Biomedical Engineering Reference
In-Depth Information
SCHEME 3.25
Regioselective Huisgen [3
+
2] cycloaddition reactions to yield 12- and
13-membered rings.
eight- to 14-membered rings were synthesized. In the pair phase three different reac-
tions were utilized successfully in ring formation: nucleophilic aromatic substitution,
ring-closing metathesis, and Huisgen [3
2] cycloaddition. In the latter, the authors
expanded their previous study [45] to extend regioselective macrocyclization under
catalyst control to a more structurally and stereochemically complex system (Scheme
3.25). 1,4- and 1,5-Macrocyclic triazoles were synthesized successfully with appre-
ciable differences in shape based on a molecular shape-diversity analysis derived from
a normalized PMI [17]. RuAAC afforded 12-membered rings. Using [Cp*RuCl]
4
as
the catalyst, all four diastereoisomers underwent macrocyclization regioselectively
(
79a
to
d
).
syn-
Aldol-derived substrates were much better substrates than
anti
-aldol-
derived substrates, which yielded triazoles in only modest yield because of dimer for-
mation. In contrast with the 12-membered-rings, 13-membered macrocyclic triazoles
were generated by intramolecular CuAAC. To achieve pseudodilution conditions and
overcome dimer formation, a polystyrene-bound copper catalyst, PS-CuPF
6
,was
selected. Macrocyclization on all four diastereomers of azido-alkyne was success-
ful with an opposite reactivity with respect to stereochemistry (
80a
to
d
). Unlike
the
anti
-aldol-derived substrates, which easily underwent intramolecular CuAAC to
yield triazoles without any dimerization, the
syn-
aldol-derived substrates afforded
the desired triazoles in moderate yield with dimer formation.
Muncipinto et al., using the build/couple/pair strategy, recently reported an efficient
and modular synthetic pathway in which readily synthesized and highly function-
alized amino alcohols underwent allylic alcohol rearrangements and intramolecular
1,3-dipolar cycloadditions to yield densely functionalized isoxazoles, isoxazolines,
+