Lactam Formation Research Articles

A Local Desymmetrization Approach to Piperidinyl Acetic Acid γ-Secretase Modulators.

A desymmetrization-based approach for the synthesis of piperidinyl acetic acid γ-secretase modulators has been developed. The synthetic sequence features the use of N-tert-butanesulfinyl imine reduction and a diastereoselective lactam formation to set up the chiral centers. The synthetic utility is demonstrated by the concise asymmetric synthesis of γ-secretase modulator GSM-1.

Homogeneous first-row transition metal catalyst for sustainable hydrogen production and organic transformation from methanol, formic acid, and bio-alcohols

The recent advances in homogeneous first-row transition-metal catalyzed for hydrogen production and important organic transformations from methanol, formic acid (FA), and bio-alcohols are the current interest, which is an important paradigm in chemical synthesis for the development of sustainable catalysis. Early work mainly based on noble metal (Ru, Ir, and Pt) catalysts, but at present the focused on mainly earth-abundant 3d base-metal (Mn, Fe, Co, and Ni) complexes, which are showing growing interest, highly elusive and demanding in the modern science due to its low cost, less toxic and more abundance. In this review, we mainly aim to describe the topics such as a) hydrogen formation and organic transformations from methanol, formic acid, and bio-alcohols; b) C-methylation, N-methylation, and formamide formation using methanol; c) N-heterocycle, lactam, lactone and hydrogen formation from diol or bioalcohols; d) hydrogen formation and storage capability of the liquid organic hydrogen carrier (LOHC) and additionally a special attention is paid to the utility of these reactions including brief reaction mechanism, and scope of reaction.

Regiodivergent alkene difunctionalizations

Lactams are ubiquitous moieties in a variety of natural products and pharmaceuticals. Due to the important biological roles of lactam-containing molecules, development of efficient methods to synthesize functionalized lactams is highly desired. In this regard, Rovis developed intramolecular cyclizations of alkenyl amides as an attractive strategy, which allows formation of lactams with concomitant installation of an additional functional group by trapping intermediates with amine and carboxylate.

A preliminary assessment of pregabalin lactam mutagenicity and remarks on “An investigation of pregabalin lactamization process and effect of various pH on reaction: A computational insight”

A computational investigation into pregabalin lactamization has been recently published, confirming that the reaction depends on pH and allowing a reasonable pathway for the formation of the impurity pregabalin lactam (prega-L) to be proposed. However, without proof or regulatory criteria, that investigation assumed that the impurity pregabalin lactam (prega-L) has high toxicity potential, which is worrisome. The present communication reports on the preliminary assessment of the prega-L toxicity by computational methods. The principles outlined in the ICH guidance M7 are followed, and statistics- and rule-based methodologies (in silico models) are used; the mutagenicity potential is considered as endpoint, and implications for qualifying this impurity in drug substances and/or drug products are discussed.

6-Hydroxymethyl Indolizidin-2-one Amino Acid Synthesis, Conformational Analysis, and Biomedical Application as Dipeptide Surrogates in Prostaglandin-F2α Modulators.

6-Hydroxymethyl indolizidin-2-one amino acids were synthesized in 10 steps from l-serine by intramolecular ring opening of a symmetrical epoxide and lactam formation. X-ray analyses indicated the bicycles replicated ideal peptide type II' β-turn central dihedral angle geometry. Inside a prostaglandin-F2α receptor modulator, the 6-hydroxymethyl analogue retained inhibitory activity on myometrial contractility.

Synthesis and Modeling of Ezetimibe Analogues.

Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl β-lactam is described starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.

Diastereoselective Access to Tetracyclic Eight-Membered Lactams through a Dearomative Heck Reaction and an Alkylative Ring-Opening Driven by Photoexcited Spiroindolines.

An external-photocatalyst-free, light-driven alkylative ring-opening of stable spiroindolines was developed to construct indolo- and benzoannulated eight-membered lactams. The spiroindolines were prepared from tetrahydro-β-carbolines by a dearomative Heck reaction. Mechanistic experimental studies on the alkylative ring opening suggested that a photoredox pathway was involved, in which the spiroindoline performed as both reagent and photosensitizer. DFT calculations showed that the radical addition toward a cyclic alkene was the key to the diastereoselective formation of tetracyclic medium-sized lactams.

Macrocyclization strategies for cyclic peptides and peptidomimetics.

Peptides are a growing therapeutic class due to their unique spatial characteristics that can target traditionally “undruggable” protein–protein interactions and surfaces. Despite their advantages, peptides must overcome several key shortcomings to be considered as drug leads, including their high conformational flexibility and susceptibility to proteolytic cleavage. As a general approach for overcoming these challenges, macrocyclization of a linear peptide can usually improve these characteristics. Their synthetic accessibility makes peptide macrocycles very attractive, though traditional synthetic methods for macrocyclization can be challenging for peptides, especially for head-to-tail cyclization. This review provides an updated summary of the available macrocyclization chemistries, such as traditional lactam formation, azide–alkyne cycloadditions, ring-closing metathesis as well as unconventional cyclization reactions, and it is structured according to the obtained functional groups. Keeping peptide chemistry and screening in mind, the focus is given to reactions applicable in solution, on solid supports, and compatible with contemporary screening methods.

Brønsted Base‐Catalyzed Formal Reductive [3+2] Annulation of 4,4,4‐Trifluorocrotonate and α‐Iminoketones

A formal reductive [3+2] annulation of 4,4,4-trifluorocrotonate and α-iminoketones was developed under Brønsted base catalysis. A single phosphazene base efficiently catalyzes the one-pot tandem reaction involving two mechanistically different elementary processes, namely the chemoselective reduction of an imine moiety of α-iminoketones with thiols as the reductant and the subsequent intermolecular Michael addition of an enolate of α-aminoketones concomitant with lactam formation. This operationally simple method provides β-trifluoromethyl-substituted γ-lactams with a tetrasubstituted carbon as a single diastereomer.

A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

Controllable Skeleton Rearrangement of 3‐Substituted Cyclobutanones under Basic Conditions†

Summary of main observation and conclusionDivergent skeleton rearrangements of cyclobutanones under simply basic conditions have been described. The reaction pathway is controlled by the nature of Z group on 3‐substituted cyclobutanones, leading to the formation of various lactones, lactams and acids. Preliminary results on enantioselective reaction were also reported.

Quantitative Analysis on Two-Point Ligand Modulation of Iridium Catalysts for Chemodivergent C-H Amidation.

The transition-metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C-N bond into diverse reactive units. While numerous selective aminations are known, understanding complex structural effects of the key intermediates on the observed chemoselectivity is still elusive in most cases. Herein, we report a designing approach to enable selective nitrenoid transfer leading to sp2 spirocyclization and sp3 C-H insertion by cooperative two-point modulation of ligands in the CpXIr(III)(κ2-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can be attributed to the desired mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the η5-cyclopentadienyl ancillary (CpX) and LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for construction of an intuitive yet robust statistical model that predicts a large set of chemoselective outcomes, implying that the catalysts' structural effects play a critical role on the chemoselective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemoselective reactivity (up to >20:1) toward a diverse array of competing sites, such as tertiary, secondary, benzylic, allylic C-H bonds, and aromatic π system.

Modified synthesis of the peptidomimetic natriuretic peptide receptor-C antagonist M372049

The Natriuretic Peptide Receptors (NPRs) regulate vascular sodium levels and have been of significant interest for the potential treatment of hypertension and related cardiovascular complications. The peptidomimetic antagonist M372049 is a valuable probe for the study of NPR-C signaling, unfortunately it is presently not commercially available. Described is a detailed protocol for its synthesis that does not require specialized apparatus and builds upon a prior patent from Veale and colleagues. Key steps include a base-mediated lactam formation and a solid-supported peptide synthetic sequence. An X-ray crystal structure of a key lactam intermediate was obtained to confirm the structure and relative stereochemistry of the compound.

A Facile Direct Route to N-(Un)substituted Lactams by Cycloamination of Oxocarboxylic Acids without External Hydrogen.

Lactams are privileged in bioactive natural products and pharmaceutical agents and widely featured in functional materials. This study presents a novel versatile approach to the direct synthesis of lactams from oxocarboxylic acids without catalyst or external hydrogen. The method involves the in situ release of formic acid from formamides induced by water to facilitate efficient cycloamination. Water also suppresses the formation of byproducts. This unconventional pathway is elucidated by a combination of model experiments and density functional theory calculations, whereby cyclic imines (5‐methyl‐3,4‐dihydro‐2‐pyrrolone and its tautomeric structures) are found to be favorable intermediates toward lactam formation, in contrast to the conventional approach encompassing cascade reductive amination and cyclization. This sustainable and simple protocol is broadly applicable for the efficient production of various N‐unsubstituted and N‐substituted lactams.

Cooperative Pd/Cu Catalysis to Spiro[indoline-2,3'-pyrrolidin]-2'-ones: Tandem Benzylation of α-Isocyano Lactams, Amine Addition, and N-Arylation.

A tandem three-component reaction has been developed for the synthesis of spirocyclic 2-indolinylformamidines through a cooperative action of palladium and copper catalysts. The Pd-catalyzed benzylation of α-isocyano lactams with 2-bromobenzyl bromides allows efficient formation of α-substituted α-isocyano lactams. A subsequent in situ Cu-catalyzed amine addition to the isocyanide moiety provides amidine intermediates that readily undergo intramolecular N-arylation via the cooperative action of Pd/Cu catalysis, allowing a facile chiral resolution of the spirocyclic 2-indolines.

Toxicokinetic studies of the four new psychoactive substances 4-chloroethcathinone, N-ethylnorpentylone, N-ethylhexedrone, and 4-fluoro-alpha-pyrrolidinohexiophenone

The presented study aimed to elucidate the toxicokinetics of the four synthetic cathinones 4-chloroethcathinone (4-CEC), N-ethylnorpentylone (N-ethylpentylone, ephylone), N-ethylhexedrone (NEH), and 4-fluoro-alpha-pyrrolidinohexiophenone (4-fluoro-alpha-pyrrolidinohexanophenone, 4-F-α-PHP, 4F-alpha-PHP, 4F-PHP). First, their metabolism was studied using human urine and blood samples. Analysis of specimens was performed by liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) and gas chromatography–mass spectrometry (GC–MS). LC-HRMS/MS was also used to analyze in vitro incubations of the new psychoactive substances using pooled human liver S9 fraction (pS9), to identify the monooxygenases involved in the initial metabolic steps, and determination of plasma concentrations after a standard addition method. Metabolic stability was tested in pooled human liver microsomes incubations analyzed by LC-ion trap MS. Using LC-HRMS/MS, 47 metabolites in total were found in patient samples and pS9 incubations. Using GC–MS, 4-CEC, ephylone, NEH, and five of their metabolites were detectable in urine. The following main phase I reactions were observed: carbonyl group reduction, N-deethylation, hydroxylation, lactam formation (4F-PHP), and demethylenation (ephylone). Mainly glucuronidations were observed as phase II reactions besides conjugates with the dicarboxylic acids malonic, succinic, and glutaric acid (4-CEC), sulfation, methylation (both ephylone), and N-acetylation (NEH). A broad range of monooxygenases was involved in the initial steps with exception of NEH (only CYP1A2 and CYP2C19). 4F-PHP had the shortest in vitro half-life (38 min) and highest intrinsic clearance (15.7 mL/min/kg). Plasma concentrations ranged from 0.8 to 8.5 ng/mL. Our results are expected to help toxicologists to reliably identify these substances in case of suspected abuse and allow them a thorough risk assessment.

Chemoenzymatic Total Synthesis of ent-Oxycodone: Second-, Third-, and Fourth-Generation Strategies.

Four distinct approaches to ent-oxycodone were designed and accomplished. All rely on the same starting material, the diene diol derived from phenethyl acetate by the whole-cell fermentation with E. coli JM109 (pDTG601A), a strain that overexpresses toluene dioxygenase. The key step in the first-generation approach involves the construction of the C-9/C-14 bond by a SmI2-mediated cyclization of a keto aldehyde. The second-generation design relies on the use of the Henry reaction to accomplish this task. In both of these syntheses, Parker's cyclization was employed to construct the D-ring. The third-generation synthesis provides an improvement over the second in that the nitrogen atom at C-9 is introduced by azidation of the C-9/C-10 olefin, followed by reduction and lactam formation between the C-9 amine and the Fukuyama-type lactone. Finally, the fourth generation takes advantage of the keto-nitrone reductive coupling to generate the C-9/C-14 linkage. The four generations of the total syntheses of ent-oxycodone were accomplished in 13, 18, 16, and 11 operations (19, 23, 24, and 18 steps), respectively. Experimental and spectral data are provided for all new compounds.

Abiotic and biotic processes of diclofenac in enriched nitrifying sludge: Kinetics, transformation products and reactions

Diclofenac (DCF), as an emerging contaminant in aquatic environments, has sparked increasing concerns about its impact on the environment. Nitrification in wastewater treatment processing has removed DCF to a large extent. However, the removal characteristics and mechanisms of DCF in the nitrification process are still poorly understood. In this study, enriched nitrifying sludge was used to investigate the transformation of DCF during the nitrification process. Elimination of DCF caused by volatilization, hydrolyzation and adsorption was limited. Abiotic nitration removal was confirmed as significant in enriched nitrifying sludge at a low pH and high nitrite concentration. Free nitrite acid was proposed as the reaction species participating in the DCF transformation process, and a regression equation was developed to predict the contribution of abiotic nitration on DCF removal in enriched nitrifying sludge. By slowly and continuously adding an ammonia stock solution and controlling the pH, we avoided the effect of abiotic nitration removal, and DCF biodegradation was positively correlated to specific ammonium oxidation rates (SAORs). The removal of DCF fit the first order kinetic model (R2 = 0.8285, p < 0.05) with an SAOR of 0.25 mg NH4+-N/(gMLSS·min). The high removal rate constant of k (0.1286 L/(gMLSS·h)) and short half-life (2.48 h) revealed the strong capability of nitrifying bacteria to transform DCF. Nine DCF transformation products were identified and three of them were quantified in the transformation process. The formation of kinetic profile 4-OH-DCF, 5-OH-DCF and DCF-Benzoic acid (DCF-BA) implied that hydroxylation may be the first reaction of DCF and DCF-BA may be a terminal product that resists further degradation. The postulated reactions concerning the transformation of DCF were hydroxylation, lactam formation and oxidation. Accordingly, a detailed degradation pathway was presented.

A Doubly-Quenched Fluorescent Probe for Low-Background Detection of Mitochondrial H2O2.

Hydrogen peroxide (H2O2) is an important product of oxygen metabolism and plays a crucial role in regulating a variety of cellular functions. Fluorescent probes have made a great contribution to our understanding of the biological role of endogenous H2O2. However, fluorescent probes for H2O2 featuring aryl boronates can suffer from moderate turn-on fluorescence responses. Strategies that can reduce the background fluorescence of these boronate-masked probes would significantly improve the sensitivity of endogenous H2O2 detection. In this work, we propose a general and reliable double-quenching concept for the design of fluorescent probes with low background fluorescence. A new fluorescent probe was developed for the detection of endogenous H2O2 in mitochondria of live cancer cells. This probe exploits a boronate-driven lactam formation and an eliminable quenching moiety simultaneously (i.e., the double-quenching effect) to reduce the background fluorescence, which ultimately results in the achievement of a >50-fold fluorescence turn-on. A linear concentration range of response between 1 and 60 μM and a detection limit of 0.025 μM can be obtained. This study not only presents a highly sensitive fluorescent probe for the detection of H2O2 but also provides a new concept for the design of fluorescent probes with a previously unachievable fluorescence off-on response ratio for other types of ROS and many other biologically relevant analytes.

Cleavable Amide Bond: Mechanistic Insight into Cleavable 4-Aminopyrazolyloxy Acetamide at Low pH.

The cleavage of amide bonds under mild acidic conditions is a rare chemical event. N-Acetamide bond of peptides is extremely stable even under the strongest organic acid trifluoromethanesulfonic acid. This report mechanistically describes a new cleavable amide bond in 4-aminopyrazolyloxy acetamide peptide analogues under mild acidic conditions such as trifluoroacetic acid (10-20%) or HCl (0.1-4.0 N) at room temperature, and the formation of unusual lactam from 4-aminopyrazolyloxy acetic acid after evaporation of solvent. This is a rare chemical event in peptide bond, which could be explored as acid-sensitive protecting group of free amines.