Iodoacetoxylation of glycals using cerium(IV) ammonium nitrate, sodium iodide, and acetic acid: stereoselective synthesis of 2-deoxy-2-iodo-alpha-mannopyranosyl acetates.

Article abstract of DOI:10.1021/ol990815g

[formula: see text] The reactions of glycals with ceric(IV) ammonium nitrate and sodium iodide in the presence of acetic acid provides 2-deoxy-2-iodo-alpha-mannopyranosyl acetates with good stereoselectivity. In the majority of the cases examined, the sel

Full text of DOI:10.1021/ol990815g

ORGANIC
LETTERS
1999
Vol. 1, No. 6
895-897
Iodoacetoxylation of Glycals Using
Cerium(IV) Ammonium Nitrate, Sodium
Iodide, and Acetic Acid: Stereoselective
Synthesis of
2-Deoxy-2-iodo-r-mannopyranosyl
Acetates
William R. Roush,* Sridhar Narayan, Chad E. Bennett, and Karin Briner1
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
roush@umich.edu
Received July 14, 1999
ABSTRACT
The reactions of glycals with ceric(IV) ammonium nitrate and sodium iodide in the presence of acetic acid provides 2-deoxy-2-iodo-r-
mannopyranosyl acetates with good stereoselectivity. In the majority of the cases examined, the selectivity was considerably better than that
from reactions using N-iodosuccinimide and HOAc.
In connection with our studies on the synthesis of 2-deoxy-
glycosides from 2-deoxy-2-iodoglycosyl donors,2-4 we were
interested in developing improved methods for the synthesis
of 2-deoxy-2-iodoglycosyl acetates of either the manno or
gluco configuration. Prior to the initiation of these studies,
we utilized the reaction of a glycal with N-iodosuccinimide
and HOAc in a suitable solvent.5,6 As summarized in Figure
1, this method provides the R-manno isomer (2) as the major
product when the reactions are performed at ambient or
subambient temperatures, with selectivity decreasing as the
(1) This research was initiated in the Department of Chemistry, Indiana
University, Bloomington, IN 47405.
Figure 1. Iodoacetoxylation of 1 using N-iodosuccinimide (NIS)
and HOAc.
(2) Roush, W. R.; Briner, K.; Sebesta, D. P. Synlett 1993, 264.
(3) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(4) Roush, W. R.; Gung, B. W.; Bennett, C. E. Org. Lett. 1999, 1, 891-
894.
(5) (a) Thiem, J.; Karl, H.; Schwentner, J. Synthesis 1978, 696. (b) For
a summary of numerous applications of this method, see: Thiem, J. In
Trends in Synthetic Carbohydrate Chemistry; Horton, D., Hawkins, L. D.,
McGarvey, G. J., Eds.; ACS Symposium Series 386; American Chemical
Society: Washington, DC, 1989; p 131.
(6) (a) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6656, and references therein. (b) For a review, see: Danishefsky, S. J.;
Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380.
reaction temperature is raised.3 In some cases, we have
obtained up to 9:1 selectivity for the R-manno iodo acetate
isomer in reactions performed at -78 °C;2 however, in most
cases selectivity for the R-manno isomer (cf., 2) is no better
than 3-4:1, as in the iodoacetoxylation of 1. On the other
10.1021/ol990815g CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/21/1999

hand, the amount of the â-gluco isomer (e.g., 3) that can be
obtained by this method reaches a maxium of approximately
50% when the reactions are performed in toluene at reflux
(i.e., selectivity is no better than ca. 50:50 under these
conditions).3 Accordingly, it was desirable to develop more
selective methods for synthesis of either iodo acetate
stereoisomer.
Stimulated by the well-known azidonitration reaction,7,8
which involves the addition of azide radical, generated from
NaN3 and ceric(IV) ammonium nitrate (CAN), to a glycal,
we decided to explore the reactions of glycals with CAN
and NaI. To our considerable delight, we found that this
reaction constitutes a very useful method for synthesis of
2-deoxy-2-iodo-R-mannopyranosyl acetates (Figure 2). These
reactions were typically performed by slow addition of 1.3
equiv of NaI to a solution of glycal, 2.6 equiv of CAN and
10 equiv of HOAc in CH3CN. Total reaction times were
generally 2-7 h. Products were isolated either by chroma-
tography or by recrystallization. The reaction stereoselectivity
was not highly temperature sensitive, although in most cases
the best yields were obtained when the reactions were
performed at temperatures ranging from -25 °C to ambient.
As indicated by the examples presented in Figure 2, a range
of standard carbohydrate protecting groups (e.g., acetate
esters, silyl and benzyl ethers) are fully compatible with this
new iodoacetoxylation reaction.
In the majority of cases that we have examined, the CAN-
NaI-HOAc protocol has proven to be much more selective
than the N-iodosuccinimide (NIS)-HOAc procedure sum-
marized in Figure 1. Thus, for example, while the iodo-
acetoxylation of 1 using NIS and HOAc provides 2 with
maximum selectivity of 75:25, use of the CAN-NaI-HOAc
protocol provides 2 with 92:8 selectivity. In other compara-
tive cases, 4 gave a 91:9 mixture of 5 and the â-gluco isomer
using the CAN-NaI-HOAc method, while with NIS and
HOAc the selectivity was 88:12 (61% yield). Similarly, 8
provided an 80:20 mixture (75%) of 7 and its â-gluco
diastereomer using NIS and HOAc, while the selectivity was
97:3 using the CAN-NaI-HOAc procedure. The one
exception is the iodoacetoxylation of 12, which with CAN-
NaI-HOAc provided a 78:22 mixture favoring 13, while
with NIS-HOAc at -78 °C a 90:10 mixture is obtained.2
However, it should be noted that the CAN-NaI-HOAc
reaction of 12 was performed in the presence of NaOAc in
order to suppress acid-catalyzed decomposition reactions of
this substrate. When this reaction was performed in the
absence of NaOAc, using the standard conditions employed
for all other substrates, 13 was obtained with 94:6 selectivity,
but in only 18% yield. The major product obtained under
these conditions was the 1,1′-disaccharide 16, resulting from
Ferrier elimination of the tertiary alcohol followed by acid-
catalyzed dimerization. The new CAN-NaI-HOAc protocol
also appears to be more selective than the recently introduced
iodoacetoxylation method involving diacetoxyiodine(I) an-
ions, based on the comparitive case provided by glycal 6
(the enantiomer of 6 provided a 73:27 mixture of ent-7 and
the gluco isomer using the diacetoxyiodine(I) anion proce-
dure).9
The mechanism of this new iodoacetoxylation process is
unclear at present. It is conceivable that the reaction could
proceed by addition of an iodine atom (I•) to C(2) of the
glycal, by analogy to the azidonitration reaction.10 Carbon-
based radicals are also known to add to glycals at the C(2)
position, but radical addition trans to the C(3) substituent is
generally favored,7,8,11 unlike the iodoacetoxylation reactions
summarized here. 2-Iodo-1R-nitrates are intermediates in the
CAN-NaI reactions of glycals and are converted to the iodo
acetates in a substitution step after the iodonitration. The
reaction mixtures become colored during the course of the
Figure 2. Iodoacetoxylation of glycals using NaI, HOAc, and
ceric(IV) ammonium nitrate (CAN) in CH3CN.
(7) Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1979, 57, 1244.
(8) Briner, K.; Vasella, A. HelV. Chim. Acta 1987, 70, 1341.
896
Org. Lett., Vol. 1, No. 6, 1999

experiments, indicating that some I2 is generated. However,
treatment of glycal 8 with I2 and HOAc in CH3CN led to
none of the desired glycosyl iodoacetate. In addition, complex
mixtures (containing none of 11) were obtained when 10
was treated with CAN, I2, and HOAc in CH3CN.12,13 Use of
CAN and I2 in alcohol solvent has been reported to be a
useful method for alkoxyiodination and iodonitration of
olefins.12,13 However, our results indicate that I2 is not an
intermediate in the CAN-NaI-HOAc iodoacetoxylation
procedure. One additional and relevant piece of information
is that complex product mixtures, again containing none of
the desired iodoacetate 11, were obtained in attempts to
perform the iodoacetoxylation of triacetyl-D-glucal (10) using
ceric(IV) sulfate in place of ceric(IV) ammonium nitrate. This
experiment indicates that the nitrate ligand on Ce(IV) plays
an important role in the reaction.
iodonium nitrate (INO3) could be an intermediate in the
CAN-NaI reaction.14,15 When cyclohexene was used as the
substrate, trans-1-iodo-2-nitratocyclohexane (17) was ob-
tained in 71% isolated yield (Figure 3). Products of alkene
Figure 3. Iodonitration of Cyclohexene using CAN-NaI-HOAc.
iodination were not obtained when ceric(IV) sulfate was used
in place of CAN in the cyclohexene experiment summarized
in Figure 3, once again pointing to the key role of the nitrate
ligands in these experiments.
This information prompts us to consider the possiblity that
In summary, we have demonstrated that the reactions of
glycals with NaI and ceric(IV)ammonium nitrate in the
presence of acetic acid consititutes an efficient, stereoselec-
tive method for synthesis of 2-deoxy-2-iodomannopyranosyl
acetates. In most cases the selectivity of this new method is
superior to that obtained by using NIS and HOAc or
diacetoxyiodine(I) anions.9 Applications of the glycosyl
iodoacetates in the synthesis of 2-deoxy-R-glycosides are
reported in the accompanying Letter.16
(9) Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998, 33.
Representative Experimental Procedure: To a stirred slurry of glycal 1
(0.985 g, 2.94 mmol), CAN (4.19 g, 7.64 mmol), and acetic acid (1.7 mL,
29.4 mmol) in 20 mL of acetonitrile at -25 °C was added NaI (0.573 g,
3.82 mmol) in 10 mL of acetonitrile over 45 min. The reaction mixture
was maintained at -25 °C for 2 h and then was allowed to warm to -5
°C. At the end of 3 h, the mixture was quenched by adding 0.1 M Na2S2O3
(until color disappeared) and saturated NaHCO3 (until solution was weakly
basic). The aqueous solution was extracted with EtOAc (3 × 100 mL), and
the organic extract was washed with brine, dried (anhydrous Na2SO4), and
concentrated under reduced pressure. The crude product was purified by
silica gel chromatography using 10% EtOAc in hexanes as the eluent to
obtain a white solid (1.17 g, 76%), consisting of iodoacetates 2 and 3 in a
92:8 ratio. The mixture was crystallized from diethyl ether to obtain a
mixture enriched in 2 (96:4). Further separation of the diastereomers was
effected by HPLC (41 mm column) with 7.5% EtOAc in hexanes as the
mobile phase.
Acknowledgment. We thank the NIH (GM 38907) for
support of this research.
Supporting Information Available: Tabulated spectro-
scopic data for iodo acetates 2, 5, 7, 9, and 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) For a brief discussion of possible mechanisms for the synthesis of
R-azido-â-nitratoalkanes from olefins, NaN3, and ceric(IV) ammonium
nitrate, see: Trahanovsky, W. S.; Robbins, M. D. J. Am. Chem. Soc. 1971,
93, 5256.
(11) Linker, T.; Sommermann, T.; Kahlenberg, F. J. Am. Chem. Soc.
1997, 119, 9377.
OL990815G
(12) Horiuchi, C. A.; Nishio, Y.; Gong, D.; Fujisaki, T.; Kiji, S. Chem.
Lett. 1991, 607.
(13) Horiuchi, C. A.; Ikeda, A.; Kanamori, M.; Hosokawa, H.; Sugiyama,
T.; Takahashi, T. T. J. Chem. Res., Synop. 1996, 60.
(14) Diner, U. E.; Lown, J. W. Chem. Commun. 1970, 333.
(15) Lown, J. W.; Joshua, A. V. Can. J. Chem. 1977, 55, 122.
(16) Roush, W. R.; Narayan, S. Org. Lett. 1999, 1, 899-902.
Org. Lett., Vol. 1, No. 6, 1999
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