Zinc Tetrafluoroborate Hydrate as a Mild Catalyst for Epoxide Ring Opening with Amines: Scope and Limitations of Metal Tetrafluoroborates and Applications in the Synthesis of Antihypertensive Drugs (<i>RS</i>)/(<i>R</i>)/(<i>S</i>)-Metoprolols

The scope and limitations of metal tetrafluoroborates have been studied for epoxide ring-opening reaction with amines, and Zn(BF4)2·xH2O has been found to be a mild and efficient catalyst affording high yields under solvent-free conditions at rt with excellent chemo-, regio-, and stereoselectivities. The catalytic efficiency followed the order Zn(BF4)2·xH2O ≫ Cu(BF4)2·xH2O > Co(BF4)2·6H2O ≫ Fe(BF4)2·6H2O > LiBF4 for reactions with cyclohexene oxide and Zn(BF4)2·xH2O ≫ Co(BF4)2·6H2O ≫ Fe(BF4)2·6H2O > Cu(BF4)2·xH2O for stilbene oxide, but AgBF4 was ineffective. For reaction of styrene oxide with aniline, the metal tetrafluoroborates exhibited comparable regioselectivity (1:99–7:93) with preferential reaction at the benzylic carbon of the epoxide ring. A reversal of regioselectivity (91:1–69:31) in favor of the reaction at the terminal carbon of the epoxide ring was observed for reaction with morpholine. The regioselectivity was dependent on the electronic and steric factors of the epoxide and the pKa of the amine and independent of amine nucleophilicity. The role of the metal tetrafluoroborates is envisaged as “electrophile nucleophile dual activation” through cooperativity of coordination, charge–charge interaction, and hydrogen-bond formation that rationalizes the catalytic efficiency, substrate reactivity, and regioselectivity. The methodology was used for synthesis of cardiovascular drug metoprolol as racemic and enriched enantiomeric forms

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases