Abstract:
A Diels-Alder approach to biaryls (DAB) has been applied towards the synthesis
of highly substituted, programmable biaryl templates. Tri- and tetra-ortho-substituted
biaryls can be produced in just three to four steps from commercially available materials
utilizing the Diels-Alder [4+2] cycloaddition. The methods described herein will
illustrate the ability of mono and disubstituted aryl acetylenic compounds to perform
effectively as dienophiles in the Diels-Alder reaction. Both acyclic and cyclic dienes have
been implemented in our DAB process, with the latter requiring milder reaction
conditions and exhibiting higher yields. The application of our DAB strategy towards the
synthesis of biaryls has provided rapid entry to challenging substitution patterns that are
not readily available by traditional coupling methods.
Aryl acetylenes that possess aryl / alkyl stannyl substituents undergo the
cycloaddition / cycloreversion reaction with bisoxygenated dienes to produce truly
programmable biaryl templates that are readily functionalized to give access to
compounds that are not readily accessible via traditional methods. Efforts to
functionalize these biaryl templates led to the discovery of a novel boroxine-based Suzuki
coupling strategy that can efficiently convert the sterically-encumbered chlorine-carbon
bond to various aryl and alkyl groups giving rise to functionalized tetra-ortho-substituted
biaryls that cannot be produced by traditional metal-mediated aryl-aryl bond formation.
The syntheses of three unique tetra-ortho-substituted biaryl compounds were
accomplished and these compounds were evaluated as potential ligands in aldol and
hetero-Diels-Alder reactions. During the course of this work, a general method for the
resolution of the biaryl compounds was illustrated that provided an efficient method for
the separation of the atropisomers of our biaryl compounds.
In addition, an efficient method for the construction of chiral biaryl amino acids
was established. During the course of this work, the ability to construct a biaryl amino
acid template was established, and the resolution of this template was accomplished using
the chiral amine, brucine. Using this template, we were able to construct a small peptide
containing a point-chiral amino acid at the C terminus of the biaryl template.
