Synthesis, Structure, and Biological Evaluation of Novel N-
and O-Linked Diinositols
Bernhard J. Paul, Jerremey Willis, Theodore A. Martinot, Ion Ghiviriga,
²
Khalil A. Abboud,
‡
and Tomas Hudlicky*
Contribution from the UniVersity of Florida, Department of Chemistry, PO Box 117200,
GainesVille, Florida 32611
Received April 15, 2002
Abstract: Several O-and N-linked inositols and/or aminoinositols have been prepared by iterative opening
of epoxides and aziridines derived from homochiral cyclohexadiene cis-diols. The three inositols and their
intermediate conduritols (conduramines) were tested against several glycosidases (R- and -glucosidase,
R- and -galactosidase, R- and -mannosidase) in an assay that measured the rate of hydrolysis of
p-nitrophenolglycosides rather than the concentration of p-nitrophenolate. Somewhat surprisingly, the best
inhibition was seen against -galactosidase with several of the compounds. The inositols linked through
oxygen or nitrogen were subjected to calcium binding studies performed in NMR experiments. Detailed
analysis of the title compounds by NMR spectroscopy has been performed, and full assignments were
made. One of the attendant benefits of the preparation of these compounds has been expressed in the
design and synthesis of new salen catalysts whose effectiveness has been compared with Jacobsen’s
catalyst in the epoxidation of styrene.
Introduction
Investigations of the biological function of sugars have
witnessed enormous progress over the last several years, and
cellular processes such as recognition events are now more
understood, allowing for the development of carbohydrate-based
drugs.
1
Unnatural derivatives of carbohydrates have been at the
forefront of bioorganic chemistry research primarily because
of their ability to mimic the structure of monosaccharides and
hence serve as inhibitors of glycosidases. Since these enzymes
are involved in a variety of different biological processes, such
research naturally leads to potential applications in the treatment
of diabetes,
2
viral infections,
3
and cancer.
3
Recent literature presents many examples of simple carbo-
hydrates in which the oxygen has been replaced with carbon
(pseudosugars),
4
nitrogen (iminosugars),
5,6
sulfur,
7
and other
atoms or groups.
8
Along with polyhydroxylated alkaloids,
9
most
such derivatives show modest to excellent inhibition of the
common glycosidases that would be involved in the initial steps
of cell penetration by the viral material. Similarly, disaccharides
and even oligosaccharides have been modified
10
and studied
further for their role in the inhibition of glycosidases.
Several years ago we disclosed the preparation of a series of
simple oligomers containing the configuration of L-chiro-inositol
as shown by the general structure 1, Figure 1.
11
The initial reason
for investigating such compounds was based on the assumption
that O-linked oligomers of this type may play a role in insulin
mediation
12
and at the same time not be sensitive to the gastric
environment, thus being potential candidates for orally admin-
istered medicines.
A number of oligomers have been prepared,
13
and some of
these compounds proved to have interesting metal chelating
properties
14
and displayed tertiary structures in solid state. In
an effort to investigate compounds that would mimic the
* Address correspondence to this author. E-mail: hudlicky@chem.ufl.edu.
²
To whom correspondence regarding NMR spectroscopy should be
addressed.
‡
To whom correspondence regarding X-ray crystallography should be
addressed.
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Angew. Chem., Int. Ed. 1999, 38, 2300-2324. (d) Alper, J. Science 2001,
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Desjardins, M.; Lallemand, M.-C.; Hudlicky, T.; Abboud, K. A. Synlett
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Published on Web 08/10/2002
10416 9 J. AM. CHEM. SOC. 2002, 124, 10416-10426 10.1021/ja0205378 CCC: $22.00 © 2002 American Chemical Society