Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

Abstract

The asymmetric Pd-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows for the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogs. The introduction of these chiral tertiary piperazines resulted in imatinib analogs that exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…Since their development of an enantioselective allylic alkylation, the Stoltz group has increased the scope of this transformation substantially to include, 1,3-dioxan-5-one- ( 9 ), 21 β-thiocyclohexenone-( 10 ), 22,23 3-ketal- ( 11 ), 24 β-alkoxy-cycloheptenone- ( 12 ), 25,26 5-alkyl- and 5-alkoxy- ( 13 ), β-aminocyclohexenone- ( 14 ), 1-alkoxypiperidine-2,6-dione- ( 15 ), dihydropyridin-4(1 H )-one- ( 16 ), 27 cyclobutanone- ( 17 ), 28 valerolactam and 2-piperazinone- ( 18 ), 29 2-aminomethylcyclohexanone- ( 19 ), 30 4-oxazolidinone- ( 20 ), morpholin-3-one- ( 21 ), 1,2-oxazepan-3-one- ( 22 ), 31 and cyclopentanone-based ( 23 ) 32 allyl β-ketoesters (Figure 2). Notably, the use of oxygen- and nitrogen-based heterocycles allows for the facile synthesis of quaternary stereocenter-bearing polyketide and pharmaceutical-type fragments in a straightforward manner.…”

Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2) Process. A Suitable Alternative towards Novel Aza-Analogues of Falipamil

“…Similarly, various bioactive products contain the pyrrolo[3,4- b ]pyridin-5-one system within their structures. Besides, piperazine is a common structural motif in bioactive products, and thus it is considered a privileged linker in medicinal chemistry [5]. For example, Kung et al described that various compounds containing the isoindolin-1-one system that are piperazine-linked to other heterocycles exhibit strong binding affinity to the 5-hydroxytryptamine 1A receptor [6].…”

Enhanced Drug Photosafety by Interchromophoric Interaction Owing to Intramolecular Charge Separation

“…Imatinib (IMT, Scheme ) is an efficient tyrosine kinase inhibitor that is widely prescribed for the treatment of Philadelphia chromosome‐positive chronic myeloid leukemia or gastrointestinal stromal tumors . Interestingly, this drug, labeled as a “magic bullet”, is the result of rational design to optimize its chemical structure on the basis of protein kinase inhibition . However, cutaneous reactions have been reported by patients who were being treated long term; these included increased photosensitivity, cutaneous reactions, psoriasis, pseudoporphyria, and squamous cell carcinoma .…”