Organic Letters
Letter
used, bromide 3a′ (20:1 β:α) or chloride 3a″ (9:1 β:α)
analogues delivered a pure β-N-glycosyl oxindole 4a, although
they were used as a mixture of β and α anomers. This result
indicates clearly that anomerization occurs during the process
when bromide or chloride substrates (3a′ or 3a″, respectively)
were used. Substrates with electron-donating (3b,c,e,f) and
electron-withdrawing (3d,g−i) substituents on various posi-
tions of the aromatic ring were also successfully converted into
the corresponding N-glycosyl oxindoles in good to excellent
yields (≤90%). Additionally, the chemoselectivity of this
coupling was examined with dihalogenated substrate 3h
bearing two different C−X bonds (C−I and C−Cl) at the
orth−ortho′ positions of the benzene ring. Interestingly, under
our optimized conditions, only the C−I reacted delivering the
corresponding glycoside 4h in 84% yield and anomeric
stereoselectivity β:α of 20:1. The presence of an aryl fused
ring was also tolerated well as shown with compound 4j.
Moreover, the N-glycosyl congested tetracycle 4k was obtained
in 84%. In addition, the spiro-oxindole N-glycosylated
compound 4l with a cyclopropyl ring at the C3 position was
prepared in good 58% yield as a pure β anomer.
Scheme 4. Further Functionalization of 4a and Application
to the Synthesis of a Glycosylated Sugen Derivative 9a
a
b
1
Yield of the isolated product. The β:α ratio was determined by H
NMR after purification via flash chromatography.
The successful synthesis of N-glucosides 4a−l from 1-
amido-glucose 3a−l encouraged us to investigate other sugar
partners on this coupling. Pleasantly, the coupling reaction was
successfully extended to substrates with various peracetylated
mono-, di-, and triglycosides (3m−p). The corresponding
oxindoles bearing a mannose (4m), a galactose (4n), a
cellobiose (4o), or a maltotriose (4p) were all prepared with
excellent yields (≤90%) and high stereoselectivity.
glucosyloxindole 7a was thus obtained in a six-step procedure,
starting from 1a, in 22% overall yield.
Finally, this methodology was applied to the synthesis of
bioactive drug analogues. As shown in Scheme 4, β-N-glucosyl
SUGEN derivative 8a, which is an N-glycosylated analogue of
semaxanib (SU5416, a tyrosine-kinase inhibitor drug used as a
cancer therapeutic), was obtained in 72% yield by post-
functionalization of the N-glycosyl oxindole 4a, via con-
densation with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde. As it
Encouraged by these results, we investigated the feasibility of
this approach with the aim of synthesizing N-glycosylated six-
membered heterocycles (Scheme 3). In this context, we were
15
was previously described, only the Z isomer of the alkene was
observed presumably because of the hydrogen bond formed
between the nitrogen of the pyrrole and the carbonyl of the
oxindole. The deprotected analogue 9a was further prepared
by removal of the acetate groups in the presence of a catalytic
amount of potassium carbonate in methanol in 84% yield.
In summary, we succeeded in synthesizing N-glycosylated
oxindoles by intramolecular Pd-catalyzed N-arylation of 1-
amidosugars. This is the first methodology reporting an
efficient way to prepare a large variety of substituted N-glycosyl
oxindoles. This coupling reaction tolerates various functional
groups and sugar moieties. Moreover, this approach was
extended to the synthesis of N-glycosylated dihydroquinoli-
none, benzoxazinone, and benzothiazinone. Finally, because of
this methodology, we described for the first time the synthesis
of an N-glycosylated SUGEN derivatives and expect to apply
this general methodology to other therapeutic compounds.
c
Scheme 3. Extending the Methodology to Other Structures
a
b
1
Yield of the isolated product. The β:α ratio was determined by H
NMR after purification via flash chromatography. Reaction
conditions: 1-amidosugar 5a−c (0.08−0.11 mmol), Pd(OAc) (10
mol %), RuPhos (40 mol %), K CO (2 equiv) in toluene (0.016−
c
2
2
3
0.018 M), 130 °C, 3 h.
ASSOCIATED CONTENT
sı Supporting Information
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*
pleased to see that substrates 5a and 5b bearing an ether
linkage or their thioether congener 5c all reacted successfully
under our reaction conditions to furnish N-glycosylated
dihydroquinolinone 6a, benzoxazinone 6b, and benzothiazi-
none 6c in 70%, 68%, and 24% yields, respectively. These
results represent the first examples of diversification of this
family of N-heterocycle glycosides through this methodology.
With substantial amounts of 4a in hand (Scheme 4), we
focused our attention on demonstrating whether our method
could be employed for molecular diversity. At first, the
unprotected glycoside-indolin-2-one 7a was synthesized by
deacetylation of 4a under Zamplen conditions. This N-
spectra of new compounds (PDF)
Corresponding Author
■
Samir Messaoudi − Universite
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D
Org. Lett. XXXX, XXX, XXX−XXX