Chiral desymmetrisation of myo-inositol 1,3,5-orthobenzoate gives rapid access to precursors for second messenger analogues

Article abstract of DOI:10.1016/j.tetasy.2005.12.008

Chiral desymmetrisation of myo-inositol 1,3,5-orthobenzoate via the formation of diastereoisomeric bis[(1S)-(-)-camphanate] esters provides a convenient and fast route to precursors for biologically important inositol phosphates and lipids, and to synthet

Full text of DOI:10.1016/j.tetasy.2005.12.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 171–174
Chiral desymmetrisation of myo-inositol 1,3,5-orthobenzoate
gives rapid access to precursors for second messenger analogues
Andrew M. Riley,a H. Yasmin Godage,a Mary F. Mahonb and Barry V. L. Pottera,*
aWolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
bDepartment of Chemistry, University of Bath, Bath BA2 7AY, UK
Received 17 November 2005; accepted 12 December 2005
Available online 23 January 2006
Abstract—Chiral desymmetrisation of myo-inositol 1,3,5-orthobenzoate via the formation of diastereoisomeric bis[(1S)-(ꢀ)-camph-
anate] esters provides a convenient and fast route to precursors for biologically important inositol phosphates and lipids, and to
synthetic analogues and probes modified at O-1 or O-3 of the inositol ring.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
biological roles of Ins(1,4,5)P3 and Ins(1,3,4,5)P4, we
required a convenient route to precursors for synthetic
Ins(1,3,4,5)P4 conjugates in which either the 1- or
3-phosphate group could be modified selectively, while
retaining the 3,4,5- or 1,4,5-trisphosphate pattern. Here
we show that by applying our desymmetrisation
approach to myo-inositol orthobenzoate 3, the metho-
dology can be developed and extended, giving fast
routes to the required chiral precursors for O-1 and
O-3 modified analogues of Ins(1,3,4,5)P4, and also for
analogues of Ins(1,4,5)P3 and phosphatidylinositol
3,4,5-trisphosphate [PtdIns(3,4,5)P3].8
myo-Inositol 1,3,5-orthoesters1 have been widely used in
recent years as intermediates in the synthesis of inositol
phosphates and lipids. The introduction of the adaman-
tane-like orthoester cage protects the O-1, O-3 and O-5
atoms of myo-inositol in a single step, leaving the OH
groups at C-2, C-4 and C-6 free for manipulation
(Fig. 1). The orthoester can also be cleaved with reduc-
ing agents to give different patterns of hydroxyl group
protection,2 and in the case of the alkyl orthoesters, acid
hydrolysis can introduce an acyl ester at various posi-
tions on the inositol ring.3 myo-Inositol orthoformate4
1 has been most extensively investigated, although
myo-inositol orthoacetate 23a,4e and other orthoesters
with alkyl chains3b,5 have also been used. myo-Inositol
1,3,5-orthobenzoate 3 has not previously been exploited
as a synthetic precursor, although an obvious advantage
of 3 is that hydrolysis of the orthoester cage should leave
a stable benzoate ester on the inositol ring, giving greater
scope for subsequent elaboration.
2. Results and discussion
2.1. General strategy
Our synthetic strategy (Scheme 1) employs chiral desym-
metrisation of myo-inositol orthobenzoate 3 using (1S)-
(ꢀ)-camphanic chloride, followed by isolation of the
required D-2,6-bis(camphanate) 4 by crystallisation.
The camphanate esters are then replaced with stable
benzyl ethers in a straightforward sequence of reactions
employing a methoxyisopropylidene (MIP) acetal for
the transient protection of the 4-OH group, thus retain-
ing the D-2,6 protection pattern. Acid hydrolysis of the
orthobenzoate cage now allows the creation of benzoate
esters at O-1 or O-3 of the myo-inositol ring, allowing dif-
ferentiation of either the 1- or the 3-hydroxyl group from
the other hydroxyl groups destined for phosphorylation.
Thus, D-1-O-benzoyl-2,6-di-O-benzyl-myo-inositol 6 is a
Previously, we have shown that chiral desymmetrisation
of 16 and 23a by the formation of diastereoisomeric 2,4-
and 2,6-bis[(1S)-(ꢀ)-camphanate] esters can provide
rapid routes to two physiologically important inositol
phosphates,7 inositol 1,3,4,5-tetrakisphosphate [Ins-
(1,3,4,5)P4]6 and inositol 1,4,5-trisphosphate [Ins(1,4,5)-
P3],3a respectively. For ongoing investigations into the
*
Corresponding author. Tel.: +44 1225 386693; fax: +44 1225
386114; e-mail: B.V.L.Potter@bath.ac.uk
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.008

172
A. M. Riley et al. / Tetrahedron: Asymmetry 17 (2006) 171–174
R
(a)
(b)
OH
OH
OH
1
HO
OPO3H2 H2O3PO
O
OR
O
O
1
5
3
4
P
1
5
4 O
3
4
5
OH
O
H2O3PO
OH
H2O3PO
OH
1
OH
6
2
OPO3H2
OPO3H2
OH
1 R = H
2 R = Me
3 R = Ph
Ins(1,3,4,5)P4 R1 = H
Ins(1,4,5)P3
PtdIns(3,4,5)P3 R1 = DAG
(c)
Ins(1,4,5)P3 and
Ins(1,3,4,5)P4 analogues
Ins(1,3,4,5)P4 and
PtdIns(3,4,5)P3 analogues
OH
O
O
2
1
Probes and conjugates
linked through O-3
or 3-phosphate
Probes and conjugates
linked through O-1,
1-phosphate or DAG
3
4
6
5
H2O3PO
OH
1-Phosphate surrogates
OPO3H2
3-Phosphate surrogates
Figure 1. (a) myo-Inositol 1,3,5-orthoesters 1, 2 and 3; (b) Inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol
3,4,5-trisphosphate; (c) Regioselectively modified analogues of Ins(1,4,5)P3, Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3 accessible from 3. Compounds are
shown with 1D-numbering. DAG = diacylglycerol.
myo-inositol with a slight excess of trimethyl ortho-
benzoate in dry DMSO at 80 ꢁC in the presence of a cat-
alytic amount of camphorsulfonic acid. By distilling off
b
a
O
O
O
O
formed MeOH (e.g., by carrying out the reaction in a
rotary evaporator), shorter reaction times can be used.
Alternatively, DMF can be used as a solvent, although
higher temperatures (>140 ꢁC) and larger amounts of
catalyst and trimethyl orthobenzoate are required. After
neutralisation with triethylamine and removal of sol-
vents, a solution of the residue in hot EtOAc is filtered
through a silica pad to remove coloured and polar mate-
rials, then reduced in volume and allowed to cool, giving
crystals of 3 [Rf 0.40 (EtOAc); mp 213–214 ꢁC] in 84%
yield. More 3 can be obtained by flash chromatography
of the mother liquor if required. A single-crystal X-ray
structure of 312 was obtained (Fig. 2).
O
O
myo-inositol
O(-)camph
OH
OH
OH
OH
O(-)camph
3
4
c
O
O
OBn
HO
HO
HO
BnO
(-)camph =
OH
8
O
d,e
O
O
O
OBn
HO
d
OBn
BzO
+
HO
OBn
HO
OBz
OH
HO
HO
OH
BnO
BnO
2.3. Isolation of D-2,6-di-O-[(ꢀ)-camphanoyl]-myo-inosi-
OBn
tol orthobenzoate 4
5
6
7
Scheme 1. Reagents and conditions: (a) Trimethyl orthobenzoate
(1.1 equiv), camphorsulfonic acid (0.02 equiv), DMSO, 80 ꢁC, 5 h,
84%; (b) (1S)-(ꢀ)-camphanic chloride (2.1 equiv), triethylamine
(2.3 equiv), DMAP (0.06 equiv), CH2Cl2, 0 ꢁC to rt, 66%; (c) (i) 2-
methoxypropene (10 equiv), PTSA (0.02 equiv), THF, 0 ꢁC to rt; (ii)
LiOHÆH2O (10 equiv), THF, MeOH, H2O; (iii) NaH, BnBr, DMF; (iv)
wet CH2Cl2, trace of TFA, 85% from 4; (d) 1.0 M HCl, ethanol, 1:2,
reflux, 5 h, 6: 48%, 7: 41%; (e) NaOH, H2O, reflux, 8: 98% from 5.
Bn = benzyl, Bz = benzoyl.
Reaction of
3
with (1S)-(ꢀ)-camphanic chloride
(2.1 equiv) in CH2Cl2 in the presence of triethylamine
and a catalytic amount of DMAP13 gave a mixture of
the 2,6-bis(camphanate) 4, together with the more polar
2,4-bis(camphanate).14 The use of other solvents (pyri-
dine, acetonitrile or DMF) was less successful, giving
substantial amounts of mono- and tris(camphanate).
The D-2,6-bis(camphanate) 4, which is the required pre-
cursor for Ins(1,4,5)P3, Ins(3,4,5)P3, Ins(1,3,4,5)P4 and
PtdIns(3,4,5)P3 analogues, has low solubility in most
organic solvents, and can be easily isolated by crystalli-
sation. The absolute configuration of 4 was determined
as described below. Crystalline 4 is stable, although
neutral or alkaline solutions of 4 show slow hydrolysis
and migration of the camphanate group at O-6.
synthetic precursor for Ins(3,4,5)P3, P-1-tethered
Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3 analogues,8 while
8,9
D-3-O-benzoyl-2,6-di-O-benzyl-myo-inositol 7 is a pre-
cursor for Ins(1,4,5)P3 and P-3-tethered Ins(1,3,4,5)P4.
They are also precursors for potential Ins(1,3,4,5)P4 bio-
isosteres, in which either the 1- or 3-phosphate group is
selectively replaced by a phosphate surrogate, such as
phosphorothioate,10 or methylphosphonate.11
2.4. Conversion of 4 into D-2,6-di-O-benzyl-myo-inositol
orthobenzoate 5
2.2. Synthesis of myo-inositol orthobenzoate 3
In the next step, the camphanate esters in 4 are replaced
with benzyl ethers. This sequence of reactions was car-
ried out without isolation of intermediates, requiring
only a final purification step by flash chromatography.
Thus, the reaction of 4 with 2-methoxypropene in the
myo-Inositol orthobenzoate 3 was prepared by a method
similar to that reported for the preparation of myo-
inositol orthopentanoate,3b using transesterification of

A. M. Riley et al. / Tetrahedron: Asymmetry 17 (2006) 171–174
173
Figure 2. Portion of lattice packing in 3, showing C–Hꢁ ꢁ ꢁp interactions. Ellipsoids are represented at the 30% probability level.
presence of a catalytic amount of PTSA in THF gives
the 4-O-MIP acetal, and addition of LiOHÆH2O in
MeOH/H2O to the solution then cleaves the campha-
nate esters in situ. After evaporation of solvents and
aqueous workup, benzylation at O-2 and O-6 followed
by selective cleavage of the MIP acetal using a trace of
acid gives 5,15 isolated by flash chromatography in
85% yield from 4.16 Thus, pure 5 can readily be obtained
on a multi-gram scale from myo-inositol.
the 1-OH or 3-OH group is now available for selective
modification. Alternatively, hydrogenolysis of 6 or 7
gives D-1-O-benzoyl-myo-inositol22 or D-3-O-benzoyl-
myo-inositol,22,23 respectively, precursors for Ins-
22,24
(2,3,4,5,6)P5
and Ins(1,2,4,5,6)P5.22,24
3. Conclusion
myo-Inositol orthobenzoate 3 is a versatile new starting
material for the synthesis of myo-inositol phosphates
and lipids. Chiral desymmetrisation of 3 allows fast
access to orthogonally protected chiral intermediates,
which are precursors for a range of analogues and
conjugates related to Ins(1,4,5)P3, Ins(1,3,4,5)P4 and
PtdIns(3,4,5)P3.
2.5. Hydrolysis and absolute configuration of 5
Hydrolysis of 5 using aqueous HCl in refluxing EtOH
gave a 1.2:1 mixture of 1-O-benzoate ester 6 and 3-O-
benzoate ester 7. No 5-O-benzoate was detected under
these conditions.17 The triols differ strikingly in their
polarity, and can be easily separated by flash chroma-
tography, giving 6 and 7 as crystalline solids.18 Hydroly-
sis of 5 followed by saponification of the resulting
mixture of 1- and 3-O-benzoates gave D-2,6-di-O-benzyl
myo-inositol 8. The absolute configuration of 8, and
thereby that of compounds 4, 5, 6 and 7 was established
by comparison of its specific rotation with the literature
values.19
Acknowledgements
We thank the Wellcome Trust for Programme Grant
support (060554) and Drs B. Cannan and P. R. J. Gaff-
ney, for helpful discussions.
References
2.6. Synthetic utility of benzoates 6 and 7
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6.91 mmol, 66%) after drying in vacuo at 30 ꢁC; mp 238–
20
240 ꢁC; ½aꢂD ¼ ꢀ19:4 (c 0.9, DMF); 1H NMR d 0.97, 0.99,
1.06, 1.07, 1.15, 1.19 (6 · s, 18H, CH3 of camph), 1.58–1.68
(m, 2H, CH2 of camph), 1.98–2.14 (m, 4H, CH2 of camph),
2.50–2.61 (m, 2H, CH2 of camph), 4.57 (dddd, appears as
dq, 1H, J = 3.8, 1.9, 1.9, 1.9 Hz, H-3), 4.72–4.77 (m, 3H,
H-1, H-4 and H-5), 5.58 (dd, appears as t, 1H, J = 1.6,
1.6 Hz, H-2), 5.67 (ddd, appears as td, 1H, J = 3.8, 3.8,
1.6 Hz, H-6), 6.37 (d, 1H, J = 4.6 Hz, 4-OH), 7.42–7.46 (m,
3H, Ph) and 7.63–7.65 (m, 2H, Ph); 13C NMR (100 MHz,
d7-DMF) d 9.75, 9.80, 16.41, 16.64, 16.71 and 16.84
(6 · CH3 of camph), 29.26, 29.32, 31.09 and 31.51 (4 · CH2
of camph), 54.76, 54.80, 55.19 and 55.31 (4 · Cq of camph),
64.69 (C-2), 67.00, 70.28, 70.46 and 71.19 (4 · inositol CH),
73.83 (C-3), 91.67 and 91.69 (2 · Cq of camph), 108.13
(PhCO3), 126.11 and 128.56 (Ph CH), 130.15 ( para-CH of
Ph) and 138.11 (ipso-C of Ph); MS (FAB+) 627 [(M+H+),
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calcd for C33H38O12 (626.65): C, 63.25; H, 6.11. Found:
C, 63.0; H, 6.10.
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favours the 2,6-bis(camphanate) 4, whose low solubility
makes isolation of the minor product [2,4-bis(campha-
nate)] more difficult. If the method is to be used specifi-
cally for synthesis of intermediates with the 2,4-protected
pattern, the reaction can be carried out using (1R)-
(+)-camphanic chloride. This material is commercially
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details of its preparation were given.
13. Typical procedure: myo-inositol orthobenzoate 3 (2.80 g,
10.5 mmol) previously dried in vacuo at 60 ꢁC, was
suspended in dry CH2Cl2 (40 mL). Dry triethylamine
(3.3 mL, 24 mmol) and a catalytic amount of DMAP
(80 mg) were added, and the mixture cooled to 0 ꢁC. Solid
(1S)-(ꢀ)-camphanic chloride (4.55 g, 21.0 mmol) was
added in portions to the stirred mixture over 15 min. After
1.5 h, the cooling bath was removed and the mixture
allowed to reach room temperature. After 2 h at room
temperature, TLC (CH2Cl2/EtOAc 3:1) showed two prod-
ucts; 2,6-bis(camphanate), (Rf 0.52) and 2,4-bis(campha-
nate) (Rf 0.42), together with a trace of monocamphanates
(Rf 0.25). A small amount of (1S)-(ꢀ)-camphanic chloride
(approx. 100 mg) was added and stirring continued for
another 1 h. This step was repeated until no trace of
monocamphanates remained. The solvents were removed
by evaporation under reduced pressure. The residue was
taken up in CH2Cl2/CH3CN (5:1, 100 mL) and the
15. Data for 5: colourless crystals from EtOAc/hexane, mp
20
84.5–85.5 ꢁC; ½aꢂD ¼ þ3 (c 1, CHCl3).
16. When alcohol 5 was esterified with (1S)-(ꢀ)-camphanic
chloride, a single product was obtained, while esterifica-
tion of racemic 5 in the same way gave two diastereoiso-
meric products, clearly distinguishable by TLC and by
1H NMR spectroscopy. Thus, no detectable migration of
camphanate or MIP groups takes place during the
conversion of 4 into 5.
17. Acid hydrolysis of 2,6-di-O-benzyl-myo-inositol ortho-
acetate under similar conditions gives only 1-O-acetyl-2,6-
di-O-benzyl myo-inositol and tetraol 8 (Liu, C.; Potter, B.
V. L., unpublished results).
18. Data for 6: Rf 0.32 (EtOAc); colourless crystals from
20
ether/hexane, mp 110–110.5 ꢁC; ½aꢂD ¼ ꢀ118:9 (c 1,
MeOH). Data for 7: Rf 0.70 (EtOAc); colourless crystals
20
from EtOAc/hexane, mp 171–173 ꢁC; ½aꢂD ¼ þ36:7 (c 1,
MeOH).
19. Data for 8: mp 144–146 ꢁC (from CHCl3); Lit.4b 145.2–
20
25
146.1 ꢁC; ½aꢂD ¼ ꢀ32:3 (c 1, EtOH); Lit.4b ½aꢂD ¼ ꢀ29:3
(c 1, EtOH).
´
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