Biomedical Engineering Reference
In-Depth Information
phosphine for its initial conjugate addition. Indeed, dramatic increases in the effi-
ciency of the reaction occurred when using more nucleophilic phosphines. With
tributylphosphine, various aryl imines
5
furnished 89 to 99% yields of the tetra-
substituted dihydropyrroles desired, favoring the cis isomers, when using
-methyl,
-ethyl,
-propyl,
-isopropyl,
-
tert
-butyl, or
-phenyl allenoate as the reaction
substrate. Employing allenoates with bulky
-substituents led to the exclusive pro-
duction of
cis
-dihydropyrroles.
In our [3
2] annulation reaction, tributylphosphine behaved as a nucleophilic
organocatalyst to facilitate the formation of 3-carbethoxyl-2,5-disubstituted-3-
dihydropyrroles in excellent yields with high diastereoselectivities. This method has
many attractive features, including short reaction times at room temperature and a
simple nonaqueous workup. In addition, the reactants were readily prepared in one
step from commercially available materials using known procedures. Gratifyingly,
the reaction efficiencies and selectivities meet the high standards for the construction
of DOS libraries.
+
4.2.1.2
[4
2] AnnulationwithN-Tosylimines toFormFunctionalizedGuvacines
+
In the [3
-substituted
allenoates
4
reacted readily with
N
-sulfonylimines in the presence of phosphine
organocatalysts to generate functionalized pyrrolines. To expand the scope of the
phosphine-catalyzed annulations of imines, we employed
+
2] annulation with imines described above, unsubstituted or
-substituted allenoates
as starting materials. Our efforts led to the development of unprecedented [4
+
2]
annulations with
N
-tosylimines, procuring highly functionalized guvacines in high
efficiency [47]. The reaction began with the 1,2-addition of intermediate
11
to the
imine
8a
, producing the vinylphosphonium species
12
, which underwent two proton
transfer steps to form the allylic phosphonium species
14
. Intramolecular conjugate
addition of the amide unit to the enoate moiety in
14
yielded the final product
9a
with
the release of PBu
3
, completing the catalytic cycle (Scheme 4.3). The 2-methylbuta-
2,3-dienoates readily served as a four-carbon synthon in this transformation.
The [4
+
2] annulation reaction works well for a variety of
N
-tosylimines
and
-substituted allenoates in the presence of 20 mol% tributylphosphine in
dichloromethane. Several characteristics of this transformation are noteworthy.
Excellent yields were obtained when electron-donating
N
-tosylimines were used,
but a slight decrease in yield was discerned when strongly electron-withdrawing
groups were attached to the imines. Interestingly,
N
-tosylpivalaldimine afforded the
desired product in good yield when we employed sodium carbonate as an addi-
tive. When we applied 2-benzyl-2,3-butadienoates as reaction partners, we obtained
2,6-diarylguvacine esters in almost quantitative yields with good to excellent diastere-
oselectivities favoring cis isomers (Scheme 4.4 and Table 4.2).
The robust [4
2] annulation with
N
-tosylimines can be employed to generate
tetrahydropyridines on large scales [71], and we have demonstrated their applica-
tion to natural product synthesis through formal syntheses of (
+
±
)-alstonerine and
±
(
)-macroline [72] and the total synthesis of hirsutine [73]. Catalytic asymmet-
ric synthesis of guvacine derivatives through the [4
+
2] annulation of imines with
allenes was described by Wurz and Fu [74] and Xiao et al. [75], respectively.
