LETTER2230
Syn hesis o Suga Oxazolines by In amolecula Ri e -Like Reac ion o
D-F uc ose P ecu so s
Syn hesis o Suga Oxazolines
José L. Jiménez Blanco,a En ique M. Rubio,b Ca men O iz Melle ,*a José M. Ga cía Fe nández*b
aDepa amen o de Química O gánica, Facul ad de Química, Uni e sidad de Se illa, Ap do. 553, 41071 Se illa, Spain
Fax +34(954)624960; E-mail: melle @us.es
bIns i u o de In es igaciones Químicas, CSIC, Amé ico Vespucio 49, Isla de la Ca uja, 41092 Se illa, Spain
Fax +34(954)460565; E-mail: joga [email protected]
Recei ed 20 May 2004
SYNLETT 2004, No. 12, pp 2230–2232
01.10.2004
Ad anced online publica ion: 04.08.2004
DOI: 10.1055/s-2004-830891; A ID: D12704ST
© Geo g Thieme Ve lag S u ga · New Yo k
Abs ac : T ea men o D- uc opy anose and D- uc o u anose
1,2-O-ace onide de i a i es wi h i lic acid in he p esence o a a-
ie y o ni iles esul s in he o ma ion o used o spi o 2-oxazo-
lines. The eac ion implies (i) ac i a ion o he anome ic cen e wi h
simul aneous isop opylidene clea age, (ii) nucleophilic addi ion o
he ni ile o he co esponding oxoca benium ca ion in e media e
and (iii) subsequen apping o he esul ing ni ilium ion species
by he emaining hyd oxyl g oup in an in amolecula Ri e -like
eac ion.
Key wo ds: ca bohyd a es, ni iles, 2-oxazolines, spi o com-
pounds, Ri e eac ion
2-Oxazolines cons i u e a wide amily o i e-membe ed
he e ocycles wi h impo an applica ions in he ields o
o ganic syn hesis,1 ca alysis,2,3 and pha macology.4 2-
Amino-2-deoxysuga 2-oxazoline de i a i es ha e been
b oadly used as glycosyl dono s in he syn hesis o na u al
oligosaccha ides5 and ha e also been p oposed as glycosi-
dase subs a es6 and inhibi o s.7 Recen ly, in e es in he
syn hesis o he isome ic glycosylamine 2-oxazoline de-
i a i es (glycosyl isooxazolines) has g own because
hese compounds can se e as in e media es in he s e eo-
selec i e cons uc ion o he glycosyl amide bond, a key
s uc u al ea u e o N-glycop o eins.8 Howe e , u he
applica ions ha e been limi ed so a due o he lack o
sui able p epa a i e me hods and he ela i e ins abili y o
he anome ic 2-oxazoline ing.
The Ri e eac ion,9 i.e., he gene a ion o a ela i ely s a-
ble ca boca ion and i s in si u apping by ni iles, o gi e
ansien ni ilium species ha can unde go u he in e o
in amolecula nucleophilic a ack by a sui ably loca ed
g oup, is an a ac i e s a egy o he p epa a ion o a a-
ie y o amide p oduc s and azahe e ocycles ha has al-
eady ound u ili y in ca bohyd a e chemis y.10 T ansien
glycosyl isooxazoline in e media es ha e been al eady in-
oked in some Ri e -like ans o ma ions.11 Ye , only in
a ew cases hey ha e been isola ed and ully cha ac e -
ized.12 In p e ious wo k, we ha e shown ha D- uc ose
isop opylidene de i a i es can be eadily ac i a ed wi h
i lic acid o gi e a ansien b-hyd oxy oxoca benium
ca ion.13 In he absence o any o he nucleophile, spi odi-
saccha ides (di-D- uc ose dianhyd ides) a e o med. We
now epo he ex ension o his s a egy o he s e eo-
selec i e p epa a ion o used and spi o glycosyl isoxazo-
lines by a Ri e -like eac ion in ol ing (i) ni ile addi ion
o he uc osyl ca ion and (ii) subsequen in amolecula
apping o he ini ially o med ni ilium ion by he icinal
ee hyd oxyl g oup (Scheme 1).
Scheme 1 Syn hesis o used and spi o glycosyl isooxazolines om
D- uc ose isop opylidene de i a i es by Ri e -like eac ion
A wide a ie y o ni iles was ound o pa icipa e in he
addi ion-cycliza ion eac ion. In he case o 1-O-benzyl-
2,3:4,5-di-O-isop opylidene-b-D- uc opy anose (1),14
he co esponding used isooxazoline wi h b-anome ic
con igu a ion (6a–d) was he only eac ion p oduc
(Figu e 1 and Table 1, en ies 1–4). The s e eochemical
ou come is go e ned in his case by he o ien a ion o OH-
3, o ma ion o a ans- used bicyclic sys em being p e-
en ed due o s e ic s ain. Con a y o ha epo ed o
p e ious p epa a ions o aldose-de i ed glycosyl isoox-
azolines, compounds 6a–d we e ound o be a he s able.
In ac , i is known ha he s abili y o he oxazolinium
ca ion inc eases wi h he numbe o elec on-dona ing
ca bon subs i uen s in he ing.15 Mo eo e , oxazolinium
O
O
O
RO
O
RO OH
O
OH
N
RO C R'
O
O
N
RO R'
O
RO
O
O
O
RO OR
OH
O
RO
OH
N
OR
OR
C
R'
O
RO
O
N
OR
R'
R'CN R'CN
acid p omo o
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LETTER Syn hesis o Suga Oxazolines 2231
Synle 2004, No. 12, 2230–2232 © Thieme S u ga · New Yo k
i la es a e s ill mo e s able, since he i la e coun e ion
is a e y weak nucleophile, which is unable o a ack he
oxazolinium ing.16
Ac i a ion o 1,2:4,5-di-O-isop opylidene-b-D- uc opy -
anose p ecu so s (2 and 3)14 wi h i lic acid in he p es-
ence o a ni ile a o ded spi o isooxazolines (7a–d and 8,
espec i ely).17 Only he b-con igu ed compounds, ha -
ing he py anose ing in he 1C4 con o ma ion, we e de-
ec ed, i espec i e o he pa icipa ing (benzoyl) o non-
pa icipa ing cha ac e (benzyl) o he hyd oxyl p o ec ing
g oup a O-3 (Table 1, en ies 5–9). I is no ewo hy ha
his si ua ion implies he axial o ien a ion o he N-subs i -
uen a he anome ic posi ion, a gene ally un a o able a -
angemen o N-glycosidic de i a i es due o he e e se
anome ic e ec .18 In ac , he p e e ence o he axial o i-
en a ion has p e iously been obse ed in he case o
glycosylace oni ilium ions, which ha e been apped as
he co esponding imides by eac ion wi h ca boxylic
acids.19 Ou esul s indica e ha his scena io is p obably
gene al o glycosylni ilium sal s. Mo eo e , he de-
c eased posi i e cha ge densi y a he isooxazoline ni o-
gen a om, as compa ed wi h amines, in combina ion wi h
he p e e ed equa o ial o ien a ion o he ca bon subs i -
uen , p obably p e en s anome iza ion o he inal com-
pounds, a ypical p oblem in he case o pe -O-p o ec ed
glycosylamine de i a i es.20
3,4,6-T i-O-p o ec ed 1,2-O-isop opylidene-b-D- uc o-
u anose de i a i es (4 and 5)21 likewise a o ded spi o
isooxazolines ha ing he b-anome ic con igu a ion a he
uc ose moie y upon eac ion wi h ace oni ile unde he
abo e eac ion condi ions (9 and 10, espec i ely,
Table 1, en ies 10 and 11). In he case o he benzoyla ed
p ecu so , howe e , he cis- used bicyclic isooxazoline
11, a ising om O-3 o O-1 acyl mig a ion p io o oxazo-
line ing closu e, was he majo eac ion p oduc (Table 1,
en y 11), in ag eemen wi h he highe s abili y o he
used isooxazoline skele on as compa ed wi h he spi o
glycosyl isooxazoline amewo k.
In summa y, he Ri e -based s a egy epo ed he ein is
e ec i e o accessing used as well as spi o glycosyl
isooxazolines om eadily ob ainable D- uc ose ace-
onides. The comme cial a ailabili y o a la ge numbe o
ni iles and he simplici y o he me hod should be a ac-
i e no only o exploi he ich chemis y o 2-oxazolines
in ca bohyd a e ans o ma ion schemes bu also o he
p epa a ion o chi al 2-oxazoline lib a ies, o in e es as
ligands in asymme ic ca alysis. Wo k in bo h di ec ions
is cu en ly being in es iga ed in ou labo a o ies.
Gene al p ocedu e: To a 0.114 M solu ion o he co esponding D-
uc ose p ecu so 1–5 and he ni ile coun e pa (10 equi ) in dis-
illed CH2Cl2 a –20 °C, T OH (1.5 equi ) was added unde A a -
mosphe e. The eac ion mix u e was allowed o wa m up o . . and
s i ed o he ime indica ed in Table 1. Then E 3N was added, he
sol en s we e e apo a ed unde educed p essu e and he p oduc s
we e pu i ied by column ch oma og aphy using mix u es o
E OAc–pe oleum e he as eluen . All p oduc s ga e sa is ac o y
MS and mic oanalysis da a in ag eemen wi h he p oposed s uc-
u es. The isola ed yields a e indica ed in Table 1.
Selec ed da a22 o 6a: R = 0.22 (1:2 E OAc–pe oleum e he ); [a]D
–90 (c 0.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 7.22 (m, 5 H,
Ph), 4.62 (d, 1 H, CH2Ph), 4.60 (dd, 1 H, H-4), 4.56 (d, 1 H, H-3),
4.55 (d, 1 H, CH2Ph), 4.13 (dd, 1 H, H-5), 3.73 (d, 1 H, H-1a), 3.71
(d, 1 H, H-6a) 3.59 (d, 1 H, H-1b), 3.31 (dd, 1 H, H-6b), 2.04 (s, 3
H, NMe), 1.39, 1.30 (2 s, each 3 H, CMe2) ppm. 13C NMR (125.7
MHz, CDCl3): d = 168.0 (CN), 138.1, 128.3, 127.6, 127.5 (Ph),
109.1 (CMe2), 98.7 (C-2), 73.5 (CH2Ph), 73.1 (C-1), 72.8 (C-3),
70.4 (C-5), 69.8 (C-4), 60.9 (C-6), 26.0, 24.3 (2 CMe2), 13.9 (NMe)
ppm.
Table 1 Glycosyl Isooxazolines Fo med by Reac ion o D-F uc ose
1,2-O-Ace onides wi h Ni iles Using T i lic Acid as P omo o a
En y D-F uc ose
p ecu so Ni ile Reac ion ime
(h) P oduc s
(yield, %)
11MeCN 1 6a (80)
21E CN 1 6b (71)
31n-P CN 5 6c (75)
41PhCN 3 6d (65)
52MeCN 1 7a (50)
62E CN 0.5 7b (63)
72n-P CN 0.5 7c (83)
82PhCN 0.5 7d (65)
93MeCN 1 8 (41)
10 4MeCN 0.5 9 (48)
11 5MeCN 3 10 (15)
11 (44)
a All eac ions we e ca ied ou in CH2Cl2 a –20 °C o . . using 10
equi o he ni ile and 1.5 equi o he acid p omo o .
Figu e 1 S uc u es o he used and spi o glycosyl isooxazolines
p epa ed in his s udy and o he co esponding D- uc ose p ecu so s
OO
O
O
O
OR
OO
N
O
O
OR
R'
O
O
O
O
O
OBn
O
N
O
O
O
OBn
R'
O
OR
RO O
O
RO
O
OR
RO O
N
RO O
OBz
BzO
O
N
OBz
2 R = Bn
3 R = Bz 4 R = Bn
5 R = Bz
6a–d 7a–d R = Bn
8 R = Bz, R' = Me
a R' = Me
b R' = E
c R' = n–P
d R = Ph
9 R = Bn
10 R = Bz 11
1
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2232 J. L. Jiménez Blanco LETTER
Synle 2004, No. 12, 2230–2232 © Thieme S u ga · New Yo k
Selec ed da a o 7a: R = 0.54 (2:1 E OAc–pe oleum e he ); [a]D
–61 (c 0.7, CH2Cl2). The co esponding 1H NMR and 13C NMR da a
we e in ag eemen wi h hose epo ed in he li e a u e.17
Selec ed da a22 o 8: R = 0.34 (1:1 E OAc–pe oleum e he ); [a]D
–132 (c 0.9, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.02–7.41
(m, 5 H, Ph), 5.44 (d, 1 H, H-3), 4.50 (dd, 1 H, H-4), 4.41 (dd, 1 H,
H-6a), 4.33 (dd, 1 H, H-5), 4.11 (d, 1 H, H-6b), 4.10 (d, 1 H, H-1a),
4.05 (d, 1 H, H-1b), 2.05 (s, 3 H, NMe), 1.62, 1.36 (2 s, each 3 H,
CMe2) ppm. 13C NMR (125.7 MHz, CDCl3): d = 169.5 (CO), 166.0
(CN), 138.1, 129.8, 129.4, 128.4 (Ph), 109.5 (CMe2), 100.7 (C-2),
75.2 (C-4), 74.2 (C-1), 74.1 (C-5), 72.9 (C-3) 61.1 (C-6), 27.8, 26.4
(2 CMe2), 14.3 (NMe) ppm.
Selec ed da a22 o 9: R = 0.25 (1:2 E OAc–pe oleum e he ); [a]D
+68 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 7.37–7.24 (m,
15 H, 3 Ph), 4.67 (d, 1 H, CH2Ph), 4.62 (d, 1 H, CH2Ph), 4.54 (b s,
2 H, H-1), 4.52 (d, 1 H, CH2Ph), 4.48 (d, 1 H, CH2Ph), 4.41 (d, 1 H,
CH2Ph), 4.32 (d , 1 H, H-5), 4.17 (d, 1 H, CH2Ph), 4.16 (d, 1 H, H-
3), 4.02 (dd, 1 H, H-4), 3.58 (dd, 1 H, H-6a), 3.53 (dd, 1 H, H-6b),
2.06 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz, CDCl3): d = 168.5
(CN), 138.0, 137.9, 137.4, 127.6, 126.9 (Ph), 107.8 (C-2), 87.9 (C-
3), 81.8 (C-4), 80.2 (C-5), 73.3 (C-1), 72.4, 72.1, 72.0, (CH2Ph),
69.7 (C-6), 14.5 (NMe) ppm.
Selec ed da a22 o 10: R = 0.53 (1:4 E OAc–pe oleum e he ); [a]D
–42 (c 1.1, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.08–7.24 (m,
15 H, Ph), 6.03 ( , 1 H, H-4), 4.81 (d, 1 H, H-3), 4.81 (dd, 1 H, H-
6a), 4.71 (dd, 1 H, H-6b), 4.56 (m, 1 H, H-5), 4.51 (d, 1 H, H-1a),
4.33 (d, 1 H, H-1b), 1.98 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz,
CDCl3): d = 169.5 (CN), 166.3, 166.0, 165.6 (CO) 133.7, 133.6,
130.1, 129.9, 128.5, 128.3 (Ph), 106.5 (C-2), 78.8 (C-5), 78.6 (C-3),
77.1 (C-4), 73.5 (C-1), 65.9 (C-6), 14.4 (NMe) ppm.
Selec ed da a22 o 11: R = 0.29 (1:4 E OAc–pe oleum e he ); [a]D
–28 (c 5.8, CH2Cl2). 1H NMR (500 MHz, CDCl3): d = 8.07–7.24 (m,
15 H, Ph), 5.70 (d, 1 H, H-3), 5.61 (dd, 1 H, H-4), 4.79 (dd, 1 H, H-
6a), 4.70 (ddd, 1 H, H-5), 4.65 (dd, 1 H, H-6b), 4.32 (s, 2 H, H-1),
2.09 (s, 3 H, NMe) ppm. 13C NMR (125.7 MHz, CDCl3): d = 169.2
(CN), 133.8, 133.5, 133.3, 129.9, 129.7, 129.2, 128.8, 128.3 (Ph),
108.7 (C-2), 82.3 (C-4), 79.8 (C-5), 79.1 (C-3), 71.5 (C-1), 63.8 (C-
6), 14.5 (NMe) ppm.
Acknowledgmen
We hank he Spanish Minis e io de Ciencia y Tecnología o inan-
cial suppo (con ac s numbe BQU2003-00937 and BCM2001-
2366-CO3-03). E. M. R. hanks he CSIC o a ellowship.
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