Biomedical Engineering Reference
In-Depth Information
natural products “yet to be discovered” (
). The products exhibited
unprecedented structural diversity represented by a 1,3-cyclohexadiene, a bicyclo
[4.2.0]octadiene, a bicyclo[3.1.0]hexane, a fused pyrone/cyclohexadiene, a bridged
endo
-peroxide/cyclohexene, and a 1,4-cyclohexadiene. It is believed that these
substrates have evolved to protect the organism against reactive oxygen species and
detrimental UV radiations, in addition to their toxic and trophic properties used in
defense mechanisms or to stimulate tissue regeneration. It is conceivable that Nature
has randomly used these pathways to sustain the existence of useful metabolites
relevant to the habitat of the organism. In that case, some of these compounds may
only be by-products of uncontrolled chemical processes, evolutionarily conserved
because they are chemically favored. Such chemical transformations offer consid-
erable potential for the synthesis of libraries of diverse and complex molecular
skeletons, even though they are low yielding and nonenantioselective, yet preventing
their use in combinatorial processes. The invention of novel catalysts to promote
torquoselective electrocyclizations, or to trigger double bond isomerizations selec-
tively, in a way that Nature has been unable to achieve will be highly challenging.
Nevertheless, this rare example demonstrates that Nature has probably already
explored diversity-oriented processes to generate chemically favored compounds
harboring widespread biological properties.
105
,
106
, and
110
15.5.3. Ruthenium-Catalyzed Metathesis Cascade
Nelson and coworkers described a remarkable folding pathway that involved ruthe-
nium-catalyzed metathesis cascades to generate a collection of 84 structurally diverse
small molecules [55]. This strategy was based on the modular coupling of three types
of unsaturated building blocks, a “fluorous-tagged linker,” a “propagating building
block,” and a “capping building block,” into diverse oligomers. The capping building
block defined the initiation point of the cascade mediated by the ruthenium catalyst.
First, a metallocarbene was formed with the terminal olefin of the capping building
block. Once it is formed, a metathesis cascade resulted in a series of ring opening and
closure with concomitant release of the substrates from the tag, thus terminating the
cascade (a subset of themolecular scaffolds created are represented in Scheme 15.10).
The propagating building blocks served as a relay for the cascade to occur. In a
typical experiment, the propagating building blocks were coupled to the tag via a
Fukuyama-Mitsunobu reaction or a silaketal formation. This was followed by
deacylation and the introduction of the capping building blocks by an additional
Mitsunobu reaction, an esterification, or another silaketal formation, depending on the
building block used. Finally, the metathesis cascade was promoted by the first-
generation Grubbs catalyst in refluxing dichloromethane, or alternatively by a
fluorinated version of the Grubbs-Hoveyda catalyst. A straightforward deprotection
of cyclic silanes in the presence of HF
Py released alcohol functionalities poised for
further diversification that were not exploited in that study. Notably, the fluorous tag
allowed the use of a large excess reagents to enhance the yield of chemical
transformations and facilitate a rapid chromatography-free purification via a conve-
nient fluorous solid-phase extraction. This resulted in the isolation of cyclized
products only, while aborted reaction cascades led to uncyclized compounds that
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