FULL PAPER DOI: 10.1002/ejoc.201402331 5-Aminopenta-2,4-dienals: Synthesis, Activation towards Nucleophiles, Molecular Modeling and Biosynthetic Implications in Relation to the Manzamine Alkaloids Lok-Hang Yan, [a] Adam Skiredj, [a] Yves Dory, [b] Bernard Delpech, [c] and Erwan Poupon* [a] Keywords: Alkaloids / Nucleophilic addition / Natural products / Aminopentadienal / Manzamine Substituted 5-aminopentadienals and glutaconaldehydes are key elements postulated in the biosynthesis of the diverse class of manzamine-type alkaloids. The activation of 5- aminopentadienals into electrophilic iminium salts and their subsequent reactivity towards various nucleophiles has per- mitted the synthesis of a series of unsaturated compounds sometimes accompanied by cascades of rearrangements. Molecular modeling of these systems carried out using DFT Introduction Highly complex and intriguing alkaloids (as represented by 1–5 in Figure 1) belonging to the “manzamine family” have stimulated an impressive amount of scientific research over the last 25 years following the isolation and structure determination of manzamine A (1) from Haliclona sp. sponges by Higa in 1986 (Figure 1). [1] Although little is known about their true biosynthetic pathway [2] and, in fact, their real origin (symbiotic bacteria within the sponges), [3] manzamine alkaloids have been the focal point of state of the art efforts directed toward their total synthesis especially when biosynthetically inspired. In- deed, two complementary biosynthetic models were put for- ward in the 1990s, following the Baldwin and Whitehead acrolein and dihydropyridinium hypothesis. [4] The Maraz- ano malonaldehyde and pyridinium hypothesis [5] further enriched a fruitful debate. Both models enabled great achievements in biomimetic synthesis and were finalized in late 2000 by way of a unified model. [6] [a] Université Paris-Sud, Laboratoire de Pharmacognosie associé au CNRS, UMR 8076 (BioCIS), LabEx LERMIT, Faculté de Pharmacie, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry, France E-mail: erwan.poupon@u-psud.fr http://www.biocis.u-psud.fr [b] Laboratoire de Synthèse Supramoléculaire, Département de Chimie, Institut de Pharmacologie, Université de Sherbrooke, 3001, 12è avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada E-mail: Yves.Dory@USherbrooke.ca [c] Institut de Chimie des Substances Naturelles, Centre de Recherche de Gif, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette CEDEX, France Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201402331. Eur. J. Org. Chem. 2014, 4973–4984 © 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4973 calculations of HOMO/LUMO was in agreement with the ex- perimental results indicating that strong electrophilic agents, such as POCl 3 are required to turn 5-aminopentadienals into electrophiles. New examples of glutaconaldehyde reactivity, especially towards pyridinium salts, are presented and bio- synthetic considerations are kept in mind throughout this study. Figure 1. Representative examples of manzamine alkaloids. Biosynthetically speaking, the key formation of pyridin- ium salts could be explained by a three-component reaction between a long-chain fatty primary amine, a similar alde- hyde and a C 3 unit such as malonaldehyde 6. [5a] Three types of acyclic C 5 reactive intermediates may be involved in the process: two different types of aminopentadienals (7') and