Transition-Metal-Free Heterocyclic Carbon-Boron Bond Formation.

Heteroaryl boronic acids and esters are extremely important and valuable intermediates because of their wide application in the synthesis of marketed drugs and bioactive compounds. Over the last couple of decades, the construction of highly important heteroaryl carbon-boron bonds has created huge attention. The transition-metal-free protocols are more green, less sensitive to air and moisture, and also economically advantageous over the transition-metal-based protocols. The transition-metal-free C-H borylation of heteroarenes and C-X (X=halogen) borylation of heteroaryl halides represents an excellent approach for their synthesis. Also, various cyclization and alkyne activation protocols have been recently established for their synthesis. The goal of this review article is to summarize the existing literature and the current state of the art for transition-metal-free synthesis of heteroaryl boronic acid and esters.

Development of Methods to the Synthesis of ß-Boryl Acyls, Imines and Nitriles.

Organoboron compounds are highly important and versatile synthetic intermediates for the preparation of a wide range of organic molecules. Organoboron compounds have drawn significant attention among organic chemists due to their Lewis acidic property, non-toxicity, and commercial availability. Over the last several decades, there has been a substantial development of new organoboron compounds, useful in organic synthesis. Among all other organoboron compounds, ß-boryl carbonyl compounds are the important ones. The ß-boryl compounds have appeared as promising intermediates for various synthetic transformations. The 1,4-conjugate addition of diboron reagents to carbon-carbon double bond in the presence of different transition-metal catalysts has been extensively reported by various research groups across the globe. This mini-review outlines the numerous racemic as well as asymmetric ß-borylation methods developed to date.

Reversal of polarity by catalytic SET oxidation: synthesis of azabicyclo[m.n.0]alkanes via chemoselective reduction of amidines.

A one-pot catalytic method has been developed for the stereoselective synthesis of cyclopropane-fused cyclic amidines using CuBr2/K2S2O8 as an efficient single electron transfer (SET) oxidative system. The generality of this mild method is demonstrated with a wide variety of substrates to furnish pharmaceutically important amidines containing aza-bicyclic and novel aza-tricyclic frameworks in very good yields. A chemoselective reduction of cyclic amidines to 2-/3-azabicyclo[m.n.0]alkanes and octahydroindoles has been developed using a NaBH4/I2 reagent system. The synthetic scope of the chemoselective reduction of the amidine functionality has been exemplified in the stereoselective synthesis of an iminosugar based (±)-epiquinamide analogue.

Synthesis and reactivity of alkynyl boron compounds.

Over the last century, there have been considerable developments in organoboron chemistry due to the stability, non-toxicity, and easy commercial availability of various boronic esters. Several organoboron reagents have emerged and play an increasingly important role in everyday organic synthesis. Among them, alkynyl boron compounds have attracted significant attention due to their easy synthesis and diverse reactivity. In this review, we summarize the advancement of research on alkynyl boron compounds, highlighting their importance in the synthesis of valuable compounds.

Functionalization of Heterocycles through 1,2-Metallate Rearrangement of Boronate Complexes.

Over the last decade, 1,2-metallate rearrangement of boronate complex has been dominating the literature of organoboron chemistry for the construction of very important C-C and C-boron bonds. Owing to the coordinative unsaturated nature of the boron atom, a nucleophile can attack on boron center for the formation of a boronate complex, which triggers 1,2-migration under electrophilic activation at the α-carbon. Apart from using stochiometric electrophilic activating reagents, several catalytic methods using transition metals in the presence or absence of light have been reported. The 1,2-migration of boronate complexes allows synthesis of many different classes of racemic and chiral compounds including a wide range of substituted heterocycles. Synthesis of chiral and achiral substituted heterocycles by using 1,2-metallate rearrangement of boronate complexes has been extensively reported by several groups owing to its prevalence in medicinal chemistry. This minireview highlights the methods known to date for the synthesis of heteroaryls by using 1,2-migration of boronate complexes, organized in a chronological manner.

Transition-Metal-Free Synthesis of Heterobiaryls through 1,2-Migration of Boronate Complex.

The synthesis of a diverse range of heterobiaryls has been achieved by a transition-metal-free sp2 -sp2 cross-coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source. The construction of heterobiaryls was carried out through electrophilic activation of the aryl-heteroaryl boronate complex, which triggered 1,2-migration from boron to the carbon atom. Subsequent oxidation of the intermediate boronic ester afforded heterobiaryls in good yield. A comprehensive 11 B NMR study has been conducted to support the mechanism. The cross coupling between two nucleophilic cross coupling partners without transition metals reveals a reliable manifold to procure heterobiaryls in good yields. Various heterocycles like furan, thiophene, benzofuran, benzothiophene, and indole are well tolerated. Finally, we have successfully demonstrated the gram scale synthesis of the intermediates for an anticancer drug and OLED material using our methodology.

Transition metal-free synthesis of alkyl pinacol boronates.

Alkyl pinacol boronic esters have been routinely used for the synthesis of complex target molecules or high-value chemicals due to their non-toxicity, stability and commercial availability. The synthesis of C-B bonds in the absence of transition metals has gained significant attention due to its added advantages. Numerous methods have been developed for the synthesis of alkyl pinacol boronates without transition metals, which include reactions using organometallic reagents, Lewis acids and bases, photoredox catalysis, and 1,2-metallate rearrangement. Herein, we have analyzed the growing resource of literature related to the transition metal-free synthesis of alkyl pinacol boronic esters based on the differences in their reaction mechanisms.

A novel technique of endoscopic submucosal dissection for circumferential ileocecal valve adenomas with terminal ileum involvement: the "doughnut resection" (with videos).

BACKGROUND: Ileocecal valve (ICV) lesions are difficult to resect endoscopically and patients are often referred for laparoscopic colectomy. ICV involvement has been shown to be related to technical failure and tumor recurrence after endoscopic mucosal resection (EMR) and represents a challenge for endoscopic submucosal dissection (ESD). Few publications have focused specifically on endoscopic management of ICV lesions. METHODS: We developed a novel ESD technique, the "doughnut resection," for circumferential ICV adenomas with terminal ileum involvement. Two circumferential mucosal incisions are performed, one in the ileum and the other in the cecum, followed by submucosal dissection of the disk of tissue between the two incisions around a guiding stent placed across the valve that helps guide the dissection as it crosses the valve orifice. The lesion is removed en bloc in the shape of a "doughnut" with two concentric assessable lateral margins. The underwater ESD technique and a gastroscope were used to facilitate the resection. RESULTS: Seven patients received the doughnut resection. The median patient age was 67 years. All patients had prior biopsy and three had prior endoscopic resection (1-6 times). The median specimen diameter was 4.5 cm (range 3-8). All resections were en bloc and R0. There was no perforation, delayed bleeding, or other clinically significant adverse events. After a median follow-up of 21 months (range 12-32), there was no tumor recurrence. CONCLUSION: The "doughnut resection" is a feasible, safe, and effective method to remove circumferential ICV lesions endoscopically even for patients with multiple prior tumor manipulations.

No apparent benefit of preemptive sorafenib therapy in liver transplant recipients with advanced hepatocellular carcinoma on explant.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced HCC; however, limited data are available on its role in OLT recipients with advanced HCC in the explant. AIM: Evaluate the role of preemptive sorafenib therapy on HCC recurrence and survival after OLT with advanced HCC on explant pathology. METHODS: We retrospectively reviewed the outcome after OLT of all HCC recipients with advanced HCC in the explant pathology from 04/2006 to 12/2012 based on preemptive treatment with sorafenib. RESULTS: During the observation period, 217 HCC recipients underwent OLT; 50 explants revealed advanced HCC. After exclusion of 5 patients who were lost to follow-up, 45 LT recipients were finally included for analysis. Recipients were grouped as sorafenib Gr (N = 25) and nonsorafenib Gr (N = 20). Both recurrence-free survival (RFS) (P = .67) and overall survival were similar between groups (P = .53) on Kaplan-Meier analysis. Additionally, sorafenib use was neither associated with HCC recurrence-free survival (HR 0.74, 95% CI [0.32-1.70]; P = .48) nor overall survival (HR 0.92, 95% CI [0.39-2.15], P = .84) on multivariate Cox proportional hazard model with sorafenib use as time-varying covariates. CONCLUSION: Preemptive treatment with sorafenib in OLT recipients with high-risk features in explant does not improve HCC recurrence-free or overall survival.

One-Pot Synthesis of Cyclopropane-Fused Cyclic Amidines: An Oxidative Carbanion Cyclization.

A novel and efficient one-pot method has been developed for the synthesis of cyclopropane-fused bicyclic amidines on the basis of a CuBr2 -mediated oxidative cyclization of carbanions. The usefulness of this unique multicomponent strategy has been demonstrated by the use of a wide variety of substrates to furnish novel cyclopropane-containing amidines with a quaternary center in very good yields. This ketenimine-based approach provides straightforward access to biologically active and pharmaceutically important 3-azabicyclo[n.1.0]alkane frameworks under mild conditions. The synthetic power of this methodology is exemplified in the concise synthesis of the pharmaceutically important antidepressant drug candidate GSK1360707 and key intermediates for the synthesis of amitifadine, bicifadine, and narlaprevir.

One pot conversion of phenols and anilines to aldehydes and ketones exploiting α gem boryl carbanions.

Functional group interconversion is an important asset in organic synthesis. Phenols/anilines being naturally abundant and the carbonyl being the most common in a wide range of bioactive molecules, an efficient conversion is of prime interest. The reported methods require transition metal catalyzed cross coupling which limits its applicability. Here we have described a method for synthesizing various aldehydes and ketones, starting from phenol and protected anilines via Csp2-O/N bond cleavage in a one-pot/stepwise manner. Our synthetic method is found to be compatible with a diverse range of phenols and anilines carrying sensitive functional groups including halides, esters, ketal, hydroxyl, alkenes, and terminal alkynes as well as the substitution on the aryl cores. A short-step synthesis of bioactive molecules and their functionalization have been executed. Starting from BINOL, a photocatalyst has been designed. Here, we have developed a transition metal-free protocol for the conversion of phenols and anilines to aldehydes and ketones.

Alkoxide-Assisted Stereoselective Functionalization of 1,2-Bis-boronic Esters Under Photoredox Catalysis.

Site-specific functionalization of the secondary C-B bond of 1,2-bis-boronic esters has been proven to be an important method for the generation of 1,2-bis-functionalized compounds in a highly stereoselective manner. We have explored previously unknown secondary selective alkenylation, allylation, alkynylation and addition to aryl vinyl trifluoromethane, which proceeds via a novel reaction mechanism: alkoxide-mediated photoredox activation to generate secondary radicals over the primary one.

Predictive Nomogram and Propensity Score Matching in Neuroendocrine Carcinoma of the Tubular Gastrointestinal Tract: A US Population-Based Clinical Outcome Study.

Background: Neuroendocrine carcinomas (NECs) of the tubular gastrointestinal tract (GI-NECs) are rare and associated with worse clinical outcomes. This population-based study aims to highlight key demographics, clinicopathological factors, and survival outcomes in the US population. Methods: Data from 10,387 patients with GI-NECs were extracted from the Surveillance, Epidemiology, and End Result (SEER) database from 2000 to 2020. Results: Most patients were >40 years old at the time of presentation with a median age of 63 years old, with almost equal ethnic distribution per US population data. The most common primary tumor site was the small intestine (33.6%). The metastatic spread was localized in 34.8%, regional in 27.8%, and distant in 37.3% of cases, and the liver was the most common site of metastasis (19.9%) in known cases of metastases. Most NEC patients underwent surgery, presenting the highest 5-year overall survival of 73.2% with a 95% confidence interval (CI) (95% CI 72.0-74.4%), while chemotherapy alone had the lowest 5-year survival of 8.0% (95% CI 6.4-10.0%). Compared to men, women had a superior 5-year survival rate of 59.0% (95% CI 57.6-60.5%). On multivariate analysis, age > 65 (HR 2.49, 95% CI 2.36-2.54%, p ≤ 0.001), distant metastasis (HR 2.57, 95% CI 2.52-2.62%, p ≤ 0.001), tumor size > 4 mm (HR 1.98, 95%, CI 1.70-2.31%, p ≤ 0.001), esophageal (HR 1.49, 95% CI 0.86-2.58%, p ≤ 0.001), transverse colon (HR 1.95, 95% CI 1.15-3.33%, p ≤ 0.01), descending colon (HR 2.12, 95% CI 1.12, 3.97%, p = 0.02) anorectal sites, and liver or lung metastases were associated with worse survival. Surgical intervention and tumors located in the small intestine or appendix showed a better prognosis. Conclusion: GI-NECs are a group of rare malignancies associated with a poor prognosis. Therefore, epidemiological studies analyzing national databases may be the best alternative to have a more comprehensive understanding of this condition, assess the impact of current practices, and generate prognosis tools.

Lupus Pancreatitis Masquerading as Pancreatic Cancer: A Rare Clinical Presentation.

Systemic lupus erythematosus (SLE) is an autoimmune multisystemic inflammatory disease. SLE-associated pancreatitis is uncommon, and pancreatic cancer in SLE is very rare. Imaging findings in SLE with pancreatitis can mimic malignancy. Endoscopic ultrasound with fine-needle aspiration/biopsy can guide in the accurate diagnosis and management of SLE-associated pancreatitis.

1,2-Metallate Rearrangement Using Indole Boronate Species to Access 2,3-Diarylindoles and Indolines.

A transition metal-free multicomponent reaction using lithiated indole, boronic ester, pyridine, and ethyl chloroformate was developed to access C2,C3 bis-arylated indoles, which are present in several marketed drugs and bioactive compounds. One-pot access to unsymmetrical C2,C3-diaryl indole from the parent indole remains a huge synthetic challenge. Our group was able to achieve this goal through a transition metal-free 1,2-metalate rearrangement of the indole boronate complex. The reaction of indole boronate species with activated pyridine allows 1,2-migration to access pyridyl-indoleboronate species, which will convert to the corresponding indole upon oxidation and indoline after deborylation. The reaction tolerates substituted pyridines, quinolone, isoquinoline, and more. Both aryl and alkyl boronic esters were accommodated under optimized reaction conditions. Apart from mechanistic studies using 11B-NMR, this methodology has been applied to the gram-scale synthesis of several bioactive compounds.

Carbonyl group directed synthesis of 3-boryl-3-substituted alkenyl oxindoles and tetrasubstituted ß-borylenones.

Transition metal-free carbonyl directed boron-Wittig reaction of α-bis(boryl)carbanions with the corresponding isatins or with the α-keto esters/amides was achieved to access alkenyl oxindoles in good yield and high stereoselectivity.

SpyGlass DS system-assisted retrieval of proximally migrated pancreatic duct stent in a patient with chronic pancreatitis.

Pancreatic duct (PD) stent migration is among the recognized complications of endoscopic retrograde cholangiopancreatography (ERCP) with PD stent placement. Proximal stent migration poses a challenge for removal due to risks of PD damage, smaller caliber, and possible stricture. Here, we present a case of SpyGlass DS system-assisted PD stent repositioning after failure with traditional tools.

Pemphigus vulgaris presenting with epigastric pain.

Pemphigus vulgaris is an autoimmune mucocutaneous disease with an involvement in gastrointestinal tract especially in oral cavity and esophagus. Ulcers can be the initial presentation even before visible mucosal or cutaneous lesions. The presenting symptoms will be in accordance with the affected organ such as throat pain, hoarseness, dysphagia, odynophagia, or even bleeding. Here, we report a case of undiagnosed pemphigus vulgaris presenting with epigastric pain whose endoscopy showed oropharyngeal involvement and isolate esophageal ulcer, which failed proton pump inhibitor treatment.

Dissociable contributions of basolateral amygdala and ventrolateral orbitofrontal cortex to flexible learning under uncertainty.

Reversal learning measures the ability to form flexible associations between choice outcomes with stimuli and actions that precede them. This type of learning is thought to rely on several cortical and subcortical areas, including highly interconnected orbitofrontal cortex (OFC) and basolateral amygdala (BLA), and is often impaired in various neuropsychiatric and substance use disorders. However, unique contributions of these regions to stimulus- and action-based reversal learning have not been systematically compared using a chemogenetic approach and particularly before and after the first reversal that introduces new uncertainty. Here, we examined the roles of ventrolateral OFC (vlOFC) and BLA during reversal learning. Male and female rats were prepared with inhibitory DREADDs targeting projection neurons in these regions and tested on a series of deterministic and probabilistic reversals during which they learned about stimulus identity or side (left or right) associated with different reward probabilities. Using a counterbalanced within-subject design, we inhibited these regions prior to reversal sessions. We assessed initial and pre-post reversal changes in performance to measure learning and adjustments to reversals, respectively. We found that inhibition of vlOFC, but not BLA, eliminated adjustments to stimulus-based reversals. Inhibition of BLA, but not vlOFC, selectively impaired action-based probabilistic reversal learning, leaving deterministic reversal learning intact. vlOFC exhibited a sex-dependent role in early adjustment to action-based reversals, but not in overall learning. These results reveal dissociable roles for BLA and vlOFC in flexible learning and highlight a more crucial role for BLA in learning meaningful changes in the reward environment.