Cu(II)/PTABS-Promoted, Chemoselective Amination of HaloPyrimidines.

Chemoselective amination is a highly desired synthetic methodology, given its importance as a possible strategy to synthesize various drug molecules and agrochemicals. We, herein, disclose a highly chemoselective Cu(II)-PTABS-promoted amination of pyrimidine structural feature containing different halogen atoms.

Cu(II)/PTABS-Promoted, Regioselective SNAr Amination of Polychlorinated Pyrimidines with Mechanistic Understanding.

Regioselective amination of polyhalogenated heteroarenes (especially pyrimidines) has extensive synthetic and commercial relevance for drug synthesis applications but is plagued by the lack of effective synthetic strategies. Herein, we report the Cu(II)/PTABS-promoted highly regioselective nucleophilic aromatic substitution (SNAr) of polychlorinated pyrimidines assisted by DFT predictions of the bond dissociation energies of different C-Cl bonds. The unique reactivity of Cu(II)-PTABS has been attributed to the coordination/activation mechanism that has been known to operate in these reactions, but further insights into the catalytic species have also been provided.

Room-Temperature Dialkylamination of Chloroheteroarenes Using a Cu(II)/PTABS Catalytic System.

The dimethylamino functionality has significant importance in industrially relevant molecules and methodologies to install these efficiently are highly desirable. We report herein a highly efficient, room-temperature dimethylamination of chloroheteroarenes performed via the in-situ generation of dimethylamine using N,N-dimethylformamide (DMF) as precursor wiith a large substrate scope that includes various heteroarenes, purines as well as commercially relevant drugs such as altretamine, ampyzine and puromycin precursor.

Strategies for the Synthesis of Fluorinated Nucleosides, Nucleotides and Oligonucleotides.

Fluorinated nucleosides and oligonucleotides are of specific interest as probes for studying nucleic acids interaction, structures, biological transformations, and its biomedical applications. Among various modifications of oligonucleotides, fluorination of preformed nucleoside and/or nucleotides have recently gained attention owing to the unique properties of fluorine atoms imparting medicinal properties with respect to the small size, electronegativity, lipophilicity, and ability for stereochemical control. This review deals with synthetic protocols for selective fluorination either at sugar or base moiety in a preformed nucleosides, nucleotides and nucleic acids using specific fluorinating reagents.

Tandem Homometallic or Multimetallic Catalysis for Assembly of Base-Modified Nucleosides.

Tandem catalysis has been at the forefront of synthesis in the past decade due to the reduction in the number of steps and purification needed for the synthesis of commercially relevant molecules. With the right combination of catalyst systems, which could be homometallic or multimetallic, one can construct complex structural motifs in a one-pot procedure without the requirement for the isolation of the intermediates, reducing both reagent waste and time. Over the years, application of tandem catalysis has certainly extended towards arene and heteroarene motifs; nucleoside modification using such a strategy has been rare. In this regard, we would like to report herein the development of numerous homometallic and multimetallic tandem catalytic protocols for the modification of nucleosides, providing efficient access to a diverse range of molecules with promising fluorescent properties, as well as pharmaceutically relevant antiviral drugs such as FV-100. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Double tandem one-pot Sonogashira/cyclization of 5-IdU for the synthesis of FV-100 and analogs Basic Protocol 2: Double tandem one-pot Heck/Suzuki-Miyaura of 5-IdU for the synthesis of fluorescent nucleoside analogs Basic Protocol 3: Double tandem one-pot Suzuki-Miyaura cross-coupling of 5-IdU for the synthesis of fluorescent nucleoside analogs Basic Protocol 4: Double tandem one-pot amination/amidation for the synthesis of Sangivamycin precursor Basic Protocol 5: Triple tandem one-pot chemoselective etherification/Sonogashira coupling/cyclization for synthesis of BCNA analogs Basic Protocol 6: Triple tandem one-pot sequential Heck/borylation/Suzuki-Miyaura reaction.

Discovery, Synthesis, and Scale-up of Efficient Palladium Catalysts Useful for the Modification of Nucleosides and Heteroarenes.

Nucleic acid derivatives are imperative biomolecules and are involved in life governing processes. The chemical modification of nucleic acid is a fascinating area for researchers due to the potential activity exhibited as antiviral and antitumor agents. In addition, these molecules are also of interest toward conducting useful biochemical, pharmaceutical, and mutagenic study. For accessing such synthetically useful structures and features, transition-metal catalyzed processes have been proven over the years to be an excellent tool for carrying out the various transformations with ease and under mild reaction conditions. Amidst various transition-metal catalyzed processes available for nucleoside modification, Pd-catalyzed cross-coupling reactions have proven to be perhaps the most efficient, successful, and broadly applicable reactions in both academia and industry. Pd-catalyzed C-C and C-heteroatom bond forming reactions have been widely used for the modification of the heterocyclic moiety in the nucleosides, although a single catalyst system that could address all the different requirements for nucleoside modifications isvery rare or non-existent. With this in mind, we present herein a review showcasing the recent developments and improvements from our research groups toward the development of Pd-catalyzed strategies including drug synthesis using a single efficient catalyst system for the modification of nucleosides and other heterocycles. The review also highlights the improvement in conditions or the yield of various bio-active nucleosides or commercial drugs possessing the nucleoside structural core. Scale ups wherever performed (up to 100 g) of molecules of commercial importance have also been disclosed.