The solid-phase synthesis of novel 14-membered macrocycles for high throughput screening

Carolina L. Lanter, Joseph W. Guiles
Hoechst Marion Roussel, Inc., Route 202-206, P.O. Box 6800, Raritan, NJ 08869, U.S.A.

Ralph A. Rivero
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406, U.S.A.

Abstract
A simple and efficient synthesis of novel 14-membered macrocycles from a resin-bound orthogonally protected lysine residue is described. Reductive alkylation of the lysine a-nitrogen introduces the first diversity element. Acylation of the resultant secondary amine with an Fmoc-amino acid introduces the second diversity element providing a resin-bound protected di-peptide precursor. Removal of the Fmoc-group is followed by acylation with a succinic anhydride to introduce the final diversity elements. Removal of the methyltrityl-group from the amino group followed by macrocyclization provides the desired macrocycles, after TFA cleavage, in excellent yield and purity.

Keywords
combinatorial, cyclic peptides, cyclization, dipeptides, diversity, macrocycles, orthogonally protected lysine, solid phase, synthesis