A stable, commercially available sulfenyl chloride for the activation of thioglycosides in conjunction with silver trifluoromethanesulfonate

Article abstract of DOI:10.1016/j.carres.2008.03.002

p-Nitrobenzenesulfenyl chloride is a stable commercially available sulfenyl chloride that, in conjunction with silver triflate, cleanly activates a wide range of thioglycosides for glycosylation at -78 °C in CH₂Cl₂.

Full text of DOI:10.1016/j.carres.2008.03.002

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1858–1862
Note
A stable, commercially available sulfenyl chloride for the activation of
thioglycosides in conjunction with silver trifluoromethanesulfonate
David Crich,* Feng Cai and Fan Yang
Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI 48202, USA
Received 8 February 2008; received in revised form 1 March 2008; accepted 4 March 2008
Available online 10 March 2008
Abstract—p-Nitrobenzenesulfenyl chloride is a stable commercially available sulfenyl chloride that, in conjunction with silver
triflate, cleanly activates a wide range of thioglycosides for glycosylation at ꢀ78 °C in CH2Cl2.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Glycosylation; Thioglycoside; Sulfenyl halide; Sulfenyl triflate
Thioglycosides1 are some of the most popular glycosyl
donors because they are easily prepared and are stable
to most functional group modifications. Although many
other thiophilic reagents, including NIS–TfOH,2 iodon-
ium dicollidine perchlorate (IDCP),3 and methyl trifluo-
romethanesulfonate (MeOTf)4 are known for the
activation of thioglycosides, the sulfenyl/sulfonium class
of thiophiles have gained considerable popularity since
the discovery of dimethyl(methylthio)sulfonium triflate5
(DMTST) as a promoter. Methanesulfenyl triflate
(MeSOTf, MeSBr–AgOTf),6 benzenesulfenyl triflate
(PhSOTf, PhSCl–AgOTf),7,8 and p-toluenesulfenyl
triflate (p-TolSOTf, p-TolSCl–AgOTf)9 have been inves-
tigated as powerful promoters capable of activating
thioglycosides rapidly and cleanly at ꢀ78 °C with the
formation of glycosyl triflates8 as intermediates and
stable disulfide byproducts. However, methanesulfenyl
bromide (MeSBr), benzenesulfenyl chloride (PhSCl),
and p-toluenesulfenyl chloride (p-TolSCl) are not com-
mercially available owing to their limited shelf-life, and
must be prepared and distilled prior to use. The 1-benz-
enesulfinyl piperidine (BSP)/trifluoromethanesulfonic
anhydride (Tf2O),10 diphenyl sulfoxide (DPSO)–
Tf2O,11,12 benzenesulfinyl morpholine–Tf2O,13 and di-
methyl disulfide–Tf2O14 protocols have been developed
as shelf-stable substitutes for this sulfenyl halide-based
chemistry and have been employed widely in oligosac-
charide synthesis. Herein, we report on the use of a
stable, commercially available p-nitrobenzenesulfenyl
chloride (p-NO2PhSCl) as an activator for glycosylation
O
OBn
OBn
O
O
p-NO2PhSCl
AgOTf
O
EtS
BnO
BnO
OBn
OBn
O
S
NO2
+
CH2Cl2, -78 o
C
O
SEt
HO
BnO
BnO
1
NHBoc
NHBoc
4
O
O
O
O
O
O
O
3
2
Scheme 1.
*
Corresponding author. Tel.: +1 313 577 1915; fax: +1 313 577 8822; e-mail: dcrich@chem.wayne.edu
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.03.002

D. Crich et al. / Carbohydrate Research 343 (2008) 1858–1862
1859
Table 1.
Entry
Donor
Acceptor
Coupling product
Yielde (%) (a:b)
OAc
O
OBn
O
OAc
O
OBn
O
AcO
AcO
HO
AcO
AcO
1
2
95b,d (b only)
O
SPh
BnO
BnO
7
AcO
BnO
OAc
BnO
5
OMe
6
OMe
OH
O
OAc
O
75b
BnO
BnO
BnO
BnO
5
BnO
BnO
OMe
OMe
8
9
OBn
O
OBn
O
OBn
Ph
Ph
O
BnO
Ph
O
BnO
O
O
O
O
3
4
72a,c (1:13)
80b,c,d (1:5)
BnO
6
BnO
SEt
10
OMe
11
O
O
O
O
O
O
O
BnO
Ph
O
O
O
BnO
O
O
O
5
6
7
88a,c (3:1)
85a,c (1:3)
82a,c (7:3)
SPh
BnO
HO
14
12
OBn
13
O
O
O
O
OBn
O
OBn
O
BnO
O
BnO
BnO
8
BnO
SPh
BnO
O
BnO
16
OBn
BnO
15
BnO
OMe
OBn
O
OH
BnO
BnO
15
BnO
O
18
17
OAc
O
OAc
O
AcO
O
AcO
AcO
AcO
AcO
8
8
20b,d (b only)
AcHN
SPh
AcO
O
BnO
20
NHAc
BnO
19
BnO
OMe
OAc
CO2Me
O
AcO
OAc
Ac2N
SPh
CO2Me
O
Ac2N
60b,c,d (1.5:1)
O
9
8
O
AcO OAc
BnO
BnO
22
AcO OAc
21
BnO
OMe
OBn
O
BnO
MeO2C
OAc
AcN
SPh
CO2Me
OAc
AcN
OBn
OAc
O
BnO
HO
AcO
OAc
O
10
77a,d (3:1)
O
O
O
OMe
OMe
24
BnO
25
O
BnO
23
O
O
a Preactivation.
b Pre-mixed.
c 1.2 equiv TTBP.
d 20% (v/v) acetonitrile.
e Determined by 1H NMR analysis on the crude reaction mixture.

1860
D. Crich et al. / Carbohydrate Research 343 (2008) 1858–1862
in conjunction with silver trifluoromethanesulfonate
(AgOTf). p-Nitrobenzenesulfenyl chloride is an orange
solid that has been previously employed as the precursor
to photolabile sulfenate esters and, thus, as a source of
alkoxy radicals.15,16
In summary, the shelf-stable, commercially available
p-NO2PhSCl–AgOTf promoter works well with different
kinds of donors. Both 1,2-trans and 1,2-cis products are
formed as major products according to the choice of
protecting group.
As a first demonstration of the method, the coupling
of mannopyranoside donor 1 and an amino acid 2 was
conducted using 1 equiv p-NO2PhSCl–2.5 equiv AgOTf
as a promoter in CH2Cl2. This reaction was complete
in 30 min at ꢀ78 °C and gave the a-anomeric product
in 80% yield. As expected, the disulfide 4 was also
obtained in 83% yield (Scheme 1).
1. Experimental
1.1. General methods
Optical rotations were determined with an Autopol III
polarimeter.1H and 13C NMR spectra were recorded
at 500 and 125 MHz, respectively, with chemical shifts
reported downfield from tetramethylsilane. All solvents
were dried by standard procedures. Commercial
reagents were used without purification. Air and/or
moisture-sensitive reactions were carried out under an
atmosphere of argon or nitrogen using oven-dried
glassware.
A number of other examples were then conducted
employing 1.2 equiv p-NO2PhSCl, 2.5 equiv AgOTf
and 1.5 equiv acceptor in CH2Cl2, occasionally in
admixture with acetonitrile17,18 or 2,4,6-tri-tert-butyl-
pyrimidine (TTBP)19 as additive. The acetate glucose
donor 5 and acceptor 6 were pre-mixed and then acti-
vated to give disaccharide 7 in 95% yield (Table 1, entry
1). The formation of the b-isomer in this example relies
on the neighboring group participation effect. The cou-
pling of 5 with a primary alcohol 8, the acetyl-transfer
product 9 predominated (Table 1, entry 2). Preactiva-
tion of the 4,6-O-benzylidene mannopyranoside 10
followed by the addition of acceptor 6 gave a 13:1
(b:a) anomeric mixture of disaccharides in 72% yield;
When 6 and 10 were pre-mixed before activation in
the presence of 20% acetonitrile, only a 5:1 (b:a) selecti-
vity was obtained (Table 1, entries 3 and 4). The pre-
activated 4,6-O-benzylidene glucopyranosyl donor 12
gave a 3:1 (a:b) anomeric mixture of disaccharides after
preactivation and then the addition of acceptor 13 as
expected on the basis of earlier work (Table 1, entry
5).6,20 The tetra-O-benzyl glucosyl donor15 exhibited a
b-selective coupling with a primary alcohol (Table 1,
entry 6) in keeping with the observation of Hashimoto21
for a related coupling. However, with a less reactive
partner 17 the more typical a-selectivity reasserted itself
(Table 1, entry 7).
With the N-acetylglucosamine based thioglycoside 19
(Table 1, entry 8), oxazoline ring formation could not be
suppressed; nevertheless, the glycosylation product 20
was formed in 20% yield. In the coupling of phenyl thio-
sialoside donor 21 and acceptor 8, the anomeric ratio
of the products was formed to be 1.5:1 (a:b) for a cou-
pling conducted in the presence of acetonitrile, compa-
rable to the result achieved with the DPSO/Tf2O22
promotion system. Encouragingly, the p-NO2PhSOTf
promoter could activate even the relatively inert phenyl
thiosialoside donor 23 at ꢀ78 °C. Thus, premixing of
donor 23 and acceptor 24 at ꢀ78 °C with acetonitrile
as additive before activation afforded the a-sialoside
(3:1) in good yield (Table 1, entry 10). This result is com-
parable to the NIS–TfOH23 activated reaction using the
more reactive 1-adamantanyl thiosialoside donor and
the same acceptor.
1.2. Typical procedure for coupling of pre-mixed donors
and acceptors
1.2.1. a-tert-Butyl c-{3,4,6-tri-O-benzyl-2-O-[30-(200-benz-
yloxy-400,600-dimethylphenyl)-30,30-dimethylpropanoyl]-a-D-
mannopyranosyl}-N-tert-butyloxycarbonyl-L-glutamate (3)
and 1-ethyl-2-(p-nitrophenyl)disulfane (4).
pension of (88 mg, 0.11 mmol),
A
sus-
1
2
(51 mg,
0.17 mmol), silver triflate (72 mg, 0.28 mmol) and
5 A molecular sieves in anhydrous CH2Cl2 (1 mL)
˚
was stirred, with the exclusion of light, for 10 min at
room temperature under N2 before it was cooled to
ꢀ78 °C. A solution of p-nitrobenzenesulfenyl chloride
(22.3 mg, 0.11 mmol, 95% purity) in anhydrous
CH2Cl2 (0.5 mL) was dropped into the above suspen-
sion at ꢀ78 °C. TLC analysis showed the reaction to
be finished after stirring for 30 min at ꢀ78 °C after
which a satd aq NaHCO3 solution (0.2 mL) was
added. The reaction mixture was diluted with CH2Cl2
(5 mL) to give a suspension, which was filtered
through Celite and the Celite pad was washed with
CH2Cl2 (10 mL). The filtrate was concentrated under
reduced pressure and the residue was purified by flash
column chromatography on silica gel (10:1?3:1,
hexane–EtOAc) to first give 4 (20 mg, 0.09 mmol,
83%) as a light yellow color oil, and then 3 (92 mg,
0.09 mmol, 80%) in the form of a viscous oil. Com-
18
16
pound 3: ½aꢁD +22.5 (c 1.0, CHCl3); lit.24 ½aꢁD +22.2
(c 1.0, CHCl3); 1H and 13C NMR spectral data
matched that reported.24 Compound 4: 1H NMR
(500 MHz, CDCl3): d: 1.33 (t, J = 7.5 Hz, 3H), 2.80
(q, J = 7.5 Hz, 2H), 7.60 (m, 2H), 8.11 (m, 2H); 13C
NMR (125 MHz, CDCl3) d: 14.5, 33.1, 124.2, 126.0,
146.4, 147.5; HRMS(EI): calcd for C8H9NO2S2[M+]:
215.0075. Found: 215.0079.

D. Crich et al. / Carbohydrate Research 343 (2008) 1858–1862
1861
1
1.3. Typical procedure for glycosylation with preactiva-
tion of the donor
together with 18a, the H and 13C NMR spectral data
matched that reported.8
1.3.1. Methyl 2,3,6-tri-O-benzyl-4-O-(2,3-di-O-benzyl-
4,6-O-benzylidene-b-D-mannopyranosyl)-a-D-glucopyran-
oside (11). A suspension of 10 (73 mg, 0.15 mmol),
TTBP (44.0 mg, 0.18 mmol, 1.2 equiv), silver triflate
1.8. Methyl 6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-
deoxy-b-D-glucopyranosyl)-2,3,4-tri-O-benzyl-a-D-gluco-
pyranoside (20)
20
25
Colorless syrup; ½aꢁD ꢀ19.9 (c 1.0, CHCl3); lit.29 ½aꢁD
˚
(95 mg, 0.37 mmol, 2.5 equiv) and 5 A molecular sieves
ꢀ20.1 (c 1.0, CHCl3); H and 13C NMR spectral data
1
in anhydrous CH2Cl2 (1 mL) was stirred, with the exclu-
sion of light, for 10 min at room temperature under N2
before it was cooled to ꢀ78 °C. A solution of p-nitro-
benzenesulfenyl chloride (35.5 mg, 0.18 mmol, 1.2 equiv,
95% purity) in anhydrous CH2Cl2 (0.5 mL) was dropped
into the above suspension at ꢀ78 °C. After 5 min, a
solution of 6 (103 mg, 0.22 mmol, 1.5 equiv) in anhy-
drous CH2Cl2 (1 mL) was dropped into this suspension.
TLC analysis showed the reaction to be finished after
stirring for 1 h at ꢀ78 °C after which a satd aq NaHCO3
solution (0.2 mL) was added. The reaction mixture was
diluted with CH2Cl2 (5 mL) to give a suspension, which
was filtered through Celite and the Celite pad was
washed with CH2Cl2 (10 mL). The filtrate was concen-
trated under reduced pressure and the residue was puri-
fied by flash column chromatography on silica gel (9:1,
toluene–EtOAc) to give 11 (95 mg, 0.11 mmol, 72%) in
matched that reported.29
1.9. Methyl [methyl 5-(N-acetylacetamido)-4,7,8,9-tetra-
O-acetyl-3,5-dideoxy-D-glycero-a-D-galacto-non-2-ulo-
pyranosylonate]-2,3,4-tri-O-benzyl-a-D-glucopyranoside
(22a) and Methyl [methyl 5-(N-acetylacetamido)-4,7,8,9-
tetra-O-acetyl-3,5-dideoxy-D-glycero-b-D-galacto-non-2-
ulopyranosylonate]-2,3,4-tri-O-benzyl-a-D-glucopyran-
oside (22b)
22a and 22b was isolated as an anomeric mixture, the 1H
and 13C NMR spectral data matched that reported.22
1.10. Methyl [methyl 5-acetamido-7,8,9-tri-O-acetyl-5-
N,4-O-carbonyl-3,5-dideoxy-D-glycero-a-D-galacto-non-
2-ulopyranosylonate]-2,4,6-tri-O-benzyl-b-D-galactopyr-
anoside (25a) and Methyl [methyl 5-acetamido-7,8,9-tri-
O-acetyl-5-N,4-O-carbonyl-3,5-dideoxy-D-glycero-b-D-
galacto-non-2-ulopyranosylonate]-2,4,6-tri-O-benzyl-b-D-
galactopyranoside (25b)
20
the form of a viscous oil. Compound 11: ½aꢁD ꢀ26.3 (c
28
1
1.0, CHCl3); lit.25 ½aꢁD ꢀ26.4 (c 1.5, CHCl3); H and
13C NMR spectral data matched that reported.25
1.4. Methyl 2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl)-a-D-glucopyranoside (7)
25a and 25b was isolated as an anomeric mixture, the 1H
and 13C NMR spectral data matched that reported.23
20
20
Colorless syrup; ½aꢁD ꢀ5.1 (c 1.1, CHCl3); lit.26 ½aꢁD
ꢀ5.0 (c 1.0, CHCl3); 13C NMR spectral data matched
that reported.27
Acknowledgment
1.5. 3-O-(2,3-Di-O-benzyl-4,6-O-benzylidene-a-D-gluco-
pyranosyl)-1,2;5,6-di-O-isopropylidene-a-D-glucofuranose
(14a)
We thank NIGMS (GM62160) for generous financial
support.
18
½aꢁD +5.9 (c 1.0, CHCl3); lit.20 [a]D +5.8 (c 0.8, CHCl3);
1H and 13C NMR spectral data matched that reported.20
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