VB Chemical Research LLC

An extraordinary advancement in the synthesis of primary α-tertiary amines via photoredox catalysis has been achieved through the collaborative efforts of #DanLehnherr's team at #Merck and #TomislavRovis's team at #ColumbiaUniversity! This breakthrough demonstrates how two bench-stable starting materials—benzylic O-benzoyl ketoximes and benzylic iminium chloride salts—can be efficiently coupled with 4-cyano-heteroarenes, showcasing a remarkable tolerance for diverse functional groups. Source: https://lnkd.in/gmbxgUJH. Why are Amines Important? Amines are essential in #drugdiscovery, valued for their versatility and their presence in biologically active molecules. Quaternary carbon-centered primary amines are particularly significant—they are rare, difficult to synthesize, and vital as core structures in #activepharmaceuticalingredients (APIs), intermediates, and ligand libraries. Their unique structural properties make them fundamental to advancing #medicinalchemistry and developing #innovativetherapeutics. Key Highlights: Photoredox Catalysis: A single-electron disconnection approach is employed to synthesize primary amines featuring a fully substituted α-carbon center (quaternary carbon) from readily available starting materials. This method provides a streamlined pathway for accessing these challenging structures. Dual Role of Photoredox Catalyst: This work identifies how the photoredox catalyst efficiently facilitates a net reductive coupling by functioning as both a reductant and a triplet sensitizer. This concurrent tandem catalysis significantly enhances the overall efficiency of the reaction. Library Synthesis of Hindered Primary Amines: This innovative approach enables the efficient synthesis of libraries of hindered primary amines through parallel photoredox processes, paving the way for high-throughput experimentation that is particularly advantageous for medicinal chemists. A versatile and practical approach: This method accommodates a broad range of functional groups—including aryl and heteroaryl compounds—bearing functional groups such as halides, trifluoromethyl, esters, ethers, heterocycles, as well as unprotected alcohols and alkynes. #vbchemicalresearch #photoredoxcatalysis #oncology #ProcessDevelopment #discoverychemistry #medicinalchemistry #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

We are thrilled to highlight a remarkable contribution from #Guodu Liu’s group at Inner Mongolia University highlights the innovative application of the Biaryl phosphine ligand (L1, 1-(tert-butyl)-7-(2,6-dimethoxyphenyl)-2,3-dihydro-1H-phosphindole) in Suzuki-Miyaura cross-coupling reactions between aryl halides or pseudohalide and #alkylboronicacids. This work opens new avenues in the field and exemplifies pioneering advancements in #TransitionMetalCatalysis. Source: https://lnkd.in/g834hMF6 Why is this reaction so special? §?Due to its versatility and robustness, the Suzuki-Miyaura cross-coupling reaction stands among the top-ranked carbon-carbon bond-forming reactions widely utilized in #drugdiscovery. §?However, the Suzuki-Miyaura cross-coupling reaction encounters a notable limitation: β-hydride elimination, a frequent side reaction associated with alkyl fragments (particularly those containing β-hydrogens) in transition metal catalysis. This side reaction often competes with and challenges the desired cross-coupling reaction. §?The innovative approach developed here effectively addresses this challenge by preventing β-hydride elimination and enabling smooth cross-coupling with alkyl partners through the selection of a suitable phosphine ligand (L1). This advancement demonstrates significant utility for industrial applications. Key Advantages of This Method: ·???????Water-Soluble Byproducts: The reaction byproducts (boric acid or borate) are water-soluble, allowing for easy removal through aqueous workup and simplifying the purification process. ·???????Robust Process: This method accommodates a wide variety of coupling partners, including aryl, heteroaryl, and alkyl groups, even when they are sterically hindered. This versatility enhances its reliability and broadens its application across complex molecules. ·???????Successful Application in Drug Synthesis: This approach contributed to the synthesis of lumacaftor, a critical component of the prescription medication #ORKAMBI? (lumacaftor/ivacaftor), used in the treatment of cystic fibrosis (CF). #vbchemicalresearch #crosscoupling #oncology #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

An impressive contribution from #AbigailDoyle’s group at #PrincetonUniversity showcases the innovative use of Machine Learning (ML) in the #Deoxyfluorination of Alcohols with Sulfonyl Fluorides, marking a significant advancement in synthetic chemistry. Source: https://lnkd.in/gweHYpTS. Why is Fluorine So Crucial in #DrugDiscovery? The role of fluorine in #drugdesign and #development is advancing rapidly due to its remarkable properties. Incorporating fluorine into a molecule can significantly improve its #conformation, #pKa, #intrinsicpotency, #membranepermeability, #metabolicstability, and #pharmacokineticproperties. This unique element is a game-changer, helping to unlock new therapeutic potential. (Source: Applications of Fluorine in Medicinal Chemistry by #EricGillis’s team at #BristolMyersSquibb [BMS], https://lnkd.in/grdHhZnp). Key Advantages of This Method: 1. Cost-effective and Stable Reagents: The fluorinating agent, Sulfonyl Fluorides, are affordable, commercially available, and exhibit higher stability compared to the traditionally used sulfur(IV) reagents, which often suffer from thermal instability. 2. Easy Accessibility: These fluorides are easily prepared from commonly found sulfonyl chlorides. 3. High-value Products: The resulting Aliphatic Fluorides are highly sought after in pharmaceutical development. 4. Machine Learning Integration: A cutting-edge ML algorithm is employed to successfully model and predict reaction outcomes, enhancing the efficiency of this process. #vbchemicalresearch #fluorination #machininelearning #oncology #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #DrugDevelopment #CMC #SmallMolecules #Intermediates #API #Manufacturing

Today's inspiring topic: PROTAC Targeted Protein Degraders Proteolysis-targeting chimeras (PROTACs) are innovative molecules that selectively eliminate unwanted proteins from cells. Unlike traditional enzyme inhibitors, PROTACs induce targeted intracellular proteolysis by harnessing the cell’s own ubiquitin-proteasome system (UPS). Targeted protein degradation (TPD) represents an emerging therapeutic strategy with the potential to address disease-causing proteins that have historically been difficult to target using conventional small molecules. Two PROTACs currently in clinical trials are ARV-110 and ARV-471 (Given below). Best Reads: PROTAC Targeted Protein Degraders https://lnkd.in/gX624nEf https://lnkd.in/g7Wzy-dq https://lnkd.in/gsT3ceAg https://lnkd.in/gHQpsMSq https://lnkd.in/geJwThPp https://lnkd.in/gEUFEpTZ https://lnkd.in/gvfGWUud https://lnkd.in/gVc95i6n #oncology #Targeting #Chimera #PROTAC #PROteolysisTargetingChimeraPROTACMarket #PROteolysis #ProcessDevelopment #DrugDevelopment #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #CMC #SmallMolecules #Intermediates #API #manufacturing

A fantastic contribution to the synthesis of fully substituted hindered primary amines by #DanLehnherr's team at #Merck and #TomislavRovis's team at #ColumbiaUniversity! #Amines are crucial structural motifs in active pharmaceutical ingredients (#APIs) and their intermediates, as well as key components in ligand libraries for both biological and catalytic applications. You can explore the full publication here: https://lnkd.in/g7_4yySd Key Highlights: 1. Electrochemical Method: A novel electrochemical approach is described to access hindered primary and secondary amines, utilizing benchtop-stable iminium salts and a cyanoarene as starting materials. 2. Mechanistic Insight: This process involves proton-coupled electron transfer (PCET) followed by heteroradical?radical coupling, with subsequent re-aromatization leading to the final products. 3. Substrate Scope: At least one aryl group is required to stabilize the α-amino radicals in the imine; alkyl iminium salts are incompatible due to lack of radical stabilization. 4. Critical Parameters: The choice of cathode material and the supporting electrolyte are crucial for the success of this reaction. Key Merits: 1. A versatile and practical approach: This method accommodates a broad range of substituted heterocycles—including pyridine, pyrimidine, pyrazine, purine, and azaindole—bearing functional groups such as halides, trifluoromethyl, esters, amides, ethers, heterocycles, as well as unprotected alcohols and alkynes. #ProcessDevelopment #DrugDevelopment #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #CMC #SmallMolecules #Intermediates #API #manufacturing

I'm glad to share that one of our synthetic methods was successfully applied by the team at #Merck, led by Cedric Hugelshofer and Jianming Bao, in their medicinal chemistry efforts. This work involved the synthesis of 4,4-disubstituted cyclic sulfone derivatives, which serve as key structural motifs for their GABAA a5 receptor PAM drug discovery program. You can explore the full publication here: https://lnkd.in/gmuNyVwU. You can also explore our original work here: https://lnkd.in/gpmFrtP4 Key Highlights: 1. The electron-rich phenolic residue in the ketimine intermediate facilitates nucleophilic addition with various organometallic reagents through a highly effective Lewis acid-base interaction, leading to an excellent yield in this transformation. 2. Mild reaction conditions – suitable for direct application to drug molecules through Late-stage functionalization. 3. Creation of a quaternary center – a well-known challenge in synthetic organic chemistry. Key Merits: 1. No chromatography required – simple acid-base extraction replaces the need for chromatography. 2. Broad scope and scalable. #ProcessDevelopment #DrugDevelopment #DrugSubstances #CDMO #CRO #networking #Pharma #Biotech #CMC #SmallMolecules #Intermediates #API #manufacturing