Biomedical Engineering Reference
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FIGURE 3.2 Synthetic strategy for assembling macrocyclic triazoles.
cycloaddition reaction of intermediate ylides with alkynes followed by retro-[4
+
2],
with Cu(I)-catalyzed [3
2] cycloaddition of alkynes with azides, to provide an effi-
cient pathway for the synthesis of macrocyclic triazoles [39]. A three-subunit system
was used to study this macrocycloaddition and its tolerance to several substitutents
and stereochemistry (Figure 3.2).
Two different options of cyclization were reported, depending on subunits A and C,
which can be interchangeable. Subunit B, on the other hand, contains two functional
groups, a carboxylic acid and an isocyanate, which can react with the amines in A
and C to generate the cyclization precursor. A cycloaddition-cycloreversion strategy
was developed to construct linear subunit B. First, a [3
+
2] cycloaddition reaction
occurred between several alkynes and the carbonyl ylide; the latter was obtained
by treating a diazoimido ester with Rh catalyst. Then the intermediate underwent a
[4
+
2] cycloreversion reaction, generating an isocyanate that was trapped by several
amines ( 62 and 63 ) (Scheme 3.21). The third subunit was installed by a simple cou-
pling reaction of amines and carboxylic acids. Therefore, by using and interchanging
several amino-azide and amino-alkyne subunits, a large number of precursors ready
to cyclize were synthesized. The Cu(I)-catalyzed macrocycloaddition of alkynes
with azides was successful regardless of stereochemistry, substituents, and ring size.
Surprisingly, a significant amount of cyclodimers was obtained only when the macro-
cycloaddition produced a 21-membered monomer. No cyclodimers and good yield
were obtained with 17-membered rings 64 and 65 .
Using functional group pairing reactions of enantioenriched Michael adducts,
Comer et al. developed a build/couple/pair pathway to access five- to 10-membered
fused and bridged rings (Figure 3.3) [40].
+
-Nitrostyrenes, with bromine, allyl, and
alkynyl substituents in the ortho position, were used in a stereoselective Michael
addition using Cinchona alkaloid derivatives as the catalyst [41]. The conjugate
addition of nucleophiles to
β
-nitrostyrenes proceeded with excellent enantiose-
lectivity, thus providing highly functionalized scaffolds ( 66 ) suitable for selective
functional group pairing reactions, such as ring-closing and enyne metathesis,
β
 
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