Convenient synthesis of (+)-valiolamine and (-)-1-epi-valiolamine from (-)-vibo-quercitol

Article abstract of DOI:10.1039/b314795a

The synthesis of (+)-valiolamine and (-)-1-epi-valiolamine using bioconversion of (-)-vibo-quercitol was investigated. The quercitols were separated and purified by combination of chromatography on ion-exchange-resin columns and recrystallization. Valiolamine was isolated from fermentation broth of antibiotic validamycins. The obtained crude ketone was subjected to C-C bond formation conditions in which diazomethane was considered adequate in polar and protic solvsnts.

Full text of DOI:10.1039/b314795a

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Convenient synthesis of (؉)-valiolamine and (؊)-1-epi-valiolamine
from (؊)-vibo-quercitol
Seiichiro Ogawa,*a Yo Ohishi,a Miwako Asada,a Akihiro Tomoda,b Atsushi Takahashi,b
Yoriko Ooki,c Midori Mori,c Masayoshi Itohc and Takashi Korenagac
a Department of Biosciences and Informatics, Faculty of Science and Technology,
Keio University, Hiyoshi, Kohoku-ku, Yokohama, 223-8522, Japan
b Central Research Laboratories, Hokko Chemical Industry Co. Ltd., Toda, Atsugi, 243-0023,
Japan
c Department of Chemistry, Tokyo Metropolitan University, Minami-Ohsawa, Hachioji, Tokyo,
192-0397, Japan
Received 20th November 2003, Accepted 5th January 2004
First published as an Advance Article on the web 18th February 2004
Convenient and practical synthesis of (ϩ)-valiolamine and (Ϫ)-1-epi-valiolamine from (Ϫ)-vibo-quercitol,
1-deoxy--myo-inositol, readily obtained by bioconversion of myo-inositol, is described.
myo-Inositol is the most abundant cyclitol occurring in nature.
Among nine stereoisomers, seven are meso compounds. There-
fore, synthetic studies of inositol derivatives of biological inter-
est have often been accompanied by some difficulty in obtaining
the desired optically active compounds. When myo-inositol is
chosen as a starting material, chemical synthesis featuring
modification and/or substitution of one of the four hydroxyl
groups on C-1(3) and 4(6) leads to compounds of racemic
modification. Their optical resolution is needed at an early
stage of the preparative processing, with determination of abso-
lute structures. Bioconversion of inositols has therefore been a
very attractive route to provide several optically pure raw
materials for cyclitol synthesis (Fig. 1), although some problems
have arisen in isolation and purification of the desired com-
pounds when complex mixtures of products are formed.
deoxyinosose 3, from which a convenient and practical syn-
thesis of biologically important valiolamine (1) can be carried
out.
Valiolamine4 1 was first isolated from fermentation broth of
antibiotic validamycins, later being found5,6 to be one of the
components of validamycin G. The absolute structure was
established by comparison7 with that of validamine. Since 1
very strongly inhibits α-glucosidase and maltase,4 its chemical
modification has been extensively investigated, leading to the
preparation of the N-(1,3-dihydroxyprop-2-yl) derivative,8
a
clinically very useful agent for control of diabetes. Several
syntheses of 1 have already been accomplished, starting from
the Diels–Alder endo-adduct9 of furan and acrylic acid,
-glucose,10,11 -quinic acid,12 and -arabinose.13
1-(1,2,4/3,5)-1,2,3,4,5-Cyclohexanepentol1,13 (2), (Ϫ)-vibo-
quercitol, which can readily be obtained by stereospecific
microbial dehydration of myo-inositol, is biochemically oxid-
ized under the influence of Gluconobacter sp. AB10277 to
produce about 80% yield of crude 2-deoxy-scyllo-inosose,14
2-(2,4/3,5)-2,3,4,5-tetrahydroxycyclohexan-1-one (3), [α]25
Ϫ27Њ (H2O) (Scheme 1). Based on its H-NMR spectral data,
D
1
this compound was shown to be a mixture of the keto and
hydrate forms in water, but the former seems to be the major
component in DMSO. Although several synthetic procedures
are possible for C–C bond formation at the keto function of
cyclitol derivatives, protection of their hydroxyl groups is usu-
ally indispensable for carrying out the process successfully. In
fact, under direct protection such as conventional acylation or
etherification, inososes often suffer serious structural changes
via epimerization and/or elimination. Therefore, we attempted
to subject the crude ketone directly to simple C–C bond-
formation conditions, among which a reaction with diazo-
methane would be considered to be adequate in polar and
protic solvents. Treatment of 3 with 2 molar equiv. of diazo-
methane–diethyl ether was carried out in methanol for 7 h at
room temperature. On addition of excess diethyl ether, a sole
spiro epoxide 4 crystallized out from the reaction mixture in
44% yield. Isolated yields are rather variable,15 partly depending
on a ratio of the keto- and hydrate-forms of 3 in the reaction
medium. Diazomethane is likely to attack the carbonyl group at
the rear of the adjacent 2-hydroxyl group in an equatorial
orientation. Hydrolysis of 4 with 3 M aqueous potassium
hydroxide for 6 h at 100 ЊC gave, after chromatography, a crys-
talline (Ϫ)-β-valiol 5 in 32% yield. On the other hand, nucleo-
philic substitution of 4 with excess of sodium acetate in 80%
aqueous DMF for 3 h at 120 ЊC afforded, after acetylation with
acetic anhydride in pyridine, the penta-O-acetyl derivative 6
Fig. 1 (ϩ)-Valiolamine and preparation of (Ϫ)-vibo-quercitol by
bioconversion of myo-inositol.
Recently, bio-deoxygenation of myo-inositol has successfully
been carried out employing bacterial strains1 to produce mainly
(Ϫ)-vibo-quercitol 2, together with (ϩ)-epi and (ϩ)-proto-
quercitol. These quercitols, or deoxyinositols, can be readily
separated and purified by a combination of chromatography on
ion-exchange-resin columns and subsequent recrystallization,
and the major product, (Ϫ)-vibo-quercitol is now commercially
available. We have become interested in application of these
optically pure cyclitols as sources for the development of bio-
logically active compounds.2,3 In this paper, we describe recent
results regarding bioconversion of 2 to the optically active
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
884

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subjected to conventional isopropylidenation conditions using
2-methoxypropene, expecting preferential formation of the
cis-1,2-O-isopropylidene group. Although generation of two di-
O-isopropylidene derivatives was observed, these compounds
were not sufficiently stable for the usual purification using a
silica gel column. When 1,1-dimethoxycyclohexane was used as
an acetalation reagent, surprisingly, the major product was
found to be the 2,3:4,5-di-O-cyclohexylidene derivative (∼80%).
Then, benzylidenation of 5 was carried out by treatment with
α,α-dimethoxytoluene and TsOHؒH2O in dry DMF for 4 h at
room temperature, giving the desired 2,7-O 7 (59%) and a spiro-
type 1,7-O-benzylidene derivative 9 (26%). Compounds 7 and 9
were converted into the tri- 8 and tetra-O-acetyl derivatives 10,
respectively, and their structures confirmed.
Compound 9 was convertible to 7 by regeneration of 5,
followed by benzylidenation.
Treatment of 7 with 2.5 molar equiv. of 2-methoxypropene
in the presence of TsOHؒH2O in DMF for 4 h at room
temperature gave a mixture of the products, which were easily
fractionated on a silica gel column to give the 3,4-11 and 4,5-O-
isopropylidene derivatives17,18 14 in 41% and 36% yields,
respectively, their structures being established by converting
them into the acetyl derivatives 12 and 15, respectively.
Treatment of 11 with excess p-toluenesulfonyl chloride in
pyridine gave the tosylate 13 (∼100%). Direct nucleophilic sub-
stitution of 13 with an azide anion in the presence of 15-crown-
5 ether in DMF proceeded smoothly at 120 ЊC to afford a single
azide 16 (88%) selectively. Formation of elimination products
was not observed. Hydrogenation of 16 with Raney nickel
catalyst in ethanol in the presence of excess acetic anhydride
gave the amide 17 (76%). This compound was deacylated with
2 M hydrochloric acid at 80 ЊC to give, after purification over a
column of Dowex 50 W × 2 (Hϩ) resin with 5% aqueous
ammonia, valiolamine 1 (90%) as a syrup. Synthetic valiol-
amine was further characterized as the penta-N,O-acetyl deriv-
1
ative 18. Physical data, including H and 13C-NMR spectral
data,6 were shown to be identical with those of authentic sam-
ples. Thus, (ϩ)-valiolamine 1 could be readily synthesized from
the crude deoxyinosose 3 through conventional processing in
more than 10% total yield.
The 1-epimer11 (β-valiolamine) 23 of 1 was also prepared
from the tosylate 13. Hydrolysis of 13 followed by conven-
tional acetylation gave the tetra-acetyl tosylate 19 (Scheme 2).
Treatment of 19 with sodium azide in aqueous 90% 2-methoxy-
ethanol proceeded via formation of an intermediate acetoxo-
nium ion by neighboring participation of 4-acetoxyl at C-4 to
give rise to two products, the 5-azide 20 (65%) and the 4-azide
21 (28%). Compound 20 was similarly hydrogenolyzed and the
penta-N,O-acetyl derivative 22 (68%) obtained converted into
the free amine 23, which showed medium inhibitory activity
toward α-glucosidase.
The present synthesis demonstrates that optically active
inositol derivatives generated by biogenesis of myo-inositol are
promising key intermediates for the preparation of biologically
interesting carba-amino sugar derivatives. The first syntheses of
two racemic 5a-carba-hexopyranoses from myo-inositol were
reported by Suami19 and one of us some time ago. Ready acces-
sibility of a quantity of the key-intermediate spiro-epoxide 4
would much improve the previous route employed, being gen-
erally applicable for provision of optically pure 5a-carba-sugars
and their derivatives. Compound 4 has also been successfully
transformed20 into the useful 5-methylene compound almost
quantitatively.
Scheme 1 Synthesis of (ϩ)-valiolamine (1) from (Ϫ)-vibo-quercitol
(2). Reagents and conditions: (a) Gluconobacter sp. AB 10277;
(b) CH2N2/Et2O, MeOH; (c) 3 M aqueous KOH, 100 ЊC; (d) NaOAc,
80% aqueous DMF; NaOMe/MeOH; (e) Ac2O, pyridine;
(f ) PhCH(OMe)2, TsOHؒH2O, DMF, 50 ЊC; (g) 2-methoxypropene (2.5
molar equiv.), TsOHؒH2O, DMF, room temperature; (h) TsCl, pyridine;
(i) NaN3 (4 molar equiv.), DMF, 120 ЊC; (j) H2, Raney Ni, EtOH, Ac2O;
(k) 2 M HCl; Dowex 50W × 2 (Hϩ) resin, aqueous 1% NH3.
(∼100%), which was treated with methanolic sodium methoxide
to give 5 quantitatively. The 1H NMR spectral data were shown
to be identical with those of known racemic16 6. These results
also verified both the proposed absolute configuration of 3 and
the stereochemistry of the spiro-epoxide 4. Thus, optically
active (Ϫ)-β-valiol 5 is readily available in large scale from myo-
inositol through a standard sequence of reactions.
Our aim was to establish a simple synthesis of biologically
valuable valiolamine 1 from 5. The important key-step was con-
sidered to be incorporation of an amino function at C-5 by
replacement of the 5-hydroxyl group via Walden-inversion.
In the initial attempts to provide 5-hydroxyl unprotected
derivatives, the primary hydroxyl group was first blocked by
a triphenylmethyl group and the trityl ether obtained was
Experimental
General methods
Melting points were determined with a Yanagimoto melting
point apparatus MP-S3 and are uncorrected. Optical rotations
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
885

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the ketone 3 (ca. 200 g, 80%), as a white powder, the 13C-NMR
spectrum (D2O, 75 MHz) of which was superimposed to those
of racemic 2-deoxy-scyllo-inosose.14 The 1H NMR spectral data
(in D2O) indicated the presence of two types of compounds,
presumably the keto- and hydrate-forms, however the signals
due to the keto-form were only observed when it was measured
in (CD3)2SO.
[α]25D = Ϫ27 (c = 1.0, H2O); 1H-NMR [300 MHz, (CD3)2SO]:
δ 2.33 (dd, 1 H, J 5.1 and 13.6 Hz, H-6eq), 2.53 (td, 1 H, J 1.3,
13.6 and 13.6 Hz, H-6ax), 3.02 (dd, 1 H, J 8.6 and 9.9 Hz, H-3),
3.30 (m, 1 H, J 5.1, 9.9 and 13.6 Hz, H-5), 3.40 (t, 1 H, J 8.6
and 9.9 Hz, H-4), 3.97 (dd, J 1.3 and 9.9 Hz, H-2); (in D2O)
(inter alia): δ 1.69 (dd, 0.3 H, J 10.0 and 10.5 Hz, H-6ax,
hydrate), 2.21 (dd, 0.3 H, J 4.5 and 10.5 Hz, H-6eq, hydrate),
2.73 (d, 0.7 H, J 0.5 Hz, H-6ax, keto), 2.77 (br s, 0.7 H, H-6eq,
keto), 3.63 (ddd, 0.3 H, J 5.0, 6.9, and 9.0 Hz, H-5, hydrate),
3.79 (dd, 0.7 H, J 9.2 and 9.2 Hz, H-4, keto), 4.34 (dd, 0.7 H,
J 0.5 and 10.1 Hz, H-2, keto); 13C-NMR [75 MHz, (CD3)2SO]:
δ 206.14 (C-1), 78.16 (C-2), 76.74 (C-4), 74.81 (C-3), 68.51 (C-
5), 45.28 (C-6); (in D2O): 207.74 (C-1), 94.11 (C-1, hydrate),
78.66 (C-2,), 77.82 (C-2 or 3, hydrate), 77.08 (C-3 or 2, hydrate),
76.88 (C-4), 74.68 (C-3), 74.36 (C-3, hydrate), 69.30 (C-5,
hydrate), 69.02 (C-5), 44.99 (C-6), 41.48 (C-6, hydrate); ITMS-
ESI (negative mode): m/z 143 [M Ϫ H2O Ϫ H]Ϫ, 161 [M Ϫ H]Ϫ.
(3S,4S,5R,6S,7R)-4,5,6,7-Tetrahydroxy-1-oxaspiro[2,5]octane
4
Scheme 2 Synthesis of (Ϫ)-1-epi-valiolamine from the tosylate 13.
Reagents and conditions: (a) 2 M HCl, 60 ЊC; Ac2O, pyridine; (b) NaN3
(4 molar equiv.), aqueous 90% MeOCH2OH, 120 ЊC; (c) H2, Raney Ni,
EtOH, Ac2O; (d) 2 M HCl, Dowex 50W × 2 (Hϩ) resin, 1% aqueous
NH3.
To a stirred solution of crude ketone 3 (20.0 g, 0.123 mmol) in
methanol (300 mL) was added cautiously dropwise diazo-
methane etherate (ca. 0.8 M, 160 mL) over 0.5 h under ice
cooling. An additional amount of the reagent (4 × 40 mL) was
added portionwise in the interval of 1 h. Stirring was further
continued until turbidity of the mixture turned clear. Diethyl
ether (400 mL) was added and an insoluble material was
removed by filtration and the filtrate was allowed to stand in a
refrigerator overnight. Crystalline product was collected by fil-
tration and washed thoroughly with diethyl ether to give the
were measured with a JASCO DIP-370 polarimeter, and [α]D
1
values are given in 10Ϫ1 deg cm2 gϪ1. H NMR spectra were
recorded for solutions in deuteriochloroform and deuterio-
methanol with internal tetramethylsilane (TMS) as a reference
with a JEOL JNM LAMDA-300 (300 MHz) instrument. 13C
NMR spectra were recorded with the same instrument
(75 MHz). IR spectra were recorded with a JASCO IR-810 or a
HITACHI Bio-Rad Digital Lab FTS-65 spectrometer. Mass
spectra were determined with a HITACHI M-8000 ion trap
mass spectrometer using electrospray ionization (ESI) and
atmospheric pressure chemical ionization (APCI). TLC was
performed on silica gel 60 F-254 (E. Merck, Darmstadt). The
silica gel used for a column chromatography was Wakogel
C-300 (Wako Junyaku Kogyo Co., Osaka, 200–300 mesh) or
silica gel 60 KO (Katayama Kagaku Kogyo Co., Osaka, 70–230
mesh). Organic solutions were dried over anhydrous Na2SO4
and concentrated at >45 ЊC under diminished pressure. New
compounds synthesized are more or less hygroscopic. Final
characterization of all the compounds has therefore been done
by mass spectra using ESI.
spiro epoxide 4 (9.7 g, 44%) as a hygroscopic powder, [α]20
=
D
1
Ϫ1.3 (c 7.4, MeOH), Ϫ37 (c 0.72, H2O); H-NMR (300 MHz,
CD3OD) δ 3.63 (d, 1 H, J 9.4 Hz, H-2), 3.58 (m, 1 H, H-5), 3.34
(m, 1 H, H-3), 3.28 (m, 1 H, H-4), 2.97, 2.56 (2 d, each 1 H,
J 5.1 Hz, CH2O), 1.95 (dd, 1 H, J 11.7 and 13.8 Hz, H-6ax),
1.55 (dd, 1 H, J 5.1 and 13.8 Hz, H-6eq); 13C-NMR (75 MHz,
CD3OD): δ 37.78 (C-8), 48.70 (C-2), 58.71 (C-3), 70.95
(C-7), 71.33 (C-4), 76.71 (C-5), 78.91 (C-6); ITMS-APCI
(negative mode): m/z 157 [M Ϫ H2O Ϫ H]Ϫ, 175 [M Ϫ H]Ϫ, 193
[M ϩ H2O Ϫ H]Ϫ.
Practically, a crude syrupy 4 (8.86 g, purity: ∼82%) was
prepared from the crude ketone 3 (8.11 g, 50 mmol) by evapor-
ation of the diethyl ether solution obtained by filtration of the
reaction mixture.
2L-(2,4/3,5)-2,3,4,5-Tetrahydroxycyclohexan-1-one 3
1L-(1,2,4/3,5)-1-C-(Hydroxymethyl)-1,2,3,4,5-cyclohexane-
pentol [1-C-(hydroxymethyl)-(؊)-vibo-quercitol, (؊)-ꢀ-valiol] 5
Compound 3 was prepared by the microbial conversion of
1-(1,2,4/3,5)-1,2,3,4,5-cyclohexanepentaol (Ϫ)-vibo-quercitol
2, which was easily obtained by stereospecific microbial
dehydration1 of myo-inositol.
The epoxide 4 (20.56 g, 0.116 mol) was dissolved in 3 M aque-
ous potassium hydroxide (20 mL) and the mixture was stirred
for 6 h at 100 ЊC. After cooling, the mixture was filtered through
a column of CM-sephadix (100 mL) and washed with water
(300 mL) thoroughly. The filtrate and washings were combined
and concentrated to 50 mL and the solution was taken up on a
column of active carbon (200 mL). Evaporation of the main
fraction gave a syrup which was crystallized from aqueous
A slant culture of Gluconobacter sp. AB10277, which was
deposited in the National Institute of Advanced Industrial
Science and Technology, Japan, with accession number of
FERMP-19320, was inoculated into 100 mL (total volume is
5 L) of the medium consisting of compound 2 (5%), -glucose
(0.5%), yeast extract (0.4%), (NH4)2SO4 (0.1%), K2HPO4
(0.7%), KH2PO4 (0.2%), and MgSO4ؒ7H2O (0.01%) (pH 7.0
before autoclaving), and the mixture was incubated for 72 h at
27 ЊC. The supernatant (5 L) combined was successively passed
through columns of Duolite C-20 (Hϩ, Sumitomo Chemical
Co., Ltd.), activated charcoal, and Duolite A368S (OHϪ, Sumi-
tomo Chemical Co., Ltd.). The eluent was evaporated to give
methanol to give 5 (7.21 g, 32%) as colorless prisms : [α]20
=
D
1
Ϫ21 (c = 3.3, MeOH), mp 188–189 ЊC; H-NMR (300 MHz,
D2O): δ 1.33 (dd, 1 H, J 11.9 and 13.8 Hz, H-6ax), 1.95 (dd, 1 H,
J 4.8 and 13.8 Hz, H-6eq), 3.07 (t, 1 H, J 9.4 Hz, H-4), 3.25 (d,
1 H, J 9.5 Hz, H-2), 3.29 (d, 1 H, J 11.4 Hz, H-7), 3.37 (t, 1 H,
J 9.4 Hz, H-3), 3.37 (d, 1 H, J 11.4 Hz, H-7), 3.56 (ddd, 1 H,
J 5.0, 9.4 and 11.9 Hz, H-5); 13C-NMR (75 MHz, CD3OD):
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
886

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δ 37.29 (C-6), 66.40 (C-7), 69.25 (C-5), 73.73 (C-2), 74.39 (C-3),
74.52 (C-1), 77.90 (C-4); ITMS-ESI (negative mode): ITMS-
ESI (negative mode): m/z 193 [M Ϫ H]Ϫ.
temperature. After addition of methanol (0.5 mL), the reaction
mixture was evaporated and the residual product was chrom-
atographed on a silica gel column (4 g, acetone–hexane 1 : 2) as
eluent to give 8 (38 mg, 92%) as crystals: [α]20 = Ϫ35 (c = 1,
D
MeOH), mp 226–229 ЊC; 1H-NMR (300 MHz, CDCl3): δ 7.45–
7.43 (m, 5 H, Ph), 5.54 (s, 1 H, PhCH ), 5.51 (dd, 1 H, J 9.6 and
9.8 Hz, H-10), 5.42 (ddd, 1 H, J 5.2, 9.6 and 11.6 Hz, H-8), 5.20
(dd, 1 H, J 9.6 and 9.6 Hz, H-9), 3.96 (d, 1 H, J 11.2 Hz, H-5),
3.81 (d, 1 H, J 9.8 Hz, H-1), 3.79 (d, 1 H, J 11.2 Hz, H-5), 2.20
(dd, 1 H, J 5.2 and 13.2 Hz, H-7eq), 2.04 (s, 3 H, Ac), 2.04
(s, 3 H, Ac), 2.02 (s, 3 H, Ac), 1.40 (dd, 1 H, J 11.6 and 13.2 Hz,
H-7ax); 13C-NMR [75 MHz, (CD3)2CO]: δ 20.54, 20.65, 20.76
(3 × CH3CO), 33.62 (C-7), 66.94 (C-6), 70.13 (C-8), 71.71
(C-10), 74.40 (C-9), 75.86 (C-5), 81.00 (C-1), 102.37 (C-3),
127.22 (C-3Ј, 5Ј), 128.75 (C-2Ј, 6Ј), 129.57 (C-4Ј), 138.91 (C-1Ј),
170.07, 170.14, 171.00 (3 × CH3CO); ITMS-ESI (positive
mode): m/z 431 [M ϩ Na]ϩ, 447 [M ϩ K]ϩ.
1L-(1,2,4/3,5)-1-C-(Acetoxymethyl)-2,3,4,5-tetra-O-acetyl-
1,2,3,4,5-cyclohexanepentol [penta-O-acetyl-(؊)-ꢀ-valiol] 6
A solution of 4 (0.10 g, 0.57 mmol) and anhydrous sodium acet-
ate (0.37 g) in 80% aqueous DMF (2.0 mL) was stirred for 3 h at
80 ЊC. The mixture was evaporated and the residue was treated
with acetic anhydride (1.3 mL) and pyridine (2.5 mL) for 13 h at
room temperature. After addition of methanol (0.5 mL), the mix-
ture was evaporated and the residue was chromatographed on a
column of silica gel (25 g, acetone–hexane 1 : 7) as eluent to give
6 (0.24 g, ∼100%) as crystals: [α]20 = Ϫ22 (c = 1.1, MeOH), mp
D
129–131 ЊC; 1H-NMR (300 MHz, CDCl3): δ 5.43 (dd, 1 H, J 9.6
and 9.6 Hz, H-3), 5.28 (ddd, 1 H, J 4.9, 9.8 and 11.6 Hz, H-5),
5.17 (dd, 1 H, J 9.6 and 9.8 Hz, H-4), 5.10 (d, 1 H, J 9.6 Hz, H-2),
3.96 (d, 1 H, J 11.4 Hz, H-7), 3.82 (d, 1 H, J 11.4 Hz, H-7), 2.26
(dd, 1 H, J 4.9 and 13.8 Hz, H-6eq), 2.06, 2.05, 1.99, 1.96 (4 s, 3,
3, 6, 3 H, 5 × Ac), 1.69 (dd, 1 H, J 11.6 and 13.8 Hz, H-6ax);
13C-NMR (75 MHz, CD3OD): δ 20.48, 20.53, 20.56, 20.64, 20.76
(5 × CH3CO), 36.12 (C-6), 67.09 (C-7) 70.20 (C-5), 72.61 (C-3),
72.75 (C-1), 73.46 (C-2), 74.75 (C-4), 171.49, 171.53, 171.58,
171.64, 172.10 (5 × CH3CO); ITMS-ESI (positive mode): m/z 427
[M ϩ Na]ϩ, 443 [M ϩ K]ϩ.
(2R,5S,6S,7R,8S,9R)- and (2S,5S,6S,7R,8S,9R)-6,7,8,9-
Tetraacetoxy-2-phenyl-1,3-dioxaspiro[4.5]decane 10a,b
The mixture (28 mg, 0.144 mmol) of 9a,b was treated with acetic
anhydride (0.5 mL) and pyridine (1.0 mL) in the usual manner.
The products were purified by silica gel chromatography (4 g,
acetone–hexane 2 : 5) to give a diastereoisomeric mixture (32 mg,
72%) of 10a,b (3.5 : 1): Rf 0.20 (acetone–hexane 2 : 5).
Conventional de-O-acetylation of 6 with methanolic sodium
methoxide in methanol afforded 5 quantitatively.
For 10a: 1H-NMR (300 MHz, CD3OD): δ 5.99 (s, 1 H, H-2),
4.00 and 3.90 (ABq, each 1 H, J 8.8 Hz, 2 × H-4); for 10b: δ 5.94
(s, 1 H, H-2), 4.12 and 3.80 (ABq, each 1 H, J 8.8 Hz, 2 × H-4);
ITMS-ESI (positive mode): m/z 473 [M ϩ Na]ϩ, 489 [M ϩ K]ϩ.
(1S,3R,6S,8R,9S,10R)-3-Phenyl-2,4-dioxabicyclo[4.4.0]decane-
6,8,9,10-tetrol 7, and (2R,5S,6S,7R,8S,9R)- and (2S,5S,6S,7R,
8S,9R)-2-phenyl-1,3-dioxaspiro-[4.5]decane-6,7,8,9-tetrol 9a,b
(1S,2S,4R,7S,9R,10S )-12,12-Dimethyl-4-phenyl-3,5,11,13-
tetra-oxatricyclo[8.3.0.02,7]tridecane-7,9-diol 11 and (1R,2S,3S,
5R,8S,10R)-12,12-dimethyl-5-phenyl-4,6,11,13-tetra-
oxatricyclo[8.3.0.03,8]tridecane-2,8-diol 14
To a solution of 6 (5.77 g, 14.3 mmol) in methanol (90 mL) was
added 1 M methanolic sodium methoxide (10 mL), and the
mixture was stirred for 1 h at room temperature. The mixture
was neutralized with Amberlite 1R B-120 (Hϩ) resin and then
evaporated to dryness. The residue was dissolved in dimethyl-
formamide (41 mL), to which were added α,α-dimethoxytoluene
(6.34 ml, 42.8 mmol) and p-toluenesulfonic acid monohydrate
(0.54 g, 2.9 mmol), and the mixture was stirred for 3 h at 50 ЊC.
After neutralization with triethylamine, the reaction mixture
was evaporated and the residue was chromatographed on a
To a solution of 7 (1.76 g, 6.23 mmol) in DMF (35 mL) was
added 2-methoxypropene (1.49 ml, 15.6 mmol) and TsOHؒH2O
(1.12 g, 0.62 mmol), and the mixture was stirred for 4 h at room
temperature. After neutralization with triethylamine, the mix-
ture was evaporated and the residue was chromatographed on a
column of silica gel (200 g, ethyl acetate–hexane 2 : 3
3 : 2) as
eluent to give the isopropylidene derivatives 11 (0.82 g, 41%) as
column of silica gel (400 g, chloroform–methanol 5 : 1
12 : 1)
crystals and 14 (0.73 g, 36%) as crystals.
as eluent to give 7 (2.37 g, 59%) as a colorless syrup: Rf 0.32
(n-butanol–acetic acid–H2O 2 : 1 : 1), and a diastereoisomeric
mixture (1.04 g, 26%) of 9a,b.
For 11: [α]20D = Ϫ37 (c = 1, MeOH), mp 182–186 ЊC; 1H-NMR
(300 MHz, CD3OD): δ 7.48–7.24 (m, 5 H, Ph), 5.56 (s, 1 H,
PhCH ), 4.05 (ddd, 1 H, J 4.7, 10.0 and 10.4 Hz, H-9), 3.80 (m,
2 H, 2 × H-4), 3.34 (dd, 1 H, J 10.0 and 10.0 Hz, H-10), 1.80 (dd,
1 H, J 4.7 and 13.3 Hz, H-8eq), 1.35, 1.32 (2 s, each 3 H, CMe2),
1.21 (dd, 1 H, J 10.4 and 13.3 Hz, H-8ax); 13C-NMR (75 MHz,
CD3OD): δ 27.06 (C-1Љ, 2Љ), 39.07 (C-8), 68.14 (C-9), 69.34 (C-7),
76.85 (C-2, 6), 82.49 (C-1), 84.25 (C-10), 103.01 (C-4), 112.25
(C-12), 127.52 (C-3Ј, 5Ј), 129.05 (C-2Ј, 6Ј), 129.94 (C-4Ј), 139.15
(C-1Ј); ITMS-ESI (positive mode): m/z 345 [M ϩ Na]ϩ.
For 7: [α]20 = Ϫ32 (c = 1.2, MeOH), mp 220–222 ЊC;
D
1H-NMR (300 MHz, CD3OD): δ 7.51–7.24 (m, 5 H, Ph), 5.50
(s, 1 H, PhCH ), 3.79 (ddd, 1 H, J 5.1, 9.0 and 11.5 Hz, H-8),
3.73 (br s, each 1 H, 2 × H-5), 3.66 (dd, 1 H, J 9.2 and 9.4 Hz,
H-10), 3.50 (d, 1 H, J 9.4 Hz, H-1), 3.16 (dd, 1 H, J 9.0 and
9.2 Hz, H-9), 1.73 (dd, 1 H, J 5.1 and 13.2 Hz, H-7eq), 1.21 (dd,
1 H, J 11.5 and 13.2 Hz, H-7ax); 13C-NMR (75 MHz, CD3OD):
δ 37.11 (C-7), 67.60 (C-6), 70.09 (C-8), 72.80 (C-10), 76.88
(C-5), 79.88 (C-9), 84.38 (C-1), 103.47 (C-3), 127.67 (C-3Ј, 5Ј),
129.00 (C-2Ј, 6Ј), 129.87 (C-4Ј), 139.48 (C-1Ј); ITMS-ESI
(negative mode): m/z 281 [M Ϫ H]Ϫ.
For 14: [α]20 = Ϫ31 (c = 1, MeOH), mp 175–178 ЊC;
D
1H-NMR (300 MHz, CD3OD): δ 7.28–7.23 (m, 5 H, Ph), 5.50
(s, 1 H, PhCH ), 3.91 (ddd, 1 H, J 4.2, 9.4 and 14.0 Hz, H-10),
3.86 (d, 1 H, J 9.7 Hz, H-3), 3.80 (m, 2 H, 2 × H-7), 3.55 (dd,
1 H, J 9.4 and 9.7 Hz, H-2), 3.28 (dd, 1 H, J 9.4 and 9.4 Hz,
H-1), 1.86 (dd, 1 H, J 4.2 and 12.2 Hz, H-9eq), 1.43 (dd, 1 H,
J 12.2 and 14.0 Hz, H-9ax), 1.34, 1.32 (2 s, each 3 H, CMe2);
13C-NMR (75 Hz, CD3OD): δ 27.12 (C-1Љ or 2Љ), 27.14 (C 2Љ or
1Љ), 33.04 (C-9), 69.47 (C-8), 70.80 (C-2), 74.97 (C-10), 77.05
(C-7), 83.59 (C-1), 86.19 (C-3), 103.95 (C-5), 111.72 (C-12),
127.65 (C-3Ј,5Ј), 129.02 (C-2Ј,6Ј), 129.93 (C-4Ј), 139.28 (C-1Ј);
ITMS-ESI (positive mode): m/z 345 [M ϩ Na]ϩ, 361 [M ϩ K]ϩ.
For 9a: 1H-NMR (300 MHz, CD3OD): δ 6.02 (s, 1 H,
PhCH ), 3.61 (t, 1 H, J 9.3 Hz, H-7), 3.40 (d, 1 H, J 9.5 Hz,
H-6), 3.26 (t, 1 H, J 9.2 Hz, H-8), 2.18 (dd, 1 H, J 4.6 and
13.3 Hz, H-10eq), 1.63 (dd, 1 H, J 12.1 and 13.3 Hz, H-10ax);
for 9b: δ 5.91 (s, 1 H, PhCH ), 3.54 (t, 1 H, J 9.2 Hz, H-7), 3.41
(d, 1 H, J 9.7 Hz, H-6), 3.28 (t, 1 H, J 9.2 Hz, H-8), 2.33 (dd,
1 H, J 4.7 and 13.7 Hz, H-10eq), 1.55 (dd, J 11.5 and 13.7 Hz,
H-10ax); ITMS-ESI (negative mode): m/z 281 [M Ϫ H]Ϫ.
(1S,3R,6S,8R,9S,10R)-8,9,10-Triacetoxy-3-phenyl-2,4-dioxa-
bicyclo[4.4.0]decan-6-ol 8
(1S,2S,4R,7S,9R,10S )-9-Acetoxy-12,12-dimethyl-4-phenyl-
3,5,11,13-tetra-oxatricyclo[8.3.0.02,7]tridecan-7-ol 12
Compound 7 (26 mg, 0.093 mmol) was treated with acetic
anhydride (0.5 mL) and pyridine (1.0 mL) for 17 h at room
Compound 11 (33 mg, 0.10 mmol) was treated with acetic
anhydride (0.5 mL) and pyridine (1.0 mL) for 13 h at room
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
887

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temperature. The product was chromatographed on a silica gel
(4 g, ethyl acetate–hexane 1 : 3) as eluent to give 12 (39 mg,
∼100%) as crystals: [α]20D = Ϫ26 (c = 1, MeOH), mp 186–188 ЊC;
1H-NMR (300 MHz, CD3OD): δ 7.60–7.36 (m, 5 H, Ph), 5.68
(s, 1 H, PhCH ), 5.33 (ddd, 1 H, J 5.1, 10.3 and 10.3 Hz, H-5),
4.12–4.03 (m, 2 H, H-2, H-1), 3.88 (ABq, each 1 H, J 11.3 Hz,
2 × H-6), 2.07 (s, 3 H, Ac), 1.46, 1.44 (2 s, each 3 H, CMe2);
ITMS-ESI (positive mode): m/z 365 [M ϩ H]ϩ, 387 [M ϩ Na]ϩ,
403 [M ϩ K]ϩ.
(C-3Ј, 5Ј), 129.08 (C-2Ј, 6Ј), 129.98 (C-4Ј), 139.06 (C-1Ј); ITMS-
ESI (positive mode): m/z 348 [M ϩ H]ϩ, 370 [M ϩ Na]ϩ, 386
[M ϩ K]ϩ.
(1S,2S,4R,7S,9S,10S )-9-Acetamido-12,12-dimethyl-4-phenyl-
3,5,11,13-tetra-oxatricyclo[8.3.0.02,7]tridecan-7-ol 17
A solution of 16 (0.170 g, 0.48 mmol) and ethanol (2.0 mL)
containing acetic anhydride (0.9 mL, 9.6 mmol) was hydro-
genated in the presence of Raney nickel (one spoonful) under
atmospheric pressure of H2 for 3 h at room temperature. The
reaction mixture was filtered through a Celite bed and the
filtrate was evaporated to dryness. The product was purified
by a silica-gel column (17 g, acetone–hexane 2 : 3) to give
the N-acetyl derivative 17 (0.134 g, 76%) as needles; Rf 0.72
(chloroform–methanol 4 : 1), 0.77 (n-butanol–acetic acid–H2O
2 : 1 : 1); [α]20D = Ϫ23 (c = 1, MeOH), mp 214–218 ЊC; 1H-NMR
(300 MHz, CD3OD): δ 7.58–7.32 (m, 5 H, Ph), 5.65 (s, 1 H,
PhCH ), 4.67 (t, 1 H, J 2.5, 3.9 and 4.2 Hz, H-9), 4.15 (dd, 1 H,
J 9.3 and 10.0 Hz, H-1), 4.01 (d, 1 H, J 10.0 Hz, H-2), 3.88
(ABq, each 1 H, J 12.9 Hz, 2 × H-6), 3.62 (dd, 1 H, J 3.9
and 9.3 Hz, H-10), 2.00 (s, 3 H, Ac), 1.74 (dd, 1 H, J 2.5 and
15.0 Hz, H-8eq), 1.67 (dd, 1 H, J 4.2 and 15.0 Hz, H-8ax), 1.42,
1.39 (2 s, each 3 H, CMe2); 13C-NMR (75 MHz, CD3OD):
δ 22.94 (CH3CO), 26.74 (C-1Љ or 2Љ), 27.18 (C-1Љ or 2Љ), 33.77
(C-8), 46.53 (C-9), 70.64 (C-7), 74.21 (C-1), 76.46 (C-6), 80.16
(C-10), 83.05 (C-2), 102.95 (C-4), 111.85 (C-12), 127.46 (C-3Ј,
5Ј), 129.08 (C-2Ј, 6Ј), 129.98 (C-4Ј), 139.08 (C-1Ј), 172.88
(CH3CO); ITMS-ESI (positive mode): m/z 364 [M ϩ H]ϩ, 386
[M ϩ Na]ϩ, 402 [M ϩ K]ϩ.
(1R,2S,3S,5R,8S,10R)-2-Acetoxy-12,12-dimethyl-5-phenyl-
4,6,11,13-tetra-oxatricyclo[8.3.0.03,8]tridecan-8-ol 15
Compound 14 was similarly converted into the acetyl derivative
15 as crystals: [α]20 = Ϫ16 (c = 1, MeOH), mp 182–186 ЊC;
D
1H-NMR (300 MHz, CD3OD): δ 7.53–7.50 (m, 5 H, Ph), 5.58
(s, 1 H, PhCH ), 5.43 (dd, 1 H, J 9.6 and 9.6 Hz, H-3), 4.13 (ddd,
1 H, J 4.2, 9.3 and 12.1 Hz, H-10), 3.88 (m, 3 H, H-2, 2 × H-7),
3.58 (dd, 1 H, J 9.3 and 9.6 Hz, H-1), 2.07 (s, 3 H, Ac), 2.01 (dd,
1 H, J 4.2 and 12.2 Hz, H-9eq), 1.55 (dd, 1 H, J 12.1 and 12.2
Hz, H-9ax), 1.43 (br s, 6 H, CMe2); ITMS-ESI (positive mode):
m/z 387 [M ϩ Na]ϩ, 403 [M ϩ K]ϩ.
(1S,2S,4R,7S,9R,10S )-12,12-Dimethyl-4-phenyl-9-tosyloxy-
3,5,11,13-tetra-oxatricyclo[8.3.0.02,7]tridecan-7-ol 13
To a solution of 11 (20.3 mg, 0.063 mmol) in pyridine (0.3 mL)
were added tosyl chloride (84 mg, 0.44 mmol) and a catalytic
amount of DMAP, and the mixture was stirred for 16 h at
room temperature. The mixture was diluted with ethyl acetate
(30 mL), and the solution was washed with saturated aqueous
sodium hydrogen carbonate and saline, dried, and evaporated.
The residue was chromatographed on a column of silica gel
(2 g, ethyl acetate–hexane 1 : 4) as eluent to give 13 (31 mg,
1L-(1,2,4,5/3)-5-Amino-1-C-(hydroxymethyl)-1,2,3,4-cyclo-
hexanetetrol [(؉)-valiolamine] 1
∼100%) as colorless crystals: [α]20 = Ϫ40 (c = 1, MeOH), mp
A solution of 17 (0.114 g, 0.31 mmol) and 2 M hydrochloric
acid (3.4 mL) was stirred for 3 h at 80 ЊC, and then evaporated.
The residual product was eluted from a column of Dowex 50
(NH4ϩ) resin (6 g) with 1% aqueous ammonia to give a
free amine 1 (54 mg, 90%): Rf 0.26 (n-butanol–acetic acid–H2O
2 : 1 : 1); [α]23D = ϩ18.5 (c = 1, H2O); ref. 6 [α]20D = ϩ18.8 (c = 1,
D
1
135–137 ЊC; H-NMR (300 MHz, CD3OD): δ 7.91–7.81 (m,
4 H, C6H4Me), 7.53–7.34 (m, 5 H, Ph), 5.62 (s, 1 H, PhCH ),
3.88 (m, 3 H, H-2, H-1, H-9), 3.58 (dd, 1 H, J 9.2 and 9.2 Hz,
H-10), 3.32 (br s, 2 H, 2 × H-6), 2.46 (s, 3 H, PhCH3), 2.05 (dd,
1 H, J 4.9 and 12.9 Hz, H-8eq), 1.59 (dd, 1 H, J 11.7 and 12.9
Hz, H-8ax), 1.34, 1.26 (2 s, each 3 H, CMe2); 13C-NMR (75
MHz, CD3OD): δ 21.57 (C-7Љ), 26.67 (C-1ٞ or 2ٞ), 26.88 (C-1ٞ
or 2ٞ), 37.03 (C-8), 69.27 (C-7), 76.35 (C-6), 76.84 (C-1), 78.60
(C-9 or 10), 80.63 (C-10 or 9), 81.59 (C-2), 102.96 (C-4), 112.69
(C-12), 127.50 (C-3Ј, 5Ј), 129.05 (C-2Ј, 6Ј), 129.28 (C-2Љ, 6Љ),
129.97 (C-4Ј), 130.81 (C-3Љ, 5Љ), 135.27 (C-4Љ), 138.97 (C-1Ј),
146.42 (C-1Љ); ITMS-ESI (positive mode): m/z 476 [M ϩ H]ϩ,
499 [M ϩ Na]ϩ, 515 [M ϩ K]ϩ.
1
H2O); H-NMR (300 MHz, D2O): δ 3.66 (dd, 1 H, J 9.5 and
9.8 Hz, H-3), 3.44 (dd, 1 H, J 4.2 and 9.8 Hz, H-4), 3.37,
3.29 (ABq, each 1 H, J 11.4 Hz, 2 × H-7), 3.26 (d, 1 H,
J 9.5 Hz, H-2), 3.22 (m, 1 H, H-5), 1.75 (dd, 1 H, J 2.8
and 15.2 Hz, H-6eq), 1.55 (dd, 1 H, J 3.8 and 15.2 Hz,
H-6ax); 13C-NMR (75 MHz, D2O): δ 32.94 (C-6), 51.10
(C-5), 66.21 (C-7), 71.87 (C-3), 74.04 (C-4), 74.42 (C-2),
76.72 (C-1); ITMS-ESI (positive mode): m/z 194 [M ϩ H]ϩ, 216
[M ϩ Na]ϩ.
The synthetic 1 has been demonstrated to possess enzyme-
inhibitory activity: IC50 1.2 and 20 µM against sucrase (rat) and
maltase (rat), respectively.
(1S,2S,4R,7S,9S,10S )-9-Azido-12,12-dimethyl-4-phenyl-
3,5,11,13-tetra-oxatricyclo[8.3.0.02,7]tridecan-7-ol 16
A mixture of 13 (0.260 g, 0.544 mmol), sodium azide (0.354 mg,
5.44 mmol), and dimethylformamide (3.9 mL) was stirred for 14
h at 120 ЊC, and then evaporated to dryness. The residue was
suspended in ethyl acetate (45 mL) and the mixture was washed
with water and saturated aqueous sodium chloride thoroughly,
dried, and evaporated. The residual product was chromato-
graphed on a column of silica gel (18 g, ethyl acetate–hexane
7 : 12) as eluent to give 16 (0.170 g, 88%) as a colorless syrup :Rf
1L-(1,2,4,5/3)-5-Acetamido-1-C-(acetoxymethyl)-2,3,4-tri-O-
acetyl-1,2,3,4-cyclohexanetetrol (penta-N, O-acetylvaliolamine)
18
Compound 1 (12 mg, 0.063 mmol) was conventionally acetyl-
ated and the product was purified by a silica-gel column (3 g,
acetone–hexane 2 : 3) to give 18 (25 mg, ∼100%) as colorless
crystals; [α]20D = Ϫ18 (c = 1, MeOH), mp 137–138 ЊC; 1H-NMR
(300 MHz, CDCl3): δ 7.06 (br d, 1 H, J 7.4 Hz, NHAc), 5.53
(dd, 1 H, J 9.9 and 9.9 Hz, H-3), 5.09 (d, 1 H, J 9.9 Hz, H-2),
4.94 (dd, 1 H, J 4.3 and 9.9 Hz, H-4), 4.75 (m, 1 H, H-5),
3.98, 3.83 (ABq, each 1 H, J 11.4 Hz, 2 × H-7), 3.33 (br s, 1 H,
OH), 2.10, 2.08, 2.02, 1.99 (4 s, 3, 3, 3, 6 H, 4 × Ac); 13C-NMR
(75 MHz, CD3OD): δ 20.53, 20.62, 20.67, 20.75, 23.11
(5 × CH3CO), 33.80 (C-6), 46 89 (C-5), 67.03 (C-7), 70.42 (C-3),
73.77 (C-4), 74.05 (C-2), 75.25 (C-1), 171.50, 171.77, 171.83,
172.08, 172.78 (5 × CH3CO); ITMS-ESI (positive mode): m/z
404 [M ϩ H]ϩ, 426 [M ϩ Na]ϩ, 442 [M ϩ K]ϩ.
0.20 (chloroform–methanol 4 : 1); Rf 0.64 (n-butanol–acetic
1
acid–H2O 2 : 1 : 1); [α]20 = Ϫ14.5 (c = 1.1, MeOH); H-NMR
D
(300 MHz, CD3OD): δ 7.57–7.33 (m, 5 H, Ph), 5.66 (s, 1 H,
PhCH ), 4.33 (dd, 1 H, J 9.3 and 10.0 Hz, H-1), 4.30 (ddd, 1 H,
J 2.3, 3.4 and 3.9 Hz, H-9), 3.96 (d, 1 H, J 10.0 Hz, H-2), 3.85
(m, 2 H, 2 × H-6), 3.68 (dd, 1 H, J 3.4 and 9.3 Hz, H-10), 1.89
(dd, 1 H, J 2.3 and 15.3 Hz, H-8eq), 1.63 (dd, 1 H, J 3.9 and
15.3 Hz, H-8ax), 1.45, 1.44 (2 s, each 3 H, CMe2); 13C-NMR
(75 MHz, CD3OD): δ 26.61 (C-1Љ or 2Љ), 27.25 (C-1Љ or 2Љ),
33.46 (C-8), 57.37 (C-9), 69.46 (C-7), 73.78 (C-1), 76.71 (C-6),
81.08 (C-10), 83.26 (C-2), 103.11 (C-4), 112.37 (C-12), 127.51
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
888

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1L-(1,2,4/3,5)-1-C-(Acetoxymethyl)-2,3,4-tri-O-acetyl-5-O-
tosyl-1,2,3,4,5-cyclohexanepentol 19
1L-(1,2,4/3,5)-5-Amino-1-C-(hydroxymethyl)-1,2,3,4-cyclo-
hexanetetrol [(؊)-1-epi-valiolamine] 23
A mixture of 13 (30 mg) and 2 M hydrochloric acid (0.9 mL)
was stirred for 0.5 h at 60 ЊC, and then evaporated to dryness.
The residue was treated with acetic anhydride (0.5 mL) and
pyridine (1 mL) for 17 h at room temperature. After being
quenched by the addition of MeOH, the mixture was evapor-
ated and the residue was chromatographed on silica gel (3 g,
acetone–hexane 1 : 3) to give 19 (25 mg, ∼100%) as a syrup: Rf
A solution of 21 (5.1 mg, 0.13 mmol) and 2 M hydrochloric
acid (0.3 mL) was stirred for 4 h at 80 ЊC and then evaporated.
The residue was chromatographed on a column of Dowex
50 W × 2 (0.5 g, 1% aqueous ammonia) to give 23 (2.4 mg,
∼100%): Rf 0.50 (H2O–AcOH–n-butanol 1 : 1 : 2); [α]20D = Ϫ17
1
(c = 0.42, H2O); ref. 9 [α]24 = Ϫ23.2 (c = 0.5, H2O); H-NMR
D
(300 MHz, D2O): δ 3.44 (dd, 1 H, J 9.4 and 9.5 Hz, H-3), 3.44,
3.35 (ABq, each 1 H, J 11.5 Hz, CH2OH), 3.29 (d, 1 H, J 9.4
Hz, H-2), 3.10 (dd, 1 H, J 9.5 and 10.1 Hz, H-4), 2.95 (ddd, 1 H,
J 4.0, 10.1 and 12.7 Hz, H-5), 1.83 (dd, 1 H, J 4.0 and 13.9 Hz,
H-6eq), 1.39 (dd, 1 H, J 12.7 and 13.9 Hz, H-6ax); ITMS-ESI
(positive mode): m/z 194 [M ϩ H]ϩ.
0.56 (acetone–hexane 1 : 1); [α]20 = Ϫ39 (c = 0.82, CHCl3);
D
1H-NMR (300 MHz, CDCl3): δ 7.80–7.35 (m, 4 H, Ph), 5.38
(dd, 1 H, J 9.7 and 9.8 Hz, H-3), 5.17 (dd, 1 H, J 9.7 and 9.8 Hz,
H-4), 5.10 (d, 1 H, J 9.8 Hz, H-2), 5.28 (ddd, 1 H, J 5.0, 9.6 and
11.8 Hz, H-5), 3.97, 3.82 (ABq, each 1 H, J 11.3 Hz, CH2OAc),
2.73 (s, 1 H, OH), 2.46 (s, 3 H, PhCH3), 2.36 (dd, 1 H, J 5.4 and
13.9 Hz, H-6eq), 2.10, 2.09, 1.96, 1.76 (4 s, each 3 H, 4 × Ac),
1.92 (dd, 1 H, J 12.0 and 13.9 Hz, H-6ax); ITMS-APCI
(positive mode): m/z 457 [M Ϫ AcO]ϩ, 499 [M Ϫ H2O ϩ H]ϩ.
Compound 23 has been shown to possess enzyme-inhibitory
activity: IC50 36 µM against α-glucosidase (yeast).
Acknowledgements
The authors sincere thank Ms. Miki Kanto for her assistance in
preparing this manuscript.
1L-(1,2,4/3,5)-1-C-(Acetoxymethyl)-2,3,4-tri-O-acetyl-5-azido-
1,2,3,4-cyclohexanetetrol 20 and 1L-(1,2,5/3,4)-1-C-(acetoxy-
methyl)-2,3,5-tri-O-acetyl-4-azido-1,2,3,5-cyclohexanetetrol 21
A mixture of 19 (0.459 g, 1.14 mmol), sodium azide (289 mg,
4.4 mmol), and aqueous 90% 2-methoxyethanol (46 mL) was
stirred for 21 h at 120 ЊC, and then evaporated. The residue was
treated with acetic anhydride (1 mL) and pyridine (2 mL) for 1 h
at room temperature. The mixture was evaporated and the
residual compounds were fractionated over a silica gel column
(50 g, ethyl acetate–hexane 1 : 2) to give 20 (224 mg, 65%) and
21 (129 mg, 28%) as a colorless syrup:
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1988, 7, 83–94.
11 H. Fukase and S. Horii, J. Org. Chem., 1992, 57, 3651–3658.
12 (a) T. K. N. Shing and L. H. Wong, Angew. Chem., Int. Ed. Eng,
1995, 34, 1643–1645; (b) T. K. M. Shing and I. H. Wan, J. Org.
Chem., 1996, 61, 8468–8479.
For 20: Rf 0.57 (ethyl acetate–hexane 2 : 1); [α]20 = Ϫ10
D
(c = 1.5, CHCl3), mp 182–186 ЊC; 1H-NMR (300 MHz,
CD3OD): δ 5.40 (dd, 1 H, J 9.8 and 9.9 Hz, H-3), 5.10 (d, 1 H,
J 9.9 Hz, H-2), 5.06 (dd, 1 H, J 9.8 and 9.9 Hz, H-4), 3.99 (m,
1 H, H-5), 3.93 (ABq, each 1 H, J 11.5 Hz, CH2OAc), 2.47 (s,
1 H, OH), 2.23–1.99 (m, 12 H, 4 × Ac); ITMS-ESI (positive
mode): m/z 370 [M Ϫ H2O ϩ H]ϩ.
For 21: Rf 0.36 (ethyl acetate–hexane 2 : 1); [α]20 = Ϫ6.6
D
(c = 0.19, CHCl3), mp 175–178 ЊC; 1H-NMR (300 MHz,
CD3OD): δ 5.54 (dd, 1 H, J 3.3 and 9.6 Hz, H-3), 5.40 (d, 1 H,
J 9.6 Hz, H-2), 5.07 (m, 1 H, H-5), 4.11 (dd, 1 H, J 3.3 and 3.5
Hz, H-4), 4.00, 3.86 (ABq, each 1 H, J 11.3 Hz, CH2OAc), 2.52
(s, 1 H, OH), 2.17–1.99 (m, 14 H, 4 × Ac, 2 × H-6); ITMS-ESI
(positive mode): m/z 370 [M Ϫ H2O ϩ H]ϩ.
13 O. Sellier, P. Van de Weghe, D. Le Nouen, C. Strehler and
J. Eustache, Tetrahedron Lett., 1999, 40, 853–856.
1L-(1,2,4/3,5)-5-Acetamido-1-C-(acetoxymethyl)-2,3,4-tri-O-
acetyl-1,2,3,4-cyclohexanetetrol [penta-N, O-acetyl-1-epi-
valiolamine] 22
14 Synthesis of racemic
3 was reported: N. Yamauchi and
K. Kakinuma, J. Antibiot., 1992, 45, 756–766. The molecular
rotation (Ϫ43Њ) of 3 is in good accordance with the value Ϫ45Њ
empirically estimated for the absolute structure assigned: R. U.
Lemieux and J. C. Martin, Carbohydr. Res., 1970, 13, 139–161. The
absolute structure was finally confirmed by its conversion into
(ϩ)-valiolamine 1.
A solution of 20 (155 mg, 0.40 mmol) in ethanol (2 mL) con-
taining acetic anhydride (0.08 mL) was hydrogenated in the
presence of Raney nickel T-4 under atmospheric pressure of H2
for 8 h at room temperature. The catalyst was removed by
filtration and the filtrate was evaporated. The residue was
chromatographed on a silica gel (20 g, acetone–hexane 2 : 3) to
give 21 (109 mg, 68%) as crystals: Rf 0.30 (acetone–toluene
2 : 1); [α]20D = Ϫ12 (c = 2.7, CHCl3), mp 214–218 ЊC; 1H-NMR
(300 MHz, CD3OD): δ 5.97–5.80 (br d, 1 H, NHAc), 5.56 (dd,
1 H, J 9.8 and 9.9 Hz, H-3), 5.08 (d, 1 H, J 9.9 Hz, H-2), 4.96
(dd, 1 H, J 9.8 and 10.3 Hz, H-4), 4.50 (dddd, 1 H, J 4.4, 7.9,
10.3 and 13.0 Hz, H-5), 4.03, 3.83 (ABq, each 1 H, J 11.3 Hz,
CH2OAc), 2.28 (dd 1 H, J 4.4 and 14.0 Hz, H-6eq), 2.08,
2.06, 1.99, 1.94, 1.60 (5 s, each 3 H, 5 × Ac), 1.60 (dd, 1 H,
J 13.0 and 14.0 Hz, H-6ax); ITMS-ESI (positive mode): m/z 404
[M ϩ H]ϩ, 426 [M ϩ Na]ϩ, 442 [M ϩ K]ϩ.
15 The hydrate-form of 3 was shown not to react with diazomethane in
this reaction conditions.
16 S. Ogawa and Y. Shibata, Carbohydr. Res., 1986, 156, 273–281.
17 Similar treatment of 7 with 1,1-dimethoxycyclohexane in DMF gave
the corresponding two O-cyclohexylidene derivatives at good yields.
However, chromatographic separation of these was found to be
rather difficult, compared to that for compounds 11 and 14.
18 Discussion concerning formation of the positional isomers was
made using the carbon atom-numbering of 5.
19 T. Suami, S. Ogawa, T. Ishibashi and I. Kasahara, Bull. Chem. Soc.
Jpn., 1976, 49, 1388–1390.
20 Iodination of 4 with hydroiodic acid in acetic acid gave, after
acetylation, the iodo penta-acetate, which was subsequently treated
with zinc powder in acetic acid, affording 1-(1,3/2,4)-5-methylene-
1,2,3,4-cyclohexanetetrol tetra-acetate (∼100%).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 8 8 4 – 8 8 9
889