Accessing Chiral Pyrrolodiketopiperazines under Organocatalytic Conditions

The production of chiral pyrrolodiketopiperazines under organocatalytic conditions demonstrates the capacity of bicyclic acylpyrrol lactims to perform as pronucleophiles in direct carbon–carbon bond forming reactions. The good performance of ureidoaminal-derived Brønsted bases in the Michael addition to nitroolefins affords these heterocyclic scaffolds with high skeleton diversity.Financial support was provided for the University of the Basque Country UPV/EHU (UFIQOSYC 11/22), the Basque Government (grant IT-1236-19), and Ministerio de Ciencia e Innovation (grant PID2019-109633GB-C21), Spain. E.D. thanks MICINN for a fellowship. We also thank SGiker (UPV/EHU) for providing NMR spectroscopy, HRMS, X-ray, and computational resources

The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine

Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring organic compounds, which are found in over 40% of newly marked small-molecule pharmaceutical drugs and medical formulations. The primary goal of this work is to underscore two major trends in the design of modern pharmaceuticals. The first is dealing with the unique structural characteristics provided by the structure of amino acids featuring an abundance of functionality and the presence of a stereogenic center, all of which bodes well for the successful development of targeted bioactivity. The second is related to fine-tuning the desired activity and pharmacokinetics by selective introduction of fluorine. Historically, both trends were developed separately as innovative and prolific approaches in modern drug design. However, in recent decades, these approaches are clearly converging leading to an ever-increasing number of newly approved pharmaceuticals containing both structural features of amino acids and fluorine.This work was funded by the National Natural Science Foundation of China (No. 21761132021), and IKERBASQUE, Basque Foundation for Science. The financial support from the University of the Basque Country UPV/EHU (UFIQOSYC11/22), Basque Government (GVgrant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GBC21) for. A. L. are also acknowledged

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

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.

DoE-driven development of an organocatalytic enantioselective addition of acetaldehyde to nitrostyrenes in water

Moving from organic solvents to water is not always an easy task, especially when a lot of variables need to be screened. The development of an enantioselective enamine-catalysed Michael addition of acetaldehyde to nitroalkenes in water was developed by using a rational approach, via chemometrics-assisted ‘Design of Experiments’ (DoE) optimisation. This way it was possible to screen 9 different parameters, their interaction with each other, and the full chemical space, with minimum experiments in an efficient manner.G.G. is grateful to PON-DOT13OV2OC for an industrial Ph.D. fellowship. F.P. and A.B. thank PON-AIM grant number 1842894 for funding this research. A. L. thanks the University of the Basque Country UPV/EHU (UFIQOSYC11/22), Basque Government (GVgrant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GBC21) for financial support. Open Access Funding provided by Università degli Studi dell′Aquila within the CRUI-CARE Agreement. Open Access Funding provided by Universita degli Studi dell'Aquila within the CRUI-CARE Agreement

Unsaturated chiral-only-at-metal rhodium(iii) complexes bearing SiN-type ligands

Enantiopure chiral-at-metal rhodium(III) unsaturated 16e complexes have been obtained from racemic [Rh(SiN)2Cl] (SiN= 8-(dimethylsilyl)quinoline) using a readily accessible chiral spiroborate as chiral resolution agent. This strategy allows an easy access to enantiopure neutral Δ/Λ-Rh(SiN)2Cl and cationic Δ/Λ-Rh(SiN)2[BAr4F] unsaturated complexes, wherein rhodium(III) is coordinated to two inert silylquinoline ligands in a propeller-like arrangement. Graphical abstract: Unsaturated chiral-only-at-metal rhodium(iii) complexes bearing SiN-type ligands In the field of asymmetric catalysis, transition metal catalysts are commonly used due to their remarkable efficiency.1 The predominant methodology in transition metal asymmetric catalysis involves the use of chiral ligands. However, there is a growing interest in a less studied method involving chiral-at-metal complexes formed by non-chiral ligands, mainly due to the seminal work of E. Meggers.2 This approach consists of a metal centre coordinated by two bidentate ligands in a propeller-type fashion. High configurational stability at the stereogenic metal centre is the main requirement for chiral metal catalysts. In addition, for the substrate to interact with the metal centre of the catalyst, the presence of labile auxiliary ligands, such as acetonitrile, is required. Two advantages of using chiral-at-metal complexes as asymmetric catalysts should be noted. First, the non-chiral ligands are easier to prepare than their chiral counterparts, thus offering a wider variety. Secondly, in chiral-at-metal catalysts, the metal centre, which is the reaction centre for catalysis, is also the stereogenic centre responsible for the overall enantioselectivity. Most of the chiral-at-metal complexes used as asymmetric catalysts reported to date are octahedral complexes with d6 transition metals.3–6 Cationic complexes of iridium(iii)3 and rhodium(iii)4 with two bidentate anionic ligands (CN ligands; Fig. 1a left) and two labile acetonitrile ligands have been widely used chiral-at-metal catalysts. More recently, ruthenium(ii)5 and iron(ii)6 di-cationic complexes bearing bidentate neutral ligands (CN ligands; Fig. 1a right) and also two labile acetonitrile ligands have also been studied.Financial support for this work was provided by UPV/EHU (EHU-G23/03), Gobierno Vasco (IT1741-22) and MCIN/AEI/10.13039/501100011033 and FEDER A way of making Europe to projects PID2019-111281GB-I00 and PID2022-139760NB-I00

Synthesis of 4,6-Difluoro-Tryptophan as a Probe for Protein 19F NMR

A scalable procedure for the synthesis of 4,6-difluorotryptophan is reported based on a deaminative coupling of a 4,6-difluorogramine with 2-benzylthio-1,5-dihydro-4H-imidazolone as glycine equivalent. Thus prepared 4,6-difluorotryptophan was incorporated into the C-terminal domain of the HIV-1 capsid protein (CA-CTD), and 19F spectra of the 4,6-difluoro Trp CA CTD were recorded and compared to the singly fluorinated counterparts.We thank the Basque Government (EJ, grant IT1583-22) and Agencia Estatal de Investigación (grants PID2019-109633GB-C21/AEI/10.13039/501100011033 and PID2022-137153NB-C21/AEI/10.13039/501100011033) for financial support. The authors are grateful for the technical and human support provided by SGIker (UPV/EHU/ERDF, EU). I.H. thanks EJ for a fellowship. R.M-P. was supported by the Health Sciences Diversity Scholars Program at the University of Pittsburgh and F.B. by a post-doctoral fellowship from the American Heart Association. The work in the Gronenborn laboratory was supported by NIH grant U54AI170791

Rigidified Bis(sulfonyl)ethylenes as Effective Michael Acceptors for Asymmetric Catalysis: Application to the Enantioselective Synthesis of Quaternary Hydantoins

The catalytic, enantio- and diastereoselective addition of hydantoin surrogates II to “rigidified” vinylidene bis(sulfone) reagents is developed, thus overcoming the inability of commonly employed β- substituted vinylic sulfones to react. Adducts are transformed in enantioenriched 5,5-disubstituted hydantoins through hydrolysis and reductive desulfonylation processes providing new structures for eventual bioassays. Density functional theory studies that rationalize the observed reactivity and stereoselectivity trends are also provided.We thank the Basque Government (EJ, grant IT-1583-22) and Agencia Estatal de Investigación (grant PID2019-109633GB-C21/AEI/10.13039/501100011033) for financial support. L.V. thanks AEI and I.H. and E.J. for a fellowship. The authors are grateful for the technical and human support provided by SGIker (UPV/EHU/ERDF, EU)