1,3,5-Triaza-7-phosphaadamantane (PTA) Derived Caged Phosphines for Palladium-Catalyzed Selective Functionalization of Nucleosides and Heteroarenes.

Phosphines have, in combination with transition metals, played a pivotal role in the rapid development of efficient catalytic processes. Caged phosphines constitute a class of three-dimensional scaffolds providing unique control over steric and electronic properties. The versatility of the caged phosphine ligands has been demonstrated elegantly by the groups of Verkade, Gonzalvi as well as Stradiotto. Our research group has also been working extensively for the past several years in the development of 1,3,5-triaza-7-phosphaadamantane-based caged ligands and in this personal note we have summarized these applications pertaining to the modification of biologically useful nucleosides and heteroarenes.

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.

Pd/PTABS: Low-Temperature Thioetherification of Chloro(hetero)arenes.

The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and low-temperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols and alkylthiols was carried out with a high efficiency. Heteroarenes of commercial relevance such as purines and pyrimidines were also found to be useful substrates for the reported transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and its preparation could be optimized. DFT studies were performed to understand the electronic effects of the tested ligands on the catalytic reaction.

Pd/PTABS: Low Temperature Etherification of Chloroheteroarenes.

A mild, general, and highly efficient catalytic etherification protocol for chloroheteroarenes was developed using the Pd/PTABS catalytic system. The protocol is selective for the etherification of chloroheteroarenes using a large variety of electron-rich and electron-deficient phenol bearing synthons which include inter alia biologically and commercially important estrone, estradiol, tyrosine, and several other molecules. The mildness of the new protocol is expected to be beneficial for the synthesis of complex drugs and drug intermediates offering late-stage modification of bioactive compounds.

Pd/PTABS: An Efficient Water-Soluble Catalytic System for the Amination of 6-Chloropurine Ribonucleoside and Synthesis of Alogliptin.

The synthesis and catalytic applications of the highly water-soluble ligand 7-phospha-1,3,5-triaza-admantane butane sultonate (PTABS) has been described. The synthesized PTABS ligand along with palladium acetate exhibits excellent reactivity towards the amination reaction of 6-chloro-9-(ß-D-ribofuranosyl)-9H-purine at ambient temperature. This protocol offers an advantage over the previously published procedures for the amination of 6-chloropurine nucleoside furnishing 6-N-substituted adenosine analogues. The validation of the present strategy has been demonstrated via synthesis of a uracil-based, anti-diabetic drug alogliptin. © 2018 by John Wiley & Sons, Inc.

An Active Palladium Colloidal Catalyst for the Selective Oxidative Heterocoupling of (Hetero)Aryl Boronic Acids.

A highly selective oxidative heterocoupling protocol for (hetero)aryl boronic acids with an active palladium colloidal catalyst was developed. The judicious choice of electronically different aryl boronic acids made possible such couplings under mild conditions, with air as oxidant, while embracing a wide substrate scope. This successful approach further allowed the development of a unique one-pot sequential oxidative heterocoupling/Suzuki-Miyaura cross-coupling tandem process for accessing substituted terphenyls.

Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes.

A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.