Introduction of 2,2,2-trichloroethyl-protected sulfates into monosaccharides with a sulfuryl imidazolium salt and application to the synthesis of sulfated carbohydrates

Article abstract of DOI:10.1002/anie.200600153

(Chemical Equation Presented) Sweet sulfur: Sulfuryl imidazolium salt 1 represents a new class of highly potent sulfating agents and is very effective for introducing trichloroethyl-protected sulfates into monosaccharides for the synthesis of sulfated oli

Full text of DOI:10.1002/anie.200600153

Angewandte
Chemie
Protecting Groups
DOI: 10.1002/anie.200600153
Introduction of 2,2,2-Trichloroethyl-Protected
Sulfates into Monosaccharides with a Sulfuryl
Imidazolium Salt and Application to the Synthesis
of Sulfated Carbohydrates**
Laura J. Ingram and Scott D. Taylor*
Sulfated polysaccharides are widespread in nature. These
compounds are implicated in a wide variety of important
biological processes such as blood clotting, cell adhesion, and
cell–cell communication.[1] However, detailed characteriza-
tion of their specific biological roles has proved very
challenging. One reason for this is that the synthesis of even
relatively small sulfated oligosaccharides still remains a
considerable challenge. The current approach to their syn-
thesis involves first protecting the hydroxy groups in the
monosaccharide building blocks. The hydroxy groups that
bear the sulfate groups in the final product are protected in a
manner orthogonal to those that are not sulfated. After
assembly of the oligosaccharide, the hydroxy groups to be
sulfated are deprotected. These groups are then sulfated,
usually with a sulfur trioxide–amine or –amide complex,
following which all other protecting groups are removed to
give the desired product.[2] There are several drawbacks to
this approach. First, intensive manipulation of protecting
groups is required at the end of the synthesis. Second, the
sulfated products are highly polar and can be difficult to
purify and manipulate for subsequent deprotections. Finally
and most significantly, good yields of the sulfation reactions
can be difficult to attain especially when multiple sulfations
are necessary. Such difficulties can potentially be removed
and/or diminished by the introduction of the sulfate groups at
the monosaccharide stage as protected sulfate diesters; this
strategy would avoid the need for selective hydroxy depro-
tections and sulfations at the end of the synthesis. Although
this alternative approach could be highly effective in the
synthesis of sulfated carbohydrates, it has received little
attention, most probably because of the difficulties in devel-
oping protecting groups for sulfate monoesters. Perlin and
Penney used phenyl chlorosulfate to introduce phenyl-
protected sulfate groups into monosaccharides.[3] However,
no further reports on the use of this protecting group in the
synthesis of sulfated monosaccharides or higher carbohy-
[*] L. J. Ingram, Prof. Dr. S. D. Taylor
Department of Chemistry, University of Waterloo
200 University Ave. West, Waterloo, ON N2L3G1 (Canada)
Fax: (+1)519-746-0435
E-mail: s5taylor@sciborg.uwaterloo.ca
[**] This research was supported by a Discovery Grant to S.D.T. from the
NaturalSciences and Engineering Research Council(NSERC) of
Canada.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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drates have appeared in the literature, possibly owing to low
sulfating agent that did not liberate a nucleophilic species
such as chloride ion could be developed. OꢀConnell and
Rapoport reported the synthesis of aryl sulfonamides and
sulfonates with highly reactive sulfonyl imidazolium triflates 5
or variable yields during removal of the phenyl group. Proud
et al. later introduced the trifluoroethyl (TFE) group as a
protecting group for sulfated carbohydrates,[4] but there are
two disadvantages to this approach. TFE was introduced by
treating sulfate monoesters with trifluorodiazoethane, a
reagent that must be freshly prepared and is highly toxic
and potentially explosive. Moreover, its removal requires
somewhat harsh conditions, that is, refluxing with KOtBu/
HOtBu. Karst et al. recently demonstrated that deprotection
of the sulfate groups proceeds in low or moderate yields when
using fully protected disaccharides as substrates.[5]
Recently, we described the use of the 2,2,2-trichloroethyl
(TCE) group as the first protecting group developed for aryl
sulfates.[6] The TCE-protected sulfate esters were prepared in
a single step by the reaction of phenols with 2,2,2-trichlo-
roethyl chlorosulfate (TCECS) in the presence of triethyl-
amine. The resulting protected sulfates were stable to a
variety of conditions, but were readily deprotected in
excellent yields under neutral conditions with Pd/C–ammo-
nium formate or zinc–ammonium formate. These studies
prompted us to examine the TCE group as a protecting group
for sulfated carbohydrates. Herein we describe the first
synthesis of a sulfuryl imidazolium salt, an entirely new
class of sulfating agents. We demonstrate that this reagent is
highly effective for introducing TCE-protected sulfates into
carbohydrates. We also show that the TCE group can be
removed in excellent yields and that this group shows
outstanding potential as a valuable tool for the
Scheme 2. Sulfonyl and sulfuryl imidazolium triflates.
(Scheme 2).[8] These reagents were particularly useful for
preparing sterically hindered sulfonates and sulfonamides, as
well as certain primary sulfonates that were difficult to
prepare with sulfonyl chlorides owing to the formation of
alkyl chloride by-products. On the basis of these studies, we
anticipated that sulfuryl imidazolium triflate[9] 6 would be a
highly effective sulfating agent and would be particularly
useful for introducing TCE-protected sulfate esters into
carbohydrates (Scheme 2). Although sulfuryl imidazolium
salts have never been reported, we found that 6 was readily
constructed. Reaction of TCECS (7)[6] with imidazole gave
sulfuryl imidazole 8 in 86% yield (Scheme 3). Reaction of 8
synthesis of sulfated carbohydrates.
Incorporation of the TCE-protected sulfate
group into carbohydrates was first examined with
diisopropylidene-d-galactose (1) as a model sub-
strate. Reaction of 1 with TCECS under a wide
Scheme 3. Synthesis of sulfuryl imidazolium triflate 6.
variety of conditions generally gave the desired
product 2 in very low yields (Scheme 1);[7] the
dominant product was often chlorosugar 3. In an
attempt to decrease the amount of chloride-displacement
product, the reactions were performed in the presence of
with methyl triflate in dry diethyl ether resulted in the
precipitation of 6, which was isolated in almost quantitative
yield by filtration of the reaction mixture (Scheme 3).[10] No
further purification of 6 was necessary. Imidazolium salt 6 is
stable and does not require storage under an inert atmos-
phere. It can be stored at room temperature for weeks or at
ꢀ208C for months without any detectable decomposition.
Imidazolium salt 6 was treated with a variety of mono-
saccharides that bear an array of hydroxy protecting groups in
the presence of N-methylimidazole (NMI) in THF (Table 1).
In most cases, primary and secondary hydroxy groups were
sulfated in good to excellent yields by subjecting them to 6
(2.0–4.7 equiv) and NMI (2.5–6.0 equiv) in THF at room
temperature for 16–48 h.[10] In the case of 12, 10.5 equivalents
of 6, 11.6 equivalents of NMI, and 72 h were required to allow
90% yield. The presence of NMI was essential for all the
reactions. Other bases (Et3N, Hünig base, pyridine, 2,6-
lutidine, piperidine) were considerably less effective.
Scheme 1. Reaction of 1 with TCECS.
various silver salts. After some experimentation, it was found
that the reaction of 1 in the presence of AgCN, Et3N, and 4-
dimethylaminopyridine (DMAP) in THF gave the desired
product 2 in approximately 50% yield. However, 3 still
accounted for a significant proportion of the products
(Scheme 1). Moreover, applying these conditions to other
monosaccharides such as benzyl 2,4,6-tri-O-benzyl-b-d-gal-
actopyranoside (4) gave little or no sulfodiester product.
Nevertheless, these results suggest that the desired com-
pounds could be formed in good yield if a highly reactive
The TCE group was removed from 2 and 14–19 in very
good yields by employing zinc–ammonium formate in meth-
anol (Table 1).[10] Apart from the presence of ZnCl2,
(HCO2)2Zn, and NH4Cl, the crude material was essentially
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Table 1: Synthesis of TCE-protected sulfocarbohydrates with 6 and deprotection of the sulfate group with Zn–HCO2NH4.
Substrate
Sulfodiester
product
Protection
yield[a,b] [%]
Deprotected
product
Deprotection
yield[b,h] [%]
1
4
2
87[c]
94[c]
20
21
99
94
14
9
15
16
90[c]
94[d]
22
23
97
96
10
11
12
13
17
18
19
91[e]
90[f]
81[g]
24
25
26
96
91
94
[a] All reactions were conducted with the carbohydrate (0.22–0.26m) in THF. [b] Yield of isolated pure product. [c] 2 equiv 6, 2.5 equiv NMI.
[d] 4.7 equiv 6, 5.3 equiv NMI. [e] 4.3 equiv 6, 5.2 equiv NMI. [f] 10.5 equiv 6, 11.6 equiv NMI. [g] 3.7 equiv 6, 6 equiv NMI. [h] HCO2NH4 (6 equiv), Zn
dust (7.6 equiv), carbohydrate (0.1m) in MeOH. Bn=benzyl, Bz=benzoyl, MP=p-methoxyphenyl, Tol=p-tolyl.
pure. These impurities were easily removed by passing the
product through a short column of silica with CH2Cl2/MeOH/
NH4OH (20:4:1) as eluent. Deprotection studies were also
performed with Pd/C–ammonium formate; however, the
yields were slightly lower than those with Zn.
was selectively cleaved to give 34 in 91% yield by irradiation
with a 250-W lamp in the presence of NBS and CaCO3.[11]
As mentioned earlier, Karst et al. removed the TFE
moiety from sulfate groups in fully protected disaccharides
with low to moderate yields.[5] We anticipated that this would
not be an issue with the TCE group as it is removed under
very mild conditions. To illustrate this, 30 was coupled to 33
(Scheme 4) in the presence of TMSOTf (TMS = trimethyl-
silyl) to give disaccharide 35 in 68% yield (unoptimized).
Deprotection of 35 with zinc–ammonium formate gave the
sulfo-deprotected product 36 in 92% yield (Scheme 4).[10]
In summary, the first synthesis of a sulfuryl imidazolium
salt 6 is reported. This compound represents a new class of
highly potent sulfating agents.[12] Compound 6 was very
effective in introducing TCE-protected sulfates into mono-
saccharides. The TCE-protected sulfates were stable to many
of the reaction conditions commonly encountered in carbo-
Preliminary studies indicate that the TCE-protected
sulfates are stable to many of the conditions commonly
encountered in carbohydrate chemistry (Table 2).[10] Selective
6-O-debenzylation and acetylation of 14 with ZnCl2/AcOH/
Ac2O gave 27 in 95% yield. Subjection of 27 to catalytic
NaOMe in MeOH gave the deacetylated product 28 in 85%
yield. Benzylidene ring opening of 16 with either TfOH (Tf =
trifluoromethanesulfonyl) or PhBCl2 in the presence of
Et3SiH gave 29, which bears a free 4-OH group, or 30,
which bears a free 6-OH group, in 96% and 87% yield,
respectively. Complete cleavage of the benzylidene group of
16 was obtained in 94% yield with TsOH (Ts = p-toluene-
sulfonyl). Subjection of 17 to N-bromosuccin-
imide (NBS) in acetone/water gave 32, with a free
anomeric OH group, in 74% yield. Reaction of
32 with trichloroacetonitrile in the presence
of catalytic 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) gave the trichloroacetimidate 33 in 80%
yield. Attempts to remove the benzyl group in 19
selectively with H2 and Pd catalyst, without
affecting the TCE-protected sulfate group, were
unsuccessful. However, the benzyl group in 19 Scheme 4. Glycosylation and TCE cleavage. M.S.=molecular sieves.
Angew. Chem. Int. Ed. 2006, 45, 3503 –3506
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Communications
Soc. Chem. Commun. 1994, 775; c) A. Lubineau, R. Lemoine,
Tetrahedron Lett. 1994, 35, 8795 – 8796; d) W. Stahl, U. Spren-
gard, G. Kretzschmar, D. W. Schmidt, H. Kunz, J. Prakt. Chem.
1995, 337, 441 – 445.
Table 2: Cleavage of selected hydroxy protecting groups from TCE-protected
sulfocarbohydrates.
Substate
Product
Yield [%][a]
95[b]
[3] C. L. Penney, A. Perlin, Carbohydr. Res. 1981, 93, 241 – 246.
[4] A. D. Proud, J. C. Prodger, S. L. Flitsch, Tetrahedron Lett. 1997,
38, 7243 – 7246.
[5] N. A. Karst, T. F. Islam, F. Y. Avci, R. J. Lindhardt, Tetrahedron
Lett. 2004, 45, 6433 – 6437.
14
27
16
27
28
29
85[c]
96[d]
87[e]
94[f]
74[g]
[6] Y. Liu, I. F. Lien, S. Ruttgaizer, P. Dove, S. D. Taylor, Org. Lett.
2004, 6, 209 – 212.
[7] The initial intention of Proud et al.[4] was to use TCE protection.
Although they anticipated that the TCE group would be easily
removed under very mild conditions using Zn/HOAc, they
reported that the yields of TCE-protected sulfated monosac-
charides with unspecified reagents and reaction conditions were
very poor. Therefore, the TFE group was examined. However,
the reaction of 2,2,2-trifluoroethylchlorosulfate with carbohy-
16
16
17
30
31
32
drates proceeded in poor yields and gave
a number of
unspecified by-products, hence the use of trifluorodiazoethane.
We found that deprotection of the TCE-protected sulfocarbo-
hydrates described herein with Zn–HOAc results in the for-
mation of desulfated products.
[8] J. F. OꢀConnell, H. Rapoport, J. Org. Chem. 1992, 57, 4775 –
4777.
[9] Although the terms sulfonyl and sulfuryl are often used
interchangeably, we designated 6 a sulfuryl imidazolium salt.
We use the term sulfuryl to differentiate it from sulfonyl
imidazolium salts, which is the term used by OꢀConnell and
Rapoport to describe their sulfonating agents.[8]
[10] For experimental details, see the Supporting Information.
[11] a) R. W. Binkley, D. G. Hehemann, J. Org. Chem. 1990, 55, 378 –
380; b) J. G. Riley, T. B. Grindley, J. Carbohydr. Chem. 2001, 20,
159 – 169.
32
19
33
34
80[h]
91[i]
[12] We have also prepared the TFE, phenyl, and other analogues of
6. Their synthesis and sulfating properties will be reported
elsewhere.
[a] Yield of isolated pure product. [b] ZnCl2 (3.7 equiv), AcOH/Ac2O, 3 h.
[c] NaOMe (0.16 equiv) in MeOH, 3 h. [d] TfOH (3.4 equiv), Et3SiH
(3.0 equiv), 4-ꢀ molecular sieves, ꢀ788C, CH2Cl2, 1 h. [e] PhBCl2
(3.4 equiv), Et3SiH (3.0 equiv), 4-ꢀ molecular sieves, ꢀ788C, CH2Cl2, 1 h.
[f] TsOH (0.1 equiv), CH2Cl2/MeOH, 458C, 16 h. [g] NBS (3.0 equiv), ace-
tone/H2O, 08C, 20 min. [h] DBU (0.2 equiv), Cl3CCN (16 equiv), ꢀ40!
ꢀ108C, CH2Cl2, 3 h. [i] NBS (3.5 equiv), CaCO3 (5 equiv), CCl4/H2O, 250-W
incandescent lamp.
hydrate chemistry. Deprotection of the sulfate group with
zinc–ammonium formate proceeded in outstanding yields.
This methodology should have a significant impact on the
synthesis of sulfated carbohydrates. More studies on the scope
of this methodology and its application to the synthesis of
complex sulfated oligosaccharides are in progress and will be
reported in due course.
Received: January 13, 2006
Published online: April 24, 2006
Keywords: carbohydrates · imidazolium · protecting groups ·
.
sulfates · sulfation
[1] T. Toida, A. Chaidedgumjorn, R. J. Linhardt, Trends Glycosci.
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[2] For examples, see: a) K. C. Nicolaou, N. J. Bockovich, D. R.
Carcanague, J. Am. Chem. Soc. 1993, 115, 8843 – 8844; b) K.
Singh, A. Fernandez-Mayoralas, M. Martin-Lomas, J. Chem.
3506
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