Rotationally Hindered Biphenyls and Terphenyls: Synthesis, Molecular Dynamics, and Configurational Assignment

Sterically hindered
naphthalene-substituted biphenyls and terphenyls
were synthesized in good yields, by Michael addition of a conjugate
base of core-substituted phenylacetones to substituted 2-oxo-2H-pyran-3-carbonitriles at room temperature under alkaline
conditions. These diversely functionalized benzenes (1,2-teraryls
or 1,3-teraryls), bearing naphthyl and substituted aryl rings, show
the phenomenon of atropisomerism, with one or two stereogenic biaryl
axes. The resolution of the respective four atropisomers of the naphthalene-substituted
biphenyls and terphenyls bearing 1,2-type or 1,3-type chiral biaryl
axes was achieved by HPLC on a chiral phase. The absolute stereostructures
of 6a and 9a were determined by the combination
of experimental electronic circular dichroism (ECD) investigations
and quantum-chemical circular dichroism (QC-CD) calculations. For
the atropisomerization of (1M,6M)-6a and (1M,5M)-9a to their (M,P)- and (P,M)-diastereomer, respectively, the possible
transition states were investigated and the interconversion barriers
(ΔG‡) were theoretically
predicted. This study provides a general protocol for the synthesis,
resolution, and stereochemical characterization of rotationally hindered
naphthalene-substituted biphenyls and terphenyls. The strategy may
be applied to investigate other, similarly hindered biaryl or teraryl
systems either derived from natural sources or prepared through synthetic
approaches.