(+)-proto-Quercitol, a natural versatile chiral building block for the synthesis of the α-glucosidase inhibitors, 5-amino-1,2,3,4-cyclohexanetetrols

Article abstract of DOI:10.1016/j.tetlet.2009.02.153

An efficient synthesis of diastereomerically pure 5-amino-1,2,3,4-cyclohexanetetrols (6 and 11) and quercitol derivatives from naturally available (+)-proto-quercitol (1) is described. The stereochemistry of 1 is perfectly set up for regioselective protec

Full text of DOI:10.1016/j.tetlet.2009.02.153

Tetrahedron Letters 50 (2009) 2189–2192
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
(+)-proto-Quercitol, a natural versatile chiral building block for the synthesis
of the
a-glucosidase inhibitors, 5-amino-1,2,3,4-cyclohexanetetrols
Sumrit Wacharasindhu a, , Wisuttaya Worawalai a,b, Wimolpun Rungprom c, Preecha Phuwapraisirisan a,
*
*
a Natural Products Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
b Center of Excellence for Petroleum, Petrochemical, and Advanced Materials, Chulalongkorn University, Bangkok 10330, Thailand
c Faculty of Science and Technology, Phra Nakorn Sri Ayutthaya Rajaphat University, Ayutthaya 13000, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of diastereomerically pure 5-amino-1,2,3,4-cyclohexanetetrols (6 and 11) and
quercitol derivatives from naturally available (+)-proto-quercitol (1) is described. The stereochemistry
of 1 is perfectly set up for regioselective protection of the hydroxy group which was further functional-
ized into the target aminocyclitol in a straightforward manner. The present approach provides a protocol
for preparing aminocyclitols in large quantities. In addition, the absolute stereochemistry of (+)-proto-
quercitol was addressed using the modified Mosher’s method. Of the synthesized aminocyclitols, 11
Received 10 November 2008
Revised 11 February 2009
Accepted 20 February 2009
Available online 25 February 2009
potentially inhibits
a
-glucosidase with an IC50 value of 12.5
lM, which is 45 times greater than that of
the standard antidiabetes drug, AcarboseÒ.
Ó 2009 Elsevier Ltd. All rights reserved.
Aminocyclitols such as valiolamine, validamine, and valien-
amine were shown to possess inhibitory activity against various
glycosidases (Fig. 1).1 Subsequent investigations regarding chemi-
cal modification, particularly of the amino scaffold, resulted in the
discovery of voglibose, a clinically potent remedy to control diabe-
tes mellitus (DM).2 The inhibitory effect of aminocyclitols has been
HO
HO
OH
OH
HO
OH
OH
OH
OH
H2N
H2N
RHN
OH
OH
OH
OH
validamine
valienamine
valiolamine R = H
voglibose R = CH(CH2OH)2
elaborated on the basis of their structural resemblance to the D-
glucopyranosyl cation possibly generated during hydrolysis of
their glycosides and strong covalent bonding to the active site of
the enzyme.3 Several syntheses of aminocyclitols have been
accomplished using cyclohexanepentols, trivially called quercitols,
as starting components.4 In fact, quercitol has 16 possible stereo-
isomers, however only (+)-proto-, (ꢀ)-proto-, and (ꢀ)-vibo-querci-
tols have been encountered abundantly in Nature.5
OH
OH
OH
OH
HO
OH
OH
HO
OH
OH
(+)-proto-quercitol (1)
(-)-vibo-quercitol
To date, there have been a few reports on the syntheses of
aminocyclitols from natural quercitols. Although Ogawa succeeded
in the preparation of 5-amino-1,2,3,4-cyclohexanetetrol analogues
from (ꢀ)-vibo-quercitol, nearly half of the product yield was lost in
the early steps.4b We considered that protection of a 1,2-diol as an
acetonide could not be carried out specifically at C-1/C-2 and C-3/
C-4, therefore yielding 3-hydroxy- and 5-hydroxy-bis-acetonide
quercitols as an inseparable mixture. In addition, a similar result
was also observed by Ogawa in the synthesis of aminocyclitols
using unnatural (ꢀ)-epi-quercitol.4a
Figure 1.
is likely to be a potential candidate due to the possibility of gener-
ating a single bis-acetonide, in addition to its natural availability.
In this Letter, we report the first synthesis of diastereomerically
pure 5S- and 5R-amino-1,2,3,4-cyclohexanetetrols (6 and 11) using
(+)-proto-quercitol (1). Furthermore, determination of the absolute
configuration of 1 using the modified Mosher’s method is also
described.
(+)-proto-Quercitol (1) utilized in this study was isolated from
the stems of Arfeuillea arborescens using the previously described
method with slight modification.6 The MeOH extract, after parti-
tioning with hexane and CH2Cl2, was concentrated to afford the de-
sired quercitol (ca. 0.6%) as colorless crystals.7 The structure and
relative configuration were determined by spectroscopic tech-
To circumvent this problem, the use of the correct stereoisomer
of quercitol is crucial. Of all the stereoisomers, (+)-proto-quercitol
* Corresponding authors. Tel.: +66 2 2187634; fax: +66 2 2187598 (S.W.).
E-mail addresses: sumrit.w@chula.ac.th (S. Wacharasindhu), preecha.p@chu-
la.ac.th (P. Phuwapraisirisan).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.153

2190
S. Wacharasindhu et al. / Tetrahedron Letters 50 (2009) 2189–2192
niques, including 2D NMR. Despite the first report of 1 from Nature
since 1961,8 the absolute configurations of all the stereogenic cen-
ters have not been addressed.
O
O
O
e
2
O
Prior to applying the modified Mosher’s approach, protection of
the hydroxy groups was required to avoid combined anisotropy ef-
fects caused by multiple MTPA moieties.9 Treatment of 1 with a
large excess of 2,2-dimethoxypropane (10 equiv) in DMF in the
presence of p-TsOH at ambient temperature yielded 1,2:3,4-di-O-
isopropylidene derivative 2 as a single product (Scheme 1).10 The
NOESY data indicated that the acetonides that formed between
C-1 and C-2 and between C-3 and C-4 were trans- and cis-oriented,
respectively (Fig. 2). The bis-acetonide 2 was then treated with (+)-
and (ꢀ)-MTPACl, separately, to furnish the desired R- and S-MTPA
54%
O
7
f, 93%
a, 78%
OH
OMs
O
O
O
O
O
O
O
O
esters. The
DdSR distribution indicated the 5R configuration, there-
3
8
fore the absolute configurations of the remaining chiral centers are
addressed as shown in Scheme 2.
a, 82%; b, 84%
b, 79%
After the absolute stereochemistry of the carbocyclic frame-
work had been established, we next investigated the synthesis of
5S-amino-1,2,3,4-cyclohexanetetrol (6) (Scheme 3). In an effort to
prepare azide 4, we first attempted to transform bis-acetonide 2
into the corresponding chloride by reaction with thionyl chloride.
Unfortunately, this was unsuccessful, presumably due to steric
hindrance from the two adjacent acetonide groups.
Alternatively, the 5-OH group of 2 was activated by converting
it to mesylate analogue 3. Reaction of 3 with an excess of sodium
azide in DMF at 100 °C in the presence of 15-crown-5 ether affor-
ded selectively the azide 4 (79%) as the sole product after flash
chromatography. The chemical shift at dH 3.35 with a large cou-
pling constant (J 5,6ax = 11.6 Hz) suggested that the azido group
was incorporated with inversion of configuration. Reduction of
azide 4 proceeded smoothly upon treatment with LiAlH4, leading
to formation of the corresponding amine 5 in good yield. Exposure
N3
N3
O
O
O
O
O
O
O
O
4
9
c, 71%
c, 43%
NH2
NH2
O
O
O
O
O
O
O
O
10
5
d, 63%
d
OH
OH
5
OH
OH
Me2C(OMe)2
DMF, -TsOH
75%
O
O
NH2
NH2
1
HO
3
OH
OH
p
OH
OH
O
OH
O
HO
HO
1
2
OH
11
OH
6
Scheme 1. Preparation of 1,2:3,4-di-O-isopropylidene derivative 2.
Scheme 3. Reagents and conditions: (a) MeSO2Cl, Et3N, DMAP; (b) NaN3, DMF, 15-
crown-5-ether, 100 °C; (c) LiAlH4; (d) TFA, THF; (e) Ac2O, DMSO; (f) LiAlH4.
of the amine 5 to trifluoroacetic acid in THF at room temperature
furnished the target molecule, aminocyclitol 6 in 63%.11
CH3
O
H
O
H
OH
1
3
2
O
CH3
H
5
6
4
H3C
H3C
CH
O
3
H
H
O
OH
O
1
3
2
5
O
6
CH
H
H-6eq
3
H-6ax
4
H C
H
3
Figure 2. Selected NOESY correlations of 2. For clarity, certain H atoms are omitted.
H
O
H3C
2
MTPAO -0.118
(+)- or (-)-MTPA Cl, py
+0.062
CH
O
3
H
H
O
H
H
O
O
-0.002
-0.001
+0.056
2
H-6eq
O
CH
3
+0.067
O
H C
HO
3
H-6ax
O
H C
3
8
O
+0.005
+0.028
4.50
4.00
3.50
3.00
2.50
2.00
Scheme 2. Preparation of S- and R-MTPA esters of
distribution.
2 and the unequal DdSR
Figure 3. Partial 1H NMR (400 MHz, CDCl3) spectra of 2 (top) and 8 (bottom).

S. Wacharasindhu et al. / Tetrahedron Letters 50 (2009) 2189–2192
2191
O
generating exclusively diastereomeric 5-hydroxy-bis-acetonide 8
(93%), with no 2 being detectable. This could be rationalized by
preferential hydride attack on the less hindered face of ketone 7.
Obviously, compounds 2 and 8 could be differentiated by 1H
NMR spectra (Fig. 3); H2-6 of the former resonated at about dH
2.04–2.11 while those of the latter were well separated [dH 2.36
(H-6 equiv) and 1.88 (H-6ax)]. With 5-hydroxy-bis-acetonide 8 in
hand, we subsequently accomplished the synthesis of the 5R-ami-
no congener 1113 in a manner similar to that of aminocyclitol 6. In
order to gain more information on the pharmacophore required for
C-5, we synthesized other cyclitol derivatives. Deprotection of 7
and 8 was carried out under the aforementioned conditions, and
subsequent purification by recrystallization afforded pure target
cyclitols 1214 and 1315 in moderate yields (Scheme 4).
OH
OH
TFA, THF
76%
7
8
12
13
HO
HO
OH
OH
OH
OH
TFA, THF
91%
OH
Scheme 4.
Table 1
-Glucosidasea inhibitory effect of compounds 1, 6, 11, 12, and 13
5-Amino-1,2,3,4-cyclohexanetetrols (6 and 11) and deprotected
a
analogues 12 and 13 were evaluated for
(Table 1) using a method reported previously.16 The synthesized
compounds showed weak inhibition (IC50 670–2890 M) than
the antidiabetes drugs (AcarboseÒ and DNJ), except for amino
cyclitol 11 (IC50 12.5 M). The very large difference in the inhibi-
tory effect of the two diastereomeric aminocyclitols 6 and 11
(IC50 2890 vs 12.5 M) suggested that the configuration of the 5-
a-glucosidase inhibition
Compound
Inhibitory effect (IC50, lM)
NIb
2890
12.5
670
921
570
173
1
6
11
12
l
l
13
AcarboseÒ
DNJ
l
NH2 was possibly essential for mimicking the conformation and
charge of the oxycarbenium ion intermediate.
a
a
-Glucosidase was obtained from Baker’s yeast.
b
Inhibitory effect less than 30% at 10 mg/mL.
In summary, we have prepared diastereomerically pure 5S- and
5R-amino-1,2,3,4-cyclohexanetetrols (6 and 11) from natural (+)-
proto-quercitol (1) via two parallel routes. The key to the success
involved the exclusive formation of bis-acetonide 2, which was
generated through cis-ketal 14 (Scheme 5). In cases where several
1,2-acetonides are possible, formation of a cis-cyclic ketal is more
favorable than that of the trans-derivative. On the other hand,
(ꢀ)-vibo-quercitol afforded an inseparable mixture of bis-aceto-
To gain insight into the relationship between the stereochemis-
try of the 5-amino group and the inhibitory effect toward -gluco-
sidase, the 5R-amino congener 11 was also prepared. Initially, bis-
acetonide 2 was subjected to oxidation using the Albright-Gold-
man reagent (DMSO/Ac2O),12 to afford ketone 7 (54%). Selective
reduction of 7 was carried out with LiAlH4 in THF as the solvent,
a
lessfavorable
lessfavorable
(
trans -diol)
(
trans -diol)
morefavorable
cis-diol)
(
OH
1
OH
1
OH
2
OH
2
3
3
OH
HO
OH
HO
HO
5
6
4
5
6
4
OH
(-)-vibo -quercitol
(+)-proto-quercitol
morefavorable
cis-diol)
(
2,2-dimethoxypropane
2,2-dimethoxypropane
H3C
H3C
HO
O
OH
OH
O
OH
OH
OH
O
H3C
H3C
15
14
O
2,2-dimethoxypropane
2,2-dimethoxypropane
OH
O
O
O
O
O
O
O
+
O
O
OH
HO
O
O
O
2
16
17
inseparable mixture
single product
Scheme 5. Mechanistic formation of bis-acetonides 2, 16, and 17 generated from (+)-proto-quercitol and (ꢀ)-vibo-quercitol.

2192
S. Wacharasindhu et al. / Tetrahedron Letters 50 (2009) 2189–2192
7. (+)-proto-Quercitol (1): colorless crystals; mp 235–236 °C; ½a D27
ꢁ
+27.9 (c 0.02,
nides 16 and 174b on treatment with 2,2-dimethoxypropane
though cis-cyclic ketal 15 was initially generated. This can be ratio-
nalized by the possible formation of a second acetonide at C-1/C-2
or C-2/C-3. Interestingly, aminocyclitol 11 displayed more striking
inhibition than the diastereomeric congener 6, indicating that the
configuration of the 5-NH2 is critical for blocking the enzyme. With
the excellent biological activity of 11, (+)-proto-quercitol could
serve as an alternative chiral pool substrate for the synthesis of di-
verse aminocyclitols and related analogues.
H2O); 1H NMR (500 MHz, DMSO-d6) dH 4.66 (1H, d, J = 3.4 Hz, OH), 4.49 (1H, d,
J = 3.7 Hz, OH), 4.42 (1H, d, J = 4.3 Hz, OH), 4.37 (1H, d, J = 4.9 Hz, OH), 4.26 (1H,
d, J = 6.1 Hz, OH), 3.67 (1H, ddd, J = 7.0, 6.7, 3.7 Hz), 3.59 (1H, dd, J = 3.7, 3.3 Hz),
3.40–3.51 (2H, m), 3.28 (1H, dt, J = 12.8, 4.0 Hz), 1.56–1.66 (2H, m); 13C NMR
(125 MHz, DMSO-d6) dC 75.0, 72.9, 71.4, 68.9, 68.4. 34.9; 1H NMR (D2O,
400 MHz) dH 3.90 (1H, dd, J = 6.4, 3.2 Hz), 3.80 (1H, dd, J = 3.2, 2.4 Hz), 3.57–
3.66 (2H, m), 3.44 (1H, dd, J = 9.6, 9.2 Hz), 1.86 (1H, ddd, J = 13.9, 3.2, 3.2 Hz),
1.69 (1H, ddd, J = 13.9, 11.6, 2.8 Hz); 13C NMR (100 MHz, D2O + one drop of
acetone-d6) dC 74.2, 71.8, 70.6, 68.5, 68.2, 32.9; ESIMS m/z [M+H]+ 165.
8. Plouvier, V. C. R. Séances Acad. Sci. Paris 1961, 253, 3047–3054.
~
´
9. Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–117.
10. We have observed the formation of 3,4-O-isopropylidene derivative 14 during
Acknowledgments
purification of the reaction mixture of 2 by silica gel column chromatography
using hexane–EtOAc (1:1)
OH
W.W. is grateful to the Center of Excellence for Petroleum, Pet-
rochemical, and Advanced Materials for a scholarship. We thank
Ms. Rattiya Wadthaisong, Valaya-Alongkorn Rajabhat University,
for the synthesis of some of the intermediates. This work was
granted by the Commission on Higher Education.
O
O
HO
OH
14
.
11. 5S-Amino-1R,2S,3S,4S-cyclohexanetetrol (6): 1H NMR (400 MHz, CD3OD) dH
1.87 (1H, m), 1.94 (1H, m), 3.29–3.25 (2H, m), 3.43 (1H, m), 3.53 (1H, m), 3.98
(1H, m); 13C NMR (100 MHz, CD3OD) dC 30.7, 48.3, 69.2, 69.4, 72.6, 74.0;
HRESIMS m/z 164.0921 [M+H]+ (calcd for C6H13NO4+H, 164.0923).
12. Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416–2423.
13. 5R-Amino-1R,2S,3S,4S-cyclohexanetetrol (11): 1H NMR (400 MHz, CD3OD)
dH 1.95 (1H, m), 2.06 (1H, m), 3.38 (1H, m), 3.53 (1H, m), 3.78 (1H, m),
3.90–3.95 (2H, m); 13C NMR (100 MHz, CD3OD) dC 31.1, 49.1, 69.0, 69.8,
70.4, 73.7; HRESIMS m/z 164.0922 [M+H]+ (calcd for C6H13NO4+H,
164.0923).
References and notes
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2. Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.; Matsui, K. J. Med Chem.
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and references cited therein.
14. Cyclitols 12 1H NMR (400 MHz, DMSO-d6) dH 2.32 (1H, dd, J = 12.0, 4.0 Hz), 2.71
(1H, dd, J = 12.0, 4.0 Hz), 3.81 (1H, br s), 3.92 (1H, br s), 3.93 (1H, br s), 4.27 (1H,
br s, 1H), 4.94 (2H, br s), 5.10 (1H, br s), 5.46 (1H, br s).
15. Cyclitol 13: 1H NMR (400 MHz, D2O) dH 1.59 (1H, m), 1.79 (1H, m), 3.25 (1H,
m), 3.32 (2H, m), 3.60 (1H, br d, J = 12.4 Hz), 3.81 (1H, br s).
16. (a) Phuwapraisirisan, P.; Puksasook, T.; Jong-aramruang, J.; Kokpol, U. Bioorg.
Med. Chem. Lett. 2008, 18, 4956–4958; (b) Schäfer, A.; Högger, P. Diabetes Res.
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6. Phuwapraisirisan, P. Chemical constituents from the stems of Arfeuillea
arborescens Pierre and their biological activity. MSc thesis, Chulalongkorn
University, 1998; 33–44.