Biomedical Engineering Reference
In-Depth Information
1
X
2
O
X
X
O
+
X
O
5
N
NH
N
3
-
N
-
+
+
4
X = NR, S, O
-
O
O
O
81
SCHEME 13.18
H
O
2
N
O
O
O
2
N
H
H
heat
steps
steps
N
S
N
H
N
+
-
N
N
O
H
N
O
AcO
AcO
O
AcO
82
83
84
(±)-Strempeliopine
85
SCHEME 13.19
1,4-dipole (i.e.,
81
) was employed to form the structural backbone of the isoschi-
zozygane alkaloids. In contrast to 1,3-dipoles, much less is known about the
cycloaddition behavior of 1,4-dipoles whose transient existence was first postulated
in 1967 [37]. This class of reactive intermediates (Scheme 13.18), while of consid-
erable theoretical interest, attracted little synthetic attention until the elements of a
1,4-dipole were incorporated into a cross-conjugated heteroaromatic betaine [38] by
the cyclocondensation of an appropriately substituted monoprotic amidine or thioa-
mide with a 1,3-dielectrophile derived from malonic acid [39]. Intramolecular 1,4-
dipolar cycloadditions of these betaines [40], or their tautomeric equivalents [41],
have resulted in ring annulations leading to bi- and tricyclic heterocycles [42] that
were not readily accessible by normal cyclocondensation routes. The overall con-
venience of this method, the ease of access to startingmaterials, and the relatively high
yields and purity of the products obtained suggested its application for a synthesis of
the hexacyclic framework of the shizozygane alkaloid (
)-strempeliopine [43].
Generation of the bright yellow isolable betaine
82
was accomplished by the
reaction of the appropriate thioamide with carbon suboxide [44] at 25
C for 5 h.
Heating a sample of
82
at 120
C for 3 h in toluene afforded
83
as a single
diastereoisomer in 66% yield as a pale yellow solid whose formation is easily
accounted for by extrusion of COS [45] from the originally formed cycloadduct
followed by a hydrogen shift. Catalytic reduction of the nitro group followed by
reaction with
N
-bromosuccinimide (NBS) resulted in the formation of the required
pentacyclic indoline framework
84
of the target alkaloid. Closure of the final ring of
the shizozygane skeleton to give the alkaloid (
)-strempeliopine
85
was carried using
an oxidative cyclization (Scheme 13.19).
13.2.4. Push-Pull Dipoles
The Rh(II)-catalyzed reaction of the related
-diazo ketoamide system
86
was also
reported [46]. Attack of the amido oxygen at the rhodium carbenoid center
produces a carbonyl ylide dipole
87
that is isomeric with the isomunchnone class
a
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