f-Block reactions of metal cations with carbon dioxide studied by inductively coupled plasma tandem mass spectrometry.

f-Block chemistry offers an opportunity to test current knowledge of chemical reactivity. The energy dependence of lanthanide cation (Ln+ = Ce+, Pr+, Nd+-Eu+) and actinide cation (An+ = Th+, U+-Am+) oxidation reactions by CO2, was observed by inductively coupled plasma tandem mass spectrometry. This reaction is commonly spin-unallowed because the neutral reactant (CO2, 1Σ+g) and product (CO, 1Σ+) require the metal and metal oxide cations to have the same spin state. Correlation of the promotion energy (Ep) to the first state with two free d-electrons with the reaction efficiency indicates that spin conservation is not a primary factor in the reaction rate. The Ep likely influences the reaction rate by partially setting the crossing between the ground and reactive states. Comparison of Ln+ and An+ congener reactivity indicates that the 5f-orbitals play a small role in the An+ reactions.

Sodium Butylated Hydroxytoluene (NaBHT) as a New and Efficient Hydride Source for Pd-Catalysed Reduction Reactions.

NaBHT (sodium butylated hydroxytoluene), a hindered and soluble base for the efficient arylation of various base-sensitive amines and (hetero)aryl halides has been found to have an unanticipated role as a hydride donor to reduce (hetero)aryl halides and allylic acetates. Mechanistic studies have uncovered that NaBHT, but not BHT, can deliver multiple hydrides through oxidation of the benzylic methyl group in NaBHT to the aldehyde. Further, performing the reduction with NaBHT-d20 has revealed that the redox-active benzylic position is not the only hydride donor site from NaBHT with one hydride in three coming, presumably, from the tert-butyl groups. The reduction works well under mild conditions and, incredibly, only consumes 20 percent of the NaBHT in the process; the remaining 80 percent can be readily recovered in pure form and reused. This, combined with the low cost of the material in ton-scale quantity, makes it practical and attractive for wider use in industry at scale.

One-Pot Sequential Kumada-Tamao-Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl.

We report a general and rapid chemoselective Kumada-Tamao-Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPentCl (C4). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo-chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.

Cross-Coupling of Primary Amides to Aryl and Heteroaryl Partners Using (DiMeIHeptCl)Pd Promoted by Trialkylboranes or B(C6F5)3.

Boron-derived Lewis acids have been shown to effectively promote the coupling of amide nucleophiles to a wide variety of oxidative addition partners using Pd-NHC catalysts. Through a combination of NMR spectroscopy and control studies with and without oxygen and radical scavengers, we propose that boron-imidates form under the basic reaction conditions that aid coordination of nitrogen to Pd(II), which is rate limiting, and directly delivers the intermediate for reductive elimination.

Pd-PEPPSI-IHept(Cl) : A General-Purpose, Highly Reactive Catalyst for the Selective Coupling of Secondary Alkyl Organozincs.

Dichloro[1,3-bis(2,6-di-4-heptylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (Pd-PEPPSI-IHept(Cl) ), a new, very bulky yet flexible Pd-N-heterocyclic carbene (NHC) complex has been evaluated in the cross-coupling of secondary alkylzinc reactants with a wide variety of oxidative addition partners in high yields and excellent selectivity. The desired, direct reductive elimination branched products were obtained with no sign of migratory insertion across electron-rich and electron-poor aromatics and all forms of heteroaromatics (five and six membered). Impressively, there is no impact of substituents at the site of reductive elimination (i.e., ortho or even di-ortho), which has not yet been demonstrated by another catalyst system to date.

N-Heteroarylation of Optically Pure α-Amino Esters using the Pd-PEPPSI-IPentCl -o-picoline Pre-Catalyst.

A robust, mild, and efficient method for the Pd-catalyzed N-heteroarylation of optically pure α-amino esters was developed. Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](o-picoline)palladium(II) (Pd-PEPPSI-IPentCl -o-picoline; PEPPSI=pyridine enhanced pre-catalyst preparation, stabilization, and initiation) was shown to effectively couple a variety of amino acids as the tert-butyl ester with heteroaryl chlorides in high yields and with excellent stereoretention of the acidic proton adjacent to the ester. Control experiments revealed that racemization is base-mediated, with no evidence of Pd-mediated ß-hydride elimination when using Pd-PEPPSI-IPentCl , and that racemization occurs only after the product is formed, that is, the non-arylated starting amino ester does not deprotonate under our reaction conditions. Studies also revealed that increasing the steric bulk of the ester moiety on the amino acid (e.g., ethyl to tert-butyl) drastically slows racemization of the product.

The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHept(Cl).

The ability to cross-couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to ß-hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non-rearranged) cross-coupled product with aryl or heteroaryl oxidative-addition partners, none have shown reliable selectivity with five-membered-ring heterocycles. In this report, a new, rationally designed catalyst, Pd-PEPPSI-IHept(Cl), is demonstrated to be effective in selective cross-coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo-fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.

Selective Monoarylation of Primary Amines Using the Pd-PEPPSI-IPent(Cl) Precatalyst.

A single set of reaction conditions for the palladium-catalyzed amination of a wide variety of (hetero)aryl halides using primary alkyl amines has been developed. By combining the exceptionally high reactivity of the Pd-PEPPSI-IPent(Cl) catalyst (PEPPSI=pyridine enhanced precatalyst preparation, stabilization, and initiation) with the soluble and nonaggressive sodium salt of BHT (BHT=2,6-di-tert-butyl-hydroxytoluene), both six- and five-membered (hetero)aryl halides undergo efficient and selective amination.

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Pleomorphic adenoma of the trachea.

Primary pleomorphic adenoma of the trachea is rare, as only 33 cases have been previously reported worldwide since 1922. We describe a new case of primary tracheal pleomorphic adenoma that was discovered incidentally in a 78-year-old man. The tumor was excised, and the patient recovered without complication. Salivary gland tumors of the trachea should be considered in the differential diagnosis of tracheal lesions; the diagnosis is confirmed by pathologic evaluation. Patients are adequately treated with sleeve resection and primary anastomosis whenever possible.

Aldol-Promoted Reaction of R106-Sarcosine: Synthesis and Conformational Analysis of Novel R106 Analogs.

A unique semisynthetic pathway has been used as a route to novel R106 derivatives. R106-sarcosine, 2, was discovered to be a key intermediate to obtain these derivatives using classical aldol alkylation conditions. Surprisingly, the site of alkylation on 2 was found to be conformationally hindered which yielded both the D and L isomers of R106-1 (aureobasidin A), 1, and other new R106 derivatives. The scope of the alkylation was found to be highly dependent upon the reactivity potential of the electrophile. Semiempirical calculations on R106-1 and 8-(N-methylthrenonine)aureobasidin A, 7, were performed to investigate the thermodynamic stabilities of the D and L isomers. By contrast to stable conformations observed by two X-ray crystal structures of aureobasidins, the calculations indicated that the D isomers were significantly more stable. Furthermore, model semiempirical calculations to probe facial selecitivty were consistent with results obtained experimentally.

Glycopeptide carboxamides active against vancomycin-resistant enterococci.

Glycopeptide antibiotics were synthesized via the PyBOP mediated condensation of aliphatic, heterocyclic and aromatic amines with the C-terminus of vancomycin, LY264826 (A82846B) and semi-synthetic derivatives of these natural products. Amides of LY264826 and vancomycin demonstrated excellent activity against staphylococci and streptococci as compared to the parent natural product. However, the amides of N-alkylated LY264826 and N-alkylated vancomycin were active against vancomycin-resistant enterococci as well as other gram-positive pathogens such as Staphylococcus aureus, S. haemolyticus, S. epidermidis and Streptococcus pneumoniae.

Periorbital emphysema as a complication of functional endoscopic sinus surgery.

Clinically significant periorbital emphysema is an unusual complication of functional endoscopic sinus surgery (FESS). In most instances, it resolves spontaneously without any serious sequelae. Rarely, it can progress rapidly and become severe enough to cause irreversible blindness. We present and discuss the management of 2 cases of periorbital emphysema after FESS.