hydride according to the method of Heras et al.5 Unfortu-
nately, when we attempted to extend this methodology to
other simple monosacharides such as per-O-acetylgluco-
pyranoside (4) and its C2 epimer, only very low yields of
the desired cyanosugars were obtained. Similarly, reaction
of per-O-acetylated monosaccharides with TMSCN in the
presence of other Lewis acids such as ZnCl2, AlCl3, and
SnCl4 failed to provide the desired cyanosugars (eq I, Scheme
2). Treatment of per-O-acetylcellobiose (5) with TMSCN
and BF3‚O(Et)2 gave only the R-cyanide (eq II, Scheme 2).
Earlier, we had shown that reaction of perbenzylated
glycosyl iodides with tetrabutylammonium cyanide gave
mixed results.9 For example, with per-O-benzylglucosyl
iodide (9) only a 32% yield of the â-cyanosugar was
obtained. The major product was the glycal (10) resulting
from elimination of HI. When per-O-benzylmannosyl iodide
(11) was reacted under the same conditions, the â-cyano
glycoside (12) was obtained as the major product (Scheme
3). We were encouraged to learn that the â-cyano functional-
Scheme 3
Scheme 2
ity could be incorporated without anchiomeric assistance
from the C-2 protecting group; nevertheless it was clear that
the elimination problem would have to be overcome.
Hindsgaul and Uchiyama reported that anomeric silyl
ethers could serve as precursors to glycosyl iodides.10 We
reasoned that the greater electron donating capability of the
silyl protecting group would decrease the acidity of the C-2
hydrogen and suppress possible E-2 reactions. Increased
electron donation would also increase the leaving ability of
the anomeric iodide, and we anticipated that these two
effects, working in concert, would lead to improved yields
of â-cyanosugars.
Per-O-silylated sugars were prepared by reacting the
starting mono- or disaccharide with TMSCl and TEA in
DMF.10 Reactions of the monosaccharides were complete
after 4 h whereas the disaccharides required an 8 h reaction
time. The silylated sugars were characterized by NMR and
high-resolution mass spectrometry. It is interesting to note
that the R anomer predominated for all the sugars with the
exception of cellobiose (Table 1). The yields for the per-O-
silylated monosaccharides ranged from 89 to 94%, and the
disaccharide yields ranged from 64 to 85%.
Meyers et al.4b reported limited success with mercuric
cyanide addition to per-O-acetylglucosyl bromide. In our
hands, similar transformations with 7 resulted in low yields,
and isolation was complicated by the formation of cyano-
ethylidene derivatives (8) (eq III, Scheme 2). Although Lewis
acid-catalyzed isomerization of 8 was attempted,6 yields were
not significantly improved and anomeric selectivity remained
poor.
In the past few years we have extensively used glycosyl
iodides in the synthesis of O-, N-, and C-glycosides.7 The
iodides are readily obtained from the anomeric acetate upon
treatment with trimethylsilyl iodide. The trimethylsilyl acetate
generated in the reaction can be easily removed by evapora-
tion, yielding the pure glycosyl iodide. Per-O-acetyl glycosyl
iodides were investigated as donors for cyanide delivery.
Several reactions were attempted with both mono- and
disaccharide derivatives. Displacement reactions with TBACN,
NaCN, or KCN in the presence of crown ethers or via
hypervalent silicates (formed by reacting TBAF with TM-
SCN) all gave 1,2-elimination compounds as the major
products.8
The corresponding glycosyl iodides were generated by the
addition of TMSI to the silylated carbohydrate in dichlo-
romethane. After an approximately 10 min reaction time at
rt, the reaction mixtures were concentrated and the residue
was azeotroped with benzene. The iodides were characterized
by NMR spectroscopy, which typically showed the anomeric
proton between δ 6.7-6.8 ppm, signifying an R anomeric
configuration (Table 1).11 All of the carbohydrate derivatives
(4) (a) Heras, F. G.; Fernandez-Resa, P. J. Chem. Soc., Perkin Trans. 1
1982, 903. (b) Myers, R. W.; Lee, Y. C. Carbohydr. Res. 1984, 132, 61.
(c) Grynkiewicz, G.; BeMiller, J. N. Carbohydr. Res. 1983, 112, 324.
(5) Heras, F. G.; Fernandez-Resa, P. J. Chem. Soc., Perkin Trans. 1 1982,
903.
(6) Myers, R. W.; Lee, Y. C. Carbohydr. Res. 1986, 154, 145.
(7) Gervay, J. Org. Synth.: Theory Appl. 1998, 4, 121.
(8) Soli, E. D.; DeShong, P. J. Org. Chem. 1999, 64, 9724.
(9) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 6961.
(10) Uchiyama, T.; Hindsgaul, O. SynLett 1996, 499.
(11) Gervay, J.; Nguyen, T. N.; Hadd, M. J. Carbohydr. Res. 1997, 300,
119.
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Org. Lett., Vol. 3, No. 13, 2001