Radical C-glycosylation reaction of pyranosides with the 2,3-trans carbamate group

Article abstract of DOI:10.1039/c1cc13172a

Radical-mediated C-glycosylation of pyranosides with the 2,3-trans carbamate group was investigated. C-Glycosylation was achieved with high α-selectivity. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13172a

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COMMUNICATION
Radical C-glycosylation reaction of pyranosides with the 2,3-trans
carbamate groupwz
Shino Manabe,*a Yoshiyuki Aiharaa and Yukishige Itoab
Received 30th May 2011, Accepted 11th July 2011
DOI: 10.1039/c1cc13172a
Radical-mediated C-glycosylation of pyranosides with the
2,3-trans carbamate group was investigated. C-Glycosylation
was achieved with high a-selectivity.
Table 1 Substituent effect at the 6-position on the stereoselectivity
under Keck allylation conditions
Glycoconjugates and oligosaccharides play important roles in
biological events, and are among the most structurally diverse
natural biopolymers.1 O-Glycosides are the most common
structures in glycoconjugates, but C-glycosides are also
found in natural compounds. For instance, C-linked protein
modification has been identified in many proteins as post/
co-translational modification,2 and C-glycosides are often
found in antibiotics, flavonoids and lignans.3 The C-glycosides
as pharmacophores may yield novel enzyme inhibitors.4
Furthermore, C-glycosides have been useful synthons in
natural product synthesis due to their multiple chiral centres.5
For these reasons, the synthesis of C-glycosides has been
studied.6,7
Entry
R1
Product Yield (%)
a : b
Yield of 3 (%)
1
2
3
1a
1b
Ac
Bn
2a
2b
2c
84
56
26
94 : 6
93 : 7
491 : 9
0
19
47
1c TBDPS
Radical mediated C–C bond formation is one of the most
common methodologies for C-glycoside preparation. Although
a-selectivities were observed in the glucosides cases,8 the
stereochemistry at the anomeric centre is significantly influenced
by the amino protecting group at the amino group in the case
of 2-deoxy-2-amino pyranosides.9 For example, the 2-acetamido
having a pyranoside shows a-selectivity under radical mediated
allylation reaction (Keck reaction) conditions,10 whereas a
2-phthalimide protected pyranoside shows b-selectivity under
the same reaction conditions. Recently, we and other groups
have demonstrated that the 2,3-trans-oxazolidinone protected
pyranosides show high 1,2-cis selectivity in O-glycosylation
reactions under various conditions.11 We are interested in
the influence of the five-membered carbamate ring on the
stereochemical outcome of radical C-glycosylation.
Substrate concentration is 0.2 M. The a/b ratios were determined by
1H-NMR integration.
reported by Bertozzi et al. (entry 1).9 Thus, a benzene solution
of 1a and allyltri-n-butylstannane was refluxed in the presence
of AIBN. The a-glycoside and b-glycoside were obtained as an
inseparable mixture in a ratio of 10 : 1.
The stereochemistry of compound 2a was determined from
the coupling constant between H-1 and H-2 (J = 5.1 Hz), and
a positive NOE enhancement between H-1 and H-2. Although,
the high a-selectivity was observed in the series of the
substrates 1a–1c, bulky protecting groups at the 6-position
reduced the yield (entries 2 and 3). In addition to products 2b
and 2c, the deacetylated by-products 3b and 3c were obtained
in significant amounts.
First, we investigated the effect of the protecting group at
the 6-position on the stereochemical outcome (Table 1). The
bromide 1a was subjected to the same reaction conditions as
A significant substitution effect was observed in the chain
radical reaction using the combination of acrylonitrile–Bu3SnH–
AIBN (Table 2). The bromide 1a gave the C-glycoside 4a in
76% yield, but the a/b ratio was quite low (entry 1). More
bulky protecting groups such as Bn and TBDPS gave higher
a-selectivities (entries 2 and 3) up to 95 : 5 (a/b), but the
reduced by-products 5b and 5c were also obtained. From the
above results, it is clear that the substituent at the 6-position
influences the stereoselectivity at the anomeric position in
the C-glycosylation reaction. More bulky protecting groups
increased the selectivity, but decreased the yield.
a RIKEN, Advanced Science Institute, Hirosawa, Wako-shi, Saitama,
Japan. E-mail: smanabe@riken.jp; Fax: +81 48 462 4680;
Tel: +81 48 467 9432
b ERATO, JST, Hirosawa, Wako-shi, Saitama, Japan
w This article is part of the ChemComm ‘Glycochemistry and glyco-
biology’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
details and 1H-NMR and 13C-NMR spectra. See DOI: 10.1039/
c1cc13172a
c
9720 Chem. Commun., 2011, 47, 9720–9722
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Table 2 Substituent effect at the 6-position on stereoselectivity under
chain radical conditions
Scheme 2 Keck allylation reaction with galactosamine derivative 9.
Table
2,3-trans carbamate group under chain radical conditions
4
C-Glycosylation stereoselectivity with the N-acetylated
Entry
R1
Product Yield (%)
a : b
Yield of 5 (%)
1
2
3
1a
1b
Ac
Bn
4a
4b
2c
76
52
43
48 : 52
91 : 9
95 : 5
0
22
28
1c TBDPS
Entry
X
R1
Product
Yield (%)
a : b
Substrate concentration is 0.2 M. The a/b ratios were determined by
1
2
3
CN
CN
CO2Me
6b
6c
6c
Ac
Bn
Bn
11a
11b
11c
56
60
74
92 : 8
499 : 1
499 : 1
1H-NMR integration.
Substrate concentration is 0.2 M. The a/b ratios were determined by
Table 3 Substituent effect at the nitrogen atom on stereoselectivity
under Keck allylation conditions
1H-NMR integration.
In addition to the glucosamine derivatives, galactosamine
derivative 9 also gave only the a-allyl adduct in 65% yield
(Scheme 2).
Since the N-acetyl group was found to be effective for
stereoselective C-glycosylation, the selectivity of the radical
chain reaction was investigated using N-acetyl substrates
(Table 4). The a-selectivity was high, especially when the
primary alcohol was protected as a benzyl group (entries 2
and 3). By synergistic effects of the protecting groups at the
N- and 6-positions, complete a-selectivity was observed in the
radical chain reaction employing acrylonitrile and methyl
acrylate (entries 2 and 3).
Entry
R1
R2
Product
Yield (%)
a : b
1
6a
6b
6b
6c
1a
H
Ac
Ac
Ac
Bn
Ac
7a
7b
7b
7c
2a
o14
76
35
41
—
2
Ac
Ac
Ac
Bn
499 : 1
499 : 1
499 : 1
94 : 6
3a
4
5
84
Substrate concentration is 0.2 M. The a/b ratios were determined by
1H-NMR integration. Two equivalents of allyltri-n-butylstannane
were used.
a
We report here the radical-mediated a-selective C-glyco-
sylation of pyranosides with the 2,3-trans carbamate group.
The selectivity is quite high when the carbamate nitrogen is
protected by an acetyl group. Although only simple C-glycosides
preparation is described in this communication, more complex
C-glycoside formation could be possible.7 Several reports
based on ESR spectra of a pyranoside radical have indicated
that the boat-like conformation of the pyranoside radical
is the origin of the a-selectivity in the radical-mediated
C-glycosylation.12 In order to enhance the interaction between
the half-occupied orbital at the radical centre and s* orbital of
the C–OR bond at the b-position of radical, the glucosides
have the boat-conformation. However, because the 2,3-trans
carbamate group locks the conformation of the pyranoside
Next, we investigated the substituent effect at the nitrogen
atom of the carbamate group (Table 3). Under Keck conditions,
bromide 6a gave a complex mixture (entry 1). Fortunately,
the N-Ac protected bromide 6b and 6c showed complete
a-selectivity in good yield (entries 2 and 4). Even when
the amount of allyltri-n-butylstannane was reduced to two
equivalents (entry 3), complete stereoselectivity was again
observed, although the yield was reduced to 35%.
The methallylation of optimized substrate 6b also exhibited
complete a-selectivity (Scheme 1).
4
into the C1 form,13 other factors for high a-selectivity must
exist.
We thank Dr Hiroyuki Koshino for NMR measurements,
and Ms Akemi Takahashi for her technical assistance. We
thank Dr Kori Otsuki and Dr Masaya Usui at the Research
Resource Centre of RIKEN’s Brain Science Centre.
S. M. thanks Grants-in-Aid for Scientific Research (C) from
the Japan Society for the Promotion of Science (Grant No.
21590036).
Scheme 1 The methallylation of compound 6b.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9720–9722 9721

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9722 Chem. Commun., 2011, 47, 9720–9722
This journal is The Royal Society of Chemistry 2011