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

Shatrughn Bhilare; Santosh Kori; Harshita Shet; Gundapally Balaram; Koosam Mahendar; Yogesh S. Sanghvi; Anant R. Kapdi

doi:10.1055/s-0040-1707260

Synthesis, Table of Contents

Synthesis 2020; 52(23): 3595-3603
DOI: 10.1055/s-0040-1707260

psp

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

Shatrughn Bhilare

^aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Email: ar.kapdi@ictmumbai.edu.in

,

Santosh Kori

^aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Email: ar.kapdi@ictmumbai.edu.in

^bInstitute of Chemical Technology-Indian Oil Odisha Campus, IIT Kharagpur Extension Centre, MouzaSamantpuri, Bhubaneswar 751013, Odisha, India

,

Harshita Shet

^aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Email: ar.kapdi@ictmumbai.edu.in

^bInstitute of Chemical Technology-Indian Oil Odisha Campus, IIT Kharagpur Extension Centre, MouzaSamantpuri, Bhubaneswar 751013, Odisha, India

,

Gundapally Balaram

^cSapala Organics Pvt. Ltd., Plots Nos. 1468 & 147, IDA Mallapur, Phase-II, Hyderabad 500076, Telangana, India

,

Koosam Mahendar

^cSapala Organics Pvt. Ltd., Plots Nos. 1468 & 147, IDA Mallapur, Phase-II, Hyderabad 500076, Telangana, India

,

Yogesh S. Sanghvi

^dRasayan Inc., 2802, Crystal Ridge Road, Encinitas, CA 92024-6615, USA

,

Anant R. Kapdi ∗

^aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh Road, Matunga, Mumbai 400019, India Email: ar.kapdi@ictmumbai.edu.in

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Abstract

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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

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References

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