Engineering Hydroxylase and Ketoreductase Activity, Selectivity, and Stability for a Scalable Concise Synthesis of Belzutifan

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CCDC 890236: Experimental Crystal Structure Determination

Related Article: Atefeh Garzan, Arvind Jaganathan, Nastaran Salehi Marzijarani, Roozbeh Yousefi, Daniel C. Whitehead, James E. Jackson, Babak Borhan|2013|Chem.-Eur.J.|19|9015|doi:10.1002/chem.201300189,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

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 <i>N</i>-Ts enamide carbonates, which can be easily converted into biologically significant 3,4-dihydroxylactams

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (<i>HalA</i>) Scale

We introduce a previously unexplored parameterhalenium affinity (<i>HalA</i>)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The <i>HalA</i> 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., have been classified on the <i>HalA</i> scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by <i>HalA</i> computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (<i>HalA</i>) Scale

We introduce a previously unexplored parameterhalenium affinity (<i>HalA</i>)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The <i>HalA</i> 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., have been classified on the <i>HalA</i> scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by <i>HalA</i> computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions

A New Tool To Guide Halofunctionalization Reactions: The Halenium Affinity (<i>HalA</i>) Scale

We introduce a previously unexplored parameterhalenium affinity (<i>HalA</i>)– as a quantitative descriptor of the bond strengths of various functional groups to halenium ions. The <i>HalA</i> 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., have been classified on the <i>HalA</i> scale. This indirect approach enables a rapid and straightforward prediction of chemoselectivity for systems involved in halofunctionalization reactions that have multiple nucleophilic sites. The influences of subtle electronic and steric variations, as well as the less predictable anchimeric and stereoelectronic effects, are intrinsically accounted for by <i>HalA</i> computations, providing quantitative assessments beyond simple “chemical intuition”. This combined theoretical–experimental approach offers an expeditious means of predicting and identifying unprecedented reactions

Development of a Thiophosphorylation Process for the Synthesis of 2′F-Thio-Adenosine Monophosphate

The process development for 2′F-thio-adenosine monophosphate, an intermediate for MK-1454, an immunooncology therapeutic, is described. Kinetic profiling, nuclear magnetic resonance monitoring, investigation of product decomposition pathways, and crystallization control identified important parameters for an efficient thiophosphorylation process. Among those identified parameters are the use of pivaloyl as the protecting group for the nucleoside starting material as well as the use of triethylphosphate as a green reaction solvent, both of which are critical for allowing a homogeneous reaction mixture and key to the success of the large-scale reaction. These insights enabled an optimized thiophosphorylation process, which delivered 2′F-thio-adenosine monophosphate in 77% overall yield at a 2.5 kg scale