Definitive evidence for inhibition of calix[6]arene ring inversion obtained from a 1,3-xylenyl-bridged chiral calix[6]arene

To design calix[6]arene-based receptor molecules which show high affinity and high selectivity toward guest molecules, the construction of more rigid and conformationally-defined analogs has been long awaited (Gutsche; Alam Tetrahedron 1988, 44, 4689). It has been predicted that in certain sterically-hindered calix[6]arenes the ring inversion is suppressed. However, evidence presented so far (mainly from NMR spectroscopy) is indirect and is valid only in the range of the NMR time scale. To find definitive evidence for the immobilization we synthesized a calix[6]arene (4), the 1,3-phenyl units of which are bridged by an asymmetrical 4-methoxy-m-xylenyl unit, and optically resolved it by an HPLC method using a chiral packed column. Since ring inversion is obligatorily accompanied by racemization, one can easily discriminate between true immobilization and NMR time-scale immobilization. The H-1 NMR studies have established that 4 adopts a cone conformation, which is unaffected up to 130 degrees C. Very importantly, it was shown that 4 does not racemize even at 100 degrees C. This provides unambiguous evidence for the immobilization of the calix[6]arene ring in 4. This paper demonstrates that the racemization of chiral calix[6]arenes is an effective (and probably sole at present) methodology to obtain the definitive evidence for ring immobilization.