Convenient divergent synthesis of a library of trehalosamine analogues

Article abstract of DOI:10.1021/ol026095m

(matrix presented) A library of seven trehalosamine analogues with various natural and non-natural binding motifs was synthesized through an expedient divergent synthetic approach. The final products were prepared in sufficient quantities and purities for

Full text of DOI:10.1021/ol026095m

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2245-2248
Convenient Divergent Synthesis of a
Library of Trehalosamine Analogues
Yu Hui and Cheng-Wei Tom Chang*
Department of Chemistry and Biochemistry, Utah State UniVersity,
0300 Old Main Hill, Logan, Utah 84322-0300
chang@cc.usu.edu
Received April 28, 2002
ABSTRACT
A library of seven trehalosamine analogues with various natural and non-natural binding motifs was synthesized through an expedient divergent
synthetic approach. The final products were prepared in sufficient quantities and purities for different types of assay against various pathogens.
Several stereo- and regioselective reactions on the trehalose scaffold were developed for rapid synthesis of all of the designed compounds.
Trehalosamine and other related aminotrehaloses derived
from trehalose belong to a family of disaccharide amino-
glycoside antibiotics bearing a 1,1′-glycosidic linkage (Figure
1).1,2 These aminoglycoside antibiotics, which can be isolated
from natural sources or synthesized chemically, have at-
tracted interest for their potential as novel antibiotics. For
example, R,R-trehalosamine isolated from Streptomyces is
active against Mycobacterium tuberculosis.1 The 4-amino-
4-deoxy-R,R-trehalose is weakly active against Escherichia
coli and Bacillus subtilis.1 The 3,3′-neotrehalosdiamine,
isolated from Bacillus pumilis, is the first example of the
trehalosamine family with an R,â-linkage. Trehalose has been
found ubiquitously in insects as the principal blood sugar.
Trehalose has also been reported to participate in the
germination of ascospores in fungi. Therefore, inhibitors of
trehalase that mimic the trehalose scaffold can potentially
be antifungal or plant-protection agents, such as trehazolin
from Amycolatopsis trehalostatica3,4 and salbastatin from
Streptomyces albus.5
Aminoglycosides exert their antibacterial activity by
entering into the cell via active transport and binding
selectively to the bacterial ribosomal RNA, thereby inhibiting
the protein synthesis of the microorganism. Many trehalos-
amine analogues have been synthesized. Examples include
(1) Hooper, I. R. Aminoglycoside Antibiotics; Springer-Verlag: New
York, 1982.
(2) Haddad, J.; Kotra, L. P.; Mobashery, S. In Glycochemistry Principles,
Synthesis, and Applications; Wang, P. G., Bertozzi, C. R., Ed.; Marcel
Dekker: New York, 2001; p 307.
(3) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. ReV. 1999, 99,
779-844.
Figure 1. Trehalose and naturally occurring trehalosamines and
(4) Kobayashi, Y. Carbohydr. Res. 1999, 315, 3.
(5) Vertesy, L.; Fehlhaber, H. W.; Shultz, A. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1844-1846.
trehalase inhibitors.
10.1021/ol026095m CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/04/2002

2,2′,6,6′-tetraazido-2,2′,6,6′-tetradeoxy-R,R-trehalose,6 6,6′-
diamino-6,6′-dideoxy-R,R-trehalose,7 6-amino-6-deoxy-R,R-
trehalose,8 3,3′-diamino-3,3′-dideoxy-R,R-trehalose,9 3-amino-
3-deoxy-R,R-trehalose, and 3,3′-neotrehalosdiamine.10 Most
of the syntheses, however, have focused on the naturally
occurring trehalosamines.2
On the basis of the common structural features of all
aminoglycosides, Wong and co-workers have proposed
several structural motifs including cis- or trans-1,2-hy-
droxyamines and gluco- and galacto-1,3-hydroxyamine
substructures that are important for the molecular recognition
of phosphodiester of RNA backbones.11,12 Our group is
interested in synthesizing various mono- or disaccharides
with designed amino group substitution patterns that may
serve as the probes for investigation of aminoglycoside-
rRNA binding. Enlightened by the proposed binding motifs
of aminoglycoside, we began to construct trehalosamine
analogues with these binding motifs. In addition, we have
proposed four additional natural and non-natural binding
motifs, gluco- and galacto-1,3-diamino and gluco- and
galacto-1,3-hydroxyamino with 4-NH2 on the trehalose
scaffold (Figure 2). The constructed aminosugar-containing
Figure 3. Designed trehalosamines.
sufficient for assays against various pathogens, we have
developed a divergent synthetic approach for such purposes.
Using commercially available trehalose as the starting
material, a series of branching into different routes are used
for adding the amino group substitution on the C-4 and/or
C-6 positions (Scheme 1). The amino groups were introduced
Scheme 1. Synthesis of Trehalose-Based Aminoglycosides
Figure 2. Proposed binding motifs of aminosugars.
trehalose or trehalosamine analogues can potentially lead to
the development of novel antibiotics or trehalase inhibitors.
As part of our research, we would like to report the
syntheses of a library of seven novel amino group-substituted
trehalose derivatives bearing various gluco- and galacto-1,3-
diamino and -hydroxyamino and cis- and trans-hydroxy-
amino binding motifs as shown in Figure 3. Compound 2
contains a reported gluco-1,3-hydroxyamine motif11,12 and
can be used as the control. Compounds 1 and 5 contain
gluco- and galacto-1,3-diamino motifs, while compounds 6
and 7 have gluco- and galacto-1,3-hydroxyamino motifs.
Compounds 3 and 4 will allow us to evaluate exclusively
the trans- and cis-1,2-hydroxyamino binding motif.
Traditional synthetic methods often involve development
of an individual route for the preparation of a single final
product. For the preparation of a library of compounds, this
approach is labor-intensive. To minimize the synthetic work
while producing the optimal structural diversity in quantities
(6) Paulsen, H.; Sumfleth, B. Chem. Ber. 1979, 3203-3213.
(7) Umezawa, S.; Tsuchiya, T.; Nakada, S.; Tatsuta, K. Bull. Chem. Soc.
Jpn. 1967, 40, 395-401.
(8) Hanessian, S.; Lavallee, P. J. Antibiot. 1972, 25, 683-688.
(9) Baer, H.; Bell, A. J. Can. J. Chem. 1978, 56, 2872-2878.
2246
Org. Lett., Vol. 4, No. 13, 2002

and masked as azido groups, which were converted into
amino groups during the final stage of the synthesis.
as the major product when Swern oxidation/NaBH4 reduction
was used. Therefore, we have to develop a longer route for
the preparation of 5.
Compound 8 was prepared from trehalose according to
the literature procedures.13 Perbenzylation of 8 provided
compound 9, which led to two distinct routes, one for the
preparation of 10 (Scheme 1), the other for the preparation
of 18 (Scheme 2). Compound 10 was obtained from
Compound 18 was synthesized from 9 using BH3-NMe3/
AlCl3 in THF (Scheme 2).15 Direct azide substitution from
18 gave 19. Compound 19 contains an intrinsically non-
natural galacto-1,3-hydroxyamino binding motif with C-4
and C-4′ amino groups. We were pleased to discover that
the hydride reduction of the ketosugar from 18 using
L-Selectride provided the desired product 20, with the
galacto-galactoside configuration. L-Selectride is expected
to enhance the stereoselectivity in favor of the axial hydroxyl
group. After the azide substitution, another novel trehalos-
amine analogue, precursor 21, was made. The C-6/C-6′
benzyl groups of 21 were selectively displaced by acetyl
groups using Ac2O and TMSOTf generating 22.16,17 A three-
step process involving hydrolysis of C-6/C-6′ acetyl groups,
tosylation of C-6/C-6′ hydroxyl groups, and azide substitu-
tion, furnished the desired product 23, with a novel and non-
natural gluco-1,3-diamino binding motif.3
Scheme 2. Synthesis of Trehalose-Based Aminoglycosides
It has been noted18,19 that the attempts for the reduction
of azido groups and the deprotection of benzyl groups under
one-pot hydrogenation often provided a mixture with in-
complete reaction. Therefore, a two-step procedure was used,
in which all seven azido/benzyl trehalosamine analogues
underwent a Staudinger reaction followed by hydrogenation
(Scheme 3).20 Generally, the final products were produced
Scheme 3. Final Synthesis of Trehalose-Based
Aminoglycosides
hydrolysis of the benzylidene groups of 9 using TsOH in
MeOH. Triflation followed by an azido substitution on the
4,6-hydroxyl groups of each glucose component provided
11, which has an intrinsically novel galacto-1,3-diamino
binding motif. Alternately, deoxygenation of the 6-OH and
6′-OH of 10 was accomplished by reducing the tosylated
derivatives with LiAlH4 generating 13. Direct incorporation
of the azido groups on the 4-OH and 4′-OH of 13 yielded
14 with 4-N3 and 4′-N3 in the axial positions. A Swern
oxidation followed by a NaBH4 reduction converted the
equatorial 4-OH and 4′-OH of 15 into axial positions,
allowing the incorporation of azido groups in the equatorial
positions, yielding 16 via an SN2 azide substitution.
Originally, we intended to synthesize trehalosamine ana-
logue 5, bearing a novel gluco-diamino binding motif, from
compound 12 based on our previous studies on the stereo-
selective reduction of ketosugars,14 However, the 4- and 4′-
hydroxyl groups of 12 could not be converted from equatorial
to axial position at the same time in the employed conditions.
A complex mixture was obtained with the galacto-glucoside
(10) Baer, H.; Bell, A. J. Carbohydr. Res. 1979, 75, 175-184.
(11) Wong, C.-H.; Hendrix, M.; Manning, D. D.; Rosenbohm, C.;
Greenberg, W. A. J. Am. Chem. Soc. 1998, 120, 8319-8327.
(12) Hendrix, M.; Alper, P. B.; Priestley, S.; Wong, C.-H. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 95-98.
Org. Lett., Vol. 4, No. 13, 2002
2247

in good purity, requiring minimum purification, with the
exception of compounds 19 and 21, where column chroma-
tography purifications were employed after the Staudinger
reaction. The final products were obtained and characterized
as acetate salts. After which, all of the analogues were
converted into chloride salt by an ion-exchange column with
Dowex 1X8-200 (Cl- form) resin.
In summary, we have prepared seven trehalosamine
analogues with natural and non-natural binding motifs. The
non-natural binding motifs can be utilized for future drug
development, which may potentially alleviate the problem
of drug resistant microorganisms, since these microorganisms
have never encountered the non-natural scaffolds. The
philosophy of divergent synthesis allows us to expediently
generate a library of compounds using traditional synthetic
methods. All the analogues were obtained with high purity
in significant amount, which permits us to pursue different
types of assay against various agents. We are currently testing
our trehalosamine analogues against E. coli and S. aureus.4
Acknowledgment. We acknowledge the financial support
from the Utah State University (New Faculty Research Grant)
and the support from Department of Chemistry and Bio-
chemistry, Utah State University.
(13) Yonehara, K.; Hashizume, T.; Ohe, K.; Uemura, S. Tetrahedron:
Asymmetry 1999, 10, 4029-4035.
(14) Chang, C.-W. T.; Hui, Y.; Elchert, B. Tetrahedron Lett. 2001, 42,
7019-7023.
(15) Hanessian, S. PreparatiVe Carbohydrate Chemistry; Marcel Dek-
ker: New York, 1997; p 53.
(16) Alzeer, J.; Vasella, A., HelV. Chim. Acta 1995, 78, 177.
(17) Angibeaud, P.; Utille, J.-P. Synthesis 1991, 737.
(18) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H., J. Am. Chem.
Soc. 1998, 120, 1965-1978.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H and 13C NMR and
mass spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(19) Greenberg, W. A.; Priestley, E. S.; Sears, P. S.; Alper, P. B.;
Rosenbohm, C.; Hendrix, M.; Hung, S.-C.; Wong, C.-H., J. Am. Chem.
Soc. 1999, 121, 6527-6541.
(20) Sucheck, S. J.; Greenberg, W. A.; Tolbert, T. J.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1080-1084.
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