Design of an organic sequence suitable for the solid phase combinatorial synthesis of libraries of macro-heterocycles

The solid as well as solution phase synthesis of two 14-membered macro-heterocycles is reported. The macrocycles are built out of four or three major building blocks and contain serine, a trans alkene and the malonate unit inside the framework. The macrocyclization was an SN2 reaction between a nucleophilic malonate anion and an allylic chloride leaving group. The first macrocycle, an ether, was obtained with an overall yield of 8% for the eleven steps on solid support similar to the 11% yield in solution. The overall yield for the second target macrolactone was 45% on solid phase for the six steps and was higher than in solution (35%). The stability of the DHP linker to various reagents and reactions conditions is noteworthy.