The Manual and Automated Solid-Phase Synthesis of α-Substituted Prolines and Homologues

Activation of N-terminal resin-bound amino acids as aldimines, followed by alkylation with α,ω-dihaloalkanes, provides key intermediates for the solid-phase preparation of racemic α-substituted proline ring homologues bearing amino acid side chains. Two intramolecular displacement strategies, one involving an amine nucleophile, the other an amide nucleophile, were used to convert the intermediate ω-chloro or ω-bromo derivatives to the desired cyclic products. Using one of these routes and a fully automated synthesizer, a 48-membered library of α-substituted prolines was prepared in a combinatorial fashion.