A stannylene strategy for regioselective acylation and phosphorylation of 1,2-cyclohexylidene-myo-inositol. Its convenient resolution and phosphatidylinositol synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.11.055

The bis(dibutylstannylene) derivative of 1,2-cyclohexylidene-myo-inositol reacted with (S)-O-acetylmandeloyl chloride and diphosphate tetraesters to give 3,6-dimandelate and 3-phosphate, respectively. Using the stannylene methodology for the optical resol

Full text of DOI:10.1016/j.tetlet.2004.11.055

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 281–284
A stannylene strategy for regioselective acylation
and phosphorylation of 1,2-cyclohexylidene-myo-inositol.
Its convenient resolution and phosphatidylinositol synthesis
Yutaka Watanabe,* Yoko Kiyosawa, Sayuri Hyodo and Minoru Hayashi
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Received 12 October 2004; revised 6 November 2004; accepted 10 November 2004
Available online 26 November 2004
Abstract—The bis(dibutylstannylene) derivative of 1,2-cyclohexylidene-myo-inositol reacted with (S)-O-acetylmandeloyl chloride
and diphosphate tetraesters to give 3,6-dimandelate and 3-phosphate, respectively. Using the stannylene methodology for the optical
resolution and regioselective phosphorylation of the ketal, a concise synthesis of phosphatidylinositol with the natural configuration
was accomplished.
Ó 2004 Elsevier Ltd. All rights reserved.
Synthesis of various inositol derivatives including physio-
logically important inositol phosphates and phosphati-
dylinositols has been reported.1 For this purpose, many
new synthetic methodologies have been developed.2
However, synthetic efficiency is still unsatisfactory,
mainly because of tedious protection–deprotection pro-
cedures. To overcome this drawback, chemo- and regio-
selective reactions of a minimally protected derivative
are required. In light of this consideration, we have
investigated selective reactions of 1,2-O-cyclohexylid-
ene-myo-inositol 1, which can be readily obtained by
ketalization of myo-inositol in good yield.3 According
to literatures concerning the reaction of 1,2-ketals (such
as 1 and camphor ketal) with electrophiles, selectivity
varied with the nature of electrophiles, and often the
yields were relatively low.4 We herein report the optical
resolution and phosphorylation of 1 via tin-mediated
regioselective acylation with O-acetylmandeloyl chloride
and phosphorylation with tetraalkyl pyrophosphate.
The utility of these results has been exemplified by rapid
synthesis of phosphatidylinositol.
meric mixture in 35% yield,4a,b accompanied with many
other products as analyzed by TLC and NMR. A sec-
ond mandeloylation of the product did not take place
selectively, yielding a complex mixture. The result was
different from that obtained by the reaction of camphor
ketal with pivaloyl chloride, where the 3,5-diacyl prod-
uct was obtained in a moderate yield.4c We then turned
our attention to employ a stannylene derivative, which
may be prepared in situ by the reaction of 1 with
2.2equiv of dibutyltin oxide in toluene under refluxing
conditions. A putative distannylene derivative of 1 thus
formed was then treated in situ in CH2Cl2 with 2.5equiv
of the chloride 2 and subsequently quenched with 3-
(dimethylamino)propylamine for easy removal of the
remaining chloride. Three diastereomeric products of
the reaction were separated easily by a flash silica gel
column chromatography, since they had quite different
Rf values. One of them was confirmed to be 3,6-diacy-
lated L-myo-inositol L-3 [42% yield, Rf = 0.35 (AcOEt/
C6H6 1:1)] and it was the only product with the L-form.5
As to a D-series of myo-inositol, 3-O-monoacyl deriva-
tive D-5 (20%, 0.10) as well as diacyl D-4 (10%, 0.55)
was isolated. When the reaction solvent was toluene,
diacylation proceeded smoothly with decrease in yield
of mono acylation products. However, the diacyl deriva-
tives obtained were contaminated with small amounts of
other positional isomers (Scheme 1).
The reaction of cyclohexylidene ketal 1 with (S)-O-acet-
ylmandeloyl chloride 2 (1.2equiv) in pyridine at ꢀ42°C
gave the expected 3-O-acylated product 5 as a diastereo-
Keywords: myo-Inositol; Cyclohexylidene-myo-inositol; Stannylene
derivative; Optical resolution; Selective phosphorylation; Phosphati-
dylinositol; O-Acetylmandelic ester.
Di- and monomandelates thus isolated were trans-
formed by hydrazinolysis to optically pure D- and L-
1,2-cyclohexylidene ketals D-1 and L-1 in quantitative
*
Corresponding author. Tel.: +81 899279921; fax: +81 899279944;
e-mail: wyutaka@dpc.ehime-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.055

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Y. Watanabe et al. / Tetrahedron Letters 46 (2005) 281–284
OAc
Cl
Ph
s
O
O
nBu2Sn=O
HO
HO
O
(2, AcMnd-Cl)
DL
toluene
reflux, 1 h
CH2Cl2
˚
OH
-20 C, 1 h
OH
DL-1
O
O
L
O
AcMndO
HO
O
O
OAcMnd
AcMndO
O
+
+
D
D
OAcMnd
AcMndO
OH
HO
OH
OH
OH
OH
L-3 (42%)
D-5 (20%)
D-4 (10%)
H2NNH2•H2O, EtOH
r.t., 3 h
99%
H2NNH2•H2O, EtOH
r.t., 3 h
96%
95%
O
L
O
O
O
OH
OH
HO
D
HO
HO
OH
OH
OH
L-1
D-1
Scheme 1. Optical resolution of cyclohexylidene-myo-inositol via mandeloylation of the stannylene intermediate.
yields, respectively. A mixture of D-series of the diacyl
and monoacyl derivatives was also converted to the
homochiral ketal D-1.5 Consequently, this chemical pro-
cedure provides a facile method for the preparation of
the synthetically important intermediate, chiral mono-
ketal. An optical resolution of the ketal 1 itself has been
only accomplished so far by the enzymatic process6 and
chemical method.4a
dramatically regulated and selectively gave 3-O-phos-
phates 6 in high yields. It should be noted that, even
though 4Mequiv of tetrabutyl pyrophosphate were
used, the monophosphate 6a was also obtained in very
good yield (95%), accompanied with no other products.
The phosphorylation position was confirmed by the
coupling multiplicity of the H-3 methine proton
(Scheme 2).8
Regioselective phosphorylation of cyclohexylidene ketal
1 via the same strategy as above was investigated. The
reaction of the stannylene derivative with dibutyl phos-
phorobromidate yielded messy products consisting of
mono-, bis-, and trisphosphates, contrary to the case
of the mandeloylation using the acid chloride. Accord-
ing to the literature, stannylene dialkoxide and tin alk-
The tin-mediated electrophilic substitutions, mainly
alkylation, acylation, and silylation are synthetically
useful tools.9 The stannylene intermediate has been of-
ten utilized for the mono-substitution of a vicinal diol
derivative, however, polyols are little used.10 The stann-
ylene strategy has now been shown to be satisfactory for
regioselective and high yield substitution reactions such
as acylation and phosphorylation of tetrol, 1,2-cyclo-
hexylidene-myo-inositol, while, in general, the selective
reaction of vicinal polyols are difficult. Indeed, direct
phosphorylation of the 1,2-ketal derived from myo-ino-
sitol and camphor with diethyl phosphorochloridate
(1.1equiv) in pyridine gave 3-O-phosphate in poor yield
oxide derived from vicinal triol or tetrol in
a
trisaccharide reacted regioselectively with dibenzyl
phosphoriodidate.7 In order to decrease the reactivity
of the phosphorylation reagent, we then chose a phos-
phoric anhydride. The reaction employing tetrabutyl
and tetrabenzyl diphosphates (pyrophosphates) was
O
O
1. nBu2Sn=O
O
HO
HO
O
(RO)2P O
O
toluene, reflux, 1 h
DL
DL
O
O
2.
OH
HO
OH
(RO)2P O P(OR)2
CH2Cl2, 0 C, 2 h,
then r.t., overnight
OH
DL-1
OH
˚
6a (R=n-Bu, 94%)
6b (R=Bn, 85%)
Scheme 2. Selective phosphorylation via a stannylene route.

Y. Watanabe et al. / Tetrahedron Letters 46 (2005) 281–284
283
O(O)CC15H31
O(O)CC15H31
O
L
O
O
O P O
OBn
1. nBu2Sn=O
O
OH
OH
O
O
HO
HO
OH
O
P
OBn
O-DPG
2.
2
OH
L-1
OH
8 (90%)
7
O(O)CC15H31
O(O)CC15H31
O
OH
O
HO
HO
P O
O- NH4
H2, 5%Pd-C
+
AcOEt
(commercial)
OH
OH
9 (86%)
Scheme 3. Synthesis of phosphatidylinositol.
(20%).4c We also found that the reaction of 1 with dibut-
yl phosphorobromidate (1.5equiv) in pyridine and
CH2Cl2 (1:1) gave a mixture of 3-O-phosphate (42%)
and 3,6-bisphosphate (11%).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2004.11.055.
References and notes
Using these results, preparation of optically active phos-
phatidylinositol was explored. Thus, the stannylene
derivative of L-1 reacted smoothly with 1,2-di-O-palmi-
toyl-sn-glycerol diphosphate 7 to furnish 1-O-phosphate
8 in 90% yield. Hydrogenolysis of 8 by 5% Pd/C in com-
mercial-grade ethyl acetate under a hydrogen atmo-
sphere resulted in the global deprotection to form the
final product 9.11 A trace of water in the AcOEt and
its nonprotic medium is likely to promote the deketaliza-
tion under co-operation with an acid catalyst of the
deprotected phosphate group, as demonstrated in a sim-
ilar compound where MeOH or aq MeOH in place of
AcOEt retarded the deketalization and the debenzylated
product was formed (Scheme 3).12
1. Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1933–1972; Prestwich, G. D. Acc. Chem. Res.
1996, 29, 503–513.
2. Beaucage, S. L.; Iyer, R. P. Tetrahedron 1993, 49, 10441–
10488; Watanabe, Y. In Studies in Natural Products
Chemistry, Stereoselective Synthesis (Part K); Rahman,
A., Ed.; Elsevier: Amsterdam, 1996; Vol. 18, pp 391–456;
Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Das, T.
Chem. Rev. 2003, 103, 4477–4503.
3. Massy, D. J. R.; Wyss, P. Helv. Chim. Acta 1990, 73,
1037–1057.
4. (a) Bruzick, C. S.; Myers, J.; Tsai, M.-D. Tetrahedron Lett.
1992, 33, 1009–1012; (b) Bruzick, C. S.; Tsai, M.-D. J. Am.
Chem. Soc. 1992, 114, 6361–6374; (c) Pietrusiewicz, K. M.;
Salamonczyk, G. M.; Bruzik, K. S. Tetrahedron 1992, 48,
5523–5542.
5. Optical purity and absolute configuration of all the three
mandeloylation products were confirmed by transforming
them individually to 1,4,5,6-tetra-O-benzoyl-myo-inositol
via hydrazinolysis, benzoylation, and deketalization.6a,b
The acylation products were shown to be isolated without
contamination of other products.
In conclusion, the stannylene strategy has been shown to
provide a useful tool for the optical resolution and reg-
ioselective phosphorylation of a synthetically versatile
intermediate, 1,2-cyclohexylidene-myo-inositol. These
methodologies have enabled a practical synthesis of
phosphatidylinositol. Transformation of the phosphoryl-
ation products such as 6 and 8 to phosphatidylinositol
phosphates and inositol phosphates is now under
investigation.
6. (a) Ling, L.; Ozaki, S. Tetrahedron Lett. 1993, 34, 2501–
2504; (b) Ling, L.; Ozaki, S. Carbohydr. Res. 1994, 256,
49–58; (c) Rudolf, M. T.; Schultz, C. Liebigs Ann. 1996,
533–537.
7. Manning, D. D.; Bertozzi, C. R.; Rosen, S. D.; Kiessling,
L. L. Tetrahedron Lett. 1996, 37, 1953–1956.
Acknowledgements
8. NMR Data of 6a: 1H NMR (400MHz, CDCl3) d 0.95 (6H,
t, J = 6.8Hz, CH3), 1.39–1.47 (4H, complex, n-BuH3),
1.50–1.75 (4H, complex, n-BuH2), 1.22–1.75 (10H, m,
cyclohexylidene H), 3.33 (1H, t, JH5–H6=JH6–H5 = 9.6Hz,
InsH5), 3.68 (1H, dd, JH6–H1 = 7.6Hz, JH6–H5 = 9.6Hz,
InsH6), 3.92 (1H, t, JH4–H3 = JH4–H5 = 9.6Hz, InsH4), 4.04
(1H, dd, JH1–H6 = 7.6Hz, JH1–H2 = 4.4Hz, InsH1), 4.16–
We appreciate Yamakawa Chemical Industry Co. Ltd.
for a generous gift of mandelic acid. We thank Venture
Business Laboratory and Advanced Instrumentation
Center for Chemical Analysis, Ehime University for
NMR and elemental analysis, respectively.
4.19 (4H, complex, n-BuH1), 4.44 (1H, td, JH3–H4
=
JH3–P = 9.6Hz, JH3–H2 = 4.4Hz, InsH3), 4.47 (1H, t,
JH2–H3 = JH3–H2 = 4.4Hz, InsH2); 31P NMR (162MHz,
Supplementary data
1
CDCl3) d ꢀ0.24. NMR data of 6b: H NMR (400MHz,
Experimental procedures and characterization data
(partial) for compounds L-3, D-4, D-5, and 6a (PDF).
CDCl3) d 1.41 (2H, br), 1.55 (6H, br), 1.78 (2H, br)
(cyclohexylidene H), 3.26 (1H, t, JH5–H6 = JH5–H4 = 9.6Hz,

284
Y. Watanabe et al. / Tetrahedron Letters 46 (2005) 281–284
InsH5), 3.64 (1H, dd, JH6–H5 = 9.6Hz, JH6–H1 = 7.6Hz,
Desai, T.; Fernandez-Mayoralas, A.; Gigg, J.; Gigg, R.;
Payne, S. Carbohydr. Res. 1990, 205, 105–123.
InsH6), 3.90 (1H, t, JH4–H5 = JH4–H3 = 9.6Hz, InsH4), 4.02
(1H, dd, JH1–H6 = 7.6Hz, JH1–H2 = 4.4Hz, InsH1), 4.47
(1H, td, JH3–H4 = JH3–P = 9.6Hz, JH3–H2 = 3.6Hz, InsH3),
4.50 (1H, dd, JH2–H3 = 3.6Hz, JH2–H1 = 4.4Hz, InsH2),
5.09–5.22 (4H, complex, benzylic H), 7.32–7.45 (10H,
complex, aromatic H); 31P NMR (162MHz, CDCl3)
d ꢀ1.25.
11. Data of 9 (white solid): Rf = 0.61 (CHCl3/MeOH/AcOH/
acetone/H2O, 60:15:13:12:8); 1H NMR (400MHz, CDCl3)
d 0.89 (6H, t, J = 6.6Hz, CH3), 1.27 (48H, br s, CH2),
1.50–1.68 (4H, complex, acyl Hb), 2.24–2.40 (4H, complex,
acyl Ha), 3.39 (H, br, InsH5), 3.59 (H, br, InsH4), 3.66(H,
br, InsH6), 3.79 (H, br, InsH3), 3.86–4.13 (4H, complex,
Gly Ha and Hc), 4.41 (H, br, InsH2, InsH1), 5.25
(H, complex, Gly Hb); 31P NMR (162MHz, CDCl3) d
ꢀ0.09 (1P, br); MS-FAB(ꢀ) [glycerol/diethanolamine
9. David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–
663; Bredenkamp, M. W. South Afric. J. Chem. 1999, 52,
56–68; Peri, F.; Cipolla, L.; Nicotra, F. Tetrahedron Lett.
2000, 41, 8587–8590; Martinelli, M. J.; Vaidyanathan,
R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau,
V. V.; Kosmrlj, B. J. Am. Chem. Soc. 2002, 124, 3578–
3585.
1:1,
M (free form of 9) = C41H79O13P] m/z 810
27
20
(MꢀH); ½aꢁD +62.2 (c 2.09, CHCl3) {lit.13 ½aꢁD +7.48 (c
0.3, CHCl3)}.
12. Han, F.; Hayashi, M.; Watanabe, Y. Tetrahedron 2003,
59, 7703–7711.
10. Qin, H.; Grindley, T. B. J. Carbohydr. Chem. 1994, 13,
475–490; Desai, T.; Gigg, J.; Gigg, R.; Payne, S.; Penades,
S.; Rogers, H. J. Carbohydr. Res. 1991, 216, 197–209;
13. Zhelvakova, E. G.; Klyashchitskii, B. A.; Shvets, V. I.;
Evstigneeva, R. P.; Preobrazhenskii, N. A. Zh. Obshch.
Khim. 1970, 40, 248.