Lactam Formation Research Articles

Photocatalytic Oxidation of α‐Substituted Amines to Lactams/Amides

AbstractWe, herein, report a base free, photocatalytic decyanation of α‐aminonitriles. A range of amides and lactams were obtained in 52–95% yields. Control experiments indicate O2 as an amide/lactam oxygen source and the reaction (lactam formation) follows radical pathway via dioxetanimine species. This methodology also applied for α‐ester/aldehyde substituted pyrrolidines in the presence of a base, probably via decarboxylation pathway.

Intramolecular lactam cross-linking of short oligoureas.

Oligourea foldamers are known to fold into 2.5-helices, stabilized by three-centered hydrogen bonds, which makes them conformationally more rigid than peptides. Nevertheless, the folding propensity and conformational stability in solution depend on the length of the oligomer, as well as the temperature, solvent, and so forth. In the peptide field, there are many approaches known for constraining the backbone in the folded conformation, including the stapling of side chains by disulfide bridges, lactam formation, ring closing metathesis reaction, and others. In this work, we linked side chains by lactam bridges of short oligoureas (four residues), containing Glu- and Lys-like residues. The designed oligoureas differed in the position of the Glu-like residue. Next, the conformational properties of linear and cyclic compounds were studied in protic solvent (methanol) by nuclear magnetic resonance and circular dichroism. Importantly, it was discovered that larger macrocycles (24-membered) are more tolerated with respect to the helical turn than smaller macrocycles (19-membered) under the studied conditions.

Ortho-quinone methide driven synthesis of kynurenic acid lactams.

Lactam formation of different KYNA amides and Mannich bases mediated by ortho-quinone methide has been investigated. The efficiency of the two routes of the cyclization process was revealed and the influence of diverse amide side chains was explored. In this regard compounds bearing a tertiary amine function in the amide side chain resulted in the formation of the lactam product, while the formation of dimer derivatives was observed in the case of other KYNA amides. Furthermore, derivatives bearing different substituents on the KYNA B ring were synthesized and their effects on the ring-closure reaction were investigated.

Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry.

Drug metabolite identification is an integrated part of drug metabolism and pharmacokinetics studies in drug discovery and development. Definitive identification of metabolic modification sides of test compounds such as screening metabolic soft spots and supporting metabolite synthesis are often required. Currently, liquid chromatography-high resolution mass spectrometry is the dominant analytical platform for metabolite identification. However, the interpretation of product ion spectra generated by commonly used collision-induced disassociation (CID) and higher-energy collisional dissociation (HCD) often fails to identify locations of metabolic modifications, especially glucuronidation. Recently, a ZenoTOF 7600 mass spectrometer equipped with electron-activated dissociation (EAD-HRMS) was introduced. The primary objective of this study was to apply EAD-HRMS to identify metabolism sites of vepdegestrant (ARV-471), a model compound that consists of multiple functional groups. ARV-471 was incubated in dog liver microsomes and 12 phase I metabolites and glucuronides were detected. EAD generated unique product ions via orthogonal fragmentation, which allowed for accurately determining the metabolism sites of ARV-471, including phenol glucuronidation, piperazine N-dealkylation, glutarimide hydrolysis, piperidine oxidation, and piperidine lactam formation. In contrast, CID and HCD spectral interpretation failed to identify modification sites of three O-glucuronides and three phase I metabolites. The results demonstrated that EAD has significant advantages over CID and HCD in definitive structural elucidation of glucuronides and phase I metabolites although the utility of EAD-HRMS in identifying various types of drug metabolites remains to be further evaluated. SIGNIFICANCE STATEMENT: Definitive identification of metabolic modification sites by liquid chromatography-high resolution mass spectrometry is highly needed in drug metabolism research, such as screening metabolic soft spots and supporting metabolite synthesis. However, commonly used collision-induced dissociation (CID) and higher-energy collisional dissociation (HCD) fragmentation techniques often fail to provide critical information for definitive structural elucidation. In this study, the electron-activated dissociation (EAD) was applied to identifying glucuronidation and oxidative metabolism sites of vepdegestrant, which generated significantly better results than CID and HCD.

Palladium(II)-catalyzed annulation of N-methoxy amides and arynes: computational mechanistic insights and substituents effects.

The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.

Adapting an acyl CoA ligase from Metallosphaera sedula for lactam formation by structure-guided protein engineering

The CoA ligase from Metallosphaera sedula (MsACL) can be used for the chemoenzymatic synthesis of amides from carboxylic acids. In this CoA-independent conversion, the enzyme catalyzes the adenylation of a carboxylic acid with the help of ATP, followed by the uncatalyzed cleavage of acyl-AMP by a nucleophilic amine to yield an amide. With ω-amino acids as substrates this reaction may result in formation of lactams, but unfortunately the substrate preference of the wild-type enzyme is rather limited. To allow structure-based protein engineering and expand the substrate scope of the enzyme, crystal structures of MsACL were solved in the thioesterification conformational state with AMP, CoA and with the reaction intermediate acetyl-AMP bound in the active site. Using substrate docking and by comparing the crystals structures and sequence of MsACL to those of related CoA ligases, mutations were predicted which increase the affinity in the carboxylic acid binding pocket for ω-amino acids. The resulting mutations transformed a non-active enzyme into an active enzyme for ε-caprolactam synthesis, highlighting the potential of the thermophilic CoA ligase for this synthetic and biotechnologically relevant reaction.

β-Alkenylation of Saturated N-Heterocycles via a C(sp3)-O Bond Wittig-like Olefination.

Although the C-Hα functionalization of N-heterocycles is, in fact, an easy chemical transformation, the C-Hβ functionalization is, on the contrary, a quite difficult chemical process. Here, we present a two-step protocol that allows the ready conversion of pyrrolidines, piperidines, and an azepane into their corresponding 3-exo-alkenyl lactams via the transient formation of 3-alkoxyamino lactams followed by a Wittig-like C(sp3)-O bond olefination with stabilized ylides from phosphonium salts mediated by t-BuOK. Additionally, as a proof of the synthetic effectiveness of this novel methodology, the first synthesis of the natural product callylactam A was achieved through a TiCl4-catalyzed double bond isomerization of a 3-exo-alkenyl 2-piperidone to its endo-isomer.

An efficient, concise synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings

An efficient, concise 5-step synthetic approach to γ-aminobutyric acid (GABA) derivatives bearing bridged bicyclo[2.2.2]octane and bicyclo[2.2.1]heptane rings was developed, which consists of Diels-Alder cycloaddition to construct the bridged bicyclic rings with a nitrile functionality, hydrogenation, LDA-mediated SN2 alkylation to introduce acetate moiety at the α-position of nitrile, reduction of the nitrile functionality to amino group followed by intramolecular formation of lactam and finally acidic hydrolysis of lactam to give the desired GABA derivatives (1 and 19 as HBr salts). The reaction conditions of Diels-Alder cycloaddition and LDA-mediated SN2 alkylation were intensively optimized to improve the yields. The stereochemistry of the SN2 reaction involved in the bicyclo[2.2.1]heptane ring system was unambiguously elucidated by single-crystal X-ray diffraction. This synthetic approach possesses advantages of less reaction steps, high overall yields and avoidance of toxic reagents, and may find wide applications in the synthesis of other GABA derivatives with similar bicyclic or polycyclic rings.

Cooperative Chiral Lewis Base/Palladium-Catalyzed Asymmetric Syntheses of Methylene-Containing δ-Lactams.

We herein report a two-step approach for the enantioselective synthesis of novel chiral δ-lactams. By using a cooperative chiral ITU/achiral Pd-catalyst system, this protocol proceeds via an asymmetric α-allylation of activated aryl esters first, followed by an acid-mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well.

Synthesis of Functionalized Pyrrolidinone Scaffolds via Smiles-Truce Cascade.

Arylsulfonamides have been found to react with cyclopropane diesters under simple base treatment to give α-arylated pyrrolidinones. This one-pot process comprises three steps: nucleophilic ring-opening of the cyclopropane, reaction of the resulting enolate in a Smiles-Truce aryl transfer, and lactam formation. The reaction represents a new, operationally simple approach to biologically active pyrrolidinones and expands Smiles-Truce arylation methods to encompass sp3 electrophilic centers in cascade processes.

Maximization of the photocatalytic degradation of diclofenac using polymeric g-C3N4 by tuning the precursor and the synthetic protocol

A green-oriented synthesis of highly photoactive nano-scaled graphitic carbon nitride (g-C3N4) is presented with water to be utilized as a critical reagent in order to tune desired physicochemical properties, and so, to elevate the photocatalytic activity. The materials’ optimization strategy involved the use of three precursors (melamine, urea or thiourea) and different thermal polycondensation (pyrolysis) durations. The synthesized materials were characterized by SEM, XRD, XPS, N2 sorption, FT-IR, and UV–vis DRS. Their photocatalytic activity against a non-steroidal anti-inflammatory pharmaceutical compound, diclofenac, was evaluated under ultraviolent irradiation, also investigating the influence of pH, photocatalyst dosage/mass and concentration of H2O2. The results revealed that the precursor, pyrolysis time and use of water effect significantly the physicochemical features and the photocatalytic activity. Urea-derived samples showed the highest specific surface areas and smallest crystalline domains, as well as the highest photocatalytic efficiency. The involved mechanisms were examined by exploring the optical properties, the role of the photo-generated radicals and the reactive oxygen species, as well as LC-MS analysis. The Orbitrap high-resolution mass-spectrometry analysis revealed the formation of 26 transformation products governed by different processes such as hydroxylation and further oxidation to keto derivatives and ring opening, decarboxylation/hydroxylation with further oxidation, dichlorination, and lactam formation.

One Reaction Served Three Ways: The On-DNA Ugi 4C-3C Reaction for the Formation of Lactams.

Developing new on-DNA reactions is paramount to the development of new encoded libraries in the pursuit of novel pharmaceutical lead compounds. Lactam-containing molecules have been shown to be effective in a wide range of therapeutic areas and therefore represent a promising target for further investigation by DNA-encoded library screening. In pursuit of this motif, we report a novel method for the introduction of lactam-containing structures onto a DNA headpiece through the Ugi four-center three-component reaction (4C-3CR). This novel method is successful in three different approaches to give unique on-DNA lactam structures: on-DNA aldehyde coupled with isonitriles and amino acids; on-DNA isonitrile coupled with aldehydes and amino acids; and on-DNA isonitrile coupled with amines and acid aldehydes.

Substituent effects on intramolecular Schmidt reactions: a theoretical study on the formation of bridged lactams.

The competitive formation of isomeric bridged lactams via acid-catalyzed intramolecular Schmidt reactions from 3-azidoethylcyclopentanones is explored using density functional theory (DFT) calculations, primarily performed at the M06-2X/6-311++G(d,p) level of theory. The results indicate that specific substituents installed at α-carbons can efficiently control the regioselectivity of the reaction by lone pair-cation interactions or steric hindrance reversing the main product preference, whereas cation-π interactions are not so effective.

Simultaneous Enantiodivergent Synthesis of Diverse Lactones and Lactams via Sequential One-Pot Enzymatic Kinetic Resolution-Ring-Closing Metathesis Reactions.

One of the goals of diversity-oriented synthesis is to achieve the structural diversity of obtained compounds. As most biologically active compounds are chiral, it is important to develop enantioselective methods of their synthesis. The application of kinetic resolution in DOS is problematic because of low efficiency (max. 50% yield) and many purification steps. The further derivatization of kinetic resolution products in DOS leads to the formation of a narrow library of compounds of the same stereochemistry. To overcome these limitations, we present a new concept in which the kinetic resolution is combined, the subsequent reaction of which in a one-pot protocol leads to the simultaneous formation of two skeletally and enantiomerically diverse platform molecules for DOS. Their further derivatization can gain access to a double-sized library of products in respect to a classical approach. The validity of our concept was evidenced in enzymatic kinetic resolution followed by a ring-closing metathesis cascade. From racemic carboxylic acid ester, a simultaneous formation of enantiopure lactones and lactams was achieved. These compounds are important building blocks in organic and medicinal chemistry and until now were synthesized in separate procedures.

Functionalization of tetrahydroindol-4-one derivatives

Available and effective methods of tetrahydroindol-4-one derivatives transformation are described, which include functionalization of the nitrogen atom, carbonyl group, side chains in positions 1,2,3,7 of the bicycle, as well as aromatization of the cyclohexene fragment in the presence of dehydrogenating agents. Original preparative approaches to the synthesis of [4,5]-fused indole derivatives (pyrroles, thiophenes, pyrazoles, isoxazoles, thiazoles, 1,2,3-triazoles, pyridazinones), implemented by introducing functional groups in the α-position to the carbonyl group with subsequent cyclocondensations (Hanch, Paal-Knorr, [4+2] and [3+2]-cyclization reactions) are reviewed. Beckman and Schmidt rearrangements in the chemistry of tetrahydroindolones are accompanied by a cycle expansion with the formation of lactams or their transformation products. The Fischer reaction allows to obtain polyheterocycles with a new indole ring at the same time as the Dimrot rearrangement allows to synthesize pyrroloquinolones. Among the ways of modifying side chains of tetrahydroindolone, the three-component Passerini reaction is the most promising one, which provides quick access to indolone-N-amino acid derivatives.

Mechanistic Investigations on N-Cα Bond Cleavages in Dibasic Peptides Containing Internal Lys and Arg Residues.

The model nonapeptide AAARAAKAG* (* indicates amide) is used to explore N-Cα bond fragmentation under CID-MS conditions. Neighboring group participation and the effect of positioning of Lys and Arg residues on N-Cα bond cleavage is established using a library of synthetic peptide analogues. The importance of the Arg residue at position 4 and the i to i+3 spacing between Arg and Lys residues in determining the formation of the N-Cα bond cleaved product ions (cn) is demonstrated by a comparative MS study of positional variants in analogue peptides. The effect of shortening of the Lys side chain has been established using ornithine (Orn) and diaminobutyric acid (Dab) analogues. The involvement of the Lys residue in mediating the N-Cα bond cleavage is further probed using Nε-dimethyl and isotopically labeled 15Nα,ε lysine residues. MSn experiments reveal that the c6 ion originates from a doubly charged dehydrated b8 ion [b8-18]2+. The mechanism of this unusual fragmentation process has been probed by using position 8 analogues (Gly, Ala, and Aib). A plausible mechanism is proposed for the origin of the c6 ion, which involves C-terminus lactam formation followed by transannular cyclization and dehydration. The results presented in this study highlight the role of reactive side chain functionalities in promoting noncanonical fragmentation pathways.

Phylogenomic analysis of the diversity of graspetides and proteins involved in their biosynthesis

BackgroundBacteria and archaea produce an enormous diversity of modified peptides that are involved in various forms of inter-microbial conflicts or communication. A vast class of such peptides are Ribosomally synthesized, Postranslationally modified Peptides (RiPPs), and a major group of RiPPs are graspetides, so named after ATP-grasp ligases that catalyze the formation of lactam and lactone linkages in these peptides. The diversity of graspetides, the multiple proteins encoded in the respective Biosynthetic Gene Clusters (BGCs) and their evolution have not been studied in full detail. In this work, we attempt a comprehensive analysis of the graspetide-encoding BGCs and report a variety of novel graspetide groups as well as ancillary proteins implicated in graspetide biosynthesis and expression.ResultsWe compiled a comprehensive, manually curated set of graspetides that includes 174 families including 115 new families with distinct patterns of amino acids implicated in macrocyclization and further modification, roughly tripling the known graspetide diversity. We derived signature motifs for the leader regions of graspetide precursors that could be used to facilitate graspetide prediction. Graspetide biosynthetic gene clusters and specific precursors were identified in bacterial divisions not previously known to encode RiPPs, in particular, the parasitic and symbiotic bacteria of the Candidate phyla radiation. We identified Bacteroides-specific biosynthetic gene clusters (BGC) that include remarkable diversity of graspetides encoded in the same loci which predicted to be modified by the same ATP-grasp ligase. We studied in details evolution of recently characterized chryseoviridin BGCs and showed that duplication and horizonal gene exchange both contribute to the diversification of the graspetides during evolution.ConclusionsWe demonstrate previously unsuspected diversity of graspetide sequences, even those associated with closely related ATP-grasp enzymes. Several previously unnoticed families of proteins associated with graspetide biosynthetic gene clusters are identified. The results of this work substantially expand the known diversity of RiPPs and can be harnessed to further advance approaches for their identification.

Carbonylation Chemistry Applied to the Synthesis of Benzimidazo[2,1‐b]quinazolin‐12‐ones

AbstractA carbonylative route towards the synthesis of benzimidazo[2,1‐b]quinazolin‐12‐ones was developed. The key step in this strategy consists of an intramolecular carbonylative lactam formation, starting from N‐(2‐bromophenyl)‐1H‐benzimidazol‐2‐amines. These precursor molecules were synthesized by two different methods to introduce a variety of substituents on the aromatic ring systems. Interestingly, only near‐stoichiometric amounts of carbon monoxide were required in the ring‐closing aminocarbonylation reaction, rendering the developed strategy also suitable for late‐stage 13C‐isotopic labelling.

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates.

The constrained dipeptide surrogates 5- and 7-hydroxy indolizidin-2-one N-(Boc)amino acids have been synthesized from L-serine as a chiral educt. A linear precursor ∆4-unsaturated (2S,8S)-2,8-bis[N-(Boc)amino]azelic acid was prepared in five steps from L-serine. Although epoxidation and dihydroxylation pathways gave mixtures of hydroxy indolizidin-2-one diastereomers, iodolactonization of the ∆4-azelate stereoselectively delivered a lactone iodide from which separable (5S)- and (7S)-hydroxy indolizidin-2-one N-(Boc)amino esters were synthesized by sequences featuring intramolecular iodide displacement and lactam formation. X-ray analysis of the (7S)-hydroxy indolizidin-2-one N-(Boc)amino ester indicated that the backbone dihedral angles embedded in the bicyclic ring system resembled those of the central residues of an ideal type II’ β-turn indicating the potential for peptide mimicry.

Ligand Enabled Pd(II)-Catalyzed γ-C(sp3)-H Lactamization of Native Amides.

γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.