A versatile intermediate for the systematic synthesis of all regioisomers of myo-inositol phosphates

Article abstract of DOI:10.1055/s-0031-1289730

Inositol phosphate derivatives are usually synthesized by repeated protection-deprotection procedures, necessitating development of an independent synthetic route for each inositol derivative. Herein, a synthetic precursor for all regioisomers of inositol phosphate is reported. A cycloadduct obtained by the Diels-Alder reaction of trans-1-methoxy-3-trimethylsilyloxybuta-1,3-diene and methyl vinyl ketone was converted into an inositol derivative by sequential introduction and immediate protection of hydroxy groups. Thus, the six hydroxy groups of the obtained inositol derivative are differentiated by different protective groups that are cleavable under independent conditions. This would enable us to prepare all regioisomers of inositol phosphate derivative. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289730

PAPER
909
A Versatile Intermediate for the Systematic Synthesis of All Regioisomers of
myo-Inositol Phosphates
Takashi Masuda,a Kensaku Anraku,b Mitsuhiro Kimura,a Kaori Sato,a Yoshinari Okamoto,a Masami Otsuka*a
a
Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University,
5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Fax +81(96)3714620; E-mail: motsuka@gpo.kumamoto-u.ac.jp
Institute of Health Sciences, Kumamoto Health Science University, 325 Izumi-machi, Kumamoto 861-5598, Japan
b
Received 9 January 2012; revised 27 January 2012
mixture in 86% yield. The ketone 2 was converted into
Abstract: Inositol phosphate derivatives are usually synthesized by
methoximes 3a and 3b, which were separated by silica gel
repeated protection-deprotection procedures, necessitating devel-
chromatography in 62% and 7% yield, respectively.9 The
opment of an independent synthetic route for each inositol deriva-
tive. Herein, a synthetic precursor for all regioisomers of inositol
compound 3a was then subjected to a modification of the
phosphate is reported. A cycloadduct obtained by the Diels–Alder Paquette rearrangement,10 affording siloxy ketone 4a
(56% yield) and 4b (1% yield).11 Ketone 4a was reduced
reaction of trans-1-methoxy-3-trimethylsilyloxybuta-1,3-diene and
according to the procedure of Acena12 using NaBH4 to
methyl vinyl ketone was converted into an inositol derivative by se-
quential introduction and immediate protection of hydroxy groups.
give alcohol 5a and 5b in 72% and 14% yield, respective-
Thus, the six hydroxy groups of the obtained inositol derivative are
ly.13 The alcohol 5a was protected by an acetyl group14 to
differentiated by different protective groups that are cleavable un-
der independent conditions. This would enable us to prepare all re-
gioisomers of inositol phosphate derivative.
give acetate 6a quantitatively (Scheme 1).
OMe
O
OMe
O
Key words: inositol phosphate, Diels–Alder reaction, oxidative re-
arrangement, asymmetric dihydroxylation, monoacylation
a
+
TBSO
TBSO
2
1b
1a
There have been many reports on naturally occurring and
synthetic inositol phosphates (InsPn)1,2 ranging from InsP1
to InsP6 that are often closely related to cell function; for
example, D-myo-inositol 1,4,5-triphosphate [Ins(1,4,5)P3],
a crucial messenger to link the extracellular information to
calcium mobilization.3 We have previously reported the
synthesis of biotinylated InsPns for the InsPn-binding
study of phospholipase A2,4 Grp1 Pleckstrin homology
domain,5 and HIV-1 Gag6 proteins. However, our synthe-
ses of InsPn derivatives were based on the repeated protec-
tion–deprotection of myo-inositol and hence we needed to
develop an independent synthetic route for each InsPn
derivative4–6 as the other research groups did.1,7 The
present study was aimed at a ‘total synthesis’ of an inosi-
tol derivative equipped with six different protective
groups that are cleavable under independent conditions.
Our approach is featured by the Diels–Alder reaction and
subsequent sequential introduction of hydroxy groups.
OMe NOMe
OMe NOMe
b
+
TBSO
TBSO
3a
3b
OMe NOMe
OMe NOMe
TBSO
TBSO
O
c
3a
+
O
4a
4b
OMe NOMe
OMe NOMe
TBSO
HO
TBSO
HO
d
4a
5a
+
5a
5b
The Diels–Alder reaction of trans-1-methoxy-3-trimeth-
ylsilyloxybuta-1,3-diene (1a) affords a six-membered
ring with oxygen substituents that are convertible into var-
ious natural products as pioneered by Danishefsky.8 We
intended to make use of the Danishefsky’s diene for the
synthesis of inositol derivatives. Thus, siloxy diene 1a and
methyl vinyl ketone (1b) were reacted in the presence of
Eu(fod)3 to give the cycloadduct 2 as a diastereomeric
OMe NOMe
TBSO
AcO
e
6a
Scheme 1 Synthesis of methoxime 6a. Reagents and conditions: a)
Eu(fod)3, CH2Cl2, r.t.; b) NH2OMe·HCl, MeOH, pyridine; c) MCPBA,
CH2Cl2, MS 4 Å; d) NaBH4, MeOH; e) pyridine–Ac2O (2:1).
SYNTHESIS 2012, 44, 909–919
Advanced online publication: 01.03.2012
DOI: 10.1055/s-0031-1289730; Art ID: F001312SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
2
The deprotection of the methoxyimino group of 6a was
not straightforward. The first attempt was done with [hy-
droxy(tosyloxy)iodo]benzene (HTIB)15 by treating com-

910
T. Masuda et al.
PAPER
OMe OMs
pound 6a with HTIB in CH2Cl2 containing 1% water.
Although ketone 7a was obtained in 30% yield, the major
product of this reaction was found to be the rearranged
product 7b (50% yield). The methoxime of 6a was even-
tually removed by the Corey’s procedure16 using
TiCl3·3THF-DIBAL to give ketone 7a in 83% yield
(Scheme 2).
TBSO
AcO
a, b
c
7a
8a
OMe
OMe
TBSO
AcO
TBSO
AcO
d, e
+
OMe NOMe
TBSO
a
9a
9b
AcO
OMe
OMe
6a
TBSO
O
TBSO
OMe
O
OMe OMe
N
O
+
TBSO
AcO
TBSO
AcO
AcO
AcO
+
O
10a
10b
7a
7b
OMe
TBSO
AcO
OTMS
OMe
O
OMe NOMe
f
g
10a
TBSO
AcO
TBSO
AcO
b
7a
6a
OMe
OMe
Scheme 2 Synthesis of methyl ketone 7a. Reagents and conditions:
a) HTIB, CH2Cl2 (1% H2O); b) TiCl3·3THF-DIBAL, toluene.
TBSO
AcO
O
TBSO
AcO
O
h
SePh
11a
As the Baeyer–Villiger oxidation of the methyl ketone 7a
did not work well, it was transformed as follows. The ke-
tone 7a was converted into mesylate 8a that was treated
Scheme 3 Synthesis of cyclohexenone 11a. Reagents and condi-
tions: a) NaBH4, MeOH–CH2Cl2; b) MsCl, Et3N, CH2Cl2; c) DBU,
with DBU to give olefin 9a and 9b (9a/9b = 2:1). Ozonol- toluene, D; d) O3, CH2Cl2–MeOH; e) Me2S; f) LiHMDS, TMSCl,
THF; g) PhSeCl, CH2Cl2; h) NaHCO3, 30% H2O2, THF.
ysis of the mixture 9a and 9b afforded cyclohexanone 10a
and aldehyde 10b in 25% and 11% overall yield based on
7a, respectively. Cyclohexanone 10a was converted into
the TMS enolate by treatment with LiHMDS and TMSCl
and further transformed to phenylselenyl ketone by treat-
ment with PhSeCl. The subsequent oxidative elimination
using H2O2 gave the desired cyclohexenone 11a in 18%
overall yield based on 10a (Scheme 3). As the acetyl
group of 11a was unexpectedly found to be labile produc-
ing a deacetylated by-product, another synthetic route was
explored.
OMe NOMe
TBSO
a
b
4a
TMSO
OMe NOMe
OMe NOMe
TBSO
O
TBSO
O
c
The alternate approach was as follows. Cyclohexanone 4a
was converted into cyclohexenone 12 in 55% overall yield
by treatment with a) LiHMDS, then TMSCl, b) PhSeCl,
and c) 30% H2O2, NaHCO3. The carbonyl group of 12 was
reduced with NaBH4 to give allyl alcohols 13a and 13b in
84% and 8% yield, respectively (Scheme 4). The stereo-
chemistry of compound 13a and 13b was determined by
converting 13a into 5a (Scheme 5) whose stereochemistry
has already been established.
12
SePh
OMe NOMe
OMe NOMe
TBSO
HO
TBSO
d
+
HO
13a
13b
Scheme 4 Synthesis of allyl alcohol 13a. Reagents and conditions:
a) LiHMDS, THF, then TMSCl; b) PhSeCl, CH2Cl2; c) 30% H2O2,
NaHCO3, THF; d) NaBH4, MeOH.
In this approach, the alcohol of 13a was protected by
MOM group (MOMCl, DIPEA) to afford the MOM de-
rivative 14 in 92% yield. The olefin 14 was converted into was converted into mono-MPM derivative 16 in 52%
cis-diols 15a and 15b in 65% and 29% yield, respectively, yield by the Nagashima–Ohno procedure using Bu2SnO/
by the application of the Armstrong’s modification of the CsF19 (Scheme 6). Unfortunately, deprotection of the
Sharpless asymmetric dihydroxylation.17,18 The diol 15a
Synthesis 2012, 44, 909–919
© Thieme Stuttgart · New York

PAPER
Synthetic Precursor for All Regioisomers of Inositol Phosphate
911
OMe NOMe
to give myo-inositol derivative 19 in 59% yield. Diol 19
was converted into the desired monoacetate 20 in 39%
yield by the Nagashima–Ohno procedure19 (Scheme 8).
OMe NOMe
TBSO
HO
TBSO
HO
a
In summary, the Diels–Alder product 2 having two oxy-
gen substituents on the cyclohexane ring was subjected to
the Paquette’s oxidative rearrangement to introduce the
third oxygen substituent. Compound 5a thus obtained was
converted into cyclohexanone 10c where the fourth oxy-
gen group was introduced by ozonolytic cleavage of the
carbon appendage. The fifth and sixth hydroxy groups
were constructed and differentiated by the asymmetric di-
hydroxylation and the subsequent Nagashima–Ohno
monoacylation. Thus, the six hydroxy groups of com-
pound 20 are differentiated by protective groups that are
cleavable under independent conditions. This would en-
able us to prepare not only all InsPn but also other inositol
derivatives.
13a
5a
Scheme 5 Stereochemical assignment of compound 13a. Reagents
and conditions: H2, Pd/C, CH2Cl2.
OMe NOMe
TBSO
a
b
13a
MOMO
14
OMe NOMe
OMe NOMe
OH
TBSO
TBSO
+
MOMO
OH
MOMO
OH
OH
15a
15b
OMe NOMe
OMe NOMe
OMe NOMe
TBSO
TBSO
TBSO
HO
c, d
a
b
15a
MOMO
OMPM
MOMO
6b
OH
5a
16
OMe
O
OMe OMs
Scheme 6 Synthesis of mono-MPM derivative 16. Reagents and
conditions: a) MOMCl, DIPEA, CH2Cl2; b) AD-mix-b, OsO4,
(DHQD)2PHAL, MeSO2NH2, t-BuOH–H2O–CH2Cl2; c) Bu2SnO,
toluene; d) CsF, MPMCl, DMF.
TBSO
TBSO
c, d
e
MOMO
MOMO
OMe
7c
8b
methoxyimino group of compound 16 by the TiCl3·3THF-
DIBAL16 procedure did not work.
OMe
TBSO
TBSO
f, g
Thus, the synthetic route was revised as follows. Cyclo-
hexanol 5a was protected by a MOM group to give com-
pound 6b in 92% yield. The methoxyimino group of 6b
was smoothly removed with TiCl3·3THF-DIBAL16 to
give methyl ketone 7c in 85% yield. Methyl ketone 7c was
converted into mesylate 8b by treatment with NaBH4 fol-
lowed by MsCl. Compound 8b was further treated with
DBU to give olefin 9c and 9d. Ozonolysis of the mixture
9c and 9d gave cyclohexanone 10c in 24% yield based on
7c and aldehyde 10d (crude). Compound 10c was con-
verted into cyclohexenone 11b in 34% yield via the TMS
enolate and the phenylselenyl ketone intermediates by the
above mentioned procedure. Unexpectedly, H2O2 treat-
ment of the phenylselenyl ketone was accompanied by
lactone 11c, the Baeyer–Villiger product, in 23% yield
(Scheme 7).
+
MOMO
MOMO
OMe
9c
9d
OMe
TBSO
O
TBSO
O
+
MOMO
MOMO
10c
10d
OMe
OMe
TBSO
OTMS
TBSO
O
h
i
10c
MOMO
MOMO
SePh
MeO
OMe
Thus, phenylselenyl ketone obtained from 10c was con-
verted into the corresponding phenylselenyl alcohol by
treatment with NaBH4 and subsequent treatment with
30% H2O2/NaHCO3 gave allyl alcohol 17a in 51% overall
yield based on 10c.20 The hydroxy group of 17a was pro-
tected by MPM group by treatment with NaH/MPMCl/
TBAI in the presence of molecular sieves and compound
18 was obtained in 40% yield. Olefin dihydroxylation of
compound 18 was achieved by the Armstrong procedure17
O
TBSO
O
TBSO
MOMO
O
j
+
MOMO
11b
11c
Scheme 7 Synthesis of cyclohexanone 11b. Reagents and condi-
tions: a) MOMCl, DIPEA, CH2Cl2; b) TiCl3·3THF-DIBAL, toluene;
c) NaBH4, MeOH–CH2Cl2; d) MsCl, Et3N, CH2Cl2; e) DBU, toluene,
Δ; f) O3, Et3N, CH2Cl2–MeOH; g) Me2S; h) LiHMDS, TMSCl, THF;
i) PhSeCl, CH2Cl2; j) NaHCO3, 30% H2O2.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 909–919

912
T. Masuda et al.
PAPER
min. The residue was roughly purified by silica gel chromatography
(silica gel 10 g, hexane–EtOAc, 20:1) and further purified by suc-
cessive silica gel chromatography (hexane–EtOAc, 20:1) to give 3a
(2.8 g, 62%) and 3b (0.31 g, 7%) as colorless oils.
OMe
OMe
TBSO
OTMS
TBSO
O
a
b
10c
MOMO
MOMO
SePh
3a
IR (film): 1665 cm–1.
OMe
OMe
1H NMR (CDCl3): d = 0.15 (s, 6 H, 2 × SiCH3), 0.92 [s, 9 H,
C(CH3)3], 1.63–1.90 (m, 5 H, 2 × CH, CH3), 1.94–2.05 (ddt,
J = 4.95, 9.89, 17.2 Hz, 1 H, CH), 2.09–2.21 (m, 1 H, CH), 2.39–
2.46 (ddd, J = 3.66, 7.88, 11.0 Hz, 1 H, CH), 3.25–3.32 (t, J = 11.9
Hz, 3 H, OCH3), 3.80–3.87 (t, J = 11.9 Hz, 3 H, OCH3), 4.07–4.13
(m, 1 H, CH), 4.97 (s, 1 H, =CH).
TBSO
OH
TBSO
OH
c
d
MOMO
SePh
MOMO
17a
13C NMR (CDCl3): d = –4.50 (SiCH3), –4.41 (SiCH3), 12.2 (CH3),
18.0 (SiC), 24.6 (CH2), 25.6 (CH3), 29.1 (CH2), 45.0 (CH), 54.8
(OCH3), 61.2 (=NOCH3), 76.4 (CH), 104 (=CH), 153 (=C), 158
(C=N).
OMe
OMe
TBSO
OMPM
TBSO
OMPM
OH
e
f
MOMO
MOMO
OH
19
MS (FAB): m/z = 314 (M + H)+.
18
Anal. Calcd for C16H31NO3Si: C, 61.30; H, 9.97; N, 4.47. Found: C,
61.03; H, 9.97; N, 4.52.
OMe
TBSO
OMPM
OH
3b
g, h
IR (film): 1660 cm–1.
1H NMR (CDCl3): d = 0.15 (s, 3 H, SiCH3), 0.17 (s, 3 H, SiCH3),
0.92 [s, 9 H, C(CH3)3], 1.72–1.80 (m, 1 H, CH), 1.87 (s, 3 H, CH3),
1.89–2.12 (m, 3 H, 3 × CH), 2.39–2.46 (ddd, J = 3.30, 3.48, 12.1
Hz, 1 H, CH), 3.27 (s, 3 H, OCH3), 3.80–3.88 (m, 4 H, CH, OCH3),
5.15–5.17 (d, J = 3.30 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –4.56 (SiCH3), –4.38 (SiCH3), 12.9 (CH3),
18.0 (SiC), 20.4 (CH2), 25.6 (CH3), 30.2 (CH2), 44.8 (CH), 56.0
(OCH3), 61.1 (=NOCH3), 75.3 (CH), 103 (=CH), 156 (=C), 159
(C=N).
MOMO
OAc
20
Scheme 8 Synthesis of protected inositol 20. Reagents and condi-
tions: a) LiHMDS, TMSCl; b) PhSeCl, CH2Cl2; c) NaBH4, MeOH; d)
NaHCO3, 30% H2O2, THF; e) NaH, MPMCl, TBAI, THF, MS 4 Å; f)
AD-mix-b, OsO4, (DHQD)2PHAL, MeSO2NH2, t-BuOH–H2O/
CH2Cl2; g) Bu2SnO, toluene; h) AcCl, CH2Cl2.
MS (FAB): m/z = 314 (M + H)+.
Reagents and solvents were purified by standard techniques. TLC
was performed using silica gel 60 F254 (Merck) and visualized by
10% solution of phosphomolybdic acid in EtOH or 0.5% solution of
KMnO4 in 1 M aq NaOH. Column chromatography was carried out
Anal. Calcd for C16H31NO3Si: C, 61.30; H, 9.97; N, 4.47. Found: C,
61.03; H, 9.99; N, 4.65.
1
(2S*,3R*,4R*)-2-(tert-Butyldimethylsilyloxy)-3-methoxy-4-[1-
(methoxyimino)ethyl]cyclohexanone (4a) and (2R*,3R*,4R*)-2-
(tert-Butyldimethylsilyloxy)-3-methoxy-4-[1-(methoxyimi-
no)ethyl]cyclohexanone (4b)
Under ice cooling, 3a (0.11 g, 0.34 mmol) was dissolved in CH2Cl2
(12 mL) and molecular sieves 4 Å (500 mg) were added. After stir-
ring for 10 min, a solution of MCPBA (92 mg, 3.7 mmol) in CH2Cl2
(2.0 mL) was slowly added. The solution was stirred for 3 h under
ice cooling and for 24 h at r.t. The reaction mixture was roughly pu-
rified by chromatography [silica gel (10 g), hexane–EtOAc, 8:1)
and further purified by successive silica gel chromatography (hex-
ane–EtOAc, 5:1) to give 4a (63 mg, 56%) and 4b (1.3 mg, 1%) as
colorless oils.
with silica gel 60 N (spherical neutral) (Kanto Chemical Co.). H
NMR and 13C NMR spectra were recorded on JNM- AL300 with re-
spect to internal standard TMS and J values are given in Hz. Mass
spectra [MS (FAB)] and high-resolution mass spectra (HRMS)
were recorded on Jeol JMS-DX303HF mass spectrometer. IR spec-
tra were recorded on Jasco FT/IR-410. Elemental analyses were
performed with Yanaco MT-5S.
(S*)-1-[4-(tert-Butyldimethylsilyloxy)-2-methoxycyclohex-3-
enyl]ethanone (2)
Eu(fod)3 (0.72 g, 0.70 mmol) and methyl vinyl ketone (1b; 2.3 mL,
28 mmol) were successively dissolved in CH2Cl2 (6 mL). To the so-
lution was added trans-3-(tert-butyldimethylsiloxy)-1-methoxybu-
ta-1,3-diene (1a; 3.0 g, 14 mmol) and the resulting solution was
stirred at r.t. for 7 h. The solution was concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–
EtOAc, 7:1) to give 2 as a mixture of diastereomers; yield: 3.4 g
(86%); yellow oil.
4a
IR (film): 1732 cm–1.
1H NMR (CDCl3): d = 0.05 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3),
0.95 [s, 9 H, C(CH3)3], 1.52–1.65 (ddd, J = 4.58, 13.6, 26.6 Hz, 1 H,
CH), 1.84–1.95 (m, 4 H, CH3, CH), 2.29–2.40 (m, 1 H, CH), 2.41–
2.48 (ddd, J = 2.93, 4.76, 13.7 Hz, 1 H, CH), 2.63–2.72 (ddd,
J = 3.85, 10.6, 12.7 Hz, 1 H, CH), 3.34–3.41 (dd, J = 9.16, 10.6 Hz,
1 H, –CH), 3.49 (s, 3 H, OCH3), 3.87 (s, 3 H, =NOCH3), 4.18–4.21
(dd, J = 0.92, 9.16 Hz, 1 H, CH).
1-[(1S*,2S*)-4-(tert-Butyldimethylsilyloxy)-2-methoxycyclo-
hex-3-enyl]ethanone O-Methyl Oxime (3a) and 1-[(1R*,2S*)-4-
(tert-Butyldimethylsilyloxy)-2-methoxycyclohex-3-enyl]etha-
none O-Methyl Oxime (3b)
NH2OMe·HCl (3.4 g, 40 mmol) was dissolved in MeOH (6.1 mL)
under ice cooling. Pyridine (2.5 mL, 31 mmol) was added to the so-
lution. The mixture was stirred for 10 min and was added to crude
2 (4.1 g, crude) under ice cooling. The solution was stirred for 45
min under ice cooling and then concentrated in vacuo at r.t. for 45
13C NMR (CDCl3): d = –5.35 (SiCH3), –4.75 (SiCH3), 12.4 (CH3),
18.5 (SiC), 25.3 (CH3), 25.9 (CH2), 38.5 (CH2), 48.5 (CH), 60.9
(OCH3), 61.4 (=NOCH3), 82.6 (CH), 85.5 (CH), 156 (C=N), 206
(C=O).
Synthesis 2012, 44, 909–919
© Thieme Stuttgart · New York

PAPER
Synthetic Precursor for All Regioisomers of Inositol Phosphate
913
MS (FAB): m/z = 330 (M + H)+.
HRMS (FAB): m/z calcd for C16H34NO4Si (M + H)+: 332.2257;
found: 332.2254.
Anal. Calcd for C16H31NO4Si: C, 58.32; H, 9.48; N, 4.25. Found: C,
58.09; H, 9.58; N, 4.23.
(1S*,2R*,3R*,4R*)-2-(tert-Butyldimethylsilyloxy)-3-methoxy-
4-[1-(methoxyimino)ethyl]cyclohexyl Acetate (6a)
Compound 5a (1.0 g, 3.1 mmol) was dissolved in a solution of py-
ridine and Ac2O (6.0 mL, pyridine–Ac2O, 2: 1). The solution was
stirred overnight at 40 °C. The reaction solution was concentrated
in vacuo. The residue was purified by silica gel chromatography
(hexane–EtOAc, 3:1) to give 6a as a colorless oil; yield: 1.2 g
(quant).
4b
IR (film): 1733 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3),
0.92 [s, 9 H, C(CH3)3], 1.56–1.87 (m, 5 H, 2 × CH, CH3), 2.02–2.12
(m, 1 H, CH), 2.56–2.65 (ddd, J = 5.50, 8.24, 13.7 Hz, 1 H, CH),
2.88–2.95 (td, J = 4.95, 6.96 Hz, 1 H, CH), 3.37 (s, 3 H, OCH3),
3.63–3.66 (dd, J = 2.93, 6.96 Hz, 1 H, CH), 3.85–3.90 (m, 3 H,
OCH3), 4.58–4.59 (dd, J = 0.92, 2.93 Hz, 1 H, CH).
IR (film): 1741 cm–1.
1H NMR (CDCl3): d = 0.09 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.88 [s, 9 H, C(CH3)3], 1.22–1.35 (m, 1 H, CH), 1.39–1.53 (m, 1 H,
CH), 1.61–1.69 (qd, J = 3.66, 13.4 Hz, 1 H, CH), 1.84 (s, 3 H, CH3),
1.99–2.05 (m, 1 H, CH), 2.05 (s, 3 H, CH3), 2.23–2.32 (ddd,
J = 3.85, 10.6, 12.5 Hz, 1 H, CH), 3.09–3.15 (dd, J = 8.61, 10.7 Hz,
1 H, CH), 3.37 (s, 3 H, OCH3), 3.51–3.57 (dd, J = 8.79, 9.16 Hz, 1
H, CH), 3.85 (s, 3 H, =NOCH3), 4.59–4.68 (ddd, J = 4.76, 9.34,
11.4 Hz, 1 H, CH).
13C NMR (CDCl3): d = –4.63 (SiCH3), –4.16 (SiCH3), 12.3 (CH2),
18.0 (SiC), 21.4 (CH3), 24.9 (CH3), 25.8 (CH3), 28.7 (CH2), 48.7
(CH), 60.5 (OCH3), 61.3 (=NOCH3) 75.6 (CH), 77.0 (CH), 84.3
(CH), 157 (C=N), 170 (OC=O).
13C NMR (CDCl3): d = –5.15 (SiCH3), –4.87(SiCH3), 13.1 (CH3),
18.3 (SiC), 24.7 (CH3), 25.8 (CH2), 36.4 (CH2), 43.6 (CH), 58.5
(OCH3), 61.5 (=NOCH3), 76.6 (CH), 84.3 (CH), 157(C=N), 209
(C=O).
HRMS (FAB): m/z calcd for C16H33NO4Si (M + H)+: 330.2101;
found: 330.2162.
1-[(1S*,2R*,3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-4-hy-
droxy-2-methoxycyclohexyl]ethanone O-Methyl Oxime (5a)
and 1-[(1S*,2R*,3R*,4R*)-3-(tert-Butyldimethylsilyloxy)-4-hy-
droxy-2-methoxycyclohexyl]ethanone O-Methyl Oxime (5b)
Under ice cooling, compound 4a (0.44 g, 1.3 mmol) was dissolved
in MeOH (5.0 mL) and NaBH4 (0.20 g, 5.3 mmol) was added. The
solution was stirred for 30 min under ice cooling. The solution was
diluted with EtOAc (50 mL), washed with H2O (50 mL) and brine
(50 mL), and dried (Na2SO4). The solution was concentrated in
vacuo. The solution was purified by silica gel chromatography
(hexane–EtOAc, 3:1) to give 5a as white crystals (0.32 g, 72%) and
5b as a colorless oil (59 mg, 14%).
HRMS (FAB): m/z calcd for C18H36NO5Si (M + H)+: 374.2363;
found: 374.2367.
(1S*,2R*,3R*,4S*)-4-Acetyl-2-(tert-butyldimethylsilyloxy)-3-
methoxycyclohexyl Acetate (7a)
Compound 6a (0.16 g, 0.42 mmol) was dissolved in toluene (20
mL) under argon atmosphere and ice cooling. A 0.25 M solution of
TiCl3·3THF-DIBAL in toluene (2.1 mL, 0.53 mmol) was added.
The solution was stirred for 20 min at r.t. A solution of TiCl3·3THF-
DIBAL in toluene (2.1 mL, 0.53 mmol) was added additionally and
the solution was stirred for 20 min. Finally a solution of
TiCl3·3THF-DIBAL in toluene (2.1 mL, 0.53 mmol) was added
again and the solution was stirred for 40 min at r.t. The reaction was
terminated by the addition of sat. aq NaOAc (20 mL) and the pH of
the solution was adjusted to 3.0 by aq citric acid. The solution was
extracted with CH2Cl2 (4 × 30 mL) and dried (Na2SO4) and the sol-
vent was evaporated in vacuo. The residue was purified by silica gel
chromatography (hexane–EtOAc, 5:1) to give 7a as white crystals;
yield: 0.12 g (83%); mp 68–70 °C.
5a
Mp 56–62 °C.
IR (KBr): 3417, 1639 cm–1.
1H NMR (CDCl3): d = 0.13 (s, 3 H, SiCH3), 0.15 (s, 3 H, SiCH3),
0.93 [s, 9 H, C(CH3)3], 1.23–1.48 (m, 2 H, CH, CH), 1.62–1.70 (m,
1 H, CH), 1.84 (s, 3 H, CH3), 1.91–1.99 (m, 1 H, CH), 2.25–2.33 (m,
4 H, OH, CH), 3.05–3.11 (dd, J = 8.61, 10.6 Hz, 1 H, CH), 3.28–
3.34 (t, J = 8.61 Hz, 1 H, –CH), 3.35 (s, 3 H, OCH3), 3.37–3.48 (m,
1 H, CH), 3.85 (s, 3 H, OCH3).
13C NMR (CDCl3): d = –4.61 (SiCH3), –4.10 (SiCH3), 12.5 (CH3),
18.2 (SiC), 25.2 (CH3), 26.0 (CH2), 30.1 (CH2), 48.9 (CH), 60.1
(OCH3), 61.3 (=NOCH3), 73.8 (CH), 80.7 (CH), 83.6 (CH), 158
(C=N).
IR (KBr): 1737, 1714 cm–1.
1H NMR (CDCl3): d = 0.09 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.88 [s, 9 H, C(CH3)3], 1.19–1.32 (m, 1 H, CH), 1.34–1.48 (dq,
J = 3.66, 12.1 Hz, 1 H, CH), 1.68–1.76 (qd, J = 3.66, 13.6 Hz, 1 H,
CH), 2.01–2.10 (m, 1 H, CH), 2.05 (s, 3 H, CH3), 2.23 (s, 3 H, CH3),
2.55–2.64 (ddd, J = 3.66, 10.3, 12.1 Hz, 1 H, CH), 3.28–3.34 (dd,
J = 8.80, 10.3 Hz, 1 H, CH), 3.38 (s, 3 H, OCH3), 3.50–3.56 (dd,
J = 8.80, 9.17 Hz, 3 H, CH), 4.57–4.65 (ddd, J = 4.77, 9.53, 11.0
Hz, 1 H, CH).
MS (FAB): m/z = 332 (M + H)+.
Anal. Calcd for C16H33NO4Si: C, 57.97; H, 10.03; N, 4.22. Found:
C, 57.72; H, 10.04; N, 4.14.
5b
IR (film): 1741 cm–1.
13C NMR (CDCl3): d = –4.58 (SiCH3), –4.18 (SiCH3), 18.0 (SiC),
21.4 (CH3), 23.7 (CH2), 25.7 (CH3), 28.7 (CH2), 31.1 (CH3), 55.0
(CH), 61.4 (OCH3), 75.3 (CH), 77.0 (CH), 84.2 (CH), 170 (OC=O),
210 (C=O).
HRMS (FAB): m/z calcd for C17H33O5Si (M + H)+: 345.2097;
found: 345.2102.
1H NMR (CDCl3): d = 0.10 (s, 3 H, SiCH3), 0.14 (s, 3 H, SiCH3),
0.93 [s, 9 H, C(CH3)3], 1.39–1.49 (m, 2 H, 2 × CH), 1.81–1.99 (m,
5 H, CH3, 2 × CH), 2.17–2.26 (ddd, J = 3.11, 10.6, 12.6 Hz, 1 H,
CH), 2.60–2.61 (d, J = 1.83 Hz, 1 H, OH), 3.35–3.41 (dd, J = 8.61,
10.6 Hz, 1 H, CH), 3.39 (s, 3 H, OCH3), 3.50–3.54 (dd, J = 3.11,
8.61 Hz, 1 H, CH), 3.85 (s, 3 H, OCH3), 3.89–3.90 (d, J = 2.75 Hz,
1 H, CH).
13C NMR (CDCl3): d = –4.92 (SiCH3), –4.63 (SiCH3), 11.8 (CH3),
17.9 (SiC), 23.0 (CH2), 25.8 (CH3), 28.6 (CH2), 48.9 (CH), 60.5
(OCH3), 61.2 (=NOCH3), 70.8 (CH), 77.6 (CH), 80.8 (CH), 158
(C=N).
(1S*,2R*,3R*,4S*)-2-(tert-Butyldimethylsilyloxy)-3-methoxy-4-
[1-(methylsulfonyloxy)ethyl]cyclohexyl Acetate (8a)
Under ice cooling, compound 7a (0.34 g, 0.99 mmol) was dissolved
in a mixture of MeOH (3.0 mL) and CH2Cl2 (2.0 mL). NaBH4 (0.19
g, 4.9 mmol) was added and the resulting solution was stirred for 30
© Thieme Stuttgart · New York
Synthesis 2012, 44, 909–919

914
T. Masuda et al.
PAPER
min. The solution was diluted with EtOAc (50 mL) and washed
with H2O (50 mL) and brine (50 mL), and dried (Na2SO4). The so-
lution was concentrated in vacuo to give a colorless oil. The ob-
tained crude alcohol (0.35 g) was dissolved in CH2Cl2 (19 mL)
under argon atmosphere and ice cooling. Et3N (1.4 mL, 10 mmol)
and MsCl (0.56 mL, 7.2 mmol) were added and the resulting solu-
tion was stirred for 1.5 h and treated with sat. aq NaHCO3 (20 mL).
The solution was extracted with CH2Cl2 (3 × 40 mL), the combined
organic layers were dried (Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–
EtOAc, 3:1) to give white crystals of 8a as a mixture of diaste-
reomers.
J = 8.07, 9.53 Hz, 1 H, CH), 3.45 (s, 3 H, OCH3), 3.62–3.68 (dd,
J = 8.07, 8.43 Hz, 1 H, CH), 4.58–4.66 (ddd, J = 4.03, 8.43, 9.90
Hz, 1 H, CH), 9.77–9.78 (d, J = 2.20 Hz, 1 H, CHO).
13C NMR (CDCl3): d = –4.64 (SiCH3), –4.31 (SiCH3), 18.0 (SiC),
20.1 (CH2), 21.4 (CH3), 25.7 (CH3), 27.4 (CH2), 54.4 (CH), 60.7
(OCH3), 74.6 (CH), 75.6 (CH), 82.7 (CH), 170 (OC=O), 202
(COH).
MS (FAB): m/z = 331 (M + H)+.
(1S*,5S*,6R*)-6-(tert-Butyldimethylsilyloxy)-5-methoxy-4-oxo-
cyclohex-2-enyl Acetate (11a)
Compound 10a (66 mg, 0.21 mmol) was dissolved in THF (6.5 mL)
under an argon atmosphere at –78 °C. A THF solution of LiHMDS
(1.6 M, 0.20 mL, 0.32 mmol) was added and the solution was stirred
for 1 h at –78 °C. TMSCl (51 mL, 0.40 mmol) was then added and
the solution was stirred for 45 min at –78 °C and for 1 h at r.t. The
solution was concentrated in vacuo and the residue was dissolved in
anhyd n-pentane (20 mL) and filtered through Celite. The filtrate
was concentrated in vacuo to give the crude intermediate TMS eno-
late as a colorless oil. The crude colorless oil was dissolved in
CH2Cl2 (6.0 mL) under argon atmosphere at –78 °C. A solution of
PhSeCl (45 mg, 0.23 mmol) in CH2Cl2 (6.0 mL) was added and the
solution was stirred for 45 min at –78 °C and for 15 min at r.t. The
solution was concentrated in vacuo to give the crude intermediate
phenylselenyl ketone as a yellow oil. The crude yellow oil was dis-
solved in THF (6.5 mL) under argon atmosphere and ice cooling.
NaHCO3 (52 mg, 0.62 mmol) and 30% H2O2 (61 mL, 0.63 mmol)
were successively added and the solution was stirred for 15 min at
the same temperature, then for 2 h at r.t. H2O (30 mL) was added
and the mixture was extracted with Et2O (3 × 40 mL). The com-
bined organic layers were washed with brine (60 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 5:1) to give 11a as
white crystals; yield: 12 mg (18% over 3 steps); mp 62–68 °C.
(1S*,2R*,3R*,E)-2-(tert-Butyldimethylsilyloxy)-4-ethylidene-3-
methoxycyclohexyl Acetate (9a) and (1S*,2R*,3R*,4R*)-2-(tert-
Butyldimethylsilyloxy)-3-methoxy-4-vinylcyclohexyl Acetate
(9b)
Compound 8a (0.35 g, 0.83 mmol) was dissolved in toluene (10
mL) and DBU (0.93 mL, 6.2 mmol) was added. The solution was
heated at reflux for 48 h. Sat. aq NH4Cl (15 mL) was added and the
solution was extracted with CH2Cl2 (3 × 20 mL). The organic layers
were combined and washed with brine (45 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–EtOAc, 20:1) to give a mixture of 9a,b
(2:1) as a colorless oil.
(1S*,2R*,3S*)-2-(tert-Butyldimethylsilyloxy)-3-methoxy-4-oxo-
cyclohexyl Acetate (10a) and (1S*,2R*,3R*,4S*)-2-(tert-Butyl-
dimethylsilyloxy)-4-formyl-3-methoxycyclohexyl Acetate (10b)
The crude mixture of 9a,b (0.14 g) was dissolved in a mixture of
CH2Cl2 (30 mL) and MeOH (6.0 mL). Et3N (0.30 mL, 1% v/v) was
added and the solution was stirred at –78 °C. O3 was bubbled until
the blue color persisted. O2 was bubbled through the reaction solu-
tion for 30 min at –78 °C. Me2S (0.22 mL, 3.1 mmol) was added and
the resulting solution was stirred for 30 min, then further stirred at
r.t. for 2 h. The reaction was terminated by the addition of sat. aq
NaHCO3 (50 mL). The aqueous layer was extracted with CH2Cl2
(2 × 30 mL) and the combined organic layers were washed with
brine (100 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–
EtOAc, 5:1) to give 10a (79 mg, 25% over 3 steps) and 10b as white
crystals (34 mg, 11% over 3 steps).
IR (KBr): 1744, 1701, 1624 cm–1.
1H NMR (CDCl3): d = 0.09 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.89 [s, 9 H, C(CH3)3], 2.14 (s, 3 H, CH3), 3.63–3.67 (d, J = 10.3
Hz, 1 H, CH), 3.64 (s, 3 H, OCH3), 3.98–4.04 (dd, J = 8.43, 10.3 Hz,
1 H, –CH), 5.58–5.62 (td, J = 2.20, 8.43 Hz, 1 H, CH), 6.06–6.10
(dd, J = 2.20, 10.6 Hz, 1 H, =CH), 6.63–6.67 (dd, J = 2.20, 10.6 Hz,
1 H, =CH).
13C NMR (CDCl3): d = –5.09 (SiCH3), –4.39 (SiCH3), 18.1 (SiC),
21.0 (CH3), 25.6 (CH3), 60.9 (OCH3), 74.3 (CH), 75.4 (CH), 86.2
(CH), 129 (=CH), 146 (=CH), 170 (OC=O), 197 (C=O).
HRMS (FAB): m/z calcd for C15H26O5Si + Na (M + Na)+: 334.1447;
found: 337.1463.
10a
Mp 77–81 °C.
IR (KBr): 1753, 1729 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3),
0.88 [s, 9 H, C(CH3)3], 1.46–1.54 (m, 1 H, CH), 2.08 (s, 3 H, CH3),
2.18–2.27 (qd, J = 4.40, 13.2 Hz, 1 H, CH), 2.41–2.46 (m, 2 H,
2 × CH), 3.47 (s, 3 H, OCH3), 3.61–3.64 (d, J = 9.16 Hz, 1 H, CH),
3.70–3.76 (t, J = 8.80 Hz, 1 H, CH), 4.97–5.05 (ddd, J = 4.40, 8.80,
11.0 Hz, 1 H, CH).
13C NMR (CDCl3): d = –4.64 (SiCH3), –4.42 (SiCH3), 18.1 (SiC),
21.2 (CH3), 25.5 (CH2), 25.7 (CH3), 35.6 (CH2), 59.6 (OCH3), 74.0
(CH), 76.3 (CH), 88.2 (CH), 170 (OC=O), 206 (C=O).
(4R*,5R*,6S*)-6-(tert-Butyldimethylsilyloxy)-5-methoxy-4-[1-
(methoxyimino)ethyl]cyclohex-2-enone (12)
Compound 4a (1.7 g, 5.0 mmol) was dissolved in THF (16 mL) un-
der argon atmosphere at –78 °C. A THF solution of LiHMDS (1.6
M, 7.5 mL, 12 mmol) was added and the solution was stirred for 1
h at –78 °C. TMSCl (0.95 mL, 7.5 mmol) was added and the solu-
tion was stirred for 45 min at –78 °C and for 1 h at r.t. The solution
was concentrated in vacuo and the residue was dissolved in anhyd
pentane (20 mL) and filtered through Celite. The filtrate was con-
centrated in vacuo to give the crude intermediate TMS enolate as a
yellow oil. The crude yellow oil was dissolved in CH2Cl2 (50 mL)
under argon atmosphere at –78 °C. A solution of PhSeCl (1.1 g, 5.6
mmol) in CH2Cl2 (10 mL) was added and the solution was stirred
for 45 min at –78 °C and for 15 min at r.t. The solution was concen-
trated in vacuo to give the crude intermediate phenylselenyl ketone
as a yellow oil. The yellow oil was dissolved in THF (40 mL) under
argon atmosphere and ice cooling. NaHCO3 (1.2 g, 15 mmol) and
30% H2O2 (1.4 mL, 15 mmol) were successively added and the so-
HRMS (FAB): m/z calcd for C15H29O5Si (M + H)+: 317.1784;
found: 317.1782.
10b
Mp 155–164 °C.
IR (KBr): 1733, 1706 cm–1.
1H NMR (CDCl3): d = 0.11 (s, 3 H, SiCH3), 0.13 (s, 3 H, SiCH3),
0.89 [s, 9 H, C(CH3)3], 1.26–1.54 (m, 2 H, 2 × CH), 1.77–1.86 (qd,
J = 4.03, 13.6 Hz, 1 H, CH), 2.03–2.12 (m, 4 H, 2 × CH), 2.41–2.46
(m, 2 H, CH3, CH), 2.41–2.52 (m, 1 H, CH), 3.29–3.35 (dd,
Synthesis 2012, 44, 909–919
© Thieme Stuttgart · New York

PAPER
Synthetic Precursor for All Regioisomers of Inositol Phosphate
915
lution was stirred for 15 min at the same temperature, then for 2 h
at r.t. H2O (60 mL) was added and the mixture was extracted with
Et2O (3 × 80 mL). The combined organic layers were washed with
brine (120 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by silica gel chromatography (hexane–
EtOAc, 5:1) to give 12 as a colorless oil; yield: 0.91 g (55% over 3
steps).
HRMS (FAB): m/z calcd for C16H31NO4Si + Na (M + Na)+:
352.1920; found: 352.1919.
Catalytic Hydrogenation of 1-[(1S*,4S*,5R*,6R*)-5-(tert-Bu-
tyldimethylsilyloxy)-4-hydroxy-6-methoxycyclohex-2-enyl]eth-
anone O-Methyl Oxime (13a) to 1-[(1S*,2R*,3R*,4S*)-3-(tert-
Butyldimethylsilyloxy)-4-hydroxy-2-methoxycyclohexyl]ethan-
one O-Methyl Oxime (5a)
To a solution of compound 13a (55 mg, 0.17 mmol) in CH2Cl2 (10
mL) was added 10% Pd/C (18 mg, 17 mmol). The mixture was
stirred for 2 h under H2 atmosphere at r.t. The solution was filtered
to remove the Pd/C, which was washed with CH2Cl2 (20 mL) and
the combined filtrates were concentrated in vacuo to give white
crystals of 5a, yield: 48 mg (87%). The NMR data of 5a thus ob-
tained were identical to that of the above described 5a.
IR (film): 1702, 1620, 1471, 1443 cm–1.
1H NMR (CDCl3): d = 0.11 (s, 3 H, SiCH3), 0.20 (s, 3 H, SiCH3),
0.97 [s, 9 H, C(CH3)3], 1.91 (s, 3 H, CH3), 3.35–3.40 (ddd, J = 2.20,
3.11, 9.52 Hz, 1 H, CH), 3.51 (s, 3 H, OCH3), 3.56–3.63 (dd,
J = 9.52, 10.3 Hz, 1 H, CH), 4.01 (s, 3 H, =NOCH3), 4.19–4.23 (d,
J = 10.3 Hz, 1 H, CH), 6.07–6.11 (dd, J = 3.11, 10.3 Hz, 1 H, =CH),
6.62–6.66 (dd, J = 2.20, 10.3 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –5.30 (SiCH3), –4.59 (SiCH3), 13.3 (CH3),
18.6 (SiC), 25.8 (CH3), 50.4 (CH), 61.0 (OCH3), 61.7 (=NOCH3),
80.3 (CH), 84.1 (CH), 129 (=CH), 146 (=CH), 155 (C=N), 198
(C=O).
HRMS (FAB): m/z calcd for C16H30NO4Si (M + H)+: 328.1944;
found: 328.1921.
1-[(1S*,4S*,5S*,6R*)-5-(tert-Butyldimethylsilyloxy)-6-meth-
oxy-4-(methoxymethoxy)cyclohex-2-enyl]ethanone O-Methyl
Oxime (14)
Compound 13a (58 mg, 0.18 mmol) was dissolved in CH2Cl2 (4.0
mL) under argon atmosphere with ice cooling. DIPEA (0.74 mL,
4.4 mmol) was added and the solution was stirred for 15 min with
ice cooling. MOMCl (0.26 mL, 3.4 mmol) was added and the solu-
tion was stirred for 24 h at r.t. The reaction was terminated by the
addition of sat. aq NH4Cl (2.0 mL) and sat. aq NaHCO3 (2.0 mL).
After 10 min of hydrolysis, the aqueous layer was extracted with
CH2Cl2 (2 × 4.0 mL), the combined organic layers were dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 10:1) to give 14 as a
colorless oil; yield: 61 mg (92%).
1-[(1S*,4S*,5R*,6R*)-5-(tert-Butyldimethylsilyloxy)-4-hy-
droxy-6-methoxycyclohex-2-enyl]ethanone O-Methyl Oxime
(13a) and 1-[(1S*,4R*,5R*,6R*)-5-(tert-Butyldimethylsilyloxy)-
4-hydroxy-6-methoxycyclohex-2-enyl]ethanone O-Methyl
Oxime (13b)
Compound 12 (85 mg, 0.26 mmol) was dissolved in a mixture of
MeOH (1.0 mL) and CH2Cl2 (1.0 mL) under ice cooling. NaBH4 (49
mg, 1.3 mmol) was added and the solution was stirred for 30 min
and the solution was diluted with EtOAc (50 mL). The organic layer
was washed with H2O (50 mL) and brine (50 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by silica gel
chromatography (hexane–EtOAc, 3:1) to give 13a as a colorless oil
(72 mg, 84%) and 13b as a yellow oil (7.0 mg, 8%).
IR (film): 1631 cm–1.
1H NMR (CDCl3): d = 0.09 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 1.81 (s, 3 H, CH3), 3.08–3.14 (dddd,
J = 2.20, 3.11, 3.30, 9.16 Hz, 1 H, CH), 3.22–3.29 (dd, J = 9.34,
9.52 Hz, 1 H, CH), 3.40 (s, 6 H, 2 × OCH3), 3.67–3.74 (dd, J = 7.69,
9.52 Hz, 1 H, CH), 3.87 (s, 3 H, =NOCH3), 4.02–4.07 (dddd,
J = 2.02, 2.20, 3.30, 7.69 Hz, 1 H, CH), 4.68–4.71 (d, J = 6.78 Hz,
1 H, CH), 4.80–4.82 (d, J = 6.78 Hz, 1 H, CH), 5.35–5.40 (ddd,
J = 2.02, 2.20, 10.3 Hz, 1 H, =CH), 5.71–5.76 (ddd, J = 2.20, 2.75,
10.3 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –4.53 (SiCH3), –4.26 (SiCH3), 12.2 (CH3),
18.1 (SiC), 26.0 (CH3), 50.1 (CH), 55.4 (OCH3), 60.7 (OCH3), 61.4
(=NOCH3), 76.7 (CH), 81.6 (CH), 81.7 (CH), 98.5 (OCH2), 126
(=CH), 130 (=CH), 157 (C=N).
13a
IR (film): 3444, 1655, 1472 cm–1.
1H NMR (CDCl3): d = 0.14 (s, 6 H, 2 × SiCH3), 0.93 [s, 9 H,
C(CH3)3], 1.81 (s, 3 H, CH3), 2.06–2.08 (d, J = 4.40 Hz, 1 H, OH),
3.11–3.17 (dq, J = 2.57, 11.4 Hz, 1 H, CH), 3.28–3.34 (d, J = 9.17
Hz, 1 H, CH), 3.41 (s, 3 H, OCH3), 3.61–3.66 (dd, J = 7.70, 9.17 Hz,
1 H, CH), 3.87 (s, 3 H, =NOCH3), 4.17–4.19 (m, 1 H, CH), 5.39–
5.44 (dd, J = 2.57, 10.3 Hz, 1 H, =CH), 5.68–5.73 (dd, J = 2.57,
10.3 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –4.67 (SiCH3), –4.21 (SiCH3), 12.4 (CH3),
18.2 (SiC), 26.0 (CH3), 50.2 (CH), 60.4 (OCH3), 61.4 (=NOCH3),
73.5 (CH), 78.1 (CH), 81.2 (CH), 127 (=CH), 130 (=CH), 157
(C=N).
HRMS (FAB): m/z calcd for C18H35NO5Si + Na (M + Na)+:
396.2182; found: 396.2196.
1-[(1S*,2R*,3S*,4S*,5S*,6S*)-3-(tert-Butyldimethylsilyloxy)-
5,6-dihydroxy-2-methoxy-4-(methoxymethoxy)cyclohexyl]eth-
anone O-Methyl Oxime (15a) and 1-[(1S*,2R*,3S*,4S*,
5R*,6R*)-3-(tert-Butyldimethylsilyloxy)-5,6-dihydroxy-2-meth-
oxy-4-(methoxymethoxy)cyclohexyl]ethanone O-Methyl Oxime
(15b)
AD-mix-b (1.3 g), OsO4 (2.3 mg, 9.4 mmol), and (DHQD)2-PHAL
(66 mg, 84 mmol) were dissolved in a mixture of H2O (5.0 mL) and
t-BuOH (5.0 mL) and the solution was stirred for 15 min. To this so-
lution were added MeSO2NH2 (89 mg, 0.94 mmol) and a solution of
compound 14 (0.18 g, 0.47 mmol) in CH2Cl2 (10 mL), and the re-
sulting solution was stirred for 2 weeks. Subsequently Na2SO3 (0.50
g, 0.41 mmol) was added and the solution was stirred for 1 h. The
aqueous layer and the organic layer were separated. The aqueous
layer was extracted with CH2Cl2 (2 × 10 mL). The combined organ-
ic layers were dried (Na2SO4) and concentrated in vacuo. The resi-
due was purified by silica gel chromatography (hexane–
EtOAc, 1:1) to give 15a as a colorless amorphous solid (0.12 g,
65%) and 15b as white crystals (55 mg, 29%).
HRMS (FAB): m/z calcd for C16H32NO4Si (M + H)+: 330.2101;
found: 330.2087.
13b
IR (film): 3550, 1701, 1471 cm–1.
1H NMR (CDCl3): d = 0.13 (s, 3 H, SiCH3), 0.16 (s, 3 H, SiCH3),
0.94 [s, 9 H, C(CH3)3], 1.83 (s, 3 H, CH3), 2.92 (s, 1 H, OH), 3.02–
3.06 (m, 1 H, CH), 3.42 (s, 3 H, OCH3), 3.44–3.50 (dd, J = 9.16,
9.53 Hz, 1 H, CH), 3.68–3.73 (dd, J = 4.40, 9.53 Hz, 1 H, CH), 3.88
(s, 3 H, =NOCH3), 4.11–4.14 (dd, J = 4.40, 4.77 Hz, 1 H, CH),
5.53–5.57 (dd, J = 2.20, 9.90 Hz, 1 H, =CH), 5.89–5.95 (ddd,
J = 2.57, 5.13, 9.90 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –5.00 (SiCH3), –4.48 (SiCH3), 11.9 (CH3),
18.0 (SiC), 25.9 (CH3), 50.5 (CH), 60.7 (OCH3), 61.5 (=NOCH3),
67.8 (CH), 74.6 (CH), 77.5 (CH), 128 (=CH), 130 (=CH), 156
(C=N).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 909–919

916
15a
T. Masuda et al.
PAPER
13C NMR (CDCl3): d = –4.41 (SiCH3), –4.16 (SiCH3), 15.3 (CH3),
18.0 (SiC), 26.0 (CH3), 48.4 (CH), 55.3 (OCH3), 55.6 (OCH3), 60.7
(OCH3), 61.4 (=NOCH3), 68.9 (CH), 71.4 (OCH2), 73.8 (CH), 76.9
(CH), 79.2 (CH), 83.2 (CH), 98.0 (OCH2), 114 (Ar), 130 (Ar), 130
(Ar), 156 (Ar), 159 (C=N).
IR (film): 1631, 3200 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3),
0.90 [s, 9 H, C(CH3)3], 1.92 (s, 3 H, CH3), 2.58–2.61 (d, J = 7.88
Hz, 1 H, OH), 2.74–2.81 (dd, J = 10.6, 11.2 Hz, 1 H, CH), 2.75 (s,
1 H, OH), 3.01–3.08 (dd, J = 8.79, 11.0 Hz, 1 H, CH), 3.31–3.35
(dd, J = 2.75, 9.52 Hz, 1 H, CH), 3.35 (s, 3 H, OCH3), 3.41 (s, 3 H,
OCH3), 3.68–3.75 (ddd, J = 2.75, 8.06, 11.0 Hz, 1 H, CH), 3.83–
3.89 (dd, J = 8.97, 9.16 Hz, 1 H, CH), 3.88 (s, 3 H, =NOCH3), 4.19–
4.21 (m, 1 H, CH), 4.68–4.71 (d, J = 6.59 Hz, 1 H, CH), 4.76–4.80
(d, J = 6.59 Hz, 1 H, CH).
HRMS (FAB): m/z calcd for C26H46NO8Si (M + H)+: 528.2993,
found: 528.2994.
1-[(1S*,2R*,3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-2-meth-
oxy-4-(methoxymethoxy)cyclohexyl]ethanone O-Methyl Oxime
(6b)
Compound 5a (1.3 g, 3.9 mmol) was dissolved in CH2Cl2 (120 mL)
under argon atmosphere and ice cooling. DIPEA (17 mL, 98 mmol)
was added and the solution was stirred for 15 min with ice cooling.
MOMCl (5.9 mL, 78 mmol) was added and the solution was stirred
for 24 h at r.t. The reaction was terminated by the addition of sat. aq
NH4Cl (60 mL) and sat. aq NaHCO3 (60 mL). After 10 min of hy-
drolysis, the aqueous layer was extracted with CH2Cl2 (2 × 120
mL). The combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. The residue was purified by silica gel chroma-
tography (hexane–EtOAc, 10:1) to give 6b as a colorless oil; yield:
1.4 g (92%).
13C NMR (CDCl3): d = –4.38 (SiCH3), –4.21 (SiCH3), 13.5 (CH3),
18.0 (SiC), 26.0 (CH3), 49.6 (CH), 55.7 (OCH3), 60.4 (OCH3), 61.5
(=NOCH3), 68.9 (CH), 72.1 (CH), 73.9 (CH), 80.0 (CH), 82.3 (CH),
98.0 (OCH2), 156 (C=N).
HRMS (FAB): m/z calcd for C18H38NO7Si (M + H)+: 408.2418;
found: 408.2410.
15b
Mp 63–70 °C.
IR (film): 1624, 3450 cm–1.
IR (film): 1613 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 2.00 (s, 3 H, CH3), 2.23–2.28 (dd, J = 1.83,
11.4 Hz, 1 H, CH), 3.36–3.40 (ddd, J = 1.47, 2.93, 8.80 Hz, 1 H,
CH), 3.41 (s, 3 H, OCH3), 3.44–3.50 (dd, J = 8.43, 8.80 Hz, 1 H,
CH), 3.45 (s, 1 H, OH), 3.45 (s, 3 H, OCH3), 3.54–3.60 (t, J = 8.80
Hz, 1 H, CH), 3.62–3.68 (dd, J = 8.43, 11.0 Hz, 1 H, CH), 3.88 (s,
3 H, =NOCH3), 4.07–4.08 (dd, J = 2.20, 2.57 Hz, 1 H, CH), 4.44 (d,
J = 1.47 Hz, 1 H, OH), 4.65–4.67 (d, J = 6.23 Hz, 1 H, CH), 4.73–
4.75 (d, J = 6.60 Hz, 1 H, CH).
13C NMR (CDCl3): d = –4.28 (SiCH3), –4.20 (SiCH3), 15.6 (CH3),
18.0 (SiC), 25.9 (CH3), 49.3 (CH), 55.8 (OCH3), 60.9 (OCH3), 61.6
(=NOCH3), 70.6 (CH), 72.7 (CH), 76.6 (CH), 81.4 (CH), 86.5 (CH),
99.3 (OCH2), 158 (C=N).
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 1.33–1.40 (m, 2 H, 2 × CH), 1.60–1.67 (m,
1 H, CH), 1.83 (s, 3 H, CH3), 2.03–2.09 (m, 1 H, CH), 2.20–2.29
(ddd, J = 3.66, 10.6, 12.3 Hz, 1 H, CH), 3.04–3.10 (dd, J = 8.43,
10.6 Hz, 1 H, CH), 3.24–3.45 (m, 2 H, 2 × CH), 3.36 (s, 3 H, OCH3),
3.38 (s, 3 H, OCH3), 3.85 (s, 3 H, =NOCH3), 4.63–4.66 (d, J = 6.78
Hz, 1 H, CH2), 4.74–4.76 (d, J = 6.78 Hz, 1 H, CH2).
13C NMR (CDCl3): d = –4.33 (SiCH3), –4.16 (SiCH3), 12.3 (CH3),
18.1 (SiC), 25.2 (CH2), 26.0 (CH3), 30.5 (CH2), 48.7 (CH), 55.3
(OCH3), 60.4 (OCH3), 61.3 (=NOCH3), 79.1 (CH), 80.7 (CH), 81.0
(CH), 97.7 (OCH2), 158 (C=N).
HRMS (FAB): m/z calcd for C18H38NO5Si (M + H)+: 376.2519;
found: 376.2536.
HRMS (FAB): m/z calcd for C18H38NO7Si (M + H)+: 408.2418;
found: 408.2417.
1-[(1S*,2R*,3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-2-meth-
oxy-4-(methoxymethoxy)cyclohexyl]ethanone (7c)
1-[(1R*,2R*,3S*,4S*,5S*,6S*)-3-(tert-Butyldimethylsilyloxy)-5-
hydroxy-2-methoxy-6-(4-methoxybenzyloxy)-4-(methoxy-
methoxy)cyclohexyl]ethanone O-Methyl Oxime (16)
Compound 6b (1.0 g, 2.7 mmol) was dissolved in toluene (50 mL)
under argon atmosphere and ice cooling. A 0.25 M solution of
TiCl3·3THF-DIBAL in toluene (14 mL, 3.5 mmol) was added. The
solution was stirred for 20 min at r.t. A solution of TiCl3·3THF-
DIBAL in toluene (14 mL, 3.5 mmol) was added additionally and
the solution was stirred for 20 min. Finally a solution of
TiCl3·3THF-DIBAL in toluene (14 mL, 3.5 mmol) was added again
and the solution was stirred for 40 min at r.t. The reaction was ter-
minated by the addition of sat. aq NaOAc (50 mL) and the pH of the
solution was adjusted to 3.0 by aq citric acid. The solution was ex-
tracted with CH2Cl2 (4 × 75 mL), the combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by silica gel chromatography (hexane–EtOAc, 5:1) to give 7c as a
colorless oil; yield: 1.6 g (85%).
Compound 15a (0.70 g, 0.17 mmol) was dissolved in toluene (80
mL) and Bu2SnO (0.50 g, 2.0 mmol) was added. The solution was
heated at reflux for 3 h while the H2O formed was removed by using
the Dean–Stark apparatus. The solvent was removed by evapora-
tion. To the residue was added CsF (0.30 g, 2.0 mmol). The result-
ing material was dried for 1 h in vacuo and dissolved in DMF (30
mL). At –41 °C, MPMCl (0.27 mL, 2.0 mmol) was added and the
solution was stirred for 24 h. The solution was concentrated in
vacuo and then dried for 24 h in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 3:1) to give 16 as a col-
orless oil; yield: 0.47 g (52%).
IR (film): 1613, 3477 cm–1.
IR (film): 1717 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3),
0.89 [s, 9 H, C(CH3)3], 1.81 (s, 3 H, CH3), 2.31 (s, 1 H, OH), 2.78–
2.85 (t, J = 11.2 Hz, 1 H, CH), 3.06–3.13 (dd, J = 8.79, 11.0 Hz, 1
H, CH), 3.24–3.28 (dd, J = 2.57, 9.34 Hz, 1 H, CH), 3.35 (s, 3 H,
OCH3), 3.41 (s, 3 H, OCH3), 3.49–3.53 (dd, J = 2.56, 11.2 Hz, 1 H,
CH), 3.80 (s, 3 H, OCH3), 3.86 (s, 3 H, =NOCH3), 3.86–3.92 (dd,
J = 8.97, 9.34 Hz, 1 H, CH), 4.22–4.24 (dd, J = 2.56, 2.56 Hz, 1 H,
CH), 4.39–4.42 (d, J = 11.5 Hz, 1 H, CH), 4.53–4.56 (d, J = 11.5
Hz, 1 H, CH), 4.70–4.73 (d, J = 6.78 Hz, 1 H, CH), 4.76–4.79 (d,
J = 6.78 Hz, 1 H, CH), 6.85–6.88 (d, J = 8.61 Hz, 2 Harom), 7.19–
7.22 (d, J = 8.61 Hz, 2 Harom).
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 1.26–1.40 (m, 2 H, CH, CH), 1.67–1.73 (m,
1 H, CH), 2.06–2.12 (m, 1 H, CH), 2.22 (s, 3 H, CH3), 2.53–2.62
(ddd, J = 3.66, 11.7, 13.6 Hz, 1 H, CH), 3.22–3.31 (m, 2 H, 2 × CH),
3.35–3.42 (dd, J = 6.23, 9.16 Hz, 1 H, CH), 3.35 (s, 3 H, OCH3),
3.38 (s, 3 H, OCH3), 4.62–4.65 (d, J = 6.97 Hz, 1 H, CH), 4.72–4.75
(d, J = 6.60 Hz, 1 H, CH).
13C NMR (CDCl3): d = –4.38 (SiCH3), –4.13 (SiCH3), 18.1 (SiC),
24.0 (CH2), 26.0 (CH3), 30.6 (CH2), 31.2 (CH3), 55.1 (CH), 55.3
Synthesis 2012, 44, 909–919
© Thieme Stuttgart · New York

PAPER
Synthetic Precursor for All Regioisomers of Inositol Phosphate
917
(OCH3), 61.2 (OCH3), 79.1 (CH), 80.8 (CH), 84.3 (CH), 97.7
(OCH2), 211 (C=O).
HRMS (FAB): m/z calcd for C15H30O5Si + Na (M + Na)+: 341.1760;
found: 341.1770.
HRMS (FAB): m/z calcd for C17H35O5Si (M + H)+: 347.2254;
found: 347.2243.
(1S*,4S*,5R*,6R*)-5-(tert-Butyldimethylsilyloxy)-6-methoxy-4-
(methoxymethoxy)cyclohex-2-enol (17a)
Compound 10c (61 mg, 0.19 mmol) was dissolved in THF (1.0 mL)
under argon atmosphere at –78 °C. A THF solution of LiHMDS
(1.6 M, 0.28 mL, 0.45 mmol) was added and the solution was stirred
for 1 h at –78 °C. TMSCl (36 mL, 0.29 mmol) was then added and
the solution was stirred for 45 min at –78 °C and for 1 h at r.t., and
concentrated in vacuo. The residue was dissolved in anhyd pentane
(20 mL) and filtered through Celite. The filtrate was concentrated in
vacuo to give the crude intermediate TMS enolate as a colorless oil.
The crude colorless oil was dissolved in CH2Cl2 (2.0 mL) under ar-
gon atmosphere at –78 °C. A solution of PhSeCl (40 mg, 0.21
mmol) in CH2Cl2 (1.0 mL) was added and the solution was stirred
for 45 min at –78 °C and for 15 min at r.t. The solution was concen-
trated in vacuo to give the crude intermediate phenylselenyl ketone
as a yellow oil. At –78 °C, the crude yellow oil was dissolved in
MeOH (2.0 mL) and NaBH4 (14 mg, 0.38 mmol) were added and
the solution was stirred for 30 min. The solution was diluted with
EtOAc (59 mL), the organic layer was washed with H2O (50 mL)
and brine (50 mL), dried (Na2SO4) and concentrated in vacuo to
give the crude intermediate phenylselenyl alcohol as a yellow oil.
The crude yellow oil was dissolved in THF (3.3 mL) under argon
atmosphere and ice cooling. NaHCO3 (49 mg, 0.58 mmol) and 30%
H2O2 (47 mL, 0.49 mmol) were successively added and the solution
was stirred for 15 min at the same temperature, then for 2 h at r.t.
H2O (30 mL) was added and the mixture was extracted with Et2O
(3 × 40 mL). The combined organic layers were washed with brine
(60 mL), dried (Na2SO4), and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–EtOAc, 5:1) to
give 17a as a colorless oil (31 mg, 51% over 4 steps).
1-[(1S*,2R*,3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-2-meth-
oxy-4-(methoxymethoxy)cyclohexyl]ethyl Methanesulfonate
(8b)
Under ice cooling, compound 7c (1.8 g, 5.1 mmol) was dissolved in
a mixture of MeOH (16 mL) and CH2Cl2 (16 mL). NaBH4 (0.58 g,
15 mmol) was added and the solution was stirred for 30 min with
ice cooling. The solution was diluted with EtOAc (50 mL), washed
with H2O (50 mL), brine (50 mL), dried (Na2SO4), and concentrated
to give the intermediate alcohol as a colorless oil. Under argon at-
mosphere and ice cooling, the crude colorless oil was dissolved in
CH2Cl2 (32 mL). Et3N (7.1 mL, 50mmol) and MsCl (2.9 mL, 37
mmol) were added and the resulting solution was stirred for 1.5 h.
To the solution was added sat. aq NaHCO3 (20 mL) and extracted
with CH2Cl2 (3 × 40 mL). The combined extracts were dried
(Na2SO4) and concentrated in vacuo. The residue was subjected to
silica gel chromatography (hexane–EtOAc, 3:1) to give crude 8b
(1.7 g) as white crystals.
tert-Butyl[(1R*,2R*,6S*,E)-3-ethylidene-2-methoxy-6-(meth-
oxymethoxy)cyclohexyloxy]dimethylsilane (9c) and tert-Bu-
tyl[(1R*,2R*,3R*,6S*)-2-methoxy-6-(methoxymethoxy)-3-
vinylcyclohexyloxy]dimethylsilane (9d)
Compound 8b (1.7 g, crude) was dissolved in toluene (50 mL) and
DBU (4.4 mL, 29 mmol) was added. The solution was heated at re-
flux for 48 h. To the solution was added sat. aq NH4Cl (75 mL) and
extracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were washed with brine (200 mL), dried (Na2SO4), and concentrat-
ed in vacuo. The residue was subjected to silica gel chromatography
(hexane–EtOAc, 20:1) to give crude 9c,d (0.74 g) as a colorless oil.
IR (film): 3246 cm–1.
1H NMR (CDCl3): d = 0.10 (s, 3 H, SiCH3), 0.14 (s, 3 H, SiCH3),
0.92 [s, 9 H, C(CH3)3], 2.35–2.37 (d, J = 5.13 Hz, 1 H, OH), 3.12–
3.17 (dd, J = 6.96, 9.16 Hz, 1 H, CH), 3.40 (s, 3 H, OCH3), 3.59 (s,
3 H, OCH3), 3.72–3.77 (dd, J = 6.60, 9.16 Hz, 1 H, CH), 4.01–4.04
(dd, J = 1.83, 6.60 Hz, 1 H, –CH), 4.15–4.22 (m, 1 H, CH), 4.68–
4.70 (d, J = 6.96 Hz, 1 H, CH), 4.77–4.79 (d, J = 6.97 Hz, 1 H, CH),
5.66–5.71 (dd, J = 1.47, 11.0 Hz, 1 H, =CH), 5.71–5.75 (dd,
J = 1.47, 11.7 Hz, 1 H, =CH).
13C NMR (CDCl3): d = –4.64 (SiCH3), –4.49 (SiCH3), 18.0 (SiC),
25.9 (CH3), 55.5 (OCH3), 61.3 (OCH3), 71.3 (CH), 75.0 (CH), 80.6
(CH), 85.6 (CH), 98.0 (OCH2), 128 (=CH), 129 (=CH).
HRMS (FAB); m/z calcd for C15H30O5Si + Na (M + Na)+: 341.1760;
found: 341.1767.
(2S*,3R*,4S*)-3-(tert-Butyldimethylsilyloxy)-2-methoxy-4-
(methoxymethoxy)cyclohexanone (10c) and (1S*,2R*,3R*,4S*)-
3-(tert-Butyldimethylsilyloxy)-2-methoxy-4-(meth-
oxymethoxy)cyclohexanecarbaldehyde (10d)
Crude compound 9c,d (0.74 g) was dissolved in a mixture of
CH2Cl2 (30 mL) and MeOH (6.0 mL). Et3N (0.30 mL, 1% v/v) was
added and the solution was stirred at –78 °C. O3 was bubbled until
the blue color persisted. O2 was bubbled through the reaction solu-
tion 30 min at –78 °C. Me2S (1.2 mL, 17 mmol) was added and the
resulting solution was stirred for 30 min and then stirred further at
r.t. for 2 h. The reaction was terminated by the addition of sat. aq
NaHCO3 (50 mL) and the aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The combined organic layers were washed with brine
(100 mL), dried (Na2SO4), and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–EtOAc, 5:1) to
give 10c (0.39 g, 24% over 3 steps) and 10d (0.16 g, crude) as col-
orless oils.
tert-Butyl[(1R*,2S*,5S*,6R*)-6-methoxy-5-(4-methoxybenzyl-
oxy)-2-(methoxymethoxy)cyclohex-3-enyloxy]dimethylsilane
(18)
Under argon atmosphere and ice cooling, compound 17a (55 mg,
0.17 mmol) was dissolved in THF (3.4 mL). NaH (42 mg, 1.0
mmol) and molecular sieves 4 Å (0.10 g) were added and the mix-
ture was warmed to r.t. and stirred for 2 h at the same temperature.
The solution was cooled to 0 °C and TBAI (6.4 mg, 17 mmol) and
MPMCl (26 mL, 0.19 mmol) were added. The solution was warmed
to r.t. and stirred for 2 d at the same temperature. To the solution
wad added H2O (5mL) and extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (15 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 20:1) to give 18 as a
colorless oil; yield: 30 mg (40%).
10c
IR (film): 1731 cm–1.
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3),
0.90 [s, 9 H, C(CH3)3], 1.55–1.65 (ddd, J = 5.49, 10.6, 12.8 Hz, 1 H,
CH), 2.21–2.30 (m, 1 H, CH), 2.34–2.45 (m, 2 H, 2 × CH), 3.39 (s,
3 H, OCH3), 3.46 (s, 3 H, OCH3), 3.56–3.59 (dd, J = 0.73, 8.79 Hz,
1 H, CH), 3.70–3.76 (dd, J = 7.33, 8.79 Hz, 1 H, CH), 3.68–3.75 (m,
1 H, CH), 4.67–4.70 (d, J = 6.78 Hz, 1 H, CH), 4.81–4.83 (d,
J = 6.78 Hz, 1 H, CH).
13C NMR (CDCl3): d = –4.58 (2 × SiCH3), 18.2 (SiC), 25.8 (CH3),
27.1 (CH2), 35.9 (CH2), 55.4 (OCH3), 59.5 (OCH3), 78.2 (CH), 79.2
(CH), 88.4 (CH), 97.5 (OCH2), 206 (C=O).
IR (film): 1613 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 909–919

918
T. Masuda et al.
PAPER
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3),
0.92 [s, 9 H, C(CH3)3], 3.19–3.25 (dd, J = 7.69, 10.3Hz, 1 H, CH),
3.38 (s, 3 H, OCH3), 3.58–3.64 (dd, J = 7.69, 10.3 Hz, 1 H, CH),
3.60 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.96–4.05 (m, 2 H, 2
× CH), 4.56–4.60 (d, J = 11.2 Hz, 1 H, CH), 4.62–4.65 (d, J = 11.0
Hz, 1 H, CH), 4.66–4.69 (d, J = 6.78 Hz, 1 H, CH), 4.77–4.80 (d,
J = 6.78 Hz, 1 H, CH), 5.60–5.64 (d, J = 10.4 Hz, 1 H, =CH), 5.66–
5.70 (d, J = 10.4 Hz, 1 H, =CH), 6.86–6.89 (dd, J = 1.83, 8.61 Hz,
2 Harom), 7.27–7.30 (dd, J = 2.01, 8.61 Hz, 2 Harom).
13C NMR (CDCl3): d = –4.58 (SiCH3), –4.28 (SiCH3), 18.2 (SiC),
26.0 (CH3), 55.3 (OCH3), 55.5 (OCH3), 61.3 (OCH3), 71.9 (OCH2),
75.9 (CH), 80.4 (CH), 81.6 (CH), 85.2 (CH), 98.5 (OCH2), 114
(Ar), 127 (=CH), 129 (=CH), 129 (Ar), 131 (Ar), 159 (Ar).
1H NMR (CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.14 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 2.06 (s, 3 H, CH3), 2.33 (s, 1 H, OH), 2.98–
3.04 (dd, J = 9.16, 9.34 Hz, 1 H, CH), 3.35–3.39 (dd, J = 2.93, 9.16
Hz, 1 H, CH), 3.38 (s, 3 H, OCH3), 3.57 (s, 3 H, OCH3), 3.79 (s, 3
H, OCH3), 3.82–3.87 (dd, J = 7.51, 9.16 Hz, 1 H, CH), 3.87–3.90
(dd, J = 7.88, 9.52 Hz, 1 H, CH), 4.18–4.20 (dd, J = 2.56, 2.75 Hz,
1 H, CH), 4.60–4.63 (d, J = 11.0 Hz, 1 H, CH), 4.67–4.69 (d,
J = 6.78 Hz, 1 H, CH), 4.73–4.77 (d, J = 10.8 Hz, 1 H, CH), 4.76–
4.78 (d, J = 6.59 Hz, 1 H, CH), 4.85–4.90 (dd, J = 2.75, 10.4 Hz, 1
H, CH), 6.85–6.88 (dd, J = 2.75, 8.79 Hz, 2 Harom), 7.21–7.24 (dd,
J = 2.75, 8.61 Hz, 2 Harom).
13C NMR (CDCl3): d = –4.35 (SiCH3), –4.28 (SiCH3), 18.1 (SiC),
21.1(CH3), 25.9 (CH3), 55.3 (OCH3), 55.8 (OCH3), 61.7 (OCH3),
70.1 (CH), 72.9 (CH), 72.9 (CH), 75.0 (OCH2), 79.2 (CH), 79.9
(CH), 85.3 (CH), 98.0 (OCH2), 114 (Ar), 129 (Ar), 131 (Ar), 159
(Ar), 170 (OC=O).
HRMS (FAB): m/z calcd for C23H38O6Si + Na (M + Na)+: 461.2335;
found: 461.2332.
(1S*,2R*,3S*,4S*,5R*,6S*)-4-(tert-Butyldimethylsilyloxy)-5-
methoxy-6-(4-methoxybenzyloxy)-3-(methoxymethoxy)cyclo-
hexane-1,2-diol (19)
HRMS (FAB): m/z calcd for C25H42O9Si + Na (M + Na)+: 537.2496;
found: 537.2527.
AD-mix-b (0.10 g), OsO4 (1.0 mg, 4.3 mmol), and (DHQD)2-PHAL
(22 mg, 28 mmol) were dissolved in a mixture of H2O (1.5 mL) and
t-BuOH (1.5 mL) and the solution was stirred for 15 min. To this so-
lution, MeSO2NH2 (14 mg, 0.14 mmol) and a solution of compound
18 (31 mg, 71 mmol) in CH2Cl2 (3.0 mL) were added and the result-
ing solution was stirred for 2 weeks. Subsequently, Na2SO3 (76 mg,
0.60 mmol) was added and the solution was stirred for 1 h. The
aqueous layer and the organic layer were separated. The aqueous
layer was extracted with CH2Cl2 (2 × 3 mL). The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The residue
was purified by silica gel chromatography (hexane–EtOAc, 1:1) to
give 19 as a colorless oil; yield: 20 mg (59%).
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research (B) (23390028) (to M.O.) from Japan Society for promo-
tion of Science, by a Grant-in-Aid for Exploratory Research
(19659025) (to M.O.) from the Japan Society for Promotion of
Science, and by the aid of a special fellowship (to K.A.) granted by
Kumamoto Health Science University for culture, education and
science.
References
IR (film): 3450 cm–1.
(1) Prestwich, G. D. Acc. Chem. Res. 1996, 29, 503.
(2) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1933.
(3) Mikoshiba, K. Trends Pharmacol. Sci. 1993, 14, 1986.
(4) Anraku, K.; Inoue, T.; Sugimoto, K.; Morii, T.; Mori, Y.;
Okamoto, Y.; Otsuka, M. Org. Biomol. Chem. 2008, 6, 1822.
(5) Anraku, K.; Inoue, T.; Sugimoto, K.; Kudo, K.; Okamoto,
Y.; Morii, T.; Mori, Y.; Otsuka, M. Bioorg. Med. Chem.
2011, 19, 6833.
1H NMR (CDCl3): d = 0.09 (s, 3 H, SiCH3), 0.14 (s, 3 H, SiCH3),
0.91 [s, 9 H, C(CH3)3], 2.35–2.36 (d, J = 4.03 Hz, 1 H, OH), 2.45 (s,
1 H, OH), 2.92–2.98 (dd, J = 9.16, 9.34 Hz, 1 H, CH), 3.29–3.33
(dd, J = 2.93, 9.52 Hz, 1 H, CH), 3.40 (s, 3 H, OCH3), 3.45–3.51 (td,
J = 3.30, 9.71 Hz, 1 H, CH), 3.60 (s, 3 H, OCH3), 3.62–3.69 (t,
J = 9.52 Hz, 1 H, CH), 3.80 (s, 3 H, OCH3), 3.84–3.90 (t, J = 9.16
Hz, 1 H, CH), 4.18 (br s, 1 H, CH), 4.63–4.67 (d, J = 10.8 Hz, 1 H,
CH), 4.68–4.70 (d, J = 6.78 Hz, 1 H, CH), 4.77–4.79 (d, J = 6.78
Hz, 1 H, CH), 4.86–4.90 (d, J = 11.0 Hz, 1 H, CH), 6.88–6.91 (dd,
J = 2.02, 8.61 Hz, 2 Harom), 7.29–7.33 (dd, J = 2.93, 8.61 Hz, 2
(6) Anraku, K.; Fukuda, R.; Takamune, N.; Misumi, S.;
Okamoto, Y.; Otsuka, M.; Fujita, M. Biochemistry 2010, 49,
5109.
Harom).
13C NMR (CDCl3): d = –4.36 (SiCH3), –4.26 (SiCH3), 18.1 (SiC),
26.0 (CH3), 55.3 (OCH3), 55.7 (OCH3), 61.5 (OCH3), 71.1 (CH),
71.5 (CH), 73.2 (CH), 75.0 (OCH2), 79.9 (CH), 81.3 (CH), 85.6
(CH), 98.0 (OCH2), 114 (Ar), 130 (Ar), 131 (Ar), 159 (Ar).
HRMS (FAB): m/z calcd for C23H40O8Si + Na (M + Na)+: 495.2390;
found: 495.2428.
(7) (a) Inoue, T.; Kikuchi, K.; Hirose, K.; Iino, M.; Nagano, T.
Bioorg. Med. Chem. Lett. 1999, 9, 1697. (b) Han, F.;
Hayashi, M.; Watanabe, Y. Tetrahedron 2003, 59, 7703.
(c) Dorman, G.; Chen, J.; Prestwich, G. D. Tetrahedron Lett.
1995, 36, 8719. (d) Thum, O.; Chen, J.; Prestwich, G. D.
Tetrahedron Lett. 1996, 37, 9017. (e) Ley, S. V.; Sternfeld,
L. Tetrahedron Lett. 1988, 29, 5305. (f) Carless, H. A. J.;
Busia, K. Tetrahedron Lett. 1990, 31, 3449.
(1R*,2S*,3S*,4R*,5S*,6R*)-3-(tert-Butyldimethylsilyloxy)-6-
hydroxy-4-methoxy-5-(4-methoxybenzyloxy)-2-(methoxy-
methoxy)cyclohexyl Acetate (20)
(8) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am.
Chem. Soc. 1979, 101, 6996.
(9) The stereochemistry of 3a and 3b was assigned by
comparing with the closely related known compound whose
stereochemistry has already been established by
Danishefsky.8
(10) (a) Paquette, L. A.; Lin, H.-S.; Gunn, B. P.; Coghlan, M.
J. Am. Chem. Soc. 1988, 110, 5818. (b) Pennanen, S. I.
Tetrahedron Lett. 1980, 21, 657. (c) Rubuttom, G. M.;
Gruber, J. M. Tetrahedron Lett. 1978, 4603. (d) Rubuttom,
G. M.; Vazquez, M. A.; Pelegria, D. R. Tetrahedron Lett.
1974, 4319.
Compound 19 (20 mg, 42 mmol) was dissolved in toluene (12 mL)
and Bu2SnO (13 mg, 51 mmol) was added. The solution was heated
at reflux for 3 h while the water formed was removed by using the
Dean–Stark apparatus. The solvent was then removed by evapora-
tion. The residue was dissolved in CH2Cl2 (2.0 mL) under argon at-
mosphere and AcCl (4.6 mL, 63 mmol) was added at –41 °C, and the
solution was stirred for 24 h. The solution was concentrated in
vacuo and then dried for 24 h in vacuo. The residue was purified by
silica gel chromatography (hexane–EtOAc, 3:1) to give 20 as a
yellow oil; yield: 8.6 mg (39%).
(11) The relative stereochemistry of 4a and 4b was assigned
IR (film): 1746, 3391 cm–1.
based on the NMR coupling constants.
Synthesis 2012, 44, 909–919
© Thieme Stuttgart · New York

PAPER
Synthetic Precursor for All Regioisomers of Inositol Phosphate
919
(12) Acena, J. A.; Arjona, O.; Manas, R.; Plumet, J. J. Org.
Chem. 2000, 65, 2580.
(13) The relative stereochemistry of 5a and 5b was assigned
based on the NMR coupling constants.
(17) Armstrong, A.; Barsanti, P. A.; Jones, L. H.; Ahmed, G.
J. Org. Chem. 2000, 65, 7020.
(18) The stereochemical assignment of 15a and 15b was based on
the NMR coupling constants.
(14) Giner, J. L. J. Org. Chem. 2005, 70, 721.
(15) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Aoe, K.; Okamura,
K.; Naito, T. J. Org. Chem. 2000, 65, 6922.
(16) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.;
Hamada, Y. Tetrahedron Lett. 1986, 27, 2199.
(19) Nagashima, N.; Ohno, M. Chem. Lett. 1987, 141.
(20) Stereochemical assignment of 17a was tentative at this stage.
The stereochemistry of compound 19 was established at a
later step.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 909–919