Abstract
The design of novel nucleoside triphosphate (NTP) analogues bearing an all-carbon quaternary center at C2′ or C3′ is described. The construction of this all-carbon stereogenic center involves the use of an intramoleculer photoredox-catalyzed reaction. The nucleoside analogues (NA) hydroxyl functional group at C2′ was generated by diastereoselective epoxidation. In addition, highly enantioselective and diastereoselective Mukaiyama aldol reactions, diastereoselective N-glycosylations and regioselective triphosphorylation reactions were employed to synthesize the novel NTPs. Two of these compounds are inhibitors of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, the causal virus of COVID-19.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus and the causal agent of coronavirus (CoV) disease 2019 (COVID-19)
The synthesis of the all-carbon quaternary stereogenic centers was based on our findings that a carbon-centered free radical flanked by an ester and a secondary carbon bearing an electronegative substituent could stereoselectively participate in kinetically controlled atom transfer reactions
The corresponding β-cytosine nucleoside analogue 11 was obtained from 9 by taking advantage of anchimeric participation by the acetate at C2
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense RNA virus and the causal agent of coronavirus (CoV) disease 2019 (COVID-19). ORF1a and ORF2 of the positive strand RNA are translated to produce non-structural protein precursors (nsp), including proteins that further cleave the precursor to form mature functional helicase and RNA-dependent RNA polymerase [1] (RdRp, or alternatively nsp 12). The latter has been recognized as an optimal target for drug design, due to its crucial role in RNA synthesis, lack of host homologues and high structural conservation between coronaviruses. The severity of SARS-CoV-2 disease has encouraged many laboratories to evaluate potential inhibitors of RdRp from related viruses. Inhibitors of single-stranded negative RNA viruses, such as Remdesivir (Figure 1A, Ebola) [2] and B-D-N4- hydroxy-cytidine NHC [3] (Molnupiravir or EIDD-1931, influenza), along with other nucleotides, were examined [4]
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