Acyl Sulfonamide Catalysts for Glycosylation Reactions with Trichloroacetimidate Donors

Article abstract of DOI:10.1055/s-2003-41493

The acyl sulfonamide functional group has been found to serve as a catalytic moiety for the glycosylation of several alcohols when glycosyl donors based on trichloroacetimidates are employed.

Full text of DOI:10.1055/s-2003-41493

CLUSTER
1923
Acyl Sulfonamide Catalysts for Glycosylation Reactions with Trichloroaceti-
midate Donors
A
cyl Sulfonamide
e
Catalysts fo
i
r
G
lyc
t
osylatio
h
n Reactions S. Griswold, Thomas E. Horstmann, Scott J. Miller*
Department of Chemistry, Boston College, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA
E-mail: scott.miller.1@bc.edu
Received 12 June 2003
explored the efficiency of glycosidic bond formation
Abstract: The acyl sulfonamide functional group has been found to
serve as a catalytic moiety for the glycosylation of several alcohols
when glycosyl donors based on trichloroacetimidates are employed.
under a variety of conditions, finding in accord with
literature precedent,6 that the coupling is acid-catalyzed.
Thus, when cyclohexanol and 1 are comixed in dichloro-
methane, in the presence of a variety of acidic additives,
appreciable amounts of product are obtained.
Key words: glycosylation, hydrogen bond, trichloroacetimidate,
organocatalysis
The glycosylation reaction is a fundamental process at the
heart of carbohydrate assembly. Among the challenges in
the field is the issue of regioselectivity when
glycosylation reactions are carried out with
polyfunctional glycosyl acceptors. This is partially due to
the fact that unprotected hydroxyl groups within the
monosaccharide acceptor often possess comparable
electronic and steric properties.1 However, their relative
reactivity differences are difficult to predict and are often
complicated by the fact that their nucleophilicity is
dependent on the monosaccharide structure and the
specific reaction conditions. In the context of
carbohydrate synthesis, enzymatic approaches certainly
represent one form of the state of the art.2 However,
variation in substrate structure may result in significant
loss of selectivity for such enzymatic reactions. In terms
of nonenzymatic chemistry, the field has seen a
tremendous range of approaches to chemical
glycosylation to meet the myriad of challenges presented
by carbohydrate structures.3
Catalyst (10 mol%)
CH2Cl2
HN
CCl3
OH
OBn
OBn
O
O
4Å M.S.
O
O
+
25 °C
BnO
OBn
BnO
OBn
OBn
OBn
1
2
(1.5 equiv)
Equation 1
Table 1 Catalyst Screen for the Coupling of 1 to Cyclohexanola
Entry Catalyst
Reaction Yield (%)b a/bc
time (h)
1
1.5
Quantita- 60:40
tive
NO2
NO2
OH
O2N
H3C
NO2
2
3
24
24
<5
70
N.D.
OH
NO2
In an effort to develop small-molecule catalysts for
glycosylation reactions, we were intrigued by the
possibility of pursuing an organocatalytic approach since
so many of the known protocols are based on Lewis-acid
activation of the glycosyl donor. In particular, we were
interested in developing catalysts that might allow for
binding of coupling partners through host-guest
interactions during the bond-forming step of a more
complicated mechanism. Given that the hydrogen bond
represents an effective Brønsted acid, and in fact may
catalyze a number of reactions that are better known to
proceed under Lewis acid catalysis,4 we sought to define
the range of hydrogen bond-containing functional groups
that could catalyze a given glycosylation reaction.
57:43
F
F
F
F
OH
F
4
5
6
24
24
1.5
<5
<5
92
N.D.
N.D.
46:54
O
HO
CH3
O
HO
CF3
O
S
H3C
OH
O
7
24
54
53:47
HN
SO3
H3C
Our studies began with the coupling of cyclohexanol to
trichloroacetimidate donor 1 (Equation 1, Table 1).5 We
a All reactions conducted at 25°C in CH2Cl2 in the presence of 4 Å
sieves. Catalyst loadings are 12 mol% with respect to alcohol.
b Yields refer to isolated yield after silica gel chromatography.
c As determined by 1H NMR (400 MHz).
SYNLETT 2003, No. 12, pp 1923–1926
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9
.0
9
.2
0
0
3
Advanced online publication: 19.09.2003
DOI: 10.1055/s-2003-41493; Art ID: Y00703ST
© Georg Thieme Verlag Stuttgart · New York

1924
K. S. Griswold et al.
CLUSTER
Among the acids screened, picric acid7 proved to be para-chloro-substituted catalyst 4 provides a faster reac-
among the most efficient, delivering coupled product 2 in tion, delivering product 2 in 80% yield within a 24 hour
quantitative yield after only 90 minutes as a 3:2 mixture period (entry 2).
of anomers (entry 1). In striking contrast, replacement of
but one of the nitro groups with a methyl group reduces
the efficiency of the reaction. Thus, use of 2,6-dinitro-4-
Table 2 Catalyst Screen for the Coupling of 1 to Cyclohexanol un-
der the Influence of Acyl Sulfonamide Catalystsa
methyl phenol as the intended catalyst results in less than
5% yield of the desired product (entry 2).
Pentafluorophenol (PFP) provides intermediate catalytic
activity, delivering product 2 in 70% isolated yield (a/
b = 57:43) after 24 hours (entry 3). Given the pKa range of
PFP (ca 6.0)8 and picric acid (ca 0.3),9 we sought to
establish whether simple carboxylic acids provided effi-
cient catalytic reactions. Of note, neither acetic acid (entry
4) nor trifluoroacetic acid (entry 5) is effective. It appears
that in these cases, donor 1 is activated by the catalyst, but
the conjugate base may outcompete the glycosyl acceptor
for the activated donor. Surmising that acid catalysts with
non-nucleophilic conjugate bases may be optimal
catalysts for this process, we found that toluenesulfonic
acid was comparable to picric acid as a catalyst (entry 6),
affording 2 in 92% isolated yield after 90 minutes, albeit
as a nearly 1:1 mixture of anomers. The buffered version,
PPTS was also competent, but resulted in attenuated
reactivity (54% yield after 24 h, entry 7).
Entry Catalyst
Reaction Yield
time (h) (%)b
a/bc
O
1
43
60
40:60
O
S
N
Me
N
H
O
3
CO2CH3
2
24
80
40:60
O
O
N
Cl
S
N
H
O
4
CO2CH3
a All reactions conducted at 25 °C in CH2Cl2 in the prescence of 4 Å
sieves. Catalyst loadings are 10 mol% with respect to alcohol.
b Yields refer to isolated yield after silica gel chromatography.
c As determined by 1H NMR (400 MHz).
While a more complete data set would allow a more
definitive explanation of the apparant rate difference, it
appears at this time that the more electron deficient
compound may be more active due to heightened acidity
of the sulfonamide proton. Of note, control experiments
show that the catalyst does not undergo hydrolysis under
the reaction conditions to afford the corresponding
catalytically active sulfonic acid. For example, when the
reaction is conducted in a deuterated solvent, no catalyst
decomposition is observed by NMR (<2%, 400 MHz, 1H
NMR). In addition, the catalyst can be recovered in >90%
yield by silica gel chromatography after the reaction has
been run to completion. Of course, a very minor degree of
hydrolysis cannot be rigorously excluded.
We then sought to extend these findings to other classes
of Brønsted acids that might be amenable to structural
modification, and ultimately the tuning of catalytic
activity. For this purpose, we turned our attention to acyl
sulfonamides, a class of compounds that have been
relatively unexplored as catalysts for organic reactions.
We chose acyl sulfonamides for this purpose since they
possess a proton with acidity that might be readily tuned
through alteration of the structure. In addition, we
speculated that the acyl sulfonamide-derived conjugate
base would be a poor nucleophile. Acyl sulfonamides are
readily available through condensation of an amine and a
sulfonyl isocyanate.10 Accordingly, we prepared
compounds 3 and 4 through coupling of Pro-OMe to
various sulfonyl isocyanates under mild conditions
(Equation 2).11
With an acyl sulfonamide-based catalyst on hand that
provided convenient reaction times, we sought to examine
its behavior with additional glycosyl acceptors. As shown
in Table 3, catalyst 4 mediates glycosidic bond formation
with a variety of alcohol acceptors.12,13 In addition to
cyclohexanol,14 n-octanol participates as an acceptor;
glycoside 6 may be obtained in 60% yield (a/b = 60:40,
entry 2).15 Phenyl glycoside 7 is obtained in somewhat
lower yield (49%, a/b = 40:60, entry 3). In addition,
glucose derivatives may be employed as the acceptor, as
illustrated by the formation of 8 (67%, a/b = 42:58, entry
4).16 In contrast, a BOC-protected serine derived acceptor
was a less efficient coupling partner, delivering glycoside
9 in a low 28% isolated yield over 48 h. The reasons for
the low yield are a matter of further study, as the
possibility of competitive hydrogen bonding between
acceptor and catalyst may play a role.17
O
O
O
O
S
N
HN
C
R
S
N
H
R
N
+
O
CO2CH3
O
O
OMe
3, R = Me, >95% Yield
4, R = Cl, >95% Yield
Equation 2
Compounds 3 and 4 do indeed prove to be catalysts for
glycosylation of cyclohexanol with a trichloroacetimidate
donor such as 1. As shown in Table 2, the tolyl substituted
compound 3 catalyzes a sluggish reaction, but it affords a
60% isolated yield of the product as a 2:3 mixture of ano-
mers (a/b) over the course of 43 hours (entry 1). However,
changing the para-substituent on the aromatic ring has a
significant impact on the catalytic activity. For example,
In summary, we have found that an appropriately
functionalized acyl sulfonamide can function as a catalyst
for glycosylation of trichloroacetimidate donors. The next
phase of this research will endeavor to explore the
tunability of these catalysts as a function of further
Synlett 2003, No. 12, 1923–1926 © Thieme Stuttgart · New York

CLUSTER
Acyl Sulfonamide Catalysts for Glycosylation Reactions
1925
Table 3 Glycosylation Reactions Performed with Acyl Sulfonamide 4 as the Catalysta
Entry
1
Acceptor
Product
Time (h)
24
Yield (%)b
92
a/bc
58:42
OH
OBn
O
O
Cyc
BnO
OBn
OBn
OBn
O
2
3
4
40
48
48
60
49
67
60:40
40:60
42:58
HO
CH3
7
O
CH3
7
BnO
OBn
OBn
6
OBn
O
OH
O
Ph
7
OBn
BnO
OBn
H3CO
O
OBn
OBn
OBn
OH
O
OCH3
OBn
OBn
BnO
BnO
O
O
OBn
OBn
8
OBn
5
48
28
57:43
OH
O
OMe
NHBOC
O
O
OMe
OBn
BnO
BOCHN
O
9
OBn
OBn
a All reactions conducted at 25 °C in CH2Cl2 in the prescence of 4 Å sieves. Catalyst loadings are 15 mol% with respect to alcohol.
b Yields refer to isolated yield after silica gel chromatography.
c As determined by 1H NMR (400 MHz).
(4) For representative recent examples of reactions where H-
bonds may play a key role as chiral Lewis acids, see:
(a) Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H.
Nature (London) 2003, 424, 146. (b) Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
(c) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012.
variations of both the aryl moiety, and also the amino acid
(and peptide) coupling partner introduced during the acyl
sulfonamide synthesis.
Acknowledgment
This research is supported by the National Institutes of Health (GM-
068649). We are also grateful to the Merck Chemistry Council and
Pfizer Global Research for research support. SJM is a Fellow of the
Alfred P. Sloan Foundation, and a Camille Dreyfus Teacher-
Scholar.
(5) (a) Pougny, J.-R.; Jaquinet, J.-C.; Nassr, M.; Duchet, D.;
Milat, M.-L.; Sinay, P. J. Am. Chem. Soc. 1977, 99, 6762.
(b) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl.
1980, 19, 731.
(6) (a) See ref.5a (b) Wessel, H. P. J. Carbohydr. Chem. 1988, 7,
263. (c) Nicolaou, K. C.; Daines, R. A.; Ogawa, Y.;
Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4696.
(d) Mukaiyama, T.; Hashihayata, T.; Mandai, H. Chem. Lett.
2003, 32, 340.
References
(1) Collins, P.; Ferrier, R. Monosaccharides: Their Chemistry
and Their Roles in Natural Products; John Wiley and Sons:
Chichester, 1995, Chap. 5.
(2) For a recent review, see: Gijsen, H. J. M.; Qiao, L.; Fitz, W.;
Wong, C.-H. Chem. Rev. 1996, 96, 443.
(7) Caution: picric acid is a potentially explosive compound
when thoroughly dried (water content <10%). We did not
observe any difficulties of this type during these
experiments.
(8) Gandler, J. R.; Jencks, W. P. J. Am. Chem. Soc. 1982, 104,
1937.
(9) (a) Iwachido, T.; Oosawa, S.; Toei, K. Bull. Chem. Soc. Jpn.
1985, 58, 2415. (b) Kolthoff, I. M.; Chantooni, M. K.;
Bhomik, S. J. Am. Chem. Soc. 1968, 90, 23.
(3) For a brief review, see: Toshima, K.; Tatsuta, K. Chem. Rev.
1993, 93, 1503.
(10) (a) Smith, J. Jr.; Brotherton, T. K.; Lynn, J. W. J. Org. Chem.
1965, 30, 1262. (b) Ulrich, H.; Tucker, B.; Sayigh, A. A. R.
Angew. Chem. Int. Ed. 1967, 6, 708.
Synlett 2003, No. 12, 1923–1926 © Thieme Stuttgart · New York

1926
K. S. Griswold et al.
CLUSTER
(11) Compounds 3 and 4 were prepared by the reaction of L-
proline methylester with either 4-chlorophenylsulfonyl
isocyanate or p-toluenesulfonyl isocyanate according to the
following procedure: To a solution of L-proline methylester
hydrogen chloride (48.0 mg, 0.289 mmol) in CH2Cl2 (720
mL) stirring at 0 °C was added Et3N (40.0 mL, 0.289 mmol).
Isocyanate was then added dropwise and the reaction was
allowed to warm to 25 °C. The reaction was allowed to stir
for 30 min at 25 °C and was then diluted with 5 mL of
CH2Cl2 and washed with 1 N HCl. The organic layer was
dried over Na2SO4 and concentrated in vacuo. The resulting
residue was chromatographed on silica gel with 0–5%
MeOH/CH2Cl2 (>95% yield). Data for 3: 1H NMR (400
MHz, CDCl3): d = 7.96 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.1
Hz, 2 H), 4.40 (dd, J = 8.4, 3.9 Hz, 1 H), 3.70 (s, 3 H), 3.56–
3.34 (m, 2 H), 2.43 (s, 3 H), 2.20–1.81 (m, 4 H). 13C NMR
(100 MHz, CDCl3): d = 172.2, 150.5, 144.4, 136.3, 129.4,
128.3, 59.1, 52.5, 46.5, 29.5, 24.5, 21.6. IR (film): 3245,
2948, 1747, 1676, 1456, 1379, 1325, 1171 cm–1. TLC: Rf =
0.50 (10% MeOH/CH2Cl2). Exact mass calcd for
by TLC, the suspension was filtered through a layer of celite
and concentrated in vacuo. The resulting residue was
subjected to flash chromatography on silica gel, eluting with
5% EtOAc/hexanes. The products are isolated as a mixture
of a/b anomers, which could be assigned by 1H NMR
spectroscopy.
(14) Compound 2 has been characterized previously: Hosono, S.;
Kim, W.-S.; Sasai, H.; Shibisaki, M. J. Org. Chem. 1995, 60,
4.
(15) (a) Characterization data for compound 6: a-anomer: 1H
NMR (400 MHz, CDCl3): d = 7.36–7.12 (m, 20 H), 4.99 (d,
J = 11.0 Hz, 1 H), 4.84–4.75 (m, 4 H), 4.66–4.59 (m, 2 H),
4.47 (d, J = 12.1 Hz, 2 H), 3.99 (t, J = 9.3 Hz, 1 H), 3.79–
3.72 (m, 2 H), 3.65–3.54 (m, 4 H), 3.44–3.39 (m, 1 H), 1.64–
1.58 (m, 2 H), 1.23 (bs, 10 H), 0.88 (t, J = 6.8 Hz, 3 H). 13
NMR (100 MHz, CDCl3): d = 138.8, 138.2, 138.1, 137.8,
128.2, 127.9, 127.8, 127.7, 127.5, 127.4, 96.8, 82.1, 80.1,
C
77.8, 75.7, 75,1, 73.5, 73.1, 70.1, 68.6, 68.3, 32.0, 29.5, 29.4,
26.3, 22.8, 14.3. IR(film): 3089, 3063, 3030, 2926, 2856 cm–
1. TLC: Rf = 0.39 (20% EtOAc/hexanes). Anal. Calcd for
C42H52O6: C, 77.27; H, 8.03. Found: C, 76.94; H, 8.05. b-
Anomer 1H NMR (400 MHz, CDCl3): d = 7.36–7.14 (m, 20
H), 4.95 (t, J = 11.0 Hz, 2 H), 4 .80 (t, J = 11.4 Hz, 2 H), 4.72
(d, J = 11.0 Hz, 1 H), 4.63–4.51 (m, 3 H), 4.39 (d, J = 7.7
Hz, 1 H), 3.99–3.94 (m, 1 H), 3.75 (dd, J = 10.8, 2.0 Hz, 1
H), 3.69–3.43 (m, 6 H), 1.68–1.62 (m, 2 H), 1.42–1.26 (m,
10 H), 0.87 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3)
d = 138.5, 138.3, 138.0, 137.9, 128.2, 128.0, 127.8, 127.7,
127.6, 127.5, 127.4, 123.6, 84.7, 82.8, 77.9, 75.7, 75.0, 74.8,
73.4, 70.1, 69.0, 31.9, 29.9, 29.5, 29.4, 26.3, 22.8, 14.2. IR
(film): 3087, 3063, 3032, 2927, 2857 cm–1. TLC: Rf = 0.50
(20% EtOAc/hexanes). Anal. Calcd for C42H52O6: C, 77.27;
H, 8.03. Found: C, 77.00; H, 8.00.
[C14H18N2O5NaS] requires m/z 349.0834. Found: 349.0827
(ESI+). Data for compound 4: 1H NMR (400 MHz, CDCl3):
d = 8.03 (d, J = 8.9 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H), 4.41
(dd, J = 8.7, 3.8 Hz, 1 H), 3.82–3.63 (m, 1 H), 3.72 (s, 3 H),
3.54–3.34 (m, 1 H), 2.20–1.86 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 172.0, 150.4, 139.7, 137.4, 129.5, 128.8,
59.1, 52.3, 46.5, 29.4, 24.1. IR(film): 3245, 2954, 1747,
1670, 1456, 1379, 1183 cm–1. TLC: Rf = 0.40 (10% MeOH/
CH2Cl2). Exact mass calcd for [C13H15 N2O5Na1S1Cl1]
requires m/z 369.0288. Found: 369.0282 (ESI+).
(12) All compounds gave satisfactory analytical data.
(13) The general experimental procedure is as follows:
Trichloroacetimidate 1 (50.0 mg, 0.0730 mmol) was
suspended in methylene chloride (300 mL). The glycosyl
acceptor (0.0487 mmol) was then introduced, followed by
the addition of activated 4 Å molecular sieves (50.0 mg).
The solution was allowed to stir at 25 °C for 10 min upon
which a stock solution of catalyst was added (50.0 mL,
0.00730 mmol). When the reaction was judged to be finished
(16) For compounds 7 and 8, see: Garcia, B. A.; Gin, D. Y. J. Am.
Chem. Soc. 2000, 122, 4269.
(17) For compound 9, see: (a) Nishizawa, M.; Garcia, D. M.;
Shin, T.; Yamada, H. Chem. Pharm. Bull. 1993, 41, 784.
(b) Mukaiyama, T.; Takashima, T.; Katsurada, M.; Aizawa,
H. Chem. Lett. 1991, 533.
Synlett 2003, No. 12, 1923–1926 © Thieme Stuttgart · New York