Regioselectivity among six secondary hydroxyl groups: Selective acylation of the least reactive hydroxyl groups of inositol

Article abstract of DOI:10.1039/c2cc17241k

We report the first, general and selective acylation of the least reactive hydroxyl group among six secondary hydroxyl groups of inositol in high yield, using very cheap and easy-to-make H₂SO₄-silica as the catalyst, providing easy access to bioactive molecules. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17241k

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COMMUNICATION
Regioselectivity among six secondary hydroxyl groups: selective
acylation of the least reactive hydroxyl groups of inositolwz
Amol M. Vibhute, Adiyala Vidyasagar, Saritha Sarala and Kana M. Sureshan*
Received 21st November 2011, Accepted 6th January 2012
DOI: 10.1039/c2cc17241k
We report the first, general and selective acylation of the least
reactive hydroxyl group among six secondary hydroxyl groups
of inositol in high yield, using very cheap and easy-to-make
H2SO4–silica as the catalyst, providing easy access to bioactive
molecules.
Unlike sugars where discrimination between primary, secondary
and anomeric hydroxyl groups is possible, selectivity among
multiple hydroxyl groups of similar nature (e.g. four or more
secondary hydroxyl groups) has not been achieved till date.
We report a general and highly regioselective acylation of
the least reactive hydroxyl group of six secondary hydroxyl
groups of inositol leaving the remaining five reactive hydroxyl
groups untouched. Very cheap and easy-to-make H2SO4–silica
mediates tandem transorthoesterification and hydrolysis to
provide 2-O-acyl myo-inositol regioselectively in high yield.
Myo-inositol (2) and its derivatives play critical roles in a
myriad of biological processes. While phosphoinositols10,11
and their lipid analogues (phosphatidylinositol phospholipids)
are involved in various cellular signalling processes, vesicular
trafficking, cytoskeletal assembly etc.,12–14 glyco-inositolphos-
pholipids (glycosylphosphatidylinositol; GPI) are involved in
protein anchoring. Currently, natural occurrence of at least
eight phosphatidylinositol lipids, 26 myo-inositol phosphates
and numerous glycosylated inositols is established. Apart from
the importance of natural products, synthetic inositol derivatives
are also attractive due to the recent interest in the chemistry and
supramolecular chemistry of this cyclitol. Thus many natural and
synthetic inositol derivatives have been the target in organic
synthesis.15,16 Most of the synthetic inositol chemistry involves a
multistep sequence of protecting group manipulations. One
important strategy for partial protection of inositol hydroxyl
groups is the acid catalyzed transorthoesterification of myo-
inositol with a trialkylorthoester to provide myo-inositol 1,3,5-
orthoester (Fig. 2).17,18 Commonly employed homogeneous acid
catalysts such as p-TSA or camphorsulfonic acid necessitate
neutralization and chromatographic separation to isolate the
orthoester. We wondered whether replacing such soluble cata-
lysts with a solid supported catalyst would make the isolation of
these orthoesters easy.
Regioselective functionalization of a particular hydroxyl
group in a polyol is an arduous task in synthetic chemistry
and hence was the subject of several elegant studies. Lewis and
Miller reported an excellent biomimetic peptide catalyzed site
selective acylation at a hydroxyl group of lower inherent
reactivity in a polyol natural product, erythromycin A.1
Several elegant strategies for selective functionalization of
one of the hydroxyl groups among one primary and three
secondary hydroxyl groups in glucopyranosides have also
been reported. Kawabata’s pyrrolidinopyridine catalyzed O4
butyrylation,2 Miller’s peptide catalyzed O4 acetylation,3
Onomura’s O2 acetylation4 and O6 acetylation reported by
Kattnig and Albert,5 Onomura et al.4 and Yoshida et al.6 are
graceful examples of regioselectivity (Fig. 1). Also, strategies
for the regioselective one pot protection of persilylated
glucopyranosides via the sequential arylidenation followed by
O3 selective reductive arylmethylation have been reported.7–9
Sulfuric acid immobilized on silica (H2SO4–silica) has proven
to be a mild and practically convenient catalyst for the ketalization
Fig. 1 Comparison of the known selective monofunctionalization of
glucopyranoside 1 and inositol 2.
School of Chemistry, Indian Institute of Science Education and
Research, Thiruvananthapuram, Kerala-695016, India.
E-mail: kms@iisertvm.ac.in; Fax: +91 4712597427
w Dedicated to Dr Mysore S. Shashidhar.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc17241k
Fig. 2 Orthoester protection of myo-inositol.
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of various monosaccharides.19 This prompted us to test the
efficacy of this solid catalyst in effecting orthoesterification of
inositol. However, treatment of myo-inositol and trimethylortho-
benzoate in the presence of H2SO4–silica, to our great surprise,
gave 2-O-benzoyl myo-inositol (see ESIz for details about struc-
tural assignments) as the only product in high yield (70–80% in
different trials). This high regioselectivity is very surprising and
interesting as 2-OH (axial) is known to be the least reactive
hydroxyl group among all the six hydroxyl groups of myo-
inositol.20 Intrigued by this unusual regioselectivity, we have
investigated the generality of this interesting acylation reaction.
Treatment of myo-inositol with various trialkyl orthoesters in the
presence of H2SO4–silica provided the corresponding 2-O-acyl-
myo-inositol selectively in very good yields (Table 1). Though a
very little amount of unreacted inositol was isolated, no trace of
other isomeric esters was detected in any case. This regioselective
acylation by H2SO4–silica is especially very interesting as other
commonly used acidic catalysts like PTSA, camphorsulfonic acid,
TfOH etc. could not effect this transformation.
Fig. 3 The role of 2-OH in the orthoester cleavage.
the initial hydrolysis (step I, Fig. 3). The resistance of orthoesters
to undergo hydrolysis when 2-OH was not free suggests that
2-OH has some role in the orthoester cleavage itself. This was
further established by the fact that 4-O-benzoate 10, having 2-OH
free, easily reacted to give the known21 2,4-di-O-benzoyl-myo-
inositol 11 under similar reaction conditions. Interestingly, the
cyclic sulfite 12, despite having 2-OH free, did not undergo
hydrolysis when treated with H2SO4–silica in methanol even
at higher temperature (80 1C). This suggests that the locked
conformation of 12 might be preventing it from the reaction.
A plausible mechanism for the formation of 2-O-acyl-myo-
inositol from inositol is proposed in Fig. 4. The orthoester II
formed by the acid catalyzed transesterification of I with
the orthoester RC(OR0)3 undergoes acid catalyzed cleavage
of the orthoester cage to give the dioxenium cation III.
In order to check the possible intermediacy of the corres-
ponding 1,3,5-orthoester 4 during the course of the 2-O-acylation,
we have monitored the H2SO4–silica catalyzed 2-O-benzoylation
reaction between inositol and trimethylorthobenzoate using TLC
by co-eluting with an unambiguously synthesized orthobenzoate
4. This experiment revealed that 4 is indeed an intermediate in the
formation of 3a. Furthermore, in an independent experiment, the
orthoester 4 was smoothly converted to 3a in quantitative yield
when treated with H2SO4–silica in wet methanol. This suggests
that H2SO4–silica at first catalyzes the transorthoesterification
reaction between a trialkylorthoester and myo-inositol to produce
the corresponding myo-inositol orthoester, which undergoes
hydrolysis and rearrangement, catalyzed by the same catalyst,
to the 2-O-acyl-myo-inositol. The possibility of orthoester hydro-
lysis to O1 (O3) ester 5 or O5 ester 6 followed by acyl migration
to O2 is ruled out as it involves energetically unfavourable
acyl migration from an equatorial O (more stable ester) to an
axial O (less stable ester) (Fig. 3). If any of these two equatorial
esters (5 or 6) is an intermediate in the reaction, they can be
trapped by arresting the subsequent acyl migration by using
2-O-protected derivatives. Hence, 2-O-protected derivatives 7–9
were treated with H2SO4–silica in methanol at 70 1C. Interest-
ingly, none of these derivatives (Fig. 3) underwent hydrolysis
under this condition. If the 2-OH has just an acceptor role in the
acyl migration process (Fig. 3), 2-O-protection would not affect
Table 1 Direct acylation at 2-OH of myo-inositol
Entry
Reagent
Time/h
Product
Yield (%)
1
2
3
4
5
PhC(OMe)3
8
6
9
8
6
3a, R = Ph
77
71
73
75
70
n-C4H9C(OEt)3
n-C3H7C(OEt)3
C2H5C(OEt)3
CH3C(OMe)3
3b, R = n-C4H9
3c, R = n-C3H7
3d, R = C2H5
3e, R = Me
Fig. 4 Plausible mechanisms for the regioselective acylation at O2.
Chem. Commun., 2012, 48, 2448–2450 2449
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The carbocyclic ring undergoes a conformational change to
a boat form IV so that the three axially orienting hydroxyl
groups adopt more stable equatorial orientation. This might
also make the heterocyclic chair to undergo a conformational
change to its boat form V so that the 2-OH can have stabilizing
interaction with dioxenium. The boat–boat conformer V can, in
principle, react to form the 1,2,3-orthoester VI. The unstable and
strained orthoester VI can undergo acid catalyzed orthoester
cleavage to the 1,2- or 2,3-dioxolenium VII which will easily
rearrange to its more stable chair form IX. Attack of the
dioxolenium IX by water adsorbed on H2SO4–silica leads to
the formation of the unstable orthoacid X, which is known22,23
to decompose into a hydroxyl ester with an axially orienting ester
and an equatorial hydroxyl group. This mechanism explains the
unreactivity of sulfite 12 as its locked conformation would not
allow the conformational change from III to IV which in turn
prevents the formation of the crucial dioxolenium intermediate
IX. While, the orthoester pathway is definitely in action for
the observed selectivity, concurrent action of other pathways
cannot be ruled out. For instance, the transformation of the
pre-synthesized orthoester 4 to the 2-O-ester 3a took longer time
when the reaction was done in dry DMF with 3 equivalents of
methanol, the exact mimic of the direct 2-O-acylation reaction
medium (in the direct 2-O-acylation reaction, for each molecule
of the intermediate orthoester produced, three molecules of
methanol will be released to the solvent). So another relatively
faster pathway also may be in action in the direct 2-O-acylation
reaction. This is not inconceivable as the kinetic and less stable
(more reactive) 1,2-orthoester of inositol VIII can also give
the dioxolenium ion IX and thus the orthoacid X under acidic
conditions.
general and high-yielding methodology for the regioselective
2-O-acylation of myo-inositol. This methodology is very attrac-
tive in the light of natural occurrence of many 2-O-acyl-myo-
inositols having interesting biological activities. Our method not
only provides easy access to these natural products and their
analogs but also the shortest route for the synthesis of the
anticancer agent myo-inositol 1,3,4,5,6-pentakisphosphate.
KMS thank DST and CSIR for a Ramanujan Fellowship
and financial support.
Notes and references
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among all the hydroxyl groups of inositol, O2 acylation is
common among inositol based natural products24,25 and is
important for the biological functions of various natural
products. For instance, GPI anchors are acylated at O2 of
inositol and this ester motif has a role in the stability of the
anchor toward Phospholipase C (PLC) action.26 Lanceolitols,
a series of 2-O-acyl-myo-inositol glycosides with diversity in
the fatty acyl chain isolated from Solanum lanceolatum, are
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These facts highlight the importance of the selective 2-O-
acylation reported here. Trifluoroacetic acid mediated28 and
Pd(OH)2 mediated29 cleavages of the benzoate 4 to the pentol
3a have been reported. Potter et al. exploited this for the
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precursor 3a in a single step from inositol in a highly selective
manner provides an easy access to this anticancer agent.
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acylation of an otherwise unreactive hydroxyl group of myo-
inositol. Ours is the first report of the regioselective mono-
functionalization among six equivalent hydroxyl groups. The
very cheap and easy-to-make H2SO4–silica catalyzed tandem
transorthoesterification–hydrolysis sequence offers a simple,
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2450 Chem. Commun., 2012, 48, 2448–2450
This journal is The Royal Society of Chemistry 2012