Biomedical Engineering Reference
In-Depth Information
bond-forming reactions that produce nonaromatic heterocycles of low molecular
weight would be an ideal platform. Nucleophilic phosphine catalysis of allenoates
and propiolates presented such an opportunity [40-45]. When performing phosphine
catalysis-based DOS and related chemical biological studies, our research activities
fit into three stages. The first phase involved the development of new reactions for
allenoates and propiolates under nucleophilic phosphine catalysis conditions as well
as compiling and testing a pilot library of diverse small molecules. The second stage
involved converting the newly developed reactions to a format for solid-phase syn-
thesis; allenoic acids and propiolic acids could be loaded onto resin-bound alcohols
simply through ester linkages, and the fact that our phosphine-catalyzed reactions
worked best in nonpolar organic solvents forecasted minimal effort in this trans-
lational stage. Upon identification of specific scaffold of compounds as biomodu-
lators, the third phase involved solid-phase combinatorial synthesis of analogs of
the hits, potentially facilitating related biological studies and the development of
therapeutic leads; more conventional medicinal chemistry could further expedite
the progression of therapeutic leads, when appropriate. The efficient preparation of
small molecules and their analogs would boost research and development in all of
these stages.
In the first stage of our DOS research, we demonstrated that various reactionmodal-
ities could be controlled through appropriate choice of the phosphine catalysts as well
as structural variations in the startingmaterials. For the allenes, we performed one-step
ring-closing reactions using either commercially available or otherwise readily avail-
able imines, maleimides, aldehydes, aziridines, electron-deficient olefins, azomethine
imines, and dinucleophiles, resulting in distinctive carbo- and heterocyclic scaffolds,
including tetrahydropyridines, pyrrolines, pyrones, dihydropyrones, dioxanes, cyclo-
hexenes, coumarins, bicyclic succinimides, tetrahydropyrazolopyrazolones, tetrahy-
dropyrazolopyridazinones, tetrahydropyrazolodiazepinones, tetrahydropyrazolo-
diazocinones, hexahydropyrazoloisoquinolines, hexahydrodiazepinoisoquinolines,
benzimidazolines, benzoxazolines, benzothiazolines, benzodioxoles, benzoxathioles,
and benzodithioles [46-58]. For electron-deficient acetylenes, one-step double-
Michael reactions with readily available dinucleophiles were effected when using a
diphenylphosphinopropane catalyst, providing several heterocyclic frames, includ-
ing oxazolidines, thiazolidines, pyrrolidines, indolines, dihydropyrrolopyridines,
benzimidazolines, tetrahydroquinolines, tetrahydroisoquinolines, dihydrobenzo-3,1-
oxazines, and dihydrobenzo-1,4-oxazines [59-61]. At the same time, phosphine-
catalyzed Michael addition followed by Heck cyclization occured with o -iodobenzyl
alcohols and electron-deficient acetylenes, giving phthalans [62]. We were especially
pleased to find that the phosphine catalysis reactions are extremely compatible with
polystyrene resin-bound allenoates, allowing the efficient construction of focused
libraries through split-and-pool synthesis [63,64]. In several bioassays we tested our
DOS libraries prepared through phosphine organocatalysis, resulting in the identifica-
tion of geranylgeranyltransferase type I (GGTase-I) inhibitors [63,65-67], activators
of endothelium-driven immunity [64], the cholesterol-lowering compound aplexone
[68], and antimigratory compounds [69].
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