1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

Asymmetric catalysis represents a very powerful tool for the synthesis of enantiopure compounds. In this context the main focus has been directed not only to the search for new efficient chiral catalysts, but also to the development of efficient pronucleophiles. This review highlights the utility and first examples of 1H-imidazol-4(5H)-ones and thiazol-4(5H)-ones as pronucleophiles in catalytic asymmetric reactions.The authors acknowledge the University of the Basque Country UPV/EHU (UFI 11/22), the Basque Government (Grant No IT-628-13) and the Ministerio de Economia y Competitividad (MEC, Grant CTQ2013-47925-C2-1-P), Spain for financial support

syn-Selective Michael reaction of α-branched aryl acetaldehydes with nitroolefins promoted by squaric amino acid derived bifunctional Brønsted bases

[EN] Here we describe a direct access to 2,2,3-trisubstituted syn γ-nitroaldehydes by addition of α-branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid-derived amino acid peptide. Different α-methyl arylacetaldehydes react with β-aromatic and β-alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn-selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E-enolate. The interaction between the substrates and the catalyst follows Pápai’s model, wherein an intramolecular H-bond interaction in the catalyst between the NH group of one of the tert-leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.Support has been provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GB-C21), Spain. A. G. and T. E. thank Basque Government and MINECO respectively for fellowships. We would like to express our gratitude to the students I. Gonzalez-Mujika and M. Campo for their participation in conducting some experiments of the reaction scope. We also thank SGIker (UPV/EHU) for providing NMR, HRMS. X-Ray and computational resources

Catalytic Asymmetric α-Functionalization of α-Branched Aldehydes

Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp2 carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward.This research was funded by Basque Government (grant IT-1583-22) and by MCIN/AEI/10.13039/501100011033 (grant PID2019-109633GB-C21)

N-(Diazoacetyl)oxazolidin-2-thiones as Sulfur Donor Reagents: Asymmetric Synthesis of Thiiranes from Aldehydes

Financial support was provided by the University of the Basque Country UPV/EHU (UFI 11/22), Basque Government (GV grant No IT-291-07), and Ministerio de Ciencia e Innovación (MICINN, Grant CTQ2007-68095-C02), Spain. A. L. thanks MICINN and European Social Foundation for a Ramón y Cajal contract. I. O. thanks MCINN for a fellowship. We also thank SGIker (UPV/EHU) for providing NMR, HRMS, X-Ray, and computational resources

Synthesis of β-Hydroxy α-Amino Acids Through Brønsted Base-Catalyzed syn-Selective Direct Aldol Reaction of Schiff Bases of Glycine o-Nitroanilide

Here we report the highly enantio- and syn-selective synthesis of β-hydroxy α-amino acids from glycine imine derivatives under Brønsted base (BB) catalysis. The key of this approach is the use of benzophenone-derived imine of glycine o-nitroanilide as a pronucleophile, where the o-nitroanilide framework provides an efficient hydrogen-bonding platform that accounts for nucleophile reactivity and diastereoselectivity.Support has been provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant IT1236-19), and Ministerio de Ciencia e Innovación (MICINN, CTQ2016-78487-C2), Spain. A.V. thanks Basque Government, and I.U. and S.d.P. thank UPV/EHU. We also thank SGIker (UPV/EHU) for providing NMR, HRMS, X-ray, and computational resources

Organocatalytic Michael Addition of Unactivated α-Branched Nitroalkanes to Afford Optically Active Tertiary Nitrocompounds

The direct, asymmetric conjugate addition of unactivated α-branched nitroalkanes is developed based on the combined use of chiral amine/ureidoaminal bifunctional catalysts and a tunable acrylate template to provide tertiary nitrocompounds in 55–80% isolated yields and high enantioselectivity (e.r. up to 96:4). Elaboration of the ketol moiety in thus obtained adducts allows a fast entry to not only carboxylic and aldehyde derivatives but also nitrile compounds and enantioenriched 5,5-disubstituted γ-lactams.We thank the Basque Government (EJ, grant IT1583-22) and Agencia Estatal de Investigación (grants PID2019-109633GB and PID2022-137153NB-C21/AEI/10.13039/501100011033) for financial support. A.G.-U. thanks EJ; B.L. thanks the Navarra Government, and M.E.-V. thanks UPNA (PJUPNA18-2022). Authors also thank SGIker (UPV/EHU/ERDF, EU) for providing NMR, HRMS, and X-ray resources

Progress in (Thio)urea‐ and Squaramide‐Based Brønsted Base Catalysts with Multiple H‐Bond Donors

Nowadays chiral (thio)urea- and squaramide-based Brønsted base catalysts are widely applied to enantioselective carbon-carbon and carbon-heteroatom bond forming reactions. In recent years, variations of these catalysts that incorporate and additional H-bond donor unit (green remark) have been shown to perform often superior in terms of activity and stereoselectivity. This Review covers aspects on these catalysts design and their applications.We thank the Basque Government (EJ, grant IT-1583-22) and Agencia Estatal de Investigación (grant PID2019-109633GB−C21/AEI/10.13039/501100011033), Spain, for financial support. A. G.-U. thanks EJ

Probing α‐Amino Aldehydes as Weakly Acidic Pronucleophiles: Direct Access to Quaternary α‐Amino Aldehydes by an Enantioselective Michael Addition Catalyzed by Brønsted Bases

The high tendency of α-amino aldehydes to undergo 1,2-additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α-amino aldehydes. Herein, it is demonstrated that the chemistry of α-amino aldehydes may be expanded beyond these limits by documenting the first direct α-alkylation of α-branched α-amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo- and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α-amino aldehyde is key for reaction stereocontrol.Support has been provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant IT1236-19), and Ministerio de Ciencia e Innovación (MINECO, Grant PID2019-109633GB-C21), Spain

β2, 2-Amino Acid N-Carboxyanhydrides Relying on Sequential Enantioselective C(4)-Functionalization of Pyrrolidin-2,3-diones and Regioselective Baeyer–Villiger Oxidation

A catalytic enantioselective entry to β2, 2-amino acids enabling their direct coupling with nucleophiles is described. The approach is based upon an effective bifunctional Brønsted base catalyzed construction of a quaternary carbon stereocenter at C4 position of pyrrolidin-2,3-diones. Subsequent regioselective Baeyer–Villiger oxidation of the resultant adducts gives β2, 2-amino acid N-carboxyanhydrides as the reactive species, which can further react with nucleophiles. Following this strategy both, β2, 2-amino acid derivatives with different functionalities at the newly created stereocenter, and spirocyclic structures can be efficiently prepared.upport has been provided by the University of The Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant No IT-628-13), and Ministerio de Economía y Competitividad (MEC Grant CTQ2016-78487-C2), Spain

Catalytic Enantioselective Synthesis of Tertiary Thiols From 5H-Thiazol-4-ones and Nitroolefins: Bifunctional Ureidopeptide-Based Brønsted Base Catalysis

The direct catalytic reaction between an enolizable carbonyl compound and an electrophile under proton-transfer conditions has emerged as a challenging versatile transformation in organic synthesis.1 Over the last years several chiral Brønsted bases have been developed to promote this transformation diastereo- and enantioselectively.2 However, successful examples are mostly limited to 1,3-dicarbonyl compounds and acidic carbon analogues as the pronucleophilic reaction partners. 5H-Thiazol-4-ones, in contrast, have been well known for a long time and have found several applications in pharmaceutical and medicinal chemistry.3 Although structurally related to 5H-oxazol-4-ones4 and 4H-oxazol-5-ones (azlactones),5 5H-thiazol-4-ones have, as far as we know, been never been used in asymmetric synthesis in spite of the fact that they may be easily deprotonated6 and in spite of the importance of thiols and organosulfur compounds in organic synthesis7 and chemical biology.8 In this context, whilst chiral secondary thiol derivatives have been the subject of most investigations, tertiary thiols have remained mostly unexplored owing to the insufficient catalytic enantioselective methodology for their preparation in optically pure form.