Efficient and direct synthesis of saccharidic 1,2-ethylidenes, orthoesters, and glycals from peracetylated sugars via the in situ generation of glycosyl iodides with I2/Et3SiH

Article abstract of DOI:10.1016/j.tetlet.2003.09.022

Peracetylated sugars can be efficiently converted into the corresponding 1,2-ethylidenes, -orthoesters, and -glycals via the in situ generation of glycosyl iodides promoted by I₂/Et₃SiH. The approach is straightforward and avoids isolation of the sensitive iodinated intermediates.

Full text of DOI:10.1016/j.tetlet.2003.09.022

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7863–7866
Efficient and direct synthesis of saccharidic 1,2-ethylidenes,
orthoesters, and glycals from peracetylated sugars via the in situ
generation of glycosyl iodides with I2/Et3SiHꢀ
Matteo Adinolfi, Alfonso Iadonisi,* Alessandra Ravida` and Marialuisa Schiattarella
Dipartimento di Chimica Organica e Biochimica, Universita` degli Studi di Napoli Federico II, Via Cynthia 4, I-80126 Napoli,
Italy
Received 29 July 2003; revised 26 August 2003; accepted 4 September 2003
Abstract—Peracetylated sugars can be efficiently converted into the corresponding 1,2-ethylidenes, -orthoesters, and -glycals via
the in situ generation of glycosyl iodides promoted by I2/Et3SiH. The approach is straightforward and avoids isolation of the
sensitive iodinated intermediates.
© 2003 Elsevier Ltd. All rights reserved.
For a long time, glycosyl iodides have been considered
impractical reagents in carbohydrate chemistry due to
their instability. However, in recent years these deriva-
tives have attracted some interest and a variety of
approaches have been published for their synthesis. For
example, glycosyl iodides have been prepared by treat-
ment of the corresponding hemiacetals with
iodoenamines1 or with a complex of polystyryl phos-
phine and iodine.2 These compounds can also be pre-
pared from glycosyl acetates with hydriodic acid in
acetic acid,3 and catalytic BiI3 with an excess of alkyl
silyl iodides.4 Quite recently, a practical access to glyco-
syl iodides from the corresponding 1-O-acetylated
derivatives has been described by Gervay and co-work-
ers.5 This procedure is based on the use of TMSI and
takes advantage of the easy removal of volatile by-
products. The same research group has shown the
feasibility of using the donors obtained in the synthesis
of O-, C-, and N-glycosides exploiting either a direct
displacement6 or an a-selective glycosidation based on
the in situ anomerization promoted by tetra-
butylammonium iodide.7 As an alternative to the
unstable and expensive TMSI, Koreeda reported a pro-
tocol for conversion of glycosyl acetates into iodides
based on the in situ generation of anhydrous HI
through the combination of cheaper and more stable
coreagents such as iodine and thiolacetic acid (or 1,3-
propandithiol).8 More recently, in the course of our
investigations on the use of the I2/Et3SiH reagent as a
glycosidation promoter, we found as an ancillary result
that this combined system could be an alternative to the
latter approach9 avoiding the use of malodorous thiols,
whose nucleophilic character could also give undesired
Keywords: glycosyl iodides; orthoesters; glycals; ethylidenes.
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.022
* Corresponding author. Fax: +39 081 674393; e-mail: iadonisi@
unina.it
Scheme 1. Synthesis of orthoester 3. Reagents and conditions:
(a) I2 (1.4 equiv.), Et3SiH (1.4 equiv.), CH2Cl2, reflux, 30–60
min; (b) lutidine (4 equiv.), EtOH (6 equiv.), (Bu4N)Br (0.4
equiv.), rt, overnight; (c) KOH, toluene, reflux, then BnBr.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.022

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M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 7863–7866
side-reactions.8 In this paper we wish to report the
exploitation of this approach for the one-pot conver-
sion of easily prepared and commercially available per-
acetylated sugars into widely used saccharidic building
blocks such as 1,2-orthoesters, 1,2-ethylidenes and 1,2-
glycals. These intermediates are typically prepared
from the corresponding glycosyl bromides, whose syn-
thesis from the corresponding 1-O-acetylated precur-
sors requires quite demanding experimental con-
ditions.10
was obtained in good overall yield (56% for three
steps).
To avoid the use of the relatively expensive acetobromo
galactose, a new synthesis of 2 was developed starting
from the cheaper pentaacetyl galactose 1 (Scheme 1).
Treatment of this with 1.4 equivalents of I2 and Et3SiH
in refluxing dichloromethane produced the correspond-
ing a-iodide (TLC and NMR analysis of an aliquot of
the crude reaction mixture). Lutidine, ethanol, and
tetrabutylammonium bromide were then added and the
mixture was left stirring overnight. NMR analysis of
the crude material showed the formation of the desired
orthoester derivative. The crude mixture was subjected
to the one-pot deacetylation–benzylation sequence to
afford compound 3 in a 50% overall yield (over four
This investigation was inspired by a problem associated
with the synthesis of the intermediate 3 starting
from acetobromo galactose, which can be achieved by
conversion into orthoester 2, via halide-promoted
anomerization (lutidine, ethanol and tetrabutyl-
ammonium bromide),11 followed by deacetylation
and benzylation. Exploiting this procedure compound 3
steps) with
a single chromatographic purification
(Scheme 1, Table 1, entry 1).
Table 1. Conversion of peracetylated sugars into 1,2-orthoesters, -ethylidenes, and glycals

M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 7863–7866
7865
Acknowledgements
The application of this strategy has been investigated
for the synthesis of a variety of useful saccharidic
building-blocks commonly prepared from peracetylated
glycosyl bromides. For example, the same synthetic
sequence was also applied to the gluco precursor 4 in
good overall yield (entry 2). It should be noted that the
orthoesterification reaction can be accomplished via a
one-pot procedure without any work-up of the iodina-
tion mixture, in contrast to the corresponding synthesis
via glycosyl bromides. In addition, the efficacy of the
whole synthetic sequence was not compromised by the
use of unpurified intermediates. The acetylated
orthoester 7 was prepared from the corresponding per-
acetylated D-mannose derivative 6 via an analogous
one-pot sequence of anomeric iodination and orthoes-
terification (entry 3). The sequence afforded the
product as a single diastereoisomer in 71% overall yield
after the final chromatographic purification.
Financial support by Ministero della Universita` e della
Ricerca Scientifica and access to the facilities of ‘Centro
di Metodologie Chimico-fisiche dell’Universita` di
Napoli’ are acknowledged.
References
1. Caputo, R.; Kunz, H.; Mastroianni, D.; Palumbo, G.;
Pedatella, S.; Solla, F. Eur. J. Org. Chem. 1999, 3147.
2. Ernst, B.; Winkler, T. Tetrahedron Lett. 1989, 30, 3081.
3. Ness, R. K.; Fletcher, H. G.; Hudson, C. S. J. Am. Chem.
Soc. 1950, 72, 2200.
4. Montero, J.-L.; Winum, J.-Y.; Leydet, A.; Kamal, M.;
Pavia, A. A.; Roque, J.-P. Carbohydr. Res. 1997, 297,
175.
5. Gervay, J.; Nguyen, T. N.; Hadd, M. J. Carbohydr. Res.
1997, 300, 119.
6. (a) Gervay, J.; Hadd, M. J. J. Org. Chem. 1997, 62, 6961;
(b) Bhat, A. S.; Gervay-Hague, J. Org. Lett. 2001, 3,
2081; (c) Ying, L.; Gervay-Hague, J. Carbohydr. Res.
2003, 338, 835.
7. (a) Hadd, M. J.; Gervay, J. Carbohydr. Res. 1999, 320,
61; (b) Lam, S. N.; Gervay-Hague, J. Org. Lett. 2002, 4,
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2002, 337, 1953.
8. Chervin, S. M.; Abada, P.; Koreeda, M. Org. Lett. 2000,
2, 369.
9. Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M.
Synlett 2002, 269.
10. For a discussion on the problems associated with the
synthesis of glycosyl bromides and related references see:
Franz, A. H.; Wei, Y. Q.; Samoshin, V. V.; Gross, P. H.
J. Org. Chem. 2002, 67, 7662.
Another interesting application of the protocol is repre-
sented by the synthesis of 1,2-ethylidenes, another class
of very useful precursors in carbohydrate chemistry.
These derivatives are routinely prepared by treating
glycosyl bromides with excess NaBH4, and (for gluco-
and galacto-derivatives) catalytic tetrabutylammonium
bromide in acetonitrile.12 The synthesis of these com-
pounds directly from peracetylated precursors has been
demonstrated starting from mannose and fucose deriva-
tives (entries 4 and 5, respectively). In these cases, after
the generation of the glycosyl iodide the initial solvent
(dichloromethane) was removed and replaced with ace-
tonitrile, then sodium borohydride and (only for entry
5) tetrabutylammoniun bromide were added. Also in
this case the one-pot sequence gave a useful yield with
minimization of the experimental operations. In addi-
tion, the generation of 1,2-ethylidenes from the interme-
diate glycosyl iodide turned out to be a faster process
than in the case of brominated intermediates.
11. Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43,
2199.
12. Betaneli, V. I.; Ovchinnicov, M. V.; Backinowsky, L. L.;
Kochetkov, N. K. Carbohydr. Res. 1982, 107, 285.
13. Hansen, T.; Krintel, S. L.; Daasbjerg, K.; Skrydstrup, N.
Tetrahedron Lett. 1999, 40, 6087.
A further application has been evaluated in the synthe-
sis of 1,2-glycals (entries 6-8). In this case the iodination
mixture was worked-up by a simple extraction and the
crude product from the organic phase was directly
subjected to elimination conditions as described for
anomeric bromides by Skrydstrup and co-workers
(Cp2Cl2Ti and manganese in THF).13 Also in this case
the elimination step required typically much shorter
times than with the corresponding glycosyl bromides
(2-4 h instead of more than 10 h).13 A practical applica-
tion of this approach was demonstrated in the synthesis
of the expensive lactal derivative 14 (entry 8).
14. General procedure for the synthesis of glycosyl iodides: the
peracetylated sugar (2 mmol) was coevaporated with dry
toluene and then dissolved in anhydrous dichloromethane
(6 mL). To the solution were added I2 (711 mg, 2.8
mmol) and triethylsilane (450 mL, 2.8 mmol). The mixture
was refluxed until TLC analysis displayed complete con-
sumption of the peracetylated sugar (the glycosyl iodides
are partially unstable on TLC, especially in the case of
the fucose derivative), and then submitted to further
reactions.
In conclusion, an efficient procedure for the synthesis of
glycosyl iodides based on the use of cheap and easily
handled reagents has been described.14 These intermedi-
ates can be efficiently converted into 1,2-orthoesters or
-ethylidenes via a one-pot approach, while 1,2-glycals
can be readily obtained after a simple extractive work-
up of the iodination mixture.14
General procedure for preparation of 1,2-orthoesters. To
the above reaction mixture were sequentially added
lutidine (930 mL, 8 mmol), ethanol (680 mL, 12 mmol)
and tetrabutylammonium bromide (258 mg, 0.8 mmol).
The mixture was left to stir overnight at rt (in the case of
galacto- and manno-derivatives) or refluxed for 4 h (gluco
derivative). When the reaction was complete (TLC), the
mixture was concentrated and chromatographed on silica
gel (entry 3) or directly submitted to the deacetylation–
benzylation one-pot procedure (entries 1 and 2).
Supplementary material: Spectral data (1H and 13C
NMR) for all products in Table 1 are available.

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M. Adinolfi et al. / Tetrahedron Letters 44 (2003) 7863–7866
General procedure for preparation of 1,2-ethylidenes. Fol-
lowing the above described synthesis of the glycosyl
iodide intermediate, dichloromethane was removed with a
stream of nitrogen. The residue was dissolved in acetoni-
trile, and then sodium borohydride (378 mg, 10 mmol)
and tetrabutylammonium bromide (258 mg, 0.8 mmol)
(only for entry 6) were sequentially added (NOTE:
exothermic reaction). On completion of the reaction
(TLC), the mixture was diluted with dichloromethane
and washed with water. Concentration of the organic
phase afforded a residue that was purified by silica gel
chromatography.
General procedure for preparation of 1,2-glycals. Follow-
ing the above described synthesis of the glycosyl iodide
intermediate, the mixture was diluted with
dichloromethane and washed with a 5% solution of
sodium bicarbonate containing sodium thiosulfate (in the
minimal amount necessary to reduce the residual iodine).
The organic phase was dried and concentrated. The
residue was dissolved in THF (5 mL) and Cp2Cl2Ti (1.25
g, 5 mmol) and manganese (50 mesh, 550 mg, 10 mmol)
were added at room temperature under argon. After
completion of the reaction (TLC) the mixture was con-
centrated and the residue chromatographed on silica gel.