A protected aldehyde was attached via a two-carbon spacer to a peptide backbone amide nitrogen during a traditional Merrifield solid-phase synthesis. Acid-mediated unmasking of the aldehyde triggered the regioselective formation of cyclic N-acyliminiums between the aldehyde and the neighboring peptide amide nitrogen. In the absence of an internal nucleophile, the cyclic iminiums formed dihydropyrazinones, a six-membered peptide backbone constraint between two peptide amides. In the presence of an internal nucleophile, tetrahydropyrazinopyrimidinediones or tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.

Polymer-supported N-(2-oxo-ethyl)-derivatized Ser/Thr/Cys-containing dipeptides were synthesized and subjected to acid-mediated tandem N-acylium ion cyclization-nucleophilic addition to yield tetrahydro-2H-oxazolo[3,2-a]pyrazin-5(3H)-ones. The reaction conditions and building-block combinations for stereoselective synthesis of the newly formed asymmetric carbon were developed. The synthesis was fully compatible with solid-phase peptide synthesis, and the products serve as conformationally constrained peptidomimetics. The traceless synthesis of bicycles is also reported as part of this work.

The stereoselective synthesis of 1,2,11,11a-tetrahydrobenzo[e]pyrazino[1,2-b][1,2,4]thiadiazin-3(4H)-one 6,6-dioxides on a solid support via tandem N-sulfonyl iminium ion cyclization, followed by nucleophilic addition is reported. The synthesis proceeded with full control of stereoselectivity at the newly formed asymmetric carbon, under mild conditions, and using commercially available building blocks. The synthetic route provided high-purity crude products.

Novel molecular scaffolds comprising two to four bridged and fused heterocycles were synthesized from amino acids using seven-membered endocyclic N-acyliminium ions as key intermediates in acid-mediated tandem reactions with internal nucleophiles. This complexity-generating synthesis proceeds with high efficiency and with full stereocontrol of the newly generated stereogenic center. These results have extended the scope of medium-sized cyclic iminium ion chemistry, making it applicable as a regio- and stereoselective synthetic strategy for the generation of complex polycyclic structures. Furthermore, its compatibility with the traditional Merrifield synthesis of peptides on solid supports allowed the incorporation of the previously unexplored conformationally restricted cyclic systems into peptides without a need to independently synthesize the scaffold.