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Optimized Synthesis of Fmoc/Boc‐Protected PNA Monomers and their Assembly into PNA Oligomers.
Author(s) -
Shaikh Ashif Y.,
Björkling Fredrik,
Nielsen Peter E.,
Franzyk Henrik
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202100278
Subject(s) - chemistry , monomer , combinatorial chemistry , self assembly , polymer chemistry , organic chemistry , polymer
Continuous advancement of application of peptide nucleic acid (PNA) oligomers encouraged exploration of rapid and efficient synthesis of PNA monomers and oligomers. Among the PNA monomers developed, only a few are commonly used in automated PNA synthesis. Herein, we report short and efficient protocols suitable for large‐scale synthesis of Fmoc/Boc‐protected PNA monomers with advantageous solubility properties; these also facilitate purification due to the traceless nature of the Boc protecting group. Initially, several coupling reagents were screened for assembly of a pentamer containing all four nucleobases, and then the most promising reagents were tested in the synthesis of a decamer. The Fmoc/Boc‐protected monomers proved compatible with both manual synthesis and assembly on an automated peptide synthesizer at room temperature or at 40 °C. As compared to the commonly used coupling agent, 1‐[bis(dimethylamino)methylene]‐1H‐1,2,3‐triazolo[4,5‐b]pyridinium 3‐oxide hexafluorophosphate (HATU), both 2‐(1H‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium hexafluorophosphate (HBTU) and [ethyl cyano(hydroxyimino)acetato−O 2 ]tri‐1‐pyrrolidinylphosphonium hexafluorophosphate (PyOxim) proved more favorable, with the latter being superior. A previously reported side reaction of guanine bases in the presence of benzotriazol‐1‐yl‐oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) was not observed with the phosphonium salts.