Divergent synthesis of all possible optically active regioisomers of myo-inositol mono- and bisphosphates

Article abstract of DOI:10.1080/07328300701540225

All possible optically active regioisomers of myo-inositol mono- and bisphosphates were synthesized using inositol derivatives suitably protected with various protecting groups (IRns) as key intermediates. A series of procedures including Novozym 435 cata

Full text of DOI:10.1080/07328300701540225

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Divergent Synthesis of All Possible Optically
Active Regioisomers of Myo‐Inositol Mono‐
and Bisphosphates
Kyung‐Chang Seo a , Seok‐Ho Yu a & Sung‐Kee Chung a
a Department of Chemistry, Pohang University of Science & Technology,
Pohang, Korea
Published online: 31 Aug 2007.
To cite this article: Kyung‐Chang Seo , Seok‐Ho Yu & Sung‐Kee Chung (2007): Divergent Synthesis of All
Possible Optically Active Regioisomers of Myo‐Inositol Mono‐ and Bisphosphates, Journal of Carbohydrate
Chemistry, 26:5-6, 305-327
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Journal of Carbohydrate Chemistry, 26:305–327, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300701540225
Divergent Synthesis of All
Possible Optically Active
Regioisomers of
Myo-Inositol Mono- and
Bisphosphates
Kyung-Chang Seo, Seok-Ho Yu, and Sung-Kee Chung
Department of Chemistry, Pohang University of Science & Technology, Pohang, Korea
All possible optically active regioisomers of myo-inositol mono- and bisphosphates were
synthesized using inositol derivatives suitably protected with various protecting groups
(IRns) as key intermediates. A series of procedures including Novozym 435 catalyzed
enzymatic resolution of (3aR,4S,7S,7aR)-rel-3a,4,7,7a-tetrahydro-2,2-dimethyl-1,3-ben-
zodioxole-4,7-diol diacetate, several protection and deprotection reactions, and acyl
migration afforded two enantiomeric pairs of IR5 and six enantiomeric pairs of IR4.
Phosphorylation of these key intermediates by the phosphitylation and oxidation pro-
cedure gave the target products after removal of the protecting groups.
Keywords Myo-inositol, Inositol phosphates, divergent synthesis, Protecting groups,
Phosphorylation
INTRODUCTION
Although inositol phosphates had long been known, renewed interests began
to rise only after the discovery in 1983 that D-myo-inositol-1,4,5-trisphosphate
Received January 7, 2006; accepted April 12, 2006.
Address correspondence to Sung-Kee Chung, Department of Chemistry, Pohang Univer-
sity of Science & Technology, Pohang 790-784, Korea. E-mail: skchung@postech.edu
305

K.-C. Seo et al.
306
[D-I(1,4,5)P3] is a Ca2þ-mobilizing second messenger in the cytosol.[1] It was
soon found that D-I(1,4,5)P3 and its dephosphorylated products, D-I(1,4)P2
and D-IP1s as well as D-I(1,3,4)P3 and D-I(1,3,4,5)P4, emerged as metabolites
when cells were stimulated. Furthermore, InsP5 and InsP6, previously
thought to be present only in plants and erythrocytes of a few animals, were
also found to be components of mammalian cells. Now the phospholipase C
(PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to
D-I(1,4,5)P3 and diacylglycerol, a PKC activator, is one of the best established
signaling pathways in cells. More recently, nuclear counterparts of similar
inositol signaling pathways also have been found.[2] myo-Inositol phosphates
other than D-I(1,3,4)P3 and D-I(1,3,4,5)P4 have become quite prominent with
newly discovered important biological functions. For example, D-I(3,4,5,6)P4
was shown to be a physiologically important inhibitor of Ca2þ-regulated Cl2
channels, whereas D-IP6 (phytic acid) was found to regulate mRNA export in
mammalian cells through its interaction with synaptotagmin[3] as well as to
play a key role in RNA editing.[4]
Mathematically, there are 39 possible optically inactive regioisomers of
myo-inositol phosphates (IPn: n ¼ 1 to 6), or 63 regioisomers, if enantiomers
are considered. Many inositol kinases and phosphatases have been identified
in the course of studying the metabolism of inositol phosphates. For instance,
one of the major metabolic pathways of D-I(1,4,5)P3 is removal of the 5-phos-
phate group by a specific 5-phophatase located in plasma membrane as well
as in the cytosol of stimulated cells to give I(1,4)P2. Other phosphatases are
responsible for the further degradation of the IP2 formed in this hydrolysis,
via I(1)P1 or I(4)P1, to give finally free inositol, which is then recycled in the
biosynthesis of PIP2.
Although the conversion of I(1,4,5)P3 into I(1,4)2 had been regarded as
merely a terminating step of the Ca2þ mobilization signal, the novel activities
of I(1,4)P2 reported as a DNA polymerase a activator[5] and cytoskeletal actin
inducer[6] suggested that IP2 might be another interesting signaling molecule.
Several other IP2s were also detected in nature, but the biological functions of
IP2s have not yet been thoroughly examined. The mammalian enzyme, myo-
inositol monophosphatase, which hydrolyzes the naturally occurring IP1
isomers D-I(1)P1, I(3)P1, and I(4)P1 to free inositol with a low substrate selectiv-
ity, is inhibited by lithium ion in an uncompetitive manner.[7] Blockade of this
enzyme would be expected to reduce the overall available inositol and thus
PIP2 production, and it was hypothesized that the lithium ion effect in the
treatment of manic depression and its accompanying CNS toxicity might be
due to the inhibition of inositol monophosphatase.[8] Studies of lithium’s
effect on myo-inositol monophosphatase polymorphisms and bipolar disorder
is a current research topic in molecular psychiatry.[9] Some of IP1 analogs
have been prepared and mechanistic studies with them as either substrate
or inhibitor have been carried out by several groups.[10] In these connections,

Synthesis of Myo-Inositols
307
Figure 1: Two enantiomeric pairs of IP1 and six enantiomeric paris of IP2.
availability of all possible optically active IP1 and IP2 regioisomers would be
highly desirable.
We previously reported the systematic and divergent syntheses of all
possible 39 optically inactive regioisomers of myo-inositol phosphates using
the acyl migration as the key strategy[11] and 32 optically active regioisomers
of myo-inositol tris-, tetrakis-,[12] and pentakis-phosphates[13] using the CRL-
catalyzed enzymatic resolution and the acyl migration. Herein we describe
the synthesis of optically active myo-inositol mono- and bisphosphate regio-
isomers (Fig. 1) via application of the divergent as well as specific synthetic
methods at the stage of various intermediates, thus now completing the synth-
eses of all possible 63 (15 meso and 24 enantiomeric pairs) regioisomers of
myo-inositol phosphates.
RESULTS AND DISCUSSION
The key issues in the synthesis of optically active regioisomers of IP1 and IP2
are (1) how to obtain enantiomerically pure inositol derivatives and (2) how

K.-C. Seo et al.
308
to efficiently prepare IR5s and IR4s, the key intermediates. Our synthetic
approaches to homochiral regioisomers of IP1 and IP2 are based on the
enzyme-catalyzed optical resolution of (3aR,4S,7S,7aR)-rel-3a,4,7,7a-tet-
rahydro-2,2-dimethyl-1,3-benzodioxole-4,7-diol diacetate with Novozym 435
(immobilized lipase from Candida antarctica, Novo Nordisk).[14] The conver-
sions of the enantiomeric diols, D-3 and L-3, to two enantiomeric pairs of all
possible IP1 and IP2 regioisomers involve the identical series of reactions
except that the corresponding substrates and products along the synthetic
route have opposite configurations. Therefore, the procedure starting from
D-3 only is described as the representative procedure.
Chiral IR5s and IR4s, the key synthetic precursors for phosphorylation,
were prepared as follows. cis-Dihydroxylation of compound D-4, which was
prepared by simple benzylation of D-3 with BnBr, NaH, and TBAI in THF,
exclusively gave D-3,6-di-O-benzyl-4,5-isopropylidene-myo-inositol (D-5), the
synthetic precursor to D-I(1,2)P2. Treatment of the chiral diol D-5 with 2-meth-
oxypropene and an acid catalyst gave the di-O-benzyl-di-O-isopropylidene
derivative D-6, and catalytic hydrogenolysis of D-6 in the presence of
NaHCO3 gave the monool D-7 (53.8%) and the diol D-8 (11.6%),[15] which
served as the synthetic precursor to D-I(3)P1 and D-I(3,6)P2, respectively
(Sch. 1).
The tetraol D-9, derived from D-7 by treatment with aq AcOH, followed by
selective monobenzoylation at the axial hydroxy group through the orthobenzo-
ate intermediate,[11d] was treated with MOMCl and DIPEA in 1,2-dichloro-
ethane to afford compound D-10. Benzyl and benzoyl groups of D-10 were
removed by hydrogenolysis with Pd(OH)2 on charcoal and subsequent
Scheme 1: a. BnBr, NaH, TBAl; b. OsO4, NMO; c. 2-methoxypropene, TSA; d. H2, 10% Pd-C,
NaHCO3.

Synthesis of Myo-Inositols
309
Scheme 2: a. (i) 80% aq AcOH, (ii) triethyl orthobenzoate, TSA; b. MOMCl, DIPEA; c. (i) H2, 20%
Pd(OH)2-C, (ii) NaOMe; d. BzCl, DMAP; e. H2, 10% Pd-C, NaHCO3.
treatment with NaOMe to give the diol D-11, which served as the precursor
to D-I(2,6)P2. After protection of 3-OH of compound D-7 as benzoyl ester by
treatment with BzCl and DMAP, subsequent deprotection of the benzyl
group by hydrogenolysis in a basic condition gave D-13 as the D-I(6)P1 pre-
cursor (Sch. 2).
Acid-catalyzed partial solvolysis of compound D-12 with a catalytic amount
of TSA in MeOH-CH2Cl2 gave the diol D-14 (68.5%) and the tetraol D-15
(25.1%). When the diol D-14 was subjected to the acyl migration condition
(60% aq. pyridine, 908C), a mixture of three regioisomers was generated.
Each of these regioisomers was readily separated and purified by silica gel
chromatography. The ratio of the regioisomers on the basis of the isolated
yields was as follows; D-14:D-16:D-17 ¼ 31:25:44 (Sch. 3).
Compound D-7 was phosphorylated by successive treatments with
dibenzyl diisopropylphosphoramidite and 1H-tetrazole, and then mCPBA to
yield D-18. Compound D-13 was phosphitylated with diethyl phosphochlori-
dite and DIPEA, and then oxidized with 30% H2O2 to give D-19. The two enan-
tiomeric pairs of inositol monophosphate in the protected forms (18 and 19)
were obtained in 70% to 82% yields (Sch. 4), and their 31P NMR chemical
shifts and optical rotations are shown in Table 1. In the final steps, all protect-
ing groups were removed by hydrogenolysis, treatment with TMSBr, and
hydrolysis with LiOH to give the desired four optically active regioisomers of
IP1 (1a and 1b) in the sodium salt form. They were fully characterized by
1H and 31P NMR spectroscopy (Sch. 4).

K.-C. Seo et al.
310
Scheme 3: a. TSA, MeOH/CH2Cl2; b. 60% aq pyridine.
All six enantiomeric pairs of IP2s in the sodium salt form (2a–f) were
prepared by phosphorylating the corresponding precursors as described for
IP1 regioisomers (Sch. 5 and 6). The 31P NMR chemical shifts and optical
rotations of the six enantiomeric pairs of IP2 in their protected form (20–25)
are listed in Table 1.
Scheme 4: a. (i) Dibenzyl disopropylphosphoramidite, 1H-tetrazole, (ii) mCPBA; b. (i) H2, 10%
Pd-C, AcOH, (ii) pH 10 (1N NaOH); c, (i) diethyl phosphorochloridite, DIPEA, (ii) 30% H2O2;
d. (i) TMSBr, (ii) 1M LiOH, (iii) Hþ ion exchange, (iv) pH 10 (1N NaOH).

Synthesis of Myo-Inositols
311
Table 1: 31P NMR chemical shifts and optical rotations of IPnR(6-n)s.
[a]2D5 (in CH2Cl2)
31P (d, ppm)
D-form
L-form
18 [I(3)P0(6)Bn(1,2:4,5)Ace2]
19 [I(6)P00(3)Bz(1,2:4,5)Ace2]
20 [I(1,2)P020(3,6)Bn2(4,5)Ace]
21 [I(3,6)P20 (1,2:4,5)Ace2]
0.63
0.89
222.8 (c 1.10)
þ30.1 (c 1.22)
213.0 (c 1.83)
23.3 (c 1.27)
þ9.9 (c 0.57)
þ18.9 (c 1.49)
20.9 (c 1.40)
þ6.7 (c 1.37)
þ20.8 (c 0.50)
230.0 (c 0.60)
þ12.4 (c 1.83)
þ3.0 (c 1.40)
210.0 (c 0.77)
220.1 (c 1.47)
þ0.6 (c 1.56)
26.4 (c 1.69)
1.81, 0.93
0.86, 0.72
1.63, 0.24
0.93, 0.63
1.28, 0.65
1.02, 0.42
22 [I(2,6)P20 (1,3:4,5)MOM4]
23 [I(4,5)P020(3)Bz(6)Bn(1,2)Ace]
24 [I(3,4)P020(5)Bz(6)Bn(1,2)Ace]
25 [I(3,5)P020(4)Bz(6)Bn(1,2)Ace]
P0, PO(OEt)2; P00, PO(OBn)2.
In conclusion, we have synthesized all optically active myo-inositol mono-
and bisphosphate regioisomers by application of the divergent as well as
specific synthetic methods at the level of various intermediates as described
herein, and now reported the complete syntheses of all possible 63 (15 meso
and 24 enantiomeric pairs) regioisomers of myo-inositol phosphates.
Scheme 5: a. (i) Dibenzyl disopropylphosphoramidite, 1H-tetrazole, (ii) mCPBA; b. (i) H2, 10%
Pd-C, AcOH, (ii) pH 10 (1N NaOH); c. (i) diethyl phosphorochloridite, DIPEA, (ii) 30 % H2O2; d. (i)
TMSBr, (ii) pH 10 (1N NaOH).

K.-C. Seo et al.
312
Scheme 6: a. (i) Dibenzyl diisopropylphosphoramidite, 1H-tetrazole, (ii) mCPBA; b. (i) H2 10%
Pd-C, AcOH, (ii) 1M LiOH, (iii) Hþ ion exchange, (iv) pH 10 (1N NaOH).
EXPERIMENTAL
General Methods
All nonhydrolytic reactions were carried out in oven-dried glassware under
anhydrous nitrogen atmosphere. All commercial reagents were used as
obtained without further purification. Solvents were purified and dried by
standard methods prior to use. Melting points were determined on a
Thomas-Hoover apparatus and are uncorrected. Analytical TLC was carried
out on Merck 60 F254 silica gel plate (0.25 mm thickness) and visualization
was done with UV light and/or spraying with a 5% solution of phosphomolybdic
acid followed by charring with a heat gun. Column chromatography was per-
formed on Merck 60 silica gel (230–400 mesh). NMR spectra were recorded
on a Bruker AM 300, DPX 300, or DRX 500 spectrometer. Tetramethylsilane
and phosphoric acid (85%) were used as internal and external standards for
1H NMR and 31P NMR, respectively. Mass spectra (FAB) were recorded on a
VG platform II system with 3-NBA and NaCl as matrices. Optical rotations
were measured with a JASCO DIP-360 digital polarimeter.
General Procedure for the Preparation of the Compounds
(4–17)
(3aR,4S,7S,7aR)- and (3aR,4S,7R,7aS)-3a,4,7,7a-Tetrahydro-2,2-dimethyl-
4,7-dibenzyl-1,3-bezodioxole-4,7-diol (D-4 and L-4)
To a solution of compound D-3 (2.98 g, 16.0 mmol)[14] and NaH (4.19 g,
96.0 mmol) in THF (76 mL) at 08C were added BnBr (5.60 mL, 48.0 mmol)
and then TBAI (1.80 g, 4.8 mmol). After 30 min, the mixture was warmed to
rt and stirred overnight. The mixture was diluted with EtOAc and successively
washed with aq. NaHCO3 and brine. The organic phase was dried (MgSO4),

Synthesis of Myo-Inositols
313
concentrated, and chromatographed to give compound D-4 (5.36 g, 91.3%) as a
solid. Similarly, compound L-4 was prepared from compound L-3.
D-4: Rf 0.56 (n-hexane:EtOAc, 4:1); mp. 55.5–56.58C; [a]2D5 þ49.4 (c 1.15,
CH2Cl2) flit.[14] [a]D20 þ 19.0 (c 2.29, CHCl3), lit.[16] [a]D20 þ 6.1 (c 1.46, CHCl3)g;
1
MS(FAB) ¼ m/z 367 (M þ H)þ, 389 (M þ Na)þ; H NMR (300 MHz, CDCl3): d
7.38–7.26 (m, 10H, Ar-H), 5.67 (s, 2H, H-5, H-6), 4.82 (d, J ¼ 11.8 Hz, 2H,
CHAHBPh), 4.65 (d, J ¼ 11.8 Hz, 2H, CHAHBPh), 4.24 (dd, J ¼ 5.3, 2.2 Hz,
2H, H-1, H-4), 3.63 (dd, J ¼ 5.3, 2.2 Hz, 2H, H-2, H-3), 1.46 (s, 6H, CMe2);
13C NMR (75 MHz, CDCl3): d 137.8, 128.6, 127.4, 127.2 (Ar-H, C-5, C-6) 110.5
(CMe2), 79.9 (2C), 76.6 (2C) [C-1, C-2, C-3, C-4], 71.3 (2C, CH2Ph), 26.7 (2C,
CMe2).
L-4: mp. 56.0–56.58C; [a]D25 251.0 (c 1.12, CH2Cl2); Rf, MS(FAB), 1H NMR,
13C NMR were identical to those of D-4.
D- and L-3,6-Di-O-benzyl-4,5-O-isopropylidene-myo-inositol (D-5 and L-5)
To a solution of compound D-4 (4.93 g, 13.5 mmol) in a mixture of acetone
and water (3.6:1, 215 mL) were added 4-methoxylmorpholine N-oxide (NMO)
(9.95 g, 73.6 mmol) and then OsO4 (ꢀ300 mg). After being stirred for 12 h at
rt, the reaction mixture was quenched with 10% NaHSO3, and the solvents
were evaporated under reduced pressure. The crude material was dissolved
in MeOH and filtered through a bed of silica gel. After removal of the solvent
by evaporation, a flash column chromatography on silica gel gave compound
D-5 (4.80 g, 89.2%) as a solid. Similarly, compound L-5 was prepared from
compound L-4.
D-5: Rf 0.58 (n-hexane:EtOAc, 1:2); mp. 125.5–127.08C flit.[14] mp. 125–
1268C, lit.[17] mp. 104–1068Cg; [a]D25 –43.8 (c 1.10, CHCl3) flit.[14] [a]2D0267.0
(c 1.02, CHCl3), lit.[17] [a]D –55 (c 1.0, CHCl3)g; MS(FAB) ¼ m/z 401 (M þ H)þ,
423 (M þ Na)þ; 1H NMR (300 MHz, CDCl3): d 7.38–7.25 (m, 10H, Ar-H),
4.89–4.66 (m, 4H, CH2Ph), 4.10 (t, J ¼ 3.2 Hz, 1H, H-2), 3.98 (t, J ¼ 9.9 Hz,
1H, H-4), 3.71 (t, J ¼ 9.2 Hz, 1H, H-6), 3.50 (dd, J ¼ 10.1, 3.0 Hz 1H, H-3),
3.42 (dd, J ¼ 8.8, 3.1 Hz, 1H, H-1), 3.29 (t, J ¼ 9.6 Hz, 1H, H-5), 2.60 (br s, 2H,
OHs), 1.39, 1.36 (2s, 6H, CMe2); 13C NMR (75 MHz, CDCl3): d 138.9, 129.2,
129.1, 128.68, 128.66 (Ar-H) 112.6 (CMe2), 80.0, 78.8, 78.3, 76.9, 74.2, 73.7,
72.5, 71.9 (inositol ring carbons, 2CH2Ph), 27.7 (2C, CMe2).
1
L-5: mp. 126–1278C; [a]2D0 þ 45.1 (c 0.93, CHCl3); Rf, MS(FAB), H NMR,
13C NMR were identical to those of D-5.
D- and L-1,2: 4.5-Di-O-isopropylidene-4-O-benzyl-myo-inositol (D-7 and L-7),
D- and L-1,2: 4.5-di-O-isopropylidene-myo-inositol (D-8 and L-8)
To a solution of D-5 (4.60 g, 11.5 mmol) and TSA (495 mg, 2.9 mmol) in
CH2Cl2 (230 mL) was added 2-methoxypropene (5.5 mL, 57.5 mmol) by
syringe. After being stirred for 1 h at rt, the reaction mixture was quenched
with triethylamine (0.4 mL), diluted with EtOAc, and successively washed

K.-C. Seo et al.
314
with aq NaHCO3 and brine. Concentration of organic layer gave a crystalline
solid, compound D-6 (5.03 g, 99.4%). A mixture of the compound D-6 (4.66 g,
10.6 mmol), Pd on charcoal (10%, 2.80 g), NaHCO3 (470 mg), and THF
(100 mL) was hydrogenated (1 atm) at rt. After 3 d, the catalyst was filtered
off through Celite and washed with CH2Cl2. The filtrate was evaporated, and
the residue was chromatographed on silica gel to give the major D-7 (2.0 g,
53.8%), the minor D-8 (320 mg, 11.6%), and the starting material D-6 (1.35 g,
28.9%). Similarly, compounds L-7 and L-8 were prepared from compound L-5.
D-7: Rf 0.45 (n-hexane:EtOAc, 1:1); mp. 131–1328C; [a]2D5 –72.3 (c 0.74,
CHCl3); MS(FAB) ¼ m/z 351 (M þ H)þ, 373 (M þ Na)þ; 1H NMR (300 MHz,
CDCl3): d 7.39–7.27 (m, 5H, Ar-H), 4.80 (s, 2H, CH2Ph), 4.44 (t, J ¼ 4.8 Hz, 1H,
H-2), 4.17 (t, J ¼ 5.7 Hz, 1H, H-1), 3.97 (dd, J ¼ 10.1, 4.5 Hz, 1H, H-3), 3.76
(t, J ¼ 9.7 Hz, 1H, H-4), 3.66 (dd, J ¼ 10.5, 6.2 Hz, 1H, H-6), 3.39 (t, J ¼ 9.9 Hz,
1H, H-5), 1.46, 1.44, 1.37, 1.34 (4s, 12H, CMe2); 13C NMR (75 MHz, CDCl3): d
137.6, 127.8, 127.1 (Ar-H), 111.9, 109.5 (CMe2), 81.2, 79.8, 77.4, 77.2, 71.5, 69.3
(inositol ring carbons, CH2Ph), 27.31, 26.53 (2C), 25.41 [CMe2].
D-8: Rf 0.40 (EtOAc); mp. 166.0–167.58C flit.[18] mp. 169–1708Cg;
[a]D25 240.1 (c 0.95, CH2Cl2) flit.[18] [a]D 241.7 (c 1.58, CH2Cl2)g; MS(FAB) ¼
m/z 261 (M þ H)þ, 283 (M þ Na)þ; 1H NMR (300 MHz, CDCl3): d 4.46
(t, J ¼ 4.8 Hz, 1H, H-2), 4.06 (t, J ¼ 5.8 Hz, 1H, H-1), 4.02 (dd, J ¼ 10.5,
4.3 Hz, 1H, H-3), 3.88 (dd, J ¼ 10.7, 6.4 Hz, 1H, H-6), 3.82 (t, J ¼ 9.8 Hz, 1H,
H-4), 3.31 (t, J ¼ 10.0 Hz, 1H, H-5), 1.52, 1.46, 1.44, 1.36 (4s, 12H, CMe2);
13C NMR (75 MHz, CDCl3): d 112.7, 110.3 (CMe2), 81.9, 78.0, 77.6, 75.0, 71.5,
70.0 (inositol ring carbons), 28.1, 26.9 (2C), 25.4 [CMe2].
L-7: mp. 131.5–133.08C flit.[15] mp. 132–1348Cg; [a]2D5 þ74.0 (c 1.11,
1
CHCl3) flit.[15] [a]D25 þ66.5 (c 1.0, CHCl3)g; Rf, MS(FAB), H NMR, 13C NMR
were identical to those of D-7.
L-8: mp. 167.0–167.58C; [a]2D5 þ38.9 (c 0.93, CHCl3); Rf, MS(FAB), 1H
NMR, 13C NMR were identical to those of D-8.
D- and L-2-O-Benzoyl-6-O-benzyl-myo-inositol (D-9 and L-9)
Compound D-7 (300 mg, 0.86 mmol) in 80% aq AcOH (85 mL) was heated
at reflux for 5 h and evaporated to dryness to give a crude product. To a
solution of crude product (60.0 mg, 0.22 mmol) and triethyl orthobenzoate
(77.8 mL, 0.44 mmol) in DMF (1.8 mL) at rt was added TSA (2.0 mg,
11.1 mmol). After being stirred for 4 h at rt, the reaction was quenched with a
few drops of 80% aq AcOH, and the solvents were removed under a stream of
N2. The product mixture was chromatographed to give compound D-9
(58.9 mg, 70.9%). Similarly, compound L-9 was prepared from compound L-7.
D-9: Rf 0.23 (EtOAc); mp. 135–1378C; [a]2D5 þ62.6 (c 0.82, MeOH);
MS(FAB) ¼ m/z 375 (M þ H)þ; 1H NMR (300 MHz, CD3OD): d 8.06–7.21
(m, 10H, Ar-H), 5.66 (t, J ¼ 2.7 Hz, 1H, H-2) 4.88 (d, J ¼ 10.8 Hz, 1H,
CHAHBPh), 4.82 (d, J ¼ 10.8 Hz, 1H, CHAHBPh), 3.78 (dd, J ¼ 9.8, 2.8 Hz,

Synthesis of Myo-Inositols
315
1H, H-1), 3.73 (t, J ¼ 9.7 Hz, 1H, H-6), 3.68 (t, J ¼ 9.4 Hz, 1H, H-5), 3.61 (dd,
J ¼ 9.9, 2.7,Hz 1H, H-3), 3.42 (t, J ¼ 9.1 Hz, 1H, H-4); 13C NMR (75 MHz,
CD3OD): d 167.9 (COPh), 140.5, 134.3, 132.0, 130.9, 129.6, 129.4, 129.3, 128.7
(Ar-H), 83.5, 77.1, 76.7, 76.3, 75.1, 72.0, 71.9 (inositol ring carbons, CH2Ph).
L-9: mp. 134.0–135.58C; [a]2D5 259.6 (c 0.78, MeOH); Rf, MS(FAB), 1H
NMR, 13C NMR were identical to those of D-9.
D- and L-2-O-Benzoyl-6-O-benzyl-1,3,4,5-tetra-O-methoxymethyl-myo-inositol
(D-10 and L-10)
A mixture of the compound D-9 (50.0 mg, 0.13 mmol), chloromethyl methyl
ether (432 mL, 5.4 mmol), DIPEA (751 mL, 5.4 mmol), and 1,2-dichloroethane
(2 mL) was heated at 508C for 12 h. The mixture was diluted with EtOAc and
successively washed with aq NaHCO3 and brine. The organic phase was
dried (MgSO4), concentrated, and chromatographed to give compound D-10
(65.2 mg, 88.7%) as a colorless oil. Similarly, compound L-10 was prepared
from compound L-9.
D-10: Rf 0.60 (n-hexane:EtOAc, 1:1); [a]2D5 212.5 (c 0.25, CH2Cl2);
1
MS(FAB) ¼ m/z 551 (M þ H)þ, 573 (M þ Na)þ; H NMR (300 MHz, CDCl3): d
8.06–7.26 (m, 10H, Ar-H), 5.85 (t, J ¼ 2.6 Hz, 1H, H-2) 4.95–4.63 (m, 10H,
CH2Ph, OCH2OCH3), 3.98 (t, J ¼ 9.7 Hz, 1H, H-4), 3.87 (t, J ¼ 9.6 Hz, 1H,
H-5), 3.77 (dd, J ¼ 10.0, 2.6 Hz, 1H, H-3), 3.69 (dd, J ¼ 10.0, 2.6 Hz, 1H,
H-1), 3.60 (t, J ¼ 9.3 Hz, 1H, H-6), 3.43, 3.40, 3.38, 3.31 (4s, 12H,
OCH2OCH3); 13C NMR (75 MHz, CDCl3): d 166.5 (COPh), 139.0, 133.9,
130.7, 130.6, 129.2, 129.0, 128.3 (Ar-H), 99.5, 99.2, 96.6, 96.4 (OCH2OCH3),
81.6, 80.2, 78.7, 76.4, 75.6, 75.4, 70.4 (inositol ring carbons, CH2Ph), 57.4,
57.1, 56.7, 56.6 (OCH2OCH3).
L-10: [a]2D5 þ12.4 (c 0.20, CH2Cl2); Rf, MS(FAB), H NMR, 13C NMR were
1
identical to those of D-10.
D- and L-1,3,4,5-Tetra-O-methoxymethyl-myo-Inositol (D-11 and L-11)
A mixture of the compound D-10 (58.0 mg, 0.11 mmol), Pd(OH)2 on
charcoal (20%, 58 mg), and EtOH (1.5 mL) was hydrogenated (45 psi) at rt over-
night. The catalyst was filtered off through Celite and washed with CH2Cl2,
and the filtrate was evaporated. To a solution of the residue in MeOH (1 mL)
was added NaOMe (25% solution in MeOH, 2.4 mL, 11.0 mmol). After being
stirred for 19 h at rt, the solution was concentrated and chromatographed to
afford compound D-11 (31.9 mg, 85.0%) as an oil. Similarly, compound L-11
was prepared from compound L-10.
D-11: Rf 0.15 (EtOAc), 0.31 (CH2Cl2:MeOH, 9:1); [a]2D5 þ29.0 (c 0.65,
1
CHCl3); MS(FAB) ¼ m/z 357 (M þ H)þ, 379 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 4.87–4.74 (m, 8H, OCH2OCH3), 4.21 (t, J ¼ 2.6 Hz, 1H, H-2), 3.94
(t, J ¼ 9.6 Hz, 1H, H-4), 3.89 (t, J ¼ 9.3 Hz, 1H, H-5), 3.52–3.40 (m, 14H,
OCH2OCH3, H-1, H-3), 3.24 (t, J ¼ 9.2 Hz, 1H, H-6); 13C NMR (75 MHz,

K.-C. Seo et al.
316
CDCl3): d 99.4, 98.9, 97.2 (2C) [OCH2OCH3], 86.0, 77.9, 77.0, 71.8, 70.6 (inositol
ring carbons), 56.82, 56.78, 56.52, 56.45 (OCH2OCH3).
1
L-11: [a]2D5–28.4 (c 1.10, CHCl3); Rf, MS(FAB), H NMR, 13C NMR were
identical to those of D-11.
D- and L-1,2: 4.5-Di-O-isopropylidene-3-O-benzoyl-6-O-benzyl-myo-inositol
(D-12 and L-12)
Benzoylation of compound D-7 (1.0 g, 2.85 mmol) was carried out with BzCl
(1.67 mL, 14.3 mmol) and DMAP (35.6 mg, 0.29 mmol) in pyridine (50 mL).
After being stirred for 6 h at rt, the reaction mixture was treated with water
(10 mL) for 30 min, diluted with EtOAc, and washed with aq NaHCO3 and
brine. The organic layer was separated, dried (MgSO4), and concentrated to
give a solid product, which was chromatographed to give compound D-12
(1.27 g, 97.7%). Similarly, compound L-12 was prepared from compound L-7.
D-12: Rf 0.86 (n-hexane:EtOAc, 1:1); mp. 158.0–159.58C; [a]2D5 þ13.2 (c 1.26,
1
CH2Cl2); MS(FAB) ¼ m/z 455 (M þ H)þ, 477 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 8.11–7.24 (m, 10H, Ar-H), 5.31 (dd, J ¼ 10.6, 4.4 Hz, 1H, H-3), 4.84
(s, 2H, CH2Ph), 4.70 (t, J ¼ 4.7 Hz, 1H, H-2), 4.23 (t, J ¼ 5.6 Hz, 1H, H-1),
4.16 (t, J ¼ 10.0 Hz, 1H, H-4), 3.74 (dd, J ¼ 10.5, 6.3 Hz, 1H, H-6), 3.56
(t, J ¼ 10.0 Hz, 1H, H-5), 1.48, 1.44, 1.36, 1.26 (4s, 12H, CMe2); 13C NMR
(75 MHz, CDCl3): d 165.6 (COPh), 137.6, 132.8, 129.6, 129.2, 127.9, 127.8,
127.6, 127.1 (Ar-H), 112.1, 109.6 (CMe2), 80.7, 79.3, 78.4, 74.8, 74.2, 71.6, 71.0
(inositol ring carbons, CH2Ph), 27.4, 26.6, 26.5, 25.4 (CMe2).
L-12: mp. 159–1618C; [a]D25 –13.8 (c 0.55, CH2Cl2); Rf, MS(FAB), 1H NMR,
13C NMR were identical to those of D-12.
D- and L-1,2: 4.5-Di-O-isopropylidene-3-O-benzoyl-myo-inositol
(D-13 and L-13)
A mixture of the compound D-12 (136 mg, 0.30 mmol), Pd on charcoal (10%,
274 mg), NaHCO3 (6 mg), and EtOH (3 mL) was hydrogenated (45 psi) at rt.
After 1 d, the catalyst was filtered off through Celite and washed with
CH2Cl2. The filtrate was evaporated, and the residue was chromatographed
on silica gel to give compound D-13 (90.0 mg, 82.0%). Similarly, compound
L-13 was prepared from compound L-12.
D-13: Rf 0.52 (n-hexane:EtOAc, 1:1); mp. 183–1858C flit.[19] mp. 183–
1848Cg; [a]2D5 þ35.7 (c 0.30, CH2Cl2); MS(FAB) ¼ m/z 365 (M þ H)þ, 387
1
(M þ Na)þ; H NMR (300 MHz, CDCl3): d 8.12–7.41 (m, 5H, Ar-H), 5.35 (dd,
J ¼ 10.6, 4.3 Hz, 1H, H-3), 4.72 (t, J ¼ 4.6 Hz, 1H, H-2), 4.19 (t, J ¼ 10.0 Hz,
1H, H-4), 4.11 (t, J ¼ 5.7 Hz, 1H, H-1), 3.96 (dd, J ¼ 10.7, 6.6 Hz, 1H, H-6),
3.48 (t, J ¼ 10.0 Hz, 1H, H-5), 1.60, 1.52, 1.49, 1.23 (4s, 12H, CMe2); 13C
NMR (75 MHz, CDCl3): d 166.8 (COPh), 134.0, 130.8, 129.2 (Ar-H), 113.6,
111.1 (CMe2), 82.5, 79.1, 76.0, 75.5, 75.2, 71.6 (inositol ring carbons), 28.9,
27.7, 27.5, 26.5 (CMe2).

Synthesis of Myo-Inositols
317
L-13: mp. 184–1858C; [a]D25–37.2 (c 0.92, CH2Cl2); Rf, MS(FAB), 1H NMR,
13C NMR were identical to those of D-13.
D- and L-1,2-O-Isopropylidene-3-O-benzoyl-6-O-benzyl-myo-inositol (D-14 and
L-14)
Compound D-12 (640 mg, 1.41 mmol) and TSA (34.4 mg, 0.28 mmol) in a
mixed solvent (MeOH:CH2Cl2 ¼ 1:5, 20 mL) were stirred at 08C for 15 h. The
reaction mixture was treated with aq NaHCO3, concentrated under reduced
pressure, and chromatographed to give compound D-14 (400 mg, 68.5%) and
a minor product, compound D-15 (133 mg, 25.1%). Similarly, compound L-14
was prepared from compound L-12.
D-14: Rf 0.34 (n-hexane:EtOAc, 1:1); mp. 190.0–191.58C; [a]2D5 þ32.2 (c
1.50, CH2Cl2); MS(FAB) ¼ m/z 415 (M þ H)þ, 437 (M þ Na)þ; 1H NMR
(300 MHz, CDCl3): d 8.10–7.24 (m, 10H, Ar-H), 5.22 (dd, J ¼ 9.3, 3.9 Hz, 1H,
H-3), 4.97 (d, J ¼ 11.5 Hz, 1H, CHAHBPh), 4.68 (d, J ¼ 11.5 Hz, 1H,
CHAHBPh), 4.56 (t, J ¼ 4.6 Hz, 1H, H-2), 4.24 (t, J ¼ 6.0 Hz, 1H, H-1), 4.07
(t, J ¼ 9.1 Hz, 1H, H-4), 3.61 (dd, J ¼ 9.8, 7.0 Hz, 1H, H-6), 3.49
(t, J ¼ 9.3 Hz, 1H, H-5), 1.47, 1.31 (2s, 6H, CMe2); 13C NMR (75 MHz,
CDCl3): d 165.8 (COPh), 137.5, 132.9, 129.6, 129.1, 128.0, 127.9, 127.7, 127.4
(Ar-H), 109.8 (CMe2), 81.1, 78.8, 73.6, 72.9, 72.8, 71.9, 70.1 (inositol ring
carbons, CH2Ph), 27.5, 26.5 (CMe2).
D-15: Rf 0.31 (n-hexane:EtOAc, 1:2); mp. 165–1678C; [a]2D5 þ27.1 (c 0.50,
1
MeOH); MS(FAB) ¼ m/z 375 (M þ H)þ, 397 (M þ Na)þ; H NMR (300 MHz,
CD3OD): d 8.12–7.23 (m, 10H, Ar-H), 3H (H-3, CH2Ph) disappeared behind
the solvent peak around 4.8 ppm, 4.16 (t, J ¼ 2.6 Hz, 1H, H-2), 4.02
(t, J ¼ 9.8 Hz, 1H, H-6), 3.69 (t, J ¼ 9.2 Hz, 1H, H-4), 3.62 (dd, J ¼ 9.6,
2.5 Hz, 1H, H-1), 3.43 (t, J ¼ 9.0 Hz, 1H, H-5); 13C NMR (75 MHz, CD3OD): d
166.0 (COPh), 132.3, 129.8, 129.0, 127.5, 127.31, 127.27, 126.6 (Ar-H), 81.1,
74.6, 74.5, 74.2, 71.1, 70.4, 70.2 (inositol ring carbons, CH2Ph).
1
L-14: mp. 188.5–190.08C; [a]2D5 –31.2 (c 0.99, CH2Cl2); Rf, MS(FAB), H
NMR, 13C NMR were identical to those of D-14.
1
L-15: mp. 164–1678C; [a]2D5 –25.1 (c 0.71, MeOH); Rf, MS(FAB), H NMR,
13C NMR were identical to those of D-15.
D- and L-1,2-O-Isopropylidene-5-O-benzoyl-6-O-benzyl-myo-inositol (D-16 and
L-16), D-and L-1,2-O-isopropylidene-4-O-benzoyl-6-O-benzyl-myo-inositol
(D-17 and L-17)
Compound D-14 (168 mg, 0.41 mmol) in a mixed solvent (pyridine:
water ¼ 6:4, 6 mL) was heated at 908C for 10 h. The reaction mixture was
cooled and concentrated under reduced pressure, and the crude mixture was
chromatographed on silica gel to yield D-14 (50.2 mg, 29.9%), D-16 (40.0 mg,
23.8%), and D-17 (70.3 mg, 41.8%). Similarly, compounds L-16 and L-17
were prepared from compound L-14.

K.-C. Seo et al.
318
D-16: Rf 0.41 (n-hexane:EtOAc, 1:1); mp. 159–1618C; [a]2D5 þ15.9 (c 0.6,
1
CHCl3); MS(FAB) ¼ m/z 415 (M þ H)þ, 437 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 8.02–7.24 (m, 10H, Ar-H), 5.08 (t, J ¼ 7.6 Hz, 1H, H-5), 4.75
(s, 2H, CH2Ph), 4.47 (dd, J ¼ 6.2, 3.7 Hz, 1H, H-2), 4.34 (t, J ¼ 6.1 Hz, 1H,
H-1), 4.01 (t, J ¼ 8.2 Hz, 1H, H-4), 3.92 (dd, J ¼ 8.9, 3.6 Hz, 1H, H-3), 3.87
(dd, J ¼ 7.6, 6.0 Hz, 1H, H-6); 13C NMR (75 MHz, CDCl3): d 167.6 (COPh),
138.5, 134.0, 130.6, 130.4, 129.1, 128.9, 128.7, 128.4 (Ar-H), 110.7 (CMe2),
79.4, 78.9, 77.6, 75.8, 73.4, 72.6, 70.7 (inositol ring carbons, CH2Ph), 27.9,
25.8 (CMe2).
D-17: Rf 0.65 (n-hexane:EtOAc, 1:2); mp. 162–1638C; [a]2D5 þ8.9 (c 2.0,
1
CHCl3); MS(FAB) ¼ m/z 415 (M þ H)þ, 437 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 8.07–7.28 (m, 10H, Ar-H), 4.95 (dd, J ¼ 6.1, 4.1 Hz, 1H, H-2), 4.86
(d, J ¼ 11.6 Hz, 1H, CHAHBPh), 4.69 (d, J ¼ 11.6 Hz, 1H, CHAHBPh), 4.33
(t, J ¼ 6.1 Hz, 1H, H-1), 4.04 (dd, J ¼ 8.9, 4.0 Hz, 1H, H-3), 3.83–3.74
(m, 2H, H-5, H-6), 1.55, 1.38 (2s, 6H, CMe2); 13C NMR (75 MHz, CDCl3): d
167.8 (COPh), 138.5, 133.9, 130.6, 130.4, 129.2, 129.1, 128.8, 128.7 (Ar-H),
110.9 (CMe2), 81.8, 78.7, 77.0, 76.3, 73.9, 73.2, 69.7 (inositol ring carbons,
CH2Ph), 28.0, 25.9 (CMe2).
1
L-16: mp. 158–1608C; [a]2D5 –15.9 (c 1.90, CHCl3); Rf, MS(FAB), H NMR,
13C NMR were identical to those of D-16.
1
L-17: mp. 159–1608C; [a]D25 –9.6 (c 0.88, CHCl3); Rf, MS(FAB), H NMR,
13C NMR were identical to those of D-17.
General Procedure for the Preparation of the Compounds
(18–25)
Phosphorylation Method A
To a solution of each regioisomer and 1H-tetrazole (10 eq) in a mixed
solvent (DMF:CH2Cl2 ¼ 1:1) at rt was added dibenzyl diisopropyl-phosphora-
midite (6 eq). After 7 h, an excess amount of mCPBA (20 eq) was added to
the mixture at 08C. After being stirred overnight at rt, the mixture was
diluted with CH2Cl2 and washed with aq Na2SO3, aq NaHCO3, and brine.
The organic layer was dried (MgSO4), concentrated, and chromatographed to
give phosphorylated regioisomers in 71% to 82% yields.
Method B
To a solution of each regioisomer in DMF at 2428C were added dropwise
DIPEA (30 eq) and then diethyl phosphorochloridite (11 eq) with vigorous
stirring. After 20 min, the reaction mixture was allowed to slowly warm up
to rt and stirred for additional 5 h. The mixture was cooled in an ice bath
and sodium phosphate buffer (1 M, pH 7) and excess 30% H2O2 were added.
After standing overnight at rt, the mixture was diluted with EtOAc and

Synthesis of Myo-Inositols
319
washed with water and brine. The organic layer was dried (MgSO4), concen-
trated, and chromatographed to give phosphorylated regioisomers in 70% to
85% yields.
D- and L-1,2: 4.5-Di-O-isopropylidene-4-O-benzyl-myo-inositol
3-mono(dibenzyl-phosphate) (D-18 and L-18)
Compounds D-18 and L-18 were prepared from D-7 and L-7, respectively,
by the method A.
D-18: Rf 0.43 (n-hexane:EtOAc, 2:1); mp. 130–1328C; [a]2D5 –22.8 (c 1.10,
1
CH2Cl2); MS(FAB) ¼ m/z 611 (M þ H)þ, 633 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 7.37–7.26 (m, 15H, Ar-H), 5.10–5.07 (m, 4H, POCH2Ph), 4.80
(s, 2H, OCH2Ph), 4.72 (m, 1H, H-3), 4.55 (t, J ¼ 4.5 Hz, 1H, H-2), 4.13
(t, J ¼ 5.5 Hz, 1H, H-1), 4.02 (t, J ¼ 9.8 Hz, 1H, H-4), 3.67 (dd, J ¼ 10.6,
6.3 Hz, 1H, H-6), 3.43 (t, J ¼ 10.0 Hz, 1H, H-5), 1.44, 1.41, 1.36, 1.24 (4s,
12H, CMe2); 13C NMR (75 MHz, CDCl3): d 137.5, 135.3, 135.2, 128.0, 127.8,
127.5, 127.4, 127.1 (Ar-H), 112.1, 109.7 (CMe2), 81.1, 79.2, 78.0, 76.2, 74.8,
74.1, 71.6 (inositol ring carbons, CH2Ph), 69.1, 68.8 (POCH2Ph), 27.4, 26.5
(2C), 25.4 [CMe2]; 31P NMR (121 MHz, CDCl3): d 0.63.
L-18: mp. 129.0–130.58C; [a]2D5 þ20.8 (c 0.50, CH2Cl2); Rf, MS(FAB),
1H NMR, 13C NMR, 31P NMR were identical to those of D-18.
D- and L-1,2: 4.5-Di-O-isopropylidene-3-O-benzoyl-myo-inositol
6-mono(diethyl-phosphate) (D-19 and L-19)
Compounds D-19 and L-19 were prepared from D-13 and L-13, respect-
ively, by the method B.
D-19: Rf 0.25 (n-hexane:EtOAc, 1:1); mp. 216–2188C; [a]2D5 þ30.1 (c 1.20,
1
CH2Cl2); MS(FAB) ¼ m/z 501 (M þ H)þ, 523 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 8.11–7.41 (m, 5H, Ar-H), 5.33 (dd, J ¼ 10.6, 4.2 Hz, 1H, H-3), 4.70
(t, J ¼ 4.5 Hz, 1H, H-2), 4.67–4.58 (m, 1H, H-6), 4.25–4.12 (m, 6H, POCH2Ph,
H-1, H-4), 3.57 (t, J ¼ 10.1 Hz, 1H, H-5), 1.57, 1.47, 1.42, 1.28 (4s, 12H,
CMe2), 1.36–1.31 (m, 6H, OCH2CH3); 13C NMR (75 MHz, CDCl3): d 165.6
(COPh), 132.9, 129.6, 128.9, 127.9 (Ar-H), 112.5, 110.2 (CMe2), 79.7, 78.9, 76.9,
74.8, 74.2, 70.5 (inositol ring carbons), 63.5, 63.4 (OCH2CH3), 27.4, 26.5, 26.4,
25.5 (CMe2), 15.6, 15.5 (OCH2CH3); 31P NMR (121 MHz, CDCl3): d 0.89.
L-19: mp. 218–2198C; [a]D25 230.0 (c 0.60, CH2Cl2); Rf, MS(FAB), 1H NMR,
13C NMR, 31P NMR were identical to those of D-19.
D- and L-3,6-Di-O-benzyl-4,5-O-isopropylidene-myo-inositol 1,2,-bis(dibenzyl-
phosphate) (D-20 and L-20)
Compounds D-20 and L-20 were prepared from D-5 and L-5, respectively,
by the method A.
D-20: Rf 0.54 (n-hexane:EtOAc, 1:1); [a]2D5–13.0 (c 1.83, CH2Cl2);
1
MS(FAB) ¼ m/z 921 (M þ H)þ, 943 (M þ Na)þ; H NMR (300 MHz, CDCl3): d

K.-C. Seo et al.
320
7.43–7.15 (m, 30H, Ar-H), 5.36 (d, J ¼ 9.4 Hz, 1H, H-1), 5.13 (d, J ¼ 6.9 Hz, 2H,
CH2Ph), 5.04–4.81 (m, 8H, CH2Ph), 4.68 (t, J ¼ 10.6 Hz, 2H, OCH2Ph), 4.46
(t, J ¼ 9.0 Hz, 1H, H-2), 3.98 (t, J ¼ 9.4 Hz, 1H, H-4), 3.95 (t, J ¼ 9.4 Hz, 1H,
H-5), 3.68 (d, J ¼ 10.2 Hz, 1H, H-3), 3.45 (t, J ¼ 9.6 Hz, 1H, H-6), 1.49, 1.46
(2s, 6H, CMe2); 13C NMR (75 MHz, CDCl3): d 137.5–127.1 (Ar-H), 111.9
(CMe2), 78.7, 76.3, 75.3, 74.5, 72.3, 71.2 (inositol ring carbons), 69.0, 68.94,
68.88, 68.81, 68.80, 68.7 (OCH2Ph), 29.5 (2C, CMe2); 31P NMR (121 MHz,
CDCl3): d 1.81, 0.93.
L-20: [a]2D5 þ12.4 (c 1.83, CH2Cl2); Rf, MS(FAB), 1H NMR, 13C NMR,
31P NMR were identical to those of D-20.
D- and L-1,2: 4.5-Di-O-isopropylidene-myo-inositol 3,6-bis(diethylphosphate)
(D-21 and L-21)
Compounds D-21 and L-21 were prepared from D-8 and L-8, respectively,
by the method B.
D-21: Rf 0.57 (EtOAc); [a]D25–3.3 (c 1.27, CH2Cl2); MS(FAB) ¼ m/z 533
1
(M þ H)þ, 555 (M þ Na)þ; H NMR (300 MHz, CDCl3): d 4.76–4.71 (m, 1H,
H-6), 4.58–4.53 (m, 2H, H-1, H-3), 4.16–4.12 (m, 9H, OCH2CH3, H-2), 4.03
(t, J ¼ 9.8 Hz, 1H, H-4), 3.42 (t, J ¼ 9.8 Hz, 1H, H-5), 1.57–1.22 (m, 24H,
OCH2CH3, CMe2); 13C NMR (75 MHz, CDCl3): d 112.3, 110.1 (CMe2), 79.62,
79.57, 78.7, 74.9, 74.8, 73.3 (inositol ring carbons), 63.8, 63.6, 63.4 (2C)
[OCH2CH3], 27.7, 26.41, 26.37, 25.4 (CMe2), 15.5 (2C), 15.49 (2C)
[OCH2CH3]; 31P NMR (121 MHz, CDCl3): d 0.86, 0.72.
1
L-21: [a]2D5 þ3.0 (c 1.40, CH2Cl2); Rf, MS(FAB), H NMR, 13C NMR, 31P
NMR were identical to those of D-21.
D- and L-1,3,4,5-Tetra-O-methoxymethyl-myo-inositol 2,6-
bis(diethylphosphate) (D-22 and L-22)
Compounds D-22 and L-22 were prepared from D-11 and L-11, respect-
ively, by the method B.
D-22: Rf 0.06 (EtOAc), 0.39 (CH2Cl2:MeOH, 9:1); [a]2D5 þ9.9 (c 0.57,
1
CH2Cl2); MS(FAB) ¼ m/z 629 (M þ H)þ, 651 (M þ Na)þ; H NMR (300 MHz,
CDCl3): d 4.95–4.55 (m, 10H, OCH2OCH3), 4.15–4.05 (m, 9H, OCH2CH3,
H-3), 3.87 (t, J ¼ 9.8 Hz, 1H, H-1), 3.59–3.40 (m, 14H, OCH2CH3, H-5, H-6),
1.27 (t, J ¼ 6.3 Hz, 12H, OCH2CH3); 13C NMR (75 MHz, CDCl3): d 98.3, 97.9,
95.8, 95.2 (OCH2OCH3), 78.2, 77.9, 75.4, 74.5, 73.4, 73.0 (inositol ring
carbons), 63.54, 63.50, 63.4, 63.3 (OCH2CH3), 56.3, 55.9, 55.8, 55.6
(OCH2OCH3), 15.8, 15.6, 15.55, 15.49 (OCH2CH3); 31P NMR (121 MHz,
CDCl3): d 1.63, 0.24.
L-22: [a]2D5 –10.0 (c 0.77, CH2Cl2); Rf, MS(FAB), 1H NMR, 13C NMR,
31P NMR were identical to those of D-22.

Synthesis of Myo-Inositols
D- and L-1,2-O-Isopropylidene-3-O-benzoyl-6-O-benzyl-myo-inositol 4,5-
321
bis(dibenzylphosphate) (D-23 and L-23)
Compounds D-23 and L-23 were prepared from D-14 and L-14, respect-
ively, by the method A.
D-23: Rf 0.30 (n-hexane:EtOAc, 1:1); [a]2D5 þ 18.9 (c 1.49, CH2Cl2);
1
MS(FAB) ¼ m/z 935 (M þ H)þ, 957 (M þ Na)þ; H NMR (300 MHz, CDCl3): d
8.13–6.93 (m, 30H, Ar-H), 5.60 (dd, J ¼ 9.5, 3.6 Hz, 1H, H-3), 5.31–4.64
(m, 13H, CH2Ph, H-2, H-3, H-4), 4.41 (t, J ¼ 5.7 Hz, 1H, H-1), 4.10 (dd,
J ¼ 9.7, 5.9 Hz, 1H, H-6), 1.47, 1.28 (2s, 6H, CMe2); 13C NMR (75 MHz,
CDCl3): d 165.2 (COPh), 137.0–127.1 (Ar-H), 109.9 (CMe2), 79.2, 77.2, 76.4,
76.1, 72.6, 72.0 (inositol ring carbons), 69.3, 69.1, 68.9 (2C), 68.7 (2C)
[OCH2Ph], 26.0, 24.0 (CMe2); 31P NMR (121 MHz, CDCl3): d 0.93, 0.63.
L-23: [a]2D5 –20.1 (c 1.47, CH2Cl2); Rf, MS(FAB), 1H NMR, 13C NMR,
31P NMR were identical to those of D-23.
D- and L-1,2-O-Isopropylidene-5-O-benzoyl-6-O-benzyl-myo-inositol 3,4-
bis(dibenzylphosphate) (D-24 and L-24)
Compounds D-24 and L-24 were prepared from D-16 and L-16, respect-
ively, by the method A.
D-24: Rf 0.41 (n-hexane:EtOAc, 1:1); [a]2D5 –0.9 (c 1.4, CH2Cl2);
1
MS(FAB) ¼ m/z 935 (M þ H)þ, 957 (M þ Na)þ; H NMR (300 MHz, CDCl3): d
8.06–6.91 (m, 30H, Ar-H), 5.40 (t, J ¼ 7.2 Hz, 1H, H-5), 5.27–4.71 (m, 12H,
CH2Ph, H-2, H-3), 4.57 (dd, J ¼ 11.7, 8.4 Hz, 1H, H-4), 4.30 (t, J ¼ 5.6 Hz,
1H, H-1), 3.81 (t, J ¼ 5.9 Hz, 1H, H-6), 1.51, 1.26 (2s, 6H, CMe2); 13C NMR
(75 MHz, CDCl3): d 165.2 (COPh), 132.7–127.1 (Ar-H), 110.0 (CMe2), 77.0,
76.9, 74.7, 73.7, 73.5, 73.3, 72.1 (inositol ring carbons, OCH2Ph), 69.1, 69.0,
68.8, 60.6 (POCH2Ph), 26.6, 24.4 (CMe2); 31P NMR (121 MHz, CDCl3): d
1.28, 0.65.
L-24: [a]2D5 þ0.57 (c 1.56, CH2Cl2); Rf, MS(FAB), 1H NMR, 13C NMR,
31P NMR were identical to those of D-24.
D- and L-1,2-O-Isopropylidene-4-O-benzoyl-6-O-benzyl-myo-inositol 3,5-
bis(dibenzylphosphate) (D-25 and L-25)
Compounds D-25 and L-25 were prepared from D-17 and L-17, respect-
ively, by the method A.
D-25: Rf 0.40 (n-hexane:EtOAc, 1:2); [a]2D5 þ6.7 (c 1.37, CH2Cl2);
1
MS(FAB) ¼ m/z 935 (M þ H)þ, 957 (M þ Na)þ; H NMR (300 MHz, CDCl3): d
8.07–6.89 (m, 30H, Ar-H), 5.94 (t, J ¼ 9.2 Hz, 1H, H-4), 5.00–4.60 (m, 13H,
CH2Ph, H-2, H-3, H-5), 4.32 (t, J ¼ 5.5 Hz, 1H, H-1), 3.92 (t, J ¼ 6.1 Hz, 1H,
H-6), 1.52, 1.27 (2s, 6H, CMe2); 13C NMR (75 MHz, CDCl3): d 165.1 (COPh),
137.0–126.9 (Ar-H), 110.2 (CMe2), 78.6, 77.5, 77.2, 73.9, 73.0, 72.4, 70.3
(inositol ring carbons, OCH2Ph), 69.1, 69.0, 68.72, 68.65 (POCH2Ph), 26.7,
24.7 (CMe2); 31P NMR (121 MHz, CDCl3): d 1.02, 0.42.

K.-C. Seo et al.
322
L-25: [a]2D5 –6.4 (c 1.69, CH2Cl2); Rf, MS(FAB), 1H NMR, 13C NMR,
31P NMR were identical to those of L-25.
General Procedure for the Preparation of the myo-Inositol
mono- (1) and bisphosphates (2)
Sodium Salt of D-myo-Inositol 3-Monophosphate (D-1a)
A mixture of compound D-18 (50.0 mg, 82.0 mmol), Pd on charcoal (10%,
25 mg), and one drop of AcOH in a mixed solvent (EtOH:MeOH ¼ 1:1, 3 mL)
was hydrogenated (50 psi) at rt. After 1 d, the catalyst was filtered off on the
short pad of Celite and silica gel and the solvent was evaporated under
reduced pressure. The reaction mixture was redissolved in a small amount of
water and the pH was adjusted to 10 by 1N NaOH and lyophilized to give
the sodium salt of D-I(3)P1 (D-1a) as a white powder in approximately 80%
yield.
1H NMR (300 MHz, D2O, pH 10): d 4.07 (t, J ¼ 2.5 Hz, 1H, H-2), 3.82 (dt,
J ¼ 9.2, 2.7 Hz 1H, H-3), 3.56 (t, J ¼ 9.6 Hz, 1H, H-4), 3.46 (t, J ¼ 9.5 Hz,
1H, H-6), 3.14 (t, J ¼ 9.3 Hz, 1H, H-5); 31P NMR (121 MHz, D2O, pH 10): d 6.73.
Sodium Salt of L-myo-Inositol 3-Monophosphate (L-1a)
Deprotection of L-18 (28.5 mg, 49.1 mmol) according to the procedures
described for D-1a gave L-I(3)P1 (L-1a) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-1a.
Sodium Salt of D-myo-Inositol 6-monophosphate (D-1b)
To a solution of D-19 (50.0 mg, 0.1 mmol) in CH2Cl2 (2 mL) at rt was added
excess bromotrimethylsilane (1 mL), and the solution was stirred overnight.
The solvent and excess reagent were evaporated and the residue was redis-
solved in MeOH (5 mL) and then treated with drops of water at 08C. After
standing at rt for 10 min, the reaction mixture was evaporated to dryness,
treated with 1 M LiOH (3 mL), and stirred at 808C for 3 h. The basic solution
was cooled and loaded on Dowex 50WX8-100 (Hþ form) and eluted with
water. The acidic effluent was collected, washed with CH2Cl2 three times,
and lyophilized to dryness. The residue was redissolved in a small amount of
water (1 mL), the pH was adjusted to 10 with 1N NaOH, and the residue
was lyophilized again to give sodium salts of D-I(6)P1 (D-1b) as a white
powder in approximately 80% yield.
1H NMR (300 MHz, D2O, pH 10): d 3.93 (q, J ¼ 10.5 Hz, 1H, H-6), 3.85
(s, 1H, H-2), 3.59–3.33 (m, 3H, H-1, H-3, H-4), 3.21 (t, J ¼ 9.2 Hz, 1H, H-5);
31P NMR (121 MHz, D2O, pH 10): d 7.19.

Synthesis of Myo-Inositols
Sodium Salt of L-myo-Inositol 6-Monophosphate (L-1b)
323
Deprotection of L-19 (15.5 mg, 31 mmol) according to the procedures
described for D-1b gave L-I(6)P1 (L-1b) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-1b.
Sodium Salt of D-myo-Inositol 1,2-Bisphosphate (D-2a)
Deprotection of D-20 (40.0 mg, 43.4 mmol) according to the procedures
described for D-1a gave D-I(1,2)P2 (D-2a) as a white powder in approximately
80% yield.
1H NMR (300 MHz, D2O, pH 10): d 4.44 (app d, J ¼ 5.9 Hz 1H, H-2), 3.86
(t, J ¼ 8.9 Hz, 1H, H-1), 3.75 (t, J ¼ 9.3 Hz, 1H, H-6), 3.66 (t, J ¼ 9.6 Hz, 1H,
H-4), 3.32 (d, J ¼ 9.9 Hz, 1H, H-3), 3.20 (t, J ¼ 9.2 Hz, 1H, H-5); 31P NMR
(121 MHz, D2O, pH 10): d 7.42, 7.10.
Sodium Salt of L-myo-Inositol 1,2-Bisphosphate (L-2a)
Deprotection of L-20 (50.0 mg, 54.3 mmol) according to the procedures
described for D-1a gave L-I(1,2)P2 (L-2a) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2a.
Sodium Salt of D-myo-Inositol 3,6-Bisphosphate (D-2b)
To a solution of D-21 (41 mg, 77 mmol) in a CH2Cl2 (3 mL) at rt was added
excess bromotrimethylsilane (1 mL), and the solution was stirred overnight.
The solvent and excess reagent were evaporated and the residue was redis-
solved in MeOH (4 mL) and then treated with drops of water at 08C. After
standing at rt for 10 min, the reaction mixture was evaporated to dryness.
The residue was washed with CH2Cl2 three times, lyophilized to dryness,
and then redissolved in a small amount of water (1 mL); the pH was adjusted
to 10 with 1 N NaOH, and the residue was lyophilized again to give sodium
salts of D-I(3,6)P2 (D-2b) as a white powder in approximately 80% yield.
1H NMR (300 MHz, D2O, pH 10): d 4.09 (t, J ¼ 2.4 Hz, 1H, H-2), 3.99
(q, J ¼ 8.9 Hz, 1H, H-6), 3.79 (dt, J ¼ 9.0, 2.6 Hz, 1H, H-3), 3.68 (t, J ¼ 9.5 Hz,
1H, H-4), 3.53 (dd, J ¼ 9.7, 2.7 Hz, 1H, H-1), 3.33 (t, J ¼ 9.1 Hz, 1H, H-5);
31P NMR (121 MHz, D2O, pH 10): d 7.27, 6.77.
Sodium Salt of L-myo-Inositol 3,6-Bisphosphate (L-2b)
Deprotection of L-21 (13.0 mg, 24 mmol) according to the procedures
described for D-2b gave L-I(3,6)P2 (L-2b) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2b.

K.-C. Seo et al.
324
Sodium Salt of D-myo-Inositol 2,6-Bisphosphate (D-2c)
Deprotection of D-22 (19.4 mg, 54 mmol) according to the procedures
described for D-2a gave D-I(2,6)P2 (D-2c) as a white powder in approximately
80% yield.
1H NMR (300 MHz, D2O, pH 10): d 4.39 (app d, J ¼ 7.2 Hz, 1H, H-2), 4.06
(q, J ¼ 8.7 Hz, 1H, H-6), 3.69 (t, J ¼ 9.6 Hz, 1H, H-4), 3.49 (d, J ¼ 9.7 Hz, 1H,
H-3), 3.35 (d, J ¼ 9.7 Hz, 1H, H-3), 3.33 (t, J ¼ 9.3 Hz, 1H, H-5); 31P NMR
(121 MHz, D2O, pH 10): d 7.36, 7.32.
Sodium Salt of L-myo-Inositol 2,6-Bisphosphate (L-2c)
Deprotection of L-22 (13.8 mg, 39 mmol) according to the procedures
described for D-2a gave L-I(2,6)P2 (L-2c) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2c.
Sodium Salt of D-myo-Inositol 4,5-Bisphosphate (D-2d)
A mixture of compound D-23 (57.0 mg, 61 mmol) and Pd on charcoal (10%,
28.5 mg) in a mixed solvent (AcOH:EtOH:MeOH ¼ 2:1:1, 4 mL) was hydrogen-
ated (50 psi) at rt. After 1 d, the catalyst was filtered off on the short pad of
Celite and silica gel and the filtrate was evaporated under reduced pressure.
The reaction mixture was treated with 1 M LiOH (6 mL) and stirred at 808C
for 3 h. The basic solution was cooled and loaded on Dowex 50WX8-100 (Hþ
form) and eluted with water. The acidic effluent was collected, washed with
CH2Cl2 three times, and lyophilized to dryness. The residue was redissolved in
a small amount of water (1 mL), the pH was adjusted to 10 with 1N NaOH, and
the residue was lyophilized again to give sodium salts of D-I(4,5)P2 (D-2d) as a
white powder in approximately 80% yield.
1H NMR (300 MHz, D2O, pH 10): d 4.01 (q, J ¼ 8.6 Hz, 1H, H-4), 3.87
(t, J ¼ 2.8 Hz, 1H, H-2), 3.74–3.65 (m, 2H, H-5, H-6), 3.55 (dd, J ¼ 9.8,
2.7 Hz, 1H, H-3), 3.45 (dd, J ¼ 9.6, 3.6 Hz, 1H, H-1); 31P NMR (121 MHz,
D2O, pH 10): d 7.46, 7.30.
Sodium Salt of L-myo-Inositol 4,5-Bisphosphate (L-2d)
Deprotection of L-23 (44.8 mg, 48 mmol) according to the procedures
described for D-2d gave L-I(1,6)P2 (L-2d) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2d.
Sodium Salt of D-myo-Inositol 3,4-Bisphosphate (D-2e)
Deprotection of D-24 (65.0 mg, 69.5 mmol) according to the procedures
described for D-2d gave D-I(3,4)P2 (D-2e) as a white powder in approximately
80% yield.

Synthesis of Myo-Inositols
325
1H NMR (300 MHz, D2O, pH 10): d 4.29 (s, 1H, H-2), 4.06 (q, J ¼ 8.7 Hz, 1H,
H-4), 3.81 (dt, J ¼ 9.7, 2.2 Hz, 1H, H-3), 3.60 (t, J ¼ 9.7 Hz, 1H, H-6), 3.48 (dd,
J ¼ 10.0, 2.8 Hz, 1H, H-1), 3.40 (t, J ¼ 9.0 Hz, 1H, H-5); 31P NMR (121 MHz,
D2O, pH 10): d 7.58, 6.02.
Sodium Salt of L-myo-Inositol 3,4-Bisphosphate (L-2e)
Deprotection of L-24 (45.0 mg, 48 mmol) according to the procedures
described for D-2d gave L-I(3,4)P2 (L-2e) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2e.
Sodium Salt of D-myo-Inositol 3,5-Bisphosphate (D-2f)
Deprotection of D-25 (39.0 mg, 41.7 mmol) according to the procedures
described for D-2d gave D-I(3,5)P2 (D-2f) as a white powder in approximately
80% yield.
1H NMR (300 MHz, D2O, pH 10): d 4.13 (t, J ¼ 2.7 Hz, 1H, H-2), 3.79 (dt,
J ¼ 7.3, 2.6 Hz, 1H, H-3), 3.68–3.57 (m, 3H, H-4, H-5, H-6), 3.50 (dd, J ¼ 9.0,
2.7 Hz, 1H, H-1); 31P NMR (121 MHz, D2O, pH 10): d 7.22, 6.48.
Sodium Salt of L-myo-Inositol 3,5-Bisphosphate (L-2f)
Deprotection of L-25 (33.5 mg, 35.8 mmol) according to the procedures
described for D-2d gave L-I(3,5)P2 (L-2f) as a white powder in approximately
80% yield.
1H NMR, 31P NMR were identical to those of D-2f.
ACKNOWLEDGMENT
This work was supported by KISTEP/KOSEF (BT-Glycobiology Program
200402087).
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