1540
W. Worawalai et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1538–1540
Table 1
Golden Jubilee Ph.D. Program (PHD/0025/2553), Chulalongkorn
a
-Glucosidase inhibitory effect of cyclitols 1, 5, 7a and 7b
University Dutsadi Phiphat and Development and Promotion of
Science and Technology Talents Project (DPST), respectively, for
scholarships.
IC50 M)
(
l
Cyclitol
Baker’s yeast
Maltasea
Sucrasea
1
5
7a
7b
NIb
NI
NI
NI
NI
NI
NI
NI
NI
Supplementary data
86.1 0.5
1256.1 1.7
475.7 0.9
403.9 0.4
Supplementary data (full experimental details and characteriza-
tion data for 2, 4, 5, 6a, 6b, 7a and 7b) associated with this article can
Acarbose
1.50 0.14
2.38 0.02
a
a
-Glucosidase was obtained from rat small intestine.
b
NI, no inhibition, inhibitory effect less than 30% at 10 mg/mL.
References and notes
inositol derivatives. Dihydroxylation of 4 using OsO4 led to the for-
mation of readily separable 3:1 diastereomeric inositols10 6a and
6b in 77% yield (Scheme 3). The selective formation of 6a over
6b could be rationalized by preferential osmylation on the less hin-
dered face of alkene. Consequently, 6a and 6b were deprotected by
Amberlyst-15 to quantitatively afford (+)-chiro-inositol (7a)11 and
(+)-epi-inositol (7b),12 respectively.
1. For recent review of conduritols see: Gültekin, M. S.; Çelik, M.; Balci, M. Curr.
Org. Chem. 2004, 8, 1159.
2. Kornienko, A.; Evidente, A. Chem. Rev. 1982, 2008, 108.
3. Borges de Melo, E.; da Silveira Gomes, A.; Carvalho, I. Tetrahedron 2006, 62,
10277.
4. (a) Phuwapraisirisan, P.; Puksasook, T.; Jong-aramruang, J.; Kokpol, U. Bioorg.
Med. Chem. Lett. 2008, 18, 4956; (b) Wacharasindhu, S.; Worawalai, W.;
Rungprom, W.; Phuwapraisirisan, P. Tetrahedron Lett. 2009, 50, 2189;
(c) Phuwapraisirisan, P.; Puksasook, T.; Kokpol, U.; Suwanborirux, K.
Tetrahedron Lett. 2009, 50, 5864.
(+)-Conduritol F (5) and inositols (7a and 7b) were evaluated for
5. (a) Duchek, J.; Adams, D. R.; Hudlicky, T. Chem. Rev. 2011, 111, 4223; (b) Klbasß,
B.; Balci, M. Tetrahedron 2011, 67, 2355; (c) Finn, K. J.; Collins, J.; Hudlicky, T.
Tetrahedron 2006, 62, 7471; (d) Ogawa, S.; Uetsuki, S.; Tezuka, Y.; Morikawa, T.;
Takahashi, A.; Sato, K. Bioorg. Med. Chem. Lett. 1999, 11, 1493.
6. (a) Cerè, V.; Mantovani, G.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron 2000, 56,
1225; (b) Chiara, J. L.; Valle, N. Tetrahedron: Asymmetry 1995, 6, 1895;
(c) Akiyama, T.; Shima, H.; Ohnari, M.; Okazaki, T.; Ozaki, S. Bull. Chem. Soc.
Jpn. 1993, 66, 3760; (d) Akiyama, T.; Shima, H.; Ozaki, S. Tetrahedron Lett. 1991,
32, 5593.
a
-glucosidase inhibitory activity using enzymes from two different
sources; baker’s yeast (type I) and rat small intestine (type II). They
selectively inhibited
-glucosidase from baker’s yeast,13 in which 5
displayed highest inhibition with an IC50 value of 86.1 M (Table 1).
a
l
A potent inhibitory effect (6–16 times) of 5 over its corresponding
diols, (+)-chiro-inositol (7a) and (+)-epi-inositol (7b), indicates that
a half-chair conformation of cyclohexene moiety is more critical in
binding active site of the enzyme than additional dihydroxy groups.
This observation was also supported by a very low inhibition of (+)-
proto-quercitol (1), a hydroxylated cyclitol of 5. However, all cycli-
7. Briefly, ground stems (1 kg) of A. arborescens were boiled with water (4 L) for
3 h. The decoction was filtered and partitioned twice with equal volume of
CH2Cl2. The aqueous layer was loaded onto a column chromatography filled
with wet Diaion HP20 (1 kg) and excessively eluted with H2O (10 L). The
combined aqueous elutes were lyophilized to afford white powder (3 g), which
was subsequently purified by crystallization using hot MeOH.
tols evaluated did not inhibit maltase and sucrase, type II
sidases from rat small intestine.
a-gluco-
8. (+)-Conduritol
F
(5): colorless oil, ½ ꢁ
a 2D5 = +79.5 (c 1.12, CH3OH); 1H NMR
In summary, we have simply and efficiently achieved short syn-
thesis steps for (+)-conduritol F and inositols: (+)-chiro- and (+)-
epi-inositols, from naturally available (+)-proto-quercitol. A key
step involves dehydration of protected (+)-proto-quercitol (2) after
addition of Tf2O in pyridine, therefore taking a total of three steps
to produce optically pure conduritol F in excellent yield. Further-
more, our method also provides rapid access to corresponding
dihydroxy analogues, (+)-chiro- and (+)-epi-inositols. A potent inhi-
(CD3OD, 400 MHz) d 5.71 (ddd, J = 9.9, 4.8, 1.9 Hz, 1H), 5.64 (dd, J = 10.1, 2.0 Hz,
1H), 4.09 (t, J = 4.4 Hz, 1H), 3.85 (d, J = 7.6 Hz, 1H), 3.54 (dd, J = 10.4, 7.7 Hz, 1H),
3.35 (dd, J = 10.3, 4.0 Hz, 1H); 13C NMR (CD3OD, 100 MHz) d 133.8, 128.0, 74.0,
73.9, 72.7, 68.0.
9. (a) Kwon, Y.-U.; Lee, C.; Chung, S.-K. J. Org. Chem. 2002, 67, 3327; (b) Heo, J.-N.;
Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697.
10. An attempt to address configurations of newly generated dihydroxy groups of
6a and 6b by NOESY could not be performed since severely overlapped signals
of hydroxylated methine protons. However, significant difference in methyl
signals of acetonides was observed; 6b showed separated four methyl
resonances whereas 6a demonstrated only three signals.
bition of conduritol F, selectively against typeI a-glucosidase, over
related compounds as well as antidiabetic drug acarbose suggests
that its half-chair conformation is critical for its biological activity.
11. (+)-chiro-Inositol (7a): pale yellow oil: ½a D25
ꢁ
= +81.9 (c 0.45, H2O); 1H NMR
(D2O, 400 MHz) d 3.81 (br s, 2H), 3.54 (br d, J = 7.2 Hz, 2H), 3.37 (br d, J = 7.2 Hz,
2H); 13C NMR (D2O, 100 MHz) d 72.8, 71.7, 70.5.
12. (+)-epi-Inositol (7b): white solid: ½a D25
ꢁ
= +36.0 (c 0.27, H2O); 1H NMR (D2O,
400 MHz) d 3.86 (br s, 1H), 3.81 (br s, 1H), 3.53 (br s, 2H), 3.37 (dd, J = 7.2,
2.4 Hz, 1H), 3.28 (dd, J = 9.6, 2.4 Hz, 1H); 13C NMR (D2O, 100 MHz) d 74.5, 72.8,
71.8, 71.7, 70.5.
Acknowledgments
13. Freeman previously reported inhibitory effect of conduritol
F
against b-
This work was supported by the Thailand Research Fund
(DBG5380037) and Faculty of Science through the Research Strate-
gic Plan (A1B1-6). W.W., E.R. and A.V. are grateful to the Royal
galactosidase with an IC50 value of 600
lM; Freeman, S.; Hudlicky, T. Bioorg.
Chem. Med. Lett. 2004, 14, 1209.