Biomedical Engineering Reference
In-Depth Information
additions of thiols to
110
and
114
gave
112
and
116
, respectively, which, upon TFA-
mediated cleavage, yielded the highly functionalized pyrrolidines
113
and piperidines
117
, respectively, as single diastereoisomers in good to excellent yields. We treated
the resin-bound tetrahydropyridines
114
with Tebbe reagent and anhydrous pyridine
to obtain the dienol ethers
118
, which give the tetrahydropyridine enones
119
in
overall yields (over four steps) of up to 53% with excellent purity (
95%,
1
H NMR).
Furthermore, endo-selective Diels-Alder reactions with the
N
-sulfonylimines
109
in
toluene produced the octahydro-1,6-naphthyridines
120
, which we hydrolyzed from
the resin using 2.5% TFA in CH
2
Cl
2
to yield, after chromatographic purification,
the octahydro-1,6-naphthyridin-4-ones
121
in overall yields (over five steps) of up
to 39% with high diastereoselectivities. Notably, this strategy for construction of
our combinatorial library is very efficient in terms of the consumption of the build-
ing blocks, because we used the
N
-sulfonylimines in both the phosphine-catalyzed
[3
>
2] annulations and the Diels-Alder reactions. Employing 19 allenoic
acids, 46
N
-sulfonylimines, and 32 thiols as building blocks, we synthesized a library
of 4388 heterocyclic compounds, featuring five distinct scaffolds, through our com-
binatorial scaffolding strategy on a solid support.
+
2]/[4
+
4.4 A DOS LIBRARY BASED ON PHOSPHINE ORGANOCATALYSIS:
BIOLOGICAL SCREENING, ANALOG SYNTHESIS, AND
STRUCTURE-ACTIVITY RELATIONSHIP ANALYSIS
Although many examples exist of collections of structurally diverse small organic
molecules serving as reservoirs of therapeutic lead compounds, we were cognizant
of the need to identify multiple biomodulators from our phosphine catalysis-driven
library. Although we did not build our library with any specific target or known
leads in mind, it exhibited intuitively desirable traits: heterocyclic compounds with
low molecular weights and conformational constraints; complexity; novelty; and
diversity. In this context, we were delighted to find that the library did, indeed, allow
the discovery of many biomodulators of therapeutic potential. Combining phosphine
organocatalysis of allenes and acetylenes with the combinatorial scaffolding strategy
allowed us to prepare a designed DOS library of up to 4600 carbo- and heterocyclic
compounds, featuring 55 distinctive scaffolds (Scheme 4.30). As a pilot library,
we arrayed 642 model compounds, selected from our DOS library, in nine 96-well
microtiter plates as 5 mM solutions in DMSO and disseminated them to our biologist
collaborators. Four different types of biological systems were used in the bioassays
of our pilot library compounds: (1) in vitro enzymatic assays by the Tamanoi group in
the Department of Microbiology, Immunology and Molecular Genetics at UCLA; (2)
endothelial cell activation bioassays by the Cruz lab in the Department of Medicine,
Division of Cardiology at UCLA; (3) cancer cell migration assays by the Fenteany
group in the Department of Chemistry at the University of Connecticut; and (4)
zebrafish developmental screens by the Chen group in the Department of Molecular,
Cell, and Development Biology at UCLA. In the following sections we provide a
summary of the results from these assays.
