Synthesis and Conformational Studies of Regio- and Conformational Isomers Derived from O-Benzylation of Tetrahydroxy[3.1.3.1]metacyclophanes

Abstract

Regioselective O-benzylations of [3.1.3.1]metacyclophanes with intraannular OH groups are described. O-Benzylation of 6,13,22,29-tetra-tert-butyl-9,16,25,32-tetrahydroxyy[3.1.3.1]metacyclophane 1 with 2 equiv. of benzyl bromide in the presence of Na2CO3 leads to exclusive formation of the monosubstituted product 3. In contrast, use of K2CO3 as the base leads to di-O-substitution, resulting in the disubstituted product, distal-4, as the major product, along with some 1,2-proximal-4, in spite of using a large excess of benzyl bromide. Under the same reaction conditions in the presence of Cs2CO3, a mixture of two conformers of the tetra-O-benzylated product 2 in a ratio of 80:20 (cone-2-1,4-alternate-2) is obtained in 83% yield. Thus, the alkali metal cation plays not only an important role with regard to the regioselectivity, but also in determining the number of O-benzylations that occur, as a consequence of the template effect. Regioselective syntheses of dimethoxy- and trimethoxy[3.1.3.1]metacyclophanes are accomplished by a protection-deprotection strategy, using the benzyl residues as protecting groups. The 1H-NMR spectra of these macrocyclic metacyclophanes are also discussed.