Biomedical Engineering Reference
In-Depth Information
accommodate up to eight components in a single flask. The use of racemic starting
materials ultimately gives four diasteromeric products
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. However, this method
can easily be used to build up structural diversity.
In addition to the direct use of MCRs to access diverse and complex small-
molecule scaffolds, the build/couple/pair (B/C/P) strategy has gained some attention
[57]. This strategy, outlined by Nielsen and Schreiber, begins with the asymmetric
synthesis of building blocks incorporating defined stereogenic units and tailored reac-
tive functionalities (build phase). These building blocks are then combined (couple
phase) through intermolecular bond-forming processes to yield a complete matrix
of stereoisomers of the main carbon framework. Finally, intramolecular joining of
strategically positioned functional groups (pair phase) takes place. When this strategy
is utilized with a multicomponent couple phase, one can obtain a diverse array of
compounds for high-throughput screening.
One of the more prominent MCRs in combinatorial chemistry and drug discovery,
especially as part of a B/C/P strategy, is the Petasis reaction. Here, an amine, aldehyde,
and vinyl- or arylboronic acid come together to form substituted amines. First reported
in 1993 as a practical method for the synthesis of the geometrically pure antifungal
agent naftifine [58], the Petasis reaction can be ascribed as a variation of the Mannich
reaction. However, rather than generating an enolate to form the substituted amine
product, the boronic acid serves as the nucleophile. In comparison to other methods of
generating substituted amines, the Petasis reaction tolerates a multifunctional scaffold
with a variety of amines and organoboronic acids as potential starting materials.
Additionally, the reaction does not require anhydrous or inert conditions, which
makes it a mild and selective synthesis.
In the first B/C/P library synthesis, the build phase consisted of the stereoselective
synthesis of
-hydroxyaldehyde
147
(protected as the lactol) and phenylalanine
methyl ester
148
[59]. A Petasis 3CR between these two components and (
E
)-2-
cyclopropylvinylboronic acid
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, followed by propargylation of the resulting amine,
was used in the couple phase. Subsequent reagent-controlled rearrangement reactions
(pair phase) between the polar and nonpolar functionalities present provided a wide
range of structurally complex small molecules (Scheme 2.19).
A more recent example of library synthesis utilizing a B/C/P strategy with a Petasis
3CR involved a Ru-alkylidene-catalyzed ring-closing metathesis reaction for the pair
phase [60]. By varying the location of the terminal alkenes, diverse arrays of five-
and seven-membered heterocycles were obtained. In addition, changing the catalyst
for the seven-membered ring substrate led to the formation of bicyclic aminals via a
tandem isomerization/
N
-alkyliminium ion cyclization sequence, providing even more
diversity from the Petasis amino alcohol products (Scheme 2.20).
Although the strictest classification of an MCR requires a mixture of at least three
chemicals without regard to precise control of the order of addition, there are many
processes that incorporate multiple components in the same product in which the
order of addition is crucial. These components can still be highly variable and lead to
a diverse array of products. The specific order of addition distinguishes this process
from that of a typical MCR. This strategy, pioneered by Martin et al. in 1991 and
referred to as a
multicomponent assembly process
(MCAP) [61], has been used in
