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H
3
C
H
3
C
CO
2
Me
CO
2
Me
D-ribo
D-ribo
O
O
O
O
TrO
TrO
TrO
TrO
CH
3
H
3
C
CO
2
Me
N
N
N
N
OHC
CH
3
O
O
O
O
179
178c
CH
3
CH
3
CH
3
+
+
175
- H
2
O
O
O
Me Me
(E)-176c
O
O
O
Me Me
180c
O
O
O
Me
Me
Me
Me
(Z)-176c
major diastereomers
+ two minor diastereomers
hexyl
∗
O
HO
N
1.)
O
hexyl
183
D-ribo
O
O
O
184
TrO
2.) FeCl
3
, MeOH
CH
2
Cl
2
81%
71:29
N
Me
Me
O
1.)
O
O
∗
176a
185
O
Me
Me
HO
∗
N
O
2.) FeCl
3
, MeOH
CH
2
Cl
2
O
O
186
71%
Me
Me
73:27
Scheme 4.29
Asymmetric 1,3-dipolar cycloadditions using
N
-glycosyl nitrone
176c,
from
acetaldehyde (
178c
) with methyl methacrylate (
179
), and
N
-glycosyl nitrone
176a,
derived
from formaldehyde, with non-activated alkenes 1-octene (
183
) and cyclohexene (
185
).
yielded the expected adducts, which were detritylated for purification. The resulting
N-
ribosyl isoxazolidines
184
and
186
were obtained in good yield but only in drs
around 70 : 30. Nevertheless these two examples are remarkable as 1,3-dipolar
cycloadditions with simple alkyl-substituted olefins are challenging.
Based on the stereochemical outcome observed for the 1,3-dipolar cycloaddition
of manno-configured nitrone
177a
with methyl methacrylate and additional mech-
anistic studies, the Vasella group suggested two plausible transition states for the
reaction (Scheme 4.30) [43, 44]. Nitrone
177a
is assumed to adopt either the O-
exo
-
or the O-
endo
-conformation, which differ in the relative orientation of the nitrone
oxygen to the carbohydrate scaffold. Of these two, the O-
endo
conformer is sup-
posedly favored due to steric reasons. To form product
(S)
-
182
the dipolarophile
179
can approach the nitrone moiety in the O-
endo
conformer either from the top
face (
syn
attack) or from the bottom face (
anti
attack), adopting a methyl
endo
or
an ester
endo
orientation with respect to the nitrone. These two attacks lead to
transition states
TS-1
and
TS-2,
respectively, of which
TS-1
is assumed to be more
favorable for stereoelectronic reasons: formation of the isoxazoline moiety during
the cycloaddition is accompanied by rehybridization of the nitrone nitrogen atom
from sp
2
to sp
3
and generation of a free electron pair. In
TS-1
the orbital contain-
ing this nonbonding electron pair is oriented parallel to the
* orbital of the
endocyclic C-O bond, which should result in an overall stabilization of the newly
formed molecule.
σ
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