Biomedical Engineering Reference
In-Depth Information
The authors suggest the concept of considering the linear ketone as a “molecular
rope” which they were then able to “tie into knots” using tandem reactions, and
so produce a range of three-dimensional scaffolds. In some ways this approach
could be considered to be a combination of the use of pluripotent functionality
(provided by the ketone and
-unsaturated ester groups) and densely functionalized
molecules (generated in situ), followed by tandem pairing reactions. However, such
a classification is largely irrelevant, and regardless of nomenclature, this 12-fold
pathway represents an ingenious use of reagent-based diversification. Overall the
work generated a range of mono-, bi-, and tricyclic scaffolds possessing fused bridged
and cyclic architecture from a single linear substrate. They then synthesized a set of
analogs of compound 27 for testing against three cancer cell lines (HL-60, THP-1,
A549), which resulted in the discovery of a number of compounds showing low
micromolar activity against all three cell lines, including their best compound 28 ,
which showed sub-10-
,
M activity against two of the cell lines.
1.9 SUBSTRATE-BASED APPROACH TO SKELETAL
DIVERSITY GENERATION
An impressive example of a folding pathway in the generation of skeletal diversity was
devised by Morton et al., who used metathesis cascade processes to produce a library
consisting of over 80 distinct scaffolds [57]. This was achieved by attaching two of
a number of building blocks (“called a propagating” building block in the center of
the molecule and a “capping” building block on the end) to a fluorous tagged linker
to give densely functionalized linear intermediates containing several unsaturated
groups able to take part in the metathesis cascade (Scheme 1.5). The fluorous tagged
linker group was also designed to take part in the metathesis cascade, with the final
cyclization intended to cleave the linker and allow easy generic purification of the
desired products from uncyclized material.
In total, 86 linear substrates were prepared, and from these 96 final products were
obtained, based around 84 molecular scaffolds. The molecules also contain a high
degree of stereochemical diversity and structural complexity and as such can be
considered to be “natural product-like.” This work represents the largest number of
scaffolds present to date in a deliberately synthesized DOS library.
As for the work of Schreiber's group, this DOS library could be considered to
follow the build/couple/pair synthetic plan. First, the fluorous tag and the propagating
and capping building blocks are built, they are then coupled together to give the linear
precursors, and finally, the unsaturated groups are paired in the metathesis cascade.
1.10 OTHER BUILD/COUPLE/PAIR EXAMPLES
As indicated by some of the examples discussed above, the build/couple/pair
paradigm has become very widespread in DOS. Two additional examples published
in 2011 will now be discussed; these are intended to illustrate the range of structural
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