Iodine/toluenesulfonic acid: A novel catalyst for isopropylidenation in carbohydrate chemistry

Article abstract of DOI:10.1135/cccc20071214

A novel catalyst for O-isopropylidenation of carbohydrates, a mixture of toluenesulfonic acid and iodine, was developed.

Full text of DOI:10.1135/cccc20071214

1214
Zhao, Zhang, Wang:
IODINE/ TOLUENESULFONIC ACID: A NOVEL CATALYST FOR
ISOPROPYLIDENATION IN CARBOHYDRATE CHEMISTRY
1
2
3,
Guilong ZHAO , Yan ZHANG and Jianwu WANG *
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, P. R. China;
1
2
e-mail: zhao_guilong@sohu.com, zhangyan782002@yahoo.com.cn,
3
jianwuwang@mail.sdu.edu.cn
Received Decem ber 15, 2006
Accepted April 29, 2007
A n ovel catalyst for O-isopropyliden ation of carboh ydrates, a m ixture of toluen esulfon ic acid
an d iodin e, was developed.
Keyw ord s: Iodin e; Toluen esulfon ic acid; Isopropyliden e; Carboh ydrates; Syn th esis; Pro-
tectin g group.
Carboh ydrates an d th eir derivatives play an im portan t role in biological
processes in an im als an d plan ts, an d h ave foun d wide application s in
ph arm aceuticals an d related fields. Th e isopropyliden e group is a con sider-
ably im portan t protective group in th e syn th esis of a variety of carboh y-
drate derivatives1–3
.
A n um ber of isopropyliden ation reagen ts h ave been developed so far,
am on g wh ich MeC(OMe)=CH2 (ref.4), Me2C(OMe)2 (ref.5), an d aceton e6,7
are m ajor on es. However, th e first two, derivatives of aceton e, are m ore ex-
pen sive th an aceton e itself an d un satisfactory in m an y cases. Th e classical
m eth od of in troduction of isopropyliden e fun ction ality is th e reaction of
th e substrate with aceton e in th e presen ce of an acid catalyst. Here, we
would like to report on a n ovel catalyst of th e reaction , a m ixture of iodin e
an d toluen esulfon ic acid.
In th e total syn th esis of a cytotoxic n atural product 4″-O-acetyl-
m an an th oside B 8, com poun d 2 was required, wh ich could be obtain ed by
isopropyliden ation of glycoside 1 (Sch em e 1).
SCHEME 1
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 9, pp. 1214–1218
© 2007 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20071214

Novel Catalyst for Isopropylidenation
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At first we em ployed th e classical reagen ts, aceton e/toluen esulfon ic acid
an d aceton e/con cen trated sulfuric acid, for isopropyliden ation ; h owever,
both th e reaction s in volvin g th e two reagen ts were sluggish , a certain
am oun t of th e substrate rem ain ed un reacted, an d several im purities were
also form ed, com plicatin g th e work-up. We th en turn ed to th e reagen t6
aceton e/I2, wh ich was sh own to work well on ly on sm all scales (less th an
0.2 g). Wh en th e reaction was scaled up to 1 g or m ore, th e reaction becam e
un reliable, an d it did n ot occur at all at room or sligh tly elevated tem pera-
ture (below reflux) even after 12 h stirrin g. Reflux was subsequen tly em -
ployed to accelerate th e reaction ; h owever, th e reaction proceeded to
com pletion in an un predictable period, ran gin g from several secon ds to
on e h our, an d th e product 2 was rapidly oxidatively cleaved (Sch em e 2).
After accum ulation of experien ce with th is reagen t, a facile an d reliable
catalyst was devised, a m ixture of iodin e an d toluen esulfon ic acid, wh ich is
capable of catalyzin g isopropyliden ation of 1 with aceton e. Th us, th e iso-
propyliden ation of 1 with aceton e in th e presen ce of iodin e an d toluen e-
sulfon ic acid as catalyst proceeded sm ooth ly with in 20 m in at 45 °C. Th e
reaction is rath er clean an d could be scaled up to several gram s.
SCHEME 2
En couraged by th e outstan din g power of th is catalyst, th e application of
th is catalyst to oth er substrates in carboh ydrate ch em istry was attem pted
(Sch em e 3). Un der alm ost th e sam e reaction con dition s, th ree carboh ydrate
substrates were readily isopropyliden ated; th e reaction s were clean an d n o
im purities were detected.
SCHEME 3
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Zhao, Zhang, Wang:
Application of th is catalyst to sim ple m on osacch arides was furth er car-
ried out, th e results bein g also satisfactory (Sch em e 4). However, it sh ould
be n oted th at isopropyliden ation of sim ple m on osacch arides such as
D-galactose (7) an d D-glucose (9) required m ore vigorous con dition s th an
th at m en tion ed above. Th us, 7 an d 9 were isopropyliden ated with aceton e
in th e presen ce of iodin e/toluen esulfon ic acid at reflux in 3 h , wh ereas
m eth yl β-L-arabin opyran oside (5) was readily con verted to isopropyliden e
derivative 6 un der m ilder con dition s.
SCHEME 4
Th e advan tage of th e iodin e/toluen esulfon ic acid catalyst over iodin e
alon e m ay be attributable to th e addition of toluen esulfon ic acid. Th e acid
appeared to im prove th e solubility of th e substrate in aceton e an d activate
iodin e. On ly a suspen sion of reagen ts form s if th e substrate an d iodin e in
aceton e were stirred even after a lon g period an d n o reaction occurred in
m ost cases or th e reaction was in itiated by an un kn own factor in an un pre-
dictable period of tim e. However, wh en toluen esulfon ic acid was added, th e
suspen sion dissolved at a reason able rate an d th e reaction proceeded
sm ooth ly an d predictably. Th us, a prelim in ary con clusion can be drawn
th at if th e substrates to be isopropyliden ated are soluble or sligh tly soluble
in aceton e (1, 2, 3a–3c an d 5), th en th e reaction can sm ooth ly proceed to
com pleten ess (45 °C, 20 m in ). If th e substrates are little soluble in aceton e
(7 an d 9), vigorous con dition s (reflux, 3 h ) are n ecessary to im prove th e sol-
ubility an d en sure an acceptable reaction rate.
EXPERIMENTAL
Th e m eltin g poin ts were m easured with an XT-4 m icroscopic apparatus an d are un corrected.
Th e 1H NMR spectra were recorded with a Bruker AV 300 or a Bruker AV 600 spectrom eter,
with CDCl3, m eth an ol-d4 or DMSO-d6 as solven t an d TMS as in tern al stan dard. Ch em ical
sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. Th e IR spectra (waven um bers
Collect. Czech. Chem. Commun. 2007, Vol. 72, No. 9, pp. 1214–1218

Novel Catalyst for Isopropylidenation
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in cm –1) were m easured on a Th erm o Nicolet Avatar 370 FT spectroph otom eter in KBr pel-
lets. Th e m ass spectra were obtain ed on an ABI MAT-212 apparatus usin g electrospray ion -
ization (ESI) tech n ique. Th e elem en tal an alyses were carried out with an Elem en tar EI Vario
III CHN an alyzer. Specific rotation s were m easured with a WZZ-2A autom atic polarim eter
un der stan dard con dition s.
A Typical Procedure of Isopropyliden ation of Carboh ydrates 1, 3a–3c an d 5
A 100-m l roun d-bottom ed flask was ch arged with substrate (1.0 g), iodin e (20 m g) an d ace-
ton e (15 m l). Th e resultin g m ixture was stirred at 45 °C to form a suspen sion , in to wh ich
toluen esulfon ic acid m on oh ydrate (20 m g) was added in on e portion . Stirrin g was con tin ued
for an oth er 20 m in un til th e in itially in soluble m ass dissolved an d TLC sh owed a com plete
con version .
On coolin g, th e m ixture could be directly subjected to colum n ch rom atograph y. Altern a-
tively, th e m ixture was diluted with dich lorom eth an e (50 m l), wash ed successively with sat-
urated aqueous sodium h ydrogen carbon ate, 5% aqueous sodium sulfite an d brin e, an d dried
over an h ydrous sodium sulfate. Th e organ ic ph ase was evaporated on a rotary evaporator to
give th e crude product, wh ich was ch rom atograph ed on silica gel with eth yl acetate an d pe-
troleum eth er as eluen ts.
4-Methoxyphenyl 3,4-O-isopropylidene-β-D-galactopyranoside (2), yield 88%, m .p. 139–139.5 °C;
ref.9 gives m .p. 133–134 °C. [α ]2D0 –30.5 (c 1.0, CHCl3). For C16H22O7 (326.3) calculated:
58.89% C, 6.79% H; foun d: 58.82% C, 6.77% H. IR: 3333 (OH); 3062 (Ar-H); 1509, 1465
(ben zen e rin g); 1384 (Me); 1230, 1080, 1041 (C–O). 1H NMR (300 MHz, DMSO-d6):
6.95–6.98, 6.83–6.86 dd, 2 H each , J = 9.0 (Ar-H); 5.53–5.55 d, 1 H, J = 5.1 (OH-2); 4.84–4.87 t,
1 H, J = 5.6 (H-4); 4.70–4.73 d, 1 H, J = 8.1 (H-1); 4.14–4.17 m , 1 H (H-5); 4.01–4.05 t, 1 H,
J = 6.2 (H-3); 3.91–3.95 t, 1 H, J = 6.2 (H-2); 3.70 s, 3 H (MeO); 3.53–3.58 m , 2 H (H-6);
3.40–3.47 m , 1 H (OH-6); 1.42, 1.27 ss, 3 H each (CMe2). 13C NMR (75 MHz, DMSO-d6):
154.52, 151.45, 117.80, 114.57 (Ar C); 108.86 (C-1); 101.22 (quatern ary C in CMe2); 79.39
(C-2); 73.51 (C-3); 73.28 (OMe); 72.32 (C-4); 60.54 (C-5); 55.49 (C-6); 28.32, 26.57 (2 Me in
CMe2). ESI-MS (m/z): 344.4 [M + H2O], 349.3 [M + Na].
Phenyl 3,4-O-isopropylidene-β-D-galactopyranoside (4a), yield 92%, m .p. 137.5–140 °C. [α ]D20
–33.7 (c 1.0, CHCl3). For C15H20O6 (296.3) calculated: 60.80% C, 6.80% H; foun d: 60.71% C,
6.83% H. IR: 3274 (OH); 3062 (Ar-H); 1601, 1591, 1493 (ben zen e rin g); 1380 (Me); 1236,
1076, 1053 (C–O). 1H NMR (600 MHz, m eth an ol-d4): 7.28–7.30 m , 2 H (Ar-H); 7.09–7.10 m ,
2 H (Ar-H); 7.01–7.02 m , 1 H (Ar-H); 4.85–4.87 d, 1 H, J = 8.1 (H-1); 4.28–4.29 d, 1 H, J =
5.47 (H-2); 4.13–4.16 t, 1 H, J = 6.3 (H-3); 4.04–4.06 m , 1 H (H-5); 3.80–3.81 m , 2 H (H-6);
3.68–3.71 m , 1 H (H-4); 1.37, 1.53 ss, 3 H each (CMe2). 13C NMR (150 MHz, m eth an ol-d4):
157.34, 128.73, 121.74, 116.07 (Ar C); 109.45 (C-1); 100.10 (quatern ary C in CMe2); 79.10
(C-2); 73.52 (C-3); 73.31 (C-4); 72.46 (C-5); 60.69 (C-6); 26.75, 24.86 (2 Me in CMe2).
ESI-MS (m/z): 314.3 [M + H2O], 319.3 [M + Na].
Phenyl 3,4-O-isopropylidene-6-O-pivaloyl-β-D-galactopyranoside (4b), yield 90%, m .p. 149.5–
151 °C. [α ]2D0 –12.1 (c 1.0, CHCl3). For C20H28O7 (380.4) calculated: 63.14% C, 7.42% H;
foun d: 63.05% C, 7.40% H. IR: 3436 (OH); 3060 (Ar-H); 1733 (C=O); 1600, 1587, 1499, 1488
(ben zen e rin g); 1387 (Me); 1227, 1071, 1053 (C–O). 1H NMR (600 MHz, CDCl3): 7.28–7.30 m ,
2 H (Ar-H); 7.05–7.08 m , 3 H (Ar-H); 4.78–4.79 d, 1 H, J = 8.3 (H-1); 4.42–4.45 m , 1 H (H-3);
4.33–4.37 m , 1 H (H-4); 4.17–4.22 m , 3 H (H-5 an d H-6); 3.87–3.89 t, 1 H, J = 7.5 (H-2);
1.39, 1.58 ss, 3 H each (CMe2); 1.23 s, 9 H (CMe3). 13C NMR (150 MHz, CDCl3): 177.99
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Zhao, Zhang, Wang:
(C=O); 156.66, 129.22, 122.79, 116.56 (Ar C); 110.48 (C-1); 100.09 (quatern ary C in CMe2);
78.35 (C-2); 73.01 (C-3); 72.97 (C-4); 71.10 (C-5); 63.04 (C-6); 38.47 ((CH3)3C); 27.80
((CH3)3C); 26.84, 26.01 (2 Me in CMe2). ESI-MS (m/z): 398.6 [M + H2O], 403.7 [M + Na].
Phenyl 6-O-benzoyl-3,4-O-isopropylidene-β-D-galactopyranoside (4c), yield 95%, m .p. 141–
143 °C. [α ]2D0 –5.6 (c 1.0, CHCl3). For C22H24O7 (400.4) calculated: 65.99% C, 6.04% H;
foun d: 65.92% C, 6.06% H. IR (KBr): 3429 (OH); 3057 (Ar-H); 1725 (C=O); 1599, 1588, 1497
(ben zen e); 1271, 1114, 1070 (C–O). 1H NMR (600 MHz, CDCl3): 8.07–8.08 m , 2 H (Ar-H of
ben zoyl); 7.49–7.63 m , 1 H (Ar-H of ben zoyl); 7.46–7.49 m , 2 H (Ar-H of ben zoyl); 7.18–7.20 m ,
2 H (Ar-H of Ph O); 7.02–7.06 m , 3 H (Ar-H of Ph O); 4.80–4.81 d, 1 H, J = 8.2 (H-1);
4.72–4.77 m , 1 H (H-2); 4.58–4.62 m , 1 H (H-4); 4.30–4.32 m , 2 H (H-6); 4.24–4.26 m , 1 H
(H-5); 3.91–3.94 t, 1 H, J = 7.7 (H-2); 1.42, 1.61 ss, 3 H each (CMe2). 13C NMR (150 MHz,
CDCl3): 166.00 (C=O); 156.61, 132.99, 129.47, 129.43 (C in ben zoyl); 129.17, 128.17,
122.74, 116.59 (C in ph en yl); 110.65 (C-1); 100.10 (quatern ary C in CMe2); 78.48 (C-2);
73.07 (C-3); 73.03 (C-4); 71.25 (C-5); 63.39 (C-6); 27.81, 26.06 (2 Me in CMe2). ESI-MS
(m/z): 418.7 [M + H2O], 423.6 [M + Na].
Methyl 3,4-O-isopropylidene-β-L-arabinopyranoside (6), yield 87%. [α ]2D0 +199.5 (c 1.0, CHCl3);
ref.10 gives [α ]D20 +199.1 (c 1.0, CHCl3).
A Typical Procedure for Isopropyliden ation of Carboh ydrates 7 an d 9
In to a 100-m l roun d-bottom ed flask substrate (1.0 g), iodin e (60 m g), toluen esulfon ic acid
m on oh ydrate (50 m g) an d aceton e (60 m l) were added. Th e m ixture was subsequen tly
refluxed for 3 h un til a clear solution form ed. On coolin g, m ost aceton e was evaporated an d
th e sam e work-up procedure as above gave th e desired products.
1,2:3,4-O-Diisopropylidene-α-D-galactopyranose (8), yield 77%, colorless oil. [α ]2D0 –54.1 (c 1.0,
CHCl3); ref.7 gives [α ]D20 –54.5 (c 1.0, CHCl3).
1,2:5,6-O-Diisopropylidene-α-D-glucofuranose (10), yield 73%, m .p. 109.5–111 °C; ref.7 gives
m .p. 110 °C.
Financial support from the Natural Science Foundation of Shandong Province (Z2004c06) is
gratefully acknowledged.
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