Biomedical Engineering Reference
In-Depth Information
SCHEME 2.26
3CR
Buchwald-Hartwig/condensation/arene-alkene
coupling
indole
synthesis.
forms an
o
-haloaniline via Buchwald-Hartwig coupling. Subsequent condensation
of the aryl amine and carbonyl group yields an enamine poised to ring-close to the
indole by an arene-alkene coupling (Scheme 2.26). A proposed mechanism was also
modeled in this work using quantum chemical calculations.
Several methods to produce a diverse array of macrocycles by MCRs have been
developed in the laboratories of Zhu and Wessjohann. The Ugi reaction and other
isonitrile-based MCRs have played a central role in these macrocycle-forming MCRs.
A general strategy has been to use long linear reactants with bifunctionality on
opposite ends. As in Scheme 2.27A, one reactant contains a terminal alkyne and
a terminal isonitrile. One oxazole-forming MCR occurs and the macrocycle then
closes with an azide dipolar [3
2] cycloaddition [73]. Scheme 2.27B demonstrates
the same oxazole-forming MCR reaction performed twice to make symmetrical
macrocycles (i.e., via one intermolecular MCR followed by one intramolecular MCR)
[74]. Wessjohann's group has taken advantage of the Ugi reaction in Scheme 2.27C
to make tri-macrocylic cage compounds from four Ugi MCRs [75].
In a particularly interesting MCR, Barluenga et al. [76] used a palladium catalyst
to synthesize spirofused ketals. Here, an alkynyl alcohol, in the presence of a transi-
tion metal catalyst, forms a vinyl ether, and a condensation between an aniline and
aromatic aldehyde forms an imine. This simultaneous in situ formation of a nucle-
ophile and an electrophile leads to a reaction producing the spiro system in a 1 : 1
mixture of diastereomers. Epimerization provides access to a single diastereomer
217
by treatment with dry perchloric acid with an overall yield of 87% (Scheme 2.28).
Ugi products have found use as precursors to benzoxazoles. Salcedo et al. [77]
subjected
o
-iodobenzoic acids and
o
-iodophenylisonitrile
218
to Ugi conditions,
giving Ugi products with bifunctional aryl iodides
220
in good yields (Scheme 2.29).
In the presence of a copper catalyst, the benzoxazole can be formed as the sole
product with no evidence of the seven-membered benzamide ring. The acidity of the
+
-proton to the benzoxazole is thus lowered, such that a palladium-catalyzed ring
closure can be performed.
A 3CR isonitrile-free multicomponent reaction is presented by Preciado et al.
(Scheme 2.30). What initially starts as a Povarov reaction is ultimately prevented by
Bredt's rule. Therefore, an opportunity to trap the oxonium intermediate is available.
The addition of several nitriles reacts with intermediate
228
, followed by cyclization.
This Mannich-Ritter reaction leads to a single diastereomer in moderate yields [78].
