Bromodimethylsulfonium bromide-silver triflate: A new powerful promoter system for the activation of thioglycosides

Article abstract of DOI:10.1002/adsc.200800190

Bromodimethylsulfonium bromide (BDMS) in combination with silver triflate provides a very efficient thiophilic promoter system, capable of activating both "disarmed" and "armed" thioglycosides for glycosidic bond formation. The usefulness of this new prom

Full text of DOI:10.1002/adsc.200800190

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DOI: 10.1002/adsc.200800190
Bromodimethylsulfonium Bromide-Silver Triflate: A New
Powerful Promoter System for the Activation of Thioglycosides
De-Cai Xiong,a Li-He Zhang,a and Xin-Shan Yea,*
a
The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue
Yuan Rd #38, Beijing 100083, Peopleꢀs Republicof China
Fax : (+86)-10-82802724; e-mail: xinshan@bjmu.edu.cn
Received: March 30, 2008; Published online: July 25, 2008
Dedicated to Professor Chi-Huey Wong on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract:
Bromodimethylsulfonium
bromide
compounds [e.g., dimethyl(thiomethyl)sulfonium tri-
fluoromethanesulfonate (DMTST),[7] methylsulfenyl
(BDMS) in combination with silver triflate provides
a very efficient thiophilic promoter system, capable
of activating both “disarmed” and “armed” thiogly-
cosides for glycosidic bond formation. The useful-
ness of this new promoter is illustrated by a success-
ful reactivity-based one-pot oligosaccharide assem-
bly.
triflate
(MeSOTf),[8]
phenylsulfenyl
triflate
(PhSOTf),[9] diphenyl sulfoxide-triflicanhydride
(Ph2SO/Tf2O),[10] benzenesulfinylpiperidine-triflican-
hydride (BSP/Tf2O),[11] N-(phenylthio)-e-caprolactam-
triflicanhydride,
[12]
benzenesulfinylmorpholine-triflic
anhydride (BSM/Tf2O),[13] dimethyl disulfide-triflic
anhydride (Me2S2/Tf2O)[14]], organoselenium com-
pounds [e.g., benzeneselenyl triflate (PhSeOTf)],[15]
and halogens [e.g., N-iodosuccinimide-triflic acid
(NIS/TfOH),[16] N-bromosuccinimide (NBS),[17] iodo-
nium dicollidine perchlorate (IDCP),[18] Ipy2BF4[19]].
Although these promoters are convenient for the as-
sembly of oligosaccharides, some drawbacks and limi-
tations have been encountered during glycosylation
Keywords:
bromodimethylsulfonium
bromide
(BDMS); glycosylation; oligosaccharides; promot-
er; thioglycosides
Understanding the role of carbohydrates in biology is processes including accessibility,[13] stability, solubility,
highly dependent on the development of new chemi- by-products,[11] purification,[20] and reagent handling
cal glycosylation techniques to provide rapid, straight- issues. New, more convenient and powerful promoters
forward access to synthetic glycoconjugates.[1] Al- for the activation of thioglycosides, especially for the
though methodology for glycosidic coupling continues low-reactivity thioglycoside donors, are still in great
to pose challenges for synthetic chemists and the syn- demand.
thesis of defined oligosaccharide sequences remains a
Bromodimethylsulfonium
bromide
(BDMS)
problem requiring great skill and experimental versa- (Figure 1),[21] a light orange solid compound, is a con-
tility, major advances have been achieved by introduc- venient “soft” electrophilic brominating reagent and
ing a variety of different types of glycosyl donors and readily binds to the “soft” sulfur atom. Since Meer-
promoter systems for their activation.[2] Among the weinꢀs discovery of BDMS,[22] it has gained considera-
various glycosyl donors, thioglycosides are one of the ble interest in the field of organicchemistry, due to its
most enduring and widely used donors due to their easy handling and low cost, as well as its easy access
stability, accessibility, and compatibility.[3] The sulfur and varied applications both as a catalyst[23] and as an
atom in a thioglycoside is a soft nucleophile, and is effective reagent. However, BDMS has never been
therefore able to react selectively with soft electro- applied to glycosylation reactions. Herein we report
philes.[4]
In the past years, many types of thiophilicpromot-
ers for the activation of thioglycosides have been de-
veloped, such as heavy metal cations [e.g., mercu-
ry(II) sulfate[5]], alkylating reagents [e.g., methyl tri-
fluoromethanesulfonate (MeOTf)[6]], organosulfur Figure 1. Bromodimethylsulfonium bromide (BDMS).
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BDMS as a new promoter for the activation of thio- (AgOTf). Using the BDMS/AgOTf system, a series of
glycosides. glycosylation reactions was investigated by varying
A preliminary screening of reaction conditions both the thioglycosides and the acceptors (Table 1).
showed that BDMS alone did not activate thioglyco- Initially, the low-reactive, “disarmed” thioglycoside
sides at all except in conjunction with silver triflate donors were chosen and evaluated. Glycosylations of
Table 1. Glycosylations promoted by BDMS/AgOTf.
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Table 1. (Continued)
[a]
General conditions: acceptor (1.0 equiv.), donor (1.2 equiv.), BDMS (1.4 equiv.),
AgOTf (3.2 equiv.), dichloromethane (DCM), À358C for 30 min, then to ambient
temperature if necessary.
DCM/Et2O=1/1.
DCM/CH3CN=3/1.
[b]
[c]
[d]
[e]
a/b ratio determined by 1H NMR spectroscopy.
Acceptor (1 equiv.), donor (1.2 equiv.), BDMS (0.7 equiv.), AgOTf (3.0 equiv.).
the “disarmed” ethyl thioglucoside donor 1 with the ed disaccharide 21 as a single anomericisomer as well
d-glucose acceptors 12, 13,[24] and 14 (entries 1–3) (entry 5). The other “disarmed” ethyl thioglycoside
having a free hydroxy group at the C-2, C-3, and C-4 donors such as galactose (entry 7), mannose (entry 8),
positions proceeded smoothly within 30 min. Interest- rhamnose (entry 9), and glucosamine (entry 10) moi-
ingly, the glycosyl coupling between donor 1 and the eties were also checked. As shown, a number of 4-O-
acceptor 15 with the C-6 hydroxy exposed resulted in linked disaccharides, which suffered from either side
low yield (entry 4), as the 6-O-acetylated acceptor products when promoted by NIS-TfOH using
was isolated in 32% yield arising from an acetyl trans- “armed” thioglycoside donors or poor yields when
fer[25] from the donor 1. This undesired process was promoted by DMTST using “disarmed” thioglycoside
avoided when the benzoylated glucosyl donor 2 was donors in the preparation procedures,[26] were pre-
employed instead of 1 (entry 6). The glycosylation re- pared in high yields when the relatively low reactive
action of donor 2 with the hindered acceptor 14 yield- acceptor 14 was used. However, the coupling of d-glu-
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Scheme 1. Reactivity-based one-pot glycosylation of 32.
cose acceptor 12 and “disarmed” p-tolyl thioglycoside well, by using the ratio of 0.55/1 (BDMS/donor) to
donor 7 in which the ethyl group of donor 1 was re- minimize the formation of side products and changing
placed by a p-tolyl group afforded disaccharide 17 in the amount of AgOTf to improve the yield, as shown
lower yield (79%, entry 11) when compared with that in Table 1 (entry 19). A substoichiometric amount of
of the coupling between 12 and 1 (96%, entry 1), pre- BDMS was used on the assumption that the reaction
sumedly due to the donorꢀs lower reactivity. It seems might provide p-TolSOTf which could, in turn, pro-
that ethyl thioglycosides are better than p-tolyl thio- mote glycosylation. Finally, as examplified in
glycosides for “disarmed” donors. In all cases, glyco- Scheme 1, a one-pot synthesis of trisaccharide 32 was
sylation reactions provided the expected 1,2-trans- carried out in satisfactory yield and with good stereo-
linked disaccharides by virtue of neighboring group selectivity, demonstrating that this novel promoter
participation, no orthoesters were detected.
system can be applied in the one-pot assembly of oli-
Subsequently, the activation of “armed” thioglyco- gosaccharides.
sides was examined. The glycosylation of perbenzylat-
In conclusion, by the use of the easy-to-handle and
ed ethyl thioglucoside 8, devoid of a participating low-cost BDMS, we have identified this reagent to be
group at the O-2 position, proceeded in excellent a new and highly powerful promoter for the activa-
yield but with no anomeric selectivity with acceptor tion of both “disarmed” and “armed” thioglycosides.
13 (entry 12). Similarly, the coupling of donor 8 with This proceeds by the in situ combination of BDMS
acceptor 14 also gave poor stereoselectivity with AgOTf, which then serves to activate the thiogly-
(entry 13). Interestingly, glycosylation of the highly coside for glycosidic bond formation. This overcomes
reactive acceptor 15 with 8 provided a slight b-linked some limitations of the current methods, and this effi-
selectivity (entry 14). Compared with donor 8, the gly- cient promoter can be employed in one-pot oligosac-
cosylations of the “armed” perbenzylated p-tolyl thio- charide assembly. We are currently attempting to find
glucoside 9 smoothly afforded disaccharides 27–29 in an alternative to the expensive co-promoter (AgOTf)
further improved yields and with poor to modest a/b and extend the scope of this new procedure.
stereoselectivity (entries 15–17). The selectivity was
shifted significantly toward the a isomer by the use of
ether or toward the b isomer by the use of acetonitrile
Experimental Section
as cosolvents, this may be explained by the participa-
tion of the solvent.[27] However, the glycosylation of
Preparation of Methyl 3-O-Benzyl-4,6-O-benzylidene-
2-O-(2,3,4,6-tetra-O-acetyl-b-d-glucopyranosyl)-b-d-
glucopyranoside (17)
the perbenzylated p-tolyl thiogalactoside 10 with the
acceptor 13 having a free hydroxy group at the C-3
position, proceeded in excellent yield and with good
a-selectivity (entry 18). Disaccharide 31, which suf-
fered from by-products when using NIS-TfOH as pro-
moter in its preparation,[26] was obtained in high yield.
It turns out that p-tolyl thioglycosides work more effi-
ciently than ethyl thioglycosides in the case of
“armed” glycosyl donors.
A
mixture of 1 (25.4 mg, 0.0645 mmol), 12 (20.0 mg,
0.0538 mmol), silver triflate (44.3 mg, 0.172 mmol), and acti-
vated AW-300 molecular sieves (0.30 g) in dichloromethane
(4.0 mL) was cooled to À358C. After stirring for 5 min, bro-
modimethylsulfonium bromide (16.8 mg, 0.0753 mmol) was
added to the mixture. The reaction mixture was stirred for
15 min at À358C, then allowed to warm to ambient temper-
ature. The mixture was quenched with triethylamine
(0.2 mL). The precipitate was filtered off through a pad of
The next issue was to determine if BDMS/AgOTf
could be used in a reactivity-based oligosaccharide
synthesis.[26,28] Indeed, this promoter system worked Celite and the filtrate was concentrated. The residue was
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purified by column chromatography on silica gel (petroleum
ether: EtOAc, 3:1) to afford 17 as a white foam; yield:
36.3 mg (96%).
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O-[2,3,6-tri-O-benzoyl-4-O-(2,3,4,6-tetra-O-benzyl-a-
d-galactopyranosyl)-b-d-glucopyranosyl]-a-d-gluco-
pyranoside (32)
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A mixture of 10 (23.7 mg, 0.0367 mmol), 16 (20.0 mg,
0.0334 mmol), silver triflate (20.6 mg, 0.0802 mmol), and ac-
tivated 4 Š molecular sieves (0.30 g) in anhydrous dichloro-
methane (2.0 mL) and diethyl ether (2.0 mL) was cooled to
À358C. After stirring for 5 min, bromodimethylsulfonium
bromide (4.5 mg, 0.0200 mmol) was added to the mixture.
The reaction mixture was stirred for 45 min at À358C, then
at À158C for 15 min. The formation of disaccharide 31 was
monitored by TLC (petroleum ether : EtOAc5:2). After
the starting materials were consumed, the reaction mixture
was cooled to À208C. Subsequently, 33 (19.7 mg,
0.0401 mmol) and silver triflate (30.9 mg, 0.120 mmol) were
added. The reaction mixture was stirred for 5 min followed
by addition of bromodimethylsulfonium bromide (5.2 mg,
0.0234 mmol). The mixture was stirred at À208C for 90 min,
then allowed to warm to the ambient temperature. After
stirred for another 30 min, the mixture was quenched with
triethylamine (0.2 mL). The precipitate was filtered off
through a pad of Celite and the filtrate was concentrated.
The residue was purified by column chromatography on
silica gel (toluene: acetonitrile, 30:1) to afford 32 as a white
foam; yield: 30.2 mg (61%).
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China, “973” and “863” grants from
the Ministry of Science and Technology of China.
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[24] We attempted to buffer the reaction medium using
TTBP, but no reaction occurred because TTBP might
probably combine with the bromonium ion. Fortunate-
ly, the benzylidene group survived under general cou-
pling conditions.
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