A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

Bronsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized gamma-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.Financial support was provided by the Ministerio de Ciencia, Innovacion, y Universidades (RTI2018-101818-B-I00, MCIU/AEI/FEDER, UE), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X. del Corte thanks Gobierno Vasco for a predoctoral grant

Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents

An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma). In view of the possibilities in the diversity of the substituents that offer the synthetic methodology, an extensive profile structure–activity is presented, measuring IC50 values up to 0.34 µM in the A549 and 9.8 µM in SKOV3 cell lines.Financial support by Ministerio de Economía, Industria y Competividad (PID2021-122558OB-I00) and Gobierno Vasco (GV-IT1701-22) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

Stereo- and Regioselective [3+3] Annulation Reaction Catalyzed by Ytterbium: Synthesis of Bicyclic 1,4-Dihydropyridines.

An ytterbium catalyzed formal [3+3] cycloaddition of cyclic enamines and α,β-unsaturated ketones catalyzed is reported. The reaction proceeds with a ‘head to tail’ regioselectivity through a conjugate addition of the enamine moiety followed by an amine-carbonyl condensation. In addition the use of chiral enamines provided a high degree of stereoselectivity, driven by a possible balance between steric and π-stacking effects. The resulting bicyclic 1,4-dihydropyridines were evaluated as antiproliferative agents against A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma) human tumor cell lines. Good toxicities were found for some of the compounds against A549 and SKOV3 cell lines, with best IC50 values of 0.89 μM for A549 and 6.69 μM for SKOV3, and a very good selectivity was observed towards MRC5 (non-malignant) cell lines.Ministerio de Economía, Industria y Competividad (MINECO, RTI2018-101818-B-I00) Gobierno Vasco (GV, IT 992–16

5-Ethoxy-1-(4-methoxyphenyl)-5-methyl-3-phenylimidazolidine-2,4-dione

The title compound is a hydantoin derivative that has been synthesized through a three-component reaction of ethyl pyruvate, p-anisidine and phenyl isocyanate. This paper provides a comprehensive spectral dataset for the title compound, including 1H and 13C{1H} NMR, IR, HRMS, and X-ray crystallography analyses. A tentative mechanism comprising two complementary pathways is provided based on additional experiments with the preformed intermediates.Financial support by Ministerio de Economía, Industria y Competividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to C=O and C=N bonds

Chiral phosphoric acids (CPAs) have been used as efficient organocatalysts since the first examples were reported 18 years ago by Akiyama and Terada. Although they were originally developed for enantioselective additions to imines, a wide reaction scope has been demonstrated using this type of catalyst. In this review, the known applications of CPA for enantioselective additions to C=O and C=N bonds are covered.Financial support by Ministerio de Economía, Industria y Competividad (MINECO, PID2021-122558OB-I00) and Gobierno Vasco (GV- IT1701-22) is gratefully acknowledged. X. del Corte thanks the Basque Country Government for a predoctoral grant

Ugi Reaction on α-Phosphorated Ketimines for the Synthesis of Tetrasubstituted α-Aminophosphonates and Their Applications as Antiproliferative Agents

An Ugi three-component reaction using preformed α-phosphorated N-tosyl ketimines with different isocyanides in the presence of a carboxylic acid affords tetrasubstituted α-aminophosphonates. Due to the high steric hindrance, the expected acylated amines undergo a spontaneous elimination of the acyl group. The reaction is applicable to α-aryl ketimines bearing a number of substituents and several isocyanides. In addition, the densely substituted α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell line A549 (carcinomic human alveolar basal epithelial cell).Financial support by Ministerio de Economía, Industria y Competividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

Asymmetric Synthesis of Tetrasubstituted α-Aminophosphonic Acid Derivatives

Due to their structural similarity with natural α-amino acids, α-aminophosphonic acid derivatives are known biologically active molecules. In view of the relevance of tetrasubstituted carbons in nature and medicine and the strong dependence of the biological activity of chiral molecules into their absolute configuration, the synthesis of α-aminophosphonates bearing tetrasubstituted carbons in an asymmetric fashion has grown in interest in the past few decades. In the following lines, the existing literatures for the synthesis of optically active tetrasubstituted α-aminophosphonates are summarized, comprising diastereoselective and enantioselective approaches.Financial support by Ministerio de Economía, Industria y Competividad (MINECO, CTQ-2015-67871R) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

[EN] A study on the reactivity of 3-amino α,β-unsaturated γ-lactam derivatives obtained from a multicomponent reaction is presented. Key features of the substrates are the presence of an endocyclic α,β-unsaturated amide moiety and an enamine functionality. Following different synthetic protocols, the functionalization at three different positions of the lactam core is achieved. In the presence of a soft base, under thermodynamic conditions, the functionalization at C-4 takes place where the substrates behave as enamines, while the use of a strong base, under kinetic conditions, leads to the formation of C-5-functionalized γ-lactams, in the presence of ethyl glyoxalate, through a highly diastereoselective vinylogous aldol reaction. Moreover, the nucleophilic addition of organometallic species allows the functionalization at C-3, through the imine tautomer, affording γ-lactams bearing tetrasubstituted stereocenters, where the substrates act as imine electrophiles. Taking into account the advantage of the presence of a chiral stereocenter in C-5 substituted γ-lactams, further diastereoselective transformations are also explored, leading to novel bicyclic substrates holding a fused γ and δ-lactam skeleton. Remarkably, an example of a highly stereoselective formal [3+3] cycloaddition reaction of chiral γ-lactam substrates is reported for the synthesis of 1,4-dihidropyridines, where a non-covalent attractive interaction of a carbonyl group with an electron-deficient arene seems to drive the stereoselectivity of the reaction to the exclusive formation of the cis isomer. In order to unambiguously determine the substitution pattern resulting from the diverse reactions, an extensive characterization of the substrates is detailed through 2D NMR and/or X-ray experiments. Likewise, applications of the substrates as antiproliferative agents against lung and ovarian cancer cells are also described.Financial support by Ministerio de Economía, Industria y Competividad (RTI2018-101818- B-I00) and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged. X.d.C. and A.L.-F. thank the Basque Country Government for a predoctoral grant

Exploring the Reactivity of Rigid 1-Azadienes Derived from Methylene γ-Lactams. Applications to the Stereoselective Synthesis of Spiro-γ-Lactams

A study on the reactivity of rigid 1-azadienes derived from methylene γ-lactams is reported. Through the functionalization of 1-amino α,β-unsaturated γ-lactam derivatives, easily available from a multicomponent reaction of amines, aldehydes, and pyruvates, it is possible to in situ generate rigid 1-azadienes locked by a γ-lactam core. The 4π-electron system of those rigid 1-azadienes can behave as both diene and dienophile species through a spontaneous cyclodimerization reaction or exclusively as dienes or dienophiles if they are trapped with imines or cyclopentadiene, respectively. The use of chiral rigid 1-azadienes as dienophiles in the cycloaddition reaction with cyclopentadiene leads to the formation of spiro-γ-lactams bearing four stereogenic centers in a highly stereospecific manner, reporting the first example of the use of methylene-γ-lactams in the synthesis of spirocycles.Financial support PID2021-122558OB-I00 funded by the Ministerio de Ciencia, Innovación y Universidades MICIU/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, and by Gobierno Vasco (GV, IT1701-22 and IT1553-22; UPV-EHU) is gratefully acknowledged. The authors are grateful for technical and human support provided by SGIker (UPV/EHU/ERDF, EU). The authors thank SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources. A.L.-F. thanks the Basque Country Government for a predoctoral grant. Open Access funding provided by University of Basque Country

Chiral self-recognition in a bispericyclic cyclodimerisation reaction of 1-azadienes

Hermaphroditism of molecules: as in nature some species behave as male or female depending on the environment, herein we report a bispericyclic dimerisation of cyclic 1-azadienes where a molecule can behave as either diene or dienophile, depending on its location at the transition state. In a symmetrical reactive complex, here represented by an arbitrary reference system, a molecule that is positioned on top acts as the diene unit, while the dienophile partner is the one situated at the bottom. In addition, a strong chiral self-recognition phenomenon is observed, where each enantiomer within a racemic mixture of chiral 1-azadienes exclusively recognises itself. In order to shed some light into the understanding of the chiral self-recognition effect, an extensive DFT study of the reaction pathway is provided, concluding that a combination of attractive π-stacking forces and repulsive steric interactions is at the origin of the high stereospecificity of the reaction.Financial support by Ministerio de Ciencia, Innovación y Universidades (MCIU-Madrid) (PID2021-122558OB-I00, UE), and Eusko Jaurlaritza (GV, IT1701-22 and IT-1553-22; UPV-EHU) is gratefully acknowledged. The authors are grateful for technical and human support provided by SGIker (UPV/EHU/ERDF, EU). The authors thank SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources. A. L.-F. thanks the Basque Country Government for a predoctoral grant