Synthesis of 1- and 3-C-(aminomethyl)-1,2,3,4,5-cyclohexanepentols from (+)-epi-quercitol

Article abstract of DOI:10.1081/CAR-100108284

Oxidation of three di-O-isopropylidene derivatives 2a-4a, newly derived from (+)-epi-quercitol (1), with acetic anhydride in DMSO gave the corresponding ketones 5-7, which underwent aldol-type condensation with nitromethane under basic conditions to give

Full text of DOI:10.1081/CAR-100108284

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SYNTHESIS OF 1- AND 3-C-(AMINOMETHYL)-1,2,3,4,5-
CYCLOHEXANEPENTOLS FROM (+)-epi-QUERCITOL
Seiichiro Ogawa a , Hiroshi Aoyama a & Yoji Tezuka a
a Department of Applied Chemistry, Faculty of Science and Engineering , Keio
University , Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan
Published online: 16 Aug 2006.
To cite this article: Seiichiro Ogawa , Hiroshi Aoyama & Yoji Tezuka (2001) SYNTHESIS OF 1- AND 3-C-
(AMINOMETHYL)-1,2,3,4,5-CYCLOHEXANEPENTOLS FROM (+)-epi-QUERCITOL , Journal of Carbohydrate Chemistry, 20:7-8,
703-717
To link to this article: http://dx.doi.org/10.1081/CAR-100108284
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J. CARBOHYDRATE CHEMISTRY, 20(7&8), 703–717 (2001)
SYNTHESIS OF 1- AND 3-C-(AMINOMETHYL)-
1,2,3,4,5-CYCLOHEXANEPENTOLS FROM
(ꢀ)-epi-QUERCITOL1
Seiichiro Ogawa,* Hiroshi Aoyama, and Yoji Tezuka
Department of Applied Chemistry, Faculty of Science and Engineering,
Keio University, Hiyoshi, Kohoku-ku, Yokohama, 223-8522 Japan
ABSTRACT
Oxidation of three di-O-isopropylidene derivatives 2a—4a, newly derived
from (ꢀ)-epi-quercitol (1), with acetic anhydride in DMSO gave the corre-
sponding ketones 5—7, which underwent aldol-type condensation with ni-
tromethane under basic conditions to give selectively the protected derivatives
8a—10a of C-nitromethyl-1,2,3,4,5-cyclohexanepentols, respectively. On
treatment with diazomethane in DMSO, the ketones 6 and 7 gave single spiro
epoxides 11 and 12, the structures of which were confirmed by converting
them into new C-(azidomethyl)cyclohexanepentols 16 and 17. The nitro com-
pounds were hydrogenated in the presence of Raney nickel to give the amines
isolated as the N-acetyl derivatives. Deprotection gave three new 1- and 3-C-
aminomethyldeoxyinositols 15c—17c. The aminocyclitols obtained and their
N-acetyl derivatives were assayed for inhibitory activity against examples of
glycosidases.
INTRODUCTION
Very recently bioconversion2 of myo-inositol has extensively been investi-
gated to provide several so far inaccessible optically active deoxy derivatives
(quercitols) and keto derivatives (dexyinososes) in quantity, which could allow us
to apply them as starting materials for development of new biologically active cy-
clitol derivatives.
In a preceding paper3 we reported a synthesis of several 1,2- and 2,3-anhy-
drodeoxyinositols, including a strong ꢁ-glucosidase inhibitor 1L-(1,2,4/3,5)-1,2-
703
Copyright © 2001 by Marcel Dekker, Inc.
www.dekker.com

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OGAWA, AOYAMA, AND TEZUKA
Scheme 1.
anhydro-1,2,3,4,5-cyclohexanepentol, from (ꢀ)-epi- (1) and (ꢂ)-vibo-quercitol,
and discussed the structure-activity relationship of inhibitors of this kind. In this
paper we describe the use of selective protected inositols to obtain branched chain
inositol derivatives with possible biological activity. Thus, the three different di-
O-isopropylidene derivatives of 1 were first oxidized to afford new versatile de-
oxyinosose derivatives 5—7, from which three new branched-chain deoxyinositol
derivatives of biological interest were obtained through selective base-catalyzed
aldol reaction with nitromethane. Alternatively, on treatment with diazomethane
the ketones 6 and 7 afforded selectively two spiro epoxides 14 and 15. Since newly
1-C-(aminomethyl)-1,2,3,4,5-cyclohexanepentols were found to be structurally re-
lated to the strong ꢁ-glucosidase inhibitor valiolamine,4,5 biological assays for gly-
cosidase inhibition were carried out here.
RESULTS AND DISCUSSION
Reaction of 1 with large excess of 2,2-dimethoxypropane (10 molar equiv) in
DMF in the presence of p-toluenesulfonic acid for 6 h at room temperature gave,

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705
after fractionation over a silica gel column, the 1,2:3,4-, 1,2:4,5-. And 2,3:4,5-di-
O-isopropylidene derivatives6 (2a, 3a, and 4a) in about 22, 22, and 33% isolated
yields, respectively, along with a small amount of a mixture of the mono-ketals.
Similar isopropylidenation was later much improved by use of 2-methoxypropene
(5 molar equiv), which resulted in shortening of the reaction time, complete con-
version into the ketals, and easy separation of the products. Alternatively, on sim-
ilar treatment with 1,1-dimethoxycyclohexane, 1 produced, after chromatography,
the respective di-O-cyclohexylidene derivatives 2b, 3b, and 4b in a yield of 22, 29,
and 24%, respectively, together with a mixture of two mono-ketals. Since the com-
pounds 2b—4a could not be separated as easily as the isopropylidene derivatives
2a—4a, the latter were chosen as the starting compounds for the present study.
Oxidation of 2a—4a with acetic anhydride in DMSO smoothly gave rise to the
respective ketones 5, 6, and 7 in 91, 70, and 96% yields, respectively. These com-
pounds are shown to exist in keto form and can be expected to be versatile synthetic
intermediates for development of a wide variety of deoxyinositol derivatives. Only
compound 6 appeared as a somewhat broad-tailing spot on silica-gel TLC analysis.
First in an attempt to obtain exo-methylene derivatives, the ketones were sub-
jected to the Wittig reaction with bromotriphenylmethane in the presence of NaH-
MDS, but this was not successful.
Scheme 2.

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Next, a base-catalyzed aldol condensation of 5—7 was investigated using an
excess of nitromethane. The reaction proceeded selectively to give moderate yields
of nitromethyl-branched derivatives 8a, 9a, and 10a as single isomers. The reac-
tion proceeded very slowly, being largely influenced by the kind of base catalyst.
Compound 7 readily reacted in the presence of sodium methoxide in MeOH to give
condensate 10a, but difficulties were encountered with 5 and 6. They only reacted
in 1 M aqueous sodium hydroxide solution, giving 8a and 9a. Considering the 1H
NMR spectral data, the ketones 5—7 adopt somewhat distorted chair-conforma-
tions related to that of 1. The selectivity of the aldol reaction seemed to be con-
trolled by the steric hindrance exerted by 1,3-diaxial protons, rather than by the
bulky isopropylidene groups which point away from the cyclose carbonyl group.
The nitro compounds 8a—10a were readily hydrogenated in ethanol containing
acetic anhydride in the presence of Raney nickel catalyst being converted into the
respective N-acetyl derivatives 8b—10b. Compound 8a, being contaminated with
inseparable unknown side-products, was without isolation converted directly into
8b. NOE experiments with 8b, 9a, and 10b clearly established the structures as de-
picted in Scheme 2. A restricted rotation of the amido function was observed in the
1H NMR spectrum for 9b.
In the next reaction sequence, construction of spiro epoxides was carried
out by exposing the ketones 5—7 to diazomethane in diethyl ether—DMSO.
Two spiro epoxides 11 and 12 were obtained selectively in moderate yields8 from
6 and 7. Cleavage of the oxirane ring with an azide ion proceeded smoothly giv-
ing rise to the azidomethyl compounds 13 (50%) and 14 (65%), respectively, the
1
structures of which were established on the basis of their H NMR spectra, and
also by comparison with those of corresponding 9a and 10a. The structures of 11
and 12 are shown in Scheme 3. Diazomethane added to the ketones 6 and 7 in a
similar fashion as observed in the aldol reaction. Attempts were not made to iso-
Scheme 3.

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707
Scheme 4.
late the side-products, including ring-expansion products9 likely to be formed in
these reaction.
De-O-isopropylidenation of 8b—10b with aqueous acetic acid, followed by
conventional acetylation with acetic anhydride in pyridine, gave the corresponding
1
hexa-N,O-acetyl derivatives 15a—17a, the H NMR spectra of which fully sup-
ported the assigned structures. In order ton assay the aminocyclitols thus obtained
for glycosidase inhibitory activity, compounds 8b—10b were transformed into
their N-acetyl derivatives 15b—17b and the free base 15c—17c, respectively, in
the usual manner.
BIOLOGICAL ASSAY
The N-acetyl derivatives and free bases 15b,c—17b,c were assayed10 for
enzyme inhibitory activity (I%) against nine glycohydrolases: ꢁ-glucosidase
(Baker’s yeast), ꢃ-glucosidase (almonds), ꢁ-mannosidase (Jack beans), ꢁ-galac-
tosidase (green coffee), ꢃ-galactosidase (bovine kidney), and ꢁ-L-fucosidase
(bovine kidney), sucrase (rat small intestine),11 and maltase (rat small intes-
tine).11 Since, as shown in conformation formulas, 17c is a ꢃ-D-galactopyranose
analogue of valiolamine,4 and 15c and 16c are related to ꢁ- and ꢃ-D-galactopy-
ranose-type cyclohexanepentols, they were expected to have some biological ac-
tivity.12 However, among them, only compounds 15b,c showed inhibitory activ-
ity, very weak and limited to ꢁ-glucosidase and ꢁ-mannosidase (I ꢄ 20—30%,
at 10ꢂ4 M).

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OGAWA, AOYAMA, AND TEZUKA
EXPERIMENTAL
General Methods. Melting points: Mel-Temp capillary melting-point ap-
paratus, uncorrected. Specific rotations: Jasco DIP-370 polarimeter, 1-dm cells. IR
spectra: Jasco A-202 or FT-IR-200. 1H NMR spectra: Jeol JNM GSX-270 f.t. (270
MHz) and Jeol Lambda-300 (300 MHz); solvent CDCl3 internal standard tetram-
ethylsiliane (TMS), D2O external acetone. Mass spectra: positive-ion electrospray
ionization on a Jasco GC-Mass GC-Mare. TLC: SilicaGel 60 GF (E. Merck, Darm-
stadt); detection by charring with concd H2SO4. Column chromatography: silica
gel 60 K070 (Katayama Chemicals, Osaka), Wakogel C-33 (silica gel, 300 Mesh,
Wako Chemical, Osaka), and Disogel sp-60 (silica gel, 60 mesh, Daiso, Osaka).
Organic solutions, after drying with anhydrous Na2SO4, were concentrated ꢅ50°C
at diminished pressure. After being characterized by spectroscopic methods, the
N-acetyl derivatives 15b—17b and the free bases 15c—17c were subjected di-
rectly to biological assay.10,11
1,2:3,4-Di-O-isopropylidene-(ꢀ)-epi-quercitol (2a), 1,2:4,5-di-O-iso-
propylidene-(ꢀ)-epi-quercitol (3a), and 2,3:4,5-di-O-isopropylidene-(ꢀ)-epi-
quercitol (4a). a) To a solution of (ꢀ)-epi-quercitol13 (1, 1.00 g, 6.10 mmol) in
DMF (20 mL) were added in turn p-toluenesulfonic acid monohydrate (63 mg) and
2,2-dimethoxypropane (10 mL, 82 mmol), and the mixture was stirred for 6 h at
room temperature. At that time, TLC showed formation of four components (RF
0.41; chloroform/MeOH, 5:1; RF 0.42, 0.45, and 0.51; butanone/toluene, 1:2),
which were thought to correspond to one mono and three di-O-isopropylidene
derivatives, respectively. After neutralization with triethylamine, the reaction mix-
ture was concentrated and the residue was chromatographed on a silica gel column
(70 g; acetone/toluene, 1:10) to give 2a (263 mg, 22%), 3a (275 mg, 22%), and 4a
(408 mg, 33%) as crystals, together with a homogenous mixture of ca. 1:2 mixture
of two mono-O-isopropylidene derivatives.
b) When compound 1 (1.00 g, 6.10 mmol) was similarly treated with
2-methylpropene (2.93 mL, 30 mmol), the reaction was shown to reach equilib-
rium within 3 h. Silicagel chromatography of the products gave 2a (439 mg,
30.4%), 3a (402 mg, 29.4%), and 4a (375 mg, 27.4%) as crystals.
25
1
2a: mp 124—126°C; [ꢁ]D ꢀ26° (c 0.84, CHCl3); H NMR (300 MHz,
CDCl3) ꢆ 1.36, 1.45, 1.47, and 1.57 (4 s, each 3 H, 2 ꢇ CMe2), 2.01 (ddd, J1,6eq
ꢄ 6.8, J5,6eq ꢄ 3.4, J6gem ꢄ 15.9 Hz, 1 H, 6eq-H), 2.17 (m, 1 H, 6ax-H), 2.42 (br
s, 1 H, OH), 3.38 (dd, J2,3 ꢄ 3.2, J3,4 ꢄ 9.8 Hz, 1 H, 3-H), 4.06 (m, 1 H, 5-H), 4.06
(dd, J4,5 ꢄ 7.3 Hz, 1 H, 4-H), 4.52 (dd, J1,2 ꢄ 6.6 Hz, 1 H, 1-H), 4.52 (dd, 1 H,
2-H).
Anal. Calcd for C12H20O5 (244.3): C, 59.00; H, 8.25. Found: C, 58.95; H,
8.19.
3a: mp 98—102°C; [ꢁ]D17 ꢂ27° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
ꢆ 1.36, 1.43, 1.47, and 1.54 (4 s, each 3 H, 2 ꢇ CMe2), 1.66 (ddd, J1,6axꢄ 9.5, J5,6ax
ꢄ 12.7, J6gem ꢄ 12.7 Hz, 1 H, 6ax-H), 2.41 (ddd, J1,6eq ꢄ 6.8, J5,6eq ꢄ 3.7 Hz, 1
H, 6eq-H), 2.50 (br s, 1 H, OH), 3.29 (ddd, J4,5 ꢄ 9.0 Hz, 1 H, 5-H), 3.77 (dd, J3,4

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709
ꢄ 10.5 Hz, 1 H, 4-H), 3.95 (dd, J2,3 ꢄ 4.2 Hz, 1 H, 3-H), 4.31 (ddd, J1,2 ꢄ 4.2 Hz,
1 H, 1-H), 4.41 (dd, 1 H, 2-H).
Anal. Calcd for C12H20O5 (244.3): C, 59.00; H, 8.25. Found: C, 58.93;
H, 8.36.
4a: mp 116—117°C; [ꢁ]D25 ꢂ15° (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
ꢆ1.39, 1.40, 1.42, and 1,44 (4 s, each 3 H, 2 ꢇ CMe2), 1.89 (ddd, J1,6eq
ꢄ 5.6, J5,6eq ꢄ 5.4, J6gem ꢄ 12.9 Hz, 1 H, 6eq-H), 2.36 (ddd, J1,6x ꢄ 6.1, J5,6ax
ꢄ 6.8 Hz, 1 H, 6ax-H), 2.45 (br s, 1 H, OH), 3.44 (dd, J1,2 ꢄ 10.0 Hz, 1 H, 1-H),
3.99 (dd, J2,3 ꢄ 7.6 Hz, 1 h, 2-H), 4.10 (ddd, J4,5 ꢄ 10.3 Hz, 1 H, 5-H), 4.27 (dd,
J3,4 ꢄ 11.2 Hz, 1 H, 4-H), 4.30 (dd, 1 H, 4-H).
Anal. Calcd for C12H20O5 (244.3): C, 59.00; H, 8.25. Found: C, 58.29;
H, 8.21.
1,2:3,4-Di-O-cyclohexylidene-(ꢀ)-epi-quercitol (2b), 1,2:4,5-di-O-cyclo-
hexylidene-(ꢀ)-epi-quercitol (3b), and 2,3:4,5-di-O-cyclohexylidene-(ꢀ)-epi-
quercitol (4b). To a solution of (ꢀ)-epi-quercitol13 (1, 500 mg, 3.05 mmol) in
DMF (10 mL) were added dimethoxycyclohexane (5.0 mL, 32.5 mmol) and
p-toluenesulfonic acid monohydrate (60 mg), and the mixture was stirred for 6 h at
room temperature. At that time, TLC revealed formation of one monoketal (RF
0.47; chloroform/MeOH, 5:1), and three diketals (RF 0.67, 0.59, and 0.53; bu-
tanone/toluene, 1:2). After neutralization with triethylamine, and the mixture was
concentrated and the residue was chromatographed on a silica gel column (30 g,
ethyl acetate/hexane, 1:5) to give 2b (205 mg, 24%), 3b (243 mg, 29%), and 4b
(177 mg, 21%) as crystals. Two monoketals were obtained as homogeneous white
solids.
2b: mp 102—104°C; [ꢁ]2D2 ꢂ10° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
ꢆ?1.44—1.72 (m, 20 H, 6ax-H, 2 ꢇ C6H10), 2.37 (ddd, J1,6eq ꢄ 7.1, J5,6eq ꢄ 3.7,
J6gem ꢄ 12.0 Hz, 1 H, 6eq-H), 2.43—2.50 (m, 1 H, OH), 3.20 (ddd, J4,5
ꢄ 9.0, J5,6ax ꢄ 13.2 Hz, 1 H, 5-H), 3.69 (dd, J3,4 ꢄ 9.0 Hz, 1 H, 4-H), 3.80—3.92
(m, 1 H, 3-H), 4.23 (ddd, J1,2 ꢄ 4.9, J1,6ax ꢄ 13.7 Hz, 1 H, 1-H), 4.34 (dd, J2,3
ꢄ 4.9 Hz, 1 H, 2-H).
Anal. Calcd for C18H28O5 (324.4): C, 66.64; H, 8.70. Found: C, 66.53; H,
8.65.
3b: mp 115—119°C; [ꢁ]2D2 ꢀ39° (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
ꢆ1.51—1.77 (m, 20 H, 2 ꢇ C6H10), 1.96 (ddd, J1,6axꢄ 6.8, J5,6ax ꢄ 12.7, J6gem ꢄ
15.9 Hz, 1 H, 6ax-H), 2.16 (s, 1 H, OH), 3.29 (dd, J2,3 ꢄ 3.2, J3,4 ꢄ 9.8 Hz, 1 H,
3-H), 3.91—4.07 (m, 2 H, 4-H, 5-H), 4.45 (ddd, J1,2 ꢄ 6.8, J1,6eq ꢄ 3.4, J1,6ax ꢄ
6.8 Hz, 1 H, 1-H), 4.48 (dd, 1 H, 2-H).
Anal. Calcd for C18H28O5 (324.4): C, 66.64; H, 8.70. Found: C, 66.37; H,
8.61.
1
4b: mp 118—120°C; [ꢁ]D20 ꢀ0.6° (c 1.2, CHCl3); H NMR (300 MHz,
CDCl3) ꢆ1.51—1.80 (m, 20 H, 2 ꢇ C6H10), 1.89 (ddd, J1,6ax ꢄ 10.7, J5,6ax ꢄ 8.1,
J6gem ꢄ 13.2 Hz, 1 H, 6ax-H), 2.36 (ddd, J1,6eq ꢄ 6.1, J5,6eq ꢄ 8.1 Hz, 1 H, 6eq-
H), 2.48—2.55 (m, 1 H, OH), 3.44 (ddd, J1,2 ꢄ 10.0 Hz, 1 H, 1-H), 4.01 (dd, J2,3
ꢄ 7.1 Hz, 1 H, 2-H), 2.05—4.14 (m, 1 H, 5-H), 4.23—4.32 (m, 2 H, 3-H, 4-H).

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OGAWA, AOYAMA, AND TEZUKA
Anal. Calcd for C18H28O5 (324.4): C, 66.64; H, 8.70. Found: C, 66.67;
H, 8.68.
(2R,3S,4S,5S)-2,3:4,5-Bis(isopropylidenedioxy)-1-cyclohexanone (5).
To a solution of 2a (150 mg, 0.61 mmol) in DMSO (4.5 mL) was added acetic an-
hydride (4.1 mL) at 10°C, and the mixture was stirred for 6 h at room temperature.
TLC showed formation of a single product (RF 0.71; butanone/toluene, 1:2). After
treatment with methanol (4.1 mL), the mixture was concentrated. The residual
syrup was diluted with ethyl acetate (30 mL), and the solution was washed thor-
oughly with water, dried, and concentrated. The residue was chromatographed on
a silica gel column (18 g; acetone/toluene, 1:15) to give 5 (135 mg, 91%) as crys-
tals: mp 130—132°C; [ꢁ]D23 ꢀ56° (c 1.0, CHCl3); H NMR (300 MHz, CDCl3)
1
ꢆ1.41 and 1,55 (2 s, each 3 H) and 1.49 (s, 6 H) (2 ꢇ CMe2), 2.55 (dd, J5,6ax ꢄ 3.9,
J6gem ꢄ 19.5 Hz, 1 H, 6ax-H), 2.85 (dd, J5,6eq ꢄ 2.6 Hz, 1 H, 6eq-H), 3.80 (dd, J2,3
ꢄ 11.2, J3,4 ꢄ 3.4 Hz, 1 H, 3-H), 4.58 (d, 1 H, 2-H), 4.70 (ddd, J4,5 ꢄ 7.3 Hz, 1 H,
5-H), 4.77 (dd, 1 H, 4-H).
Anal. Calcd for C12H18O5 (242.3): C, 59.49; H, 7.49. Found: C, 59.49;
H, 7.50.
(2S,3S,5R,6S)-2,3:5,6-Bis(isopropylidenedioxy)-1-cyclohexanone (6).
To a solution of 3a (800 mg, 3.27 mmol) in DMSO (24 mL) was added acetic an-
hydride (22 mL) at 10°C, and the mixture was stirred for 5.5 h at room tempera-
ture. TLC showed formation of a single product (RF 0.65; butanone/toluene, 1:2).
The mixture was processed as in the preparation of 5, and the residue was chro-
matographed on a silica gel column (30 g; acetone/toluene, 1:15) to give 6 (533 mg,
70%) as crystals: mp 93—94°C; [ꢁ]D22 ꢂ50° (c 1.1, CHCl3); 1H NMR (300 MHz,
CDCl3) ꢆ 1.35, 1.46, 1.50, and 1.58 (4 s, each 3 H, 2 ꢇ CMe2), 2.03 (ddd, J3,4ax
ꢄ 7.8, J4ax,5 ꢄ 12.7, J4gem ꢄ 12.5 Hz, 1 H, 4ax-H), 2.71 (ddd, J3,4eq ꢄ 7.6, J4eq,5
ꢄ 4.2 Hz, 1 H, 4eq-H), 3.64 (ddd, J5,6 ꢄ 10.7 Hz, 1 H, 5-H), 4.28 (d, J2,3 ꢄ 5.1 H,
1 H, 2-H), 4.55 (ddd, 1 H, 3-H), 4.64 (d, 1 H, 6-H).
Anal. Calcd for C12H18O5 (242.3): C, 59.49; H, 7.49. Found: C, 59.51;
H, 7.40.
(2R,3R,4S,5R)-2,3:4,5-Bis(isopropylidenedioxy)-1-cyclohexanone (7).
To a solution of 4a (1.50 g, 6.14 mmol) in DMSO (45 mL) was added acetic an-
hydride (41 mL) at 10°C, and the mixture was stirred for 6 h at room temperature.
TLC showed formation of a single product (RF 0.67; butanone/toluene, 1:2). The
mixture was processed similarly as in the preparation of 5. The residue was chro-
matogeraphed on a silica gel column (30 g; ethyl acetate/hexane, 1:5) to give 7
(1.42 g, 96%) as crystals: mp 129—130°C; [ꢁ]D27 ꢂ77° (c 1.0, CHCl3); 1H NMR
(300 MHz, CDCl3) ꢆ 1.39, 1.47, 1.49, and 1.51 (4 s, each 3 H, 2 ꢇ CMe2), 2.49
(dd, J5,6ax ꢄ 11.0, J6gem ꢄ 18.1 Hz, 1 H, 6ax-H), 3.00 (dd, J5,6eq ꢄ 7.1 Hz, 1 H,
6eq-H), 3.57 (dd, J3,4 ꢄ 7.6, J4,5 ꢄ 10.3 Hz, 1 H, 4-H), 4.13 (ddd, 1 H, 5-H), 4.49
(d, J2,3 ꢄ 8.5 Hz, 1 H, 2-H), 4.65 (dd, 1 H, 3-H).

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711
Anal. Calcd for C12H18O5 (242.3): C, 59.49; H, 7.49. Found: C, 59.20;
H, 7.43.
3-Deoxy-1,6:4,5-di-O-isopropylidene-2-nitromethyl-L-neo-inositol (8a)
and 2-(Acetamidomethyl)-3-deoxy-1,6:4,5-di-O-isopropylidene-L-neo-inositol
(8b). To a solution of 5 (100 mg, 0.410 mmol) in nitromethane (2 mL) was added
aqueous 1 M sodium hydroxide (0.4 mL), and the mixture was stirred for 4 days at
room temperature. After neutralization with Amberlite IR-120B (Hꢀ) resin, the
mixture was concentrated. The residue was diluted with ethyl acetate, and the so-
lution was washed thoroughly with aqueous sodium chloride, dried, and concen-
trated. The residue was chromatographed on a silica gel column (14 g; ethyl ac-
etate/hexane, 1:7) to give a mixture of products. The mixture composed of 8a as a
major product was, without further isolation, hydrogenated in ethanol (2 mL) con-
taining acetic anhydride (0.03 mL) in the presence of Raney nickel T-4 for 2 h at
room temperature. The catalyst was removed by filtration and the filtrate was con-
centrated to dryness. The residue was treated with acetic anhydride (0.25 mL) in
pyridine (0.5 mL) overnight at room temperature. After treatment with a small
amount of methanol, the mixture was concentrated. The residue was chro-
matographed on a silica gel column (6 g; acetone/toluene, 1:1) to give 8b (32 mg,
25%) as a syrup: TLC (chloroform/MeOH, 1:1) RF 0.54; IR (neat) 1650, 1555
(amide) cm-1; [ꢁ]D21 ꢂ29° (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.35, 1.46,
1.47, and 1.56 (4 s, each 3 H, 2 ꢇ CMe2), 1.61 (dd, J3ax,4 ꢄ 3.7, J3gem ꢄ 15.9 Hz,
1 H, 3ax-H), 2.01 (s, 3 H, NAc), 2.19 (dd, J3eq,4 ꢄ 3.2 Hz, 1 H, 3eq-H), 3.42 (d,
J7,NH ꢄ 5.6 Hz, 2 H, CH2NHAc), 3.82 (dd, J1,6 ꢄ 10.3, J5,6 ꢄ 3.4 Hz, 1 H, 6-H),
3.94 (d, 1 H, 1-H), 4.52 (ddd, J4,5 ꢄ 7.3 H, 1 H, 4-H), 4.59 (dd, 1 H, 5-H), 6.13 (br
d, 1 H, NH).
Anal. Calcd for C15H25NO6 (315.4): C, 57.13; H, 7.99; N, 4.44. Found:
C, 57.06; H, 7.95; N, 4.37.
6-Deoxy-1,2:4,5-di-O-isopropylidene-1-nitromethyl-D-myo-inositol (9a).
A solution of 6 (50 mg, 0.20 mmol) in nitromethane (1 mL) was treated with aque-
ous 1 M sodium hydroxide (0.4 mL) for 3 days at room temperature. After neu-
tralization, the mixture was processed as in the preparation of 8a. The product was
chromatographed on a silica gel column (8 g; ethyl acetate/hexane, 1:15) to give 9a
(45 mg, 73%) as a syrup: TLC (butanone/toluene, 1:2) RF 0.71; [ꢁ]D23 ꢂ5.5° (c 1.4,
CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.33, 1.41, 1.43, and 1.48 (4 s, each 3 H, 2
ꢇ CMe2), 1.68 (ddd, J1,6ax ꢄ 9.5, J5,6ax ꢄ 12.9, J6gem ꢄ 11.7 Hz, 1 H, 6ax-H), 2.47
(ddd, J1,6eq ꢄ 7.1, J5,6eq ꢄ 3.7, 1 H, 6eq-H), 3.28 (s, 1 H, OH), 3.55 (d, J4,5 ꢄ 9.0
Hz, 1 H, 4-H), 3.91 (ddd, 1 H, 5-H), 4.23 (d, J1,2 ꢄ 4.9 Hz, 1 H, 2-H), 4.42 (dd, 1
H, 1-H), 4.72 and 4.80 (ABq, Jgem ꢄ 12.6 Hz, CH2NO2).
Anal. Calcd for C13H21NO7 (303.3): C, 51.48; H, 6.98; N, 4.62. Found:
C, 51.65; H, 7.00; N, 4.69.
1-(Acetamidomethyl)-6-deoxy-1,2:4,5-di-O-isopropylidene-D-myo-inosi-
tol (9b). A solution of 9a (86 mg, 0.28 mmol) in ethanol (8 mL) containing acetic

ORDER
REPRINTS
712
OGAWA, AOYAMA, AND TEZUKA
anhydride (0.054 mL, 0.57 mmol) was stirred under an atmospheric pressure of hy-
drogen in the presence of Raney nickel T-4 for 3.5 h at room temperature. The re-
action mixture was filtered to remove catalyst and the filtrate was concentrated.
The residue was chromatographed on a silica gel column (6.5 g; acetone/toluene,
1:5) to give 9b (64 mg, 71%) as a syrup: TLC (butanone/toluene, 1:1) RF 0.49; IR
(neat) 1655, 1555 (amide) cm-1; [ꢁ]D22 ꢂ3.9° (c 1.3, CHCl3); 1H NMR (300 MHz,
CDCl3) ꢆ 1.33, 1.43, 1.46, and 1.48 (4 s, each 3 H, 2 ꢇ CMe2), 1.61 (ddd, J1,6ax
ꢄ 9.5, J5,6ax ꢄ 12.7, J6gem ꢄ 11.7 Hz, 1 H, 6ax-H), 2.05 (s, 3 H, NAc), 2.45 (ddd,
J1,6eq ꢄ 7.1, J5,6eq ꢄ 3.8 Hz, 1 H, 6eq-H), 3.53 (d, J4,5 ꢄ 9.8 Hz, 1 H, 4-H), 3.55
(dd, J7a,NH ꢄ 6.8, J7gem ꢄ 14.4 Hz, 1 H) and 3.77 (dd, J7b,NH ꢄ 5.1 Hz, 1 H)
(CH2NHAc), 3.91 (ddd, 1 H, 5-H), 4.04 (d, J1,2 ꢄ 4.9 Hz, 1 H, 2-H), 4.07 (s, 1 H,
OH), 4.41 (ddd, 1 H, 1-H), 6.06 (dd, 1 H, NH).
Anal. Calcd for C15H25NO6 (315.4): C, 57.13; H, 7.99; N, 4.44. Found:
C, 56.88; H, 7.97; N, 4.33.
2-Deoxy-3,4:5,6-di-O-isopropylidene-1-nitromethyl-D-chiro-inositol
(10a). A solution of 7 (50 mg, 0.20 mmol) in nitromethane (1 mL) was treated
with methanolic 1 M sodium methoxide (0.8 mL) for 5 days at room temperature.
After neutralization, the mixture was processed as in the preparation of 8a and the
product was chromatographed on a silica gel column (9 g; acetone/toluene, 1:20)
to give 10a (49 mg, 79%) as a syrup: TLC (acetone/toluene, 1:5) RF ꢄ 0.40; [ꢁ]D23
ꢀ35° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.26 and 1.44 (2 s, each 3 H)
and 1.37 (s, 6 H) (2 ꢇ CMe2), 1.68 (dd, J2ax,3 ꢄ 12.2, J2gem ꢄ 12.2 Hz, 1 H, 2ax-
H), 2.14 (dd, J2eq,3 ꢄ 3.4 Hz, 1 H, 2eq-H), 3.42 (dd, J3,4 ꢄ 9.5, J4,5 ꢄ 9.3 Hz, 1 H,
4-H), 3.61 (s, 1 H, OH), 3.74 (ddd, 1 H, 3-H), 4.10 (d, J5,6 ꢄ 5.1 H, 1 H, 6-H), 4.32
(dd, 1 H, 5-H), 4.49 and 4.65 (ABq, Jgem ꢄ 13.4 Hz, CH2NO2).
Anal. Calcd for C13H21NO7 (303.3): C, 51.48; H, 6.98; N, 4.62. Found:
C, 51.17; H, 6.91; N, 4.79.
1-(Acetamidomethyl)-2-deoxy-2,3:4,5-di-O-isopropylidene-D-chiro-inos-
itol (10b). A solution of 10a (223 mg, 0.73 mmol) in ethanol (20 mL) containing
acetic anhydride (0.14 mL, 1.5 mmol) was stirred under an atmospheric pressure
of hydrogen in the presence of Raney nickel T-4 for 3.5 h at room temperature. The
reaction mixture was filtered to remove the catalyst and the filtrate was concen-
trated. The residue was chromatograped on a silica gel column (25 g; acetone/
toluene, 1:5) to give 10b (147 mg, 63%) as a syrup: TLC (butanone/toluene, 1:1)
RF 0.28; IR (neat) 1650, 1555 (amide) cm-1; [ꢁ]D22 ꢂ33° (c 1.1, CHCl3); 1H NMR
(300 MHz, CDCl3) ꢆ 1.39 (s, 6 H), 1.33 and 1.48 (2 s, each 3 H) (2 ꢇ CMe2),
1.45—1.65 (m, 1 H, 2ax-H), 2.00—2.20 (m, 1 H, 2eq-H), 2.04 (s, 3 H, NAc), 3.42
(dd, J3,4 ꢄ 9.3, J4,5 ꢄ 9.3 Hz, 1 H, 4-H), 3.30 and 3.65 (2 dd, J7,NH ꢄ 14.5, J7gem
ꢄ 14.5 Hz, each 1 H, CH2NHAc), 3.77 (ddd, J2ax,3 ꢄ 12.0, J2eq,3 ꢄ 3.7, J3,4 ꢄ 9.3
Hz, 1 H, 3-H), 4.04 (d, J5,6 ꢄ 4.6 Hz, 1 H, 6-H), 4.32 (dd, 1 H, 3-H), 5.01 (s, 1 H,
OH), 6.05 (br d, 1 H, NH).
Anal. Calcd for C13H21NO7 (303.3): C, 51.48; H, 6.98; N, 4.62. Found:
C, 57.15; H, 7.99; N, 4.29.

ORDER
REPRINTS
(ꢀ)-epi-QUERCITOL
713
3,7-Anhydro-6-deoxy-3-(hydroxymethyl)-1,2:4,5-di-O-isopropylidene-
D-myo-inositol (11). To a solution of 6 (220 mg, 0.90 mmol) in DMSO (2.5 mL)
was added dropwise 0.8 M diazomethane etherate, prepared by treatment of
1-methyl-3-nitro-1-nitrosoguanidine with aqueous 40% KOH/diethyl ethyl, at
10°C until the mixture turned yellow. The reaction mixture was stirred for 4 days
at room temperature, and then the excess reagent was decomposed with acetic acid.
After neutralization with triethylamine, the mixture was dissolved in water (20
mL) and the solution was extracted with diethyl ether (3 ꢇ 40 mL). The extracts
were concentrated to dryness. TLC showed formation of a single compound (RF
0.64; acetone/toluene, 1:4). The residue was chromatographed on a silica gel col-
umn (20 g; acetone/hexane, 1:30) to give 11 (126 mg, 55%) as a white solid: [ꢁ]1D8
ꢂ31° (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.25, 1.34, 1.39, and 1.52 (4
s, each 3 H, 2 ꢇ CMe2), 1.68 (dd, J1,6ax ꢄ 3.9, J5,6ax ꢄ 12.7, J6gem ꢄ 12.0 Hz, 1 H,
6ax-H), 2.54 (ddd, J1,6eq ꢄ 7.3, J5,6eq ꢄ 3.7 Hz, 1 H, 6eq-H), 2.87 and 3.03 (ABq,
Jgem ꢄ 4.9 Hz, CH2O), 3.62 (d, J1,2 ꢄ 5.1 Hz, 1 H, 2-H), 3.69 (ddd, J4,5 ꢄ 9.5 Hz,
1 H, 5-H), 3.96 (d, 1 H, 4-H), 4.40 (ddd, 1 H, 1-H). HRMS (EI) Calcd for C13H20O5
(Mꢀ): 256.1311. Found: 256.1295.
1,7-Anydro-2-deoxy-1-(hydroxymethyl)-3,4:5,6-di-O-isopropylidene-D-
chiro-inositol (12). To a solution of 7 (250 mg, 1.03 mmol) in DMSO (3.5 mL)
was added ca. 0.8 M diazomethane etherate at 10°C until the mixture turned yel-
low. The reaction mixture was processed as in the preparation of 11. TLC showed
formation of a single compound (RF 0.74; acetone/toluene, 1:4). The product was
purified by chromatography on silica gel (20 g; ethyl acetate/toluene, 1:30) to give
12 (109 mg, 41%) as a white solid: [ꢁ]1D8 ꢂ19° (c 1.2, CHCl3); 1H NMR (300 MHz,
CDCl3) ꢆ 1.30, 1.41, 1.42, and 1.51 (4 s, each 3 H, 2 ꢇ CMe2), 1.71 (dd, J2eq,3
ꢄ 3.9, J2gem ꢄ 13.0 Hz, 1 H, 2eq-H), 2.26 (dd, J2ax,3 ꢄ 12.5 Hz, 1 H, 2ax-H), 2.79
and 2.92 (ABq, Jgem ꢄ 4.5 Hz, CH2O), 3.55 (dd, J3,4 ꢄ 9.2, J4,5 ꢄ 8.6 Hz, 1 H,
4-H), 3.66 (d, J5,6 ꢄ 5.9 Hz, 1 H, 6-H), 3.63—3.74 (m, 1 H, 3-H), 4.33 (dd, 1 H,
5-H). HRMS (EI) Calcd for C13H21N3O5 (Mꢀ): 255.1233. Found: 255.1209.
3-(Azidomethyl)-6-deoxy-1,2:4,5-di-O-isopropylidene-D-myo-inositol
(13). A mixture of 11 (27 mg, 0.10 mmol), sodium azide (27 mg, 0.42 mmol),
ammonium chloride (8 mg, 0.15 mmol), and DMF (0.5 mL) was stirred for 22 h at
60°C. At that time, TLC showed formation of a single product (RF 0.61;
acetone/toluene, 1:4). The reaction mixture was concentrated and the residue was
dissolved in ethyl acetate (15 mL), and the solution was washed thoroughly with
water, dried, and concentrated to dryness. The residue was chromatographed on a
silica gel column (3 g; ethyl acetate/hexane, 1:10) to give 13 (24 mg, 76%) as a
white solid: [ꢁ]D21 ꢀ42° (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.36, 1.41,
1.46, and 1.70 (4 s, each 3 H, 2 ꢇ CMe2), 1.64 (dd, J1,6ax ꢄ 9.8, J5,6ax ꢄ 12.8, J6gem
ꢄ 13.9 Hz, 1 H, 6ax-H), 2.46 (br s, 1 H, OH), 2.46 (ddd, J1,6eq ꢄ 7.0, J5,6eq ꢄ 3.7
Hz, 1 H, 6eq-H), 3.53 (d, J4,5 ꢄ 9.0 Hz, 1 H, 4-H), 3.56 and 3.62 (ABq, Jgem ꢄ 12.7
Hz, CH2N3), 3.87 (dd, 1 H, 5-H), 4.15 (d, J1,2 ꢄ 4.6 Hz, 1 H, 2-H), 4.42 (ddd, 1 H,
1-H). ERMS (EI) Calcd for C13H21N3O5 (Mꢀ): 299.1481. Found: 299.1471.

ORDER
REPRINTS
714
OGAWA, AOYAMA, AND TEZUKA
1-(Azidomethyl)-2-deoxy-3,4:5,6-di-O-isopropylidene-D-chiro-inositol
(14). A mixture of 12 (31 mg, 0.12 mmol), sodium azide (39 mg, 0.61 mmol),
ammonium chloride (13 mg, 0.24 mmol), and DMF (0.6 mL) was stirred for 3 days
at 60°C. At that time, TLC showed formation of a single product (RF 0.57; ace-
tone/toluene, 1:5). The reaction mixture was processed as in the preparation of 13,
and the residual product was chromatographed on a silica gel column (3 g; ethyl
acetate/hexane, 1:15) to give 14 (34 mg, 92%) as a white solid: [ꢁ]D21 ꢀ2.1° (c 1.7,
CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ1.43 (s, 6 H), and 1.38 and 1.52 (2 s, each
3 H) (2 ꢇ CMe2), 1.67 (dd, J2ax,3 ꢄ 12.2, J2gem ꢄ 12.5 Hz, 1 H, 2ax-H), 2.10 (dd,
J2eq,3 ꢄ 3.4 Hz, 1 H, 2eq-H), 2.47 (s, 1 H, OH), 3.48 (dd, J3,4 ꢄ 9.5, J4,5 ꢄ 8.8 Hz,
1 H, 4-H), 3.34 and 3.73 (ABq, Jgem ꢄ 12.2 Hz, CH2N3), 3.73—3.84 (m, 1 H,
3-H), 4.07 (d, J5,6 ꢄ 4.9 Hz, 1 H, 6-H), 4.35 (dd, 1 H, 5-H). HRMS (EI) m/z Calcd
for C13H20N3O5 (M ꢂH): 298.1403; Found: 298.1406.
Hexa-N,O-acetyl-1-(aminomethyl)-3-deoxy-L-neo-inositol (15a). A so-
lution of 8b (30 mg, 0.095 mmol) in aqueous 80% acetic acid (1.3 mL) was stirred
fro 3 h at 50°C, and then concentrated to dryness. The product was treated with
acetic anhydride (0.12 mL) and pyridine (0.23 mL) in the presence of DMAP (3
mg) for 3 days at 50°C, and after routine processing the product was chro-
matographed on a silica gel column (5g; acetone/toluene, 1:5) to give 15a (30 mg,
71%) as a syrup: TLC (butanone/toluene, 2:1) RF 0.40: IR (neat) 1750 (CO), 1650,
1555 (amide) cm-1; [ꢁ]D20 ꢀ33° (c 1.5, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.98,
1.99, 2.03, 2.11, 2.16, and 2.17 (6 s, each 3 H, NAc, 5 ꢇ OAc), 1.80—2.20 (m, 1
H, 3ax-H), 2.68 (dd, J2,3eq ꢄ 4.4, J3gem ꢄ 14.4 Hz, 1 H, 3eq-H), 3.53 (dd, J7a,NH
ꢄ 7.3, J7gem ꢄ 14.7 Hz, 1 H) and 4.05 (dd, J7b,NH ꢄ 5.9 Hz, 1 H) (CH2NHAc), 5.02
(ddd, J3ax,4 ꢄ 12.5, J3eq,4 ꢄ 4.4, J4,5 ꢄ 2.7 Hz, 1 H, 4-H), 5.24—5.35 (m, 2 H,
1-H, 6-H), 5.57—5.35 (m, 1 H, 5-H), 6.43 (dd, 1 H, NH).
Anal. Calcd for C19H27NO11 (445.4): C, 51.23; H, 6.11; N, 3.14. Found:
C, 51.47; H, 6.22; N, 3.01.
Hexa-N,O-acetyl-3-(aminomethyl)-6-deoxy-D-myo-inositol (16a). A so-
lution of 9b (59 mg, 0.20 mmol) in aqueous 80% acetic acid (1.8 mL) was stirred
for 2 h at 50°C, and then concentrated to dryness. The residue was acetylated in the
preparation of 15a, and the product was chromatographed on a silica gel column (8
g; acetone/toluene, 1:5) to give 16a (55 mg, 66%) as a syrup: TLC (butanone/
toluene, 2:1) RF 0.59; IR (neat) 1750 (CO), 1680, 1520 (amide) cm-1; [ꢁ]D22 ꢂ52°
(c 0.92, CHCl3); 1H NMR (300 MHz, CDCl3) ꢆ 1.85—2.23 (m, 2 H, 6,6-H2), 1.90,
1.97, 2.04, 2.09, 2.14, and 2.23 (6 s, each 3 H, NAc, 5 ꢇ OAc), 3.16 (dd, J7a,NH
ꢄ 2.4, J7gem ꢄ 15.6 Hz, 1 H) and 4.26 (dd, J7b,NH ꢄ 10.3 HZ, 1 H) (CH2NHAc),
5.05 (ddd, J1,2 ꢄ 2.1, J1,6ax ꢄ 12.7, J1,6eq ꢄ 4.9 Hz, 1 H, 1-H), 5.18 (ddd, J4,5 ꢄ
9.9, J5,6ax ꢄ 11.7, J5,6eq ꢄ 5.4 Hz, 1 H, 5-H), 5.44 (d, 1 H, 4-H), 5.82 (d, 1 H, 2-
H), 6.67 (dd, 1 H, NH).
Anal. Calcd for C19H27NO11 (445.4): C, 51.23; H, 6.11; N, 3.14. Found:
C, 51.73; H, 6.12; N, 3.09.

ORDER
REPRINTS
(ꢀ)-epi-QUERCITOL
715
Hexa-[cf‘1]N,O-acetyl-1-(aminomethyl)-2-deoxy-D-chiro-inositol (17a).
A solution of 10b (29 mg, 0.095 mmol) in aqueous 80% acetic acid (0.9 mL) was
stirred for 3 h at 50°C, and then concentrated to dryness. The residue was acety-
lated as in the preparaion of 15a, and the product was chromatographed on a silica
gel column (4.5 g; acetone/hexane, 1:3) to give 17a (36 mg, 85%) as a syrup: TLC
(butanone/toluene, 2:1) RF 0.40; IR (neat) 1750 (CO), 1650, 1555 (amide) cm-1;
[ꢁ]2D2 ꢀ14° (c 1.1, CHCl3); H NMR (300 MHz, CDCl3) ꢆ 1.83—2.00 (m, 1 H,
1
2ax-H), 1.56, 1.88, 1.91, 2.10, and 2.12 (6 s, each 3 H, NAc, 5 ꢇ OAc), 2.61 (dd,
J2eq,3 ꢄ 4.8, J2gem ꢄ 13.9 Hz, 1 H, 2eq-H), 3.62—3.68 (m, 2 H, CH2NHAc), 5.00
(ddd, J2ax,3 ꢄ 12.0, J3,4 ꢄ 10.0 Hz, 1 H, 3-H), 5.09 (dd, J4,5 ꢄ 10.0, J5,6 ꢄ 3.2 Hz,
1 H, 5-H), 5.31 (dd, 1 H, 4-H), 5.49 (d, 1 H, 6-H), 6.15 (dd, J7a,NH ꢄ 6.0, J7b,NH ꢄ
6.4 Hz, 1 H, NH). HRMS (EI) m/z Calcd for C18H23NO11 (M ꢂCH3, ꢂH):
429.1270; Found 429.1269.
2-(Acetamidomethyl)-3-deoxy-L-neo-inositol (15b). A solution of 8b (25
mg, 0.080 mmol) in aqueous 80% acetic acid (0.75 mL) was stirred for 2 h at 50°C,
and then concentrated to give 15b (17 mg, 89%) as a white solid: TLC (1-bu-
tanol/acetic acid/H2O, 3:1:1) RF 0.35; IR (neat) 3410 (OH), 1655, 1565 (amide)
cm-1; [ꢁ]D21 ꢀ41° (c 0.54, H2O); 1H NMR (300 MHz, D2O) ꢆ 1.52—1.68 (m, 2 H,
3,3-H2), 1.87 (s, 3 H, Ac), 3.13 and 3.20 (ABq, Jgem ꢄ 14.3 Hz, CH2NHAc), 3.39
(d, J1,6 ꢄ 10.0 Hz, 1 H, 2-H), 3.57 (dd, J5,6 ꢄ 3.0 Hz, 1 H, 6-H), 3.79 (ddd, J3ax,4
ꢄ 8.6, J3eq,4 ꢄ 8.3, J4,5 ꢄ 2.7 Hz, 1 H, 4-H), 3.88 (dd, 1 H, 5-H).
3-(Acetamidomethyl)-6-deoxy-D-myo-inositol (16b). A solution of 9b
(18 mg, 0.058 mmol) in aqueous acetic acid 80% acetic acid (0.55 mL) was stirred
for 1.5 h at 50°C, and then concentrated. The residue was chromatographed on a
silica gel column (Disogel sp-60: 0.2 g; chloroform/MeOH, 3:1) to give 16b (12
mg, 88%) as a white solid: TLC (1-butanol/acetic acid/H2O, 3:1:1) RF 0.37; IR
(neat) 3380 (OH), 1635, 1560 (amide) cm-1; [ꢁ]D21 ꢀ22° (c 0.32, H2O); 1H NMR
(300 MHz, D2O) ꢆ 1.54 (ddd, J1,6ax ꢄ 12.1, J5,6ax ꢄ 11.7, J6gem ꢄ 12.0 Hz, 1 H,
6ax-H), 1.81—1.88 (m, 1 H, 6eq-H), 1.89 (s, 3 H, Ac), 3.30 and 3.42 (ABq, Jgem
ꢄ 14.4 Hz, CH2NHAc), 3.28 (d, J4,5 ꢄ 4.9 Hz, 1 H, 4-H), 3.50 (d, J1,2 ꢄ 3.2 Hz,
1 H, 2-H), 3.60 (ddd, J5,6eq ꢄ 4.9 Hz, 1 H, 5-H), 3.86 (ddd, 1 H, 3-H).
1-(Acetamidomethyl)-2-deoxy-D-chiro-inositol (17b). A solution of 10b
(21 mg, 0.065 mmol) in aqueous 80% acetic acid (0.62 mL) was stirred for 2 h at
50°C, and then concentrated. The residue was chromatographed on a silica gel col-
umn (Disogel sp-60: 0.2 g; chloroform/MeOH, 3:1) to give 17b (14 mg, 90%) as a
white solid: TLC (1-butanol/acetic acid/H2O, 3:1:1) RF 0.37; IR (neat) 3370 (OH),
1625, 1590 (amide) cm-1; [ꢁ]D21 ꢀ18° (c 0.47, H2O): 1H NMR (300 MHz, D2O) ꢆ
1.48 (dd, J2ax,3 ꢄ 11.7, J2gem ꢄ 13.6 Hz, 1 H, 2ax-H), 1.67 (dd, J2eq,3 ꢄ 4.9 Hz, 1
H, 2eq-H), 1.88 (s, 3 H, Ac), 3.07 and 3.26 (ABq, Jgem ꢄ 13.8 Hz, CH2NHAc),
3.36 (dd, J3,4 ꢄ 9.3, J4,5 ꢄ 9.8 Hz, 1 H, 4-H), 3.47—3.57 (m, 2 H, 3-H, 6-H), 3.59
(dd, J5,6 ꢄ 3.4 Hz, 1 H, 5-H).

ORDER
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716
OGAWA, AOYAMA, AND TEZUKA
2-(Aminomethyl)-3-deoxy-D-neo-inositol (15c). A solution of 8b (36 mg,
0.11 mmol) and 2 M hydrochloric acid (1 mL) was stirred for 5 h at 80°C, and then
concentrated. The product was chromatographed on a column of Dowex 50W 2
(Hꢀ) resin (1 mL) with 1% aqueous ammonia to give 15c (22 mg, ꢀ100%) as a
white powder: TLC (1-butanol/acetic acid/H2O, 4:1:1, twice development) RF
0.35; IR (neat) 3400 (OH), 1580 (amine) cm-1; [ꢁ]D20 ꢀ39° (c 0.55, H2O); 1H NMR
(300 MHz, D2O) ꢆ 1.52—1.68 (m, 2 H, 3,3-H2), 2.55 and 2.72 (ABq, Jgem ꢄ 13.6
Hz, CH2NHAc), 3.43 (dd, J1,6 ꢄ 13.4, J5,6 ꢄ 9.8 Hz, 1 H, 6-H), 3.58 (dd, J4,5
ꢄ 2.7 Hz, 1 H, 5-H), 3.82 (ddd, J3ax,4 ꢄ 13.9, J3eq,4 ꢄ 5.4 Hz, 1 H, 4-H), 3.87—
3.92 (m, 1 H, 1-H).
3-(Aminomethyl)-6-deoxy-D-myo-inositol (16c). A solution of 9b (30
mg, 0.094 mmol) and 2 M hydrochloric acid (1 mL) was stirred for 3 h at 80°C,
and then concentrated. The product was chromatographed on a column of Dowex
50W 2 (Hꢀ) resin (1 mL) with 1% aqueous ammonia to give 16c (15 mg, 85%) as
a white powder: TLC (1-butanol/acetic acid/H2O, 4:1:1, twice development) RF
0.34; IR (neat) 3350 (OH), 1580 (amine) cm-1; [ꢁ]D20 ꢀ1.8° (c 0.56, H2O); 1H NMR
(300 MHz, D2O) ꢆ 1.54 (ddd, J1,6ax ꢄ 11.7, J5,6ax ꢄ 11.7, J6gem ꢄ 12.2 Hz, 1 H,
6ax-H), 1.85 (ddd, J1,6eq ꢄ 5.4, J5,6eq ꢄ 4.6 Hz, 1 H, 6eq-H), 2.74 and 2.81 (ABq,
Jgem ꢄ 13.9 Hz, CH2NHAc), 3.28 (d, J4,5 ꢄ 9.3 Hz, 1 H, 4-H), 3.52—3.67 (m, 2
H, 2-H, 5-H), 3.88 (ddd, J1,2 ꢄ 2.9 Hz, 1 H, 1-H).
1-(Aminomethyl)-2-deoxy-D-chiro-inositol (17c). A solution of 10b (19
mg, 0.061 mmol) and 2 M hydrochloric acid (1 mL) was stirred for 9 h at 80°C,
and then concentrated. The product was chromatographed on a column of Dowex
50W 2 (Hꢀ) resin (1 mL) with 1% aqueous ammonia to give 17c (12 mg, ꢀ100%)
as a white powder: TLC (1-butanol/acetic acid/H2O, 4:1:1, twice development) RF
0.25; IR (neat) 3350 (OH), 1575 (amine) cm-1; [ꢁ]D20 ꢀ7.1° (c 0.65, H2O); 1H NMR
(300 MHz, D2O) ꢆ 1.44 (dd, J2ax,3 ꢄ 11.7, J2gem ꢄ 13.6 Hz, 1 H, 2ax-H), 1.71 (dd,
J2eq,3 ꢄ 4.2 Hz, 1 H, 2eq-H), 2.56 and 2.67 (ABq, Jgem ꢄ 13.8 Hz, CH2NHAc),
3.37 (dd, J3,4 ꢄ 9.3, J4,5 ꢄ 9.3 Hz, 1 H, 4-H), 3.88 (m, 3 H, 3-H, 5-H, 6-H).
ACKNOWLEDGMENTS
The authors thank Miss L. Zao for performing elementary analyses, and Drs.
A. Takahashi and K. Sato (Hokko Chemical Industry Co. Ltd., Atsugi, Japan) for
providing us with (ꢀ)-epi-quercitol and for carrying out a part of the biological as-
say.
REFERENCES
1. Dedicated to Prof. Joachim Thiem on the occasion of his 60th anniversary.
2. Takahashi, A.; Kanbe, K.; Tamamura, T.; Sato, K. The First International Sympo-
sium on Disease Prevention by IP6 and Other Rice Components, Kyoto, June 8–9,

ORDER
REPRINTS
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sion of myo-inositol to Rare Cyclic Sugar Alcohols. Anticancer Res. 1999, 3807.
3. Ogawa, S.; Uetsuki, Y.; Tezuka, Y. Synthesis and Evaluation of Glucocerebrosidase
Inhibitory Activity of Anhydro Deoxyinositols from (ꢀ)-epi- and (-)-vibo-Querci-
tols. Bioorg. Med. Chem. Lett. 1999, 9, 1493–1498.
4. Kameda, Y.; Asano, N.; Yoshikawa, M.; Takeuchi, M.; Yamaguchi, T.; Matsui, K.;
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Kameda, Y.; Asano, N.; Takeuchi, M.; Yamaguchi, T.; Matsui, K.; Horii, S.; Fukase,
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lamine through Ring Expansion of 5-Amino-2,3,4-trihydroxycyclopentane-1-one
derivatives with Diazomethane. Carbohydr. Lett. 1999, 3, 277–284.
6. The structures of 2a—4a were further confirmed on the basis of the 1H NMR spectra
(300 MHz, CDCl3) of their corresponding tosyl esters:3 the signals due to the hydro-
gen atoms on the carbons bearing the tosyloxy groups appeared at ꢆ 4.83, 4.76, and
4.82 as a ddd (J4,5 ꢄ 7.5, J5,6 ꢄ 10.5, J5,6eq ꢄ 3.1 Hz), a dd (J2,3 ꢄ 4.1, J3,4 ꢄ 10.2
Hz), and a ddd (J1,2 ꢄ 3.6, J1,6ax ꢄ 7.8, and J1,6eq ꢄ 3.6 Hz), respectively.
7. A complex mixture of products was formed when catalysts other than Raney nickel
were used.
8. The reaction conditions have not fully optimized to furnish the spiro epoxides selec-
tively.
9. The ring expansion products were formed preferentially when the reaction was car-
ried out in diethyl ether.4
10. Uchida, C.; Kimura, H.; Ogawa, S. Synthesis and Biological Evaluation of Potent
Glycosidse Inhibitors: N-Phenyl Cyclic Isourea Derivatives of 5-Amino- and 5-
Amino-C-(hydroxymethyl)-1,2,3,4-cyclopentanetetraols. Bioor. Med. Chem. 1997,
5, 921–939.
11. Biological assay toward sucrase and maltase was carried out by Dr. A. Takahashi.
12. Very recently, 5a-carba-L-fucopyranose derivatives, having a branched-aminomethyl
function at C-1, have been demonstrated to possess a strong inhibitory activity against
ꢁ-L-fucosidase (bovine kidney): Ogawa, S.; Maruyama, A.; Odagiri, T.; Yuasa, H.;
Hashimoto, H. Synthesis and Biological Evaluation of ꢁ-L-Fucosidase Inhibitors: 5a-
Carba-ꢁ-L-fucopyranosylamine and Related Compounds. Eur. J. Org. Chem. 2001,
967–974.
13. (ꢀ)-epi-Quercitol was provided by Drs. A. Takahashi and K. Sato: colorless crystals:
mp 190—192°C (from H2O/EtOH); [ꢁ]D23 ꢀ7°(c 1.0, H2O).
Received March 14, 2001
Accepted Septemeber 12, 2001

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