Regioselective Glycosylation of Neamine Core: A Facile Entry to Kanamycin B Related Analogues

Article abstract of DOI:10.1021/ol0363927

(Matrix presented) Introduction of a sugar unit at either the O5 or O6 position of various neamine derivatives in excellent selectivity and yields is described here. Application to the synthesis of kanamycin analogues is also highlighted.

Full text of DOI:10.1021/ol0363927

ORGANIC
LETTERS
2004
Vol. 6, No. 4
585-588
Regioselective Glycosylation of Neamine
Core: A Facile Entry to Kanamycin B
Related Analogues
Chien-Hung Chou,† Chung-Shieh Wu,† Ching-Hui Chen,† Lung-Dai Lu,‡
,†
Suvarn S. Kulkarni,† Chi-Huey Wong,§ and Shang-Cheng Hung*
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan, Department of Chemistry,
National Tsing Hua UniVersity, Hsinchu 300, Taiwan, and Genomics Research Center,
Academia Sinica, Taipei 115, Taiwan
schung@chem.sinica.edu.tw
Received December 8, 2003
ABSTRACT
Introduction of a sugar unit at either the O5 or O6 position of various neamine derivatives in excellent selectivity and yields is described here.
Application to the synthesis of kanamycin analogues is also highlighted.
Aminoglycosides are a group of structurally diverse and
clinically important antibiotics with a unique ability to
recognize RNA specifically.1 They function through binding
to specific sites in the bacterial ribosome and interfere with
protein biosynthesis in a cascade of events that ultimately
leads to bacterial cell death.2 Structural3 and synthetic4 studies
over the past few years have contributed significantly to our
understanding of small molecule-RNA interactions.5 The
emergence of bacterial resistance6 to these antibiotics has,
however, triggered a search for new, smaller, and simpler
structures that would essentially retain the antibiotic activity
but avoid the problems of resistance.
The 2-deoxystreptamine-based antibiotics share a common
pseudodisaccharide core, neamine (Scheme 1), which is
regioselectively glycosylated either at the O5 (e.g., neomycin
B) or O6 position (e.g., kanamycin B) with various saccha-
rides. Neamine, is one such optimal structural motif that has
received much of the attention7-10 owing to its structural
† Institute of Chemistry.
‡ Department of Chemistry.
§ Genomics Research Center.
(1) Aminoglycoside Antibiotics Umezawa, H., Hooper, I. H., Eds.:
Springer-Verlag: NewYork, Heidelberg, 1982.
(2) (a) Moazed, D.; Noller, H. F. Nature 1987, 327, 389-394. (b)
Woodcock, J.; Moazed, D.; Cannon, M.; Davies, J.; Noller, H. F. EMBO J.
1991, 10, 3099-3103.
(3) (a) Fourmy, D.; Recht, M. I.; Blanchard, S. C.; Puglisi, J. D. Science
1996, 274, 1367-1371. (b) Fourmy, D.; Yoshizawa, S.; Puglisi, J. D. J.
Mol. Biol. 1998, 277, 333-345. (c) Fourmy, D.; Recht, M. I.; Puglisi, J.
D. J. Mol. Biol. 1998, 277, 347-362. (d) Yoshizawa, S.; Fourmy, D.;
Puglisi, J. D. EMBO J. 1998, 17, 6437-6448.
(4) Kotra, L. P.; Mobashery, S. Curr. Org. Chem. 2001, 5, 193-205.
(5) (a) Hermann, T.; Westhof, E. Curr. Opin. Biotechnol. 1998, 19, 66-
73. (b) Tor, Y. Angew. Chem., Int. Ed. 1999, 38, 1579-1582. (c) Ecker,
D. J.; Griffey, R. H. Drug DiscoV. Today 1999, 4, 420-429. (d) Walter,
F.; Vicens, Q.; Westhof, E. Curr. Opin. Chem. Biol. 1999, 3, 694-704. (e)
Hermann, T. Angew. Chem., Int. Ed. 2000, 39, 1890-1905. (f) Sucheck,
S. J.; Wong, C.-H. Curr. Opin. Chem. Biol. 2000, 4, 678-686.
(6) Haddad, J.; Vakulenko, S.; Mobashery, S. J. Am. Chem. Soc. 1999,
121, 11922-11923 and references therein.
(7) (a) Park, W. K. C.; Auer, M.; Jaksche, H.; Wong, C.-H. J. Am. Chem.
Soc. 1996, 118, 10150-10155. (b) Nunns, C. L.; Spence, L. A.; Slater, M.
J.; Berrisford, D. J. Tetrahedron Lett. 1999, 40, 9341-9345. (c) Ding, Y.;
Swayze, E. E.; Hofstadler, S. A.; Griffey, R. H. Tetrahedron. Lett. 2000,
41, 4049-4052.
(8) (a) 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. (b) Sucheck, S. J.; Wong, A. L.; Koeller, K. M.;
Boehr, D. D.; Draker, K.; Sears, P.; Wright, G. D.; Wong, C.-H. J. Am.
Chem. Soc. 2000, 122, 5230-5231.(c) Sucheck, S. J.; Greenberg, W. A.;
Tolbert, T. J.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39, 1080-1084.
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10.1021/ol0363927 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004

Scheme 1
Table 1. Regioselective Protection of the Neamine-Derived
Tetraol 1
yield (%)
recovered
entry
x
6
7
8
yield (%) of 1
1
2
3
4
5
6
7
1
2
3
4
5
6
7
17
33
33
58
58
42
42
8
7
66
26
27
17
15
25
16
17
25
8
17
17
17
20
13
13
6
13
20
simplicity, its ease of accessibility, and its ability to be readily
modified chemically compared with the parent antibiotic. A
chemical approach to create libraries of neomycin and related
analogues of therapeutic potential via O5-assembly of the
tri-OBn8,9 or tri-OAc10 analogues of 2 with a variety of
molecules has been intensely investigated. In comparison,
O6-functionalization has proven more challenging and only
one literature report has appeared on this topic, which
exploited a lengthy procedure to introduce a 6-O-allyl group
and several other groupings at this position.11 Surprisingly,
there has been no literature precedent for O6-glycosylation
on neamine derivatives. Herein, we now report a novel and
straightforward approach for coupling a sugar unit to the
neamine core at either O5 or O6 to provide a concise
synthesis of various glycosylated kanamycin B analogues.
Our synthesis (Scheme 2) commenced with regioselective
benzoylation of the neamine derivative 1, obtained from
commercially available neomycin B by sequential methan-
olysis7a followed by amino-azido conversion.12 Treatment
of 1 with a mild benzoylation reagent (1-N-benzoyloxy-
benzotriazole, BzOBT) afforded the 3′,4′,6-tri-OBz derivative
2 as a major product in 55% yield. To test the viability of 2
as a glycosyl acceptor, its coupling with D-mannopyranosyl
thioglycoside 3 was promoted via a combination of N-
iodosuccinimide (NIS) and trifluoromethanesulfonic acid
(TfOH), and the corresponding R-linked trisaccharide 4 was
obtained in 67% yield. The concomitant de-O-benzoylation
proceeded smoothly under standard conditions to give triol
5 almost quantitatively. This constitutes a short and efficient
route for the synthesis of neomycin B analogues.
Next, we turned our attention to the regioselective protec-
tion-glycosylation of the tetraol derivative 1, so as to access
kanamycin B analogues. Of the various protective groups
tried for the regioselective discrimination of the two trans-
diequatorial dihydroxy motifs, Ley’s method of 1,2-butane
diacetal (BDA) formation13 worked the best. Treatment of
compound 1 with various amounts of 2,3-butanedione and
trimethylorthoformate in the presence of boron trifluoride
Scheme 2
(10) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem.
Soc. 1998, 120, 1965-1978.
(11) Haddad, J.; Kotra, L. P.; Llano-Sotelo, B.; Kim, C.; Azucena, E.
F., Jr.; Liu, M.; Vakulenko, S. B.; Chow, C. S.; Mobashery, S. J. Am. Chem.
Soc. 2002, 124, 3229-3237.
(12) (a) Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996,
37, 6029-6032. (b) Nyffeler, P. T.; Liang, C.-S.; Koeller, K. M.; Wong,
C.-H. J. Am. Chem. Soc. 2002, 124, 10773-10778.
(13) (a) Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson,
J.-F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin Trans. 1 1997,
2023-2031. (b) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.;
Ince, S. J.; Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53-
80.
586
Org. Lett., Vol. 6, No. 4, 2004

Table 2. Regioselective Glycosylation of the Diol 6 Followed by Sequential Deprotections to Kanamycin Analoguesa
a Reagents and conditions: (a) donors 9a-i, NIS/TESOTf, CH2Cl2, -78 °C; (b) 90% TFA; (c) for 12a,b,e-i: Pd(OH)2, H2, EtOH/H2O/CHCl3 ) 2/2/1;
for 12c,d: (i) NaOMe, MeOH; (ii) Pd(OH)2, H2, EtOH/H2O/CHCl3 ) 2./2/1.
etherate as a catalyst furnished the required 3′,4′-diketal 6,
together with other isomers in variable ratios. Table 1
summarizes our efforts to tune the reaction conditions in
favor of one of the isomers. As shown in entries 1-3, mostly
unreacted starting material 1 was recovered, and the desired
monoacetal 6 was isolated in low yields. Use of 4 (entry 4)
or 5 equiv (entry 5) of 2,3-butanedione led to the formation
of 5,6-diol 6 (58%) as a major product along with other two
isomers 7 and 8 in minor proportions. Increasing the reagent
concentration (entries 6 and 7) progressively resulted in the
formation of higher proportions of the bis-acetal 8. Com-
pound 6 could be easily separated by column chromatogra-
phy, as a diastereomeric mixture,14 while the remaining
mixture was subjected to hydrolysis conditions using 90%
aqueous trifluoroacetic acid to recover tetraol 1 almost
quantitatively.
provide the corresponding trisaccharides 10a (78%, R only),
10b (80%, R/â ) 4/1), 10c (67%, â only), 10d (65%, â only),
10e (82%, R/â ) 5/1), 10f (82%, R/â ) 2/1), 10g (85%,
R/â ) 2/1), 10h (81%, R/â ) 6/1), and 10i (84%, R/â )
3/1), respectively. Cleavage of the BDA-protecting group
with aqueous trifluoroacetic acid followed by immediate
removal of the reagent under diminished pressure yielded
the corresponding triol derivatives 11a-11i in very good
yields, respectively. It should be noted that, particularly in
the D-galacto case, the time factor of the TFA-hydrolysis
reaction was very crucial. A delay in the evaporation of
reagent showed a marked drop in the yield, presumably via
the cleavage of the newly formed glycosidic linkage. All of
these triols were carefully characterized through the analyses
of their 1H, 13C, 1H-1H COSY, 13C-1H COSY, and NOESY
NMR spectra, respectively.15 Compound 11e showed no
resemblance with the previously synthesized analogue 5,
With the key synthon 6 in hand, the regioselective O6-
glycosylation to the kanamycin B analogues was further
investigated. As illustrated in Table 2, coupling of diol 6
with the thioglycoside donors 9a-i at -78 °C using NIS/
TESOTf proceeded with excellent O6-regioselectivity to
(15) A standard structural elucidation protocol involved 1H, 13C, and 2D
NMR analysis. The anomeric carbons and protons were clearly distinguished
from the 13C-1H COSY spectrum. 1H-1H COSY spectral analysis then
established the correlation between all of the protons on each ring. The
regioselectivity of glycosylation (O5 or O6) was determined by observation
of the correlation with the OH protons in the COSY spectrum, wherever
possible, and also judged from the multiplicity of H5 and H6 protons.
NOESY spectral analysis was finally used to reaffirm the assignments. The
R and â configurations were determined on the basis of coupling constant
measurements of the respective anomeric protons (see the Supporting
Information).
(14) In the BDA-protection of diol 1, although, the anomeric effect at
the two acetal centers favored the formation of the isomer with anti-
periplanar arrangement of OMe groups, the other isomer was also formed
in minor proportion. This was not separated and the mixture was used as
such for ensuing glycosylations. After the removal of BDA protecting group,
individual products were obtained in pure form.
Org. Lett., Vol. 6, No. 4, 2004
587

further reaffirming the well-analyzed regiochemical out-
come of glycosylation. Hydrogenolysis of 11a, 11b, and
11e-i and debenzoylation-hydrogenolysis of 11c and 11d
afforded the desired kanamycin B analogues 12a-i, respec-
tively.
analogues of kanamycins and structurally related amino-
glycosides.
Acknowledgment. We thank Academia Sinica for finan-
cial support.
In conclusion, we have successfully developed an efficient
strategy for the assembly of kanamycin B-like aminoglyco-
sides via regioselective glycosylation of compound 6 at O6
in excellent yields. The strategy works well with commonly
used glycosyl donors and holds a great promise to rapidly
construct previously inaccessible and biologically significant
Supporting Information Available: 1H, 13C, and 2D
NMR spectra for all new compounds and selected experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0363927
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Org. Lett., Vol. 6, No. 4, 2004