Biomedical Engineering Reference
In-Depth Information
little resemblance to each other. Furthermore, the pathway exemplified above was
applied to substrates
65
and
66
, structurally distinct from
49
but comprising the same
reactive elements. This strategy based on chemical transformations controlled by the
reagent has demonstrated a relevance to DOS. Indeed, compounds
66
displayed sufficient structural diversitywhilemaintaining a common reactive element.
Therefore, it is conceivable that these substrates could potentially react as a mixture to
provide additional diversity in a split-pool protocol. The development of a catalyst to
favor an
anti
-Petasis condensation could potentially give rise to the
syn
-adduct isomer
of
49
,
65
, and
49
that could potentially double the size of the final library.
15.4.4.3. Built/Couple/Pair as a General Optimized Strategy
Nielsen and
Schreiber proposed a general strategy based on three phases that facilitates both the
thinking and the practical achievement of the optimized synthetic planning [43]. This
approach involves the identification of partners of reactive elements strategically
placed around a scaffold to confer differential modes of conversion to the substrate,
potentially leading todifferent skeletons.Thefirst phase, called“build”phase, includes
the preparation of building blocks containing orthogonal reactive elements and
stereogenic centers obtained either from the chiral pool or by means of asymmetric
synthesis. Ideally, all stereochemical possibilities should be accessible to maximize
the final stereochemical diversity. In the second phase, called the “couple” phase, the
building blocks are assembled using the available functionalities. Preferably, the
couple phase is carried out in a way that does not generate
de novo
asymmetric
centers unless all stereogenic outcomes can be controlled. Finally, the “pair” phase
consists of a coupling of complementary functional groups introduced in the build
phase to generate structures with increased rigidity. Porco and coworkers originally
introduced the notion of “functional group pairing” that focuses on functional groups
that can react with one another, usually in an intramolecular manner to produce cyclic
structures [44]. Pairing steps at the origin of additional reactive centers, poised for the
subsequent introduction of novel side appendages, are obviously appealing to DOS.
The strategic placement and nature of the functional groups is critical for a successful
pathway as it dictates the structural outcome of the process. A modular synthetic
approach ultimately integrates a variation of the positions of each reactive element that
can be paired, resulting in a variation of the skeletal outcome.
For example, Oguri and Schreiber extended the scope of a tandem rhodium
carbenoid cyclization/1,3-dipolar cycloaddition, previously established by Padwa
and coworkers [45-47], to synthesize a collection of rigid polycyclic structures
reminiscent of complex alkaloids (Scheme 15.7). Compounds
were prepared in
the build phase and assembled in the couple phase, placing reactive elements around a
common six-membered lactam scaffold to produce substrates
67
-
75
76
-
77
. On the other
hand, compound
was synthesized using a straightforward four-component Ugi
reaction. The introduction of alkoxy side chains potentially allowed the adaptation of
the synthetic method to solid-phase synthesis, or alternatively the loading of small
molecules in microarray format to facilitate a rapid biological evaluation. A rhodium
catalyst was used to trigger the formation of a carbonyl ylide that underwent a
cycloaddition with the indole 2,3-double bond providing fused polycyclic structures
79
78
-
81
. Stereogenic centers were initially introduced at C2 in the couple phase,
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