Synthesis of heterocyclic N-(beta-d-glucopyranosyl)carboxamides for inhibition of glycogen phosphorylase
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G aphical abs ac
pp xxx–xxxSyn hesis o he e ocyclic N-(b-
DD
-glucopy anosyl)ca boxamides o inhibi ion o glycogen phospho ylase
Bálin Kónya, Tibo Docsa, Pál Ge gely, László Somsák
*
O
OAc
AcO
AcO
OAc H
N
O
O
OH
HO
HO
OH H
N
O
N
N
N
R
O
OH
HO
HO
OH H
N
O
N
O
R
Key s eps:
1,3-dipola
cycloaddi ions
R-N
3
R-C N O
Bes inhibi o s a
g
ains abbi muscle
g
l
y
co
g
en phospho lase b
R = 3,5-(CH
3
)
2
-C
6
H
3
-
K
i
= 34 µM
R = Indol-2-yl
K
i
= 164 µM
CAR 6067 No. o Pages 1, Model 5G
8 Feb ua y 2012
1
Syn hesis o he e ocyclic N-(b-D-glucopy anosyl)ca boxamides o inhibi ion
o glycogen phospho ylase
Bálin Kónya
a
,Tibo Docsa
b
,Pál Ge gely
b,c
,László Somsák
a,
⇑
a
Depa men o O ganic Chemis y, Uni e si y o Deb ecen, PO Box 20, H-4010 Deb ecen, Hunga y
b
Cell Biology and Signaling Resea ch G oup o he Hunga ian Academy o Sciences a he Depa men o Medical Chemis y, Medical and Heal h Science Cen e, Uni e si y o Deb ecen,
Egye em é 1, H-4032 Deb ecen, Hunga y
c
Depa men o Medical Chemis y, Medical and Heal h Science Cen e, Uni e si y o Deb ecen, Egye em é 1, H-4032 Deb ecen, Hunga y
10
a icle in o
A icle his o y:
Recei ed 4 Decembe 2011
Recei ed in e ised o m 19 Janua y 2012
Accep ed 22 Janua y 2012
A ailable online xxxx
Keywo ds:
Azide–alkyne cycloaddi ion
Ni ile-oxide–alkyne cycloaddi ion
1,2,3-T iazole-4-ca boxamide
Isoxazole-5-ca boxamide
N-(b-
D
-Glucopy anosyl)ca boxamide
Glycogen phospho ylase
abs ac
In a DCC-media ed coupling 2,3,4,6- e a-O-ace yl-b-D-glucopy anosylamine and p opiolic acid ga e
N-p opynoyl-2,3,4,6- e a-O-ace yl-b-D-glucopy anosylamine which was ans o med by 1,3-dipola
cycloaddi ions wi h a oma ic azides and ni ile-oxides o he co esponding O-pe ace yla ed N-(b-D-glu-
copy anosyl)-1-subs i u ed-1,2,3- iazole-4-ca boxamides and N-(b-D-glucopy anosyl)-3-subs i u ed-
isoxazole-5-ca boxamides, espec i ely. These compounds we e O-deace yla ed by Zemplén’s p o ocol
o be es ed as inhibi o s o abbi muscle glycogen phospho ylase b. The bes inhibi o s o he wo se ies
we e N-(b-D-glucopy anosyl)-1-(3,5-dime hyl-phenyl)-1,2,3- iazole-4-ca boxamide (K
i
=34
l
M) and
N-(b-D-glucopy anosyl)-3-(indol-2-yl)-isoxazole-5-ca boxamide (K
i
= 164
l
M).
Ó2012 Else ie L d. All igh s ese ed.
1. In oduc ion
Inhibi o s o glycogen phospho ylase (GP) enzymes ha e been
40
conside ed as possible means o he apeu ic in e en ion in fi s
o all ype 2 diabe es bu also o he diseased s a es. Fo he bio-
chemical a ionale behind hese conside a ions he eade is kindly
e e ed o ecen e iew a icles.
1–6
As pa o an ongoing p ojec
o syn hesize new glucose de i a i es
7
o he inhibi ion o GP N-
acyl-b-
D
-glucopy anosylamines
8
(Cha 1,I:e.g. o R = 2-naph hyl
K
i
(agains abbi muscle GPb, RMGPb) 10
l
M
8
o 13
l
M
9
) as well
as N-acyl-N
0
-b-
D
-glucopy anosyl u ea de i a i es
4
II (R = 2-naph-
hyl: K
i
(RMGPb) 0.35
l
M) ha e been aken as lead s uc u es.
Non-classical bioisos e ic eplacemen o he NHCO moie y in I
50
by he he e ocyclic linke A e ealed high simila i y o he amide
(see K
i
o Iabo e) and he 1,2,3- iazole ype ( o IA R = 2-naph-
hyl: K
i
(RMGPb) 16
l
M
9
) inhibi o s bo h in binding s eng h and
s uc u al ea u es o he enzyme–inhibi o complexes.
9,10
Applying he isome ic B,C, and Dmoie ies as linke s esul ed in
inhibi o s o a ying e ficiency,
11,12
whe eby he 3-a yl-5-b-
D
-
glucopy anosyl-1,2,4-oxadiazole (ID ype) de i a i es p o ed o
be he mos po en compounds ( o he bes inhibi o whe e
R = 2-naph hyl he K
i
(RMGPb) was 2.4
l
M
12
). Ve y ecen ly we
ha e epo ed on he syn hesis and enzyma ic e alua ion o a
60
se ies o compounds o ype II wi h linke 1 and linke 2 being
1,2,3- iazoles Aand Fas well as 1,3,4-oxadiazole Bin a ious cou-
pling pa e ns.
13
The bes inhibi o s agains RMGPb we e e ec i e
in he uppe mic omola ange (linke 1 = A, linke 2 = B, R = Ph: K
i
854
l
M; linke 1 = B, linke 2 = F, R = 2-naph hyl: K
i
745
l
M).
0008-6215/$ - see on ma e Ó2012 Else ie L d. All igh s ese ed.
doi:10.1016/j.ca es.2012.01.020
⇑
Co esponding au ho . Tel.: +36 52 512 900x22348; ax: +36 52 512 744.
E-mail add ess: [email p o ec ed] (L. Somsák).
O
HO
HO
HO
OH H
NR
O
lin
k
e
O
HO
HO
HO
OH H
NH
N
O O
R
linke 1 linke 2
O
HO
HO
HO
OH H
NH
N
O O
R
linke
lin e s
N
N
N
N
O
N
N
N
O
O
N
N
ON
I
II
III
A
B
C
D
E
N
N
N
F
Cha 1.
Q1
Q2
Ca bohyd a e Resea ch xxx (2012) xxx–xxx
Con en s lis s a ailable a SciVe se ScienceDi ec
Ca bohyd a e Resea ch
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CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
He ein we epo on he syn hesis and enzyma ic es o some
compounds o ype III wi h isoxazole Eand 1,2,3- iazole Fas
linke s.
2. Resul s and discussion
Fo he p epa a ion o compounds o ype IIIE and IIIF cons uc-
70
ion o he he e ocyclic pa s by 1,3-dipola cycloaddi ions
14
o an
alkyne and ni ile-oxides
15
as well as azides,
16,17
espec i ely, was
en isaged. As he di ec ans o ma ion o azide 1
18
by acyla ion o
an in si u gene a ed iminophospho ane
19
wi h p opiolic acid ailed,
he necessa y p o ec ed N-p opynoyl-b-
D
-glucopy anosylamine 3
was ob ained om glucosylamine 2
20
and p opiolic acid by a
DCC-media ed coupling in high yield (Scheme 1).
The coppe (I) ca alyzed cycloaddi ion eac ion (CuAAC) o 3
wi h a oma ic azides was in es iga ed fi s (Scheme 2). The non-
comme cial azides we e p epa ed ei he in si u om he co e-
80
sponding bo onic acids ollowing a ecen ly published p ocedu e
21
o om he ela ed aniline de i a i es ia diazonium sal s.
22
The
widely used sys em CuSO
4
–
L
-asco bic acid was applied o gene a e
he ca alys , and he cycloadduc s 4–8 we e ob ained in high
yields. A ial wi h a ecen ly published ca alys Cu(PPh
3
)
2
NO
323
in 2 mol % loading unde he same condi ions did no significan ly
imp o e he yield o 4(93%).
Alkyne 3was nex ans o med wi h ni ile-oxides which we e
oxida i ely gene a ed in si u om a oma ic aldoximes by using
domes ic bleach.
24
The a ge compounds 14–20 we e ob ained
90
in modes o accep able yields, among which he indole de i a i es
19 and 20 ha ing an NH g oup could be isola ed in he lowes
yields.
O-Ace yl p o ec ing g oups we e emo ed by he Zemplén p o-
ocol o gi e he es compounds 9–13 and 21–27 (Schemes 2 and
3, espec i ely) in high yields.
P o on and ca bon NMR spec a o iazoles 4–13 and isoxazoles
14–27 con ained esonances o he suga pa and he amide
moie y o he compounds as expec ed. In he
13
C NMR spec a
signals o he iazole C-4 (qua e na y) and C-5 (CH) appea ed in
100
he 140–143 and 116–121 ppm ange, espec i ely, he eby co -
obo a ing he an icipa ed 1,4-disubs i u ion pa e n o he 1,2,3-
iazole in analogy wi h p e iously epo ed compounds.
10
The
isoxazole C(4)–H appea ed in he 7.2–7.3 ppm ange o he p o-
ec ed de i a i es 14–20, and in he 7.5–7.9 ppm ange o he
unp o ec ed 21–27. HMBC spec a allowed o iden i y isoxazole
C3 (155–163 ppm) and C5 (162–166 ppm) esonances in he whole
se ies 14–27. Fu he mo e, de ec ion o c osspeaks be ween isox-
azole C–H and bo h he amide CO and a qua e na y ca bon o he
a oma ic subs i uen indica ed he o ma ion o 3-a yl-isoxazole-
110
5-ca boxamides 14–20 (con a y o he possibili y o 3-a yl-isox-
azole-4-ca boxamide de i a i es).
The he e ocyclic N-(b-
D
-glucopy anosyl) ca boxamides we e
es ed o hei inhibi o y ac i i y agains abbi muscle glycogen
phospho ylase b as desc ibed ea lie ,
8
and he ob ained da a, o-
ge he wi h some ele an li e a u e alues, a e collec ed in Table
1. The iazole de i a i es 9and 11–13 had inhibi o cons an s in
he mic omola ange. The inac i i y o he 2-naph hyl compound
O
OAc
AcO
AcO
O
Ac
N
3
O
OAc
AcO
AcO
Ac
NH
2
O
OAc
AcO
AcO
OAc H
N
O
HC C COOH
HC C COOH
2.
1. PMe
3
88 %
H
2
/Ra-Ni
12
3
DCC
Scheme 1.
O
OAc
AcO
AcO
OAc H
N
O
3
A N
3
CuSO
4
.5 H
2
O (5 mol%)
L
-asco bic acid (15 mol%)
CH
2
Cl
2
-H
2
O 1:1, 50 °C
A B(OH)
2
NaN
3
CuSO
4
.5 H
2
O (10 mol%)
MeOH
NaOMe
MeOH
O
OR
RO
RO
OR H
N
O
N
N
N
A
A R = Ac R = H
Ph 4 (91 %) 9 (88 %)
2-Naph hyl 5 (75 %) 10 (61 %)
3,5-di-Me-C
6
H
3
6 (78%) 11 (87 %)
4-CF
3
-C
6
H
4
7 (79 %) 12 (70 %)
4-
Bu-C
6
H
4
8 (85 %) 13 (79 %)
4-89-13
A NH
2
+
owa ds
5 and 6
owa ds
7 and 8
1. NaNO
2
, HCl, 0
o
C
2. NaN
3
Scheme 2.
O
OAc
AcO
AcO
Ac H
N
O
O
OR
RO
RO
OR H
N
O
N
O
A
A CH=NOH,
NaOCl, THF-H
2
O
A R = Ac R = H
Ph 14 (55 %) 21 (97 %)
2-Naph hyl 15 (52 %) 22 (91 %)
Benzo-[b]- u an-2-yl 16 (50 %) 23 (88 %)
Benzo-[b]- hiophen-2-yl 17 (51 %) 24 (95 %)
Benzo hiazol-2-yl 18 (30 %) 25 (90 %)
Indol-2-yl 19 (24 %) 26 (76 %)
Indol-3-yl 20 (20 %) 27 (70 %)
3
NaOMe
MeOH
14-20 21-27
Scheme 3.
2B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
10 was su p ising especially in he ligh o e y s ong inhibi ion
by 2-naph hyl de i a i es in o he se ies o glucose based inhibi-
120
o s,
7
o example, acyl u eas 28–32 om which 29 had he highes
a fini y. While in hese la e cases he inhibi ion became s onge
wi h inc easing size o he a oma ic pa o he molecules, his en-
dency seemed o be e e sed among iazoles 9–13. The ela i ely
weak binding o a mo e o less simila iazole de i a i e 33 was
a ibu ed o he diminished numbe o in e ac ions o he inhibi-
o wi h he p o ein as well as o he s e ic bulk o he aglycone
inducing un a o able changes in he icini y o he binding si e
(mo e specifically he so-called 280s loop nex o he ca aly ic
cen e ).
25
The p esen obse a ions migh ha e a simila o igin.
130
In addi ion, he bioisos e ic ela ionship o he amide and he
1,2,3- iazole moie ies, which p o ed o be alid o N-acyl-b-
D
-
glucopy anosylamines and 1-b-
D
-glucopy anosyl-4-subs i u ed-
1,2,3- iazoles
9
ou lined in he in oduc ion, canno be jus ified
o he case o he ‘second’ NHCO g oup o he N-acyl-N
0
-b-
D
-gluco-
py anosyl u ea ype GP inhibi o s.
Inhibi ion o RMGPb by he isoxazoles 21–27 was e en weake .
Thus, phenyl-isoxazole 21 had a mo e han wice less a fini y han
i s iazole coun e pa 9. An inc ease in he size o he a oma ic
moie y as in compounds 22–25 esul ed in a comple e loss o ac i -
140
i y. In e es ingly, he indole de i a i es 26 and 27, in which he
s e ic bulk o he ings mus be essen ially he same as in 23–25,
showed weak binding simila o ha o 21. This migh be due o
he hyd ogen bond dono capaci y o his ing sys em. I can also
be en isaged ha hese compounds bind o he so-called new
allos e ic (o indole binding) si e o he enzyme whe e some glu-
cose de i a i es we e also shown o be accommoda ed.
4,26,27
These
poin s need u he in es iga ions.
In summa y, 1,3-dipola cycloaddi ions o a oma ic azides and
ni ile-oxides we e used as he key s eps in he syn hesis o N-
150
(b-
D
-glucopy anosyl)-1-subs i u ed-1,2,3- iazole-4-ca boxamides
and N-(b-
D
-glucopy anosyl)-3-subs i u ed-isoxazole-5-ca boxam-
ides, espec i ely. The new compounds inhibi ed abbi muscle
glycogen phospho ylase b in he low mic omola ange. The
amide-1,2,3- iazole bioisos e ism could no be e ified o he
‘second’ NHCO pa o N-acyl-N
0
-b-
D
-glucopy anosyl u eas.
3. Expe imen al
3.1. Gene al me hods
Mel ing poin s we e measu ed in open capilla y ubes o on a
Kofle ho -s age and a e unco ec ed. Op ical o a ions we e de e -
160
mined on a Pe kin–Elme 241 pola ime e a oom empe a u e.
NMR spec a we e eco ded wi h B uke WP 360 SY (360/90 MHz
o
1
H/
13
C) and Va ian UNITYINOVA 400 WB (400/100 MHz o
1
H/
13
C) spec ome e s. Chemical shi s a e e e enced o Me
4
Si as
he in e nal e e ence (
1
H) o he esidual sol en signal (
13
C).
Thin-laye ch oma og aphy (TLC) was ca ied ou on aluminum
shee s coa ed wi h Silica Gel 60 F
254
(Me ck). TLC pla es we e in-
spec ed by UV ligh (k= 254 nm) and a e gen le hea ing o he
ca bohyd a e de i a i es. Silica gel column ch oma og aphy was
Table 1
Inhibi ion o abbi muscle glycogen phospho ylase b (RMGPb, K
i
[
l
M])
O
OH
HO
HO
OH H
N
O
N
N
N
R
R
O
HO
HO
HO
O
HH
NH
N
O
O
R
975 28 4.6
4
10 No inhibi ion 29 0.35
4
11 34
CH3
CH
3
30 0.9
28
12 51
CF
3
31 1.8
4
13 143
C(CH
3
)
3
32 0.7
4
O
OH
HO
HO
O
HH
N
O
N
N
N
33
179
25
R
O
OH
HO
HO
OH H
N
O
N
O
R
X
21 172
a
22 no inhibi ion 23 X=O
24 X = S no inhibi ion
N
S
N
H
N
H
25 no inhibi ion 26 164
a
27 207
a
a
Calcula ed om he IC
50
alues by he Cheng–P uso equa ion
29
:K
i
=IC
50
/(1 + [S]/K
m
).
B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx 3
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
pe o med wi h Silica Gel Si 60 (40–63
l
m) pu chased om Me ck
170
(Da ms ad , Ge many). O ganic solu ions we e d ied o e anhy-
d ous MgSO
4
, and concen a ed a diminished p essu e a 40–
50 °C (wa e ba h). A oma ic aldoximes we e p epa ed in he usual
way
30
om he co esponding aldehydes pu chased om Sigma-
Ald ich.
3.2. N-P opynoyl-2,3,4,6- e a-O-ace yl-b-
D
-glucopy anosyl
amine (3)
2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosylamine
20
(2,1g,
2.882 mmol) was dissol ed in d y CH
2
Cl
2
(20 mL), p opiolic acid
(355
l
L, 2 equi ) and DCC (0.565 g, 1.05 equi ) we e added. The
180
mix u e was s i ed a and moni o ed by TLC (1:1 E OAc–hex-
ane). A e consump ion o he amine he sol en was e apo a ed
and he esidue was pu ified by column ch oma og aphy (eluen :
1:1 E OAc–hexane) o gi e 1.01 g (88%) yellow sy up. R
= 0.5
(1:1 E OAc–hexane); [
a
]
D
31 (c0.22, CHCl
3
);
1
H NMR (CDCl
3
,
360 MHz) d(ppm) 7.27 (d, 1H, J= 9.0 Hz, NH), 5.20 ( , 1H, J= 9.4,
9.4 Hz, H-1), 5.03–4.80 (m, 2H, H-3, H-4), 4.19 (dd, 1H, J= 12.0,
3.3 Hz, H-6a), 4.00 (m, 2H, H-2, H-6b), 3.76 (ddd, 1H, J= 9.2, 5.0,
3.3 Hz, H-5), 2.97 (s, 1H, CH), 1.97, 1.95, 1.92, 1.91 (m, 12H,
4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 171.4, 171.3, 170.6,
190
170.3 (4xOCOCH
3
), 153.0 (NHCO), 78.3 (C-1), 77.2 (CCH), 74.3,
73.6, 71.0, 68.7 (C-2–C-5), 61.1 (C-6), 49.7 (CCH), 21.7, 21.4 21.2,
21.2 (4 OCOCH
3
). Anal. Calcd o C
17
H
21
NO
10
(399.35): C, 51.13;
H, 5.30; N, 3.51. Found: C, 51.33; H, 5.12; N, 3.41.
3.3. Gene al p ocedu e o he Zemplén deacyla ion
An O-pe acyla ed compound (100 mg) was dissol ed in d y
MeOH (1 mL) and a solu ion o NaOMe (1 M in MeOH) was added
o he solu ion in a ca aly ic amoun . The eac ion mix u e was
kep a . When he eac ion was comple e (TLC, 7:3 CHCl
3
–MeOH)
he solu ion was neu alized wi h a ca ion exchange esin Ambe -
200
lys 15 (H
+
o m). Fil a ion and emo al o he sol en esul ed in
he co esponding deace yla ed suga de i a i e which, i neces-
sa y, was pu ified by column ch oma og aphy.
3.4. Gene al p ocedu es o he Cu(I) ca alyzed azide–alkyne
cycloaddi ion
3.4.1. In CH
2
Cl
2
–wa e mix u es wi h o ganic azides
Equimola amoun s o N-p opynoyl-2,3,4,6- e a-O-ace yl-b-
D
-
glucopy anosylamine (3) and an azide we e dissol ed in CH
2
Cl
2
(7 mL/mmol alkyne). Wa e ( he same olume as ha o CH
2
Cl
2
),
CuSO
4
5H
2
O(5mol %),
L
-asco bic-acid (15 mol %) we e added and
210
he mix u e was s i ed a 50 °C and moni o ed by TLC (1:1
E OAc–hexane). A e disappea ance o he s a ing ma e ials he
eac ion mix u e was dilu ed wi h wa e and CH
2
Cl
2
, he phases
we e sepa a ed, and he aqueous laye was washed wi h CH
2
Cl
2
(2 10 mL/mmol). The combined o ganic laye was d ied, he sol-
en e apo a ed, and he esidue pu ified by column ch oma og a-
phy (eluen : 1:1 E OAc–hexane).
3.4.2. In CH
2
Cl
2
–wa e mix u es wi h o ganic azides p epa ed
in si u om bo onic acids
Bo onic acid (1 equi ) and NaN
3
(1.2 equi ) we e dissol ed in
220
MeOH (5 mL/mmol o bo onic acid). CuSO
4
5H
2
O (0.10 equi )
was added and he mix u e was s i ed o e nigh a . CH
2
Cl
2
and wa e (10 mL o each/mmol o bo onic acid), N-p opynoyl-
2,3,4,6- e a-O-ace yl-b-
D
-glucopy anosylamine (3, 0.75 equi )
and
L
-asco bic acid (0.5 equi ) we e added and he eac ion mix-
u e was hea ed o 50 °C. A e consump ion o he alkyne (TLC,
1:1 E OAc–hexane) he eac ion mix u e was dilu ed wi h wa e
and CH
2
Cl
2
, he phases we e sepa a ed and he aqueous laye
was washed wi h CH
2
Cl
2
(2 10 mL/mmol). The combined o ganic
laye was d ied, he sol en e apo a ed, and he esidue pu ified by
230
column ch oma og aphy (eluen : 1:1 E OAc–hexane).
3.4.3. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-1-phenyl-
1,2,3- iazole-4-ca boxamide (4)
P epa ed by gene al p ocedu e gi en in Sec ion 3.4.1 om 3
(335 mg, 0.841 mmol) and PhN
3
o 1 day. Yield: 396 mg (91%)
whi e c ys als. R
= 0.43 (1:1 E OAc–hexane); Mp: 232–234 °C
[
a
]
D
6.9 (c0.54, DMSO)
1
H NMR (DMSO-d
6
, 360 MHz) d(ppm)
9.39 (s, 1H, iazole CH), 9.37 (b s, 1H, NH), 7.97 (d, 2H,
J= 7.6 Hz, A H), 7.64–7.54 (m, 3H, A H), 5.66 ( , 1H, J= 9.1,
9.1 Hz, H-1), 5.41, 5.24, 4.92 (3 pseudo , J= 9.1, 10.6 Hz in each,
240
H-2, H-3, H-4), 4.19–4.44 (m, 2H, H-6a, H-5), 4.01 (dd, 1H,
J= 11.9, 3.0 Hz, H-6b), 2.01, 2.01, 1.95, 1.91 (4s, 12H, 4CH
3
);
13
C NMR (DMSO-d
6
, 90 MHz) d(ppm) 171.0, 170.8, 169.9, 169.0
(CO), 157.3 (NHCO), 140.8 ( iazole C-4), 129.2, 128.8, 128.8,
128.5, 125.5, 125.5 (A ), 116.7 ( iazole C-5), 78.1 (C-1), 73.9,
73.1, 70.6, 68.5 (C-2–C-5), 62.0 (C-6), 20.3, 20.2, 20.0 (CH
3
). Anal.
Calcd o C
23
H
26
N
4
O
10
(518.47): C, 53.28; H, 5.05; N, 10.81. Found:
C, 52.88; H, 4.86; N, 10.94.
3.4.4. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-1-(2-
naph hyl)-1,2,3- iazole-4-ca boxamide (5)
250
P epa ed by gene al p ocedu e gi en in Sec ion 3.4.2 om 3
(696 mg, 1.744 mmol) and 2-naph hylazide (p epa ed in si u om
naph halene-2-bo onic acid (300 mg, 1.744 mmol)). Yield: 743 mg
(75%) whi e c ys als. R
= 0.33 (1:1 E OAc–hexane); Mp: 223–
225 °C[
a
]
D
1.1 (c0.27, DMSO)
1
H NMR (CDCl
3
, 360 MHz) d
(ppm) 8.61 (s, 1H, iazole CH), 8.14 (b s, 1H, NH), 7.89 (m, 5H,
A H), 7.55–7.52 (m, 2H, A H), 5.45 ( , 1H, J= 9.3, 9.3 Hz, H-1),
5.31, 5.11, 5.10 (3 pseudo , 1H each, J= 9.5, 10.5 Hz in each, H-2,
H-3, H-4), 4.25 (dd, 1H, J= 12.2, 3.8 Hz, H-6a), 4.08 (dd, 1H,
J= 12.2, 1.9 Hz, H-6b), 3.85 (m, 1H, H-5), 2.03, 1.99, 1.98, 1.96
260
(4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 170.8,
170.5, 170.2, 169.7 (CO), 160.3 (NHCO), 142.8 ( iazole C-4),
133.9, 133.3, 130.5 128.5, 128.1, 127.9, 127.6, 119.2 (A ), 118.8 ( i-
azole C-5), 78.1 (C-1), 73.8, 73.2, 70.6, 68.3 (C-2–C-5), 61.8 (C-6),
20.9, 20.7 (CH
3
). Anal. Calcd o C
27
H
28
N
4
O
10
(568.53): C, 57.04;
H, 4.96; N, 9.85. Found: C, 56.64; H, 4.77; N, 9.98.
3.4.5. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-1-(3,5-
dime hyl-phenyl)-1,2,3- iazole-4-ca boxamide (6)
P epa ed by gene al p ocedu e gi en in Sec ion 3.4.2 om 3
(798 mg, 2.00 mmol) and 3,5-dime hyl-phenyl-azide (p epa ed
270
in si u om 3,5-dime hyl-phenylbo onic acid (300 mg,
2.00 mmol)). Yield: 852 mg (78%) yellow sy up. R
= 0.48 (1:1
E OAc–hexane) [
a
]
D
29 (c0.34, CHCl
3
)
1
H NMR (CDCl
3
,
360 MHz) d(ppm) 8.49 (s, 1H, iazole CH), 7.94 (d, 1H, J= 9.5 Hz,
NH), 7.32 (s, 2H, A H), 7.09 (s, 1H, A H), 5.49 ( , 1H, J= 9.5,
9.5 Hz, H-1), 5.37, 5.16, 5.13 (3 pseudo , 1H each, J= 9.5, 10.1 Hz
in each, H-2, H-3, H-4), 4.30 (dd, 1H, J= 11.9, 4.0 Hz, H-6a), 4.13
(dd, 1H, J= 11.9, 1.9 Hz, H-6b), 3.90 (m, 1H, H-5), 2.39 (s, 6H,
2CH
3
), 2.07, 2.03, 2.02, 1.99 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
,
90 MHz) d(ppm) 170.8, 170.4, 170.2, 169.6 (CO), 160.4 (NHCO),
280
142.4 ( iazole C-4), 140.1, 136.4, 136.4, 131.2, 131.2, 124.3 (A ),
118.8 ( iazole C-5), 78.0 (C-1), 73.7, 73.1, 70.5, 68.2 (C-2–C-5),
61.8 (C-6), 21.4, 21.4 (CH
3
), 20.8, 20.7 (CH
3
). Anal. Calcd o
C
25
H
30
N
4
O
10
(546.53): C, 54.94; H, 5.53; N, 10.25. Found: C,
54.54; H, 5.34; N, 10.38.
3.4.6. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-1-(4-
ifluo ome hyl-phenyl)-1,2,3- iazole-4-ca boxamide (7)
P epa ed by gene al p ocedu e gi en in Sec ion 3.4.1 om 3
(426 mg, 1.069 mmol) and 4-CF
3
–C
6
H
4
–N
3
o 1 day. Yield:
495 mg (79%) colo less oil. R
= 0.48 (1:1 E OAc–hexane) [
a
]
D
4B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
290
1.2 (c0.30, DMSO)
1
H NMR (CDCl
3
, 360 MHz) d(ppm) 8.77 (s, 1H,
iazole CH), 8.12 (d, 1H, J= 9.5 Hz, NH), 7.97 (d, 2H, J= 8.4 Hz,
A H), 7.83 (d, 2H, J= 8.4 Hz, A H), 5.56 ( , 1H, J= 9.4, 9.4 Hz, H-1),
5.40 ( , 1H, J= 9.7, 9.7 Hz, one o H-2, H-3, H-4), 5.18–5.05 (m,
2H, wo o H-2, H-3, H-4), 4.30 (dd, 1H, J= 11.2, 4.0 Hz, H-6a),
4.10 (dd, 1H, J= 11.2, 4.0 Hz, H-6b), 3.96 (m, 1H, H-5), 2.05, 2.02,
2.00, 1.98 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm)
170.7, 170.5, 170.0, 169.9 (CO), 160.0 (NHCO), 143.0 ( iazole C-
4), 138.8, 131.2 (q, C–CF
3
,J= 34.9 Hz), 127.3, 126.0, 124.9, 124.4
(A ), 121.9 (q, CF
3
,J= 277 Hz), 120.8 ( iazole C-5), 77.9 (C-1),
300
73.7, 73.0, 70.5, 68.2 (C-2–C-5), 61.7 (C-6), 20.7, 20.6 (CH
3
). Anal.
Calcd o C
24
H
25
F
3
N
4
O
10
(586.47): C, 49.15; H, 4.30; N, 9.55. Found:
C, 48.75; H, 4.11; N, 9.69.
3.4.7. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-1-(4- bu yl-
phenyl)-1,2,3- iazole-4-ca boxamide (8)
P epa ed by gene al p ocedu e gi en in Sec ion 3.4.1 om 3
(456 mg, 1.143 mmol) and 4- Bu–C
6
H
4
–N
3
o 1 day. Yield:
558 mg (85%) whi e c ys als. R
= 0.49 (1:1 E OAc–hexane); Mp:
194–196 °C[
a
]
D
5.4 (c0.33, DMSO)
1
H NMR (CDCl
3
, 360 MHz) d
(ppm) 8.55 (s, 1H, iazole CH), 8.00 (d, 1H, J= 9.5 Hz, NH), 7.64
310
(d, 2H, J= 8.6 Hz, A H), 7.51 (d, 2H, J= 8.6 Hz, A H), 5.52 ( , 1H,
J= 9.5, 9.5 Hz, H-1), 5.36, 5.16, 5.10 (3 pseudo , 1H each, J= 9.5,
9.5 Hz in each, H-2, H-3, H-4), 4.26 (dd, 1H, J= 11.2, 4.0 Hz, H-
6a), 4.08 (dd, 1H, J= 11.2, 2.1 Hz, H-6b), 3.90 (m, 1H, H-5), 2.02,
1.99, 1.99, 1.96 (4s, 12H, 4CH
3
), 1.31 (s, 9H, C(CH
3
)
3
);
13
C NMR
(CDCl
3
, 90 MHz) d(ppm) 170.7, 170.3, 170.1, 169.5 (CO), 160.4
(NHCO), 152.9 (A ), 142.5 ( iazole C-4), 134.0, 126.8, 126.8,
124.2, 124.2 (A ), 120.4 ( iazole C-5), 77.8 (C-1), 73.6, 73.1, 70.5,
68.2 (C-2–C-5), 61.8 (C-6), 34.9 (C(CH
3
)
3
), 31.2 (C(CH
3
)
3
), 20.7,
20.6 (CH
3
). Anal. Calcd o C
27
H
34
N
4
O
10
(574.58): C, 56.44; H,
320
5.96; N, 9.75. Found: C, 56.20; H, 5.76; N, 9.94.
3.4.8. N-(b-
D
-Glucopy anosyl)-1-phenyl-1,2,3- iazole-4-
ca boxamide (9)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 4
(200 mg, 0.386 mmol) o 1 h. Yield: 119 mg (88%) whi e c ys als.
R
= 0.53 (7:3 CHCl
3
–MeOH); Mp: 199–201 °C[
a
]
D
+3.4 (c0.15,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 9.38 (s, 1H,
iazole CH), 7.98 (d, 2H, J= 7.6 Hz, A H), 7.58 (m, 3H, A H), 4.89
(d, 1H, J= 8.9 Hz, H-1), 3.67 (dd, 1H, J= 12.3, 2.9 Hz, H-6a), 3.25–
3.09 (m, 5H, H-2, H-3, H-4, H-5, H-6b);
13
C NMR (DMSO-
330
d
6
+D
2
O, 90 MHz) d(ppm) 160.7 (NHCO), 143.4 ( iazole C-4),
133.3, 131.7, 128.7, 127.9 (A ), 118.4 ( iazole C-5), 80.0 (C-1),
72.9, 71.2 70.1, 68.9 (C-2–C-5), 62.2 (C-6). Anal. Calcd o
C
15
H
18
N
4
O
6
(350.33): C, 51.43; H, 5.18; N, 15.99. Found: C, 51.01;
H, 4.98; N, 16.05.
3.4.9. N-(b-
D
-Glucopy anosyl)-1-(2-naph hyl)-1,2,3- iazole-4-
ca boxamide (10)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 5
(180 mg, 0.317 mmol) o 2 h. Yield: 77 mg (61%) whi e c ys als.
R
= 0.51 (7:3 CHCl
3
–MeOH); Mp: 275–277 °C (decomp.) [
a
]
D
+4.4
340
(c0.34, DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 9.35
(s, 1H, iazole CH), 8.50 (s, 1H, A H), 8.17 (d, 1H, J= 8.9 Hz, A H),
8.12–7.98 (m, 3H, A H), 7.69–7.59 (m, 2H, A H), 4.95 (d, 1H,
J= 9.0 Hz, H-1), 3.66 (dd, 1H, J= 10.9, 2.0 Hz, H-6a), 3.50–3.33 (m,
2H, H-3, H-6b), 3.29–3.10 (m, 3H, H-2, H-4, H-5);
13
C NMR
(DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 160.3 (NHCO), 142.0 ( iazole
C-4), 134.6, 131.9, 129.6, 129.4, 128.0, 127.7, 127.1, 124.4 (A ),
119.1 ( iazole C-5), 80.2 (C-1), 72.1, 71.3 70.1, 68.7 (C-2–C-5),
62.1 (C-6). Anal. Calcd o C
19
H
20
N
4
O
6
(400.39): C, 57.00; H, 5.03;
N, 13.99. Found: C, 56.60; H, 4.86; N, 14.04.
350
3.4.10. N-(b-
D
-Glucopy anosyl)-1-(3,5-dime hyl-phenyl)-1,2,3-
iazole-4-ca boxamide (11)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 6
(180 mg, 0.317 mmol) o 1 h. Yield: 104 mg (87%) whi e c ys als.
R
= 0.74 (7:3 CHCl
3
–MeOH); Mp: 145–147 °C[
a
]
D
+1.7 (c0.33,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 9.15 (s, 1H,
iazole CH), 7.52 (s, 2H, A H), 7.15 (s, 1H, A H), 4.93 (d, 1H,
J= 9.0 Hz, H-1), 3.65 (dd, 1H, J= 11.0, 2.1 Hz, H-6a), 3.51–3.32 (m,
2H, H-3, H-6b), 3.31–3.12 (m, 3H, H-2, H-4, H-5), 2.34 (s, 6H,
2xCH
3
);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 160.7 (NHCO),
360
143.3 ( iazole C-4), 140.2, 136.5, 133.2, 127.1, 126.4, 126.0 (A ),
118.3 ( iazole C-5), 80.0 (C-1), 72.7, 71.2, 70.3, 68.8 (C-2–C-5),
61.9 (C-6). Anal. Calcd o C
17
H
22
N
4
O
6
(378.38): C, 53.96; H, 5.86;
N, 14.81. Found: C, 53.56; H, 5.73; N, 14.94.
3.4.11. N-(b-
D
-Glucopy anosyl)-1-(4- ifluo ome hyl-phenyl)-
1,2,3- iazole-4-ca boxamide (12)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 7
(200 mg, 0.341 mmol) o 2 h. Yield: 100 mg (70%) whi e c ys als.
R
= 0.57 (7:3 CHCl
3
–MeOH); Mp: 241–243 °C[
a
]
D
+4.5 (c0.60,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 9.35 (s, 1H,
370
iazole CH), 8.16 (d, 2H, J= 8.3 Hz, A H), 7.98 (d, 2H, J= 8.6 Hz,
A H), 4.94 (d, 1H, J= 9.0 Hz, H-1), 3.64 (dd, 1H, J= 12.9, 2.4 Hz, H-
6a), 3.41–3.35 (m, 2H, H-3, H-6b), 3.29–3.06 (m, 3H, H-2, H-4, H-
5);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 160.5 (NHCO),
143.8 ( iazole C-4), 139.4, 130.0, 129.7 (q, C–CF
3
,J= 30.4 Hz),
128.0, 127.7, (A ), 122.7 (q, CF
3
,J= 273.2 Hz), 116.7 ( iazole C-5),
80.0 (C-1), 72.4, 71.3, 70.4, 69.0 (C-2, C-3, C-4, C-5), 62.0 (C-6).
Anal. Calcd o C
16
H
17
F
3
N
4
O
6
(418.32): C, 45.94; H, 4.10; N,
13.39. Found: C, 45.54; H, 3.91; N, 13.53.
3.4.12. N-(b-
D
-Glucopy anosyl)-1-(4- bu yl-phenyl)-1,2,3-
380
iazole-4-ca boxamide (13)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 8
(200 mg, 0.348 mmol) o 2 hou . Yield: 111 mg (79%) whi e c ys-
als. R
= 0.62 (7:3 CHCl
3
–MeOH); Mp: 207–209 °C[
a
]
D
+1.9 (c0.34,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 9.06 (s, 1H,
iazol CH), 7.75 (d, 2H, J= 8.4 Hz, A H), 7.58 (d, 2H, J= 8.5 Hz,
A H), 4.94 (d, 1H, J= 8.9 Hz, H-1), 3.65 (dd, 1H, J= 11.4, 2.3 Hz, H-
6a), 3.51–3.34 (m, 2H, H-3, H-6b), 3.23 (m, 3H, H-2, H-4, H-5),
1.25 (s, 9H, C(CH
3
)
3
);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm)
161.5 (NHCO), 153.4 (A ), 143.5 ( iazole C-4), 134.5, 127.9,
390
127.6, 121.4, 121.1 (A ), 120.2 ( iazole C-5), 80.3 (C-1), 72.1,
71.2, 70.3, 69.1 (C-2–C-5), 61.9 (C-6), 35.4 (C(CH
3
)
3
), 31.8
(C(CH
3
)
3
). Anal. Calcd o C
19
H
26
N
4
O
6
(406.43): C, 56.15; H, 6.45;
N, 13.79. Found: C, 55.78; H, 6.25; N, 13.95.
3.5. Gene al p ocedu e o he ni ile-oxide cycloaddi ion
A solu ion o N-p opynoyl-2,3,4,6- e a-O-ace yl-b-
D
-glucopy -
anosyl-amine (0.5 mmol) and an a eneca baldoxime (0.55 mmol,
1.1 equi ) in THF (4 mL) was s i ed a unde A gon. 0.2 M NaOCl
solu ion (20 mL) was slowly added d opwise in 5 h wi h a sy inge
pump. The eac ion was s i ed a o an addi ional 12 h, hen he
400
eac ion mix u e was dilu ed wi h wa e and E OAc, he phases
we e sepa a ed and he aqueous laye was washed wi h E OAc
(2 30 mL/mmol). The combined o ganic laye was d ied, he sol-
en e apo a ed, and he esidue pu ified by column ch oma og a-
phy (eluen : 2:3 E OAc–hexane).
3.5.1. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-phenyl-
isoxazole-5-ca boxamide (14)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(248 mg, 0.621 mmol) and benzaldoxime (83 mg, 0.683 mmol).
B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx 5
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
Yield: 177 mg (55%) whi e c ys als. R
= 0.31 (2:3 E OAc–hexane);
410
Mp: 212–214 °C[
a
]
D
4(c0.21, CHCl
3
)
1
H NMR (CDCl
3
,
360 MHz) d(ppm) 7.82–7.79 (m, 2H, A H), 7.41 (d, 1H, J= 9.2 Hz,
NH), 7.40–7.35 (m, 3H, A H), 7.20 (s, 1H, isoxazole CH), 5.37,
5.32, 5.07 (3 pseudo , 4H, J= 9.5, 9.5 Hz in each, H-1, H-2, H-3,
H-4), 4.30 (dd, 1H, J= 11.9, 2.8 Hz, H-6a), 4.14 (dd, 1H, J= 12.6,
2.2 Hz, H-6b) 3.82 (ddd, 1H, J= 9.2, 4.0, 2.6 Hz, H-5), 2.01, 1.98
(2s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 170.9,
170.7, 170.0, 169.6 (CO), 165.5 (isoxazole C-5), 162.6 (isoxazole
C-3), 156.1 (NHCO), 130.8, 129.2, 129.2, 127.9, 127.0, 127.0 (A ),
106.4 (isoxazole CH), 78.2 (C-1), 74.0, 72.8, 70.6, 68.2 (C-2–C-5),
420
61.7 (C-6), 20.8, 20.7 (OCOCH
3
). Anal. Calcd o C
24
H
26
N
2
O
11
(518.47): C, 55.60; H, 5.05; N, 5.40. Found: C, 55.20; H, 4.87; N,
5.57.
3.5.2. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(2-
naph hyl)-isoxazole-5-ca boxamide (15)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(388 mg, 0.972 mmol) and naph halene-2-ca baldoxime (200 mg,
1.069 mmol). Yield: 288 mg (52%) whi e c ys als. R
= 0.40 (2:3
E OAc–hexane); Mp: 202–204 °C[
a
]
D
7.8 (c0.24, CHCl
3
)
1
H
NMR (CDCl
3
, 360 MHz) d(ppm) 8.12 (s, 1H, A H), 7.83–7.76 (m,
430
4H, A H), 7.62 (d, 1H, J= 9.2 Hz, NH), 7.46–7.43 (m, 2H, A H),
7.31 (s, 1H, isoxazole CH), 5.42, 5.34, 5.12, 5.08 (4 pseudo , 4H,
J= 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4), 4.32 (dd, 1H, J= 11.9,
5.1 Hz, H-6a), 4.14 (dd, 1H, J= 11.9, 2.8 Hz, H-6b) 3.89 (ddd, 1H,
J= 9.2, 5.1, 2.8 Hz, H-5), 2.00, 1.99, 1.98, 1.96 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 171.2, 171.0, 170.4, 170.0
(CO), 163.7 (isoxazole C-5), 163.0 (isoxazole C-3), 156.5 (NHCO),
134.6, 133.5, 129.4, 128.9, 128.2, 127.8, 127.4, 127.3, 125.5, 124.0
(A ), 106.8 (isoxazole CH), 78.5 (C-1), 74.2, 73.2, 70.9, 68.5 (C-2–
C-5), 62.1 (C-6), 21.1, 21.0 (CH
3
). Anal. Calcd o C
28
H
28
N
2
O
11
440
(568.53): C, 59.15; H, 4.96; N, 4.93. Found: C, 58.85; H, 4.77; N,
5.07.
3.5.3. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(benzo-
[b]- u an-2-yl)-isoxazole-5-ca boxamide (16)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(200 mg, 0.501 mmol) and benzo-[b]- u an-2-ca baldoxime
(89 mg, 1.551 mmol). Yield: 141 mg (50%) yellow oil. R
= 0.39
(2:3 E OAc–hexane) [
a
]
D
6.7 (c0.45, CHCl
3
)
1
H NMR (CDCl
3
,
360 MHz) d(ppm) 7.62–7.55 (m, 2H, A H), 7.47 (d, 1H, J= 9.2 Hz,
NH), 7.32–7.19 (m, 3H, A H, isoxazole CH), 5.40, 5.33, 5.10, 5.08
450
(4 pseudo , 4H, J= 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4), 4.27
(dd, 1H, J= 12.1, 5.2 Hz, H-6a), 4.06 (dd, 1H, J= 12.1, 2.8 Hz, H-
6b), 3.84 (ddd, 1H, J= 9.2, 5.2, 2.8 Hz, H-5), 2.01, 1.99, 1.98, 1.96
(4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 170.9,
170.7, 170.0, 169.6 (CO), 162.6 (isoxazole C-5), 156.0 (isoxazole
C-3), 155.7 (NHCO), 155.4, 144.5, 127.8, 126.4, 123.8, 122.0 (A ),
106.3 (isoxazole CH), 78.2 (C-1), 74.0, 72.9, 70.6, 68.2 (C-2–C-5),
61.7 (C-6), 20.8, 20.7 (CH
3
). Anal. Calcd o C
26
H
26
N
2
O
12
(558.49):
C, 55.91; H, 4.69; N, 5.02. Found: C, 55.50; H, 4.50; N, 5.18.
3.5.4. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(benzo-
460
[b]- hiophen-2-yl)-isoxazole-5-ca boxamide (17)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(204 mg, 0.513 mmol) and benzo-[b]- hiophen-2-ca baldoxime
(100 mg, 0.564 mmol). Yield: 151 mg (51%) yellow c ys als.
R
= 0.29 (2:3 E OAc–hexane); Mp: 192–194 °C (decomp.) [
a
]
D
7
(c0.21, CHCl
3
)
1
H NMR (CDCl
3
, 360 MHz) d(ppm) 7.77 (d, 1H,
J= 9.3 Hz, NH), 7.70–7.68 (m, 2H, A H), 7.59 (s, 1H, A H), 7.32–
7.29 (m, 2H, A H), 7.21 (s, 1H, isoxazole CH), 5.40, 5.33, 5.11,
5.07 (4 pseudo , 4H, J= 9.2, 9.5 Hz in each, H-1, H-2, H-3, H-4),
4.32 (dd, 1H, J= 12.0, 2.9 Hz, H-6a), 4.13 (dd, 1H, J= 12.0, 5.3 Hz,
470
H-6b), 3.90 (ddd, 1H, J= 9.2, 5.3, 2.9 Hz, H-5), 2.00, 1.99, 1.98,
1.96 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 171.0,
170.8, 170.0, 169.6 (CO), 162.7 (isoxazole C-5), 159.0 (isoxazole
C-3), 155.9 (NHCO), 129.3, 126.2, 125.6, 125.0, 124.5, 122.6 (A ),
106.4 (isoxazole CH), 78.2 (C-1), 73.9, 72.9, 70.6, 68.2 (C-2–C-5),
61.8 (C-6), 20.8, 20.7, 20.6 (CH
3
). Anal. Calcd o C
26
H
26
N
2
O
11
S
(574.56): C, 54.35; H, 4.56; N, 4.88. Found: C, 53.93; H, 4.36; N,
5.03.
3.5.5. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(benzo-
[b]- hiazol-2-yl)-isoxazole-5-ca boxamide (18)
480
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(200 mg, 0.501 mmol) and benzo-[b]- hiazol-2-ca baldoxime
(98 mg, 0.551 mmol). Yield: 86 mg (30%) whi e c ys als. R
= 0.39
(2:3 E OAc–hexane); Mp: 179–181 °C[
a
]
D
7.6 (c0.19, CHCl
3
)
1
H NMR (CDCl
3
, 360 MHz) d(ppm) 8.10 (d, 1H, J= 9.2 Hz, NH)
8.01 (m, 2H, A H), 7.59–7.52 (m, 2H, A H), 7.27 (s, 1H, isoxazole
CH), 5.47, 5.39, 5.18, 5.14 (4 pseudo , 4H, J= 9.2, 9.6 Hz each, H-
1, H-2, H-3, H-4), 4.38 (dd, 1H, J= 11.9, 5.3 Hz, H-6a), 4.17 (dd,
1H, J= 11.9, 2.8 Hz, H-6b), 3.94 (ddd, 1H, J= 9.2, 5.3, 2.8 Hz, H-5),
2.06, 2.06, 2.04, 2.03 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
,
490
90 MHz) d(ppm) 171.0, 170.8, 170.0, 169.6 (CO), 162.4 (isoxazole
C-5), 161.1 (benzo hiazole C-2), 158.3 (isoxazole C-3), 156.3
(NHCO), 152.5, 136.3, 126.9, 125.5, 123.7, 122.7 (A ), 102.8 (isoxaz-
ole CH), 78.0 (C-1), 73.8, 72.6, 71.0, 68.8 (C-2–C-5), 61.8 (C-6), 20.8,
20.7, 20.6 (CH
3
). Anal. Calcd o C
25
H
25
N
3
O
11
S (575.54): C, 52.17; H,
4.38; N, 7.30. Found: C, 51.87; H, 4.20; N, 7.45.
3.5.6. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(indol-2-
yl)-isoxazole-5-ca boxamide (19)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(300 mg, 0.752 mmol) and indol-2-ca baldoxime (132 mg,
500
0.827 mmol). Yield: 100 mg (24%) yellow oil. R
= 0.44 (2:3
E OAc–hexane) [
a
]
D
8.1 (c0.23, CHCl
3
)
1
H NMR (CDCl
3
,
360 MHz) d(ppm) 8.24 (s, 1H, indol NH), 7.70–7.41 (m, 5H, A H, in-
dol CH), 7.29 (s, 1H, isoxazole CH), 5.50, 5.42, 5.15, 5.11 (4 pseudo ,
4H, J= 9.2, 9.6 Hz each, H-1, H-2, H-3, H-4), 4.35 (dd, 1H, J= 11.9,
5.3 Hz, H-6a), 4.22 (dd, 1H, J= 11.9, 2.9 Hz, H-6b), 4.00 (ddd, 1H,
J= 9.2, 5.3, 2.9 Hz, H-5), 2.02, 2.00, 1.99, 1.98 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 171.2, 170.8, 170.1, 169.5
(CO), 162.6 (isoxazole C-5), 158.8 (isoxazole C-3), 156.9 (NHCO),
137.1, 135.2, 128.4, 122.6, 121.9, 121.3 118.4 (A , indol C-2),
510
101.0, 100.2 (isoxazole CH, indol CH), 78.1 (C-1), 74.0, 72.7, 71.0,
68.4 (C-2–C-5), 61.9 (C-6), 20.5, 20.5, 20.4, 20.4 (CH
3
). Anal. Calcd
o C
26
H
27
N
3
O
11
(557.51): C, 56.01; H, 4.88; N, 7.54. Found: C,
55.61; H, 4.69; N, 7.68.
3.5.7. N-(2,3,4,6-Te a-O-ace yl-b-
D
-glucopy anosyl)-3-(indol-3-
yl)-isoxazole-5-ca boxamide (20)
P epa ed by gene al p ocedu e gi en in Sec ion 3.5 om 3
(400 mg, 1.00 mmol) and indol-3-ca baldoxime (177 mg,
1.10 mmol). Yield: 110 mg (20%) yellow oil. R
= 0.49 (2:3 E OAc–
hexane) [
a
]
D
5.6 (c0.15, CHCl
3
)
1
H NMR (CDCl
3
, 360 MHz) d
520
(ppm) 7.75 (s, 1H, indol NH), 7.64–7.36 (m, 5H, A H, indol CH),
7.28 (s, 1H, isoxazole CH), 5.49, 5.40, 5.17, 5.10 (4 pseudo , 4H,
J= 9.2, 9.6 Hz each, H-1, H-2, H-3, H-4), 4.24 (dd, 1H, J= 11.9,
5.3 Hz, H-6a), 4.19 (dd, 1H, J= 11.9, 3.0 Hz, H-6b), 4.01 (ddd, 1H,
J= 9.2, 5.3, 3.0 Hz, H-5), 2.02, 2.00, 1.99, 1.98 (4s, 12H, 4CH
3
);
13
C NMR (CDCl
3
, 90 MHz) d(ppm) 171.4, 171.2, 170.4, 170.0
(CO), 164.9 (isoxazole C-5), 160.0 (isoxazole C-3), 156.1 (NHCO),
139.1, 133.0, 125.5, 121.5, 120.0, 119.6 112.8 (A , indol C-2),
101.9, 101.0 (isoxazole CH, indol CH), 78.5 (C-1), 73.7, 73.0, 71.1,
68.2 (C-2–C-5), 61.5 (C-6), 20.7, 20.6 (CH
3
). Anal. Calcd o
530
C
26
H
27
N
3
O
11
(557.51): C, 56.01; H, 4.88; N, 7.54. Found: C, 55.32;
H, 4.59; N, 7.64.
6B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020
3.5.8. N-(b-
D
-Glucopy anosyl)-3-phenyl-isoxazole-5-
ca boxamide (21)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 14
(80 mg, 0.154 mmol) o 1 hou . Yield: 52 mg (97%) whi e solid.
R
= 0.47 (7:3 CHCl
3
–MeOH); Mp: 215–217 °C (decomp.) [
a
]
D
+7.8
(c0.23, DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm)
7.92–7.90 (m, 2H, A H), 7.80 (s, 1H, isoxazole CH), 7.55–7.53 (m,
3H, A H), 4.88 ( , 1H, J= 9.3, 9.3 Hz, H-1), 3.68–3.35 (m, 3H, H-6a,
540
H-2, H-3), 3.27–3.08 (m, 3H, H-6b, H-5, H-4);
13
C NMR (DMSO-
d
6
+D
2
O, 90 MHz) d(ppm) 164.0 (isoxazole C-5), 162.5 (isoxazole
C-3), 156.2 (NHCO), 130.8, 130.7, 129.4, 129.3, 127.9, 126.7, (A ),
105.0 (isoxazole CH), 80.1 (C-1), 79.0, 77.3, 71.6, 69.9 (C-2–C-5),
61.0 (C-6). Anal. Calcd o C
16
H
18
N
2
O
7
(350.32): C, 54.86; H, 5.18;
N, 8.00. Found: C, 54.47; H, 5.00; N, 8.14.
3.5.9. N-(b-
D
-Glucopy anosyl)-3-(2-naph hyl)-isoxazole-5-
ca boxamide (22)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 15
(160 mg, 0.281 mmol) o 1.5 h. Yield: 102 mg (91%) whi e solid.
550
R
= 0.51 (7:3 CHCl
3
–MeOH); Mp: 218–220 °C (decomp.) [
a
]
D
+6.0
(c0.25, DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 8.54
(s, 1H, A H), 8.10–7.99 (m, 4H, A H), 7.88 (s, 1H, isoxazole CH),
7.65–7.62 (m, 2H, A H), 5.12–4.93 (m, 4H, H-1, H-2, H-3, H-4),
3.70 (dd, 1H, J= 12.0, 5.0 Hz, H-6a), 3.22 (ddd, 1H, J= 9.0, 5.0,
3.0 Hz, H-5), 3.12 (dd, 1H, J= 12.0, 3.0 Hz, H-6b);
13
C NMR
(DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 164.0 (isoxazole C-5), 162.2
(isoxazole C-3), 156.0 (NHCO), 133.8, 132.9, 129.0, 128.6, 128.6,
127.9, 127.6, 127.1, 127.0, 126.9, 125.2, 123.5 (A ), 105.4 (isoxazole
CH), 79.8 (C-1), 79.0, 77.5, 71.9, 70.0 (C-2–C-5), 61.0 (C-6). Anal.
560
Calcd o C
20
H
20
N
2
O
7
(400.38): C, 60.00; H, 5.03; N, 7.00. Found:
C, 59.64; H, 4.89; N, 7.20.
3.5.10. N-(b-
D
-Glucopy anosyl)-3-(benzo-[b]- u an-2-yl)-
isoxazole-5-ca boxamide (23)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 16
(120 mg, 0.215 mmol) o 1 h. Yield: 74 mg (88%) yellow solid.
R
= 0.55 (7:3 CHCl
3
–MeOH); Mp: 196–198 °C[
a
]
D
+9 (c0.18,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 7.79–7.72
(m, 4H, A H, benzo u an CH, isoxazole CH), 7.48–7.33 (m, 2H,
A H), 4.87 (d, 1H, J= 9.3 Hz, H-1), 3.46–3.10 (m, 6H, H-2, H-3, H-
570
4, H-5, H-6a, H-6b);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm)
164.0 (isoxazole C-5), 155.0 (isoxazole C-3), 154.9 (NHCO), 154.6
(benzo u an C-2), 145.6, 127.5, 126.6, 123.9, 123.0, 122.4 (A ),
111.8 (benzo u an C-3), 108.9 (isoxazole CH), 79.9 (C-1), 79.0,
77.4, 71.9, 69.9 (C-2–C-5), 60.9 (C-6). Anal. Calcd o C
18
H
18
N
2
O
8
(390.34): C, 55.39; H, 4.65; N, 7.18. Found: C, 54.89; H, 4.46; N,
7.32.
3.5.11. N-(b-
D
-Glucopy anosyl)-3-(benzo-[b]- hiophen-2-yl)-
isoxazole-5-ca boxamide (24)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 17
580
(120 mg, 0.209 mmol) o 1 h. Yield: 81 mg (95%) yellow solid.
R
= 0.51 (7:3 CHCl
3
–MeOH); Mp: 234–236 °C[
a
]
D
+7.8 (c0.25,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 8.16 (s, 1H,
benzo hiophen CH), 8.08–7.95 (m, 2H, A H), 7.83 (s, 1H, isoxazole
CH), 7.48–7.46 (m, 2H, A H), 5.07 (d, 1H, J= 9.2 Hz, H-1), 4.97–
4.91 (m, 2H, H-2, H-3), 3.70 (ddd, 1H, J= 9.0, 3.7, 2.6 Hz, H-5),
3.46–3.17 (m, 3H, H-4, H-6a, H-6b);
13
C NMR (DMSO-d
6
+D
2
O,
90 MHz) d(ppm) 163.9 (isoxazole C-5), 155.7 (isoxazole C-3),
155.0 (NHCO), 154.8 (benzo hiophen C-2), 144.6, 127.6, 126.6,
124.0, 122.3, 122.0 (A ), 112.0 (benzo hiophen C-3), 109.0 (isoxaz-
590
ole CH), 80.0 (C-1), 79.2, 77.4, 72.0, 70.0 (C-2–C-5), 61.0 (C-6). Anal.
Calcd o C
18
H
18
N
2
O
7
S (406.41): C, 53.20; H, 4.46; N, 6.89. Found:
C, 52.81; H, 4.28; N, 7.03.
3.5.12. N-(b-
D
-Glucopy anosyl)-3-(benzo-[b]- hiazol-2-yl)-
isoxazole-5-ca boxamide (25)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 18
(80 mg, 0.139 mmol) o 1 h. Yield: 51 mg (90%) yellow solid.
R
= 0.55 (7:3 CHCl
3
–MeOH); Mp: 223–225 °C[
a
]
D
+5.8 (c0.19,
DMSO)
1
H NMR (DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 7.90–7.82
(m, 2H, A H), 7.78 (s, 1H, isoxazole CH), 7.67–7.51 (m, 2H, A H),
600
4.78 ( , 1H, J= 9.3, 9.3 Hz, H-1), 4.60–4.44 (m, 2H, H-2, H-3),
3.54–3.31 (m, 3H, H-6a, H-6b, H-4), 3.22 (ddd, 1H, J= 9.3, 4.0,
2.3 Hz, H-5);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 166.5
(isoxazole C-5), 161.9 (isoxazole C-3), 160.3 (benzo hiazole C-2),
158.9 (NHCO), 150.4, 136.5, 127.3, 126.3, 125.5, 123.2 (A ), 108.4
(isoxazole CH), 81.8 (C-1), 73.6, 71.5, 70.9, 69.7 (C-2–C-5), 62.5
(C-6). Anal. Calcd o C
17
H
17
N
3
O
7
S (407.40): C, 50.12; H, 4.21; N,
10.31. Found: C, 49.72; H, 4.03; N, 10.50.
3.5.13. N-(b-
D
-Glucopy anosyl)-3-(indol-2-yl)-isoxazole-5-
ca boxamide (26)
610
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 19
(100 mg, 0.179 mmol) o 2 h. Yield: 53 mg (76%) yellow oil.
R
= 0.45 (7:3 CHCl
3
–MeOH) [
a
]
D
+1 (c0.10, DMSO)
1
HNMR
(DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 7.61–7.51 (m, 3H, A H, isoxaz-
ole CH), 7.35–7.19 (m, 2H, A H,indol CH), 4.97 (d, 1H, J= 10.6 Hz,
H-1), 3.50–3.07 (m, 6H, H-2, H-3, H-4, H-5, H-6a, H-6b);
13
CNMR
(DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 164.0 (isoxazole C-5), 156.8
(isoxazole C-3), 155.4 (NHCO), 147.9, 136.0, 132.3, 125.9, 123.6,
121.5, 118.9 (A , indol C-2), 113.3, 110.2 (isoxazole CH, indol CH),
80.6 (C-1), 79.9, 77.7, 73.0, 70.3 (C-2–C-5), 61.6 (C-6). Anal. Calcd
620
o C
18
H
19
N
3
O
7
(389.36): C, 55.53; H, 4.92; N, 10.79. Found: C,
55.13; H, 4.73; N, 10.93.
3.5.14. N-(b-
D
-Glucopy anosyl)-3-(indol-3-yl)-isoxazole-5-
ca boxamide (27)
P epa ed by gene al p ocedu e gi en in Sec ion 3.3 om 20
(100 mg, 0.179 mmol) o 1.5 h. Yield: 49 mg (70%) yellow oil.
R
= 0.40 (7:3 CHCl
3
–MeOH) [
a
]
D
+3 (c0.10, DMSO)
1
HNMR
(DMSO-d
6
+D
2
O, 360 MHz) d(ppm) 7.90 (s, 1H, isoxazole CH),
7.60–7.42 (m, 2H, A H), 7.34–7.02 (m, 3H, A H, indol CH), 4.96 (d,
1H, J= 9.2 Hz, H-1), 3.53–3.12 (m, 6H, H-2, H-3, H-4, H-5, H-6a,
630
H-6b);
13
C NMR (DMSO-d
6
+D
2
O, 90 MHz) d(ppm) 163.6 (isoxaz-
ole C-5), 157.2 (isoxazole C-3), 156.0 (NHCO), 139.1, 133.0, 129.8,
125.6, 124.0, 122.0, 119.1 (A , indol C-2), 111.9, 107.3 (isoxazole
CH, indol CH), 80.2 (C-1), 79.7, 78.2, 72.4, 69.9 (C-2–C-5), 61.0 (C-
6). Anal. Calcd o C
18
H
19
N
3
O
7
(389.36): C, 55.53; H, 4.92; N,
10.79. Found: C, 55.25; H, 4.69; N, 10.88.
Acknowledgemen s
This wo k was suppo ed by he Hunga ian Scien ific Resea ch
Fund (OTKA CK77712, CNK80709) and TÁMOP 4.2.1./B-09/1/
KONV-2010-0007 p ojec implemen ed h ough he New Hunga y
640
De elopmen Plan, co-financed by he Eu opean Social Fund. Some
compounds we e made du ing a s ay o BK a he Uni e si y o
Lyon wi h J.-P. P aly suppo ed by a join p og am o F ench CNRS
and he Hunga ian Academy o Sciences (PICS 4576). The au ho s
hank K. E. Kö é o he ad ice on HMBC spec a.
Re e ences
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B. Kónya e al. / Ca bohyd a e Resea ch xxx (2012) xxx–xxx 7
CAR 6067 No. o Pages 9, Model 5G
8 Feb ua y 2012
Please ci e his a icle in p ess as: Kónya, B.; e al. Ca bohyd . Res. (2012), doi:10.1016/j.ca es.2012.01.020