Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor.

The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity in vitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation.

A Mechanistically Inspired Halenium Ion Initiated Spiroketalization: Entry to Mono- and Dibromospiroketals.

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2-tetrahydropyranyl(THP)-protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α-deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals.

Mechanistic Insights into the Origin of Stereoselectivity in an Asymmetric Chlorolactonization Catalyzed by (DHQD)PHAL.

Electrophilic halofunctionalization reactions have undergone a resurgence sparked by recent discoveries in the field of catalytic asymmetric halocyclizations. To build mechanistic understanding of these asymmetric transformations, a toolbox of analytical methods has been deployed, addressing the roles of catalyst, electrophile (halenium donor), and nucleophile in determining rates and stereopreferences. The test reaction, (DHQD)PHAL-catalyzed chlorocyclization of 4-arylpent-4-enoic acid with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), is revealed to be first order in catalyst and chlorenium ion donor and zero order in alkenoic acid substrate under synthetically relevant conditions.

Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance Mutations.

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for -mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in -either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation.

Absolute and relative facial selectivities in organocatalytic asymmetric chlorocyclization reactions.

Though (DHQD)PHAL-catalyzed chlorocyclizations of 1,1-disubstituted olefins show useful (and in some cases, reversible) asymmetric induction, stereochemically complete descriptions of these alkene additions have remained largely unknown. Herein, based on a combination of NMR, derivative, isotope labeling, and computational studies, we present detailed stereochemical analyses of chlorocyclizations of nucleophile-tethered 1,1-disubstituted styryl systems. The selectivities of the two asymmetric bond-forming processes, namely electrophilic chlorine attack and nucleophilic ring closure, are thus mapped out independently.

Mechanistically Inspired Route toward Hexahydro-2H-chromenes via Consecutive [4 + 2] Cycloadditions.

Utilizing two robust C-C bond-forming reactions, the Baylis-Hillman reaction and the Diels-Alder reaction, we report a highly enantio-, regio-, and diastereoselective synthesis of hexahydro-2H-chromenes via two sequential [4 + 2] cycloadditions. These tandem and formal cycloadditions have also been performed as a "one-pot" sequence to access the corresponding heterocycles constituting up to five contiguous stereocenters in excellent yields and stereoselectivity.

Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent.

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step.

A new tool to guide halofunctionalization reactions: the halenium affinity (HalA) scale.

We introduce a previously unexplored parameter-halenium affinity (HalA)- as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The HalA scale ranks potential halenium ion acceptors based on their ability to stabilize a "free halenium ion". Alkenes in particular but other Lewis bases as well, such as amines, amides, carbonyls, and ether oxygen atoms, etc.

Dissecting the stereocontrol elements of a catalytic asymmetric chlorolactonization: syn addition obviates bridging chloronium.

We report absolute and relative stereochemistry of addition in enantioselective chlorolactonizations of 4-phenyl-4-pentenoic acid and its related t-butyl ester, catalyzed by (DHQD)2PHAL. Predominant syn addition of the chlorenium and the nucleophile across the olefin is observed. As shown by isotopic labeling, NMR spectroscopy, and derivative studies, the two new stereocenters formed by addition across the double bond are set independently and influenced by different factors.

3,4-Dihydroxypyrrolidines via modified tandem aza-Payne/hydroamination pathway.

The outcome of a tandem aza-Payne/hydroamination reaction is modified via the use of a latent nucleophile. The latter initially serves as an electrophile to intercept the aziridine alkoxide and afterward turns into a nucleophile thereby performing the aziridine ring opening, out competing the intramolecular aza-Payne pathway. Subsequent hydroamination in the same pot provides N-Ts enamide carbonates, which can be easily converted into biologically significant 3,4-dihydroxylactams.

Development of a formal catalytic asymmetric [4+2] addition of ethyl-2,3-butadienoate with acyclic enones.

Allene esters are unique not only as excellent electrophiles but also because of their ability for subsequent reactivity after the initial nucleophilic attack. A mechanistically inspired cyclization using ethyl-2,3-butadienoate and acyclic enones to provide dihydropyrans in excellent yields and enantioselectivity under solvent-free conditions at room temperature is reported.