FMOC MEDIATED SYNTHESIS OF PEPTIDE NUCLEIC-ACIDS

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 P NA backbone 1 is prepared as a stable hydrochloride salt. The base ace tic acids of adenine (4) and cytosine (3) were prepared by Cbz protect ion of the exocyclic amino groups followed by alkylation with t-butylb romoacetate and subsequent acid hydrolysis of the t-butyl ester. Allyl ation of 6-chloro-2-aminopurine followed by acid hydrolysis, Cbz prote ction with N-(benzyloxycarbonyl)imidazole, ozonolytic cleavage, and ox idation afforded the Cbz-protected guanine acetic acid (5). The base a cetic acids (2, 3, 4 and 5) were coupled to the backbone (1) with eith er EDC (2 and 3) or BOP reagent (4 and 5). Acid hydrolysis of the resu lting t-butyl esters and transesterification afforded the correspondin g pentafluorophenyl esters (20, 23, 26 and 29). Oligomerization is con ducted on a 0.05 mmol scale with a mere 2 fold excess of monomer in ea ch coupling cycle. The N-terminal Fmoc group is retained on the final oligomer, following HF cleavage and deprotection, providing a convenie nt lipophilic handle for HPLC purification.