Optimized Synthesis of Fmoc/Boc-Protected PNA Monomers and their Assembly into PNA Oligomers.
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Optimized Synthesis of Fmoc/Boc-Protected PNA Monomers and their Assembly into PNA Oligomers. / Shaikh, Ashif Y.; Björkling, Fredrik; Nielsen, Peter E.; Franzyk, Henrik.
In: European Journal of Organic Chemistry, Vol. 2021, No. 19, 2021, p. 2792-2801.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Optimized Synthesis of Fmoc/Boc-Protected PNA Monomers and their Assembly into PNA Oligomers.
AU - Shaikh, Ashif Y.
AU - Björkling, Fredrik
AU - Nielsen, Peter E.
AU - Franzyk, Henrik
N1 - Publisher Copyright: © 2021 Wiley-VCH GmbH
PY - 2021
Y1 - 2021
N2 - 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−O2]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.
AB - 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−O2]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.
KW - Building blocks
KW - Heating automation
KW - Oligomerization
KW - Peptide nucleic acids
KW - Solid-phase synthesis
U2 - 10.1002/ejoc.202100278
DO - 10.1002/ejoc.202100278
M3 - Journal article
AN - SCOPUS:85108276914
VL - 2021
SP - 2792
EP - 2801
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
SN - 1434-193X
IS - 19
ER -
ID: 273132184