A two-pronged method for the synthesis of fused diketopiperazines using iminium cyclization reactions is presented. Tripeptides were conveniently assembled on HMBA-functionalized PEGA resin using standard solid-phase synthesis procedures, generally positioning an aromatic amino acid immediately before an N-alkylated residue, to which a serine moiety was installed (Pathway 1). Subsequent oxidative cleavage and acid-mediated intramolecular Pictet-Spengler type cyclization gave the desired trans-tetrahydroisoquinolines with excellent product purities. The broad scope of the methodology is illustrated by the application of ring-substituted and a-alkylated phenylalanine as well as heteroaromatic, olefinic and heteroatomic residues, in combination with N-alkylated and cyclic amino acids. The stereochemical versatility of the method was assessed by using combinations of D- and L- amino acids. Finally, cis-tetrahydroisoquinoline products were accessed using an intermolecular Pictet-Spengler reaction (Pathway 2). In summary, we have developed methodology that provides efficient access to natural product-like compound libraries with excellent control of skeletal and stereochemical structural elements.

Solid-phase iminium cyclization reactions for the synthesis of natural product-like diketopiperazines

245th National Meeting (2013)

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