Scale-Up of a Heck Alkenylation Reaction: Application to the Synthesis of an Amino-Modifier Nucleoside ‘Ruth Linker’

Dedicated to the memory of Jerry Lynn Ruth who first demonstrated the utility of this molecule for DNA labeling

Abstract

Ruth linker is a C5 pyrimidine modified nucleoside analogue widely utilized for the incorporation of a primary amine in a synthetic oligonucleotide. The increasing demand for non-radioactive labeling, detection of biomolecules, and assembly of COVID-19 test kits has triggered a need for scale-up of Ruth linker. Herein, an efficient protocol involving a palladium-catalyzed Heck alkenylation is described. The synthesis has been optimized with a goal of low catalyst concentration, column-free isolation, high product purity, reproducibility, and shorter reaction time. The scalability and utility of the process have been demonstrated successfully on a 100 g scale (starting material). Additionally, for scale-up of the Heck alkenylation protocol, 7-phospha-1,3,5-triaza-adamantanebutane sulfonate (PTABS) as the coordinating caged phosphine ligand was also synthesized on a multigram scale after careful optimization of the conditions.

Key words

nucleosides - Heck reaction - alkenes - palladium - catalysis - cross-coupling - homogeneous catalysis

Publication History

Received: 06 June 2020

Accepted after revision: 01 August 2020

Article published online:
08 September 2020

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