a lack or a decrease in the activity.13 To avoid the decrease
in activity, we have developed a general method for the
synthesis of pyranmycins, which consists of a neamine core
and variable pyranoses as the ring III component. We have
also identified the lead structure at ring III of pyranmycins.5b
We wish to further explore the possible site(s) for the
attachment of additional functionalities at the ring III
pyranose of pyranmycin. To achieve this goal, we synthe-
sized seven derivatives of pyranmycins by extending the
amino group or hydroxyl group away from the ring III
pyranose of pyranmycin (Figure 2). The identification of the
optimal site(s) will allow us to introduce more complex
structural components in the future.
extended arms at both O-2′′ and O-3′′ positions, such as
TC025 and TC031. By comparing to the single extended
arm constructs (O-3′′) like TC026, TC028, and TC032, we
can evaluate the effect of the extended arm at O-2′′.
The syntheses of single extended arm pyranmycins require
the preparation of several glycosyl donors 5, 13, 17, 22, and
25 (Schemes 1, 2, and 3). The synthesis of 5 begins from
methyl 6-deoxy-2,3-di-O-benzyl-R-D-glucopyranoside.6 Al-
lylation of 4-OH followed by ozonolysis and reductive
workup provides 3 with a hydroxyethyl group at O-4
(Scheme 1). The benzyl and methyl groups were converted
Scheme 1. Synthesis of Glycosyl Donora
a Conditions: (a) Allyl bromide, NaH, TBAI, THF. (b) (i) O3,
CH2Cl2; (ii) NaBH4, MeOH. (c) Ac2O, cat. H2SO4. (d) (i) NH2NH2-
HOAc, DMF; (ii) CCl3CN, DBU, CH2Cl2.
into acetyl groups by using Ac2O and a catalytic amount of
H2SO4 concomitant with the acetylation of the hydroxyl
group on the extended arm. Selective deprotection of the
anomeric acetyl group followed by reacting with trichloro-
acetonitrile and DBU gave the desired glycosyl donor, 5.
The synthesis of 13 begins with 615 (Scheme 2). Allylation
of 3-OH followed by the deprotection of benzylidene group
generated a diol, 7. Selective tosylation of 6-OH followed
by LiAlH4 reduction gave the 6-deoxygenated compound,
Figure 2. Structures of the designed pyranmycins.
As more diverse structural scaffolds are incorporated, the
overall contour of the modified pyranmycins will deviate
from their predecessors that resemble neomycin. Thus, these
modified pyranmycins are expected to become poor sub-
strates for the aminoglycoside-modifying enzymes. There-
fore, if the high potency of these extended arm-modified
pyranmycins can be maintained, we can generate effective
new aminoglycoside antibiotics against resistant strains of
bacteria.
Scheme 2. Synthesis of Glycosyl Donora
Our previous work elucidates the importance of having a
6′′-CH3 group.5 Therefore, all of the constructs will follow
this trait except TC024. We began our approach by extending
the 4′′-OH by two carbons creating TC023. It is difficult to
install a single extended arm at the O-2′′ position while
maintaining the crucial â-glycosidic bond during the glyco-
sylation.14 Therefore, we synthesized compounds with double
a Conditions: (a) (i) Allyl bromide, NaH, TBAI, THF; (ii)
TsOH-H2O, MeOH. (b) (i) TsCl, py.; (ii) LiAlH4, THF. (c) (i)
(COCl)2, DMSO; DIPEA; (ii) NaBH4, MeOH. (d) (i) Tf2O, py.,
CH2Cl2; (ii) NaN3, DMF. (e) (i) O3, CH2Cl2; (ii) NaBH4, MeOH.
(f) Ac2O, cat. H2SO4. (g) (i) NH2NH2-HOAc, DMF; (ii) CCl3CN,
DBU, CH2Cl2.
(11) Kotra, L. P.; Haddad, J.; Mobashery, S. Antimicrob. Agents
Chemother. 2000, 44, 3249-3256..
(12) Mingeot-Leclercq, M.-P.; Glupczynski, Y.; Tulkens, P. M. Antimi-
crob. Agents Chemother. 1997, 43, 727-737.
(13) 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.
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Org. Lett., Vol. 5, No. 4, 2003