Effects of Shape on Thermodynamic Cyclizations of Cinchona Alkaloids

Thermodynamic cyclizations of a series of cinchona alkaloid derivatives are investigated. An extended quinine monomer 2:HO − Ce − OMe is prepared and cyclized to produce a mixture of cyclic oligomers. Combining the extended monomer 2:HO − Ce − OMe with the previously reported cinchonidine monomer 1b:HO − Cc − OMe under thermodynamic control produces a library of quinine-derived macrocycles. Two quinidine-derived methyl ester monomers 10:HO − Cd − OMe and 16:HO − Ca − OMe are also reported. Both are preorganized to form cyclic dimers; upon carrying out the thermodynamic cyclization on a mixture of both monomers only a small percentage (5%) of the hetero-dimer is obtained. Thermodynamic cyclization of the corresponding cinchonidine derived methyl ester 1b:HO − Cc − OMe with 10:HO − Cd − OMe results in the self-sorting of the two diastereoisomers.