Versatile synthesis of myo-inositol phospholipid precursors

Article abstract of DOI:10.1039/a703044d

Homochiral myo-inositol derivatives 16 and 20 and their corresponding enantiomers possessing either the natural or unnatural ring stereochemistry for inositol phospholipids are synthesised from myo-inositol derivatives 8 and 9 respectively using camphor d

Full text of DOI:10.1039/a703044d

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Versatile synthesis of myo-inositol phospholipid precursors
Simon J. A. Grove,a Ian H. Gilbert,a Andrew B. Holmes,*a,b Gavin F. Paintera,b and Malcolm L. Hillc
a Cambridge Centre for Molecular Recognition, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW
b Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Pembroke Street, Cambridge,
UK CB2 3RA
c GlaxoWellcome, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK SG1 2NY
Homochiral myo-inositol derivatives 16 and 20 and their
corresponding enantiomers possessing either the natural or
unnatural ring stereochemistry for inositol phospholipids
are synthesised from myo-inositol derivatives 8 and 9
respectively using camphor dimethyl acetals in a resolution–
protection sequence.
MeO
MeO
(–)-10
OMe
OMe
(+)-10
The biological importance of various inositol phosphates and
inositol phospholipids in cell signal transduction and related
processes is well documented.1 In most cases these compounds
are not readily available in any quantity from natural sources
owing to their low cellular concentrations.2 Consequently their
synthesis3 has received extensive attention in recent years.
Despite this effort many inositol derivatives are still not readily
available, owing in part to the lack of availability of suitably
protected homochiral myo-inositol derivatives.4 Here we pre-
sent concise routes to differentially protected ring enantiomers
of myo-inositol compounds which are suitable starting materials
for the synthesis of myo-inositol phospholipids.
The readily available triol 15 was chemoselectively p-meth-
oxybenzylated6 to give the diol 2 which was then benzylated to
afford the fully protected derivative 3 (Scheme 1).† A
regioselective DIBAL-H reduction7,8 of the orthoformate 3
furnished the liberated alcohol 4 as a single isomer in high yield,
the structure of which was confirmed by NMR experiments
performed on the acetate 5. Benzylation or allylation of the
alcohol 4 afforded the required intermediates 6 and 7,
respectively. Acidic hydrolysis resulted in the simultaneous
cleavage of the acetal and p-methoxybenzyl ether groups to give
the racemic triols 89 and 9 in overall yields of 58 and 56%,
respectively, from the triol 1.
Treatment4 of 8 with (1R)-(+)-camphor dimethyl acetal 10
afforded a diastereoisomeric mixture of acetals 11–14 (Scheme
2). This procedure allowed simultaneous protection–resolution
of (±)-8.
O
O
O
O
O
OR
iii
R1O
BnO
98%
R1O
BnO
OR2
From this mixture the acetal (+)-11 was isolated by flash
chromatography in a yield of 31%, and the remaining acetals
were obtained in a combined yield of 59%. The stereochemistry
of the acetal (+)-11 was determined by chemical correlation and
NMR experiments. Mild acid hydrolysis (MeOH–AcCl) af-
forded the triol (+)-8,10,11 which corresponds to the unnatural
ring configuration for inositol phospholipids.
OPMB
1 R1 = R2 = H
2 R1 = H, R2 = PMB
3 R1 = Bn, R2 = PMB
4 R = H
i
iv
ii
69%
v
97%
93%
6 R = Bn
7 R = Allyl
5 R = Ac
92%
ii
94%
vi
91–96%
BnO
OH
OBn
OR
Acetylation of the hydroxy group of (+)-11 gave the acetate
(+)-15 for which a positive NOE was observed between the
signal due to the d-1-inositol ring proton and that of the
HO
OH
(±)-8 R = Bn
(±)-9 R = Allyl
1
camphor 3A-Hendo methylene proton in the H NMR spectrum.
Since no enhancement of the methyl resonances was observed
upon irradiation of the d-1-inositol ring proton, the stereoche-
mistry of 15 was assigned as 1d-1-O-endo-6-O-exo (Fig. 1).
The chromatographically inseparable mixture of acetals
enriched in 13 and 14 is also a source of (2)-11 (Scheme 3).
Scheme 1 Reagents and conditions: i, NaH, p-MeOC6H4CH2Cl (PMBCl),
DMF, 0 °C to room temp.; ii, NaH, BnBr, DMF, 0 °C to room temp.; iii,
DIBAL-H (2.5 equiv.), CH2Cl2–hexanes, 0 °C to room temp.; iv, NaH, allyl
bromide, DMF, 0 °C to room temp.; v, Ac2O, DMAP, pyridine, room temp.;
vi, HCl, MeOH, reflux.
BnO
O
BnO
RO
BnO
O
BnO
HO
OH
O
OH
i
O
(±)-8
OBn
OBn
O
OBn
OBn
OBn
+
+
+
O
OBn
O
OBn
(+)-11 R = H
(+)-15 R = Ac
O
OBn
12
ii
iii
97%
BnO
OH
14
13
OH
OBn
HO
(+)-8
OBn
Scheme 2 Reagents and conditions: i, (+)-10 (2.3 equiv.), TsOH (cat.), CH2Cl2, reflux; ii, Ac2O, DMAP, pyridine, room temp.; iii, AcCl, CH2Cl2–MeOH
(2:1)
Chem. Commun., 1997
1633

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3-hydroxy group using Gigg’s procedure12 (dibutytin oxide,
Bu4NBr and BnBr) furnished the 4-alcohol (2)-22 in 60%
yield. Cleavage of the 5-allyloxy ether would then lead to a
suitable precursor for the preparation of PtdIns(4,5)P2.
In conclusion, the combination of a meso starting material,
high yielding protection–deprotection sequences and especially
a combined resolution–protection strategy, involving the cam-
phor acetals 10, provides ready access to a number of myo-
inositol phospholipid precursors. In the accompanying commu-
nication we describe the reduction of this concept to practice.
We thank the EPSRC and BBSRC for financial support and
provision of the Swansea Mass Spectrometry Service, Glaxo
Wellcome and SmithKline Beecham Pharmaceuticals for
CASE studentships (to S. J. A. G. and I. H. G. respectively), and
Drs D. R. Marshall and R. Young for their interest in this
work.
OBn
O
AcO
H
BnO
BnO
Me
O
H
H
NOE
Me
Me
(+)-15
Fig. 1 Assignment of relative stereochemistry of the acetal (+)-15 by NOE
measurement
i
93%
BnO
OR
BnO
HO
i, ii
OPMB
OBn
OBn
12–14
+
inseparable
acetals
OBn
OBn
O
O
OH
(–)-16
Footnotes and References
* E-mail: abh1@cus.cam.ac.uk
(–)-11 R = H
(–)-23 R = PMB
iii
98%
† All new compounds exhibited satisfactory spectroscopic and analytical
data. Selected data (J values in Hz) for (2)-16: mp 153–154 °C; [a]2D2 214.9
(c 1.6 in CHCl3); dH(400 MHz; CDCl3) 7.39–7.23 (17 H, m), 6.86–6.83 (2
H, m), 5.04 (1 H, d, J 11.5), 4.94 (1 H, d, J 10.7), 4.93 (1 H, d, J 11.2), 4.82
(1 H, d, J 10.8), 4.75 (1 H, d, J 11.5), 4.67–4.60 (3 H, m and 1 H, t, J 9.4),
3.98 (1 H, t, J 2.6), 3.82 (1 H, td, J 9.6, 2.0), 3.80 (3 H, s), 3.46 (1 H, dd, J
9.8, 2.4), 3.36 (1 H, ddd, J 9.7, 7.8, 3.8), 3.31 (1 H, t, J 9.2), 2.42 (1 H, d,
J 2.1), 2.25 (1H, d, J 7.8). For (2)-20: mp 136 °C; [a]2D2 25.9 (c 1.6 in
CHCl3); dH(400 MHz; CDCl3) 7.34–7.23 (12 H, m), 6.86–6.83 (2 H, m),
5.03 (1 H, d, J 11.5), 4.97 (1 H, d, J 11.2), 4.74 (1 H, d, J 11.2), 4.66 (1 H,
d, J 11.5), 4.62 (2 H, s), 3.99 (1 H, t, J 2.6), 3.82 (1 H, t, J 9.4), 3.80 (3 H,
s), 3.73 (1 H, br t, J 9.4), 3.44 (1 H, dd, J 9.7, 2.4), 3.38–3.33 (2 H, m), 2.95
(1 H, br s), 2.72 (1 H, br s), 2.46 (1 H, d, J 7.9).
Scheme 3 Reagents and conditions: i, AcCl, CH2Cl2–MeOH (2:1); ii,
(2)-10, TsOH, CH2Cl2, reflux; iii, NaH, PMBCl, DMF
Hydrolysis of the mixture, followed by reacetalisation with the
enantiomeric camphor dimethyl acetal (2)-10 afforded after
purification (2)-11 in 40% yield (25% from racemic 8).
p-Methoxybenzylation of (2)-11 gave the PMB ether (2)-23
which yielded the diol (2)-1610 on mild acidic hydrolysis. The
diol (2)-16 contains a suitable functional group array for
elaboration to PtdIns(3,4)P2.
In a similar protection–resolution sequence using the 5-ally-
loxy-1,3,4-triol 9, the enantiomeric acetals (2)-17 and (+)-17
were obtained in 27 and 24% yield, respectively, (Scheme 4). p-
Methoxybenzylation of the 1-hydroxy group of (2)-17 gave
(2)-18. Cleavage of the 5-allyloxy and 3,4-acetal groups gave
(2)-20.11 The triol 20 is a suitable precursor for elaboration to
PtdIns(3,4,5)P3.
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Finally, mild acidic hydrolysis of the 3,4-acetal (2)-18
afforded the diol (2)-21 (Scheme 5). Monobenzylation of the
BnO
HO
BnO
O
OH
OR
i– iii
OBn
OAll
OBn
OAll
+
BnO
HO
O
OH
(±)-9
O
O
OAll
OBn
(+)-17
iv
99%
(–)-17 R = H
(–)-18 R = PMB
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v, ii
81%
BnO
OPMB
OBn
OH
HO
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OH
(–)-20
Scheme 4 Reagents and conditions: i, (2)-10, TsOH, CH2Cl2, reflux, then
separate; ii, AcCl, CH2Cl2–MeOH (2:1); iii, (+)-10, TsOH, CH2Cl2, reflux;
iv, NaH, PMBCl, DMF; v, (Ph3P)3RhCl, DABCO, EtOH–toluene–H2O
(7:3:1), reflux
11 A. M. Riley, R. Payne and B. V. L. Potter, J. Med., Chem., 1994, 37,
3918.
BnO
BnO
OPMB
OPMB
ii
12 T. Desai, A. Fernandez-Mayoralas, J. Gigg, R. Gigg, C. Jaramillo,
S. Payne, S. Penades and N. Schentz, in Inositol Phosphates and
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463, p. 86.
i
OBn
OAll
OBn
OAll
(–)-18
HO
BnO
85%
60%
OH
(–)-21
OH
(–)-22
Scheme 5 Reagents and conditions: i, AcCl, CH2Cl2–MeOH (2:1); ii,
Bu2SnO, Bu4NBr, BnBr, MeCN, reflux
Received in Glasgow, UK, 6th May 1997; 7/03044D
1634
Chem. Commun., 1997