Thermal effect in β-selective glycosylation reactions using glycosyl iodides

Article abstract of DOI:10.1016/j.tetlet.2005.07.129

The unique reactivity of glycosyl iodides and the fact that they react under neutral conditions makes them the donors of choice in our glycosylation strategies. Glycosyl iodides are generated in situ from either the anomeric acetate or the anomeric silyla

Full text of DOI:10.1016/j.tetlet.2005.07.129

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 6727–6728
Thermal effect in b-selective glycosylation reactions
using glycosyl iodides
Mohamed H. El-Badry and Jacquelyn Gervay-Hague*
Department of Chemistry, University of California, Davis, CA 95616, USA
Received 8 July 2005; revised 18 July 2005; accepted 25 July 2005
Available online 15 August 2005
Abstract—The unique reactivity of glycosyl iodides and the fact that they react under neutral conditions makes them the donors of
choice in our glycosylation strategies. Glycosyl iodides are generated in situ from either the anomeric acetate or the anomeric sily-
lated derivative yielding the a-iodide. In the reported glycosylation reactions, protected glucosyl, galactosyl, and mannosyl iodides
were reacted with trimethylene oxide asthe acceptor, yielding the b-anomer asthe major product. In the ab se nce of neighboring
group participation, b-selectivity is thought to arise from nucleophilic displacement of the a-iodide in an S 2-like mechanism, while
N
the a-product isthe re su lt of nucleophilic attack on the b-iodide. In this study, increased b-selectivity using an inverse thermal effect
isdemon st rated.
ꢀ
2005 Elsevier Ltd. All rights reserved.
Recent studies in our laboratory have shown the unique
reactivity and selectivity of oxacyclic ethers as acceptors
and from nucleophilic displacement of the b-glycosyl
iodide (8) generated from in situ anomerization
(Fig. 2). We reasoned that lower reaction temperatures
1
in glycosylation reactions with glycosyl iodides. Highly
2
3
strained cyclic ethers such as trimethylene oxide proved
would suppress the formation of 5, and since at the
especially useful due to symmetrical ring opening upon
exposure to the iodide. b-Selectivity isbelieved to arise
onset of the reaction the concentration of iodide anion
islow, the combination of the se two factorswould lead
to increased b-selectivity. Thus we initiated the current
study on the thermal effect of b-glycosidation using
glycosyl iodides.
from an S 2-like displacement of the a-iodide (1) by
N
acceptor (2) leading to the formation of the b-oxonium
ion (3), which is susceptible to ring opening by the
iodide to yield the b-glycoside (4) (Fig. 1).
Glycosyl iodides4 are quantitatively generated from
either the anomeric acetate or the anomeric silylated
While we were able to achieve ashigh as8:1 b-selectiv-
ity, a-glycoside (7) formation could not be avoided. Our
current hypothesis is that a-glycosidation occurs from a
combination of ring opening of the a-oxonium ion (6)
resulting from addition to oxonium intermediate (5)
5
derivative by treatment with TMSI. The side product
of the acetate reaction isTMSOAc, which iscapable
of reforming the glycosyl acetate. This problem may
6
be overcome by azeotroping the iodide with toluene
1
or by introducing MgO asan effective trap. A typical
experimental example isthe galac tyo l sa tion of
2
_
RO
RO
RO
I
RO
_
RO
RO
O
RO
+
.
.
I
O
+
O
O
O
O
I
3
O
O
n(RO)
n(RO)
n(RO)
n(RO)
O
+
n(RO)
_
O
I
I
..
1
3
4
1
I
_
5
O
6
I
Figure 1. Mechanism of b-glycoside formation.
RO
RO
O
O
n(RO)
n(RO)
I
O
6
Keywords: Glycosyl iodide; b-Selective glycosidation.
Corresponding author. Tel.: +1 5307549577; fax: +1 5307528995;
e-mail: gervay@chem.ucdavis.edu
8
7
O
I
*
Figure 2. Mechanism of a-glycoside formation.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.129

6728
M. H. El-Badry, J. Gervay-Hague / Tetrahedron Letters 46 (2005) 6727–6728
R6
R6
little difference between performing the reactionsat
R5
R5
R1
1.5 eq.
CH2Cl2
, 2 eq. MgO
R1
room temperature and 0 ꢁC, but dramatic differences
were observed at lower temperatures. At À60 ꢁC, only
2% a-galactoside (entry 4), and less than 4% a-glucoside
O
O
O
R4
R4
O
I
R3
R3
R2
R2
I
(entry 12) wasformed. b-Selectivity wasnot asgreat for
Gal (9): R1, R4=H; R2, R3, R5, R6=OBn
the mannopyranoside as 10% of the a-mannoside was
present in the product distribution and the reaction took
more than 6 daysfor completion. Achieving b-selectivity
in mannosidations is notoriously difficult as neither the
anomeric effect nor the axial group at C2 favorsthis
Man (10): R2, R5=H; R1, R3, R4=OBn; R6=OAc
Glc (11): R1, R5=H; R2, R3, R4, R6=OBn
Si Glc (12): R1, R5=H; R2, R3, R4, R6=OTMS
Scheme 1.
7
conversion. Finally, entries13–16 su pport our hypoth-
esis that the a-anomer arises at least in part from the
formation of the oxacarbenium ion 5. The electron
donating capacity of silyl protecting groups is known
to stabilize formation of the oxacarbenium ion, which
we predicted would lead to diminished b-selectivity.
trimethylene oxide in which a mixture of 2,3,4,6-tetra-O-
benzyl-D-galactopyranosyl acetate (1 equiv) and MgO
(
(
2 equiv) in CH Cl (0.17 M) is st irred at 0 ꢁC and TMSI
8
2
2
1.1 equiv) isthen added. The reaction mixture is st irred
for 2 h at 0 ꢁC to give galactosyl iodide 9 (Scheme 1).
Trimethylene oxide (1.5 equiv) is subsequently added
at 0 ꢁC and the mixture is then stirred at the selected
temperature (Table 1). Upon the completion of the reac-
tion, the mixture isdiluted with EtOAc (20 mL) and
washed with saturated aq Na S O (3·10 mL), then with
Indeed, this was the case; the selectivity dropped from
2
1
9:1 b:a with per-O-benzylated glucosyl iodide (entry
2) to 10:1 b:a (entry 16) when using the per-O-silylated
analogue.
2
2
3
In conclusion, the thermal effect is a useful strategy for
the efficient formation of b-glycosides using glycosyl
iodide donors. Increased b-selectivity is inversely pro-
portional to the temperature and the highest reactivity
and stereoselectivity were obtained when using per-O-
benzylated galactopyranosyl iodide. Steric effects in
mannose hinder nucleophilic attack of the acceptor via
saturated aq NaCl (2·10 mL). The organic extract is
then dried over Na SO , stripped of solvent in vacuo,
2
4
and the concentrated residue is purified by FCC to af-
ford the corresponding galactoside as a mixture of ano-
mersin the yield sp ecified in Table 1. The b:a ratio can
be obtained from integration of the anomeric signals in
1
13
the H and C NMR spectra (d 4.95 (b-anomer), 5.05
H
an S 2-like mechanism and the electronic effects of sil-
N
(
a-anomer); d 104.2 (b-anomer), 98.2 (a-anomer)).
C
icon increase the propensity for oxonium ion formation;
both of which lead to lower b-selectivity.
All of the reactionsreported in Table 1 were performed
a minimum of three times, and the average of the
selectivity was calculated and reported. Galactosyl,
mannosyl, and glucosyl iodides were studied. Mannosyl
iodide 10 wasemployed in ts ead of the perbenzylated
Acknowledgments
analogue to avoid glycal formation resulting from
Financial support for this research was gratefully
received from the National Science Foundation
CHE-0196482, NSF CRIF program (CHE-9808 183),
NSF Grant OSTI 97-24412, and NIH Grant RR11973
provided funding for the NMR spectrometers used in
thisproject.
6
1
4
,2-elimination. In general terms, the reactivity of 2,3,
,6-tetra-O-benzyl-a-D-galactopyranosyl iodide > 2,3,4,6-
tetra-O-benzyl-a-D-glucopyranosyl iodide > 6-O-acetyl-
,3,4-tri-O-benzyl-a-D-mannopyranosyl iodide.
2
Asillut sr ated in
Table 1, b-selectivity exponentially
increased upon lowering the temperature. There was
References and notes
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