Expanding the substrate scope of ugi five-center, four-component reaction U-5C-4CR): ketones as coupling partners for secondary amino acids

Maciej Dawidowski 0 1 2 Sawomir Sobczak 0 1 2 Marcin Wilczek 0 1 2 Artur Kulesza 0 1 2 Jadwiga Turo 0 1 2 0 M. Wilczek Laboratory of NMR Spectroscopy, University of Warsaw , Pasteura 1 Str., 02-093 Warsaw, Poland 1 S. Sobczak Medical University of Warsaw , Z wirki i Wigury 61 Str., 02-091 Warsaw, Poland 2 A. Kulesza Faculty of Chemistry, University of Warsaw , Pasteura 1 Str., 02-093 Warsaw, Poland Various symmetrical and unsymmetrical ketones were successfully coupled with secondary amino acids in the course of Ugi five-center, four-component reaction (U-5C-4CR), thus expanding the molecular diversity possible to be achieved by the reaction. The chemical yields depended on the degree of hindrance of the components employed and were satisfactory in view of possible steric interactions in the U-5C-4CR zwitterionic intermediate. The sense of diastereoinduction for reactions employing unsymmetrical ketones was examined by converting the resulting Ugi adducts into the corresponding rigid 2,6diketopiperazine derivatives. - Over the past several decades, multicomponent reactions (MRCs) have become attractive tools in modern synthetic organic chemistry. Among their many advantages, they allow the creation of large chemical libraries of diverse, complex molecular structures, starting from simple materials within a short time frame. Not surprisingly, these particular features have made MCRs especially appealing to medicinal chemists [16]. The well-known Ugi four-component reaction (U-4CR, Scheme 1) is one of the most widely used isocyanide-based multicomponent reactions (IMCRs). The classical variant of U-4CR comprises a one-pot sequential condensation of an amine, a carbonyl compound, an isocyanide and a carboxylic acid, to produce a linear, peptidelike adduct with high yield and high atom economy [79]. Since its discovery in 1959, the U-4CR has received growing attention for its potential to quickly assemble complex molecules. Initially, use of U-4CR in this capacity was restricted by limited availability of various isocyanide components. Since then, these components, including the so-called convertible isocyanides [1013], have become readily available, expanding the molecular diversity that can be achieved using the reaction. Numerous variants and post-condensation modifications of the original U-4CR have emerged [1418]. One of them is an Ugi five-center four-component reaction (U-5C-4CR, Scheme 1), which differs from the parent U-4CR not only in the number of reacting functional groups, but also in its mechanism. It is based on the condensation of a carbonyl compound, an isocyanide, a nucleophile and an amino acid as a bifunctional component. The reaction is initiated by the reversible formation of the zwitterionic imine I from the amino acid and carbonyl components. The subsequent addition of the isocyanide and intramolecular addiScheme 1 Ugi U-4CR and U-5C-4CR tion of the carboxylate give the cyclic intermediate II, which undergoes irreversible nucleophilic attack to form the 1,1 iminodicarboxylic acid derivative III. It is important to note that reaction usually proceeds with high diastereoselectivity if a chiral amino acid is used as an input [19]. Despite its high potential to generate interesting adducts for medicinal chemistry purposes, U-5C-4CR variant has received less attention when compared to parent U-4CR. The reaction has been applied to - and -amino acids, aldehydes, ketones, isocyanides and simple alcohols [1925]. However, while ketones have been reported to react successfully with primary amino acids in the course of the U5C-4CR and related Ugi five-center three component reaction (U-5C-3CR) [21,23,26,27], their condensation with secondary amino acids has not been explored. Arguably, these coupling partners can be regarded as insufficiently reactive because of possible steric interactions in the initial imine zwitterionic intermediate of the postulated reaction mechanism (Scheme 1). Further, conversely to the condensations of primary amines or amino acids, in case of secondary amino acids the imine intermediates can not be preformed. Recently, we described the application of U-5C-4CR adducts derived from aldehydes and secondary amino acids as intermediates for biologically active 2,6-diketopiperazine (2,6-DKP) derivatives [28]. Encouraged by the wide substrate scope of U-5C-4CR encountered, we decided to investigate the possible use of various aliphatic ketones as carbonyl inputs for the condensations with secondary amino acids. Since U-5C-4CR of an enantiopure amino acid and an unsymmetrical ketone proceeds with the formation of a new stereogenic centre, we investigated the degree and the sense of diastereoinduction. Results and discussion We chose L-proline, acetone, tert-butyl isocyanide and methanol as model inputs for preliminary experiments (Table 1). Propitiously, the Ugi product 1a formed with an acceptable yield, after 1 day, at room temperature, without use of any catalyst (Entry 1). When the reaction time was prolonged to 3 days (Entry 2), the yield improved, indicating that U-5C-4CRs of secondary amino acids with ketones might require longer completion times than analogous processes for aldehydes. The reaction was inhibited by addition of 1 eq. of an organic base (Entry 3), whereas a significant improvement of chemical yields was achieved with catalytic amounts of Lewis acids (Entries 45). TiCl4 proved superior to FeCl3 and was chosen for further studies. Neither increasing the time of the catalysed reaction to 5 days (Entry 6) nor performing the reaction at the lower (20 C) or higher (50 C) temperature (Entries 78) improved the reaction yield. With the optimized reaction conditions in hand (Table 1, Entry 5), we initiated investigations of the substrate scope and limitations of the U-5C-4CR of secondary amino acids and ketones (Fig. 1). We initially examined symmetrical ketones as coupling partners for L-proline, tert-butyl isocyanide and methanol (Fig. 2). Chemical yields ranged from 0 to 61 % and were largely dependent on the steric properties of the ketones employed. The highest yield was achieved for the derivative of the least bulky acetone, 1a; however, when the aliphatic side chains of the ketone were expanded with methyl groups in 1b, a markedly lower yield was observed. Given these results, we were surprised to see no further drop of yield when using more sterically hindered dibenzyl ketone for 1c. Conversion (%)b a Unless stated otherwise, the reactions were carried out in 0.1 M MeOH solutions on a 0.2 mmol scale. b Estimated by HPLC. c 1.0 eq. d 5 mol% Table 1 Optimization of U-5C-4CRconditions TEAc No desired product was formed when -branched diisopropyl ketone was used as a substrate.1 The results obtained for 1ad indicated that the outcome of U-5C-4CR is determined by the degree of steric hindrance 1 In cases where either no U-5C-4CR products were formed or low yields were observed, the starting materials could b (...truncated)