Fmoc mediated synthesis of Peptide Nucleic Acids

• Published in: Tetrahedron Vol. 51; no. 22; pp. 6179 - 6194
• Main Authors: Thomson, Stephen A., Josey, John A., Cadilla, Rodolfo, Gaul, Micheal D., Fred Hassman, C., Luzzio, Michael J., Pipe, Adrian J., Reed, Kathryn L., Ricca, Daniel J., Wiethe, Robert W., Noble, Stewart A.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 29.05.1995; Elsevier
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; PNA; RECOGNITION; DNA; ANTISENSE; ESTERS; THYMINE; GUANINE; ADENINE; CYTOSINE; OLIGONUCLEOTIDE ANALOGS
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/0040-4020(95)00286-H

The syntheses of the Fmoc-protected Peptide Nucleic Acid (PNA) monomer pentafluorophenyl esters of adenine ( 26), cytosine ( 23), guanine ( 29) and thymine ( 20), and their oligomerization are described. The Fmoc PNA backbone 1 is prepared as a stable hydrochloride salt. The base acetic acids of adenine ( 4) and cytosine ( 3) were prepared by Cbz protection of the exocyclic amino groups followed by alkylation with t-butylbromoacetate and subsequent acid hydrolysis of the t-butyl ester. Allylation of 6-chloro-2-aminopurine followed by acid hydrolysis, Cbz protection with N-(benzyloxycarbonyl)imidazole, ozonolytic cleavage, and oxidation afforded the Cbz-protected guanine acetic acid ( 5). The base acetic acids ( 2, 3, 4 and 5) were coupled to the backbone ( 1) with either EDC ( 2 and 3) or BOP reagent ( 4 and 5). Acid hydrolysis of the resulting t-butyl esters and transesterification afforded the corresponding pentafluorophenyl esters ( 20, 23, 26 and 29). Oligomerization is conducted on a 0.05 mmol scale with a mere 2 fold excess of monomer in each coupling cycle. The N-terminal Fmoc group is retained on the final oligomer, following HF cleavage and deprotection, providing a convenient lipophilic handle for HPLC purification. The synthesis of Fmoc-protected Peptide Nucleic Acid monomers and their oligomerization is described.