Iodine catalyzes C-glycosidation of D-glucal with silylacetylene

Article abstract of DOI:10.1016/S0040-4039(03)01540-5

A convenient method for C-glycosidation (alkynylation) with various silylacetylenes to D-glucal by iodine molecule via iodo-oxonium intermediates provided exclusively the α-acetylene glycoside products. Eleven successful examples are shown under this cond

Full text of DOI:10.1016/S0040-4039(03)01540-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6211–6215
Iodine catalyzes C-glycosidation of
D-glucal with silylacetylene
Rungnapha Saeeng,a,* Uthaiwan Sirion,a Poolsak Sahakitpichanb and Minoru Isobec,*
aDepartment of Chemistry, Faculty of Science, Burapha University, Sangsook, Chonburi 20131, Thailand
bChulabhorn Research Institute (CRI), Vibhavadee-Rangsit Highway, Bangkok 10210, Thailand
cLaboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa,
Nagoya 464-8601, Japan
Received 22 May 2003; revised 13 June 2003; accepted 20 June 2003
Abstract—A convenient method for C-glycosidation (alkynylation) with various silylacetylenes to D-glucal by iodine molecule via
iodo–oxonium intermediates provided exclusively the a-acetylene glycoside products. Eleven successful examples are shown under
this condition.
© 2003 Elsevier Ltd. All rights reserved.
The direct formation of carbonꢀcarbon bonds at the
anomeric center of sugar nuclei still presents a signifi-
cant challenge to synthetic chemists and several solu-
tions to this problem have evolved.1 C-Glycosidation is
one of the key reactions for the introduction of carbon
chain to a sugar ring. Silylacetylenes are considered to
be sufficiently reactive to form acetylene glycosides
which can be used as a carbon chiral pool for the
synthesis of polyether natural products.2 C-Glycosida-
tion with silylacetylene compounds have been reported
to proceed under various conditions by using Lewis
acid3 such as SnCl4, BF3·OEt2, TiCl4 and recently4
InBr3. We reported here an easy handling and inexpen-
sive iodine method to work in place as an efficient
catalyst to promote the C-glycosidation of
silylacetylenes.
Tri-O-acetyl-D-glucal 1 was treated with various silyl-
acetylenes and iodine (1 equiv.) at room temperature to
afford exclusively the a-acetylene glycoside products in
high yields under mild conditions (Table 1).
The iodine-catalyzed C-glycosidation was first opti-
mized with bis-trimethylsilylacetylene (entry 1). The
reaction was carried out using iodine 0.5 M in
dichloromethane (condition a)7 to afford acetylene gly-
coside 2 in 78% isolated yield. In a dilute concentration
solution of I2 (0.08 M, condition b), only low yield of
acetylene glycoside was observed. No reaction was
obtained when using DMF as the solvent (condition c).
Complete reaction was observed in 40 min (condition
d) in acetonitrile. However the acetylene glycoside 2
was observed in lower yield than using CH2Cl2. Based
on these results, the condition a was used as a general
procedure for the C-glycosidation of other silylacetyl-
Iodine has been employed as a catalyst to promote the
O-glycosidation5 and recently C-glycosidation of
allytrimethylsilane.6 However, no literature has been
reported to date for the C-glycosidation of silyl-
acetylene due to questions of potential reactivity
between the acetylene moiety and iodine. We described
now application of iodine to the C-glycosidation of
tri-O-acetyl-D-glucal and silylacetylene with various
types of R group at the other end of acetylene moiety
(Eq. (1)).
enes; thus, the tri-O-acetyl-D-glucal (1 equiv.), silyl-
acetylene (2 equiv.) and I2 (1 equiv.) in 0.5 M
concentration in dichloromethane. The methyl, phenyl
and phenylthio groups at the other end of silylacetyl-
enes were examined in entries 2–4, respectively. The
reactions were completed in 45 min to 1 h due to the
electronic effect of the electron donating substituents
accompanied with the b-silyl stabilized carbocation
intermediate. In the case of trimethylsilylphenyl-
(1)
* Corresponding authors. Fax.: +66-38-390-354 (R.S.); Fax.: +81-52-789-4111 (M.I.); e-mail: rungnaph@buu.ac.th; isobem@agr.nagoya-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01540-5

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-glucal with various silylacetylenes
Table 1. C-Glycosidation of tri-O-acetyl-
D

R. Saeeng et al. / Tetrahedron Letters 44 (2003) 6211–6215
6213
thioacetylene (entry 4), the 1:1.3 mixture of acetylene
glycoside and diiodovinylsulfideglycoside were
obtained in 87% total yeilds. The formation of
diiodovinylsulfide (49%) was resulted from the iodine
addition to acetylene moiety.8 Without substituent at
the end of acetylene, no reaction was observed due to
the lack of substitution stabilized effect (entry 5).3
In terms of reaction mechanism, this process could
involve the generation of different oxonium cation spe-
cies from the Ferrier rearrangement of Lewis acid cata-
lyzed C-glycosidation as depicted in Schemes 1 and 2.
5
We believe the C-glycosidation reaction was initiated
by the attack of a soft electrophilic iodonium to the
double bond of tri-O-acetyl-D-glucal to form an iodo–
Extended carbon bonds of silylacetylenes were investi-
gated in entries 6–119,10 to result in the formation of the
acetylene glycosides in moderate to high yields. In the
case of entries 8–10, when the homologation of carbon
chain between the acetylene and TBDPS–ether was
increased, the reaction was completed in the shorter
time due to the relief of the destabilization effect by the
ether group.10 The efficiency of iodine was also tested
to promote the C-glycosidation on the larger silyl-
acetylene compounds (entries 12 and 13). The silyl-
oxonium carbocation 1411 (mechanism 1, Scheme 1)
rather than attack to the acetate group at C-3 as Ferrier
rearrangement in mechanism 2 (Scheme 2). This inter-
mediate 14 can coordinate with silylacetylene at the
anomeric position C-1 from the a-side. Concerted elim-
ination of iodide and acetyl group at the C-3 position
of intermediate 16b resulted in the formation of acetyl-
ene glycoside. The iodo–oxonium mechanism was pro-
posed on the basic of our result of the O-glycosidation
of
D-glucal with ethanol by iodine as shown in Scheme
acetylene glycoside 2 failed to react with the
D
-glucal
3. It was observed that, upon treatment with 1.5 equiv.
EtOH in CH2Cl2, the O-glycoside product was
obtained as a 5:1 mixture of 20 and 21. Without
CH2Cl2, the O-glycosidation proceeds smoothly to give
exclusively the iodo–tetrahydropyran product 2111 in
the case of EtOH as a solvent. This result seems to
indicate that the glycosidation should proceed via the
(entry 12) because of the destabilized effect of the ether
ring oxygenation. Contrast to the result in entry 13,
silylpropargyl-sugar 12 smoothly reacted with
D-glucal
to furnish exclusively the a-acetylene glycoside product
13 in 88% yield proving the generality of this
methodology.
Scheme 1. Plausible mechanism 1.
Scheme 2. Ferrier rearrangement mechanism 2.

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R. Saeeng et al. / Tetrahedron Letters 44 (2003) 6211–6215
Scheme 3. O-Glycosidation of
D-glucal and EtOH.
Figure 1. Chemical shifts of the a- and b-acetelene glycosides.
iodo–oxonium intermediate 14 to obtain the iodo–tetra-
hydropyran intermediate 16a, then followed by iodine–
acetate elimination.
(Burapha University) and JSPS Core University
Exchange Program to R.S. Special thanks are due to
Dr. Masaki Kuse (Nagoya University) and Dr. Roder-
ick Bates (CRI) for mechanism discussion and to Mr.
S. Kitamura for combustion analyses. The first author
R.S. stayed in Nagoya University during the period of
March–June, 2003.
The stereochemistry at the C-1 position of the acetylene
glycoside products was proved to be exclusively a-ori-
entation in all cases. The a-acetylene glycoside products
were chemically proven through partial hydrogenation
of the acetylene group to the corresponding vinyl one,
the vinyl a-proton showing NOE with the H-5. Here we
have established an empirical rule as follow. The chem-
References
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ical shifts of the H-5 in H NMR were found between
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(Fig. 1). Comparing with the b-acetylene glycosides
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H-5 were observed between 3.74 and 3.77 which were
summarized from a report by Tanaka et. al.12 from
epimerization product via cobalt complex. All of the
H-5 chemical shifts of acetylene glycoside products in
our experiments were observed at 4.05–4.18 ppm.13
These results confirmed the a-oreintation of the acetyl-
ene glycoside products.
In conclusion, we have developed a convenient and
easy procedure with high stereoselectivity for the C-gly-
cosidation with various silylacetylenes using iodine-pro-
moted reaction. The possible iodo–oxonium mechanism
is also proposed in this report.
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Acknowledgements
7. General procedure: To a solution of tri-O-acetyl-D-glucal
(0.5 mmol) and the trimethylsilylacetylene nucleophile
(1.0 mmol) in anhydrous CH2Cl2 was added iodine (0.5
mmol) at room temperature. After TLC showed the
This research was financially supported by a grant from
Thailand Toray Foundation, Faculty of Science

R. Saeeng et al. / Tetrahedron Letters 44 (2003) 6211–6215
6215
complete conversion, the reaction was diluted with
CH2Cl2 and washed with a 5:1 (v/v) mixture of satd aq.
Na2S2O3 and satd aq. NaHCO3, dried with MgSO4 and
concentrated in vacuo. The residue was purified by silica
gel column chromatography.
from the trans-relationship of the proton at C-1 and C-2
of a-ethoxy-b-iodo glycoside 21 which show the coupling
constant value J2,3=4.5 Hz.
12. (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron
Lett. 1993, 34, 5757–5760; (b) Tanaka, S.; Isobe, M.
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8. The diiodovinylsulfideglycoside was obtained as a mix-
ture in 49%.
13. Compound 2: Mp=61–62°C; [h]2D6=−47.8 (c 1.95,
CHCl3); 1H NMR (500 MHz, CDCl3): l 1.85 (3H, d,
J=2.0 Hz, H-3%), 2.07 (3H, s, Ac), 2.09 (3H, s, Ac), 4.09
(1H, ddd, J=9.0, 5.0, 3.0 Hz, H-5%), 4.20 (1H, dd,
J=12.0, 3.0 Hz, H-6a), 4.24 (1H, dd, J=12.0, 5.0 Hz,
H-6b), 4.92 (1H, m, H-1), 5.27 (1H, ddd, J=9.0, 4.0, 2.0
Hz, H-4), 5.73 (1H, dt, J=10.0, 2.0 Hz, H-2), 5.86 (1H,
ddd, J=10.0, 4.0, 2.0 Hz, H-3); 13C NMR (125 MHz,
CDCl3): l 3.7, 20.8, 21.0, 63.1, 64.1, 64.9, 69.7, 75.1, 83.3,
124.8, 129.9, 170.4, 171.0; IR (KBr): 2956, 2923, 2287,
2219, 1740, 1437, 1371, 1230, 1053, 809 cm−1. Anal calcd
for C13H6O5: C, 61.90; H, 6.39. Found: C, 61.93; H, 6.33.
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11. The electrophilic iodonium attacks at the b-side due to
stereoelectronic effect. This evidence can be observed