Synthesis and conformational studies of regio- and conformational isomers derived by O-alkylation of tetrahydroxy[3.1.3.1]metacyclophane 1

The synthesis and structure of O-alkylated tetrahydroxy[3.1.3.1]metacyclophanes are described. 6,13,22,29-Tetra-tert-butyl-9,16,25,32-tetrahydroxy[3.1.3.1] metacyclophane 3 was tetra-O-alkylated with alkyl bromides (RBr: R = Et, Pr and Bu) in the presence of Cs 2 CO 3 to yield one pure stereoisomer in each case (i.e. the 1,4-alternate conformer) 5b–d as a major product; other possible isomers were not observed. Ring inversion by oxygen-through-the-annulus rotation is allowed for tetraethoxy and tetrapropoxy derivatives 5b,c (for 5c; coalescence temperature ca. 90 °C) but inhibited for the tetrabutoxy derivative 5d. In contrast, alkyl halides having larger alkyl groups than ethyl afforded poor yields of the corresponding tetra-O-alkylated compounds 5 although a significant amount of 1,3-di-O-substitution products 4 resulted when NaH was used as a base. On the other hand, the tetraol 3 was tetra-O-alkylated with benzyl bromide in the presence of NaH to yield exclusively the cone conformer cone-5f in quantitative yield. Only when the cation-π interactions between the alkali-metal cations and the π-electrons of the benzyl group(s) are able to hold the latter and the oxide group(s) on the same side of the [3.1.3.1]MCP is the conformation immobilized to the cone. The template effect of the sodium cation plays an important role in this benzylation. The 1 H NMR spectral behaviour of these macrocyclic metacyclophanes is also discussed.