Convenient synthesis of branched-chain glycosamines by radical addition of nitromethane to glycals

Article abstract of DOI:10.1021/ol703062s

(Chemical Equation Presented) Radical addition-reduction-acetylation is the simple three-step sequence for the synthesis of branched-chain glycosamines 3 from glycals 1 and nitromethane (2). The intermediary formed 2-C-nitromethyl-pyranosides are valuable

Full text of DOI:10.1021/ol703062s

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1361-1364
Convenient Synthesis of Branched-Chain
Glycosamines by Radical Addition of
Nitromethane to Glycals
Elangovan Elamparuthi and Torsten Linker*
Department of Chemistry, UniVersity of Potsdam, Karl-Liebknecht-Strasse 24-25,
D-14476 Potsdam, Germany
linker@chem.uni-potsdam.de
Received January 4, 2008
ABSTRACT
Radical addition−reduction−acetylation is the simple three-step sequence for the synthesis of branched-chain glycosamines 3 from glycals 1
and nitromethane (2). The intermediary formed 2-C-nitromethyl-pyranosides are valuable precursors for the synthesis of C-2 branched
disaccharides.
Glycosamines represent important biomolecules, which have
been discussed as potential drugs for the treatment of
arthritis.1 In the N-acetylated or -sulfated form they are
constituents of the naturally occurring polysaccharides chitin2
and heparin.3 More recently, glycosamine analogs have been
investigated as promising candidates for enzyme inhibition.4
Attractive structures are C-2 branched glycosamines 1, which
have been incorporated into unnatural sialic acids.5
cosamines 1 from 2-uloses require many steps.5,7 The best
approach until now is Chmielewski’s [2 + 2] cycloaddition
to glycals, which affords the D-gluco and D-galacto config-
ured products in moderate yields.8
Herein we describe a convenient and general two-step
entry into branched-chain glycosamines 1 by radical addition
of nitromethane (2) to glycals 3 and subsequent reduction.
The new method is applicable to hexoses, pentoses, and di-
saccharides, and provides 2-deoxy-2-C-nitromethyl-pyrano-
sides 4 as intermediates, which allow access to further
functionalized carbohydrate 2-C-analogs.
Cerium(IV) ammonium nitrate (CAN) is a versatile one-
electron oxidant for radical generation with manifold uses
However, very few synthetic procedures for preparing such
analogs 1 exist in the literature. The epoxide opening of 2,3-
anhydropyranosides by nitrile containing reagents and sub-
sequent reduction is not always applicable for their con-
struction, due to the formation of the wrong regioisomer.6
In contrast, the selective syntheses of C-2 branched gly-
(3) (a) Heparin and Related Polysaccharides; Lane, D. A., Bjo¨rk, I.,
Lindahl, U., Eds.; Springer: Berlin, 1992. (b) Chemistry and Biology of
Heparin and Heparan Sulfate; Garg, H. G., Linhardt, R. J., Hales, C. A.,
Eds.; Elsevier: New York, 2005.
(4) (a) Islam, T.; Linhardt, R. J. Carbohydrate-Based Drug DiscoVery;
Wiley-VCH: Weinheim, 2003, 407. (b) Lazarevic, D.; Thiem, J. Carbohydr.
Res. 2006, 341, 569. (c) Chen, H.-M.; Withers, S. G. Carbohydr. Res. 2007,
342, 2212.
(5) Koppert, K.; Brossmer, R. Tetrahedron Lett. 1992, 33, 8031.
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658. (b) Hall, R. H.; Bischofberger, K.; Brink, A. J.; de Villiers, O. G.;
Jordaan, A. J. Chem. Soc., Perkin I 1979, 781.
(7) (a) Sarda, P.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1992, 229,
161. (b) Kazmir, S. N.; Ahmed, Z.; Malik, A.; Afza, N.; Voelter, W. Z.
Naturforsch. B 1994, 50, 294.
(1) (a) Clouatre, D. Glucosamine Sulfate and Chondroitin Sulfate;
Keats: Lincolnwood, IL, 1999. (b) Elkins, R. Glucosamine/Chondroitin;
Woodland Publishing: Orem, UT, 2003. (c) Theodosakis, J.; Adderly, B.;
Buff, S. The Arthritis Cure; St. Martin’s Press: New York, 2004.
(2) (a) Roberts, G. A. F. Chitin Chemistry; The Macmillan Press Ltd.:
London, 1992. (b) Brine, C. J.; Sandford, P. A.; Zikakis, J. P. AdVances in
Chitin and Chitosan; Elsevier: London, 1992. (c) Uragami, T.; Kurita K.;
Fukamizo, T. Chitin and Chitosan; Kodansha Scientific Ltd.: Tokyo, 2001.
(8) (a) Mostowicz, D.; Belzecki, C.; Chmielewski, M. J. Carbohydr.
Chem. 1988, 7, 805. (b) Mostowicz, D.; Zegrocka, O.; Chmielewski, M.
Carbohydr. Res. 1991, 212, 283.
10.1021/ol703062s CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/11/2008

in organic synthesis that were summarized in a recent
review.9 We developed the first C-C bond formation with
this reagent in carbohydrate chemistry, with a special
emphasis on the addition of malonates to glycals.10 More
recently, we became interested in the reaction of other CH
acidic substrates11 and the transformation of the addition
products.12 However, two adjacent acceptor groups were
essential in the precursors, for the radical generation with
CAN under mild conditions.
Table 1. Addition of Nitromethane (2) to Various Glycals
3a-g
The synthesis of the branched-chain glycosamines 1
required the addition of nitromethane (2), which reacts with
cerium(IV) ammonium nitrate (CAN) much slower than
dimethyl malonate or other nitroalkanes.9,13 Furthermore,
applications of nitroalkyl radicals in carbohydrate chemistry
were hitherto unknown. Therefore, we first optimized the
conditions for the reaction of nitromethane (2) with the gluco
configured glycals 3a and 3b (Table 1, entries 1-6). No
conversion of tri-O-acetyl-D-glucal (3a) was observed with
the conventional CAN protocol (method A), even with 10
equiv of the CH acidic precursor (entry 1).
In contrast, tri-O-benzyl-D-glucal (3b) afforded decom-
position products under such conditions (entry 4), due to
undesired deprotections and Ferrier rearrangements.14 There-
fore, we added sodium hydrogen carbonate to the reaction
mixture (method B), which was advantageous for the addition
of malonates,12 but no conversion was observed (entries 2
and 5). Thus, stronger bases for the deprotonation of nitro-
methane (2) were required, since the corresponding nitronate
anion is oxidized by cerium(IV) ammonium nitrate (CAN)
much faster.13 Best conditions were found with 10 equiv of
nitromethane (2), 2 equiv of KOH, and 4 equiv of CAN
(method C). Although tri-O-acetyl-D-glucal (3a) underwent
deprotection, the benzylated glucal 3b reacted smoothly at
0 °C. Finally, the 2-deoxy-2-C-nitromethyl-pyranosides 4b
were isolated in 71% yield in analytically pure form (entry
6, Supporting Information). The diastereoselectivity of the
addition of nitromethane was clearly in favor of the equatorial
attack (gluco/manno 5:1), but somewhat lower than the
corresponding reaction of malonates (gluco/manno 6:1).12
This result can be rationalized by the sterically less demand-
ing nitroalkyl in comparison to malonyl radicals.
The successful method C was applied to other benzyl
glycals 3c-g, which are easily available on a large scale.15
Thus, tri-O-benzyl-D-galactal (3c) afforded the 2-deoxy-2-
C-nitromethyl-pyranosides 4c in similar yields and stereo-
(9) Recent review: Nair, V.; Deepthi, A. Chem. ReV. 2007, 107,
1862.
(10) (a) Linker, T.; Hartmann, K.; Sommermann, T.; Scheutzow, D.;
Ruckdeschel, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1730-1732. (b)
Linker, T.; Sommermann, T.; Kahlenberg, F. J. Am. Chem. Soc. 1997, 119,
9377-9384. (c) Gyo´llai, V.; Schanzenbach, D.; Somsa´k, L.; Linker, T.
Chem. Commun. 2002, 1294-1295. (d) Linker, T. J. Organomet. Chem.
2002, 661, 159-167.
(11) (a) Sommermann, T.; Kim, B. K.; Peters, K.; Peters, E.-M.; Linker,
T. Chem. Commun. 2004, 2624. (b) Kim, B. G.; Schilde, U.; Linker, T.
Synthesis 2005, 1507.
(12) (a) Yin, J.; Spindler, J.; Linker, T. Chem. Commun. 2007, 2712.
(b) Yin, J.; Sommermann, T.; Linker, T. Chem.-Eur. J. 2007, 13,
10152.
(13) Arai, N.; Narasaka, K. Chem. Lett. 1995, 987. (b) Arai, N.; Narasaka,
K. Bull. Chem. Soc. Jpn. 1997, 70, 2525.
a Method A: 4 equiv CAN. Method B: 4 equiv CAN, 4 equiv NaHCO3.
Method C: 2 equiv KOH, then 4 equiv CAN, MeOH, 0 °C. b Yields of
isolated products after column chromatography.
selectivities (Table 1, entry 7). The products 4b, 4f, and 4g
were obtained in almost identical diastereomeric ratios
(entries 6, 10, and 11), since the unsaturated rings have
always the gluco configuration. In contrast, for the arabino
isomer 3e the 2-deoxy-2-C-nitromethyl-pyranoside arabino-
4e was the main product (entry 9), due to the pseudoaxial
O-benzyl group in the 3-position. This anti attack of the
(14) Ferrier, R. J.; Prasad, N. J. Chem. Soc. C 1969, 581.
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Org. Lett., Vol. 10, No. 7, 2008

radicals to functional groups in the 3-position is in accord-
ance with our previous studies with dimethyl malonate.10,12
The methyl glycosides are formed by CAN oxidation of the
adduct radicals 5 to cations 6 and trapping with the solvent,
exhibiting excellent 1,2 trans selectivity, which can be
explained by a neighboring effect of the adjacent nitro group
(Scheme 1).
Scheme 2. Reductions of the Nitromethane Addition Products
4b-g to the Branched-Chain Glycosamines 7 and 1
Scheme 1. Mechanism for the Formation of the Methyl
Glycosides 4 via Radicals 5 and Cations 6
Pentoses 3d and 3e gave lower yields (entries 8 and 9),
due to the formation of oxidative side-products. However,
the desired xylo (4d) and arabino (4e) isomers were isolated
in analytically pure form by column chromatography. Finally,
disaccharides 3f and 3g reacted smoothly with nitromethane
(2) to afford the 2-deoxy-2-C-nitromethyl-pyranosides 4f and
4g in good yields (Table 1, entries 10 and 11).
In summary, we could apply CH acidic radical precursors
with only one acceptor group in carbohydrate chemistry for
the first time. Since benzyl glycals 3b-g can be easily
synthesized on a large scale and nitromethane is a very
inexpensive reagent, the one-step procedure offers an easy
access to 2-C-nitromethyl substituted hexoses, pentoses and
disaccharides in moderate to good yields. The regioselectivity
is excellent for all additions, due to the electrophilic character
of the nitroalkyl radicals and good to high stereoselectivities
were observed. The experimental procedure is very conve-
nient, since the excess of the radical precursor can be easily
removed by distillation and all products were isolated in
analytically pure form by column chromatography (Support-
ing Information). Finally, the nitro group allows various
further transformations and the 2-deoxy-2-C-nitromethyl-
pyranosides 4 may serve as precursors for the synthesis of
C-disaccharides.16
nitro group and cleaved the benzyl protecting groups in the
same step, and the C-2 branched glycosamines 1 were
isolated in good yields in analytically pure form (Scheme 2,
Supporting Information).
In conclusion, we have developed a rapid two-step entry
into branched-chain glycosamines from glycals. For the first
time, nitromethane was applied in transition-metal-mediated
radical reactions in carbohydrate chemistry; these afforded
2-deoxy-2-C-nitromethyl-pyranosides in moderate to good
yields with high stereoselectivities. The method is applicable
to hexoses, pentoses, and disaccharides, and the addition
products are valuable precursors for the synthesis of C-2
branched disaccharides. Reduction of the nitro group was
accomplished by two different methods that allowed the
direct synthesis of protected or unprotected branched-chain
glycosamines. Future work will focus on various further
transformations of the nitro group, like Henry reactions,
To gain access to the required C-2 branched-chain gly-
cosamines 1, the nitro group had to be reduced and various
methods for this transformation have been described in
literature.17 First we selected the reaction with lithium
aluminum hydride (method D), which after acetylation
afforded the protected amides 7 in good yields (Scheme 2).
In contrast, catalytic hydrogenation (method E) reduced the
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Kobertz, W. R.; Bertozzi, C. R.; Bednarski, M. D. J. Org. Chem. 1996,
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Recent Review: Yuan, X.; Linhardt, R. J. Curr. Top. Med. Chem. 2005, 5,
1393.
(17) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. LiAlH4: Reddy, B. G.; Vankar, Y. D. Angew. Chem.,
Int. Ed. 2005, 44, 2001. Catalytic hydrogenation: von Roedern, E.; Kessler,
H. Angew. Chem., Int. Ed. Engl. 1994, 33, 687.
Org. Lett., Vol. 10, No. 7, 2008
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which should provide access to a variety of C-2 branched
saccharides.
Supporting Information Available: Experimental pro-
cedures and full characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was generously supported
by the Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (Li 556/7-3).
OL703062S
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Org. Lett., Vol. 10, No. 7, 2008