Published on the web July 27, 2011
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Studies on the Selectivity between Glycosylation and Intermolecular Aglycone Transfer
of Thioglucoside in Synthesis of Lactose Derivatives
Marie Kato,1,2 Go Hirai,1 and Mikiko Sodeoka*1,2,3
1RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198
2Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510
3Sodeoka Live Cell Chemistry Project, ERATO, Japan Science and Technology Agency, Wako, Saitama 351-0198
(Received May 19, 2011; CL-110423; E-mail: sodeoka@riken.jp)
Glycosylation reaction of 2,3-di-O-benzoyl-protected galac-
tosyl donors with ethyl thioglucoside acceptor to prepare lactose
derivatives was investigated. The presence of benzyl ether
moieties at the 4 and 6 positions of the donor drove the
glycosylation reaction to completion and blocked the inter-
molecular aglycone transfer reaction with thioglucoside. On the
other hand, the presence of benzoyl moieties at those positions
promoted the intermolecular aglycone transfer reaction with
thioglucoside.
Thioglycosides are convenient glycosyl donors for the
synthesis of oligosaccharides and glycosylated natural prod-
ucts,1,2 because the thiol group at the anomeric position is easy
Scheme 1. Synthetic plan for CF2-linked ganglioside analogs
and structure of model glycosyl donor 5.
to install and several reliable activation methods have already
been developed. Glycosyl sulfoxides, sulfones, and halides,
which are readily available from thioglycoside, are also useful
glycosyl donors,1 so thioglycosides are recognized as important
intermediates for synthesis of complex carbohydrate molecules.
Moreover, since the relative reactivity of thioglycosides with
various protecting groups has been systematically and compre-
hensively studied,3 rapid synthesis of oligosaccharides should be
possible even when different thioglycosides are used as glycosyl
donors/acceptors.
electron-withdrawing ability of the protecting groups on donors/
acceptors decreases the reactivity of the hydroxy group of the
acceptors and the leaving group of the donors.7 In this letter, we
report systematic investigations of the glycosylation with
thioglycoside 38 of model monosaccharide donors 5 possessing
a participating 2-OBz substituent and a 3-OBz group which
plays the role of the 3-CF2 functionality in 2, serving to block
the AGT reaction by tuning the protecting group.
On the other hand, aglycone transfer (AGT) reaction of
thioglycoside is a serious side reaction, in which an oxacarbe-
nium ion intermediate generated from the glycosyl donor reacts
with sulfur of the glycosyl acceptor to give another thioglyco-
side.4 In fact, we were faced with this problem. We have
reported the design, synthesis, and biological activity of a
sialidase-resistant ganglioside GM4 analog, in which the
O-linked ¡(2,3)-sialylgalactose unit was replaced with a CF2-
linked unit.5 To synthesize more complex ganglioside analogs
such as CF2-linked GM3 (1, Scheme 1), ¢-glycosylation of
sialylgalactose donor 2 with a glucose unit is required. We
planned to construct the analog 1 by sequential glycosylation
with ceramide chain 4 after connection with glucose. For this
purpose, glycosylation of a donor having electron-withdrawing
groups at C3 (CF2-group) and 2-O (neighboring participating
group to obtain the ¢-glycoside) with the “disarmed” thiogluco-
side 3 acceptor, which is at risk for AGT reaction, seemed to be
one of the most promising and straightforward combinations.
Although until recently systematic studies of the AGT reaction
have been limited, Gildersleeve reported two methods for
preventing undesired AGT reaction, based on their mechanistic
studies; one is the use of the bulky 2,6-dimethylphenylsulfanyl
group as an anomeric substituent on glycosyl acceptors,6 and the
other is tuning of the combination of donors and acceptors based
on the “armed-disarmed” concept, in which the increased
N-Phenyltrifluoroacetimidate was employed as a leaving
group of donors for this glycosylation study.9 First, four types of
donors 5a-5d having different protecting groups on 4-O and 6-O
were prepared (Scheme 2). Donor 5a was synthesized according
to the literature,10 and synthesis of 5b was performed from
known 711 via a conventional three-step sequence. During the
deprotection of the 4-methoxyphenyl group of 8 at the anomeric
position with Ce(NO3)6(NH4)2 (CAN), a small amount of the
migration product of the 2-OBz group to C1 was observed,
affording 10. Synthesis of 5c was also performed from 7, but
formation of the benzyl ether at 4-O was quite difficult in the
presence of the neighboring benzoyl group.12 Although several
other attempts failed, the use of 2-benzyloxy-1-methylpyridi-
nium triflate13 allowed the direct formation of 11 in 18% yield.
Treatment of 11 with CAN gave 12 with concomitant formation
of the migration product 13. Finally, introduction of imidate
functionality into the lactol derivative 12 afforded 5c. Donor 5d
was prepared similarly from 6 (Scheme 2).11
Glycosylation of 5a-5c with 3 was conducted under standard
glycosylation conditions as described below. A solution of donor
and acceptor in dichloromethane was treated with TMSOTf at
¹40 or ¹20 °C in the presence of molecular sieves AW-300. As
we feared, in the case of donor 5a, the AGT product 17a was
obtained as a major product at both ¹20 and ¹40 °C (Entries 1
and 2, Table 1). A small amount of lactose 16a was obtained at
Chem. Lett. 2011, 40, 877-879
© 2011 The Chemical Society of Japan
Kato, Marie
