Synthesis of α-fluorosulfonate and α-fluorosulfonamide analogues of a sulfated carbohydrate

Article abstract of DOI:10.1021/ol062357z

The first synthesis of sulfonamide and sulfonate analogues of a sulfated carbohydrate in which the ester oxygen of the sulfate is replaced with a CHF or CF₂ group is reported. This was accomplished by electrophilic fluorination of the protected

Full text of DOI:10.1021/ol062357z

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5617-5620
Synthesis of
r-Fluorosulfonate and
r
-Fluorosulfonamide Analogues of a
Sulfated Carbohydrate
Latifeh Navidpour, Wallach Lu, and Scott D. Taylor*
Department of Chemistry, UniVersity of Waterloo, 200 UniVersity AVenue West,
Waterloo, Ontario, Canada, N2L 3G1
s5taylor@sciborg.uwaterloo.ca
Received September 25, 2006
ABSTRACT
The first synthesis of sulfonamide and sulfonate analogues of a sulfated carbohydrate in which the ester oxygen of the sulfate is replaced
with a CHF or CF2 group is reported. This was accomplished by electrophilic fluorination of the protected sulfonate and sulfonamide precursors.
Sulfated carbohydrates play key roles in numerous biological
functions such as viral cell recognition, cell-cell interactions,
blood clotting, inhibition, and promotion of tumor growth
to name but a few.1a,b The sulfation of carbohydrates is
accomplished by a class of enzymes known as sulfotrans-
ferases which transfer a sulfate group from 3′-phospho-
adenosine 5′-phosphosulfate (PAPS) to the hydroxyl group
of the carbohydrate.1b Another class of enzymes, the sulfa-
tases, remove the sulfate groups.2 Inhibitors and probes of
these enzymes would be very useful as tools for studying
how these enzymes work in conjunction to control the
sulfation state of carbohydrates, which is essential to
understanding the role these enzymes have in regulating
certain biological processes. One approach to the design of
inhibitors of the sulfatases is to prepare nonhydrolyzable
analogues of sulfated carbohydrates such as replacing the
ester oxygen of the sulfate moiety with a CH2, CHF, or CF2
unit. This approach has been used extensively to obtain
phosphonate-based inhibitors of phosphatases.3,4 We recently
demonstrated that the CF2 group can be used as a stable
replacement for the bridging oxygen in estrone sulfate in
that the CF2 sulfonate is a good competitive inhibitor of
steroid sulfatase and was approximately 10-fold more potent
than its nonfluorinated analogue.5 Since both the fluorinated
and nonfluorinated estrone sulfate analogues have pKa values
that are far below physiological pH we reasoned that their
difference in potency was due to the fluorines interacting
with residues in the active site perhaps by fluorine H-bonding
with His-290, which is believed to act as a general acid
during the cleavage of the S-O bond.5 The active site in
sulfatases is highly conserved,6 which suggests that carbo-
hydrate sulfate analogues in which the ester oxygen is
replaced with a CF2 or CFH group might also be effective
inhibitors of sulfatases that act upon sulfated carbohydrates.
However, the synthesis of such compounds presents certain
challenges. Benzylic R-fluorinated sulfonates, such as the
estrone sulfate analogue mentioned above, can be readily
prepared by electrophilic fluorination (EF) of the R-carban-
ions of their neopentyl-protected sulfonate precursors with
N-fluorobenzene sulfonimide (NFSi).7a-d These reactions
generally proceed well because the in situ generated car-
banion is stabilized by the protected sulfonate group as
(1) (a) Toida, T.; Chaidedgumjorn, A.; Linhardt, R. J. Trends Glycosci.
Glycotech. 2003, 15, 29. (b) Honke., K.; Taniguchi, N. Med. Res. ReV. 2002,
22, 637.
(2) Hanson, S. R.; Best, M. D.; Wong, C. H. Angew. Chem., Int. Ed.
2004, 43, 5736.
(3) Engel, R. Chem. ReV. 1977, 77, 349.
(5) Lapierre, J.; Ahmed, V.; Chen, M.-J.; Ispahany, M.; Guillemette, J.
G.; Taylor, S. D. Bioorg. Med. Chem. Lett. 2004, 14, 151.
(6) Ghosh, D. Methods Enzymol. 2005, 400, 273.
(4) Blackburn, G. M. Chem. Ind. 1981, 134.
10.1021/ol062357z CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/27/2006

well as the phenyl ring. Indeed, EF usually works best on
“acidic” substrates in which the resulting carbanion is
stabilized by two adjacent electron withdrawing groups
(EWG’s) and the vast majority of these reactions are per-
formed on such substrates.8 There are only a few examples
in the literature describing the electrophilic difluorination of
less acidic substrates8,9 and this has never been reported for
sulfonates in which the resulting carbanion is not stabilized
by an additional EWG as would be the case with a carbo-
hydrate sulfonate as substrate. This letter describes the results
of our preliminary investigations into the preparation of
R-fluorinated sulfonate and sulfonamide analogues of a
sulfated carbohydrate by electrophilic fluorination. We report
that this approach can be used to prepare both the mono-
and difluorinated derivatives. In addition, we demonstrate
stereochemistry of the monofluorinated sulfonate can be
controlled to a certain degree by the counterion of the base
used to generate the carbanion. Finally, we show that this
methodology can also be used to prepare the corresponding
R-fluorinated sulfonamide carbohydrates.
pylori glycosulfatase.11 We anticipated that 6c ould be readily
constructed from iodo carbohydrate 812 using Widlanski’s
sulfonation procedure and that the benzyl and neopentyl
protecting groups would be compatible with our EF condi-
tions yet would be easily removed under neutral conditions
at the end of the synthesis. However, reacting lithiated
neopentyl (nPt) methanesulfonate (7) with compound 8 under
Widlanski’s conditions gave sulfonate 6 in only a 38% yield.
Berkowitz and co-workers have shown that the phosphonate
analogue of 6 can be prepared in good yield by reacting
triflate 9 with lithiated diethyl methanephosphonate in THF/
HMPA at -78 °C.13 Employing these conditions with
compounds 7 and 9, carbohydrate sulfonate 6 was obtained
in 75% yield.
Electrophilic difluorination of 6 was initially attempted
with use of conditions similar to those we developed for the
difluorination of benzylic sulfonates.7a-d Thus, 2.5 equiv of
Na HMDS in THF was added to 6 at -78 °C in THF. The
mixture was stirred for 2 h and then 3.3 equiv of N-
fluorobenzene sulfonimide (NFSi) in THF was added, the
mixture was stirred for 1 h at -78 °C, and then the reaction
was warmed to rt and then stirred for a further 16 h. 19F
NMR analysis of the crude reaction product indicated that,
although peaks corresponding to the mono- and difluorinated
products 10 and 11 (Scheme 2) were evident, many other
products were formed and compounds 10 and 11 were
formed in very low yields. Further studies revealed that the
fluorination reaction proceeded quite readily within the first
30 min but significant decomposition occurred upon warming
the reaction mixture or with prolonged reaction times.
Nevertheless, it was found that by maintaining the reaction
at -78 °C and subjecting 6 to 2.5 equiv of KHMDS for just
15 min and then adding 3.0 equiv of NFSi dropwise over
15 min and reacting for an additional 15 min the reaction
was cleaner and compounds 10 and 11, which could be
separated by chromatography, were isolated in 18% and 52%
yields, respectively.
To our knowledge only a single report has appeared in
the literature describing the synthesis of a pyranoside
sulfonate in which the ester oxygen of the corresponding
sulfate is replaced with a methylene group. This was achieved
by Musicki and Widlanski, who reacted the 6-iodo carbo-
hydrate derivative 3 with lithiated isopropyl methanesulfonate
(4) in the presence of DMPU in THF to give carbohydrate
sulfonate 5 in 57% yield (Scheme 1).10 We wished to prepare
Scheme 1. Widlanski Synthesis of Sulfonate 5
Before further EF studies were undertaken deprotection
of the sulfonate moiety in compounds 10 and 11 was
examined. Subjecting 11 to LiBr in refluxing butanone7a for
48 h resulted in less than 50% deprotection and in the case
of compound 10 very little deprotection was achieved in this
time frame. Roberts et al. have described the removal of
neopentyl groups from sulfonates using tetramethyl am-
monium chloride in DMF at 160 °C.14 However, this also
proceeded very slowly.
pyranoside sulfonate 6 (Scheme 2) and use it as a model
system for our investigations. Compound 6 is the protected
sulfonate analogue of glucose-6-sulfate, a component of
mucus glyceroglucolipids and a substrate for Helicobacter
Scheme 2. Synthesis of Sulfonates 6, 10, and 11
(7) (a) Kotoris, C.; Chen, M-J.; Taylor, S. D. J. Org. Chem. 1998, 63,
8052. (b) Chen, M-J.; Taylor, S. D. Tetrahedron Lett. 1999, 40, 2669. (c)
Liu, S.; Dockendorf, C.; Taylor, S. D. Org. Lett. 2001, 3, 1571. (d) Leung,
C.; Lee, J.; Meyer, N.; Jia, C.; Grzyb, J.; Liu, S.; Hum, G.; Taylor, S. D.
Bioorg. Med. Chem. 2002, 10, 2309.
(8) Taylor, S. D.; Kotoris, C.; Hum, G. H. Tetrahedron 1999, 55, 12431.
(9) Konas, D. W.; Coward, J. K. Org. Lett. 1999, 1, 2105.
(10) Musicki, B.; Widlanski, T. S. J. Org. Chem. 1990, 55, 4231.
(11) Slomiany, B. L.; Murty, V. L.; Piotrowski, J.; Grabska, M.;
Slomiany, A. Am. J. Gastroenterol. 1992, 87, 1132.
(12) Berkowitz, D. B.; Eggen, M-J.; Shen, Q.; Sloss, D. G. J. Org. Chem.
1993, 58, 6174.
(13) Berkowitz, D. B.; Bose, M.; Pfannestiel, T. J.; Doukov, T. J. Org.
Chem. 2000, 65, 4498.
(14) Roberts, J. C.; Gao, H.; Gopalsomy, A.; KongsJahju, A.; Patch, R.
J. Tetrahedron Lett. 1997, 38, 335.
5618
Org. Lett., Vol. 8, No. 24, 2006

Due to the difficulties associated with removing the
neopentyl group, we decided to examine the isobutyl moiety
as a sulfonate protecting group since it is easier to remove.15
Reaction of lithiated isobutyl methanesulfonate (12) with
carbohydrate 9 gave sulfonate 13 in 75% yield (Scheme 3).
in a 59% yield favoring the upfield diastereomer in a ratio
of 7:1, which also shows that the de is dependent upon the
concentration of base. The best yield of difluorinated
compound 15 was obtained with 3.0 equiv of Na HMDS
and 3.5 equiv of NFSi, which gave 15 in a 48% yield.
19F NMR analysis of the crude reaction products from all
of the above reactions indicated that one particular byproduct
was sometimes formed in substantial amounts. The amount
of this byproduct increased as the amount of base and NFSi
increased above 1 equiv, if the reaction times were prolonged,
or if the temperature was allowed to warm above -78 °C
after the addition of NFSi. This byproduct was isolated and
found to be compound 16 (Scheme 3). Once 15 is formed,
the â-proton is acidic enough to be removed by the base
and elimination of SO2 and isobutoxide occurs. This result
may account, at least in part, for our difficulty in obtaining
15 in yields greater than 48%.
Scheme 3. Synthesis of Carbohydrates 14 and 15
Deprotection of the sulfonate group in compounds
13-15 was achieved by treating them with an excess of LiBr
in refluxing THF for several hours, which gave sulfonates
17-19 in 81-91% yield (Scheme 4). Removal of the benzyl
Treatment of 13 with 2.0 equiv of base at -78 °C in THF
for 15 min followed by the addition of 2.5 equiv of NFSi
and stirring at -78 °C for 15 min gave a mixture of mono-,
14, and difluorinated, 15, products (entries 1-4 in Table 1).
Scheme 4. Deprotection of 13-15
Table 1. Electrophilic Fluorination of 13 with Various Bases
and N-Fluorobenzenesulfonimide
entry
base
yield of 14d
yield of 15
1
2
3
4
5
6
NaHMDSa
KHMDSa
LiHMDSa
BuLia
NaHMDSb
NaHMDSc
23 (1:21)
4 (1:9)
20 (4:1)
52 (5.3:1)
59 (1:7.2)
17
31
31
4
17
12
48
groups with Pd(OH)2/H2 gave carbohydrate sulfonates
20-22 in 74-96% yield. The de of compound 21 did not
change significantly from that of compound 14.16
a 2.0 equiv of base, 2.5 equiv of NFSi. b 1.2 equiv of base, 1.5 equiv of
NFSi. c 3.0 equiv of base, 3.5 equiv of NFSi. d Shown in parentheses is
the ratio of the downfield diastereomer (δ -177) to the upfield diastereomer
(δ -183) as determined by 19F NMR.
We recently reported that the R,R-difluoromethyl sulfon-
amide analogue of estrone sulfate is also a good inhibitor of
steroid sulfatase.17 Therefore, we decided to examine whether
the sulfonamide equivalents of compounds 20-22 could be
constructed. We recently demonstrated that R-fluorosulfon-
amides can be prepared by EF of bis(dimethoxybenzyl)-
protected sulfonamides.18 R,R-Difluoroalkyl sulfonamides
were best obtained by treating the sulfonamide with 1.3 equiv
of n-BuLi or n-BuK in the presence of 5 equiv of HMPA
followed by 1.5 equiv of NFSi at -78 °C in THF and then
With NaHMDS as base, 14 and 15 were obtained in yields
of 23% and 31%. With KHMDS, 14 and 15 were obtained
in 31% and 4% yields, respectively. With LiHMDS, the
overall yield was low with the monofluorinated product
predominating. With n-BuLi, the monofluoro product 14
dominated and was obtained in a 52% yield. In all cases
compound 14 was formed as a mixture of diastereomers as
determined by 19F NMR. Interestingly, the stereochemical
outcome of the fluorination reaction was dependent upon
the cation of the base. When lithium was the cation
(LiHMDS and n-BuLi) formation of the downfield diaste-
reomer at δ -177 was favored (5.3:1 with n-BuLi). However,
when Na or K was the cation, formation of the upfield
diastereomer at δ -183 was favored (21:1 with NaHMDS).
The best yield of 14 was obtained by reacting 13 with 1.2
equiv of NaHMDS and 1.5 equiv of NFSi, which gave 14
(16) We were unable to obtain the crystal structure of the monofluorinated
diastereomers and therefore we were unable to determine their absolute
stereochemistry, which makes rationalizing the effect of the counterion on
the stereochemistry very difficult. In contrast to the significant number of
theoretical and synthetic studies on R-carbanions of sulfones, studies related
to R-carbanions of sulfonate esters and sulfonamides are scarce. As with
the sulfones, many factors may affect their structure and reactivity patterns
such as negative hyperconjugation, complexation of the cations with the
sulfonate group or carbanion, π-cation and cation-solvent interactions,
differences in the sizes of the cations, etc. For a discussion on the structure
of R-carbanions of sulfones see: Raabe, G.; Gais, H-J.; Fleishhauer, J. J.
Am. Chem. Soc. 1996, 118, 4622 and references therein.
(17) Liu, Y.; Ahmed, V.; Hill, B.; Taylor, S.D. Org. Biomol. Chem. 2005,
3, 3329.
(15) Xie, M.; Widlanski, T. S. Tetrahedron Lett. 1996, 37, 4443.
Org. Lett., Vol. 8, No. 24, 2006
(18) Hill, B.; Liu, Y.; Taylor, S. D. Org. Lett. 2004, 6, 4285.
5619

warming to rt. The purified monofluoro derivatives, which
were obtained in yields of 41-69%, were subjected to the
same conditions which gave the difluoro compounds in
modest yields.18
Scheme 6. Deprotection of 23-25
Sulfonamide carbohydrate 24 was obtained in a 65% yield
by reacting triflate 9 with the lithium salt of N,N-bis(2,4-
dimethoxybenzyl)methane sulfonamide (23).19 The condi-
tions described above for monofluorination of less complex
alkyl sulfonamides18 were not suitable for sulfonamide 24
since a large number of byproducts formed upon warming
the reaction to rt. After some experimentation it was found
that the monofluoro sulfonamide 25 could be isolated in
50-55% yield by treating 24 with 4 equiv of KHMDS or
2.5 equiv of n-BuLi at -78 °C, stirring for 15 min, and then
adding 2.5 equiv of NFSi and reacting at -78 °C for
15-30 min (Scheme 5). The reaction with KHMDS pro-
groups in primary sulfonamides 27-29 by hydrogenolysis
gave carbohydrate sulfonamides 29-32 in 88-95% yields.
In summary, the first synthesis of the CHF and CF2
sulfonate and sulfonamide analogues of a sulfated carbohy-
drate is reported. This was accomplished by EF of the
protected sulfonate and sulfonamide precursors. To the best
of our knowledge, this is the first example of an EF of an
unactivated sulfonate. The stereochemistry of the mono-
fluorosulfonates was dependent upon the counterion of the
base but this was not the case with the monofluorosulfon-
amides. Knowledge of the absolute stereochemistry of these
compounds would be helpful in determining the origin of
the effect of the counterion on the stereochemistry of these
reactions and we are in the process of preparing other
monofluorinated carbohydrate sulfonates and sulfonamides
that we anticipate will be more amenable to X-ray crystal-
lographic studies. Further studies on applying this methodol-
ogy to the synthesis of R-fluorinated sulfonate and sulfon-
amide analogues of other biologically relevant sulfated
carbohydrates are also in progress. Also worthy of note is
the use of reagent 23 to prepare the first CH2 sulfonamide
analogue of a sulfated carbohydrate. Reports describing the
synthesis of an alkyl sulfonamide via a nucleophilic substitu-
tion reaction using a monolithiated methane sulfonamide are
rare.21 Reagent 23 may prove to be very useful as a general
reagent for preparing compounds bearing a primary sulfon-
amide moiety, an important pharmacophore in medicinal
chemistry.
Scheme 5. Electrophilic Fluorination of 24
duced exclusively compound 25 while the reaction with
n-BuLi also produced about 10% difluorinated compound
26, which could be separated by careful chromatography.
19F NMR revealed that the stereoselectivity was not affected
by the cation as both KHMDS and n-BuLi gave the same
diastereomer in very high de (95-96%).16
We were unable to obtain even modest amounts (>15%)
of compound 26 directly from 24 and converting pure 25 to
26 proved to be challenging. Nevertheless, after considerable
experimentation we were able to obtain 26 from 25 in a
modest 34% yield by briefly treating 25 with n-BuK at -78
°C followed by reaction with 2.5 equiv of NFSi for 30 min.20
Deprotection of the sulfonamide moiety in 24-26 was
achieved in excellent yields (82-91%) with TFA in
CH2Cl2 (Scheme 6). Further deprotection of the hydroxyl
Acknowledgment. This work was supported by a Natural
Sciences and Engineering Research Council (NSERC) of
Canada Discovery grant to S.D.T.
Supporting Information Available: Preparation proce-
dures and characterization data for 6, 10, 11, and 13-32.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) See the Supporting Information for the synthesis of reagent 23.
(20) We did not detect compound 16 as a byproduct in these reactions.
However, 19F NMR analysis of the crude reaction products suggested a
byproduct resulting from the attack of the carbanion on the sulfur of NFSi
may have formed. This side reaction was shown to occur during the
fluorination of other alkyl sulfonamides (see ref 18).
OL062357Z
(21) (a) Eisleb, Chem. Ber. 1941, 74, 1433. (b) Klein, U.; Sucrow, W.
Chem. Ber. 1977, 110, 161.
5620
Org. Lett., Vol. 8, No. 24, 2006