Substituent modification in tri-o-thymotide and its effects on host geometry and guest enclathration .1. synthesis

A new synthesis is described for the preparation of tri-o-thymotide (1, TOT) and some TOT analogues. The methodology is based on the sequential coupling of appropriately substituted and protected salicylic acid monomers followed by cyclization of the deprotected open-chain trimers. A variety of protecting methodologies and coupling sequences are discussed. The procedure seems generally applicable for the preparation of salicylides and has been used to prepare TOT in 25% overall yield (for the coupling-deprotection-coupling-deprotection-cyclization sequence). In addition, two new modified TOT-analogues 9 (25%, and 10 (14% were prepared in which the isopropyl group(s) ortho to the phenolic units is TOT is replaced by one (9) or two (10) ethyl groups. A third analogue 66. where the methyl group ortho to the carboxyl group is removed in one of the salicylic acid monomer units of TOT, requires only the last cyclization step for completion of its synthesis. This methodology represents an important breakthrough for the controlled preparation of selected thymotide (salicylide) trimers and allows easy access to a variety of modified thymotides (salicylides) for structural, conformational and host-guest studies.