Synthesis, modification, and characterization of a family of homologues ofexo-calix[4]arene: exo-[n.m.n.m]metacyclophanes, n,m >= 3

A general strategy for the preparation of the family of exo-[n.m.n.m]metacy clophanes (n,m greater than or equal to 3) in B-steps (starting from 2-brom oanisole) that utilizes a [2 + 2] approach to furnish the exo- metacyclopha ne ring in good to moderate yield is described. The soluble copper catalyst [CuBr-LiSPh-LiBr-THF] is used to efficiently couple Grignard and alkyl or ether tosylate reagents in several of the synthetic steps, including the ri ng construction in the final step. The ezo-[n.m.n.m]metacyclophane ring is conformationally mobile on the NMR time scale, and X-ray crystallography re veals that exo-[3.3.3.3]metacyclophane 2a assumes a cone conformation, and that exo-[6.6.6.6]-metacyclophane 6a assumes a chair conformation. Molecula r mechanics calculations show that both conformations for each exo-metacycl ophane are very similar in energy. Regiocontrol over the alkylation and acy lation of the phenolic oxygens of 2b is problematic, although the preparati on of the tetraacetylated 18 and alkylation of 2b with CH2BrCl to furnish t he methylene-linked mono-and bis-adducts 19 and 20 are straightforward.