SELECTION OF PROTECTIVE GROUPS UPON OPTIMIZING THE SYNTHESIS OF γ-PNA BASED ON L-GLU

• Main Authors: I. A. Prokhorov, A. A. Melkumova, A. S. Abdelbaky, O. V. Esipova, Yu. G. Kirillova
• Format: Article
• Language: Russian
• Published: MIREA - Russian Technological University 2018-10-01
• Series: Тонкие химические технологии
• Subjects: γ-пнк; boc-протокол; γ-pna; boc protocol; cyclohexyl protecting group; mitsunobu condensation; removal of ortho-nitrobenzenesulfonic group by thiolysis
• Online Access: https://www.finechem-mirea.ru/jour/article/view/165

This work is devoted to optimization of the synthesis of γ-S-carboxyethyl monomers of PNA based on L-Glu. PNA are promising compounds that hybridize with DNA or RNA, and due to their properties they are used in molecular biology, personalized medicine, and can also be used to create nanomaterials. To increase the yield of the desired monomers, it has been proposed to replace the benzyl protecting group with the carboxy function of the side radical by cyclohexyl one. Two synthetic schemes were proposed. In the first of them, γ-benzyl-N-Boc-glutamic acid, which was reduced to β-amino alcohol, was the starting compound. The hydroxyl group was protected by a dimethyl-tert-butylsilyl group. The benzyl ester in the side radical was cleaved by reduction on a palladium catalyst using ammonium formate. However, the subsequent acylation of cyclohexyl alcohol failed. In the second of the proposed schemes, a known sequence of reactions was used, which led to the formation of a cyclic derivative of Cbz-protected glutamic acid. Then, the resulting compound was acylated with cyclohexyl alcohol to give the desired ester. The subsequent transformation of the protective groups of the ester resulted in the diprotected L-glutamic acid in three stages. Subsequent reduction gave the desired protected β-amino alcohol containing a cyclohexyl protecting group in the side radical. This compound was further used in the Mitsunobu reaction to obtain a completely protected core of the PNA monomer. Subsequent thiolysis reaction resulted in the formation of the target secondary amine, the stability of which substantially exceeded the stability of its analog with benzyl protection, obtained and investigated before. The structure of the new compounds obtained is confirmed by 1H-NMR spectroscopy.