Transformation of quercitols into 4-methylenecyclohex-5-ene-1,2,3-triol derivatives, precursors for the chemical chaperones N-octyl-4-epi-β- valienamine (NOEV) and N-octyl-β-valienamine (NOV)

Article abstract of DOI:10.1016/j.bmcl.2011.09.067

(+)-proto-Quercitol (1) and (-)-vibo-quercitol (2), both of which could be readily prepared by the bioconversion of myo-inositol, were successfully converted into the corresponding 4-methylenecyclohex-5-ene-1,2,3-triol derivatives. These compounds were demonstrated to be suitable precursors, preserving their configurations, for bioactive carba-aminosugars such as the potent chemical chaperone drug candidates, N-octyl-4-epi-β-valienamine (NOEV, 3) and N-octyl-β-valienamine (NOV, 4).

Full text of DOI:10.1016/j.bmcl.2011.09.067

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7189–7192
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Transformation of quercitols into 4-methylenecyclohex-5-ene-1,2,3-triol
derivatives, precursors for thechemical chaperones N-octyl-4-epi-b-valienamine
(NOEV) and N-octyl-b-valienamine (NOV)
Shinichi Kuno a, , Atsushi Takahashi a, Seiichiro Ogawa b
⇑
a Central Research Laboratories, Hokko Chemical Industry Co. Ltd, Toda, Atsugi 243-0023, Japan
b Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2011
Revised 16 September 2011
Accepted 17 September 2011
Available online 24 September 2011
(+)-proto-Quercitol (1) and (ꢀ)-vibo-quercitol (2), both of which could be readily prepared by the biocon-
version of myo-inositol, were successfully converted into the corresponding 4-methylenecyclohex-
5-ene-1,2,3-triol derivatives. These compounds were demonstrated to be suitable precursors, preserving
their configurations, for bioactive carba-aminosugars such as the potent chemical chaperone drug
candidates, N-octyl-4-epi-b-valienamine (NOEV, 3) and N-octyl-b-valienamine (NOV, 4).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbasugar
Quercitol
Valienamine
Carbohydrate mimics
Glycosidase inhibitors
Structure–activity relationship
Chemical chaperone
Deoxyinositols, namely quercitols, are naturally occurring
cyclohexanepentaols. There are 10 possible diastereoisomers (four
meso and six optically active) for a quercitol. Recent extensive
studies on the bioconversion of myo-inositol have provided us with
(+)-proto-quercitol (1), (ꢀ)-vibo-quercitol (2) and (+)-epi-quercitol
(Fig. 1).1 They have been employed as useful chiral starting mate-
rials for syntheses of various bioactive compounds.2 However, the
major synthetic strategies for valienamine-type carbasugars re-
ported so far have not started from quercitols.3 For instance, one
of the authors synthesized valienamine derivatives via conjugated
dienes starting from Diels–Alder adducts of furan and acrylic acid.4
These routes have been reliably accepted for the synthesis of car-
basugars but required optical resolution when chiral compounds
were desired.5 Thus, a novel synthetic correlation between querc-
itols and chiral diene intermediates would provide a short, concise
route to chiral unsaturated valienamine-type carbasugars while
eliminating the cumbersome optical resolution.
the conversion of quercitols to the diene intermediates could be
accomplished with minimum chemical conversion, and they were
shown to be transformed into the valienamine analogs 3 and 4, which
are drug candidates. First, (+)-proto-quercitol (1) obtained by the
bioconversion of myo-inositol was converted to the corresponding
arabino-type 4-methylenecyclohex-5-ene-1,2,3-triol derivative (7).
Next, the diene 7 was transformed into the valienamine derivative
3. On the other hand, (ꢀ)-vibo-quercitol (2), similarly derived from
myo-inositol, was employed as a chiral starting material for the
synthesis of 4 via the xylo-type intermediate (12).
OH
HO
HO
OH
OH
HO
HO
OH
HO
OH
(+)-
-Quercitol (1)
(-)-
-Quercitol (2)
vibo
proto
Among some biologically interesting carbasugar derivatives,
much attention has recently focused on N-octyl-4-epi-b-valienamine
(NOEV, 3) and N-octyl-b-valienamine (NOV, 4) because they show
curative activities toward lysosomal storage disorders that are cate-
gorized as rare interactive diseases.6 In the present communication,
HO
HO
OH
OH
HO
HO
NH(CH2)7CH3
NH(CH2)7CH3
HO
HO
NOEV (3)
NOV (4)
⇑
Corresponding author. Tel.: +81 46 228 5881; fax: +81 46 228 0164.
E-mail address: kuno-s@hokkochem.co.jp (S. Kuno).
Figure 1. (+)-proto-Quercitol (1), (ꢀ)-vibo-quercitol (2), N-octyl-4-epi-b-valien-
amine (NOEV, 3) and N-octyl-b-valienamine (NOV, 4).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.067

7190
S. Kuno et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7189–7192
Isopropylidenation of (+)-proto-quercitol (1) with 2,2-dime-
thoxypropane and a catalytic amount of ( )-10-camphorsulfonic
O
a
OH
HO
HO
2
HO
acid
and
then
successive
Parikh–Doering
oxidation
Å
ðSO3 py=Et3N=DMSOÞ gave ketone 5 (53%) (Scheme 1). Treatment
of 5 with a catalytic amount of pyridinium-p-toluenesulfonate in
methanol selectively removed the acetal attached to the trans-diol
to afford a dihydroxy ketone. The ketone could be isolated in pure
form as enol-benzoate 6 (60%) by treatment with benzoyl chloride
in pyridine. Under Wittig reaction conditions with an excess of
methyltriphenylphosphonium bromide and n-BuLi, elimination of
the benzoyloxy group and methylenation of 6 successively oc-
curred to give the diene 7 (66%).7 Thus, (+)-proto-quercitol (1)
was readily converted to the intermediate 7 in five steps.
10
c
O
b
d
AcO
AcO
AcO
AcO
AcO
AcO
11
12
X
OH
f
AcO
AcO
HO
HO
NH(CH2)7CH3
Br
The 1,4-addition of a slight excess of bromine to compound 7
gave an 85% yield of ca. 1:1 diastereomeric mixture of the dibromo
HO
AcO
compounds 8
mono- ,b-bromo compounds 9
ate in DMF. Debenzoylation of 9
tions afforded an
-bromo8 diol (47%) and an epoxide (26%).9 The
two products were first considered to be diastereomeric - and
a
and 8b. The mixture was easily converted to the
and 9b (91%) with sodium benzo-
and 9b under Zemplén condi-
4
13 , : X = Br
α β
14 , : X = OAc
α β
e
a
a
a
Scheme 2. Synthesis of NOV (4) from (ꢀ)-vibo-quercitol (2) via a tri-O-acetylated
diene (12). Reagents and conditions: (a) bacterial bioconversion; (b) BF3/diethyl-
ether complex (2.4 mol equiv), Ac2O, 1.5 h, 0 °C to rt, and AcOH, 2.5 h, reflux, 83%;
(c) Nysted reagent (3 mol equiv), TiCl4 (2 mol equiv), THF, CH2Cl2, 1 h, ꢀ15 °C to rt,
25%; (d) Br2 (1 mol equiv), CCl4, 15 min, rt, 96%; (e) NaOAc (1.2 mol equiv), DMF,
19 h, rt, 53%; (f) n-octylamine (5 mol equiv), MeCN, 4 h, 50 °C, and NaOMe
(1 mol equiv), MeOH, 2 h, rt, 31%.
a
a
b-bromo diols, but the b-bromo compound was likely to undergo
a neighboring attack of the hydroxyl under basic conditions to af-
ford an epoxide. Both the
a-bromo and epoxy compounds that
were obtained were expected to generate a single b-diastereomer
through a front-side SN2 nucleophilic substitution.
The mixture containing
a-bromo and epoxy compounds was
treated with n-octylamine in acetonitrile, followed by deprotection
of the acetal group using aqueous acetic acid. Purification of a
crude amine salt on a silica gel column (10:86:4 ? 1:6:3 acetic
acid/CHCl3/methanol) and a Duolite 20 (H+) resin column (80%
aqueous methanol ? 4:1 methanol/25% ammonia) resulted in the
isolation of a single N-octyl b-amine NOEV (3)10 (47% based on
previously reported procedure.2b Next, treatment of 10 with a Le-
wis acid, BF3/diethyl ether complex, in acetic anhydride gave the
tetra-O-acetyl derivative of 10. The reaction mixture was, without
separation, diluted with EtOAc and quenched with saturated aque-
ous NaHCO3; the organic layer was successively washed with
water and brine and then dried and co-evaporated with toluene
and ethanol. The residue was refluxed in acetic acid to give the
the mixture of the two compounds obtained from 9a and 9b).
The synthesis of NOV (4) was accomplished starting from (ꢀ)-
vibo-quercitol (2) following a similar strategy to the synthesis of
NOEV (Scheme 2). First, 2 was transformed quantitatively to (ꢀ)-
2-deoxy-scyllo-inosose (10) by bio-oxidation according to the
a,b-unsaturated ketone 11 (83% from 10). It was noteworthy that
the attempted acylation of 10 under basic conditions with pyridine
or triethylamine resulted in a facile elimination of acetoxyl groups
to give a complex mixture containing an aromatic compound.11
Alternatively, the application of other Lewis acids instead of the
BF3/diethyl ether complex gave different results. For example,
treatment of 10 with trimethylsilyl triflate (4 mol equiv) in acetic
anhydride for 19 h between 0 °C and room temperature afforded
ca. a 10:3 mixture of the ketone 11 and the aromatic side-prod-
uct11 in 82% yield. Exomethylenation of 11 with Nysted reagent12
afforded the triacetyl derivative 12 in 25% yield.13 In this methyle-
nation reaction, a basic environment, such as Wittig reaction
conditions, seemed to facilitate the undesirable elimination of
the b-acetoxyl group.
O
O
a
O
O
1
O
5
O
OBz
OBz
O
b
c
f
O
O
The diene intermediate 12 was similarly treated with bromine,
as mentioned above, to give a mixture of the 1,4-addition products
BzO
BzO
13
bromo compounds 14
acetate. The reaction of 14
a
and 13b (96%), which was converted to the isomeric mixture of
and 14b (53%) by treatment with sodium
and 14b with an excess of n-octyl-
6
7
a
HO
HO
O
d
e
a
OH
NH(CH2)7CH3
X
amine gave a single protected N-octyl b-amine,14 which was then
subjected to Zemplén conditions to remove the remaining acetyl
groups. After purification on a silica gel column (10:86:4 ? 1:8:1
acetic acid/CHCl3/methanol) and a column of a Duolite 20 (H+) re-
sin (80% aqueous methanol ? 4:1 methanol/25% ammonia), NOV
O
Br
HO
BzO
3
8 , : X = Br
α β
9 , : X = OBz
α β
(4) was obtained in 31% yield based on 14a
and 14b.15
Scheme 1. Synthesis of NOEV (3) from (+)-proto-quercitol (1) via a diene benzoate
(7). Reagents and conditions: (a) 2,2-dimethoxypropane (10 mol equiv), CSA
(0.2 mol equiv), acetone, 19 h, rt; SO3Åpy (3 mol equiv), Et3N (2 mol equiv), DMSO,
4.5 h, 0 °C to rt, 53% for two steps; (b) PPTS (0.2 mol equiv), MeOH, 23 h, 4 °C; BzCl
(8 mol equiv), py, 21 h, 0 °C to rt, 60% for two steps; (c) Ph3PCH3Br (6 mol equiv), n-
BuLi (4 mol equiv), THF, 21 h, ꢀ78 °C to 4 °C, 66%; (d) Br2 (1.1 mol equiv), NaHCO3
(2 mol equiv), CCl4, 20 min, rt, 85%; (e) NaOBz (1.2 mol equiv), DMF, 47 h, rt, 91%; (f)
Using the appropriate quercitols as starting materials, valien-
amine-type unsaturated carba-amino sugars, such as the potent
drug candidates NOEV and NOV, could be conveniently prepared
as optically pure forms via 4-methylenecyclohex-5-ene-1,2,3-triol
derivatives.
Enzyme inhibitory activity: Free amines 3 and 4 were quantita-
tively converted to the hydrochloride salts 15 and 16 with 1 M
HCl (aq) in order to increase their water solubility for biological
NaOMe (1 mol equiv), MeOH, 2 h, rt, 47% for an
a-bromo diol and 26% for an
epoxide; n-octylamine (3.5 mol equiv), MeCN, 16 h, 60–70 °C, and 80% aqueous
AcOH, 4 h, 80 °C, 47%.

S. Kuno et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7189–7192
7191
Table 1
Enzyme inhibitory activity of the amine hydrochlorides 15 and 16 against four glycosidases
HO
OH
N+
OH
H
H
N+
HO
HO
HO
(CH2)7CH3
(CH2)7CH3
HO
HO
H
Cl-
H
Cl-
15
16
Compound
IC50 (lM)
b-Galactosidase (bovine liver)
b-Galactosidase (Aspergillus oryzae)
b-Glucosidase (almonds)
a-Galactosidase (green coffer beans)
15a
16
4.5
2.9
85
NT
8.1
47
4.5
NI
NI, IC50 >1 mM; NT, not tested.
a
This compound did not show any notable inhibitory activity against b-mannosidase (helix pomatia),
a
-fucosidase (human placenta), or a-mannosidase (jack beans).
assay. 15 was first assayed16 for inhibitory activity against seven
commercially available glycosidases: b-galactosidase (bovine liver
and aspergillus oryzae), b-glucosidase (almonds), b-mannosidase
Gehrke, S.; Erfan, S.; Cribiu, R. Carbohydr. Res. 2008, 343, 1675; (f) Krishna, P. R.;
Reddy, P. S. Synlett 2009, 2, 209; (g) Ramstadius, C.; Hekmat, O.; Eriksson, L.;
Stalbrand, H.; Cumpstey, I. Tetrahedron: Asymmetry 2009, 20, 795; (h) Chang,
Y.-K.; Lo, H.-J.; Yan, T.-H. Org. Lett. 2009, 11, 4278; (i) Shing, T. K. M.; Cheng, H.
M. J. Org. Chem. 2010, 75, 3522.
(helix pomatia),
(green coffee beans), and
hand, 16 was tested against b-galactosidase (bovine liver), b-gluco-
sidase (almonds), and -galactosidase (green coffee beans). As
listed in Table 1 and 15 possessed inhibitory activities against
two b-galactosidases, b-glucosidase, and -galactosidase. Mean-
a-fucosidase (human placenta),
a-galactosidase
4. Suzuki, Y.; Ogawa, S.; Sakakibara, Y. Perspect. Med. Chem. 2009, 3, 7.
5. Ogawa, S.; Iwasawa, Y.; Nose, T.; Suami, T.; Ohba, S.; Ito, M.; Saito, Y. J. Chem.
Soc., Perkin Trans. 1 1985, 903.
a-mannosidase (Jack beans). On the other
6. For relevant reports, see: (a) Ogawa, S.; Ashiura, M.; Uchida, C.; Watanabe, S.;
Yamazaki, C.; Yamagishi, K.; Inokuchi, J. Bioorg. Med. Chem. Lett. 1996, 6, 929;
(b) Ogawa, S.; Matsunaga, Y. K.; Suzuki, Y. Bioorg. Med. Chem. 2002, 10, 1967; (c)
Matsuda, J.; Suzuki, O.; Oshima, A.; Yamamoto, Y.; Noguchi, A.; Takimoto, K.;
Itoh, M.; Matsuzaki, Y.; Yasuda, Y.; Ogawa, S.; Sakata, Y.; Nanba, E.; Higaki, K.;
Ogawa, Y.; Tominaga, L.; Ohno, K.; Iwasaki, H.; Watanabe, H.; Brady, R. O.;
Suzuki, Y. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 15912; (d) Lin, H.; Sugimoto, Y.;
Ohsaki, Y.; Ninomiya, H.; Oka, A.; Taniguchi, M.; Ida, H.; Eto, Y.; Ogawa, S.;
Matsuzaki, Y.; Sawa, M.; Inoue, T.; Higaki, K.; Nanba, E.; Ohno, K.; Suzuki, Y.
Biochim. Biophys. Acta Mol. Basis Dis. 2004, 1689, 219; (e) Ogawa, S.; Sakata, Y.;
Ito, N.; Watanabe, M.; Kabayama, K.; Itoh, M.; Korenaga, T. Bioorg. Med. Chem.
2004, 12, 995; (f) Lei, K.; Ninomiya, H.; Suzuki, M.; Inoue, T.; Sawa, M.; Iida, M.;
Ida, H.; Eto, Y.; Ogawa, S.; Ohno, K.; Suzuki, Y. Biochim. Biophys. Acta Mol. Basis
Dis. 2007, 1772, 587; (g) Suzuki, Y. Cell. Mol. Life Sci. 2008, 65, 351; (h) Luan, Z.;
Ninomiya, H.; Ohno, K.; Ogawa, S.; Kubo, T.; Iida, M.; Suzuki, Y. Brain Dev. 2010,
32, 805; (i) Luan, Z.; Li, L.; Ninomiya, H.; Ohno, K.; Ogawa, S.; Kubo, T.; Iida, M.;
Suzuki, Y. Blood Cells Mol. Dis. 2010, 44, 48; (j) Jo, H.; Yugi, K.; Ogawa, S.; Suzuki,
Y.; Sakakibara, Y. J. Proteomics Bioinform. 2010, 3, 104.
a
a
while, 16 was shown to have a cross-inhibitory activity toward
b-galactosidase (bovine liver) and b-glucosidase. It is interesting
to note that 15, with a b-galacto configuration, inhibited both b-
galactosidase and b-glucosidase,17 moreover, its activity against
b-glucosidase was stronger than that exhibited by b-gluco-type
16. Conversely, 16 inhibited b-galactosidase (bovine liver) more
effectively than b-glucosidase. Although a design of new glycosi-
dase inhibitors has been carried out on the basis of a simple
assumption that potent inhibitors are likely to be good structural
mimics of the related substrates, the present results allow us to
give further consideration to
relationship.
a structure–inhibitory activity
7. Characterization data for compound 7: ½a 2D5 +220° (c 1.0, CHCl3); 1H NMR
ꢁ
(400 MHz, CDCl3):
d 1.42 and 1.50 (2s, each 3H, CMe2), 4.37 (t, 1H,
J1,2 = J2,3 = 5.3 Hz, H-2), 4.76 (d, 1H, J2,3 = 5.5 Hz, H-3), 5.42, 5.45 (2s, each
1H, CH2), 5.67 (m, 1H, H-1), 5.78 (broad d, 1H, J5,6 = 10.1 Hz, H-5), 6.32 (dd,
1H, J1,6 = 1.8, J5,6 = 10.1 Hz, H-6), 7.40–7.42 (m, 2H, Ph), 7.52–7.54 (m, 1H, Ph),
8.03–8.05 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3): d 26.22, 27.89, 71.06,
73.30, 76.43, 109.25, 120.54, 125.23, 128.29, 129.71, 129.88, 130.15, 133.08,
138.31, 165.84; HR-ESI-MS: 309.1100 (C17H18O4Na+, [M+Na]+; calcd
309.1097).
Acknowledgments
The authors would like to thank Drs. Ryuichi Sawa and Yoji
Umezawa (Institute of Microbial Chemistry, Tokyo) for the mea-
surement of high resolution mass spectra, Professors Katsumi Hi-
gaki, Eiji Nanba, and Kousaku Ohno for the bioassays (Tottori
University, Yonago), Ms. Yoko Sakata for the discussion on prepara-
tive work, and Messrs. Masanori Yamaguchi, Akihiro Tomoda and
Yuichi Kita (Hokko Chemical Industry Co. Ltd, Atsugi) for their kind
provision of (+)-proto- and (ꢀ)-vibo-quercitols.
8. To avoid ambiguity, this compound should be named as 3,4-O-isopropylidene-
5a-carba-b-L-arabino-hex-5(5a)-enopyranosyl bromide according to the
carbasugar nomenclature. Nevertheless, the authors use the term ‘
diol’ instead of ‘b-bromo diol’ in the text. The reason is why we regard this
intermediate compound as an -valienamine derivative, which is a versatile
precursor to N-ocyl-4-epi-b-valienamine (NOEV). Additionally, the
conformations of the b-arabino carbasugars are well coincident with the
a-bromo
a
a-
galacto configured compounds. For the nomenclature of carbasugars, see the
IUPAC-IUBMB Nomenclature of Carbohydrates (Recommendation 1996:
Carbohydr. Res. 1997, 297, 1).
References and notes
9. The structures of the
a-bromo diol and the epoxide were assigned as shown
1. (a) Ogawa, S.; Uetsuki, S.; Tezuka, Y.; Morikawa, T.; Takahashi, A.; Sato, K.
Bioorg. Med. Chem. Lett. 1999, 9, 1493; (b) Takahashi, A.; Kanbe, K.; Tamamura,
T.; Sato, K. Anticancer Res. 1999, 3807.
below. The two compounds were completely separable using
column and were fully characterized.
a silica gel
O
2. For relevant reports, see: (a) Ogawa, S.; Aoyama, H.; Tezuka, Y. J. Carbohydr.
Chem. 2001, 20, 703; (b) Ogawa, S.; Ohishi, Y.; Asada, M.; Tomoda, A.;
Takahashi, A.; Ooki, Y.; Mori, M.; Itoh, M.; Korenaga, T. Org. Biomol. Chem. 2004,
2, 884; (c) Ogawa, S.; Asada, M.; Ooki, Y.; Mori, M.; Itoh, M.; Korenaga, T. Bioorg.
Med. Chem. 2005, 13, 4306; (d) Ogawa, S.; Tezuka, Y. Bioorg. Med. Chem. Lett.
2006, 16, 5238; (e) Ogawa, S.; Kanto, M. J. Nat. Prod. 2007, 70, 493; (f)
Wacharasindhu, S.; Worawalai, W.; Rungprom, W.; Phuwapraisirisan, P.
Tetrahedron Lett. 2009, 50, 2189.
3. For recent references concerning synthetic approaches to valienamine
derivatives: (a) Chang, Y.-K.; Lee, B.-Y.; Kim, D. J.; Lee, G. S.; Jeon, H. B.; Kim,
K. S. J. Org. Chem. 2005, 70, 3299; (b) Cumpstey, I. Tetrahedron Lett. 2005, 46,
6257; (c) Lysek, R.; Schuetz, C.; Favre, S.; O’Sullivan, A. C.; Pillonel, C.; Kruelle,
T.; Jung, P. M. J.; Clotet-Codina, I.; Este, J. A.; Vogel, P. Bioorg. Med. Chem. 2006,
14, 6255; (d) Scaffidi, A.; Stubbs, K. A.; Dennis, R. J.; Taylor, E. J.; Davies, G. J.;
Vocadlo, D. J.; Stick, R. V. Org. Biomol. Chem. 2007, 5, 3013; (e) Cumpstey, I.;
O
OH
OH
O
O
HO
Br
O
10. The spectroscopic data of the synthetic NOEV as a free amine was identical to
previously reported data6c,e; ½a 2D5 +3.0° (c 1.0, MeOH); 1H NMR (400 MHz,
ꢁ
CD3OD): d 0.89 (t, 3H, J7 ,8 = 6.9 Hz, H-80), 1.30–1.37 (10H, H-30, 40, 50, 60, and
70), 1.48–1.56 (m, 2H, H-20), 2.54–2.58, 2.72–2.76 (each m, each 1H, H-10a and
H-10b), 3.11 (dd, 1H, J1,5a = 1.8, J1,2 = 8.2 Hz, H-1), 3.44 (dd, 1H, J3,4 = 4.1,
J2,3 = 10.1 Hz, H-3), 3.70 (dd, 1H, J1,2 = 8.2, J2,3 = 10.1 Hz, H-2), 4.12 (broad s, 2H,
CH2), 4.15 (d, 1H, J3,4 = 4.1 Hz, H-4), 5.71 (d, 1H, J1,5a = 2.3 Hz, H-5a); 13C NMR
(100 MHz, CD3OD): d 14.43, 23.71, 28.42, 30.38, 30.60, 30.88, 32.98, 46.87,
61.78, 63.89, 68.13, 70.78, 73.85, 125.13, 140.73. In addition, biological
activities were found to be in accordance with the sample prepared by the
reported procedure.6c
0
0

7192
S. Kuno et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7189–7192
11. The structure of this compound could be assigned as 1,2,4-triacetoxybenzene
on the basis of 1H NMR analysis: 1H NMR (300 MHz, CDCl3): d 2.21 (s, 9H, 3 Ac),
6.95–7.00, 7.13–7.16 (m, 3H, Ph).
participation, the amination of the relevant bromo compounds resulted in the
generation of the nonstereospecific products (Cumpstey, I.; Ramstadius, C.;
Borbas, K. E. Synlett, 2011, 12, 1701).
12. (a) Nysted, L. N. U.S. Patent 3,865,848, 1975. This reagent was purchased from
Sigma–Aldrich Co. (St. Louis, MO, USA).; (b) Matsubara, S.; Sugihara, M.;
Utimoto, K. Synlett 1998, 313.
15. The spectroscopic data of the synthetic NOV as a free amine were shown to be
well similar to that of the acetic acid salt reported previously6a; ½a D25
-69° (c
ꢁ
1.0, MeOH); 1H NMR (400 MHz, CD3OD): d 0.89 (t, 3H, J7 ,8 = 6.9 Hz, H-80),
1.30–1.33 (10H, H-30, 40, 50, 60, and 70), 1.49–1.53 (m, 2H, H-20), 2.52–2.57,
2.71–2.76 (each m, each 1H, H-10a and H-10b), 3.19–3.20 (m, 1H, H-1), 3.40 (t,
1H, J1,2 = J2,3 = 9.2 Hz, H-2), 3.48 (dd, 1H, J3,4 = 7.6, J2,3 = 9.8 Hz, H-3), 4.10–4.16
(3H, H-4, CH2), 5.63 (s, 1H, H-5a), assigned by H-H COSY; 13C NMR (100 MHz,
CD3OD): d 14.41, 23.71, 28.41, 30.38, 30.61, 30.86, 32.98, 47.19, 61.33, 62.99,
73.92, 78.26, 122.82, 141.20. Biological activity was also in accordance with
that of an authentic sample.6d
0
0
13. Characterization data for compound 12: ½a 2D5 +110° (c 2.0, CHCl3); 1H NMR
ꢁ
(400 MHz, CDCl3): d 2.01, 2.03 and 2.10 (3s, each 3H, 3 Ac), 5.02 (br s, 1H, CH2),
5.15 (br d, 1H, J3,CH2 = 2.3 Hz, CH2), 5.25 (dd, 1H, J1,2 = 7.8, J2,3 = 10.5 Hz, H-2),
5.57–5.62 (2H, H-1 and H-5), 5.67 (dt, 1H, J3,CH2 = 2.1, J2,3 = 10.5 Hz, H-3), 6.24-
6.26 (m, 1H, H-6), assigned by H-H COSY; 13C NMR (100 MHz, CDCl3): d 20.57,
20.66, 20.84, 70.35, 71.58, 72.28, 114.39, 125.71, 129.82, 138.37, 169.89,
170.25; HR-ESI-MS: 291.0833 (C13H16O6Na+, [M+Na]+; calcd 291.0839). The 1
H
NMR data corresponds well to that of racemic 12 (Ogawa, S.; Toyokuni, T.;
Omata, M.; Chida, N.; Suami, T. Bull. Chem. Soc. Jpn. 1980, 53, 455).
16. All glycosidases were purchased from Sigma–Aldrich. The glycosidase
inhibitory activities were determined spectrometrically with the
corresponding p-nitrophenyl glycosides (Sigma–Aldrich).
14. The formation of the single b-amine through direct amination of
a- and b-
bromo compounds was mechanistically explained by presuming a neighboring
group participation (Ref. 6e, and also see: Toyokuni, T.; Ogawa, S.; Suami, T.
Bull. Chem. Soc. Jpn. 1983, 56, 2999). In contrast, without neighboring group
17. Similar biochemical features were observed in the case of free amine 3 toward
b-galactosidase (bovine liver) and b-glucosidase (almonds).6e