Stereoselective cyclotetramerization of a 3-(Hydroxymethyl)salicylaldehyde

Both 3-(hydroxymethyl)-5-methylsalicylaldehyde and its acetonide condense in the presence of hydrogen chloride in ether to form macrocyclic S(4)-symmetric tetraacetal 2. The reaction is completely oligo- and stereoselective, forming only the tetramer and only the achiral (R,S,R,S)-stereoisomer. Acid-catalyzed equilibration studies and molecular mechanics calculations indicate that the stereoselectivity is thermodynamic in origin. In the crystal the saddle-shaped molecules of 2 form coaxial stacks reminiscent of the packing of Pringles potato chips.