Biomedical Engineering Reference
In-Depth Information
SCHEME 4.26
Armstrong's multiple-core structure library. (Adapted from [13], with per-
mission; copyright
C
1997 American Chemical Society.)
We chose the dihydropyrrole and tetrahydropyridine scaffolds as starting points
to explore the generation of a library with high skeletal diversity library when using
the combinatorial scaffolding strategy. When the C
-unsaturated
ester in the dihydropyrrole and tetrahydropyridine compounds is methylenated, the
resulting dienol ether (an electron-rich diene) can undergo Diels-Alder reactions
with different electron-deficient dienophiles to generate a variety of fused hetero-
cyclic compounds possessing distinctive frameworks (Scheme 4.27) [69]. Indeed,
Diels-Alder reactions of Tebbe reaction products and electron-deficient dienophiles
provided a key skeleton-diversifying branch in our DOS pathway.
To begin exploring this concept, we prepared, as starting materials, the dihydropy-
rroles
85
and the tetrahydropyridines
87
through phosphine-catalyzed annulations
between the allenoates
83
and the imines
84
, in excellent yields (90 to 97%) on multi-
gram scales. Methylenation of the
=
O moiety of an
,
-unsaturated esters with Tebbe reagent gave the
corresponding ethoxy dienes with good reaction efficiencies (50 to 82%). Through
screening of dienophiles, we identified maleimides,
N
-phenyl triazolinedione, tetra-
cyanoethylene, imines, benzoquinone, and 2,6-dichlorobenzoquinone as very good
reaction substrates for the Diels-Alder reactions of the ethoxy dienes. Although the
reaction yields were only moderate to good (35 to 85%), the reaction stereoselec-
tivities were excellent. Furthermore, the enol ether units could be hydrolyzed to
the corresponding ketone products, single diastereoisomers, upon treatment with a
solution of aqueous HCl in acetone. Scheme 4.28 displays 16 representative com-
pounds, each possessing a distinct scaffold that we synthesized through a sequence
,
