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amine (
195
) yielded products
trans
- and
cis
-
196
in good combined yield. Cleavage
of the isoxazoline products from the carbohydrate scaffold followed by N-benzyla-
tion and reduction of the ester to a primary alcohol yielded
trans
- and
cis
-
197
in
50% yield but only in a very modest ratio of 1 : 2; however, the enantiomeric purity
of the diastereomeric products was excellent. Attempts to use cyclohexylidene-
modified nitrones of d-ribose and d-mannose in an analogous fashion led to
significantly lower ees for
trans
- and
cis
-
197
[47b]. Both diastereomers were used
in the synthesis of peptide-like target compounds in a six-step sequence, including
reductive cleavage of the isoxazolidine N-O bond, that yielded (
+
)-negamycin (
198
)
from
trans
-
197
and (
)-epinegamycin (
199
) from
cis
-
197
[47a, b].
Whitney and coworkers used the successful ribose-derived nitrone
176a
in the
stereoselective preparation of acivicin (
203
) using methylidene-protected vinylgly-
cine derivative
200
as dipolarophile (Scheme 4.34) [48]. The cycloaddition gave the
adducts
(S)
- and
(R)
-
201
and acidic cleavage of the carbohydrate scaffolds with
subsequent oxidation using NCS yielded isoxazolines
(S)
- and
(R)
-
202
in good
overall yield and excellent dr. After chlorination of the isoxazoline moiety and
removal of all protective groups acivicin (
203
) was isolated in 39% overall yield.
−
O
O
O
O
O
TrO
TrO
TrO
O
N
N
O
H
O
H
N
N
N
O
O
O
CO
2
Me
CO
2
Me
O
+
+
N
CHCl
3
O
O
O
O
O
O
MeO
2
C
Me
Me
Me
Me
Me
Me
200
(S)-201
(R)-201
176a
O
O
CO
2
O
O
1.) HCO
2
H
2.) NCS, CH
2
C
l
2
Cl
+
acivicin
N
N
NH
3
O
H
O
H
O
H
N
N
N
39% from
200
CO
2
Me
CO
2
Me
(S)-202
(R)-202
203
80% (S)/(R) > 19:1
Scheme 4.34
Stereoselective synthesis of acivicin (
203
) via 1,3-dipolar cycloaddition of
ribo-configured nitrone
176a
with vinyl glycine derivative
200.
Sakamoto has published an elegant stereoselective synthesis of the N-terminal
amino acid part of nikkomycin Bz [49], an unusual dipeptide natural product
containing a nucleosidic motif (Figure 4.1). The synthetic approach used cyclohex-
ylidene-protected oxime
ent
-
193a,
which was obtained from l-gulonic-
-lactone
(
ent
-
192
). The corresponding d-gulo configured oxime
193
had previously been
designed by Kibayashi [47] (Scheme 4.33). Condensation of
ent
-
193a
with methyl-
glyoxalate hemiacetal
178f
yielded nitrone
ent
-
194a,
which was subjected to
Lewis-acid-catalyzed transesterification with methoxy cinnamyl alcohol (
205
).
The resulting nitrone
206
underwent a highly diastereoselective intramolecular
1,3-dipolar cycloaddition, affording adduct
207
in 75% yield as a single diastere-
γ
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