Suzuki-Miyaura Cross-Coupling as a Synthetic Tool for Nucleoside and Nucleotide Modification

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2’-deoxyuridine (or cytidine)

“…Palladium-catalyzed Suzuki-Miyaura cross-couplings have been an essential tool for the synthesis of many functionalised molecules including modified nucleoside analogues [50]. The ease of employing and handling of the boronic acids as well as the ready availability of these reagents makes Suzuki-Miyaura couplings a preferred protocol.…”

PTABS: A Unique Water-Soluble π-Acceptor Caged Phosphine

“…Besides the requirement of the industry to employ water as the reaction solvent, previous reports in literature for the synthesis of modified nucleosides analogues being performed in volatile organic solvents further supported our vision. 19 Complexation of PTA as a water-soluble ligand with Pd precursor was achieved as a part of a long-standing collaboration with J. Serrano 15 in Spain giving access to [Pd(Nimidate)2(PTA)2] complexes with an appreciable watersolubility of ~100 mg/ml (Scheme1). 23 Complexation was achieved based on the concept of using stabilizing pseudohalides such as imidates 24 24 was undertaken by Vijay Gayakhe from the first batch of Ph.D. students in my group.…”

“…He was able to quickly identify that besides the Suzuki-Miyaura cross-coupling of nucleosides was carried out using environmentally harmful volatile organic solvents, the requirement of multiple catalytic systems for the functionalization of all 4 different nucleosides such as deoxyuridine (dU), deoxycytidine (dC), deoxyadenosine (dA) and deoxyguanosine (dG) was a bigger problem for the chemical biologists, biochemists intending to employ the modified nucleosides for further applications. 19 We envisaged the development of a single catalytic system that could address both these issues and provide an easier access to derivatized nucleosides. Vijay performed extensive optimization followed by scope with the water-soluble [Pd(N-imidate)2(PTA)2] complexes for Suzuki-Miyaura cross-coupling of all the four nucleosides with different aryl/heteroaryl boronic acids creating a library of substituted nucleosides in good to excellent yields 25,26 ( Scheme2).…”

“…Nucleosides, which are the basic building blocks of DNA and RNA, are considered privileged scaffolds and are commonly derivatized/functionalized to enhance their photophysical and biological properties as they find varied applications as fluorescent probes, 16 antivirals 17 and anticancer agents. 18 To target these structural motifs, my research group strategized to develop water-soluble Pd-based catalysts that could promote Suzuki–Miyaura cross-couplings, 19 one of the most employed catalytic reactions in the literature for nucleoside modifications besides the Stille coupling, of nucleosides 20 in water as the sole solvent. 1,3,5-Triaza-7-phosphaadamantane (PTA), 9 21 as a caged phosphine ligand, was identified as the most probable candidate due to its reasonable water solubility and its ability to be employed as a coordinating ligand 22 for the development of Pd-based water-soluble complexes.…”

Imine-Palladacycles as Phosphine-Free Precatalysts for Low-Temperature Suzuki–Miyaura Synthesis of Nucleoside Analogues in Aqueous Media

“…Among the various catalytic processes employed in the literature for the modification of nucleosides, Suzuki–Miyaura cross-coupling is the one that has found the most applications due to its simplicity and ease of implementation . With regard to uridine, several research groups have been involved in the development of efficient protocols for the Suzuki–Miyaura modification of 5-iodo-2′-deoxyuridine with boronic acids .…”