Hepatic Mac2-BP expression depends on liver fibrosis and inflammation due to fat accumulation in patients with metabolic dysfunction-associated steatotic liver disease.

AIM: Data on the upregulation of Mac-2 binding protein (M2BP) expression associated with fat accumulation in the liver are limited. Therefore, we aimed to assess the relationship between hepatic M2BP expression and changes in the liver microenvironment due to fat accumulation in patients with metabolic dysfunction associated steatotic liver disease (MASLD). METHODS: Liver specimens obtained from 46 patients with MASLD were subjected to immunohistochemical staining to visualize M2BP expression in the liver. The staining intensity in the hepatocytes and sinusoidal cells was classified as high or low grade. First, the correlation between hepatic M2BP expression and microenvironmental changes caused by fat accumulation was examined. Then, the influence of hepatic M2BP expression on serum M2BP glycosylation isomer levels in patients with MASLD was evaluated. RESULTS: The staining grade of M2BP was higher in the sinusoidal cells than in the hepatocytes (p = 0.015). The patients with high staining grade in their hepatocytes had more severe lobular inflammation than those with low staining grade (p = 0.037). Additionally, the patients with high staining grade in their sinusoidal cells presented more severe fibrosis than those with low staining grade (p = 0.018). The staining grade in the hepatocytes correlated positively with serum M2BP glycosylation isomer levels (p = 0.023), whereas no correlation was observed between sinusoidal staining grade and serum M2BP glycosylation isomer levels (p = 0.393). CONCLUSIONS: Fat accumulation in patients with MASLD leads to M2BP expression in hepatocytes due to liver inflammation and that in sinusoidal cells due to fibrosis.

Concise Synthesis of Cyctetryptomycin A and B Enabled by Zr-Catalyzed Dimerization.

A concise synthetic strategy utilizing a Zr-catalyst for the construction of cyctetryptomycin A and B is herein reported. Cyctetryptomycin A and B are recently isolated, complex tetrameric natural products for which total synthesis has not been previously reported. This study presents a practical approach for the construction of two consecutive quaternary carbon centers via a Zr-catalyst. Furthermore, the first total synthesis of cyctetryptomycin A and B was achieved by this Zr-catalyzed radical coupling. The radical dimerization reaction mediated by the Zr-catalyst required dppe as an indispensable additive. Through both experimental and theoretical investigations into the mechanism of this Zr-catalyzed reaction, the specific role of dppe was elucidated. In addition, the synthetic approach was extended to enable the practical synthesis of other dimeric natural products, including tetratryptomycin A, dibrevianamide F, and ditryptophenaline. Finally, the synthetic mechanism of cyctetryptomycin A and B, through the oxidative macrocyclization of tetratryptomycin A by CttpC, was newly elucidated by both experimental and docking simulations.

C1-4 Alkylation of Aryl Bromides with Light Alkanes enabled by Metallaphotocatalysis in Flow.

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C-H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of complex organic molecules. In particular, the formation of C(sp2)-C(sp3) bonds is crucial for constructing biologically active molecules, including pharmaceuticals and agrochemicals. In this study, we present the previously elusive coupling between gaseous alkanes and (hetero)aryl bromides, achieved through a combination of Hydrogen Atom Transfer (HAT) photocatalysis and nickel-catalyzed cross coupling at room temperature. Utilizing flow technology allowed us to conduct this novel coupling reaction with reduced reaction times and in a scalable fashion, rendering it practical for widespread adoption in both academia and industry. Density Functional Theory (DFT) calculations unveiled that the oxidative addition constitutes the rate-determining step, with the activation energy barrier increasing with smaller alkyl radicals. Furthermore, radical isomerization observed in propane and butane analogues could be attributed to the electronic properties of the bromoarene coupling partner, highlighting the crucial role of oxidative addition in the observed selectivity of this transformation.

Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at Phosphorus (V): Improved Generality, Efficiency and Modularity.

A broadly improved second generation catalytic two-phase strategy for the enantioselective synthesis of stereogenic at phosphorus (V) compounds is described. This protocol, consisting of a bifunctional iminophosphorane (BIMP) catalyzed nucleophilic desymmetrization of prochiral, bench stable P(V) precursors and subsequent enantiospecific substitution allows for divergent access to a wide range of C-, N-, O- and S- substituted P(V) containing compounds from a handful of enantioenriched intermediates. A new ureidopeptide BIMP catalyst/thiaziolidinone leaving group combination allowed for a far wider substrate scope and increased reaction efficiency and practicality over previously established protocols. The resulting enantioenriched intermediates could then be transformed into an even greater range of distinct classes of P(V) compounds by displacement of the remaining leaving group as well as allowing for even further diversification downstream. Density functional theory (DFT) calculations were performed to pinpoint the origin of enantioselectivity for the BIMP-catalyzed desymmetrization, to rationalize how a superior catalyst/leaving group combination leads to increased generality in our second-generation catalytic system, as well as shed light onto observed stereochemical retention and inversion pathways when performing late-stage enantiospecific SN2@P reactions with Grignard reagents.

Endoscopic Evacuation of Putaminal Hemorrhage Using the Trans-Middle Temporal Gyrus Approach: Technical Notes and Case Presentations.

BACKGROUND: The development of minimally invasive endoscopic neurosurgery has enabled widespread application of endoscopic surgery via the ipsilateral transfrontal approach for putaminal hematoma evacuation. However, this approach is unsuitable for putaminal hematomas that extend into the temporal lobe. We adopted the endoscopic trans-middle temporal gyrus approach, instead of the conventional surgical approach, for the management of these complicated cases and determined its safety and feasibility. METHODS: Twenty patients with putaminal hemorrhage underwent surgical treatment at the Shinshu University Hospital between January 2016 and May 2021. Of these, two patients with left putaminal hemorrhage that extended into the temporal lobe underwent surgical treatment using the endoscopic trans-middle temporal gyrus approach. The procedure entailed the use of a thinner transparent sheath to reduce the technique's invasiveness, a navigation system to determine the location of the middle temporal gyrus and the sheath's trajectory, and an endoscope with a 4K camera for higher image quality and utility. The sylvian fissure was compressed superiorly using our novel "port retraction technique" (i.e., by tilting the transparent sheath superiorly) to avoid damage to the middle cerebral artery and Wernicke's area. RESULTS: The endoscopic trans-middle temporal gyrus approach allowed sufficient hematoma evacuation and hemostasis under endoscopic observation without any surgical complexities or complications. The postoperative course was uneventful in both patients. CONCLUSION: The endoscopic trans-middle temporal gyrus approach for putaminal hematoma evacuation helps avoid damage to normal brain tissue, which could result from the wide range of motion of the conventional technique, particularly when the hemorrhage extends to the temporal lobe.

Cobalt-Catalyzed Enantio- and Regioselective C(sp3 )-H Alkenylation of Thioamides.

An enantioselective cobalt-catalyzed C(sp3 )-H alkenylation of thioamides with but-2-ynoate ester coupling partners employing thioamide directing groups is presented. The method is operationally simple and requires only mild reaction conditions, while providing alkenylated products as single regioisomers in excellent yields (up to 85 %) and high enantiomeric excess [up to 91 : 9 enantiomeric ratio (er), or up to >99 : 1 er after a single recrystallization]. Diverse downstream derivatizations of the products are demonstrated, delivering a range of enantioenriched constructs. Extensive computational studies using density functional theory provide insight into the detailed reaction mechanism, origin of enantiocontrol, and the unusual regioselectivity of the alkenylation reaction.

The efficacy of a visiting surgical service versus that of a hospital-based surgical service in providing endoscopic endonasal surgery to remove nonfunctioning pituitary adenomas in rural communities.

PURPOSE: To satisfy the increasing demand for endoscopic endonasal approach (EEA) to treat pituitary tumors, especially in rural areas, the "mobile EEA" system, a visiting surgical service, has been established We report this unique system for maintaining community healthcare and evaluate the surgical results of mobile EEA. METHODS: A retrospectively acquired database of 225 consecutive cases of EEA at Shinshu University Hospital (i.e., "home EEA") and its affiliated hospitals (i.e., "away EEA") between May 2018 and May 2022 was reviewed. A total of 105 consecutive patients who fulfilled the criterion of a diagnosis of new-onset nonfunctioning pituitary adenoma (PA) were included. Clinical characteristics and postoperative clinical outcomes were statistically compared between the home EEA and away EEA groups to assess the presence of a home advantage and/or an away disadvantage. RESULTS: Patients were stratified into two cohorts: patients treated at our hospital (home EEA: n = 41 [39.0%]) and those treated in the visiting surgical service at an affiliated hospital (away EEA: n = 64 [61.0%]). Postoperative clinical outcomes, such as the extent of tumor resection (p = 0.39), operation time (p = 0.80), visual function (p = 0.54), and occurrence of surgical complications (p = 0.53), were comparable between the groups. There were no visiting surgical service-related adverse events or accidents caused by physicians' driving to away hospitals. CONCLUSION: Pituitary surgeries performed via the mobile EEA system for nonfunctioning PAs may help maintain local community healthcare. Furthermore, this system can also contribute to the efficient training of surgeons by the same experienced pituitary surgeon using the same protocol.

Ligand-Controlled Regiodivergence in Nickel-Catalyzed Vinylcyclopropane Rearrangement.

A ligand-controlled regiodivergence in Ni-catalyzed rearrangement of vinylcyclopropanes to 1,4- or 1,5-disubstituted cyclopentenes is reported. The 1,4- or 1,5-disubstituted cyclopentene is selectively obtained depending on the choice of ligands. Detailed kinetic studies and density functional theory calculations on the catalytic cycle revealed that the product selectivity is determined at the reductive elimination step from the six-membered η1 -allyl intermediate.

Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,ß-Unsaturated Esters and Amides.

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters.

Molecules that contain a stereogenic phosphorus atom are crucial to medicine, agrochemistry and catalysis. While methods are available for the selective construction of various chiral organophosphorus compounds, catalytic enantioselective approaches for their synthesis are far less common. Given the vastness of possible substituent combinations around a phosphorus atom, protocols for their preparation should also be divergent, providing facile access not only to one but to many classes of phosphorus compounds. Here we introduce a catalytic and enantioselective strategy for the preparation of an enantioenriched phosphorus(V) centre that can be diversified enantiospecifically to a wide range of biologically relevant phosphorus(V) compounds. The process, which involves an enantioselective nucleophilic substitution catalysed by a superbasic bifunctional iminophosphorane catalyst, can accommodate a wide range of carbon substituents at phosphorus. The resulting stable, yet versatile, synthetic intermediates can be combined with a multitude of medicinally relevant O-, N- and S-based nucleophiles.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,ß-Unsaturated Esters.

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,ß-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including ß-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.

Enantioselective Total Synthesis of (-)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones.

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a ß-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Frontal Encephalocele Plus Epilepsy: A Case Report and Review of the Literature.

An encephalocele is a pathological brain herniation caused by osseous dural defects. Encephaloceles are known to be regions of epileptogenic foci. We describe the case of a 44-year-old woman with refractory epilepsy associated with a frontal skull base encephalocele. Epilepsy surgery for encephalocele resection was performed; however, the epilepsy was refractory. A second epilepsy surgery for frontal lobectomy using intraoperative electroencephalography was required to achieve adequate seizure control. Previous reports have shown that only encephalocele resection can result in good seizure control, and refractory epilepsy due to frontal lobe encephalocele has rarely been reported. To the best of our knowledge, this is the first report of frontal encephalocele plus epilepsy in which good seizure control using only encephalocele resection was difficult to achieve. Herein, we describe the possible mechanisms of encephalocele plus epilepsy and the surgical strategy for refractory epilepsy with encephalocele, including a literature review.

Low Creatinine Clearance Is a Risk Factor for Severe Cardioembolic Stroke in Japanese Female Patients.

BACKGROUND/AIM: The relationship between renal function and severity of cardioembolic stroke (CES) stratified by sex remains poorly understood. PATIENTS AND METHODS: A total of 640 consecutive CES patients within 48 h after stroke onset and with a modified Rankin Scale (mRS) score of 0 or 1 before onset were studied. The patients were divided into three groups based on their CCr values: low creatinine clearance (CCr) (L-CCr) (n=71, <30 ml/min), middle CCr (M-CCr) (n=227, 30 to <50 ml/min), and high CCr (H-CCr) (n=342, ≥50 ml/min). We compared the severity and functional outcomes of stroke among the three groups according to sex. RESULTS: On admission, using the National Institutes of Health Stroke Scale, the L-CCr group had the most severe stroke, followed by the M-CCr and H-CCr groups (p<0.0001). Functional outcomes at discharge, assessed using the mRS, were the worst in the L-CCr group, followed by the M-CCr and H-CCr groups (p<0.0001). Multivariable analyses revealed that L-CCr was a significant determinant of severe stroke on admission and poor functional outcomes at discharge. According to sex, L-CCr was a significant determinant of severe stroke on admission and poor functional outcomes at discharge in female patients, but not in male patients. CONCLUSION: Low CCr is a risk factor for severe stroke on admission and unfavorable functional outcomes at discharge in Japanese CES patients, and particularly in female patients.

Immunovascular microenvironment in relation to prognostic heterogeneity of WNT/ß-catenin-activated hepatocellular carcinoma.

AIM: WNT/ß-catenin-activated hepatocellular carcinoma (W/B subclass HCC) is considered a molecularly homogeneous entity and has been linked to resistance to immunotherapy. However, recent studies have indicated possible heterogeneity in the immunovascular microenvironment in this subclass. We set out to test the hypothesis that specific immunovascular features might stratify W/B subclass HCCs into tumors having distinct aggressive natures. METHODS: In this study, we analyzed 352 resected HCCs including 78 immunohistochemically defined W/B subclass HCCs. The density of tumor-infiltrating CD3+ T cells and the area ratio of vessels encapsulating tumor clusters (VETC) were calculated on tissue specimens. The gene expressions of angiogenic factors were measured by quantitative reverse transcription-polymerase chain reaction. Disease-free survival (DFS) was assessed using multivariable Cox regression analyses. RESULTS: The T-cell density of W/B subclass HCCs was regionally heterogenous within tumor tissues, and focally reduced T-cell density was observed in areas with VETC. VETC-positivity (defined as VETC area ratio greater than 1%) was inversely associated with T-cell infiltration in both W/B subclass and non-W/B subclass HCCs. Fibroblast growth factor 2 (FGF2) gene expression was higher in W/B subclass than in non-W/B subclass HCCs. The VETC-positivity and low T-cell density correlated with increased expression of FGF2 in W/B subclass HCCs. Additionally, VETC-positive HCCs showed significantly shorter DFS in W/B subclass HCCs. CONCLUSIONS: In conclusion, the immune and vascular microenvironments are interrelated and are also correlated with clinicopathological heterogeneity in W/B subclass HCC. These results could inform clinical practice and translational research on the development of therapeutic stratification of HCCs.

Nail insertion points in semi-extended nailing of tibial fractures and their influence on alignment: A retrospective cohort study comparing two nail insertion techniques.

INTRODUCTION: Semi-extended tibial nailing techniques include the extra-articular technique (EAT) and the patellar eversion technique (PET). These approaches differ regarding the exposure of the patellar retinaculum and the size of the surgical field. This study compared the postoperative alignment and intramedullary nailing entry points between the EAT and PET for tibial fractures. PATIENTS AND METHODS: A total of 54 patients (aged ≥18 years) who had undergone intramedullary nailing by the EAT (n = 29) or PET (n = 25) for a tibial shaft fracture were evaluated. The intramedullary nailing entry point and postoperative alignment were measured, and the 1-year postoperative follow-up results were compared. RESULTS: For the EAT and PET, the intramedullary nailing entry point was located at a mean distance of 4.04 mm medial to the optimal entry point and 0.27 mm lateral to the optimal entry point, respectively. The mean angular deformation observed in anteroposterior radiographs following surgery using the EAT and PET were 2.49° and 0.32° valgus, respectively. CONCLUSION: The intramedullary nailing entry point affected postoperative alignment. Intramedullary nailing may result in malalignment while performing the EAT due to the interference of the patella at the time of nailing.

Characterization of the PRAETORIAN score in Japanese patients undergoing subcutaneous implantable cardioverter-defibrillator implantation.

BACKGROUND: The PRAETORIAN score was developed to evaluate the implant position and predict defibrillation success in patients implanted with a subcutaneous implantable cardioverter-defibrillator (S-ICD). However, usefulness of the PRAETORIAN score for Japanese patients is unknown. METHODS: We evaluated usefulness of this score, which was determined by width of sub-coil fat, sub-generator fat, and anterior positioning of the S-ICD generator by post-operative chest X-ray, in consecutive 100 Japanese S-ICD implanted patients [78 men, median age 59 (IQR 46.5-67.0) years, median body mass index (BMI) 24.2 (21.3-27.2) kg/m2]. RESULTS: The median PRAETORIAN score was 30 (30-45) and 93 patients were classified as a low risk of conversion failure. The remaining seven were at an intermediate risk. Almost all patients were classified as an optimal pulse-generator position in the second and third steps of the PRAETORIAN score. The only difference observed was in the width of sub-coil fat in the first step. To further evaluate its significance, patients were divided into the Thicker group (sub-coil fat >1 coil width, n = 19) and the Thinner group (sub-coil fat ≤1 coil width, n = 81). BMI and post-shock impedance were both higher in the Thicker group than in the Thinner group [27.1 (25.6-31.6) versus 23.1 (20.9-25.7) kg/m2, p < 0.001, and 75 (68-88) versus 63 (55-74) Ω, p = 0.003, respectively]. During the median follow-up periods of 888 (523-1418) days, 7 patients experienced appropriate shock therapy for spontaneous ventricular tachyarrhythmias, who were all at a low risk. No conversion failure was observed. Inappropriate shock (IAS) occurred in 11 patients, and there was no difference in IAS rate between the Thicker group (n = 2) and the Thinner group (n = 9) (p = 0.747 by log-rank test). CONCLUSIONS: Most Japanese patients were classified as at low risk of conversion failure. The PRAETORIAN score may be useful for the evaluation of conversion failure in Japanese S-ICD implanted patients.

Infective endocarditis caused by Streptococcus pneumoniae from sinusitis: A case report.

Since the advent of the pneumococcal vaccine, cases of infective endocarditis (IE) from Streptococcus pneumoniae have become rare. Pneumococcal endocarditis (PE) may be the initial presentation in Austrian syndrome, which is very lethal. PE needs early detection and treatment and more commonly develops from pneumonia. To our knowledge, this is the first report of PE caused by sinusitis after pneumococcal vaccination. Here, a 71-year-old male presented with low back pain and right ankle joint pain. He had no dental history or pneumonia and received a pneumococcal vaccine 2 years prior. Blood tests showed high inflammatory response. We suspected IE due to the high inflammatory response and oligoarthritis. Transthoracic echocardiography showed vegetation at the aortic valve. As IE was probable, empiric antibiotic therapy was promptly initiated. Blood cultures detected S. pneumoniae. IE was diagnosed based on Duke's diagnostic criteria. After starting antibiotic treatment, lumbar magnetic resonance imaging (MRI) showed an abscess in the right erector spinae. Cranial MRI showed bilateral maxillary sinusitis. Sinusitis was considered the possible initial focus of infection. IE should be considered a differential in patients with S. pneumoniae detected in blood cultures without pneumonia even after pneumococcal vaccination as PE sometimes follows a fatal course. .

Prognostic Impact of Diabetes Mellitus on Clinical Outcomes in Lean Patients With Acute Myocardial Infarction.

BACKGROUND/AIM: Little is known about the impact of diabetes mellitus (DM) on clinical outcomes in lean patients with acute myocardial infarction (AMI). We conducted this study to evaluate the impact of DM on clinical outcomes in AMI patients based on body mass index (BMI) level. PATIENTS AND METHODS: A total of 1,282 consecutive AMI patients who underwent emergent percutaneous coronary intervention within 24 hours from onset were retrospectively studied. The patients were divided into 2 groups based on BMI: Underweight group (BMI <18.5 kg/m2, n=61) and non-Underweight group (BMI ≥18.5 kg/m2, n=1,221). The primary endpoint was all-cause death, and the secondary endpoint was major adverse cardiovascular and cerebrovascular events. The median follow-up period was 3.8 (1.7-5.0) years. RESULTS: The Underweight patients were older and included more females than the non-Underweight patients, and had a lower prevalence of coronary risk factors including DM. The primary and secondary endpoints were significantly higher in the Underweight patients (both p<0.05 by the Log-rank test). When divided by the presence of DM, the secondary endpoint was significantly higher in the non-Underweight patients with DM than in those without DM (p<0.05). However, there was no significant difference between Underweight patients with DM and those without DM. Multivariate analyses showed that DM was an independent predictor for the primary and secondary endpoints in non-Underweight patients, but not in Underweight patients. CONCLUSION: DM was associated with worse clinical outcomes in normal-weight or obese AMI patients, but not in underweight AMI patients.

Difluoroalkylation of Tertiary Amides and Lactams by an Iridium-Catalyzed Reductive Reformatsky Reaction.

An iridium-catalyzed, reductive alkylation of abundant tertiary lactams and amides using 1-2 mol % of Vaska's complex (IrCl(CO)(PPh3)2), tetramethyldisiloxane (TMDS), and difluoro-Reformatsky reagents (BrZnCF2R) for the general synthesis of medicinally relevant α-difluoroalkylated tertiary amines is described. A broad scope (46 examples), including N-aryl- and N-heteroaryl-substituted lactams, demonstrated an excellent functional group tolerance. Furthermore, late-stage drug functionalizations, a gram-scale synthesis, and common downstream transformations proved the potential synthetic relevance of this new methodology.