Issue 58, 2020

P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

Abstract

3′-N-(2-Thio-1,3,2-oxathiaphospholane) derivatives of 5′-O-DMT-3′-amino-2′,3′-dideoxy-ribonucleosides (NOTP-N), that bear a 4,4-unsubstituted, 4,4-dimethyl, or 4,4-pentamethylene substituted oxathiaphospholane ring, were synthesized. Within these three series, NOTP-N differed by canonical nucleobases (i.e., AdeBz, CytBz, GuaiBu, or Thy). The monomers were chromatographically separated into P-diastereomers, which were further used to prepare NNPSN′ dinucleotides (3), as well as short P-stereodefined oligo(deoxyribonucleoside N3′→O5′ phosphoramidothioate)s (NPS-) and chimeric NPS/PO- and NPS/PS-oligomers. The condensation reaction for NOTP-N monomers was found to be 5–6 times slower than the analogous OTP derivatives. When the 5′-end nucleoside of a growing oligomer adopts a C3′-endo conformation, a conformational ‘clash’ with the incoming NOTP-N monomer takes place, which is a main factor decreasing the repetitive yield of chain elongation. Although both isomers of NNPSN′ were digested by the HINT1 phosphoramidase enzyme, the isomers hydrolyzed at a faster rate were tentatively assigned the RP absolute configuration. This assignment is supported by X-ray analysis of the protected dinucleotide DMTdGiBuNPSMeTOAc, which is P-stereoequivalent to the hydrolyzed faster P-diastereomer of dGNPST.

Graphical abstract: P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

Supplementary files

Article information

Article type
Paper
Submitted
05 jun 2020
Accepted
15 sep 2020
First published
23 sep 2020
This article is Open Access
Creative Commons BY license

RSC Adv., 2020,10, 35185-35197

P-stereocontrolled synthesis of oligo(nucleoside N3′→O5′ phosphoramidothioate)s – opportunities and limitations

E. Radzikowska, R. Kaczmarek, D. Korczyński, A. Krakowiak, B. Mikołajczyk, J. Baraniak, P. Guga, K. A. Wheeler, T. Pawlak and B. Nawrot, RSC Adv., 2020, 10, 35185 DOI: 10.1039/D0RA04987E

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