2,6‐Disubstituted cuneane has potential as a p‐disubstituted benzene bioisostere and a novel chiral scaffold. It is a constitutional isomer of a 1,4‐disubstituted cubane obtained via a metal‐catalyzed skeletal rearrangement. Unlike the highly symmetrical 1,4‐disubstituted cubane, the isomerized 2,6‐disubstituted cuneane is a chiral molecule possessing C2 symmetry. Examining various chiral catalysts revealed that the Pd‐pincer catalyst provides a good asymmetric induction.
The unique polyfused cyclic hydrocarbon, cuneane, was obtained by structural isomerization of cubane. Eaton has reported that 1,4-cubanedicarboxylic acid ester is selectively isomerized to 2,6-cubanedicarboxylic acid ester catalyzed by silver (I). The cuneane has C2 symmetry. Chiral resolution of bis(2-phenylethyl) 2,6-cuneanedicarboxylate by chiral HPLC was performed; determination of the absolute configuration of each enantiomer was performed based on ECD (Electronic Circular Dichroism) spectra and DFT calculation.
The
first diastereoselective synthesis of trisubstituted cubanes
was achieved using a chiral auxiliary. To establish chirality within
the cubane skeleton, at least three substituents must be introduced
at the appropriate positions. Ready conversion of cubane carboxylic
acid to a chiral amide followed by sequential ortho-selective deprotonations and electrophilic trapping afforded the
corresponding 1,2,3-trisubstituted cubanes with high diastereoselectivity.
This route opens new possibilities for the preparation of enantio-enriched
cubanes.
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