70.6,
76.0 (2 × d, C-1 and C-3, C-4 and C-6), 107.8 (s, O3CPh), 125.3,
127.9 (2 × d, Ar-Cortho and Ar-Cmeta), 129.3 (d, Ar-Cpara), 136.9 (s, Ar-
Cipso); HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H21O6
309.1338, found 309.1333. Anal. Calcd for C16H20O6 (308.33): C,
62.33; H, 6.54. Found C, 62.30; H, 6.43. 1H NMR (400 MHz,
CF3CO2D and CDCl3) δH 3.62 (6H, s, C-4-OCH3 and C-6-OCH3),
3.63 (3H, s, C-2-OCH3), 4.36 (2H, br s, Ins-H), 4.53 (1H, br d, Ins-
H), 5.47 (2H, br s, Ins-H), 7.61 (2H, br t, Ar-Hmeta), 7.87 (1H, br s,
Ar-Hpara), 8.09 (2H, br s, Ar-Hortho).
2,4,6-Tri-O-benzyl myo-Inositol 1,3,5-Orthobenzoate (25).
Sodium hydride (3.15 g of a 60% dispersion in oil, 78.9 mmol) was
added portionwise to a solution of 3 (3.5 g, 13.1 mmol) in dry DMF
(20 mL) at 0 °C. The resulting suspension was stirred for 10 min, and
benzyl bromide (9.4 mL, 78.9 mmol) was added. Stirring was
continued for a further 2 h, after which time TLC (ethyl acetate)
showed the complete conversion of starting material (Rf 0.4) to a
product (Rf 0.7), and the excess sodium hydride was destroyed by the
dropwise addition of methanol. The solvents were removed under
reduced pressure and the residue was dissolved in dichloromethane
(200 mL), washed with water (200 mL) and brine (200 mL), dried
(MgSO4), and evaporated in vacuo. The resulting compound was
purified by column chromatography (hexane/ethyl acetate, 4:1) to
afford 25 (6.7 g, 95%) as a white solid: mp 84−85 °C (ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 4.13 (1H, t, J1,2 = J2,3 = 1.6 Hz, C-2-
H), 4.48 (2H, t, J1,6 = J3,4 = J4,5 = J5,6 = 3.9 Hz, C-4-H and C-6-H), 4.52
(2H, dd, J1,5 = J3,5 = 1.6 Hz, C-1-H and C-3-H), 4.53 (2H, d, JAB = 11.5
Hz, part of a AB system of C-4 and C-6 CH2Ph), 4.57−4.59 (1H, m,
C-5-H), 4.66 (2H, d, JAB = 11.5 Hz, part of a AB system of C-4 and C-
6 CH2Ph), 4.70 (2H, s, C-2 CH2Ph), 7.23−7.38 (16H, m, Ar-H),
7.41−7.43 (2H, m, Ar-H), 7.67−7.69 (2H, m, Ar-H); 13C NMR
(100.6 MHz, (CDCl3) δC 66.1 (d, C-2), 69.0 (d, C-5), 71.2 (t, C-2
CH2Ph) 71.6 (t, C-4 and C-6 CH2Ph), 71.9 (d, C-1 and C-3), 74.0 (d,
C-4 and C-6), 107.8 (s, O3CAr), 125.3 (d, O3CAr-Cmeta), 127.6, 127.7,
127.8, 127.9, 128.0, 128.2, 128.4 (7 × d, Ar-C), 129.4 (d, O3CAr-
Cpara), 137.1 (s, C-2 Ar-Cipso), 137.6 (s, C-4 and C-6 Ar-Cipso), 138.0 (s,
1
myo-inositol in a ratio of 1.7:1.2:1, respectively: H NMR (400 MHz,
D2O) δ 3.11 (1H, t, J4,5 = J5,6 = 9.4 Hz, inositol C-5-H), 3.17 (1H, t,
J4,5 = J5,6 = 9.4 Hz, 2-O-formyl inositol C-5-H), 3.22 (1H, t, J4,5 = J5,6
=
9.4 Hz, 1/3-O-formyl inositol C-5-H), 3.36 (2H, dd, J1,2 = J2,3 = 2.7
Hz, J1,6 = J3,4 = 9.8 Hz, inositol C-1-H and C-3-H), 3.43−3.53 (6H, m,
inositol C-4-H and C-6-H, 2-O-formyl inositol C-4-H and C-6-H, 1/3-
O-formyl inositol C-1/3-H and C-4/6-H), 3.59 (2H, dd, J1,2 = J2,3 = 2.8
Hz, J1,6 = J3,4 = 10.2 Hz, 2-O-formyl inositol C-1-H and C-3-H), 3.70
(1H, t, J = 9.4 Hz, 1/3-O-formyl inositol C-4/6-H), 3.89 (1H, t,
inositol C-2-H), 4.03 (1H, t, J1,2 = J2,3 = 2.2 Hz, 1/3-O-formyl inositol
C-2-H), 4.71 (1H, dd, J = 2.2 Hz and J = 10.2 Hz, 1/3-O-formyl
inositol C-1/3-H), 5.28 (1H, app s, 2-O-formyl inositol C-2-H); 13C
NMR (100.6 MHz, D2O) δC 69.3 (d, 2-O-formyl inositol C-1 and C-
3), 69.8 (d, 1/3-O-formyl inositol C-2), 70.0 (d, 1/3-O-formyl inositol
C-4/6), 70.5 (d, 1/3-O-formyl inositol C-3/4 or C-1/6), 71.0 (d,
inositol C-1 and C-3), 72.0, 72.1 (2 × d, inositol C-2 and 1/3-O-
formyl inositol C-3/4 or C-1/6), 72.3 (d, inositol C-4 and C-6), 72.4
(d, 2-O-formyl inositol C-4 and C-6), 73.7 (d, 1/3-O-formyl inositol
C-1/3), 73.8 (d, inositol C-5), 74.0 (d, 2-O-formyl inositol C-5), 74.2
(d, 1/3-O-formyl inositol C-5), 74.9 (d, 2-O-formyl inositol C-2),
162.9, 163.5 (2 × s, 2-O-formyl inositol CO2H and 1/3-O-formyl
inositol CO2H); HRMS (ESI-TOF) m/z [M + H]+ calcd for 1/3/2-O-
formyl myo-inositol, C7H13O7 209.0661, found 209.0656; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C7H12O7Na 231.0481, found
231.0475.
myo-Inositol 1,3,5-Orthobutanoate (4). Trimethyl orthobuty-
rate (1.0 mL, 6.11 mmol) was added to a suspension of oven-dried
myo-inositol (1.0 g, 5.55 mmol) and PTSA (316.7 mg, 1.67 mmol) in
anhydrous DMF (10 mL), and the resulting mixture was heated at 140
°C for 3 h. Extra trimethyl orthobutyrate (0.5 mL, 3.05 mmol) was
then added and heated for a further 15 min at 140 °C, after which time
TLC (ethyl acetate) indicated the complete consumption of starting
material (Rf 0.0) and the formation of a major product (Rf 0.5). The
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Featured Article
resulting solution was allowed to cool and the catalyst was neutralized
by addition of triethylamine (0.22 mL). The reaction mixture was then
concentrated under reduced pressure, and the resulting residue was
purified by column chromatography (ethyl acetate) to afford 4 (1.12 g,
68.9, 69.0, 69.4, 69.5, 69.5 (5 × t, 10 × CH2Ar), 70.4, 74.0 (2 × d, C-1
and C-3, C-4 and C-6), 74.1 (d, C-5), 77.2 (d, C-2), 128.3, 128.9,
129.1, 129.2, 129.3, 129.3, 129.3, 129.3, 129.9, 134.1, 135.0, 135.1,
135.6, 135.7 (14 × d, 36 × Ar-C), 165.1 (s, CO2Ph); HRMS (ESI-
TOF) m/z [M + H]+ calcd for C53H52O22P5 1195.1638, found
1195.1633.
1
87%) as a white crystalline solid: mp 139−140 °C (ethyl acetate); H
NMR (400 MHz, CD3OD) δ 0.88 (3H, t, J = 7.4 Hz,
O3C(CH2)2CH3), 1.41−1.51 (2H, m, O3CCH2CH2CH3), 1.58−1.62
(2H, m, O3CCH2CH2CH3), 4.08−4.11 (4H, m, C-1-H, C-2-H, C-3-H
and C-5-H), 4.35−4.37 (2H, m, C-4-H and C-6-H); 13C NMR (100.6
MHz, CD3OD) δC 14.4 (q, O3C(CH2)2CH3), 17.0 (t,
O3CCH2CH2CH3), 40.4 (t, O3CCH2CH2CH3), 60.3 (d, C-2/C-5),
69.0 (d, C-4 and C-6), 70.7 (d, C-2/C-5), 76.5 (d, C-1 and C-3),
110.2 (s, O3C(CH2)2CH3); HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C10H16O6Na 255.0845, found 255.0839; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C10H17O6 233.1025, found 233.1020. Anal. Calcd
for C10H16O6 (232.23): C, 51.72; H, 6.94. Found: C, 51.70; H, 7.01.
2-O-Butanoyl myo-Inositol (7). A mixture of TFA (5 mL) and
water (0.5 mL) was added to orthobutanoate 4 (300 mg, 1.29 mmol),
and the solution was stirred for 5 min after which time TLC (ethyl
acetate) indicated the complete conversion of starting material (Rf 0.6)
to a product (Rf 0.0). The reaction mixture was then coevaporated
with water in vacuo to obtain 7 (323 mg, quantitative) as a white solid:
mp 143−161 °C (methanol and water); 1H NMR (400 MHz, D2O) δ
0.72 (3H, t, J = 7.4 Hz, CO2(CH2)2CH3), 1.42 (2H, sextet, J = 7.4 Hz,
CO2CH2CH2CH3), 2.24 (2H, t, J = 7.4 Hz, CO2CH2CH2CH3), 3.10
(1H, t, J4,5 = J5,6 = 9.4 Hz, C-5-H), 3.41 (2H, t, J1,6 = J3,4 = 9.8 Hz, C-4-
H and C-6-H), 3.49 (2H, dd, J1,2 = J2,3 = 2.7 Hz, C-1-H and C-3-H),
5.22 (1H, t, C-2-H); 13C NMR (100.6 MHz, D2O) δC 12.8 (q,
CO2(CH2)2CH3), 17.8 (t, CO2CH2CH2CH3), 35.7 (t,
CO2CH2CH2CH3), 69.6 (d, C-1 and C-3), 72.5 (d, C-4 and C-6),
74.0 (d, C-2), 74.2 (d, C-5), 176.3 (s, CO2(CH2)2CH3); HRMS (ESI-
TOF) m/z [M + H]+ calcd for C10H19O7 251.1131, found 251.1125;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C10H18O7Na 273.0950,
found 273.0945. Anal. Calcd for C10H18O7 (250.25): C, 48.00; H, 7.25.
Found: C, 47.90; H, 7.31.
2-O-Benzoyl 1,3,4,5,6-Pentakis-O-[bis(benzyloxy)-
phosphoryl]-myo-Inositol (48). To a solution of 6 (950 mg, 3.3
mmol) and 5-phenyltetrazole (4.88 g, 33.4 mmol) in dry dichloro-
methane (10 mL) under an atmosphere of argon was added
bis(benzyloxy)(N,N-diisopropylamino)phosphine (7.86 mL, 23.4
mmol). Stirring was continued for 1.5 h at room temperature, after
which time TLC (1:1, ethyl acetate/pet. ether) confirmed the
complete consumption of starting material (Rf 0.0) to product (Rf
0.8) of which 31P NMR (109.4 MHz, CDCl3) showed signals at δ
140.54 (2P, d, JP1,P6 = JP3,P4 = 17.4 Hz, phosphite at C-1 and C-3)
142.44 (2P, t, JP4,P5 = JP5,P6 = 29.0 Hz, phosphite at C-4 and C-6),
143.74 (1P, t, phosphite at C-5). The reaction mixture was cooled to
−40 °C and 77% m-CPBA (7.49 g, 33.4 mmol) was added portionwise
while stirring. The cooling bath was removed, and the mixture was
allowed to reach room temperature. After 15 min, TLC (1:1, ethyl
acetate/pet. ether) showed complete oxidation of pentaphosphite to
pentaphosphate (Rf 0.3), the reaction mixture was diluted with
dichloromethane (150 mL), washed with 10% sodium sulfite solution
(2 × 150 mL), and dried, and solvent was evaporated in vacuo. The
residue was purified by column chromatography (chloroform/acetone,
6:1) to afford 48 (4.98 g, 94%) as a colorless oil: 31P NMR (161.9
MHz, H-decoupled, CDCl3) δ −1.70 (2P, s), −1.39 (2P, s), −0.92
(1P, s, phosphate at C-5); 1H NMR (400 MHz, CDCl3) δ 4.73−4.99,
5.01−5.28 (3H:22H, m, C-1-H, C-3-H, C-4-H, C-5-H, C-6-H and 10
× CH2Ar), 6.38 (1H, br s, C-2-H), 7.16−7.29 (50H, m, Ar), 7.44−
7.47 (2H, m, Bz-Hmeta), 7.59−7.63 (1H, m, Bz-Hpara), 8.13−8.16 (2H,
m, Bz-Hortho); 13C NMR (100.6 MHz, CDCl3) δC 68.3 (d, C-2), 69.3,
69.3, 69.4, 69.4, 69.4, 69.4, 69.5, 69.5 (8 × t, 10 × CH2Ar), 72.7, 74.6
(2 × d, C-1, C-3, C-4 and C-6), 74.1 (d, C-5), 127.6, 127.6, 127.7,
127.8, 127.9, 127.9, 128.0, 128.0, 128.0, 128.1, 128.1, 128.3, 128.4,
128.5, 129.7, 133.3, 135.2, 135.2, 135.2, 135.3, 135.4, 135.4, 135.5,
135.5, 135.6 (25 × d, 66 × Ar-C) 164.6 (s, CO2Ph); HRMS (ESI-
TOF) m/z [M + H]+ calcd for C83H82O22P5 1585.3986, found
1585.3980. Anal. Calcd for C83H81O22P5 (1585.39): C, 62.88; H, 5.15.
Found: C, 62.80; H, 5.28.
2-O-Butanoyl (COCD2CH2CH3) myo-Inositol (44): 1H NMR
(400 MHz, D2O) δ 0.75 (3H, t, J = 7.4 Hz, CO2CD2CH 2CH3), 1.45
(2H, q, J = 7.1 and 14.5 Hz, CO2CD2CH2CH3), 3.14 (1H, t, J4,5 = J5,6
= 9.3 Hz, C-5-H), 3.44 (2H, t, J1,6 = J3,4 = 9.8 Hz, C-4-H and C-6-H),
3.53 (2H, dd, J1,2 = J2,3 = 2.7 Hz, C-1-H and C-3-H), 5.26 (1H, t, C-2-
2
H); H NMR (400 MHz, D2O) δ 2.26 (br s, CO2CD2CH2CH3); 13C
2-O-Benzoyl myo-Inositol 1,3,4,5,6-Pentakisphosphate (9).
Compound 47 (800 mg, 0.67 mmol) was dissolved in methanol (60
mL), and water (15 mL) and 10% palladium hydroxide on activated
charcoal (400 mg) were added. The resulting suspension was stirred at
room temperature overnight under an atmosphere of hydrogen in a
hydrogenator. The catalyst was filtered through a PTFE syringe filter,
and the filtrate was evaporated under reduced pressure to give 9 (460
mg, quantitative) as a hygroscopic white foam: 31P NMR (109.4 MHz,
H-decoupled, D2O) δ −0.02 (2P, s), 0.79 (2P, s), 1.09 (1P, s,
phosphate at C-5); 1H NMR (270 MHz, D2O) δ 4.34 (1H, ap.
NMR (100.6 MHz, D2O) δC 12.7 (q, CO2CD2CH2CH3), 17.6 (t,
CO2CD2CH2CH3), 35.2−35.7 (t, CO2CD2CH2CH3), 69.6 (d, C-1
and C-3), 72.5 (d, C-4 and C-6), 74.0 (d, C-2), 74.2 (d, C-5), 176.3 (s,
CO2CD2CH 2CH3); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C10H17D2O7 253.1256, found 253.1251; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C10H16D2O7Na 275.1076, found 275.1070.
2-O-Benzoyl 1,3,4,5,6-Pentakis-O-[(O-xylene-α,α-diyldioxy)-
phosphoryl]-myo-Inositol (47).39 To a solution of 6 (200 mg, 0.7
mmol) and 5-phenyltetrazole (1.03 g, 7.0 mmol) in dry dichloro-
methane (5 mL) under an atmosphere of argon was added N,N-
diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine (1.14 mL,
5.3 mmol). Stirring was continued for 2 h at room temperature,
after which time TLC confirmed the complete consumption of starting
material and 31P NMR (109.4 MHz, H-decoupled, CDCl3) showed
signals at δ 133.59 (2P, s), 133.94 (2P, s), 134.13 (1P, s, phosphite at
C-5). The reaction mixture was cooled to −40 °C, and m-CPBA (2.13
g, 7.0 mmol) was added portionwise while stirring. The cooling bath
was removed, and the mixture was allowed to reach room temperature
and diluted with dichloromethane (50 mL), washed with 10% sodium
sulfite solution (2 × 100 mL), dried and solvent evaporated in vacuo.
The residue was purified by column chromatography (chloroform/
acetone, 4:1→1:1) to afford 47 (806 mg, 96%) as a white crystalline
solid: mp 239−240 °C (chloroform/methanol); 31P NMR (161.9
MHz, H-decoupled, CDCl3) δ −4.99 (2P, s), −4.30 (1P, s, phosphate
quartet, dt, J4,5 = J5,6 = JH,P = 9.4 Hz, C-5-H), 4.44 (2H, ddd, J1,2 = J2,3
=
2.7 Hz, J1,6 = J3,4 = JH,P = 9.4 Hz, C-1-H and C-3-H), 4.57 (2H, ap.
quartet, ddd, JH,P = 9.4 Hz, C-4-H and C-6-H), 5.90 (1H, t, C-2-H),
7.32−7.37 (2H, m, Ar-Hmeta), 7.47−7.53 (1H, m, Ar-Hpara), 7.86−7.88
(2H, m, Ar-Hortho); 13C NMR (100.6 MHz, D2O) δC 71.5 (d, C-2),
72.5 (m, C-1 and C-3), 76.6 (m, C-4 and C-6), 76.9 (m, C-5), 128.5
(s, Ar-Cipso), 128.8 (d, Ar-Cmeta), 129.9 (d, Ar-Cortho), 134.2 (d, Ar-
Cpara), 166.9 (s, CO2Ph); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C13H22O22P5 684.9291, found 684.9285.
Catalytic hydrogenolysis of compound 48 (4.0g, 2.52 mmol) was
also carried out as above in methanol (110 mL) and water (10 mL)
with 10% palladium hydroxide on activated charcoal (400 mg) to
afford 9 (1.75 g) in quantitative yield. The free acid 9 was then
converted to the triethyl ammonium salt by neutralization with 1 M
triethylammonium bicarbonate buffer followed by coevaporation with
methanol to remove excess buffer.
1
at C-5), −3.37 (2P, s); H NMR (400 MHz, CDCl3) δ 4.92−5.23,
5.30−5.37, 5.45−5.61 (m, 15H:4H:6H, C-1-H, C-3-H, C-4-H, C-5-H,
C-6-H and 10 × CH2Ar), 6.34 (br s, 1H, C-2-H), 7.17−7.36 (m, 20H,
Ar-H), 7.38−7.42 (m, 2H, Bz-Hmeta), 7.51 (t, 1H, J = 7.4 Hz, Bz-Hpara),
7.99−8.00 (m, 2H, Bz-Hortho); 13C NMR (100.6 MHz, CDCl3) δC
myo-Inositol 1,3,4,5,6-Pentakisphosphate (11). Compound 9
(600 mg, 0.88 mmol) was dissolved in concentrated aqueous ammonia
solution (30 mL) and heated at 60 °C overnight in a Pyrex pressure
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Featured Article
tube. After evaporation of solution under vacuum, the residue was
dissolved in water and the benzamide byproduct was removed by
washing with dichloromethane to afford the pure ammonium salt of 11
(600 mg) as a hygroscopic white solid: 31P NMR (109.4 MHz, H-
decoupled, D2O) δ 1.93 (2P, s), 2.98 (1P, s, phosphate at C-5), 3.69
(10) Sureshan, K. M.; Shashidhar, M. S. Sulfonate Protecting Groups.
Regioselective O-Sulfonylation of myo-Inositol Orthoesters. Tetrahe-
dron Lett. 2001, 42, 3037−3039.
(11) Gilbert, I. H.; Holmes, A. B.; Young, R. C. Synthesis of
Protected myo-Inositols. Tetrahedron Lett. 1990, 31, 2633−2634.
(12) Gilbert, I. H.; Holmes, A. B.; Pestchanker, M. J.; Young, R. C.
Lewis Acid Catalysed Rearrangements of myo-Inositol Orthoformate
Derivatives. Carbohydr. Res. 1992, 234, 117−130.
(13) Conway, S. J.; Gardiner, J.; Grove, S. J. A.; Johns, M. K.; Lim, Z.-
Y.; Painter, G. F.; Robinson, D. E. J. E.; Schieber, C.; Thuring, J. W.;
Wong, L. S.-M.; Yin, M.-X.; Burgess, A. W.; Catimel, B.; Hawkins, P.
T.; Ktistakis, N. T.; Stephens, L. R.; Holmes, A. B. Synthesis and
Biological Evaluation of Phosphatidylinositol Phosphate Affinity
Probes. Org. Biomol. Chem. 2010, 8, 66−76.
(14) Painter, G. F.; Grove, S. J. A.; Gilbert, I. H.; Holmes, A. B.;
Raithby, P. R.; Hill, M. L.; Hawkins, P. T.; Stephens, L. R. General
Synthesis of 3-Phosphorylated myo-Inositol Phospholipids and Their
Derivatives. J. Chem. Soc., Perkin Trans. 1 1999, 923−936.
(15) Yeh, S. M.; Lee, G. H.; Wang, Y.; Luh, T. Y. Chelation-Assisted
C−O Bond Cleavage of Ortho Esters. A Convenient Synthesis of myo-
Inositol Derivatives Having Free Hydroxy Group(s) at Specific
Position(s). J. Org. Chem. 1997, 62, 8315−8318.
(16) Riley, A. M.; Mahon, M. F.; Potter, B. V. L. Rapid Synthesis of
the Enantiomers of myo-Inositol-1,3,4,5-Tetrakisphosphate by Direct
Chiral Desymmetrization of myo-Inositol Orthoformate. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1472−1474.
(17) Lee, H. W.; Kishi, Y. Synthesis of Mono and Unsymmetrical Bis
Ortho-esters of scyllo-Inositol. J. Org. Chem. 1985, 50, 4402−4404.
(18) Garrett, S. W.; Liu, C. S.; Riley, A. M.; Potter, B. V. L. Rapid and
Practical Synthesis of D-myo-Inositol 1,4,5-Trisphosphate. J. Chem. Soc.,
Perkin Trans. 1 1998, 1367−1368.
(19) Praveen, T.; Shashidhar, M. S. Convenient Synthesis of 4,6-Di-
O-benzyl-myo-Inositol and myo-Inositol 1,3,5-Orthoesters. Carbohydr.
Res. 2001, 330, 409−411.
(20) Sureshan, K. M.; Shashidhar, M. S. Sulfonate Protecting Groups.
Regioselective O-Acylation of myo-Inositol 1,3,5-Orthoesters: The
Role of Acyl Migration. Tetrahedron Lett. 2000, 41, 4185−4188.
(21) Riley, A. M.; Godage, H. Y.; Mahon, M. F.; Potter, B. V. L.
Chiral Desymmetrisation of myo-Inositol 1,3,5-Orthobenzoate Gives
Rapid Access to Precursors for Second Messenger Analogues.
Tetrahedron Asymm. 2006, 17, 171−174.
1
(2P, s); H NMR (270 MHz, D2O) δ 3.87−4.04 (3H, m, J = 9.4 Hz,
C-1-H, C-3-H and C-5-H), 4.26 (2H, app quartet, ddd, J = 9.4 Hz, C-
4-H and C-6-H), 4.51 (1H, br s, C-2-H); HRMS (ESI-TOF) m/z [M
− H]− calcd for C6H16O21P5 578.8872, found 578.8878. Anal. Calcd
for hexaammonium salt of 11 C6H35N6O21P5 (682.24): C, 10.56; H,
5.17; N, 12.32. Found: C, 10.30; H, 5.38; N, 12.40.
The ammonium salt of 11 was converted into the free acid by quick
filtration [since prolonged exposure causes migration] through Dowex
H+ resin (10-fold excess, previously washed with miliQ water) and
then to its hexasodium salt by titration to pH 7.42 with 0.1 M sodium
hydroxide followed by lyophilization: 31P NMR (161.9 MHz, H-
decoupled, D2O) δ 1.05 (2P, s), 1.18 (2P, s), 1.46 (1P, s, phosphate at
C-5); 1H NMR (400 MHz, D2O) δ 3.93−3.97, 4.22−4.26 (6H, 2 × m,
C-1-H, C-2-H, C-3-H, C-4-H, C-5-H and C-6-H).
ASSOCIATED CONTENT
* Supporting Information
■
S
Supporting figures; 1H, 13C, and 31P NMR spectra for
compounds 4, 6, 7, 9, 15−25, 31, 44, 47, and 48;
computational data for compound 20; and crystallographic
data for compound 7 (CIF) (CCDC deposition no. 921722).
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: b.v.l.potter@bath.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Wellcome Trust for financial support
(Programme Grant No. 082837) to B.V.L.P. and A.M.R. and
Dr. A. Nathubhai for proofreading this manuscript.
(22) Godage, H. Y.; Riley, A. M.; Woodman, T. J.; Potter, B. V. L.
Regioselective Hydrolysis of myo-Inositol 1,3,5-Orthobenzoate via a
1,2-Bridged 2′-Phenyl-1′,3′-dioxolan-2′-ylium Ion Provides a Rapid
Route to the Anticancer Agent Ins(1,3,4,5,6)P5. Chem. Commun. 2006,
28, 2989−2991.
(23) Falasca, M.; Chiozzoto, D.; Godage, H. Y.; Mazzoletti, M.; Riley,
A. M.; Previdi, S.; Potter, B. V. L.; Broggini, M.; Maffucci, T. A Novel
Inhibitor of the PI3K/Akt Pathway Based on the Structure of Inositol
1,3,4,5,6-Pentakisphosphate. Br. J. Cancer 2010, 102, 104−114.
(24) Piccolo, E.; Vignati, S.; Maffucci, T.; Innominato, P. F.; Riley, A.
M.; Potter, B. V. L.; Pandolfi, P. P.; Broggini, M.; Iacobelli, S.;
Innocenti, P.; Falasca, M. Inositol Pentakisphosphate Promotes
Apoptosis through the PI3-K/Akt Pathway. Oncogene 2004, 23,
1754−1765.
(25) Maffucci, T.; Piccolo, E.; Cumashi, A.; Iezzi, M.; Riley, A. M.;
Saiardi, A.; Godage, H. Y.; Rossi, C.; Broggini, M.; Iacobelli, S.; Potter,
B. V. L.; Innocenti, P.; Falasca, M. Inhibition of the Phosphatidyli-
nositol 3-Kinase/Akt Pathway by Inositol Pentakisphosphate Results
in Antiangiogenic and Antitumor Effects. Cancer Res. 2005, 65, 8339−
8349.
(26) Biamonte, M. A.; Vasella, A. An Advantageous Synthesis of 1D-
and 1L-1,2,3,5/4-Cyclohexanepentol. Helv. Chim. Acta 1998, 81, 688−
694.
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