Synthesis of 2,3-unsaturated o-glycosides from optically active alcohols via ferrier rearrangement: configurational studies

Article abstract of DOI:10.4067/S0717-97072015000400004

4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanones 4a-e have been reduced to optically active 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanols 5a-e with baker's yeast. We subjected the alcohols possessing (S)-configuration to Ferrier' rearrangement with tri-O-acetyl-D

Full text of DOI:10.4067/S0717-97072015000400004

J. Chil. Chem. Soc., 60, Nº 4 (2015)
SYNTHESIS OF 2,3-UNSATURATED O-GLYCOSIDES FROM OPTICALLY ACTIVE ALCOHOLS VIA FERRIER
REARRANGEMENT: CONFIGURATIONAL STUDIES
JOÃO RUFINO FREITAS FILHOa*, JUCLEITON JOSÉ RUFINO DE FREITASb, LOUIS COTTIERc, DENIS
SINOUc AND RAJENDRA MOHAN SRIVASTAVAb
aDepartamento de Química, Universidade Federal Rural de Pernambuco, Av. Dom Manoel de Medeiros, s/n, 52171-900, Recife, PE, Brazil.
bDepartamento de Quıímica Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, 50.740-540 Recife, PE, Brazil.
cLaboratoire de Synthèse Asymétrique, UMR 5181 CNRS, C.P.E. Lyon,Université Claude Bernard Lyon 1, 43 Boulevard du 11 novembre 1918, F-69622
Villeurbanne, France
ABSTRACT
4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanones 4a-e have been reduced to optically active 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanols 5a-e with baker’s yeast. We
subjected the alcohols possessing (S)-configuration to Ferrier’ rearrangement with tri-O-acetyl-D-glucal 6 which furnished new unsaturated O-glycosides 7a-e.
The crystallographic data of the glycosides 7b confirmed the (S)-configuration for the aglycone portion of the carbon atom.
Keywords: Configuration; Crystallographic data; baker’s yeast
(230 – 400 mesh) was employed for liquid chromatography. All commercially
available reagents were used directly without purification unless otherwise
stated. All the solvents used in reactions were distilled for purity.
INTRODUCTION
1,2,4-oxadiazoles can be considered as bioisosters of amides and esters.1a-c
Their biological importance is well documented.2 Their properties make this
class of compounds quite attractive to the pharmaceutical industry. Many
articles indicate that a number of researchers, including those in our own group,
have been trying to synthesize 1,2,4-oxadiazole with asymmetric center on the
side-chain to improve the performance of these molecules as drugs.3,4,1a,5a,b,6 In
recent years, new methods have been used for the synthesis of 1,2,4-oxadiazole
with one or more stereocenters.7,8 Thus, Porcheddu et al.7 proposed a
methodology for the synthesis of various disubstituted 1,2,4-oxadiazoles for the
preparation of heterocycles with a stereocenter with 100% enantiomeric purity.
Asymmetric reduction of prochiral ketones into chiral non-racemic secondary
alcohols is a fundamental process in the synthesis of organic compounds of
biological interest.6,7 Though numerous chemical methodologies are known
in the synthesis of these secondary chiral alcohols, difficulties still remain
in attaining high yields with enantiomeric excess.7 For example, the sodium
borohydride (NaBH4) reduction of ketones may apparently be promoted either
by the electrophilic activation of the substrate or the nucleophilic activation of
the reagent—or, of course, both. This, in fact, leads to a possible asymmetric
variant of the borohydride reaction, catalysis by an optically active alcohol in
an inert solvent.8 Several oxidoreductases are capable of efficiently reducing
ketones with a combination of co-factors such as NADPH or NADH.9 The use
of whole cells, such as in baker’s yeast (Saccharomyces cerevisiae), for chiral
reduction is economically attractive due to its availability, low cost and ease of
handling and disposal.9 Because of the great significance of 1,2,4-oxadiazoles,
and in particular oxadiazoles containing stereocenter in their side-chain which
are being synthesized, we focused our attention first on reducing the side-chain
keto group to alcohol. In this paper, we report on a asymmetric reduction of
4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanones 4a-e using bakers’ yeast. These
alcohols were characterized and later on allowed to react with tri-O-acetyl-D-
glucal to obtain 2,3-unsaturated O-glycosides.
General Procedure for the Synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-
yl]-butan-2-ones
The reaction of 1a–e was with levulinic acid 2 and conducted according to
the method of Srivastava et al.10,11
Synthesis of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butanols
In a shaker with suspension of baker´s yeast ( 50g ), and sucrose (12g)
in deionized water (400 mL ) a solution of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-
2-butanones (1.30g, 6.01 mmol) was added. The suspension was shaken at
room temperature and the reduction followed by TLC. After 72h, the product
was extracted into ethyl acetate (3 x 100mL) followed by separation of the
layers. The combined organic extracts were dried (Na2SO4), filtered, and the
solvent removed under vacuum. The crude product was purified immediately
by chromatography over silica gel using hexane/ethyl acetate (8:2) producing
chromatographically pure 5a-e (Figure 1). The details are given below.
EXPERIMENTAL
Instruments and reagents
Melting points were determined on using an Electrothermal digital melting
point apparatus (model IA9100) and are uncorrected. IR spectra were recorded
as KBr films on a Brucker IFFS66 series Fourier transform spectrophotometer.
Specific rotations were measured with a Perkin–Elmer polarimeter model
241. NMR spectra were recorded with a Varian Unity Plus instrument (300/75
Figure 1. 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butanols (5a-e)-
1
MHz for H/13C) spectrometer, using CDCl3 as the solvent. Chemical shifts
4-[3-phenyl-1,2,4-oxadiazol-5-yl]-2-butanol (5a): Yield 60%, Rf=0.23
(dichromethane–ethyl acetate, 9:1); [α]D25=+7°± 2° (c=0.59, CHCl3); IR νmax
(KBr): 3414, 1590, 1365, 1026, 757 cm−1; 1H NMR (CDCl ): δ 8.07–8.04 (m,
2H, H-2’ and H-6’), 7.49–7.45 (m, 3H, H-3’, H-4’ and H-5’),33.95 (m, 1H, H-8),
3.10 (t, 2H, J 7.7 Hz, H-6 and H-6”), 2.11 (s, 1H, OH), 2.07-2.04 (m, 2H, H,
H-7 and H-7”), 1.28 (d, 3H, J 6.2 Hz, CH ); 13C NMR (CDCl3): δ 179.9 ( C=N),
168.2 (C=N), 131.1 (C-1’), 128.8 (C-4’),3127.4 (C-3’), 126.7(C-2’), 67.2( C-8),
are reported in parts per million (ppm) downfield from an internal TMS
(trimethylsilane) reference. Elemental analysis was performed with a Carlo
Erba instrument model E-1110. Silica gel coated plates with a fluorescent
indicator (PF254) were used for thin-layer chromatography (TLC), and the
spots were detected under ultraviolet light. The solvent system for running the
TLC plates was a mixture of 1:9 ethyl acetate–dichlromethane. Silica gel 60
e-mails: joaoveronice@yahoo.com.br
2646

J. Chil. Chem. Soc., 60, Nº 4 (2015)
35.7 (C-7), 24.0 (C-6), 23.2 (CH3). Anal. Calcd for (C12H14O7N2.1/8H2O): C,
65.36; H, 6.48; N, 12.70 Found: C, 65.12; H, 6.81; N, 12.38.
(S)-1-Methyl-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propyl-4,6-di-O-acetyl-
2,3-dideoxy-α-d-eryhtro-hex-2-enopyranoside (7a): Yield 72%; Rf=0.65
(dichromethane–ethyl acetate, 9:1); mp 65.4–66.3°C; [α]D20=+61° (c=0.53,
4-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl]-2-butanol (5b): Yield 64%, Rf=0.32
(dichromethane–ethyl acetate, 9:1); [α]D25=+11.25 (c=1.2, CHCl3); IR νmax
(KBr): 3410, 1570, 1365, 760 cm−1; 1H NMR (CDCl ): δ 7.97 (d, 1H, J 7.5,
H-2’), 7.39–7.28 (m, 3H, H-2’, H-3’ and H-4’), 3.97 (3m, 1H, H-8), 3.11 (t, 2H,
J 7.5 Hz, H-6 and H-6”), 2.62 ( s, 3H, Ph-CH3 ), 2.20 (s, 1H, OH), 2.03 (m,
2H, H, H-7 and H-7”), 1.28 (d, 3H, J 6.0 Hz, CH3); 13C NMR (CDCl3): δ 179.2
( C=N), 169.1 (C=N), 138.5 (C-1’), 131.7 (C-2’), 130.9 (C-3’), 130.3 (C-6’),
126.4(C-5’), 126.3(C-4’), 67.7( C-8), 60.8 (C-7), 35.6 (C-6), 23.8 (CH3), 23.2
(Ph-CH3). Anal. Calcd for (C13H16O7N2): C, 67.22 H, 6.94; N, 12.06 Found: C,
67.12; H, 6.46; N, 12.30.
4-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl]-2-butanol (5c): Yield 59%, Rf=0.32
(dichromethane–ethyl acetate, 9:1); [α]D25=+6.6 (c=0.65, CHCl3); IR νmax
(KBr): 3400, 1570, 1350, 750 cm−1; 1H NMR (CDCl3): δ 7.87-7.84 (m, 2H,
Ph-H), 7.38–7.27 (m, 2H, Ph-H), 4.15 (m, 1H, H-8), 3.11 (dt, 2H, J 1.3Hz, J
8.8Hz, H-6 and H-6”), 2.41 (s, 1H, OH), 2.01 (s, 3H, Ph-CH3), 1.98 (m, 2H,
H, H-7 and H-7”), 1.28 (d, 3H, J 6.0 Hz, CH ); 13C NMR (CDCl3): δ 180.2 (
C=N), 171.5 (C=N), 139.0 (C-1’), 132.2 (C-33’), 129.1 (C-4’), 128.2 (C-6’),
126.9 (C-5’), 124.8 (C-2’), 67.1( C-8), 60.7 (C-7), 35.7 (C-6), 23.8 (CH3), 21.4
(Ph-CH3). Anal. Calcd for (C13H16O7N2): C, 67.22 H, 6.94; N, 12.06 Found: C,
67.10; H, 6.48; N, 12.26.
4-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]-2-butanol (5d): Yield 58%, Rf=0.37
(dichromethane–ethyl acetate, 9:1); [α]D25=+ 11.4 (c=1.2, CHCl3); IR νmax
(KBr): 3400, 1590, 1355, 767 cm−1; 1H NMR (CDCl ): δ 7.96 (d, 2H, J 8.1
Hz, H-2’), 7.28 (d, 2H, J 7.7 Hz, H-3’), 3.95 (m, 13H, H-8), 3.08 (t, 2H, J
7.5 Hz, H-6 and H-6”), 2.40(s, 3H, Ph-CH3), 2.15 (s, 1H, OH), 2.01 (m, 2H,
H, H-7 and H-7”), 1.28 (d, 3H, J 6.2 Hz, CH3); 13C NMR (CDCl3): δ 180.1(
C=N), 168.5 (C=N), 141.8 (C-1’), 129.9 (C-3’), 127.7 (C-2’), 124.3 (C-4’),
67.3 ( C-8), 35.6 (C-7), 24.0 (C-6), 23.5 (CH3), 21.9 (Ph-CH3). Anal. Calcd for
(C H16O7N ): C, 67.22 H, 6.94; N, 12.06 Found: C, 67.35; H, 6.68; N, 12.15.
13 4-[3-(p2-bromo)-1,2,4-oxadiazol-5-yl]-2-butanol (5e): Yield 55%, Rf=0.33
(dichromethane–ethyl acetate, 9:1); [α]D25=+ 4.47 (c=1.7, CHCl3); IR νmax
(KBr): 3410, 1590, 1350, 767 cm−1; 1H NMR (CDCl3): δ 7.94 ((dd, 2H, J 1.8
Hz J 6.7 Hz, H-2’), 7.27 (dd, 2H, J 1.8 Hz J 6.9 Hz, H-3’), 3.92 (m, 1H, H-8),
3.09(dt, 2H, J 1.5 Hz, J 9.0 Hz, H-6 and H-6”), 2.15 (s, 1H, OH), 2.02 (m, 2H,
H, H-7 and H-7”), 1.28 (d, 3H, J 6.2 Hz, CH ); 13C NMR (CDCl3): δ 180.5(
C=N), 167.8 (C=N), 140.7 (C-1’), 132.5 (C-33’), 129.2 (C-2’), 126.1(C-4’),
67.2( C-8), 38.2 (C-7), 24.0 (C-6), 23.5 (CH3). Anal. Calcd for (C12H13O7N2Br):
C, 48.50 H, 4.41; N, 9.43 Found: C, 48.46; H, 4.61; N, 9.23.
1
CHCl ); IR νmax (KBr): 1745, 1571, 1368, 1229, 1033, 757 cm−1; H NMR
(CDC3l3): δ 8.08–8.03 (m, 2H, H-2’ and H-5’), 7.49–7.47 (m, 3H, H-3’, H-4’
and H-5’), 5.95 (d, 2H, J 10.5 Hz, H-3), 5.85 (dd, 1H, J 10.5 Hz, J 2.7 Hz,
H-2), 5.33 (dd, 1H, J 9.9 Hz, J 1.5 Hz, H-4), 5.04 (s, 1H, H-1), 4.28–4.16 (m,
2H, H-6 and H-6′), 4.15 (dd, 1H, J 9.9 Hz, H-5), 4.09 (m, 1H, H-7), 3.80 (m,
2H, H-9 and H-9′), 3.59 (m, 2H, H-8 and H-8′), 2.09 (s, 3H, OAc), 2.08 (s,
3H, OAc), 1.26 (d, J 6.0 Hz, CH ); 13C NMR (CDCl3): δ 180 (OAc), 171.1
(C=N), 168.6 (C=N), 131.4 (C-1’3), 129.4 (C-3), 129.3 (C-3’), 128.3 (C-2),
128.2 (C-2’); 127.2 (C-4’), 94.6 (C-1), 73.1 (C-7), 67.5 ( C-5), 64.7 (C-6),
64.6 (C-4), 61.5 (C-8), 34.1 (C-9), 21.3 (C-12), 15.6 (CO-CH ). Anal. Calcd
for (C H26O7N2): C, 61.38; H, 6.08; N, 6.50 Found: C, 61.59; H3, 6.14; N, 6.36.
2(2S)-Methyl-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-acetyl-
2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (7b): Yield 73%; Rf=0.84
(dichromethane–ethyl acetate, 9:1); mp 72–73°C; [α]D20=+80.4° (c=0.7,
CHCl3); IR ν (KBr): 1743, 1370, 1223, 1033, 741 cm−1; 1H NMR (CDCl3):
δ 7.97-795 (dm, a1x H, J 7.3 Hz, H-2’), 7.37–7.27 (m, 3H, H-3’, H-4’ and H-5’),
5.87 (d, 1H, J 19.3 Hz, H-3), 5.78 (tt, 1H, J=10.3 and 2.0 Hz, H-2), 5.29 (d,
1H, J 8.4 Hz, H-4), 5.17 ( s, 1H, H-1), 4.28-4.15 (m, 4H, H-5, H-6, H-6’and
H-7), 4.11–3.98 (m, 2H, H-12 and H-8), 3.19-3.04 (m, 2H, H-9 and H-9′), 2.62
(s, 3H, Ar-CH3), 2.15-2.10 (m, 2H, H-8 and H-8’), 2.10 (s, 3H, OAc), 2.09
(s, 3H, OAc), 1.25 (d, 3H, J 6.2 Hz, CH ). 13C NMR (CDCl ): δ 181 (OAc),
171.3(C=N), 170.1 (C=N), 139.6 (C-1’),3138.5 (C-2), 131.7 3(C-3), 130.8 (C-
2’), 130.3 (C-3’); 129.5 (C-6’), 128.3(C-5’), 126.0 (C-4’), 91.3 (C-1), 72.2 (C-
7), 67.2( C-5), 65.8 (C-6), 63.5 (C-4), 34.6(C-8), 23.6 (C-9), 21.3 (C-12),
21.1(CO-CH3), 20.6 (CH ). Anal. Calcd for (C22H26O7N2): C, 62.15; H, 6.35;
N, 6.30. Found: C, 62.26;3H, 6.44; N, 6.22.
(S)-Methyl-[3-(m-tolyl)-1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-acetyl-
2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (7c): Yield 73%; Rf=0.84
(dichromethane–ethyl acetate, 9:1); mp 68–69°C; [α]D20=+67.1° (c=1.35,
CHCl3); IR ν (KBr): 1740, 1595, 1353, 1030, 735 cm−1; 1H NMR (CDCl3):
δ 7.88–7.85 (mda,x 2H, J 9.7 Hz H-6’ and H-2’), 7.38–7.27 (m, 2H, H-3’ and
H-4’), 5.87 (d, 2H, J 9.9 Hz, H-3), 5.79 (d, 2H, J 9.9 Hz, H-2), 5.27 (d, 1H, J
9.4 Hz, H-4), 5.16 (s, 1H, H-1), 4.29–4.19 (m, 2H, H-6 and H-6′), 4.15–3.99
(m, 1H, H-5 and H-7), 3.19–3.03 (m, 2H, H-9 and H-9’), 2.42 (s, 3H, Ph-CH3)
2.15-2.07 (m, 2H, H-8 and H-8’), 2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc), 1.24
(d, 3H, J 6.0 Hz, CH ); 13C NMR (CDCl ): δ 179.9 (OAc), 171.1(C=N), 170.4
(C=N), 139.0 (C-1’3), 132.2 (C-2), 1293.4 (C-3), 129.1 (C-2’), 128.3 (C-3’);
128.1 (C-5’), 127.0(C-4’), 124 (C-6’), 91.5 (C-1), 72.2 (C-7), 67.6 ( C-5), 65.5
(C-6), 63.5 (C-4), 34.1 (C-8), 23.6 (C-9), 21.6 (C-12), 21.3(CO-CH ), 19.6
(Ph-CH3). Anal. Calcd for (C22H26O7N2): C, 62.15; H, 6.35; N, 6.30. Fo3und: C,
62.23; H, 6.53; N, 6.05.
General Procedure for the Synthesis of (S)-1-methyl-[3-(aryl)-1,2,4-
oxadiazol-5-yl]-propyl-4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-
enopyranosides (7a–e)
The reaction of 5a–e with compound 6 were conducted according to the
1-(S)-Methyl-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-acetyl-
2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (7d): Yield 70%; Rf=0.85
(dichromethane–ethyl acetate, 9:1); mp 71–72°C; [α]D20=+43.5° (c=1.06,
CHCl3); IR ν (KBr): 1744, 1370, 1034, 756 cm−1; 1H NMR (CDCl ): δ 7.94
(d, 2H, J 8.1mHaxz, H-2’), 7.27 (d, 2H, J 7.7 Hz, H-3’), 5.90 (d, 1H, J310.2 Hz,
H-3), 5.82 (d, 1H, J 10.2 Hz, H-2), 5.26 (d, 1H, J 9.4 Hz, H-4), 5.12 (s, 1H,
H-1), 4.27–4.12 (m, 2H, H-6 and H-6′), 4.01–3.86 (m, 2H, H-5 and H-7), 3.05
(m, 2H, H-9 and H-9′), 2.41 (s, 3H, Ar-CH3), 2.15 (m, 2H, H-8 and H-8′),
2.08 (s, 3H, OAc), 2.07 (s, 3H, OAc), 1.24 (d, 3H, J 6.0 Hz, CH ). 13C NMR
(CDCl3): δ 179.8 (OAc), 171.1(C=N), 170.6 (C=N), 141.8 (C-1’), 3129.9 (C-2),
129.4 (C-3), 128.3 (C-2’), 127.6 (C-3’); 124.4 (C-4’), 91.9 (C-1), 67.6 (C-7),
65.5( C-6), 63.5 (C-6), 34.1(C-8), 23.6 (C-9), 21.9 (C-12), 21.4(CO-CH3), 19.8
(Ph-CH3). Anal. Calcd for (C22H26O7N2): C, 62.15; H, 6.35; N, 6.30. Found: C,
62.58; H, 6.69; N, 6.15.
method of Toshima et al.12 Figure 2.The details are given below.
(S)-Methyl-[3-(p-bromophenyl)-1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-
acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (7e): Yield 69%; Rf=0.89
(dichromethane–ethyl acetate, 9:1); [α]D20=+83.9° (c=0.28, CHCl3); IR νmax
(KBr): 1735, 1590, 1370, 760 cm−1; 1H NMR (CDCl ): δ 7.86 (d, 2H, J=8.4 Hz,
H-2’), 7.54 (d, 2H, J=8.4 Hz, H-3’), 5.83 (d, 1H, J 39.9 Hz, H-3), 5.71 (d, 1H,
J 9.9 Hz, H-2), 5.22 (d, 1H, J 9.4 Hz, H-4), 5.08 (s, 1H, H-1), 4.21–4.06 (m,
2H, H-6 and H-6′), 4.02 (m, 2H, H-5 and H-7), 3.02 (m, 2H, H-9 and H-9′),
3.27 (m, 2H, H-8 and H-8’), 2.02 (s, 3H, OAc), 2.00 (s, 3H, OAc), 1.18 (d, 3H,
J 6.0 Hz, CH ). 13C NMR (CDCl3): δ 180.5 (OAc), 173.4 (C=N), 167.6 (C=N),
140.0 (C-1’),3 132.5 (C-2), 129.4 (C-3), 129.1 (C-2’), 126.1 (C-3’), 126.0 (C-
4’), 92.0 (C-1), 72.2 (C-7), 67.6 (C-5), 65.1( C-6), 63.4 (C-4), 34.1(C-8), 30.0
(C-9), 21.3 (C-12), 21.1(CO-CH3). Anal. Calcd for (C22H25O7N2Br): C, 51.88;
Figure 2. (S)-1-methyl-[3-(aryl)-1,2,4-oxadiazol-5-yl]-propyl-4,6-di-O-
acetyl-2,3-dideoxy-α-d-erythro-hex-2-enopyranosides (7a–e).
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J. Chil. Chem. Soc., 60, Nº 4 (2015)
H, 4.95; N, 5.50. Found: C, 51.58; H, 4.68; N, 5.19.
originally superimposed methylene and methine multiplets will begin to be
resolved.
X‐ray single crystal structure determination
Single crystal X‐ray diffraction data of the title compound were collected
at room temperature on a Nonius BV diffractometer using Mo‐Kα radiation
(λ = 0.71073 Å) through the program COLLECT [19]. Details of the crystal
structure of C22H25N2O7 are listed in Table 1. The crystal structure has been
solved and refined in the triclinic symmetry, space group P‐1, using the WINGX
environment [21] and based on SHELXS-97 [22] and SHELXL-97 [23]. The
cell dimensions were determined by least-squares fit of angular settings of 2897
reflections in the q range from 1.700 to 28.910. The intensities were measured
by j scan mode for q range from 1.700 to 28.910 with hkl values (0 ≤ ℎ ≤ 6,
−12≤ k ≤13, −16≤ l ≤16). 2897 reflections were treated as observed (I >2s(I)).
The models were refined by full-matrix least squares on F2 using SHELXL-97
[34]. The program ORTEP-3 [35] was used for graphic representation and the
program WINGX [36] to prepare material for publication.
Table 1. Baker’s yeast reduction of compounds 4a-e
Reaction
Time (h)
Yielda
(%)
ee
Entry
Product
[α]D20(CHCl3)
(%)b
+7°± 2°
(c=0.59)
+11.25 (c=1.2)
+6.6 (c=0.65)
+11.4 (c=1.2)
+4.47 (c=1.7)
1
2
3
4
5
5a
5b
5c
5d
5e
72
72
72
72
72
60
64
59
58
55
92(S)
90(S)
94(S)
93(S)
84(S)
a Isolated yield
bAbsolute configuration in parenthesis.
1
The H NMR spectra of 7a-e show chemical shifts at 1.24 ≤ d ≤ 1.26
ppm, respectively; as a doublet with a coupling constant 6.0 ≤ J ≤ 6.2 Hz,
which is due to the methyl group of the aglycone. The methyl group of the
aglycone of 2,3-unsaturated glycosides with configuration (R) absorbs at a
slightly lower field (d 1.32 ppm).13 The products 7a-e produced an anomeric
proton at δ 5.04-5.17 ppm as a singlet indicating the axial configuration of the
1-methyl-[3-(aryl)-1,2,4-oxadiazol-5-yl]-propyl group. Hence, it is concluded
that compounds 7a-e are exclusively the α-anomer.
RESULTS AND DISCUSSION
Initially 4- [3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-one was prepared by
using an appropriate benzamidoxime or arylamidoxime and levulinic acid in
the presence of DCC in methylene chloride to get O-acyl intermediates, which
were cyclized to 1,2,4-oxadiazoles following the common procedure.10,11 The
mechanism of formation of 1,2,4-oxadiazoles from amidoximes and an acid,
employing DCC as a carbonyl group activator is straight forward. The first
step is the intermediate 3a-e production followed by thermal cyclodehydration
to generate 4a-e.10,11 The compounds 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-
butan-2-one 4a-e were reduced by use of bakers’ yeast under conventional
conditions.7 Optically active 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-2-butanols 5a-
e is a useful intermediate for the synthesis of O-glycoside. Compounds 5a–e
were used to carry out Ferrier’s rearrangement.12,13 Reaction of these alcohols
individually with tri-O-acetyl-d-glucal 6 after short reaction times produced
the corresponding alkyl 2,3-unsaturated glycosides 7a-e in good yields, with
the α-anomer being the greater or the exclusive product (Scheme 1).
The 13C NMR spectrum of the compounds 7a-e exhibits between 18 and
21 carbon atoms, all approximately equal in height; several of them have
characteristic chemical shifts. The presence of a peak between 91.5-94.6 ppm
is typical of anomeric carbons of glucosides (C-1); additional peaks at 129.4,
128.3, 67.5, 64.7 and, 64.6 ppm support the idea that the compound contains
α-glucopyranose moiety. A DEPT spectrum reveals that the peaks lathes 179.8-
180.5 (OAc), 173.4-171.1 (C=N), 167.6-170.6(C=N), and 131.4-141.8 (C-1’)
ppm lack protons, those at 23.9 (C-9), 34.6 and 65.8 (C-6) ppm are methylene
groups, and all other carbons bear one hydrogen.
The compound 7b, which had better crystals, was subjected to X-ray
crystallography. These crystals had the configuration (S) at the carbon atom
containing the methyl group in the aglycone moiety. The crystallographic
data provided precise information regarding the configuration (at C-11). As
expected, the configurations at C(12), C(13) and C(14) are (R), (S) and (S),
respectively. The ortep diagram is shown in Figure 3.
Scheme 1. Synthesis of 1-(S)-methy-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl]
propyl 2,3-dideoxy-α-d-erythro-hex-2-enopyranoside (7a-e)
Excellent enantiopurity of each of the generated alcohols 5a-e was attained
1
(>90% ee). H NMR spectroscopy in the presence of the chiral shift reagent
europium
tris[3-heptafluoropropylhydroxymethylene)-(+)-camphorate,
conducted on both racemic and enantiopure samples, determined that each of
the products isolated 5a-e was enantiopure, demonstrating that baker’s yeast
was capable of effecting selective reduction. Thus, the compounds 5a-e can fit
into the active site of the yeast reductase to facilitate hydride delivery to the
carbonyl group.
The results of the baker’s yeast reduction of these compounds are shown
in the Table 1. Since the spectra of both (+)- and (- )- 4-[3-(aryl)-1,2,4-
oxadiazol-5-yl]-butanols are identical, the usual chemical shift reagent would
not help our analysis. However, if one uses a chemical shift reagent that is
itself chiral, one can begin to distinguish the two enantiomers by their NMR
spectra. The two enantiomers, which are chiral, will interact differently with
the chiral shift reagent. The complexes formed from the (R) and (S) isomers
and with (+)-camphor containing the shift reagent will be diastereomers.
Diastereomers usually have different physical properties, and the NMR spectra
are no exception. The two complexes will be formed with slightly differing
geometries. Although the effect is small, it is large enough to begin to see
differences in the NMR spectra of the two enantiomers. In particular, the
Figura 3. Ortep diagram of compound 1-(S)-methy-[3-(o-tolyl)-1,2,4-
oxadiazol-5-yl] propryl 2,3-dideoxy-α-d-erythro-hex-2-enopyranoside 7b.
The crystallographic data supported the attributions made from the
proton magnetic resonance spectroscopy. All distances and angles for (7b) are
consistent with the expected values. The crystal data and structure refinement
for (S)-Methyl-[3-(o-tolyl)-1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-acetyl-2,3-
dideoxy-α-d-erythro-hex-2-enopyranoside (7b) is shown in Table 2.
2648

J. Chil. Chem. Soc., 60, Nº 4 (2015)
Table 2. Crystal data and structure refinement for (S)-Methyl-[3-(o-tolyl)-
1,2,4-oxadiazol-5-yl] propyl 4,6-di-O-acetyl-2,3-dideoxy-α-d-erythro-hex-2-
enopyranoside (7b):
(S) enantiomers of Fmoc-protected 1,2,4-oxadiazole-containing β3-amino
acids from Fmoc-(R)-β-HAsp(OtBu)-OH. Tetrahedron Lett. 44, 6079-
6082 (2003).
6.- Pace; P. Pierro. The new era of 1,2,4-oxadiazoles. Org. Biomol. Chem., 7,
4337–4348 (2009).
7.- A. Porcheddu; R. Cadoni; L. De Luca. A fast and efficient one-pot
microwave assisted synthesis of variously di-substituted 1,2,4-oxadiazoles.
Org. Biomol. Chem., 9, 7539- 7546 (2011).
8.- R. A. W. Neves Filho; D. C. B. da Silva-Alves; J. V. dos Anjos; R. M.
Srivastava. One-Step Protection-Free Synthesis of 3-Aryl-5-hydroxyalkyl-
1,2,4-Oxadiazoles as Building Blocks. Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic
Chemistry., 43, 2596-2602 (2013).
Empirical formula
Formula weight
Temperature (K)
Radiation wavelength (A˚)
Crystal system
C
H 25N2O7
42292.44
293 (2)
0.71073
Triclinic
P1
Space group
Unit cell dimensions
6.- a) J. B. Jones. Tetrahedron report number 203: Enzymes in organic
synthesis. Tetrahedron 42, 3351-3403 (1986). b) R. Bruni; G. Fantin;
A. Medici; P. Pedrinib; G. Sacchettib. Plants in organic synthesis: an
alternative to baker’s yeast. Tetrahedron Lett. 43, 3377-3379 (2002).
7.- H. Jacobs; K. Berryman, J. Jones; A. Gopalan. Bakers’Yeast Reductions of
Alkyl Levulinates: Synthesis of (R)-(+) and (S)-(-)4-methylbutyrolactones.
Synthetic Commun., 20, 999-1010 (1990).
a (A˚)
b (A˚)
c (A˚)
4.6485(9), α=75.76°(3)
10.170(2), β=89.62° (3)
12.373(3), δ=81.02°(3)
Volume (A˚ 3)
559.66(19)
1
1.274
Z
Calculated density
8.- S. Chandrasekhar; R. Hota. Enantioselective reduction of ketones with
NaBH4/diglyme possibly catalysed by trialkyl borate: optically active sec-
alcohols from prochiral ketones with catalytic (−)-menthol: autocatalysis
option. Tetrahedron Asymmetry 16, 751–754 (2005).
9.- A. Wolfson; C. Dlugy; D. Tavor; J. Blumenfeld; Y. Shotland. Baker’s
yeast catalyzed asymmetric reduction in glycerol. Tetrahedron Asymmetry
17, 2043–2045 (2006).
10.- J. J. R. de Freitas; J. C. R. Freitas; L. P. da Silva; J. R. Freitas Filho; G.
Y. V. Kimura; R. M. Srivastava. Microwave-induced one-pot synthesis
of 4-[3-(aryl)-1,2,4-oxadiazol-5-yl]-butan-2-ones under solvent free
conditions. Tetrahedron Lett., 48, 6195-6198 (2007).
11.- N. M. Miranda Bezerra; S. P. De Oliveira; R. M. Srivastava; J. R. da
Silva. Synthesis of 3-aryl-5-decapentyl-1,2,4-oxadiazoles possessing anti-
inflammatory and antitumor properties. Farmaco II 60, 955–960 (2005).
12.- a) K. Toshima; T. Ishizuka; G. Matsuo; M. Nakata. Practical Glycosidation
Method of Glycals Using Montmorillonite K-10 as an Environmentally
Acceptable and Inexpensive Industrial Catalyst. Synlett 4, 306-308
(1995). b) J. R. Freitas Filho; R. M. Srivastava; Y. Soro; L. Cottier; G.
Descotes. Synthesis of new 2,3-unsaturated O-glycosides through ferrier
rearrangement. J. Carbohydr. Chem., 20, 561–568 (2001).
Absorption coefficient
F(000)
Crystal size (mm)
Theta Range for data collection
Limiting índices
Reflections collected/unique
Completeness to theta = 28.91
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F 2
Final R indices [I>2s(I)]
R indices (all data)
0.096
227
1.0·0.2·0.2
1.70–28.91
0 ≤ h ≤ 6, -12 ≤ k ≤ 13, -16 ≤ l ≤ 16
2897/2897 [R int=0.0000]
98.0
None
Full-matrix least-squares on F2
2897/3/293
0.776
R 1=0.0486, wR2=0.1565
R 1=0.0628, wR2=0.1792
-0.5(12)
Absolute structure parameter
Largest diff.peak and hole.
0.239 and -0.260 e.A
CONCLUSIONS
In summary, we have been able to synthesize the unsaturated O-glycosides
7a–e by Ferrier’ rearrangement of tri-O-acetyl-D-glucal 2 with 4-[3-(aryl)-
1,2,4-oxadiazol-5-yl] butanols 4a-e. The reaction of 4-[3-(aryl)-1,2,4-
oxadiazol-5-yl] butanones 3a-e with baker’s yeast provided optically active
alcohols 4a-e possessing the (S)-configuration. The crystallographic data of
the glycosides 7b confirmed the (S)-configuration at the carbon atom in the
aglycone portion.
13.- R. M. Srivastava; J. R. de Freitas Filho; M. J. da Silva; S. C. M. Souto;
G. B. Carpenter; W. M. Faustino. Synthesis, separation and configuration
determination of diastereoisomers of (R,S)-1-methyl-3-[3-(aryl)-1,2,4-
oxadiazol-5-yl] propyl 2,3-dideoxy-α-D-erythro-hex-2-enopyranosides.
Tetrahedron 60, 10761-10769 (2004).
CONFLICT OF INTERESTS
The authors declare that there is no conflict of interests regarding the
publication of this paper.
REFERENCES
1.- a) A. R. Katritzky; A. A. Shestopalov; K. Suzuki. ARKIVOC (vii), 36-55
(2005); (b) S. Borg; R. C. Vollinga; M.; K. Payza; L. Terenius; K. Luthman.
Design, synthesis, and evaluation of Phe-Gly mimetics: heterocyclic
building blocks for pseudopeptides. J. Med. Chem., 42, 4331-4342 (1999);
c) A. L. Braga; D. S. Lüdtke; E. E. Alberto; L. Dornelles; W. A. Severo
Filho; V. A. Corbellini; D. M. Rosa; R. S. Schwab. ‘One-Pot’ Synthesis of
Chiral N-Protected α-Amino Acid-Derived 1,2,4-Oxadiazoles. Synthesis,
1589-1594 (2004).
SUPPLEMENTARY INFORMATION
The crystallographic data (CCDC) for compound 7b were deposited at
Cambridge structural database. These data can be obtained free of charge from
the director, CCDC, 12 Union road, Cambridge CB21EZ, UK (fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk or http://www.ccdc.cam.ac.uk).
2.- R. M. Srivastava; A. de Almeida Lima; O. S. Viana; M. J. da Costa Silva;
M. T. J. A. Catanho; J. O. F. de Morais. “Antiinflammatory Property of
3-Aryl-5-(n-propyl)-1,2,4-oxadiazoles and Antimicrobial Property of
3-Aryl-5-(n-propyl)-4,5-dihydro-1,2,4-oxadiazoles: Their Syntheses and
Spectroscopic Studies. Bioorg. Med. Chem., 11, 1821-1827 (2003).
3.- S. J. De Melo;A. D. Sobral; H. de Lima Lopes; R. M. Srivastava. Synthesis
of Some 3-Aryl-1,2,4-oxadiazoles Carrying a Protected L-Alanine Side
Chain. J. Braz. Chem. Soc., 9, 465-468 (1999).
ACKNOWLEDGMENTS
The authors express their gratitude to CAPES (Brazil), CNPq (Brazil) and
CNRS (France) for financial help. One of us (J. R. F. Filho) is thankful to
CAPES/COFECUB for a fellowship. We also thank Alain Thozet, Université
Claude Bernard Lyon 1, Villeurbanne, France, for obtaining the crystallographic
data.
4.- V. M. L. Braga; S. J. De Melo; R. M.. Srivastava; E. P. D. Falcão. Synthesis
of New 1,2,4-Oxadiazoles Carrying (1’S,2’S)-t-Butyloxycarbonyl-1-
amino-2-methyl-1-butyl and (1’S)-t-Butyloxycarbonyl-1’-amino-1’-ethyl
Groups at C-5. J. Braz. Chem. Soc., 15, 603-607 (2004).
5.- a) A. Hamzé; J. F. Hernandez; P. Fulcrand; J. Martinez. Synthesis of
Various 3-Substituted 1,2,4-Oxadiazole-Containing Chiral β3 and α-Amino
Acids from Fmoc-Protected Aspartic Acid. J. Org. Chem., 68, 7316-7321
(2003); b) A. Hamzé; J. F. Hernandez; J. Martinez. Synthesis of (R) and
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