Use of the dithiasuccinoyl (Dts) amino protecting group for solid-phase synthesis of protected peptide nucleic acid (PNA) oligomers

"Peptide nucleic acid" (PNA) oligomers replace the oligonucleotide backbone of DNA with an achiral and neutral poly[N-(2-aminoethyl)glycine] backbone, and the four-natural nucleobases are attached through methylene carbonyl l inkages to the glycine nitrogens. The present work describes the efficient conversion of N-omega-Boc/side-chain Z-protected PNA monomers to the corres ponding derivatives protected by the thiolyzable N-omega-dithiasuccinoyl (D ts) function. After acidolytic removal of Boc, treatment with bis(ethoxythi ocarbonyl) sulfide gave the N-omega-ethoxythiocarbonyl (Etc) derivatives, w hich were silylated at the alpha-carboxyl and converted to the heterocycle by reaction with (chlorocarbonyl)sulfenyl chloride. Net yields of homogeneo us monomers were 71-78%. Conditions in the solid-phase mode for thiolytic r emoval of the Dts group, and for coupling of protected monomers, have been studied extensively and optimized. A protocol featuring (i); Dts removal wi th dithiothreitol (DTT) (0.5 M) in acetic acid (HOAc) (0.5 M)-CH2Cl2 (2 + 8 min) (ii) short neutralization with N,N-diisopropylethylamine (DIEA)-CH2Cl 2 (1:19, 1 + 2 min); and (iii) coupling mediated by HBTU-DIEA (3:1) in N-me thyl-2-pyrrolidinone (NMP) (3 h) pas applied to the solid-phase synthesis o f Dts-T-4-Gly-NH2, Dts-G(Z)-G(Z)-T-A(Z)-Gly-NH2, Dts-A(Z)-T-C(Z)-G(Z)-Gly-N H2, and Dts-G(Z)-C (Z)-A(Z)-T-Gly-NH2. The indicated protected PNA derivati ves were released from the support, and their structures were verified by m ass spectrometry.