Synthesis of tetrazole-fused glycosides by a tandem fragmentation- cyclization reaction

Article abstract of DOI:10.1021/ol3013638

The fragmentation of anomeric alkoxyl radicals (ARF) and the subsequent intramolecular cyclization promoted by hypervalent iodine reagents provide an excellent method for the synthesis of tetrazolo-sugars. This new reaction offers additional advantages for the synthesis of these compounds, including the ready availability of the starting materials, experimental simplicity, mild conditions, and good yields.

Full text of DOI:10.1021/ol3013638

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3388–3391
Synthesis of Tetrazole-Fused Glycosides
by a Tandem FragmentationꢀCyclization
Reaction
ꢀ
ꢀ
Nieves R. Paz, Andres G. Santana, Cosme G. Francisco, Ernesto Suarez, and
ꢀ
Concepcion C. Gonzalez*
ꢀ
´
Instituto de Productos Naturales y Agrobiologıa del C.S.I.C., Avenida Astrofısico
Francisco Sanchez 3, 38206 La Laguna, Tenerife, Spain
´
ꢀ
ccgm@ipna.csic.es
Received May 17, 2012
ABSTRACT
The fragmentation of anomeric alkoxyl radicals (ARF) and the subsequent intramolecular cyclization promoted by hypervalent iodine reagents
provide an excellent method for the synthesis of tetrazolo-sugars. This new reaction offers additional advantages for the synthesis of these
compounds, including the ready availability of the starting materials, experimental simplicity, mild conditions, and good yields.
The numerous therapeutic applications of iminosugars
have helped maintain synthetic interest in this type of
substrates at its highest level. This has led to a continuous
search for new and more efficient approaches for accessing
new structures and original synthetic methodologies.1
However, the synthesis of hybrid structures, which are
both carbohydrates and aromatic heterocycles (Figure 1),
has been comparatively less studied as a source of potential
glycosidase inhibitors.2
(1) (a) Iminosugars: From Synthesis to Therapeutic Applications;
Compain, P., Martin, O. R., Eds.; Wiley: Chichester, 2007. (b) Iminosugars
as Glycosidase Inhibitors: Nojirimycin and Beyond; St€utz, A. E., Ed.;
Wiley-VCH: Weinheim, 1999. (c) Stocker, B. L.; Dangerfield, E. M.;
Win-Mason, A. L.; Haslett, G. W.; Timmer, M. S. M. Eur. J. Org. Chem.
2010, 1615–1637.
(2) (a) Zhong, M.; Meng, X.-B.; Li, Z.-J. Carbohydr. Res. 2010, 345,
1099–1106. (b) Worch, M.; Wittmann, V. Carbohydr. Res. 2008, 343,
2118–2129. (c) Anegundi, R. I.; Puranik, V. G.; Hotha, S. Org. Biomol.
Chem. 2008, 6, 779–786. (d) Couri, M. R.; Luduvico, I.; Santos, L.;
Alves, R.; Prado, M. A.; Gil, R. F. Carbohydr. Res. 2007, 342, 1096–
1100. (e) Li, J.; Zheng, M.; Zhu, W.; Li, T.; Zuo, J.-P.; Liu, H.; Jiang, H.
Bioorg. Med. Chem. Lett. 2006, 16, 5009–5013. (f) Koumbis, A. E.;
Gallos, J. K. Curr. Org. Chem. 2003, 7, 771–797. (h) Popsavin, M.;
Torovic, L.; Spaic, L.; Stankov, S.; Kapor, A.; Tomic, Z.; Popsavin, V.
Figure 1. Examples of bioactive compounds with hybrid struc-
tures: (a) Nucleoside mimic (ref 2h) ; (b) Zanamivir analog (ref 2e);
(c) Vasella’s tetrazolo-sugar (ref 5a, d); (d) Nagstatine (ref 3).
ꢀ
Tetrahedron 2002, 58, 569–580. (i) Esperon, M. F. M.; Fascio, M. L.;
D’Accorso, N. B. J. Heterocycl. Chem. 2002, 39, 221–224.
(3) Isolation of nagstatine: (a) Aoyama, T.; Naganawa, H.; Suda, H.;
Uotami, K.; Aoyagi, T.; Takeuchi, T. J. Antibiot. 1992, 45, 1404–1408.
Total synthesis: (b) Tatsuka, K.; Miura, S. Tetrahedron Lett. 1995, 36,
6721–6724. Analogue synthesis: (c) Gessier, F.; Tschamber, T.; Tarmus,
C.; Neuburger, M.; Huber, W.; Streith, J. Eur. J. Org. Chem. 2001, 4111–
4125. (d) Frankowski, A.; Deredas, D.; Streith, J.; Tschamber, T.
Tetrahedron 1998, 54, 9033–9042. (e) Tatsuka, K.; Miura, S.; Ohta, S.;
Gunji, H. Tetrahedron Lett. 1995, 36, 1085–1088. (f) Hua, D. H.; Zhang,
F.; Chen., J. J. Org. Chem. 1994, 59, 5084–5087.
Within this group, nagstatine,3 a polyhydroxylated tetra-
hydropyrimidine-imidazole (Figure 1d), is the only naturally
occurring product that contains an aromatic nitrogenated
heterocycle attached to the pseudoanomeric position of a
carbohydrate analog, and it shows strong inhibitory effects
against several hexosaminidases. From the study of different
r
10.1021/ol3013638
Published on Web 06/13/2012
2012 American Chemical Society

analogs and regioisomers of nagstatine, it was concluded
that the presence of an sp2ꢀhybridized nitrogen atom in the
anomeric position was necessary for inhibitory activity.4
Therefore, novel compounds similar to nagstatine were
designed, in which the imidazole ring was replaced by a
tetrazole ring,5 whose structure is similar, yet presents
enhanced metabolic stability. Tetrazoles can also be used
as precursors of other heterocycles and can be considered
as bioisosteres of carboxylic acids and cis-amide bonds.6
Previous approaches to these compounds by Vasella and
Fleet5 centered on the intramolecular [3 þ 2] dipolar
cycloaddition between an azide and a nitrile, as shown in
Figure 2a. Herein we present a new strategy for the synthesis
of tetrazole-fused glycosides where the key step is a tandem
fragmentationꢀcyclization process (Figure 2b).
research in recent years.7 The application of this protocol
allowed us to transform aldoses into ketoses and has been
very useful for the preparation of chiral synthons. This
methodology relies on the initial formation of an alkoxyl
anomeric radical (A) originated by the action of a hyper-
valent iodine reagent in the presence of iodine and
presumably proceeds through an alkyl hypoiodite inter-
mediate. Subsequently, the alkoxyl radical undergoes a
fragmentation of the C1ꢀC2 bond, giving rise to a C2
radical (B) that is afterward oxidized by an excess of
reagent to the oxycarbenium ion (C). Finally, intramolec-
ular nucleophilic cyclization affords the required sugar
derivatives (Scheme 1).
Scheme 1. Mechanism of the ARFꢀCyclization Reaction
Recently, we have been interested in applying this reac-
tion to synthesize new compounds that may behave as
glycosidase inhibitors.8 Taking these results as a starting
point, we decided to carry out the synthesis of tetrazolo-
sugars via tandem ARF and subsequent intramolecular
cyclization.
In Scheme 2, our retrosynthetic analysis of these tetra-
zolo-sugars is depicted. These would come from the corre-
sponding carbohydrates tethered with a 1H-tetrazol-5-yl
substituent, easily obtainable from a nitrile group. The
synthesis of nitrile derivatives from sugars is well
documented in the literature, as well as the cycloaddi-
tion reaction with different azides to generate tetrazole
rings.9
Figure 2. Synthesis of tetrazolo-sugars: comparison between
dipolar cycloaddition and ARF-cyclization.
The study of the fragmentation reaction of anomeric
alkoxyl radicals (ARF) has been one of our main topics of
(4) (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev.
2002, 102, 515–553. (b) See ref 1.
(5) (a) Heightman, T. D.; Ermert, P.; Klein, D.; Vasella, A. Helv.
Chim. Acta 1995, 78, 514–532. (b) Davis, B.; Brandstetter, T. W.; Smith,
C.; Hackett, L.; Winchester, B. G.; Fleet, G. W. J. Tetrahedron Lett.
1995, 36, 7507–7510. (c) Davis, B.; Brandstetter, T. W.; Smith, C.;
Hackett, L.; Winchester, B. G.; Fleet, G. W. J. Tetrahedron Lett. 1995,
36, 7511–7514. (d) Ermert, P.; Vasella, A. Helv. Chim. Acta 1991, 74,
2043–2053.
(6) Chen, F.; Qin, C.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2011,
50, 11487–11491.
(7) β-Fragmentation of alkoxyl radicals: (a) Francisco, C. G;
The novelty of this project would stem from its first use
of the β-fragmentation reaction to provide this type
of aromatic heterocycle for use as an internal nucleophile.
In addition, the cyclization products would present a
pseudoanomeric alcohol unlike other tetrazolo-sugars
ꢀ
ꢀ
Gonzalez, C. C.; Kennedy, A. R; Paz, N. R; Suarez, E. Chem.;Eur.
J. 2008, 14, 6907–6912. (b) Alonso-Cruz, C. R.; Kennedy, A. R.;
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guez, M. S.; Suarez, E. J. Org. Chem. 2008, 73, 4116–4122. (c)
Rodrı
Alonso-Cruz, C. R.; Kennedy, A. R.; Rodrı
Tetrahedron Lett. 2007, 48, 7207–7210. (d) Francisco, C. G.; Gonzalez,
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guez, M. S.; Suarez, E.
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C. C.; Kennedy, A. R.; Paz, N. R.; Suarez, E. Tetrahedron Lett. 2006, 47,
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(8) (a) Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Leon, E. I.;
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35–38. (e) Alonso-Cruz, C. R.; Leon, E. I.; Ortiz-Lopez, F. J.;
Riesco-Fagundo, C.; Suarez, E. J. Org. Chem. 2001, 66, 1861–1866. (b)
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guez, M. S.; Suarez, E. Tetrahedron Lett. 2005, 46, 5265–5268.
Rodrı
(f) Francisco, C. G.; Gonzalez, C. C.; Kennedy, A. R.; Paz, N. R.;
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Francisco, C. G.; Freire, R.; Gonzalez, C. C.; Suarez, E. Tetrahedron:
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Asymmetry 1997, 8, 1971–1974.
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Suarez, E. Tetrahedron: Asymmetry 2004, 15, 11–14. (g) Gonzalez, C. C.;
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Kennedy, A. R.; Leon, E. I.; Riesco-Fagundo, C.; Suarez, E. Chem.;
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(9) (a) Rama, V.; Kanagaraj, K.; Pitchumani, K. J. Org. Chem. 2011,
76, 9090–9095. (b) Gutmann, B.; Roduit, J.-P.; Roberge, D.; Kappe,
C. O. Angew. Chem., Int. Ed. 2010, 49, 7101–7105. (c) Das, B.; Reddy,
C. R; Kumar, D. N.; Krishnaiah, M.; Narender, R. Synlett 2010, 391–
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Eur. J. 2003, 9, 5800–5809. (h) Gonzalez, C. C.; Leon, E. I.; Riesco-
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Fagundo, C.; Suarez, E. Tetrahedron Lett. 2003, 44, 6347–6350. (i)
Francisco, C. G.; Martı
2099–2109. (j) de Armas, P.; Francisco, C. G.; Suarez, E. J. Am. Chem.
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394. (d) Hanessian, S.; Simard, D.; Deschenes-Simard, B.; Chenel, C.;
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Haak, E. Org. Lett. 2008, 10, 1381–1384. (e) Brase, E.; Gil, C.; Knepper,
Angew. Chem., Int. Ed. Engl. 1992, 31, 772–774. For a review, see:
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Suarez, E.; Rodrıguez, M. S. β-Fragmentation of Alkoxyl Radicals:
Synthetic Applications. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; WileyꢀVCH: Weinheim, 2001; Vol. 2, pp 440ꢀ454.
K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188–5240. (f)
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4139–4141.
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Table 1. Synthesis of the Intermediate Compounds
Scheme 2. Retrosynthetic Analysis
already published. From our experience, the tetrazole ring
meets the characteristics needed for the reaction to
proceed.
The syntheses of the different nitriles that were used in
this study were carried out by two different procedures.
Nitriles 1aꢀd were synthesized by the activation of the
corresponding alcohol, in the form of triflate, and its
substitution with KCN (Scheme 3, path a), while nitriles
1eꢀg were obtained by oxidation of the alcohol to the
corresponding aldehyde,10 oxime formation, and subse-
quent dehydration with MsCl (Scheme 3, path b).11 All
nitriles were obtained in very good yields.
Scheme 3. Synthesis of Nitriles 1aꢀg
In initial attempts to synthesize the tetrazole ring, NaN3
in DMF at 115 °C was used, providing the desired tetra-
zoles in very low yield. However, when TMSN3 and
catalytic dibutyltin oxide were used at 120 °C in a sealed
tube, compounds 2aꢀg were obtained in good to excellent
yields, as stated in Table 1. The deprotection of the
anomeric position wascarriedout either by hydrogenolysis
at 6 atm to remove the benzyl group (entries 1, 5, and 6) or
by reaction with CAN in aqueous acetonitrile (entries
2ꢀ4), providing the corresponding hemiacetals 3aꢀg in
good yields.
a TMSN3 (3 equiv), Bu2SnO (0.2 equiv), dry toluene (5 mL/mmol),
120 °C, 16 h. b H2 (6 atm), Pd(OH)2/C, EtOAc/HOAc or CAN (3 equiv),
MeCN/H2O (10 mL/mmol, 10:1), 0 °C, 2 h. c Isolated yield.
high polarity of the hemiacetals 3aꢀg. After trying various
solvents and conditions, we found that dry ethyl acetate
was the most suitable solvent for effecting this reaction.
Thus, compounds 3aꢀg were dissolved in dry ethyl
acetate and treated with iodosylbenzene and iodine at
reflux under the irradiation of two tungsten lamps. The
different tetrazolo-sugars thus obtained are summarized
in Table 2.
To perform the ARF reaction, we had to modify our
classical reaction conditions (PhIO, I2, DCM)8 due to the
(10) For the synthesis of compound 1e, the aldehyde was synthesized
from 4-methoxybenzyl 2,3-O-isoproplidene-R-D-mannofuranoside by
fragmentation of the diol with sodium periodate; for further details,
see Supporting Information.
(11) (a) Frederickson, M.; Grigg, R.; Redpath, J.; Thorthon-Pett,
M. Tetrahedron 1994, 50, 5495–5502. (b) Laroche, C.; Behr, J.-B.;
Szymoniak, J.; Bertus, P.; Plantier-Royon, R. Eur. J. Org. Chem.
2005, 5084–5088.
The reaction of the hemiacetal 3a afforded, under the
conditions described above, the corresponding tetra-
zole- derivative 4a in 70% yield as a white solid. The
change of ribose for lyxose (3b) produced no significant
change, and the product 4b was now obtained in 66%
yield.
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Org. Lett., Vol. 14, No. 13, 2012

derivatives 4c or 4d in satisfactory yield (entry 3). When 3e
was reacted the tricyclic pyrrolidine 4e was obtained in
56%yield. Itshouldbenotedthatthe fragmentationofthis
compound provided another minor product (5e, 9%) that
camefrom hydrolysis of the sensitive formategroupduring
the purification step.
Table 2. Synthesis of Tetrazolo-sugarsa
The ARF reaction of the models discussed so far has
led to the synthesis of several tetrazole-fused hetero-
cycles with ring sizes ranging from five- to seven-
membered, where all of them incorporated a dioxolane
moiety and their respective precursors were in furanose
form.
In the last two models, sugars in pyranose form were
used in order to check whether the size of the hemiacetal
ringaffectedthe reaction. Thefragmentation of compound
3f led to 4f in 68% yield, while the fragmentation of 3g
afforded two isomers in an equimolecular ratio. It is worth
mentioning that the products resulting from the photolysis
of 3gwere not stable under the purification conditions. For
that reason, the formate group was previously hydro-
lyzed, obtaining compounds 4g in 80% yield after
two steps. Unlike the precedent models, which con-
tained an isopropylidene group and yielded only a
single product, the fragmentation of 3g afforded two
epimers, as expected from the cyclization onto a planar
oxycarbenium ion.
In summary, the methodology described herein repre-
sents, to our knowledge, the only general method
presently available for the formation of tetrazolo-
sugars that are oxidized in the pseudoanomeric posi-
tion. The reaction takes place under mild conditions
and in good yields. It should be emphasized that the
efficiency of the reaction sequence, and the possibility
of using different monosaccharides as starting materials,
makes this approach suitable for structureꢀactivity
relationship studies, which will be reported in due
course.
Acknowledgment. This work was supported by the
Gobierno de Canarias (Research Program ProID20100088)
and the investigation program no. CTQ2007-67492/BQU of
ꢀ
the Ministerio de Educacion y Ciencia (Spain) cofinanced
with the Fondo Europeo de Desarrollo Regional (FEDER).
A.G.S. thanks the I3P-CSIC Program for a fellowship.
a Reaction conditions: All reactions were performed in dry EtOAc
(20 mL) under irradiation with two 80 W tungsten-filament lamps at
reflux temperature for 1 h containing PhIO (2.2 mmol) and I2 (1.2 mmol)
per mmol of substrate. b Isolated yield.
Supporting Information Available. Experimental pro-
1
cedure, characterization data, and H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In order to study the scope of the reaction, the fragmenta-
tion of 3c or 3d generated the corresponding tetrazole-azepane
The authors declare no competing financial interest.
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