Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, ) and foscarbidopa (FCD, carbidopa 4'-monophosphate, ) were identified as water-soluble prodrugs of levodopa (LD, ) and carbidopa (CD, ), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD () and FCD () drug substances and their manufacture at pilot scale. The synthesis of FLD () employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry.

Asymmetric Synthesis of Remote Quaternary Centers by Copper-Catalyzed Desymmetrization: An Enantioselective Total Synthesis of (+)-Mesembrine.

Catalytic asymmetric syntheses of remote quaternary stereocenters have been developed by copper-catalyzed 1,4-hydrosilylation of γ,γ-disubstituted cyclohexadienones. A variety of cyclohexenones have been synthesized in good yield and excellent enantioselectivity. Versatile 2-silyloxy diene intermediates bearing γ,γ-disubstituted all carbon stereogenic centers can be isolated from the mild reaction conditions.

Oxidopyrylium-Alkene [5 + 2] Cycloaddition Conjugate Addition Cascade (C) Sequences: Scope, Limitation, and Computational Investigations.

Oxidopyrylium-alkene [5 + 2] cycloaddition conjugate addition cascade (C) sequences are described. Intramolecular cycloadditions involving terminal alkenes, enals, and enones were investigated. Substrates with tethers of varying lengths delivered five- and six-membered carbocycles and heterocycles thus demonstrating the scope and limitation of the cycloaddition-conjugate addition cascade.

Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays.

Copper-Catalyzed Aerobic Oxidative Amidation of Benzyl Alcohols.

A Cu-catalyzed synthesis of amides from alcohols and secondary amines using the oxygen in air as the terminal oxidant has been developed. The methodology is operationally simple requiring no high pressure equipment or handling of pure oxygen. The commercially available, nonprecious metal catalyst, Cu(phen)Cl, in conjunction with di-tert-butyl hydrazine dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent yields.