Synthesis of L-α-phosphatidyl-D-myo-inositol 3,5-bisphosphate from D-glucose

Article abstract of DOI:10.1016/S0040-4039(01)01946-3

Efficient synthesis of L-α-phosphatidyl-D-myo-inositol 3,5-bisphosphate was achieved from 1,2,5,6-diisopropylidene-D-glucose by utilizing ring-closing metathesis and catalytic OsO₄ dihydroxylation.

Full text of DOI:10.1016/S0040-4039(01)01946-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9195–9198
Synthesis of
L
-a-phosphatidyl-
D
-myo-inositol 3,5-bisphosphate
from
D-glucose
Asuka Nishikawa,a,b Shintaro Saito,a Yuichi Hashimoto,b Kenji Kogaa and Ryuichi Shiraia,*
aResearch and Education Center for Materials Science, Nara Institute of Science and Technology, 8916-5 Takayama-cho,
Ikoma-shi, Nara 630-0101, Japan
bInstitute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
Received 7 September 2001; revised 9 October 2001; accepted 12 October 2001
Abstract—Efficient synthesis of
L
-a-phosphatidyl-
D-myo-inositol 3,5-bisphosphate was achieved from 1,2,5,6-diisopropylidene-D-
glucose by utilizing ring-closing metathesis and catalytic OsO4 dihydroxylation. © 2001 Elsevier Science Ltd. All rights reserved.
L
-a-Phosphatidyl-
D
-myo-inositol (PI) and its phos-
To supply suitably protected optically active myo-inosi-
tol derivatives with appropriate stereogenic centers,
Ferrier rearrangement,9,10 pinacol coupling11 and ring-
closing metathesis (RCM)12 of chiral intermediates
derived from precursors such as carbohydrates have
been performed in addition to optical resolution of
myo-inositol derivatives. In 1996, we reported the facile
asymmetric synthesis of myo-inositol derivatives via a
1,7-diene intermediate, which was synthesized from tar-
taric acid with complete stereocontrol.11d Since then,
several reports have appeared by other groups employ-
ing 1,7-dienes as key synthetic intermediates.11e,12,13 In
this communication, we describe an efficient asymmet-
ric synthesis of PI 3,5P2 (1b), a novel lipid analog of
1a,14,† by RCM of a properly protected 1,7-diene (4)
phates (PIPn) play important roles as second messen-
gers in intracellular signal transduction.1 We have
already reported the synthesis of various lipid analogs
of PIPns as artificial second messengers and biochemi-
cal probes.2–4 Recently,
L
-a-phosphatidyl-D-myo-inosi-
tol 3,5-bisphosphate (PI 3,5-P2, 1a) was identified as a
novel phosphoinositide (Fig. 1).5 In mouse cells, PI
3,5-P2 is synthesized by phosphorylation of PI 3-P at
the
D
-5 position by Fab 1.6 Several studies have shown
that PI 3,5-P2 production is essential for sorting mem-
brane proteins into the lumen of the yeast vacuole7 and
for the maintenance of vacuolar size.8 Although PI
3,5-P2 may be important for membrane homeostasis,
its biological role has not yet been defined clearly.
OR1
R2O
OH
O
(NaO)2OPO
HO
O P O
ONa
PI 3,5-P2 (1a): R1=stearoyl, R2=arachidonoyl
(1b): R1=stearoyl, R2=butyryl
OH
OPO(ONa)2
Figure 1.
Keywords: asymmetric synthesis; cyclitols; hydroxylation; inositols; metathesis; phospholipids; phosphoramidites.
* Corresponding author. Tel.: +81-743-72-6171; fax: +81-743-72-6179; e-mail: rshirai@ms.aist-nara.ac.jp
†
According to our previous results, PI and PIP3 lipid analogs having a short saturated side chain at the sn-2 position were excellent substrates
of PI 3-kinase and PIP3 5-phosphatase, respectively, while analogs with a long saturated side chain were not. Therefore, we employed butyrate
as the sn-2 side chain of PI 3,5-P2, taking account of the potential biochemical application. See Ref. 3.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01946-3

9196
A. Nishikawa et al. / Tetrahedron Letters 42 (2001) 9195–9198
O
O
OH
H
R1O
R2O
OH
cat. OsO4 R1O
R2O
R1O
R2O
RCM
O
O
OR2
OR2
OR2
HO
O
OR1
OR1
OR1
key intermediate
1,7-diene (4)
1,2,5,6-O-diisopropylidene-
D-glucose (5)
3
2
Scheme 1.
H
H
OHC
BnO
H
O
O
a, b, c
d
e, f
O
O
HO
BnO
BnO
BnO
5
O
OH
OH
O
O
6
7
8
HO
HO
PMBO
BnO
g
j
h
i
BnO
OBn
BnO
OBn
OBn
OPMB
OH
OH
9
11
10
OH
OH
OH
OBz
PMBO
BnO
OH
PMBO
BnO
OH
PMBO
BnO
OBz
OBn
PMBO
BnO
OH
k
+
+
OBn
OPMB
OBn
OPMB
OBn
OPMB
OPMB
12a
1 : 1
12b
13a
13b
Scheme 2. (a) NaH, BnBr, DMF, 89%; (b) 60% aq. AcOH, rt, 95%; (c) NaIO4, aq. NaHCO3, CH2Cl2, rt, 2 h, 73%; (d)
vinylmagnesium bromide (3.0 equiv.), CuBr–Me2S (3.4 equiv.), THF–Me2S, −40°C“rt, 2 h, 59%; (e) NaH, BnBr, DMF, 95%; (f)
80% AcOH, 70°C, 2 days, 92%; (g) MePPh3Br, n-BuLi, ether, rt, overnight, 68%; (h) Cl2(PCy3)2RuꢀCHPh (10 mol%), CH2Cl2,
rt, 1 h, 85%; (i) NaH, PMBCl, DMF, 92%; (j) OsO4 (5 mol%), quinuclidine (5 mol%), NMO, CH2Cl2, rt, overnight, 98% (1:1
mixture of diastereoisomers); (k) BzCl (1.2 equiv.), pyridine, DMAP, 67% (+dibenzoates 27%).
derived from
dihydroxylation (Scheme 1).
D
-glucose, followed by catalytic OsO4
the C-2 hydroxy group as the benzyl ether, isopropyli-
dene acetal was hydrolyzed with aq. AcOH to give the
hemiacetal (8), which was subjected to Wittig methylena-
tion to give the 1,7-diene (9). Ring-closing metathesis of
9 using Grubbs’ catalyst Cl2(PCy3)2RuꢀCHPh17 gave the
cyclohexene (10) in 85% yield, and then two hydroxyl
groups were protected as the PMB ether. The dihydroxy-
lation of 11 utilizing a catalytic amount of osmium
tetroxide with quinuclidine and NMO as co-oxidant gave
the cis-diols (12a, 12b) in 98% yield as an equimolar
mixture of diastereoisomers by 1H NMR analysis. Selec-
tive benzoylation of equatorially oriented hydroxyl
groups of this mixture gave the benzoates (13a, 13b),
which were separated by silica gel column chromatogra-
phy. Benzyloxymethylation of the desired 13a followed
by methanolysis of the benzoate afforded the appropri-
ately protected myo-inositol (15) (Scheme 3).
The 1,2-addition of an organocopper reagent prepared
from vinylmagnesium bromide and CuBr–Me2S to the
known aldehyde (6) prepared from 1,2,5,6-diisopropyli-
dene- -glucose gave the desired allyl alcohol (7) as
D
the sole product (Scheme 2).15,16,‡ After protection of
‡ The 1,2-addition of vinylmagnesium bromide to the aldehyde 6 took
place with no selectivity (7:epi-7=1.25:1). Stereochemistry of these
products was established by the comparison of the 1H NMR
spectrum of 11 derived from a known bisallyl alcohol. See Ref. 11d.
1H NMR of 11 (CDCl3, 500 MHz) l 3.68 (1H, d, J=5.1 Hz), 3.69
(1H, d, J=5.1 Hz), 3.79 (6H, s), 4.17 (1H, d J=5.1 Hz), 4.18 (1H,
d, J=5.1 Hz), 4.60 (1H, d, J=11.1 Hz), 4.64 (1H, d, J=11.1 Hz),
4.67 (1H, d, J=11.6 Hz), 4.71 (1H, d, J=11.6 Hz), 4.77 (1H, d,
J=10.4 Hz), 4.84 (1H, d, J=10.4 Hz), 4.85 (1H, d, J=11.0 Hz),
4.92 (1H, d, J=11.0 Hz), 5.69 (1H, s), 5.70 (1H, s), 6.82 (2H, d,
J=8.6 Hz), 6.84 (2H, d, J=8.6 Hz), 7.22–7.26 (4H, m), 7.28–7.37
(10H, m)
The coupling of 15 with phosphoramidite (16), in the
presence of 1H-tetrazole, followed by m-CPBA oxida-

A. Nishikawa et al. / Tetrahedron Letters 42 (2001) 9195–9198
9197
OBOM
OBOM
OH
PMBO
BnO
OBz
PMBO
BnO
a
b
13a
OBn
OBn
OPMB
15
OPMB
14
Scheme 3. (a) BOMCl, diisopropylethylamine, tetra-n-butylammonium bromide, CH2Cl2, 70°C, 2 days, 30% (recovered 13a 68%);
(b) K2CO3, MeOH, rt, 4 h, quant.
OCOC17H35
OCOC17H35
C3H7CO2
OBOM O
C3H7CO2
OH
OCOC17H35
O
C3H7CO2
(NaO)2OPO
HO
O P O
ONa
PMBO
BnO
O P O
OBn
OBn
OPMB
b, c, d
a
O
P
OH
i-Pr2N
OBn
OPO(ONa)2
16
1b
17
Scheme 4. (a) 15, 1H-tetrazole (8.0 equiv.), CH2Cl2, rt, 2.5 h, then m-CPBA (4.2 equiv.), −78°C“rt, 45 min, quant.; (b) DDQ
(3.0 equiv.), wet CH2Cl2, rt, 2.5 h, 52%; (c) (BnO)2PNEt2 (5.7 equiv.), 1H-tetrazole (6.0 equiv.), CH2Cl2, rt, 2.5 h, then m-CPBA
(8.0 equiv.), −78°C“rt, 30 min, 82%; (d) H2 (4.3 kgf/cm2), Pd black, NaHCO3, tert-BuOH/H2O, quant.
tion gave the phosphodiester 17 (Scheme 4). PMB
protecting groups of 17 were oxidatively removed by
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and
the free hydroxyl groups were phosphorylated by the
amidite method to give the fully protected PI 3,5-P2
precursor. Finally, hydrogenolysis with Pd black as a
catalyst in the presence of NaHCO3 gave PI 3,5-P2 (1b)
as the sodium salt.§
8347–8350.
2. PI lipid analogs: Shirai, R.; Morita, K.; Nishikawa, A.;
Nakatsu, N.; Fukui, Y.; Morisaki, N.; Hashimoto, Y.
Tetrahedron Lett. 1999, 40, 1693–1696.
3. PIP3 lipid analogs: (a) Sawada, T.; Shirai, R.; Matsuo, Y.;
Kabuyama, Y.; Kimura, K.; Fukui, Y.; Hashimoto, Y.;
Iwasaki, S. Bioorg. Med. Chem. Lett. 1995, 5, 2263–2266;
(b) Sawada, T.; Shirai, R.; Iwasaki, S. Chem. Pharm. Bull.
1997, 45, 1521–1523; (c) Shirai, R.; Morita, K.; Nakatsu,
N.; Fukui, Y.; Hashimoto, Y. Tetrahedron Lett. 1998, 39,
9485–9488; (d) Morisaki, N.; Morita, K.; Nishikawa, A.;
Nakastsu, N.; Fukui, Y.; Hashimoto, Y.; Shirai, R. Tetra-
hedron 2000, 56, 2603–2614; (e) Morisaki, N.; Masaoka,
M.; Shirai, Y.; Hashimoto, Y. Biol. Pharm. Bull. 2000, 23,
1088–1089.
4. PIP3 binding protein: (a) Tanaka, K.; Imajoh-Ohmi, S.;
Sawada, T.; Shirai, R.; Hashimoto, Y.; Iwasaki, S.;
Kaibuchi, K.; Kanaho, Y.; Shirai, T.; Terada, Y.; Kimura,
K.; Nagata, S.; Fukui, Y. Eur. J. Biochem. 1997, 245,
512–519; (b) Shirai, T.; Tanaka, K.; Terada, Y.; Sawada,
T.; Shirai, R.; Hashimoto, Y.; Nagata, S.; Iwamatsu, A.;
Okawa, K.; Li, S.; Hattori, S.; Mano, H.; Fukui, Y.
Biochim. Biophys. Acta 1998, 1402, 292–302; (c) Yoko-
gawa, T.; Nagata, S.; Nishio, Y.; Tsutsumi, T.; Ihara, S.;
Shirai, R.; Morita, K.; Umeda, M.; Shirai, Y.; Saito, N.;
Fukui, Y. FEBS Lett. 2000, 473, 222–226; (d) Nishio, Y.;
Nagata, S.; Umeda, M. Shirai, R.; Yokogawa, T.; Ihara,
S.; Fukui, Y. Anal. Biochem. 2000, 285, 270–273.
5. Dove, S. K.; Cooke, F. K.; Douglas, M. R.; Sayers, L. G.;
Parker, P. J.; Michell, R. H. Nature 1997, 390, 187–192.
6. Whiteford, C. C.; Brearley, C. A.; Ulug, E. T. Biochem. J.
1997, 323, 597–601.
In conclusion, we achieved efficient construction of the
key 1,7-diene intermediate, which is adaptable for the
synthesis of not only a series of inositol analogs, but
also various six-membered cyclitols such as condritol B,
and we also successfully completed the total synthesis
of PI 3,5-P2 utilizing RCM and catalytic OsO4 dihy-
droxylation. Clarification of the biochemical function
of PI 3,5-P2 as a second messenger using this synthetic
product as a biological tool is in progress.
Acknowledgements
This work was supported in part by Grant-in-Aid for
Scientific Research (C) and a JSPS Fellowship (A.N.)
from the Japan Society for the Promotion of Science.
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