Synthesis of Peptide Nucleic Acid Monomers via N‐Alkylation of Nosyl‐protected Amino Acids with N‐Boc Bromoethyl Amine

Abstract

We have developed an alternate and effective pathway for completely protected peptide nucleic acid (PNA) monomer synthesis. The process involves alkylation of nosyl protected amino acids with N-Boc protected bromoethyl amine followed by deprotection of the nosyl group and condensation of thymine-1-acetic acid which was chosen as a nucleobase. The key intermediates, chiral/achiral PNA backbone, were obtained with an average overall yield of 50-60%. The glycine, valine, alanine and serine derived PNA monomers were prepared in four steps, starting from readily available materials and this result suggests that our approach is executable in all amino acids.

A safety-catch protecting group strategy compatible with Boc-chemistry for the synthesis of peptide nucleic acids (PNAs)

“…Although this appears to be a simple reaction, there are many precedents in the literature studying the acylation of the secondary amine of the Aeg backbone with the protected nucleobase derived as carboxylic acid. Some of the these reagents include the following: carbodiimides such as dicyclohexylcarbodiimide (DCC), 8,10,11,26–31 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide·HCl (EDC·HCl), 9,32–34 and diisopropylcarbodiimide (DIC); 35,36 aminium salts such as N -[(1 H -benzotriazol-1-yloxy)(dimethylamino)methylene]- N -methylmethanaminium hexafluorophosphate N -oxide (HBTU) 37 and N -[(dimethylamino)-1 H -1,2,3-triazolo[4,5- b ]-pyridin-1-ylmethylene]- N -methylmethanaminium hexafluorophosphate N -oxide (HATU); 38,39 and some phosphonium salts such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) 9,38,40 and bromotri(pyrrolidino) phosphonium hexafluorophosphate (PyBroP). 8,26,27,29,41 Considering all the above-cited coupling reagents, we decided to first use COMU/DIEA to activate the free carboxylic acids of the protected nucleobases, followed by the slow addition of Boc–Aeg–OBn ( 3 ).…”

“…Scheme 2 Synthetic steps for the preparation of (N 6 -Msz-adenine-9-yl)acetic acid ( 4) and (N 4 -Msz-cytosine-1-yl)acetic acid (5). propylcarbodiimide (DIC); 35,36 aminium salts such as N-[(1Hbenzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU) 37 and…”

“…This journal is © The Royal Society of Chemistry 2023 propylcarbodiimide (DIC); 35,36 aminium salts such as N-[(1Hbenzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU) 37 and…”

The challenge of peptide nucleic acid synthesis

“…Unlike the aforementioned approach where the EDA was alkylated by haloacetate derivatives, here the α-amino group of the Gly ester was alkylated by N -Boc-bromoethylamine. 109 Thus, the glycine ester was first N-protected by o -nosyl chloride, followed by the alkylation reaction with the protected amine alkyl halide in the presence of DBU to obtain the fully protected AEG backbone. The o -nosyl protection was essential to prevent an over-alkylated side-product.…”

Submonomeric Strategy with Minimal Protection for the Synthesis of C(2)-Modified Peptide Nucleic Acids

“…The main strategies proposed to solve the first problem exploit reductive amination, 17 Mitsunobu reaction, 18 and alkylation of Nosyl- protected amino acids 19 for the synthesis of the chiral backbone, followed by introduction of the carboxymethyl nucleobase. However, the use of complete monomers (i.e., bearing the nucleobase) require careful control of the reaction conditions for the synthesis of C(2)-modified PNAs, as, being α-acilated amino acid derivatives, they are prone to racemization on their chiral center.…”