Copper-catalyzed multicomponent reaction of ß-trifluoromethyl ß-diazo esters enabling the synthesis of ß-trifluoromethyl N,N-diacyl-ß-amino esters.

An efficient multicomponent reaction of newly designed ß-trifluoromethyl ß-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper-catalyzed conditions has been developed, which affords various unsymmetrical ß-trifluoromethyl N,N-diacyl-ß-amino esters in good to excellent yields. The reaction features mild conditions, a wide scope of ß-amino esters and carboxylic acids, and also applicability to large-scale synthesis, thus providing an efficient way for the synthesis of ß-trifluoromethyl ß-diacylamino esters. Furthermore, this reaction represents the first example of a Mumm rearrangement of ß-trifluoromethyl ß-diazo esters.

Cascade Detrifluoroacetylation, C-S Bond Cleavage, and SN2' Reaction of α,α-Difluorinated Gem-Diols with MBH Esters.

A new SN2' reaction type of Morita-Baylis-Hillman (MBH) ester with sulfonyl anion, generated in situ via detrifluoroacetylation as a nucleophile is developed. Experimental results and DFT calculations disclose that the reaction proceeds via C-C bond cleavage to generate a PhSO2CF2 anion, C-S bond cleavage to generate a sulfonyl anion with the release of CF2 carbene, and an SN2' reaction with the MBH ester. The reaction features operational simplicity, wide substrate scope, high yields, and excellent stereoselectivity, which represents a new reaction mode of fluorinated gem-diols and also provides an efficient way to obtain ß,γ-unsaturated sulfones.

Pd(II) Complexes of Chiral Proline-Derived Ligands: Application for Dynamic Thermodynamic Resolution of α-Amino Acids and Their Antibacterial Activities.

Novel type of Pd(II) complexes have been synthesized under operationally simple and convenient conditions and applied in the dynamic thermodynamic resolution of racemic N,C-unprotected α-amino acids. After rapid hydrolysis, these Pd(II) complexes produced the corresponding α-amino acids in satisfactory yields and enantioselectivities, accompanied by the recyclable proline-derived ligand. In addition, the method can be readily applied for S/R interconversion to obtain unnatural (R)-α-amino acids from readily available (S)-α-amino acids. Furthermore, biological assays showed that Pd(II) complexes (S,S)-3i and (S,S)-3m exhibited significant antibacterial activities similar to vancomycin, which may represent promising lead structures for further development of antibacterial agents.

Chemical Aspects of Human and Environmental Overload with Fluorine.

Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.

New Approved Drugs Appearing in the Pharmaceutical Market in 2022 Featuring Fragments of Tailor-Made Amino Acids and Fluorine.

The strategic fluorination of oxidatively vulnerable sites in bioactive compounds is a relatively recent, widely used approach allowing us to modulate the stability, bio-absorption, and overall efficiency of pharmaceutical drugs. On the other hand, natural and tailor-made amino acids are traditionally used as basic scaffolds for the development of bioactive molecules. The main goal of this review article is to emphasize these general trends featured in recently approved pharmaceutical drugs.

Synthesis of Aminoalkyl Sclareolide Derivatives and Antifungal Activity Studies.

Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4-6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.

Cu(II) Complexes with Proline-Derived Schiff Base Ligand: Chemical Resolution of N,C-Unprotected α-Amino Acids and Their Antibacterial Activity.

An operationally simple and convenient resolution method via Cu(II) complexes was reported, efficiently providing valuable enantiopure N,C-unprotected α-amino acids. This protocol features synthetically attractive yields and a stereochemical outcome, using a recyclable Schiff base ligand and inexpensive easily accessible metal copper salts. These novel Cu(II) complexes can be obtained in an enantiopure state by means of column chromatography or recrystallization. Furthermore, all the Cu(II) complexes were evaluated for their antibacterial activities. Among them, complexes (S,2S)-3a, (S,2S)-3g, and (S,2S)-3o showed significant antibacterial activities against Staphylococcus aureus Mu50. Further biological evaluation indicated that they were effective against most of Gram-positive bacteria. It is the first study on the biological activities of transition metal complexes with this type of proline-derived Schiff base ligand.

New pharmaceuticals approved by FDA in 2020: Small-molecule drugs derived from amino acids and related compounds.

Amino acids (AAs) play an important role in the modern health industry as key synthetic precursors for pharmaceuticals, biomaterials, biosensors, and drug delivery systems. Currently, over 30% of small-molecule drugs contain residues of tailor-made AAs or derived from them amino-alcohols and di-amines. In this review article, we profile 12 AA-derived new pharmaceuticals approved by the FDA in 2020. These newly introduced drugs include Tazverik (epithelioid sarcoma), Gemtesa (overactive bladder), Zeposia (multiple sclerosis), Byfavo (induction and maintenance of procedural sedation), Cu 64 dotatate, and Gallium 68 PSMA-11 (both PET imaging), Rimegepant (acute migraine), Zepzelca (lung cancer), Remdesivir (COVID-19), Amisulpride (nausea and vomiting), Setmelanotide (obesity), and Lonafarnib (progeria syndrome). For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.

Asymmetric Michael Addition in Synthesis of ß-Substituted GABA Derivatives.

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, ß-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity.

Tailor-Made Amino Acids in Pharmaceutical Industry: Synthetic Approaches to Aza-Tryptophan Derivatives.

Over the recent years there has been a noticeable upsurge of interest in aza-analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza-tryptophan derivatives are profiled, including aza-substitution in the positions 2, on the five-membered ring, as well as in positions 4, 5, 6, and 7 on the six-membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza-tryptophans is presented and general facets of the biological properties and most promising applications are discussed.

Asymmetric synthesis of (S)-3-methyleneglutamic acid and its N-Fmoc derivative via Michael addition-elimination reaction of chiral glycine Ni (II) complex with enol tosylates.

The use of chiral Ni (II)-complexes of glycine Schiff bases has recently emerged as a leading methodology for asymmetric synthesis of structurally diverse Tailor-Made Amino Acids™, playing a key role in the design of modern pharmaceuticals. Here, we report first example of enantioselective preparation of (S)-3-methyleneglutamic acid and its N-Fmoc derivative via a new type of Michael addition-elimination reaction between chiral nucleophilic glycine equivalent and enol tosylates. This reaction was found to proceed with excellent yield (91%) and diastereoselectivity (>99/1 de) allowing straightforward asymmetric synthesis of (S)-3-methyleneglutamic acid derivatives and analogues. The observed results bode well for general application of this Ni (II) complex approach for preparation and biological studies of this previously unknown type of Tailor-Made Amino Acids™.

Comparative study of different chiral ligands for dynamic kinetic resolution of amino acids.

Dynamic kinetic resolution (DKR) of unprotected amino acids (AAs), via intermediate formation of Ni(II) complexes, is currently a leading methodology for preparation of natural and tailor-made AAs in enantiomerically pure form. In this work, we conduct a comparative case study of synthetic performance of four different ligands in DKR of six AAs representing aryl-, benzyl-, alkyl-, and long alkyl-type derivatives. The results of this study allow for rational selection of ligand/AA type to develop a practical procedure for preparation of target enantiomerically pure AAs.

A Call for a Change in Policy Regarding the Necessity for SDE Tests to Validate the Veracity of the Outcome of Enantioselective Syntheses, the Inherent Chiral State of Natural Products, and Other Cases Involving Enantioenriched Samples.

We wish to draw attention to an important issue concerning scientific practice with regard to enhancing the quality of publications in Molecules (as well as for other journals) [...].

Recommended Tests for the Self-Disproportionation of Enantiomers (SDE) to Ensure Accurate Reporting of the Stereochemical Outcome of Enantioselective Reactions.

The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation.

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes.

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012-2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.

Which Stereoinductor Is Better for Asymmetric Functionalization of α-Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations.

The results of extended comparative investigation of nickel(II) Schiff base complexes (containing various auxiliary chiral moieties) commonly used as a methodological platform for the asymmetric synthesis of tailor-made α-amino acids are provided. The following issues are addressed: 1) redox activity (determining the possibility for electrochemically induced reactions); 2) quantitative estimation of the reactivity of deprotonated complexes towards electrophiles; and 3) quantum-chemical estimation of noncovalent interactions in the metal coordination environment (which shed light on the origin of the stereochemical outcome observed for different stereoinductors). Possible mechanisms that determine the relationship between the stereochemical configuration of a molecule and its electronic structure are discussed. The DFT-calculated HOMO-LUMO energies and localization, as well as relative energies for the (S)- and (R)-alanine derivatives, that determine the stereoinduction efficiency in thermodynamically controlled reactions in nickel(II) coordination are provided. The computational data are supported by experimental results on the monobenzylation of glycine derivatives.

Tailor-Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals.

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

Tailor-made amino acid-derived pharmaceuticals approved by the FDA in 2019.

Amino acids (AAs) are among a handful of paramount classes of compounds innately involved in the origin and evolution of all known life-forms. Along with basic scientific explorations, the major goal of medicinal chemistry research in the area of tailor-made AAs is the development of more selective and potent pharmaceuticals. The growing acceptance of peptides and peptidomimetics as drugs clearly indicates that AA-based molecules become the most successful structural motif in the modern drug design. In fact, among 24 small-molecule drugs approved by FDA in 2019, 13 of them contain a residue of AA or di-amines or amino-alcohols, which are commonly considered to be derived from the parent AAs. In the present review article, we profile 13 new tailor-made AA-derived pharmaceuticals introduced to the market in 2019. Where it is possible, we will discuss the development form drug-candidates, total synthesis, with emphasis on the core-AA, therapeutic area, and the mode of biological activity.

Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs.

New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C-F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C-F stereogenic centers constitute less than 1% of all fluorine-containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches.

Asymmetric synthesis of (S)-α-(octyl)glycine via alkylation of Ni(II) complex of chiral glycine Schiff base.

Over last decade, the use of Ni(II) complexes, derived from of glycine Schiff bases with chiral tridentate ligands, has emerge as a leading methodology for preparation of structurally diverse Tailor-Made Amino Acids, the key structural units in modern medicinal chemistry, and drug design. Here, we report asymmetric synthesis of derivatives of (S)-α-(octyl)glycine ((S)-2-aminodecanoic acid) and its N-Fmoc derivative via alkylation of chiral nucleophilic glycine equivalent with n-octyl bromide. Under the optimized conditions, the alkylation proceeds with excellent yield (98.1%) and diastereoselectivity (98.8% de). The observed stereochemical outcome and convenient reaction conditions bode well for application of this method for large-scale asymmetric synthesis of (S)-2-aminodecanoic acid and its derivatives.