Synthesis and antiacetylcholinesterase activity of new D-glyceraldehyde heterocyclic derivatives

Article abstract of DOI:10.1590/S0103-50532010000100008

We report herein the convenient procedures for the syntheses of different heterocyclic compounds from 2,3-O-isopropylidene-D-glyceraldehyde using intramolecular cyclization, 1,3-dipolar cycloaddition or bimolecular coupling reactions. The products were ch

Full text of DOI:10.1590/S0103-50532010000100008

J. Braz. Chem. Soc., Vol. 21, No. 1, 43-48, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Synthesis and Antiacetylcholinesterase Activity of
New D-Glyceraldehyde Heterocyclic Derivatives
Cecilia M. Scorzo,a Mirta L. Fascio,a Norma B. D’Accorso,*,a
Margarita Gutiérrez Cabrerab and Luís Astudillo Saavedrab
a CIHIDECAR-CONICET. Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Buenos Aires, Argentina
b Laboratorio de Síntesis Orgánica, Instituto de Química de Productos Naturales,
Universidad de Talca, Casilla 747, Talca, Chile
Neste trabalho são apresentados os procedimentos para a síntese de diferentes compostos
heterocíclicos a partir do 2,3-O-isopropilideno-D-gliceraldeído: ciclização intramolecular,
cicloadição 1,3-dipolar e reação de acoplamento bimolecular. Os produtos sintetizados foram
1
caracterizados por espectroscopia de H RMN e 13C RMN e análise elementar. Os novos
heterocíclicos e seus derivados (12 compostos) foram testados como inhibidores da enzima
acetilcolinesterase.
We report herein the convenient procedures for the syntheses of different heterocyclic
compounds from 2,3-O-isopropylidene-D-glyceraldehyde using intramolecular cyclization,
1,3-dipolar cycloaddition or bimolecular coupling reactions. The products were characterized by
1H and 13C NMR spectroscopy and elemental analysis. The new heterocycles and their derivatives
were evaluated as inhibitors of acetylcholinesterase enzyme.
Keywords: D-glyceraldehyde, heterocyclic compounds, cycloaddition, acetylcholinesterase,
Alzheimer´s disease
Introduction
significant inhibitory activity on this enzyme, including
three of the four AD drugs currently on the market.4
The series of heterocycles known as benzoisoxazoles
have been developed as potent and selective inhibitors of
the enzime AChE with IC50 values between 0.8-14 nM.5
In addition, ester derivatives of tetrahydroazocines were
synthesized and evaluated as inhibitors of the enzyme
AChE, showing to be selective to the enzyme with IC50
values in the range of 5-40 mM.6 A series of tacrine
analogues has also been synthesized and evaluated as
inhibitors of acetylcholinesterase/butyrylcholinesterase
and modulators of Ca+2 channels and nicotinic
receptors.7
In the present study, a series of new D-glyceraldehyde
heterocyclic derivatives were synthesized and were
evaluated as potential inhibitors of acetylcholinesterase,
so that current approaches to the treatment of cognitive
and behavioral symptoms of AD make use of structurally
diverse cholinesterase inhibitors.
Alzheimer´s disease (AD) is a progressive, degenerative,
and irreversible disorder that causes intellectual impairment
and cognitive dysfunction.1 In the last decade, treatment for
AD has been based on the “cholinergic hypothesis”.2 This
hypothesis suggested that patients with AD suffer from a
deficit of cholinergic function in the brain such as decrease
in hipocampal and cortical levels of acetylcholine (ACh)
and associated enzyme choline transferase. Inhibition of
acetylcholinesterase (AChE), an enzyme responsible for
the metabolic break-down of ACh, can restore the level
of ACh in the brain.3 Hence the development of drugs for
more serious AD is essential.
In the search for new molecules with the potential
effect of inhibiting the enzyme acetylcholinesterase it
is important to note that many heterocycles have shown
*e-mail: norma@qo.fcen.uba.ar

44
Synthesis and Antiacetylcholinesterase Activity
J. Braz. Chem. Soc.
Results and Discussion
heterocyclization(compound 3)or1,3-dipolarcycloaddition
(compounds 8 and 15), there is no any chiral induction.
The compounds 3, 5-8 and 11-17 (Scheme1) were
evaluated as potential inhibitors of the enzymeAChE.AChE
inhibitory activity was measured at room temperature by
the colorimetric method previously described.12 The results
of enzymatic inhibition are shown in Table 1 expressly as
IC50 in mg mL-1 and mM.
All compounds showed moderate inhibitory activity of
AChE, being compounds 3, 5 and 7 with IC50 values of 110,
220 and 190 mM respectively. The most active compounds
possess one of the following structural characteristics: a
dioxolanic ring (3, 5 and 7), an acetate group (3), a larger
number of carbon atoms (5, 7).
The heterocyclic compounds and their derivatives were
synthesized from 2,3-O-isopropylidene-D-glyceraldehyde
using simple and efficient methodologies (Scheme 1).
Compound 3 was obtained using intramolecular
heterocyclization as we have previously described.8
In turn compounds 5, 6 and 8 were synthesized by
1,3-dipolar cycloaddition from the 2,3-O-isopropylidene-
D-glyceraldehyde oxime using alkynes9 or alkenes10 as
dipolarophiles. The 1,2,4-oxadiazole derivatives (11 and
12) were obtained by cyclization of O-acyl amidoxime,
which were synthesized using the technique described
in the literature.11 Compounds 13-17 were obtained by
deprotection of the corresponding precursors with acid
medium. After purification by chromatographic column
or recrystallization, compounds 2, 5-7, 11-14, 16 and 17
were obtained with moderate yields (see experimental) and
were characterized by NMR spectroscopy. Spectroscopic
data were in full agreement with those expected.
Conclusion
In summary, a new group of heterocyclic derivatives of
2,3-O-isopropylidene-D-glyceraldehyde with protected and
unprotected hydroxyl groups were efficiently synthesized.
Thenewderivativeswerecharacterizedby1HNMR,13CNMR
and 2D heteronuclear techniques. Twelve compounds were
evaluated as inhibitors of acetylcholinesterase showing
moderate to low activity. The most active compounds were
3, 5 and 7 with IC50 less than 220 mM.
The syntheses of 3, 8 and 15 involved the formation
of new asymmetric centre. Spectroscopic analysis of
these compounds showed both diasteromers, in quasi-
equimolecular ratio. These facts can be explained
because during the process of cyclization, intramolecular
N
HON
HON
O
NH2
H
H
C
C
f
g
c
C
C
O
O
O
O
O
O
O
O
1
9
10
4
d
e
a
h
H
R2
O
O
S
O
N
NHCNH2
S
N
R1
O
N
N
N
O
N
O
O
2
O
O
O
8
O
5 R1 = Ph
b
6 R1 = CH2OH
7 R1 = CH2OBz
11 R2 = Ph
12 R2 = o-ClPh
i
j
AcHN
S
j
j
N
N
S
N
R1
O
R2
O
Ac
O
O
O
H
N
N
N
N
HO
HOH2C
HO
HOH2C
HO
HOH2C
3
H
H
H
13 R1 = Ph
14 R1 = CH2OBz
15
16 R2 = Ph
17 R2 = o-ClPh
a) NH2CSNHNH2, EtOH; b) (CH3CO)2O, Py; c) NH2OH.HCl, Na2CO3, H2O; d) Chloramine-T,
phenylacetylene, EtOH-H2O (5); chloramine-T, propargyl alcohol (6); e) 4-methyl-5-vinylthiazole, chloramine-
T, EtOH-H2O; f) SOCl2, Na2CO3, CH2Cl2 (anhydrous); g) NH2OH.HCl, Na2CO3, MeOH-H2O; h) PhCO2H
(11) or o-Cl-PhCO2H (12), DCC, CH2Cl2 (anhydrous), 3 h at rt, then 110-120º C; i) PhCOCl, Py; j) TFA, H2O.
Scheme 1

Vol. 21, No. 1, 2010
Scorzo et al.
45
Table 1. IC50 for AChE inhibition for some selected compounds
2-Acetamido-4-N-acetyl-5-[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]-1,3,4-thiadiazoline (3)
Compound
mg mL-1
31
mM
110
220
1370
190
730
520
680
1120
-
Thiosemicarbazone 2 (0.19 g, 0.95 mmol), acetic
anhydride (3 mL) and pyridine (3 mL) were heated at
reflux and the reaction was monitored by TLC until the
starting material disappeared. The reaction was left at room
temperature and then stopped by adding some water. The
reaction mixture was extracted with chloroform and the
organic phase was dried, evaporated and the residue purified
using flash chromatography (silica gel, cyclohexane/
acetone, 8:2). After purification, a diasteromeric mixture
(54:46 ratio), of thiadiazoline 3 (91.3 mg, 33.0%) was
obtained as a amorphous white solid. 1H NMR (200 MHz,
CDCl3): d 1.32 (s, 3H), 1.33 (s, 3H), 1.44 (s, 3H), 1.46
(s, 3H), 2.21 (s, 3H), 2.22 (s, 3H), 2.23 (s, 3H), 2.24 (s,
3H) (methyl protons); 3.85-4.10 (m, 2H), 3.90 (m, 1H),
4.04 (m, 1H), 4.37 (m, 1H), 4.51(m, 1H) (carbohydrate
protons); 5.95 (d, 1H), 6.13 (d, 1H) (thiadiazolyl protons);
10.00 (s, 1H), 10.03 (s, 1H) (amide proton). 13C NMR (50
MHz, CDCl3): d 21.74, 21.77, 22.97, 23.02, 24.83, 25.17,
26.01, 26.13 (methyl carbons); 65.02, 66.62, 66.37, 66.97
(carbohydrate carbons); 110.07, 110.29 (isopropylidene
carbon); 75.27, 76.47, 148.23, 148.27 (thiadiazolyl
carbons); 169.08, 169.22, 169.82, 169.96 (carbonyl
carbons). ElementalAnal. Calc. for C11H17N3O4S: C, 45.98;
H, 5.96. Found: C, 45.68; H, 6.08.
3
5
54
6
272
56
7
8
196
127
191
230
> 500
114
> 500
178
1.1
11
12
13
14
15
500
-
16
17
740
3.0
Galanthamine
Experimental
Optical rotations were recorded at 20 °C on a Perkin
Elmer 343 polarimeter, and the melting points were
uncorrected. 1H NMR and 13C NMR spectra were recorded
on a BrukerAC-200 spectrometer at 200 MHz and 50 MHz.
Elemental analyses were performed by UMYMFOR,
CONICET-University of Buenos Aires, Argentina.
Analytical TLC was conducted on Silica Gel 60G (Merck)
on precoated plates and visualization was made by UV
light and ethanol/sulfuric acid (10:1) or cerium molibdate,
followed by heating. Column-chromatographic separations
were performed on Silica Gel (240-400 mesh, Merck).
Solvents were reagent grade and, in most cases, dried and
distilled before use according to standard procedures.
General procedure 1: synthesis of isoxazol and isoxazoline
derivatives (5, 6, 8)
An ethanolic solution of 2,3-O-isopropylidene-D-
glyceraldehydeoxime14 (4) (1.00 g, 6.90 mmol) was added
slowly, at room temperature, to an ethanolic solution of
dipolarophiles with an excess of chloramine-T. The reaction
was monitored by TLC (cyclohexane/acetone, 7:3). The
product was purified by column chromatography (silica gel,
cyclohexane/acetone, with different ratio). The respectively
compounds were characterized as follows.
2,3-O-Isopropylidene-D-glycerothiosemicarbazone (2)
The 2,3-O-isopropylidene-D-glyceraldehyde13 (0.98 g,
7.50 mmol) was dissolved in ethanol and heated with a small
excess of thiosemicarbazide. The reaction was monitored by
TLC until no starting material was observed. The reaction
medium was evaporated and the residue purified by flash
chromatography (alumina, cyclohexane/ethyl acetate, 7:3).
Compound 2 was obtained as yellow syrup (1.20 g, 78.3%).
1H NMR (200 MHz, CDCl3): d 1.33 (s, 3H), 1.37 (s, 3H)
(methyl protons); 3.88 (dd, 1H), 4.12 (dd, 1H), 4.57 (dd, 1H)
(carbohydrate protons); 7.10 (s, 1H), 7.30 (s, 1H), 7.33 (s,
1H) (thiourea protons); 10.65 (s, 1H) (CH=N). 13C NMR (50
MHz, CDCl3): d 25.25, 26.40 (methyl carbons); 67.05, 74.79
(carbohydrate carbons); 110.26 (isopropylidene carbon);
144.56 (imine carbon), 178.19 (thiocarbonyl carbon).
Elemental Anal. Calc. for C7H13N3O2S: C, 41.36; H, 6.45;
N, 20.67. Found: C, 41.35; H, 6.54; N, 20.41.
3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5-phenyl-
isoxazole (5)
General procedure 1 was applied using phenylacetylene
(1.30 mL) as the dipolarophile yielding compound 5
(0.56 g, 33%) as a syrup, [a]D + 9.7 (c 1, CHCl3 ). 1H NMR
(CDCl3): d 1.47 (s, 3H), 1.53 (s, 3H) (methyl protons);
4.09 (dd, 1H), 4.39 (dd, 1H), 5.25 (t, 1H) (carbohydrate
protons); 6.59 (s, 1H) (isoxazolyl proton); 7.33-7.90 (m,
5H) (aromatic protons). 13C NMR (CDCl3): d 25.38,
26.38 (methyl carbons); 68.94, 70.36 (carbohydrate
carbons); 110.34 (isopropylidene carbon); 125.72, 127.14,
128.88, 130.19 (aromatic carbons); 97.60, 164.24, 170.26

46
Synthesis and Antiacetylcholinesterase Activity
J. Braz. Chem. Soc.
(isoxazolyl carbons). ElementalAnal. Calc. for C14H15NO3:
C, 68.57; H, 6.12. Found: C, 68.30; H, 6.22.
1H), 4.27 (dd, 1H), 4.98 (m, 1H), 5.00 (m, 1H) (carbohydrate
protons); 3.02 (dd, 1H), 3.07 (dd, 1H), 3.52 (dd, 1H),
3.57 (dd, 1H), 5.87 (dd, 1H), 5.90 (dd, 1H) (isoxazolidyl
protons); 8.68 (s, 1H), 8.67 (s, 1H) (thiazolyl protons).
13C NMR (CDCl3): d 14.90, 15.19, 24.88, 24.90, 26.09
(methyl carbons); 66.88, 66.97, 70.78, 70.82 (carbohydrate
carbons); 110.36, 110.38 (isopropylidene carbons); 41.86,
41.89, 75.35, 75.56, 150.38, 150.42 (isoxazolidyl carbons);
129.43, 130.75, 151.13, 151.32, 157.88, 157.99 (thiazolyl
carbons). ElementalAnal. Calc. for C12H16N2O3S: C, 53.71;
H, 6.01. Found: C, 53.64; H, 5.78.
5-Hydroxymethyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]
isoxazole (6)
General procedure 1 was applied to 2-propyn-1-ol
(5.1 mL) as the dipolarophile yielding compound 6
(0.81 g, 59%) as a syrup which was purified by column
chromatography (silica gel, toluene/ethyl acetate, 8:2).
1
[a]D +16.8 (c 1, CHCl3). H NMR (CDCl3): d 1.38 (s,
3H), 1.41 (s, 3H) (methyl protons); 3.93 (dd, 1H), 4.27
(dd, 1H), 5.11 (t, 1H) (carbohydrate protons); 4.64 (s, 2H)
(methylenic protons); 6.25 (s, 1H) (isoxazolyl proton).
13C NMR (CDCl3): d 25.18, 26.17 (methyl carbons);
55.89 (methylenic carbon); 68.73, 70.04 (carbohydrate
carbons); 110.39 (isopropylidene carbon); 99.99, 163.55,
172.19 (isoxazolyl carbons). Elemental Anal. Calc. for
C9H13NO4: C, 54.26; H, 6.58; N, 7.03. Found: C, 54.04;
H, 6.57; N, 7.37.
2,3-O-Isopropylidene-D-glyceronitrile (9)
Anhydrous CH2Cl2 (20 mL) was added to a mixture of
414 (1.23 g, 8.5 mmol) and Na2CO3 (3.87 g, 36.5 mmol) in
Ar atmosphere. The reaction mixture was cooled at 0 °C
and 1 mL of SOCl2 was added slowly. The reaction was
monitored by TLC until the starting material disappeared.
The reaction was poured into finely crushed ice and the
product was extracted with CH2Cl2.The solution was dried
with anhydrous Na2SO4, filtered and evaporated. Compound
9 was obtained as a syrup (0.73 g, 68%), [a]D +9.3 (c 1,
5-Benzoyloxymethyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-
4-yl]isoxazole (7)
1
The 5-hydroxymethyl-3-[(4S)-2,2-dimethyl-1,3-
dioxolan-4-yl)isoxazole (6) (0.42 g, 2.09 mmol) was
suspended in 2 mL of pyridine and benzoyl chloride (0.3mL,
2.58 mmol) was added. The reaction was monitored by
TLC until no starting material was observed. The reaction
medium was evaporated and the residue purified by flash
chromatography (silica gel, cyclohexane/acetone, 8:2).
Compound 7 (0.51 g, 81%) was obtained as a syrup,
[a]D +11.7 (c 1, CHCl3). 1H NMR (CDCl3): d 1.45 (s, 3H),
1.49 (s, 3H) (methyl protons); 4.04 (dd, 1H), 4.36 (dd,
1H), 5.22 (dd, 1H) (carbohydrate protons); 5.41 (s, 2H)
(methylenic protons); 6.46 (s, 1H) (isoxazolyl proton);
7.40-8.11 (m, 5H) (aromatic protons). 13C NMR (CDCl3): d
25.34, 26.36 (methyl carbons); 56.64 (methylenic carbon);
68.86, 70.18 (carbohydrate carbons); 110.43 (isopropylidene
carbon); 102.43, 163.85, 167.16 (isoxazolyl carbons);
128.44, 128.98, 129.78, 133.47 (aromatic carbons); 165.65
(carbonyl carbon). Elemental Anal. Calc. for C16H17NO5:
C, 63.36; H, 5.65. Found: C, 63.19; H, 5.99.
CHCl3). H NMR (CDCl3): d 1.40 (s, 3H), 1.55 (s, 3H)
(methyl protons); 4.19 (dd, 1H), 4.29 (dd, 1H), 4.77 (dd,
1H) (carbohydrate protons). C NMR (CDCl3): d 25.41,
25.66(methylcarbons);63.11, 67.97(carbohydratecarbons);
112.66 (isopropylidene carbon); 118.21 (cyano carbon).
13
2,3-O-Isopropylidene-D-glyceroamidoxime (10)
A methanolic solution of compound 9 (0.72 g,
5.65 mmol) and a aqueous solution of hydroxylamine
[prepared from hydroxylamine hydrochloride (0.77 g,
11.1 mmol) and sodium carbonate (0.59 g, 5.6 mmol)
in 5 mL of water] was heated at 60 °C; the reaction
mixture was monitored by TLC until the starting material
disappeared. The reaction medium was evaporated and
the residue purified by flash chromatography (silica gel,
cyclohexane/acetone, 8:2). Compound 10 (0.51 g, 57%)
was obtained as a syrup. 1H NMR (CDCl3): d 1.39 (s, 3H),
1.49 (s, 3H) (methyl protons); 3.99 (dd, 1H), 4.18 (dd,
1H), 4.55 (dd, 1H) (carbohydrate protons); 4.84 (br. s, 2H)
(amine protons); 8.30 (s, 1H) (hydroxyl proton). 13C NMR
(CDCl3): d 25.02, 26.17 (methyl carbons); 67.95, 72.88
(carbohydrate carbons); 110.22 (isopropylidene carbon);
152.93 (amidoxime carbon). Elemental Anal. Calc. for
C6H12N2O3: C, 44.99; H, 7.55. Found: C, 45.02; H, 7.99.
3-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-5-(4-
methylthiazolyl)isoxazoline (8)
General procedure 1 was applied using 4-methyl-5-
vinylthiazole (1.6 mL) as the dipolarophile yielding a
diastereomeric mixture (56:44 ratio) of 8 (0.94 g, 51%) as
a syrup, which was purified by column chromatography
(silica gel, mixture cyclohexane/acetone, starting from 9:1).
1H NMR (CDCl3): d 1.41 (s, 3H), 1.46 (s, 3H), 2.42 (s, 3H)
(methyl protons); 4.04 (dd, 1H), 4.06 (dd, 1H), 4.26 (dd,
5-Phenyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2,4-
oxadiazole (11)
Benzoic acid (0.38 g, 3.15 mmol) was added to a solution
of compound 10 (0.25 g; 1.56 mmol) in anhydrous CH2Cl2

Vol. 21, No. 1, 2010
Scorzo et al.
47
(15 mL), followed by DCC (0.65 g, 3.15 mmol), and the
reaction mixture was stirred at room temperature under
a N2 atmosphere for 3 h. The solid was filtered off, the
solvent was evaporated and the residue was subjected to
the cyclodehydration reaction at 110-120 °C for 4 h. The
product was purified by column chromatography (silica gel,
cyclohexane/acetone, 9:1) yielding compound 11 (0.30 g,
78%) as a syrup, [a]D +16.7 (c 1, CHCl3). 1H NMR (CDCl3):
d 1.51 (s, 3H), 1.59 (s, 3H) (methyl protons); 4.32 (dd, 1H),
4.43 (dd, 1H), 5.30 (t, 1H) (carbohydrate protons); 7.36-8.25
(m, 5H) (aromatic protons). 13C NMR (CDCl3): d 25.66,
26.06(methylcarbons);67.89, 69.88(carbohydratecarbons);
111.21 (isopropylidene carbon); 123.84, 128.11, 128.99,
132.85 (aromatic carbons); 169.78, 176.25 (oxadiazolyl
carbons). Elemental Anal. Calc. for C13H14N2O3: C, 63.40;
H, 5.73; N, 11.38. Found: C, 63.71; H, 5.87; N, 11.30.
5-Benzoyloxymethyl-3-[(1S)-ethanediol-1-yl]isoxazole (14)
Compound 14 was obtained as an amorphous solid
recrystallized from water (0.33 g, 78 %; mp 75-76 °C).
1
[a]D +5.7 (c 1, methanol). H NMR ((CD3)2CO): d 3.78
(d, 2H), 4.86 (t, 1H) (carbohydrate protons); 5.49 (s, 2H)
(methylenic protons); 6.61 (s, 1H) (isoxazolyl proton);
7.32-8.15 (m, 5H) (aromatic protons). 13C NMR ((CD3)2CO):
d 57.74 (methylenic carbon); 66.21, 68.51 (carbohydrate
carbons);129.53, 130.22, 130.90, 134.53(aromaticcarbons);
103.78, 166.52, 168.27 (isoxazolyl carbons); 166.91
(carbonyl carbon). Elemental Anal. Calc. for C13H13NO5:
C, 59.31; H, 4.98; N, 5.32. Found: C, 58.94; H, 4.78; N, 5.35.
3-[(1S)-Ethanediol-1-yl]-5-(4-methylthiazolyl)isoxazoline
(15)
A diastereomeric mixture (56:44 ratio) was obtained
as an amorphous solid purified by silica gel flash
chromatography using toluene:ethanol 8:2 as eluent
(0.23 g, 54%; mp 102-104 °C). 1H NMR (CD3OD): d
2.44 (s, 6H) (methyl protons); 3.72 (d, 4H), 4.53 (t, 2H)
(carbohydrate protons); 3.07 (ddd, 1H), 3.08 (ddd, 1H),
3.61 (ddd, 1H), 3.63 (ddd, 1H), 5.93 (dd, 2H) (isoxazolidyl
protons); 8.86 (s, 2H) (thiadiazolyl protons). 13C NMR
(CD3OD): d 14.94 (methyl carbon); 65.04, 65.09, 69.17,
69.27 (carbohydrate carbons); 43.22, 43.41, 76.33,
150.98, 151.02 (isoxazolidyl carbons); 133.36, 133.48,
153.72, 161.66, 161.69 (thiadiazolyl carbons). Elemental
Anal. Calc. for C9H12N2O3S: C, 47.35; H, 5.30. Found:
C, 47.17; H, 5.09.
5-(2-Chlorophenyl)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]-1,2,4-oxadiazole (12)
Applying the same procedure described for compound
11 but using o-chlorobenzoic acid (0.49 g, 3.15 mmol),
instead of benzoic acid, yielded compound 12 (0.17 g, 38%)
1
as a syrup, [a]D +12.6 (c 1, CHCl3). H NMR (CDCl3):
d 1.51 (s, 3H), 1.60 (s, 3H) (methyl protons); 4.33 (dd,
1H), 4.43 (dd, 1H), 5.34 (t, 1H) (carbohydrate protons);
7.32-8.19 (m, 4H) (phenyl protons). 13C NMR (CDCl3):
d 25.76, 26.12 (methyl carbons); 68.07, 69.90 (carbohydrate
carbons); 111.37 (isopropylidene carbon); 127.02, 128.76,
130.83, 131.42, 131.98, 133.25 (phenyl carbons); 169.66,
174.90 (oxadiazolyl carbons). Elemental Anal. Calc. for
C13H13N2O3Cl: C, 55.62; H, 4.67. Found: C, 55.45; H, 4.27.
5-Phenyl-3-[(1S)-ethanediol-1-yl]-1,2,4-oxadiazole (16)
Compound 16 was obtained as an amorphous solid
recrystallized from toluene (0.11 g, 26.4%; mp 84-85 °C).
[a]D +6.9 (c 1, methanol).1H NMR ((CD3)2CO): d 3.97 (d,
2H), 4.93 (t, 1H) (carbohydrate protons); 7.49-8.33 (m, 5H)
(aromatic protons). 13C NMR ((CD3)2CO): d 65.22, 68.24
(carbohydrate carbons); 125.00, 128.65, 130.15, 133.74
(aromatic carbons); 172.34, 176.22 (oxadiazolyl carbons).
Elemental Anal. Calc. for C10H10N2O3: C, 58.25; H, 4.89;
N, 13.59. Found: C, 58.00; H, 4.76; N, 13.29.
General procedure 2: deprotection of nucleoside analogues
A mixture of 2.04 mmol of 2,3-O-isopropylidene
derivatives (5, 7, 8, 11, 12), 2 mL of TFA and 2 mL of
water was stirred at room temperature for 4 h. The reaction
mixture was evaporated and the deprotected compounds
were purified as described in each cases.
3-[(1S)-Ethanediol-1-yl]-5-phenylisoxazole (13)
Compound 13 was obtained as an amorphous solid
recrystallized from toluene (0.29 g, 70%; mp 88-89 °C).
[a]D +13.6 (c 1, methanol). 1H NMR ((CD3)2CO): d 3.67-
3.90 (m, 2H), 4.86 (dd, 1H) (carbohydrate protons); 6.89
(s, 1H) (isoxazolyl proton); 7.38-8.03 (m, 5H) (aromatic
protons). 13C NMR (CD3OD): d 66.50, 68.54 (carbohydrate
carbons); 126.39, 128.49, 129.97, 130.94 (aromatic
carbons); 99.34, 166.59, 169.96 (isoxazolyl carbons).
Elemental Anal. Calc. for C11H11NO3: C, 64.38; H, 5.40;
N, 6.83. Found: C, 64.15; H, 5.25; N, 7.01.
5-(2-Chlorophenyl)-3-[(1S)-ethanediol-1-yl]-1,2,4-
oxadiazole (17)
Compound 17 was obtained as an amorphous solid
recrystallized from toluene (0.17 g, 39.5%; mp 76-78 °C).
[a]D +5.9 (c 1, methanol).1H NMR (CD3OD): d 3.85-3.95
(m, 1H), 3.92-4.01 (m, 1H), 4.93 (t, 1H) (carbohydrate
protons); 7.45-8.16 (m, 4H) (aromatic protons). 13C NMR
(CD3OD): d 66.13, 69.32 (carbohydrate carbons); 125.51,
129.43, 133.30, 133.98, 135.39, 135.64 (aromatic carbons);
173.23, 176.88 (oxadiazolyl carbons). Elemental Anal.

48
Synthesis and Antiacetylcholinesterase Activity
J. Braz. Chem. Soc.
Calc. for C10H9N2O3Cl: C, 49.91; H, 3.77; N, 11.64. Found:
C, 49.77; H, 3.64; N, 11.58
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Financial support from CONICET (PIP 5011),ANPCyT
(PICT13922)andUBA(X058)aregratefullyacknowledged.
C.M.S. is a research fellow of the National Research Council
ofArgentina (CONICET) and N.B.D. is a Research Member
of the CONICET. Luis Astudillo Saavedra acknowledges
Fondecyt Project 1050985 and Anillo PBCT ACT-38.
Margarita Gutierrez Cabrera acknowledges Project PBCT
(PSD-16) for a postdoctoral grant.
Received: February 26, 2009
Web Release Date: October 9, 2009