A Concise Enantioselective Synthesis of Fluorinated Pyrazolo-Piperidine GSK3901383A Enabled by an Organocatalytic Aza-Michael Addition.

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl (E)-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

Antibody-Proteolysis Targeting Chimera Conjugate Enables Selective Degradation of Receptor-Interacting Serine/Threonine-Protein Kinase 2 in HER2+ Cell Lines.

Proteolysis targeting chimeras (PROTACs) are a family of heterobifunctional molecules that are now realizing their promise as a therapeutic strategy for targeted protein degradation. However, one limitation of existing designs is the lack of cell-selective targeting of the protein degrading payload. This manuscript reports a cell-targeted approach to degrade receptor-interacting serine/threonine-protein kinase 2 (RIPK2) in HER2+ cell lines. An antibody-PROTAC conjugate is prepared containing a protease-cleavable linkage between the antibody and the corresponding degrader. Potent RIPK2 degradation is observed in HER2+ cell lines, whereas an equivalent anti-IL4 antibody-PROTAC conjugate shows no degradation at therapeutically relevant concentrations. No RIPK2 degradation was observed in HER2- cell lines for both bioconjugates. This work demonstrates the potential for the cell-selective delivery of PROTAC scaffolds by engaging with signature extracellular proteins expressed on the surface of particular cell types.

An Alkynylpyrimidine-Based Covalent Inhibitor That Targets a Unique Cysteine in NF-κB-Inducing Kinase.

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure-activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.

Synthesis of C2 Substituted Benzothiophenes via an Interrupted Pummerer/[3,3]-Sigmatropic/1,2-Migration Cascade of Benzothiophene S-Oxides.

Functionalized benzothiophenes are important scaffolds found in molecules with wide ranging biological activity and in organic materials. We describe an efficient, metal-free synthesis of C2 arylated, allylated, and propargylated benzothiophenes. The reaction utilizes synthetically unexplored yet readily accessible benzothiophene S-oxides and phenols, allyl-, or propargyl silanes in a unique cascade sequence. An interrupted Pummerer reaction between benzothiophene S-oxides and the coupling partners yields sulfonium salts that lack aromaticity and therefore allow facile [3,3]-sigmatropic rearrangement. The subsequently generated benzothiophenium salts undergo a previously unexplored 1,2-migration to access C2 functionalized benzothiophenes.

Regioselective synthesis of C3 alkylated and arylated benzothiophenes.

Benzothiophenes are heterocyclic constituents of important molecules relevant to society, including those with the potential to meet modern medical challenges. The construction of molecules would be vastly more efficient if carbon-hydrogen bonds, found in all organic molecules, can be directly converted into carbon-carbon bonds. In the case of elaborating benzothiophenes, functionalization of carbon-hydrogen bonds at carbon-number 3 (C3) is markedly more demanding than at C2 due to issues of regioselectivity (C3 versus C2), and the requirement of high temperatures, precious metals and the installation of superfluous directing groups. Herein, we demonstrate that synthetically unexplored but readily accessible benzothiophene S-oxides serve as novel precursors for C3-functionalized benzothiophenes. Employing an interrupted Pummerer reaction to capture and then deliver phenol and silane coupling partners, we have discovered a directing group-free method that delivers C3-arylated and -alkylated benzothiophenes with complete regioselectivity, under metal-free and mild conditions.

Sulfoxide-directed metal-free cross-couplings in the expedient synthesis of benzothiophene-based components of materials.

A metal-free approach combining sulfoxide-directed metal-free C-H cross-couplings with tuneable electrophile-mediated heterocyclizations and carbocyclative dimerizations, allows expedient access to benzothiophene-based systems that are components of important materials or are proven organic materials in their own right. As benzothiophene-based materials are typically prepared using Pd-catalyzed cross-coupling processes, our approach allows potential issues of metal cost and supply, and metal-contamination of products, to be avoided.

Sulfoxide-Directed Metal-Free ortho-Propargylation of Aromatics and Heteroaromatics.

A sulfoxide-directed, metal-free ortho-propargylation of aromatics and heteroaromatics exploits intermolecular delivery of a propargyl nucleophile to sulfur followed by an intramolecular relay to carbon. The operationally simple cross-coupling procedure is general, regiospecific with regard to the propargyl nucleophile, and shows complete selectivity for products of ortho-propargylation over allenylation. The use of secondary propargyl silanes allows metal-free ortho-coupling to form carbon-carbon bonds between aromatic and heteroaromatic rings and secondary propargylic centres. The 'safety-catch' nature of the sulfoxide directing group is illustrated in a selective, iterative double cross-coupling process. The products of propargylation are versatile intermediates and they have been readily converted into substituted benzothiophenes.