2-Deoxy-2-iodo- and 2-deoxy-2-bromo-α-glucopyranosyl trichloroacetimidates: Highly reactive and stereoselective donors for the synthesis of 2-deoxy-β-glycosides

Article abstract of DOI:10.1021/ol9908070

(equation presented) 2-Deoxy-2-iodo-and 2-deoxy-2-bromoglucopyranosyl trichloroacetimidates 8-10 and 22 are extremely useful precursors of 2-deoxy-β-glycosides. These reactive glycosyl donors undergo highly stereoselective glycosidation reactions at -78°C

Full text of DOI:10.1021/ol9908070

ORGANIC
LETTERS
1999
Vol. 1, No. 6
891-893
2-Deoxy-2-iodo- and
2-Deoxy-2-bromo-r-glucopyranosyl
Trichloroacetimidates: Highly Reactive
and Stereoselective Donors for the
Synthesis of 2-Deoxy-â-glycosides
William R. Roush,* Benjamin W. Gung,1 and Chad E. Bennett
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received July 13, 1999
ABSTRACT
2-Deoxy-2-iodo- and 2-deoxy-2-bromoglucopyranosyl trichloroacetimidates 8−10 and 22 are extremely useful precursors of 2-deoxy-â-glycosides.
These reactive glycosyl donors undergo highly stereoselective glycosidation reactions at −78 °C with a range of glycosyl acceptors using
TBS-OTf as the activating agent. â-Glycosides are obtained with g 19:1 selectivity in six of the seven examples reported herein.
We recently reported a highly stereoselective synthesis of
2-deoxy-2-iodo-â-glucopyranosides, precursors of 2-deoxy-
â-glycosides, using 2-deoxy-2-iodo-glucopyranosyl acetates
as the glycosyl donors.2 We observed that certain donors,
such as the 6-deoxy-glucosyl acetate 1, are highly reactive
and undergo rapid, high-yielding glycosidation reactions at
-78 °C, as illustrated by the coupling of 1 and 2 (Figure 1).
The high reactivity of 1 is due in part to the fact that this
compound exists in a twist boat conformation (see 1′), which
increases the reactivity of this donor compared to those in
the normal chair conformation.2 The lack of oxygenation at
C(6) also increases the reactivity of the anomeric center.3,4
In contrast, all other glycosyl donors that adopt the normal
4C1 conformation and/or have deactivating heteroatom sub-
stituents at C(6) required much higher glycosidation reaction
temperatures, as illustrated by the glycosidation reaction of
2 and 4. One additional complication with the use of glycosyl
acetates such as 4 is that under the reaction conditions the
â-glycosyl acetates equilibrate with the R-acetate anomers,
which are considerably less reactive as glycosylating agents.
Although the R-acetates can be used as substrates for these
reactions, the R-anomers generally require temperatures 20-
30 °C warmer for productive couplings than for the â-gly-
cosyl acetates. Consequently, 2-deoxy-2-iodoglycosyl acetate
donors such as 4 are not suitable substrates for glycosidation
with glycals or other acceptors containing Lewis acid
sensitive functionality.
These considerations prompted us to identify a more
reactive glycosyl activating group that would permit the
synthesis of 2-deoxy-2-iodo-â-glycosides to be performed
at -78 °C. Glycosyl trichloroacetimidates have proven to
be an extremely useful class of glycosyl donors.5,6 On the
basis of our experience with 2-deoxy-2-thiophenylglycosyl
trichloroacetimidates,7,8 we anticipated that 2-deoxy-2-iodo-
glycosyl trichloroacetimidates would have the reactivity
characteristics that we desired. Accordingly, we have de-
veloped and report herein the glycosidation reactions of these
new donors.
(1) On sabbatical leave from the Department of Chemistry and Bio-
chemistry, Miami University, Oxford, OH 45056.
(2) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(3) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962,
3429.
The preparation of the glycosyl trichloroacetimidate 8 is
representative.9 Selective benzoylation (C6H5COCl, pyridine,
(4) Buncel, E.; Bradley, P. R. Can. J. Chem. 1967, 45, 515.
10.1021/ol9908070 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

Figure 1. â-Selective glycosidation reactions of iodo acetate donors
1 and 4.2
CH2Cl2, 74%) of C(4)-OH of the readily available anhydro
sugar 610,11 followed by silylation of C(3)-OH (TBS-OTf,
2,6-lutidine, CH2Cl2, 0 °C, 99%) and acetolysis of the
anhydro bridge (TFA, Ac2O, 23 °C, 97%) provided 7 as an
anomeric mixture in 71% overall yield. Selective cleavage
of the anomeric acetate using aqueous hydrazine in MeOH
(99%)12 and then treatment of the pyranose with excess NaH
in Cl3CCN (as solvent)7 at -40 °C to -20 °C gave the
R-imidate 8 in 79% yield (78% from 7). Glycosyl donors 9
and 10 were similarly prepared starting from 6 (Figure 2).
However, in both of these cases the efficiency of the
trichloroacetonitrile activation step was somewhat diminished
(64% and 46%, respectively), owing to the high reactivity
and poor chemical stability of these particular compounds.
Figure 3. Highly â-selective glycosidation reactions of 2-iodogly-
cosyl trichloroacetimidates 8-10.
Results of representative glycosidation reactions of the
2-iodoglycosyl imidate donors 8-10 with monosaccharide
acceptors 2, 11, 13, 15, and 17 are summarized in Figure 3.
These reactions were performed at -78 °C in CH2Cl2 using
1.5-3 equiv of the donors in the presence of 0.05-0.3 equiv
of TBS-OTf as the activator. In most cases the reactions were
complete within a 0.5-1.5 h period. (In other work we have
observed that TBS-OTf is superior to TMS-OTf for glycosi-
dations of sensitive substrates.8,13) As is clearly evident from
these examples, the efficiency and especially the stereose-
lectivity of these reactions are excellent. It is noteworthy
that the â-glycosides were produced with g 10:1 selectivity
in all cases, with the reaction of 8 and 15 being the only
case that proceeded with less than 19:1 â-selectivity. The
(5) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem. Biochem. 1994,
50, 21.
(6) Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212.
(7) Roush, W. R.; Sebesta, D. P.; James, R. A. Tetrahedron 1997, 53,
8837.
(8) Roush, W. R.; Hartz, R. A.; Gustin, D. J. J. Am. Chem. Soc. 1999,
121, 1990.
(9) The spectroscopic and physical properties (e.g., 1H NMR, 13C NMR,
IR, mass spectrum, and/or C, H analysis) of all new compounds were fully
consistent with the assigned structures.
(10) Leteux, C.; Veyrieres, A.; Robert, F. Carbohydr. Res. 1993, 242,
119.
(11) Tailler, D.; Jacquinet, J.-C.; Noirot, A.-M.; Beau, J.-M. J. Chem.
Soc., Perkin Trans. 1 1992, 3163.
(12) Excoffier, G.; Gagnaire, D.; Utille, J.-P. Carbohydr. Res. 1975, 39,
368.
Figure 2. Synthesis of 2-deoxy-2-iodo-R-glucosyl trichloroacet-
imidates 8-10.
(13) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899-902.
892
Org. Lett., Vol. 1, No. 6, 1999

conditions are sufficiently mild that the very acid sensitive
glycal 15 can be glycosylated efficiently. Owing to the poor
solubility of 13 under the reaction conditions (-78 °C, CH2-
Cl2), the coupling of 13 and 8 did not go to completion and
26% of 13 was recovered. Nevertheless, the successful use
of 13 as a glycosyl acceptor attests to the significantly greater
reactivity of the 2-deoxy-2-iodoglycosyl imidates compared
to the 2-deoxy-2-iodoglycosyl acetates, thereby enabling the
synthesis of disaccharides (e.g., 14) already suitably activated
for a subsequent glycosidation reaction at higher reaction
temperature.2
Glycosyl donors 8 and 9 containing strong electron
withdrawing C(4)-acyl substituents are considerably more
stable and less reactive than 10, which is quite sensitive to
handling and decomposes readily even upon attempted
storage. Because we anticipated the need to use glycosyl
donors containing C(4)-silyloxy or C(4)-ether protecting
groups, it was desirable to develop a more stable glycosyl
donor as an equivalent of 10. We anticipated that the
analogous 2-bromo-2-deoxyglycosyl imidate 22 would be
less reactive and more stable than 10, due to the greater
electronegativity of the 2-bromo substituent which should
inductively destabilize the transition state leading to oxonium
ion intermediates. Thiem has previously demonstrated that
2-bromo-2-deoxyglycosyl bromides are useful precursors to
2-deoxy-â-glycosides via silver silicate promoted glycosi-
dations (although the stereoselectivity of these reactions is
generally e 6:1).14,15
Figure 4. Synthesis and â-selective glycosidation reactions of
2-deoxy-2-bromo-R-glucosyl trichloroacetimidate 22.
In summary, we have demonstrated that 2-deoxy-2-
iodoglycosyl imidates 8-10 and 2-deoxy-2-bromoglycosyl
imidate 22 are highly reactive glycosyl donors. These donors
undergo highly stereoselective glycosidation reactions with
a range of monosaccharide acceptors to give 2-deoxy-2-iodo-
and 2-deoxy-2-bromo-â-glycosides, precursors of 2-deoxy-
â-glycosides, with g 19:1 selectivity. It is noteworthy that
the 2-deoxy-2-iodoglycosyl imidates are substantially more
reactive than the 2-deoxy-2-iodoglycosyl acetates previously
reported from our laboratory.2 Application of this methodol-
ogy to the synthesis of biologically relevant 2-deoxy-â-
glycosides is in progress and will be reported in due course.
2-Bromo-2-deoxyglycosyl imidate 22 was synthesized
starting from tri-O-acetyl-D-glucal, 20. Anhydro sugar 21 was
prepared by methanolysis of 20 followed by intramolecular
bromoetherification (NBS, (Bu3Sn)2O, CH3CN; 64% from
21) and then selective protection of the C(4)-OH as a TBS
ether. The bromoetherification sequence employed here is
an improvement over the literature procedure that involves
the reaction of the stannylated glucal with Br2 in CHCl3 and
provides a 9:1 mixture of the 1,6-anhydro-2-bromo-gluco-
and -manno isomers.10 Acetolysis of the anhydro linkage of
21 followed by deprotection of the anomeric acetate and then
activation of the pyranose gave the imidate 22 in ca. 40%
overall yield using the conditions described for the synthesis
of 8 from 7. Imidate 22 indeed proved to be more robust
than 10 and underwent highly â-selective glycosidation
reactions with acceptors 2 and 24, as summarized in Figure
4.
Acknowledgment. This research was supported by a
grant from the NIH (GM 38907).
Supporting Information Available: Representative ex-
perimental procedures for synthesis of the 2-deoxy-2-iodo-
and 2-deoxy-2-bromo-R-glucosyl trichloroacetimidates and
their glycosidation reactions; spectroscopic data for 8-10,
12, 14, 16, 18, 19, 21-23, and 25. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Thiem, J.; Gerken, M.; Boch, K. Liebigs Ann. Chem. 1983, 462.
(15) Thiem, J.; Gerken, M. J. Org. Chem. 1985, 50, 954, and references
therein.
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