Constrained peptidomimetics: Medium-sized fused bicycles incorporation into peptide backbone

AGUSTINA LA VENIA; PILAR VENTOSA-ANDRES; CARLOS A BAREA RIPOLL; VIKTOR KRCHNAK

San Diego

Conferencia; 10th Drug Discovery Chemistry Conference; 2015

Medium-sized heterocycles are importantkey intermediates in the synthesis of complex molecules, as well as corestructures in natural and pharmaceutical compounds.1 In addition, thesecyclic moieties can be incorporated into peptide backbones as conformational constraintsunits. Therefore the synthesis of this class of heterocyles remains achallenging task for organic chemists. Herein, we present the synthesis of molecular scaffolds consistingof seven-, eight-, and nine-membered rings included in bicyclic systems which were obtained ingood overall yields and with high and full stereocontrol of the newly generatedchiral carbon. The acyclicprecursors were assembled using traditional Merrifield solid-phase peptidesynthesis, andthe double cyclizations were carried out via acid-mediatedtandem endocyclic N-acyliminium ions formation, followed by nucleophilic addition withinternal nucleophiles.2The use of amino acids as main building blocks enableda broad structural diversity, covering a varied pattern of ring sizes, including[7+5], [7+6], [8+5] and [9+5] fused rings, as well as allowing the incorporation of differentheteroatoms into the bicycles such as N, O, and S. Furthermore,C-nucleophiles contained in electron-rich aromatic rings at the side chain of the aminoacids provided complex tri- andtetracycles via C-C bond formation. This synthetic strategy provides a route to heterocyclic systems whichare interesting by themselves, and moreover, facilitates the incorporation ofthese moieties for the construction of potential constrained peptidomimetics. References1. a) H. Ohno,H. Hamaguchi, M. Ohata, S. Kosaka, and T. Tanaka, J. Am. Chem. Soc., 2004,126, 8744. b) U. Nubbemeyer, Eur. J. Org. Chem., 2001, 1801.2. a) A. La-Venia, B. Lemrova, and V. Krchnak, ACSComb. Sci., 2013, 15 (1), 59. b) A. La-Venia, B. Dolensky,and V. Krchnak, ACSComb. Sci., 2013, 15 (3), 162. c) P. Ventosa-Andres, L. Hradilova, and V. Krchnak, ACSComb. Sci., 2014, 16(7), 359, d) A. La-Venia, P.Ventosa-Andres, L. Hradilova, and V. Krchnak, J. Org. Chem., 2014, 79 (21), 10378.