Christian Wolf

The utility of well-defined transition-metal coordination complexes for separation-free enantioselective optical analysis has received significant traction due to its promise to speed up chiral compound screening workflows. Herein, chiroptical sensing of a broad selection of carboxylic acids with metallocene dihalides is introduced. Cp2TiCl2 and Cp2MoCl2 undergo smooth chloride exchange under mild conditions toward carboxylate complexes, displaying quantifiable circular dichroism signals at long wavelengths. Spectroscopic titration experiments and crystallographic analysis show that both chlorides in Cp2TiCl2 are readily displaced, while Cp2MoCl2 forms a monocarboxylate complex. In either case, characteristic CD inductions are observed that allow accurate er analysis across a wide range of enantiomeric compositions.

Background/Objectives: Fusion-positive rhabdomyosarcoma (FP-RMS) is characterized by the presence of tumor-specific chromosomal translocation products, most commonly PAX3::FOXO1, and typically results in lower survival rates compared to fusion-negative RMS cases. PAX3::FOXO1 plays a critical role in FP-RMS oncogenesis in both tumor initiation and maintenance, making it an excellent target for therapeutic intervention in FP-RMS. Methods: We created Proteolysis Targeting Chimeras (PROTACs) by combining PAX3::FOXO1-binding small molecules with E3 ligase recruiters for cereblon (CRBN) or S-Phase Kinase Associated Protein 1 (SKP1). Results: The PROTACs achieved up to 70% degradation of the endogenous PAX3::FOXO1 protein in FP-RMS cell lines in a concentration-, time-, and proteasome-dependent manner. Moreover, the PROTAC-mediated targeted degradation of PAX3::FOXO1 in FP-RMS cells deregulated the endogenous PAX3::FOXO1 gene expression signature and induced myogenic differentiation. Importantly, treatment of FP-RMS cells with PAX3::FOXO1-PROTACs synergized with vincristine treatment and impaired >80% of anchorage-independent growth in soft agar. Conclusions: Taken together, we demonstrate the proof of principle of PROTACs targeting the oncogenic fusion protein PAX3::FOXO1 in FP-RMS cells. The PROTACs created in this study will not only be useful tools in studying PAX3::FOXO1 biology in laboratory models but could also serve as molecular scaffolds for designing clinical-grade molecules to assess the therapeutic potential of PAX3::FOXO1-targeting PROTACs in FP-RMS patients.

Pd-catalyzed asymmetric fluoroalkylation of difluorostyrenes allows concomitant Csp ³ –F and Csp ³ –Csp ³ bond formation with control of two chirality centers.

Separation-free analysis of samples containing glucosamine, mannosamine and galactosamine is achieved using a chiroptical sensing array with small-molecule reagents and chemometric data processing.

The well‐known, readily available Sanger reagent is used for quantitative chiroptical sensing of the amount and enantiomeric composition of amines, amino alcohols, and amino acids. A practical assay that is fast, adaptable to a variety of solvents, and only requires mixing of the sample and probe in the presence of triethylamine prior to the CD and UV measurements is introduced. The analyte tagging generates characteristic CD and UV signals at 405 and 345 nm, respectively, which allow accurate concentration and er analysis without any workup or tedious sample preparation.

The thermodynamic stability of unactivated Csp ³ ─F and Csp ³ ─Csp ³ bonds remains a major challenge in organic synthesis as methods that achieve effective cleavage and high‐yielding functionalization under mild conditions are rare. Herein, we introduce a cascade reaction involving heterolytic activation of 4‐halopiperidines with organoaluminum reagents which is followed by fast ring opening toward a thermodynamically favored iminium ion that undergoes C─C bond formation via aryl or alkyl transfer from a concomitantly generated fluoroaluminate counteranion. Fluoropiperidines were found to be more reactive than other halides and are smoothly transformed into tertiary homoallyl amines with good to excellent yields. This reaction occurs at room temperature with high functional group tolerance and without noticeable by‐product formation. Similarly, Csp ³ ─F bond scission is observed with 4,4‐difluoropiperidines, giving rise to monofluorinated alkene products as the Csp ² ─F bond generated during this process does not react. X‐ray crystallographic analysis of two cationic reaction intermediates simultaneously isolated in a single crystal provides a snapshot of the ring‐opening process and together with chemical trapping and control experiments is in agreement with an ionic mechanism and a three‐step reaction sequence. By contrast, defluorinative halide exchange leaving the piperidinyl ring intact prevails when 4‐fluoro‐ and 4,4‐difluoropiperidines are treated with aluminum trihalide Lewis acids.

The thermodynamic stability of unactivated Csp ³ ─F and Csp ³ ─Csp ³ bonds remains a major challenge in organic synthesis as methods that achieve effective cleavage and high‐yielding functionalization under mild conditions are rare. Herein, we introduce a cascade reaction involving heterolytic activation of 4‐halopiperidines with organoaluminum reagents which is followed by fast ring opening toward a thermodynamically favored iminium ion that undergoes C─C bond formation via aryl or alkyl transfer from a concomitantly generated fluoroaluminate counteranion. Fluoropiperidines were found to be more reactive than other halides and are smoothly transformed into tertiary homoallyl amines with good to excellent yields. This reaction occurs at room temperature with high functional group tolerance and without noticeable by‐product formation. Similarly, Csp ³ ─F bond scission is observed with 4,4‐difluoropiperidines, giving rise to monofluorinated alkene products as the Csp ² ─F bond generated during this process does not react. X‐ray crystallographic analysis of two cationic reaction intermediates simultaneously isolated in a single crystal provides a snapshot of the ring‐opening process and together with chemical trapping and control experiments is in agreement with an ionic mechanism and a three‐step reaction sequence. By contrast, defluorinative halide exchange leaving the piperidinyl ring intact prevails when 4‐fluoro‐ and 4,4‐difluoropiperidines are treated with aluminum trihalide Lewis acids.

Cross-coupling of alkyl fluorides and organolithium compounds is achieved by liquid-assisted stirring and mild heating without the need for expensive catalysts or additives. The reaction proceeds with a variety of primary, secondary, and tertiary fluorides; several functional groups, including alkyl halides, ether, amide, and heteroaryl groups, are tolerated; and both aryl and alkyllithium compounds can be used. Mechanistic studies indicate that the reaction involves heterolytic C–F bond activation and proceeds either via generation of short-lived carbocation intermediates or through a concerted pathway, which probably predominates with primary substrates, while the formation of thermodynamically stable lithium fluoride is the driving force.

High‐throughput asymmetric reaction development of an organocatalytic Michael addition is achieved by using a readily available isatin molecule as an amine protecting group, reagent for reactivity Umpolung, and as a chiroptical yield and enantioselectivity reporter. The use of UV and circular dichroism inductions allows on‐the‐fly, chromatography‐free parallel screening of a hundred reaction conditions to identify a catalytic procedure that converts a primary amine to either enantiomer of an a‐branched chiral product in excellent yields and ee’s. The isatin is recyclable and can be quantitatively recovered if desired. This case study shows how chiroptical high‐throughput screening with a multitasking reagent can increase method development speed and reduce cost and waste compared to traditional reaction optimization workflows by streamlining the analysis of small‐scale reaction setups and eliminating time‐consuming work‐up protocols.

Atropisomeric organocatalysis with fluorinated oxindoles and 4-halo-3-nitrocoumarins produces a Csp ² –Csp ³ chirality axis and an adjacent tetrasubstituted stereogenic carbon center.