Efficient synthesis of triazoles from D-arabinose and L-fucose

Article abstract of DOI:10.1016/S0040-4039(00)01356-3

The efficient synthesis of sugar-derived triazoles via a one-pot substitution-cyclization-oxidation procedure is presented. Starting from D-arabinose and L-fucose, triazole structures as potential enzyme inhibitors were obtained in six to eight steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01356-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7805–7808
Efficient synthesis of triazoles from
-fucose
D-arabinose and
L
Timo Flessner and Chi-Huey Wong*
Department of Chemistry, The Scripps Research Institute and the Skaggs Institute for Chemical Biology,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 26 June 2000; revised 3 August 2000; accepted 7 August 2000
Abstract
The efficient synthesis of sugar-derived triazoles via a one-pot substitution–cyclization–oxidation
procedure is presented. Starting from -arabinose and -fucose, triazole structures as potential enzyme
D
L
inhibitors were obtained in six to eight steps. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: carbohydrates; iminosugars; triazoles.
Various iminosugars have been shown to be very potent inhibitors of glycosidases1 and
glycosyltransferases.2 Due to their ability to resemble the transition states3 of the sugars involved
in these processes, a variety of monocyclic4 and bicyclic5 iminosugars have been synthesized or
isolated from natural sources over the years.
We have been involved in the synthesis of numerous compounds designed to inhibit glycosyl
transfer enzymes, especially a-fucosidase and the family of fucosyltransferases.5a Herein, we
would like to report a short and efficient synthesis of novel bicyclic triazoles starting from
naturally occurring carbohydrates. The main structural features of triazoles include: an sp2-
configured anomeric carbon, the presence of lone-pair donating nitrogens, and flattened
conformation of the six-membered ring, that might closely resemble the proposed transition
state conformation of the natural substrates in the enzyme catalyzed reaction. Even though
triazoles have been shown to be generally poor inhibitors of numerous b-glycosidases, possibly
due to a lack of a lone-pair donating heteroatom next to the anomeric center in the triazole
system,6 we considered them as useful targets for synthesis and as interesting structures for
evaluation as enzyme inhibitors.
Starting from
D
-arabinose 1 and -fucose 2 the sugars were transformed into their tri-O-2,3,4-
L
benzyl-derivatives 3 and 4 by known procedures (Scheme 1).7,8 The a,b-unsaturated esters 5 and
* Corresponding author. Fax: +858-784-2409; e-mail: wong@scripps.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01356-3

7806
6 were formed in high yields from 3 and 4 as a 2:1 mixture of trans:cis isomers after
Horner–Wittig–Emmons reaction.9 Subsequently, 5 and 6 were converted to the tosylate 7 and
the mesylate 8, respectively.
Scheme 1. Reagent and conditions: (a) methyl-(triphenylphosphoranylidene)-acetate, toluene, 80°C, 16 h, 94%; (b)
methyl-(triphenylphosphoranylidene)-acetate, toluene, 80°C, 16 h, 81%; (c) TsCl, DMAP, pyridine, 40°C, 24 h, 89%;
(d) MsCl, DMAP, pyridine, rt, 24 h, 91%
Even though the formation of triazolines by intramolecular addition to a,b-unsaturated esters
has been studied,10 lengthy routes accompanied the introduction of the azido group. In hopes to
introduce the azide and directly convert this intermediate to the triazoline in a one-pot
procedure, by first displacement with azide and then subsequent cyclization with the unsaturated
ester, both the tosylate 7 and the mesylate 8 were treated with sodium azide followed by
1,8-diazabicyclo-[5.4.1]-undec-7-ene (DBU)11 in DMF (Scheme 2).12 Surprisingly, triazoles 11
and 12 were obtained in 30% overall yield.13 It is likely that the triazoline intermediates 9 and
10 in this three-step–one-pot reaction were easily aromatized by air oxidation.
Scheme 2. (a) i: NaN3, DMF, 80°C, 1 h, ii: DBU, 80°C, 1 h, 30%; (b) i: NaN3, DMF, 80°C, 1 h, ii: DBU, 80°C,
1 h, 30%
In order to investigate the one-pot cyclization sequence of an azide with an unsaturated
aldehyde, tosylate 7 was converted to the allylic alcohol 13 in two steps (Scheme 3). The allylic
alcohol 13 was then oxidized with tetrapropylammonium perruthenate (TPAP)14 to give the
aldehyde intermediate 14 which was transformed to triazole 15 after further oxidation with
TPAP with NMO (1.5 equiv.) as co-oxidant.

7807
Scheme 3. (a) 1 M DIBAL in THF, toluene, 0°C, 35 min, 85%; (b) NaN3, DMF, 70°C, 73% (+11% of starting
material); (c) TPAP, NMO, molecular sieves, CH2Cl2, rt, 5 h, 26%
The triazoles were deprotected to give the corresponding compounds 16 and 17; reduction of
the methyl ester, followed by deprotection gave the corresponding compound 18 (Scheme 4).15
Future plans include the use of these triazoles as building blocks for the development of enzyme
inhibitors and further development of the three-step process described herein.
Scheme 4. (a) Pd/C, H2, MeOH/AcOH 1/1, rt, 48 h, 95%; (b) Pd/C, H2, MeOH/AcOH 1/1, rt, 40 h, 77%; (c) LiAlH4,
THF, 0°C, 10 min, 88%; (d) Pd/C, H2, MeOH/AcOH 1/1, rt, 48 h, 95%
Acknowledgements
This research was supported by the NIH (GM44154). T.F. thanks Deutsche Forschungsge-
meinschaft for a fellowship.
References
1. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH: Weinheim, 1999.
2. (a) Hayashi, T.; Murray, B.; Wang, R.; Wong, C.-H. Bioorg. Med. Chem. 1997, 5, 497. (b) Murray, B. W.;
Wittmann, V.; Burkart, M. D.; Hung, S.-C.; Wong, C.-H. Biochemistry 1997, 36, 823.
3. (a) Withers, S. G.; Street, I. P. J. Am. Chem. Soc. 1988, 110, 8551. (b) Sinnott, M. L.; Chem. Rev. 1990, 90, 1171.
(c) Kirby, A. J. Nature 1996, 3, 107. (d) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750.
4. (a) Wischnat, R.; Martin, R.; Takayama, S.; Wong, C.-H. Bioorg. Med. Chem. Lett. 1998, 8, 3353. (b)
Takebayashi, M.; Hiranuma, S.; Kanie, Y.; Kajimoto, T.; Kanie, O. J. Org. Chem. 1999, 64, 5280.
5. (a) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046. (b) Elbein, A. D.; Molyneux, R.
J. In Comprehensive Natural Products Chemistry; Barton, D.; Nakanishi, K.; Meth-Cohn, O., Eds.; Pergamon
(Elsevier): Oxford, 1999; Vol. 3.
6. Heightman, T. D.; Locatelli, M.; Vasella, A. Helv. Chim. Acta 1996, 79, 2190.
7. (a) Tejima, S.; Fletcher, Jr., H. G. J. Am. Chem. Soc. 1963, 2999. (b) Hudson, C. S. J. Am. Chem. Soc. 1925, 265.
8. (a) Dejter-Juszynski, M.; Flowers, H. M. Carbohydr. Res. 1971, 18, 219. (b) Zehavi, U.; Sharon, N. J. Org. Chem.
1972, 2141.
9. (a) Scho¨nenberger, B.; Summermatter, W.; Ganter, C. Helv. Chim. Acta 1982, 65, 2333. (b) Oka, T.; Fujiwara,
K.; Murai, A. Tetrahedron 1998, 54, 21.

7808
10. Kru¨lle, T. K.; de la Fuente, C.; Pickering, L.; Aplin, R. T.; Tsitsanou, K. E.; Zographos, S. E.; Oikonomakos,
N. G.; Nash, R. J.; Griffiths, R. C.; Fleet, G. W. J. Tetrahedron: Asymmetry 1997, 22, 3807.
11. DBU was added to the reaction mixture in order to avoid side products resulting from Michael-type reaction of
azide to the unsaturated ester.
12. Standard procedure for the formation of triazoles from tosylate 7 (same procedure starting from mesylate 8): 850
mg (1.348 mmol) of the tosylate 7 and 350 mg (5.390 mmol) of sodium azide were stirred in 8 ml of DMF at 80°C
for 45 min. 405 ml (2.696 mmol) of DBU were added at room temperature. After 30 min at 80°C the reaction
mixture was poured into a 1/1 mixture of H2O/Et2O, extracted with Et2O, washed with H2O and brine, and dried
over Na2SO4. Purification via column chromatography (EtOAc/hexanes 1/4) yielded 202 mg (30%) of the triazole
11.
13. The comparable stepwise cyclization–oxidation sequence starting from an appropriate azide-containing alkene
gives a yield of 45% over two steps (Ref. 10).
14. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
1
15. Selected analytical data for the deprotected triazoles 16, 17, and 18. 16: H NMR (500 MHz, CD3OD): l=3.89
(s, 3 H), 4.04 (dd, J=4.4, 1.8 Hz, 1 H), 4.23 (dd, J=12.9, 8.5 Hz, 1 H), 4.41 (ddd, J=8.5, 5.5, 1.8 Hz, 1 H), 4.58
(dd, J=12.9, 5.5 Hz, 1 H), 5.09 (d, J=4.4 Hz, 1 H); HRMS: MH+ calcd for M=C8H11N3O5 230.0771, found
1
230.0777. 17: H NMR (600 MHz, CD3OD): l=1.71 (d, J=6.5 Hz, 3 H), 3.84 (s, 3 H), 3.95 (dd, J=8.8, 2.2 Hz,
1 H), 4.00 (dd. J=4.0, 2.2 Hz, 1 H), 4.32 (dq, J=8.3, 6.6 Hz, 1 H), 5.06 (d, J=4.0 Hz, 1 H); 13C NMR (150
MHz, CD3OD): l=17.37, 52.53, 56.81, 64.39, 71.41, 72.50, 137.70, 139.92, 162.71; HRMS: MH+ calcd for
1
M=C9H13N3O5 244.0928, found 244.0933. 18: H NMR (500 MHz, D2O): l=4.12 (m, 1 H), 4.53 (m, 1 H), 4.57
(m, 1 H), 4.64 (m, 1 H), 4.80 (m, 1 H), 4.82 (m, 1 H), 5.06 (d, J=7.4 Hz, 1 H); 13C NMR (125 MHz,
CD3OD/D2O): l=50.66, 55.90, 65.48, 67.60, 74.02, 134.47, 145.88.
.
.