JIC Granada

1
A Novel Transformation of Nitro Sugars into
Seven Membered Azasugars Amalia M. Estéveza,
Antonio Gil-Fortesb, Gemma Gearya, Raquel G.
Soengasb, Juan C. Estéveza, and Ramón J.
Estéveza, a Departamento de Química Orgánica
and Centro Singular de Investigación en Química
Biolóxica e Materiais Moleculares, Universidade
de Santiago, 15782 Santiago de Compostela, SPAIN.
b Universidade do Minho, Departamento de Química,
Campus de Gualtar, 4710-057, Braga, PORTUGAL. c
Departamento de Química Fundamental, Universidade
de A Coruña, A Coruña, SPAIN. Tel. [phone]
100 ext. 14242, Fax [phone], e-mail
ramon.estevez_at_usc.es
1. INTRODUCTION Glycosidase inhibitors have been
extensively investigated over the last two
decades due to their potential as therapeutic
agents.1 These compounds are involved in several
important biological processes such as digestion,
biosynthesis of glycoproteins and catabolism of
glycocon-jugates, and some examples have already
been tested or approved for use in the treatment
of various diseases such as Gauchers disease,
diabetes, cancer, and viral infections, including
AIDS.2 Tri and tetrahydroxylated azepanes 1a and
1b were prepared by Paulsen and Todt in 1967 and
they have been extensively studied since then.3
Some of these derivatives are glycosidase or
protease inhibitors while others exhibited
anticancer activity. In 2004 Sinay
et al. reported the preparation and biological
evaluation of a number of 1,6-dideoxy-1,6-iminohep
titols 2, a novel family of polyhydroxylated
azepanes that are higher homologues of
deoxynojirimycin.4 Some of these derivatives show
potent and specific glycosidase inhibition. On
the other hand, due to the unusual spatial
distribution of the hydroxyl groups, these
azepanes not only display a different inhibition
profile compared to the previously reported
polyhydroxylated azepanes but they are also more
prone to form hydrogen bonds with nitrogenated
bases, thus improving their ability to bind to
the minor groove of DNA.5 More recently we
started a program aimed at the preparation of
branched 1,6-dideoxy-1,6-iminoheptitols 3, in
order to test their activity against a range of
glycosidases and to determine whether the
introduction of a branch can alter the
biologically activitity.6 Bleriot et al.
reported recently the preparation and biological
evaluations of the novel seven-membered azasugars
4, 5 and 6, which were assayed with a range of
glycosidases. Surprisingly, carboxylic acid
derivative 6 was found to be a selective and very
potent bovine kidney L-fucosidase inhibitor,
being the most potent polyhydroxyazepane-based
inhibitor reported so far. 7
2. OBJECTIVES As a continuation of our work on
new synthetic applications of nitro sugars and on
new synthetic approaches to branched
iminosugars,8 herein we describe a novel strategy
for the enantiospecific synthesis of the known
azepanes 4, 5 and 6, and the novel azepane 7.
3. CHEMICAL SYNTHESIS The synthesis of azepane 6
starts with an stereocontrolled addition of a
carboxyl synthetic equivalent to the sugar
nitroolefin 8. Thus, an anti Felkin-Ahn
favoured Michael addition of the lithium salt of
1,3-dithiacyclohexane to this nitroolefin
resulted in the formation of a 103.3 epimeric
mixture 9a9b, from which the major isomer was
isolated by column chromatography. After, the
1,3-dithiacyclohexyl of 9a was converted intro
the carbomethoxy substituent of 11 and finally a
reaction sequence including a reductive amination
provided the novel azepane 7. A similar protocol
using the lithium salt of tris(phenylthio)metane
as the carboxyl synthetic equivalent, provided as
with a 101.2 epimeric mixture 10a10b, where the
major component was now the Felkin-Ahn adduct
10a. Procceding as for 9a, compound 10a was
converted into the know azepane 6.
As compounds 6 and 7 are synthetic precursos of
4 and 5, respectively, this synthetic approach
can formaly be considered as a synthesis of
thesetwo later azepanes. Biological evaluation
of compound 7 is now in progress.

• ACKNOWLEDGEMENTS.
• We thank the Spanish Ministry of Science and
  Innovation and the Xunta de Galicia for financial
  support, and the former for a grant to Amalia
  Estévez. A. Gil Fortes also thanks to FCT for
  financial support and to Professor Ramon J.
  Estévez for receiving him in his laboratory
  during a sabatic leave.
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