Diastereoselective and regioselective synthesis of adenosine thionucleoside analogues using an acyclic approach

Abstract

An acyclic approach to synthesize thiofuranoside N-glycosides bearing an adenine nucleobase is presented herein. This approach provides a significant improvement in terms of regio- and diastereoselectivity compared with the current paradigms used for their formation. Activation of acyclic dithioacetal substrates bearing either a C2′-alkoxy or fluoro group and coupling with purine nucleobases selectively generates 1′,2′-syn thioaminals. The regiochemistry of the nucleobase coupling (N7 or N9) can also be controlled by using either silylated or unsilylated purines. A subsequent SN2-like cyclization of these 1′,2′-syn acyclic thioaminals results in the desired 1′,2′-cis thionucleoside analogues.

Synthesis of 4′-Thionucleoside Analogues Bearing a C2′ Stereogenic All-Carbon Quaternary Center

“…A second category involves Pummerer-type reactions with oxidation of tetrahydrothiophenes (6) followed by nucleobase addition onto in situ-generated thionium ions [7]. A third approach consists of an intramolecular cyclization of thioaminals (10) formed from stereoselective nucleobase addition onto acyclic dithioacetals 9. Scheme 1.…”

“…Molecules 2024, 29, x FOR PEER REVIEW 3 of 27 Scheme 2. (a) Acyclic approach for the intramolecular cyclization of 1′,2′-syn thioaminals leading to either 1′,2′-trans furanosides through an O4′-to-C1′ cyclization or 1′,2′-cis 4′-thioanalogues through a S1′-C4′ cyclization [9,10]. (b) Transition state for the stereoselective addition of the silylated nucleobase [11].…”

“…(b) Transition state for the stereoselective addition of the silylated nucleobase [11]. (c) Acyclic approach for the synthesis of C2 ′ F 4 ′ -thiofuranosides in addition to those bearing an all-carbon quaternary center at C3 ′ (d) [10,12].…”

“…DFT transition state calculations indicated that this selectivity could be attributed to the preferred addition opposite to the R group and the counteranion of thiocarbenium intermediates having the C2-alkoxy group gauche to the thioether moiety (Scheme 2b) [11]. With this approach, 4 ′ -thionucleosides bearing a C2 ′ -alkoxy or fluoride have been successfully synthesized in both the L-and D-series (Scheme 2a,c) [9,10,12].…”