Biomedical Engineering Reference
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starting material. Specifically, the dienophile ester could be cleaved and appended
with an acylated amino alcohol to intermediate 119 , depending on the stereochemistry
of the amino alcohol [48]. In most cases, the racemic core structure was coupled
with an enantiomerically pure amino alcohol, and the resulting diastereomers were
separated. The stereochemistry at R 4 completely dictated whether the metathesis
reaction proceeded similarly to 121 (i.e., by formation of two new rings or following
an alternative macrocyclization pathway to give 120 ). In related studies, Ikoma et al.
showed that the two amide termini could be allylated selectively by tuning the
N-substituents (i.e., by replacing R 3 and Bn of 116 with various substituents) [49].
Later studies used ( Z )-2-iodoacrylic acid in the initial Ugi reaction to produce 122 ,
which was used to alkylate allyl and butenyl amides and alcohols. These intermediates
underwent high-yielding ring-opening-, ring-closing-, and cross metathesis when
treated with Grubbs's catalyst and vinyl acetate [50,51]. Although the final products
are formed in short sequences from the initial 4CR, final products 120 , 121 , and 126
barely resemble the Ugi products from which they emanate.
Propargyl/allyl amines have found applications in Ugi reactions [52]. By running
a Ugi reaction with nitrocarboxylic acid 128 , the product is situated conveniently
to form either a six- or a seven-membered ring by an intramolecular nitrile oxide
cyclization (INOC) reaction (Scheme 2.17). Treatment of the alkyl nitro group with
phosphorus oxychloride forms the dipole, which proceeds to do a cycloaddition on
the dipolarophile from the amine-containing component 127 .
The Ugi reaction has been combined with the click reaction to easily form a variety
of diverse triazoles. Compounds 131 - 135 were prepared by an initial Ugi reaction
in methanol at room temperature for 48 h (Figure 2.3). The Ugi product containing
an azide and alkyne can then form the triazole by a copper-free intramolecular click
reaction. The cycloaddition was performed in benzene at reflux. Seven examples
were presented in this paper by Akritopoulu-Zanze et al. [53].
The combination of multiple multicomponent reactions can exponentially increase
product diversity. Orru's group [54,55] has demonstrated one-pot procedures of these
tandem MCRs, as shown in Scheme 2.18. Imidazolines 139 can be formed by a Van
Leusen type reaction [56]. An acetate salt can be carried unaffected through this
procedure and can then participate in the following three-component Ugi reaction.
A bis-isonitrile ( 140 ) was utilized in this four-component reaction, and the second
isonitrile participated in a series ending Ugi reaction. This unique transformation can
SCHEME 2.17
Ugi-dipolar cycloaddition.
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