Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• , Zaporizhzhya National University, Zhukovsky str., 66, Zaporizhzhya, 69600, Ukraine 10.3762/bjoc.19.53 Abstract Peptidomimetics with a substituted imidazo[1,2-a]pyridine fragment were synthesized by a tandem of Groebke–Blackburn–Bienaymé and Ugi reactions. The target products contain substituted imidazo[1,2-a

• 8b is rather low in Ugi reactions. Antibacterial activity In the following experiment, we tested a specific group of compounds for their ability to act as antibacterial agents against Bacillus subtilis (strain 1211), Staphylococcus aureus (strain 2231) (Gram-positive), Escherichia coli (strain 1257

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• elaborated allowing to upgrade the Passerini and Ugi adducts into potentially bioactive heterocycles [25][26][27][28][29][30][31][32]. While both Passerini and Ugi reactions proved to be quite robust towards different classes of substrates and possess broad functional group tolerance, the difficulties

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• and on the acyclovir-resistant strains), as they interfered with late steps in the viral replication cycle [25]. An interesting feature of the Ugi reactions shown with ketosteroids having additional carboxylic and aldehyde groups (see Scheme 1 and Figure 2B) is the lack of side reaction at the ketone

• functionality. This can be explained by the higher reactivity of the aldehyde functionalities upon imine formation with both aliphatic and aromatic amines. However, steroidal ketones can also participate in Ugi reactions if no additional, more reactive carbonyl components are present. As shown in Scheme 6, this

• Passerini and Ugi reactions. 3 Synthesis of steroid-fused heterocycles The modification of the steroidal nucleus by attaching a heterocycle to this hydrophobic scaffold has been traditionally used as an effective way to modulate the biological activity of these biomolecules. In this regard, pentacyclic

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• ) three-component Ugi reactions of formylbenzoic acids 33, amines 2 and isocyanides 42. Proposed mechanism for the enantioselective formation of isoindolinones 46. Three-component reaction of benzoic acids 33 or 54, amines 2 and TMSCN (52). Several variations of the three-component reaction of

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• the basis of a large group of reactions in organic chemistry, especially in isocyanide-based multicomponent reactions (IMCRs) [2][3], such as the Passerini and Ugi reactions, which are reactions that have been widely used in the synthesis of peptides, peptidomimetics and heterocycles [4][5][6][7][8

• products has been reviewed [15][16] and this review will focus only on IMCRs. Consecutive IMCRs Synthesis of small-ring heterocycles (tetrazoles, ketopiperazines, imidazoles, imidazolines and thiazoles) The use of consecutive Ugi reactions in the synthesis of heterocycles was first described in 2001 by Ugi

• mixture of diastereomers). Recently, our research group [22] carried out the synthesis of bis(1,5-disubstituted tetrazoles) 14 using two consecutive Ugi reactions (Scheme 4). The synthetic strategy was based on two hydrazino-Ugi-azide reactions and a hydrazinolysis step for the synthesis of acylhydrazino

Synthesis of a novel category of pseudo-peptides using an Ugi three-component reaction of levulinic acid as bifunctional substrate, amines, and amino acid-based isocyanides

• Maryam Khalesi,
• Azim Ziyaei Halimehjani and
• Jürgen Martens

Beilstein J. Org. Chem. 2019, 15, 852–857, doi:10.3762/bjoc.15.82

• peptidomimetics with potential pharmaceutical applications. Therefore, the development of innovative Ugi reactions is crucial for the synthesis of novel chemical libraries for various purposes [12]. In recent years, one of the modifications for Ugi reactions is the introduction of bifunctional substrates into the

• for Ugi reactions because it has two functional groups in its structure. By the way, using bifunctional chemicals in Ugi four-component condensation reaction (4CC) converts it to an Ugi three-component condensation reaction (3CC) and this is identified as an Ugi-4-centre-3-component reaction (U-4C-3CR

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• reactants (Scheme 10A) [38]. Similarly, a suitably substituted aldehyde participates in a GBB MCR to yield an adduct which participated in standard Ugi–Passerini processes through the carboxylic acid functional group, untouched in the first MCR (Scheme 10B) [39]. Furthermore, Reissert or Reissert/Ugi

• reactions can be linked with Povarov MCRs through the intermediacy of the enamine-containing adducts from the former processes (Scheme 10C) [40]. Many additional combinations arise from the Union concept, such as Bredereck–Passerini [41], pyridone-cyclocondensation/Passerini–Ugi [42], azadiene-keteneimine

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2017, 13, 2596–2602, doi:10.3762/bjoc.13.256

• . The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles. Keywords: acylhydrazines; consecutive Ugi reactions; 1,5-disubstituted tetrazoles; isocyanide-based multicomponent reactions (IMCRs

• tetrazole moieties. The term ‘hydrazino-Ugi’ was first proposed for the synthesis of hydrazinopeptides [16] in 2010. The application of consecutive hydrazino-Ugi reactions has also been described in the literature [17]. Besides this, the introduction of the hydrazino group into several classes of compounds

• the hydrazino groups. The resulting unique secondary structures can improve the proteolytic stability of these compounds [22]. An acylhydrazine (hydrazide) was first reported in Ugi reactions back in 1961 [23] and also some natural products contain this moiety, such as the vitamin B6 antagonist

Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

• Andreas C. Boukis,
• Baptiste Monney and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2017, 13, 54–62, doi:10.3762/bjoc.13.7

• Passerini or Ugi reactions in a sequential one-pot procedure [32]. Furthermore, up to eight components were reacted by the combination of three multicomponent reactions [33]. In 2010, the Ugi reaction and the Ugi–Smiles reaction were combined by Westermann et al. [34]. In addition, the Ugi reaction was used

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

• Angélica de Fátima S. Barreto,
• Veronica Alves dos Santos and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2016, 12, 2865–2872, doi:10.3762/bjoc.12.285

• peptidomimetics with potential biological activity. Keywords: acylhydrazino-peptomers; consecutive Ugi reactions; peptide-peptoid hybrid; peptomer; Introduction In the last decades, increasing efforts have been extensively carried out to improve the pharmacological properties of natural peptides by structural

• peptidomimetics, which we have called acylhydrazino-peptomers (Figure 4), by analogy with the existing classes of peptidomimetics shown in Figure 1, using consecutive Ugi and hydrazino-Ugi reactions, respectively. These compounds comprise both a peptoid and a peptide moiety (hence a peptomer) along with an

• TFE as the solvent for the hydrazino-Ugi reaction was important because the same reaction carried out in methanol, often the solvent of choice for Ugi reactions, provided the formation of a complex mixture. This fact has already been reported [34]. To further functionalize the acylhydrazino-peptomers

Application of heterocyclic aldehydes as components in Ugi–Smiles couplings

• Katelynn M. Mason,
• Michael S. Meyers,
• Abbie M. Fox and
• Sarah B. Luesse

Beilstein J. Org. Chem. 2016, 12, 2032–2037, doi:10.3762/bjoc.12.191

• aldehydes have been employed in standard Ugi reactions for the preparation of druglike heterocycles [26][27][28], N-arylamides 4a,b represent the first examples of analogous Ugi–Smiles adducts incorporating a thienyl-substituted aldehyde component. Conclusion In summary, Ugi–Smiles couplings have been

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• , no report of valuable diastereocontrol by them has appeared so far. Successful examples of diastereoselective Ugi reactions have been reported only with chiral amines [15][16][17][18][19] or with chiral cyclic imines (Ugi–Joullié reaction) [20][21][22][23], although in the latter case, racemization

• , the usefulness of this approach relies on an efficient and diversity-oriented preparation of the required amines in high enantiomeric excess. Chiral aminoalcohols can be ideal substrates for diastereoselective Ugi reactions: the additional hydroxy group can both help in modulating diastereoselectivity

• and be employed for post-condensation transformations in order to add further fragments or to form heterocyclic structures. We have previously developed some syntheses of heterocycles through Ugi reactions with 1,2-aminoalcohols followed by nucleophilic substitutions [28], whereas chiral 1,2

Consecutive isocyanide-based multicomponent reactions: synthesis of cyclic pentadepsipeptoids

• Angélica de Fátima S. Barreto,
• Otilie E. Vercillo,
• Ludger A. Wessjohann and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2014, 10, 1017–1022, doi:10.3762/bjoc.10.101

• explored yet. In this paper, we describe the synthesis of six pentadepsipeptoid analogues of San A (Figure 3). The synthetic route for the synthesis of cyclic pentadepsipeptoids via consecutive Ugi reactions allows only three side chains connected to three nitrogen atoms. The pentapeptide of San A has in

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• - [31], elastase- [32][33][34][35], and HIV-1 protease [36] and papain [37]. For the design of β-lactams, the Staudinger reaction involving a [2 + 2] cycloaddition of ketenes and imines is the most common method used [38]. However, Ugi reactions starting form β-amino acids are also described. In 2002

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• benzyl azides by nucleophilic substitution, followed by azide reduction. This strategy required in any case protection of the phenol moiety. As a matter of fact, in preliminary attempts, we found out that Ugi reactions employing free para-hydroxybenzylamines proceed in very poor yields (<25%), probably

• chromatography at the level of 9. With these optimized conditions in hand, we performed a series of Ugi reactions using azides 2a–d, glycolic acid, various aldehydes and isocyanides (Scheme 2). After a fast purification through a short silica gel column, the Ugi adducts 9a–n were submitted to hydrogenolysis and

Synthetic studies towards bottromycin

• Stefanie Ackermann,
• Hans-Georg Lerchen,
• Dieter Häbich,
• Angelika Ullrich and
• Uli Kazmaier

Beilstein J. Org. Chem. 2012, 8, 1652–1656, doi:10.3762/bjoc.8.189

• ring system in a straightforward manner. Keywords: amidines; antibiotics; bottromycin; peptides; thiopeptides; Ugi reactions; Introduction Natural products are excellent sources as lead structures for the development of new antibiotics. Over millions of years microorganisms, such as bacteria and

• highly fascinating from a synthetic point of view. In our previous investigations we observed that for the synthesis of sterically demanding peptides, especially those containing N-alkylated amide bonds, Ugi reactions are especially suited [33][34]. For N-unsubstituted peptides the Ugi reactions should

• trifluoroethanol, which is the best solvent for ammonia Ugi reactions [35], the expected endothiopeptide 1 was formed in high yield as a 1:1 diastereomeric mixture (Scheme 1). With this building block in hand, we were interested to see whether we would be able to generate the required cyclic endothiopeptide and if

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• analogues possess a protease-resistant peptoid scaffold and this might lead to an enhanced activity [19][20]. In this endeavor, all Ugi reactions were initiated by pre-imine formation of 5 and reaction with formaldehyde as the oxo-component, after which the multicomponent reaction was completed by the

Ugi post-condensation copper-triggered oxidative cascade towards pyrazoles

• Aurélie Dos Santos,
• Laurent El Kaim,
• Laurence Grimaud and
• Caroline Ronsseray

Beilstein J. Org. Chem. 2011, 7, 1310–1314, doi:10.3762/bjoc.7.153

• possible Ugi pathways to introduce an alkene moiety that is prone to undergo an intramolecular [3 + 2] cycloaddition with a hydrazone, we selected the Ugi coupling between α-hydrazonocarboxylic acids and allylamine as the most straightforward path. There are several reports on the use of hydrazones in Ugi

• reactions [14][15][16][17][18][19][20][21][22][23], however, to the best of our knowledge, there is no report involving α-hydrazonocarboxylic acids. Hydrazone 1a was prepared through condensation of pyruvic acid with phenylhydrazine. Adding 1a to aqueous formaldehyde, allylamine and tert-butylisocyanide in

A straightforward approach towards combined α-amino and α-hydroxy acids based on Passerini reactions

• Ameer F. Zahoor,
• Sarah Thies and
• Uli Kazmaier

Beilstein J. Org. Chem. 2011, 7, 1299–1303, doi:10.3762/bjoc.7.151

• chelated enolates and subsequent oxidation/Passerini reaction. This protocol works with both, aldehyde and ketone intermediates, as long as the ketones are activated by electron-withdrawing groups. In principle Ugi reactions are also possible, allowing the generation of diamino acid derivatives. Keywords

• : amino acids; chelated enolates; epoxides; Passerini reactions; Ugi reactions; Introduction Multicomponent reactions (MCR) are a very popular and powerful tool in modern organic synthesis [1][2][3][4]. Besides a wide range of heterocycle syntheses [5] and catalytic cross coupling reactions [6], the

• our chelated enolate (Scheme 1) [29]. In this case an amino acid 4 with an allyl alcohol side chain was formed which could be oxidized to the α,β-unsaturated aldehyde 5. Although these types of aldehydes are critical candidates in Passerini and Ugi reactions [30], we were interested to see if we could

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• good yields, nine different tetrahydro[f][1.4]benzoxazepines 6, equipped with three diversity points. As shown in Table 1, all the tested Ugi reactions proceeded with remarkably high diastereoselectivity, if one considers that the R1 substituent is quite far away from the imine carbon. This long range

• conformation of imine 5a, as minimized using CSC Chem3D (MOPAC-PM3). a) TBAD [(t-BuO2C−N=)2], PPh3, THF, −15 °C → rt, 49% (3a), 62% (3b); b) LiAlH4, Et2O–THF, 0 °C, 90% (4a), 88% (4b); c) HCl, CH2Cl2–H2O, rt; d) R2NC, R3CO2H, MeOH, rt. Possible explanation of diastereoselectivity in Ugi reactions of imines 5

• . Results of Ugi reactions of imines 5a,b. Supporting Information Supporting Information File 133: Complete experimental procedures. Supporting Information File 134: NMR characterization of products 6 and NMR spectra. Acknowledgements We wish to thank Benedetta Pollarolo for her collaboration to this work