Direct and Catalytic C‐Glycosylation of Arenes: Expeditious Synthesis of the Remdesivir Nucleoside**

Abstract

Since early 2020, scientists have strived to find an effective solution to fight SARS‐CoV‐2, in particular by developing reliable vaccines that inhibit the spread of the disease and repurposing drugs for combatting its effects on the human body. The antiviral prodrug Remdesivir is still the most widely used therapeutic during the early stages of the infection. However, the current synthetic routes rely on the use of protecting groups, air‐sensitive reagents, and cryogenic conditions, thus impeding a cost‐efficient supply to patients. We have, therefore, focused on the development of a straightforward, direct addition of (hetero)arenes to unprotected sugars. Here we report a silylium‐catalyzed and completely stereoselective C‐glycosylation that initially yields the open‐chain polyols, which can be selectively cyclized to provide either the kinetic α‐furanose or the thermodynamically favored β‐anomer. The method significantly expedites the synthesis of Remdesivir precursor GS‐441524 after a subsequent Mn‐catalyzed C−H oxidation and deoxycyanation.

A selective and atom-economic rearrangement of uridine by cascade biocatalysis for production of pseudouridine

“…Compared to chemical syntheses of Ψ, the one-pot rearrangement of U into Ψ reported here offers fundamental improvements in process efficiency and sustainability, which both arise from the innovative cascade reaction development. Our considerations take into account recent developments in chemo-catalytic synthesis of C-nucleosides by List and co-workers 34 , even though the application to Ψ has not been shown in their study. Besides the core features of the synthetic transformation already discussed, the absence of an isolated intermediate in the multistep reaction sequence, the avoidance of excess reagents or organic solvents used, and the consistent usage of simple process operations are important engineering characteristics of the biocatalytic process.…”

“…The chemical structure of the Ψ is verified by 1 H, 13 C, and 31 P-NMR (Supplementary Figs. [32][33][34][35][36][37][38] and the purity is shown as ≥99% by HPLC and assay for free phosphate.…”

“…1b) [21][22][23][24] have been the reconstruction of the uracil nucleobase on a C1′-funcionalized D-ribofuranosyl moiety [25][26][27][28] or the coupling of a suitably primed heteroaryl with a glycosyl reagent, such as glycal or pentonolactone 18,20,[29][30][31][32][33] . Despite considerable efforts in method development, stereo-direction (β:α) remains an important issue 29,30,[33][34][35] . Starting from D-ribonic acid 1,4-lactone in a most advanced synthesis, Ψ is obtained in 40% yield over three steps (Fig.…”

Synthesis of Remdesivir by Direct Lithiation of Pyrrolo[2,1‐f][1,2,4]triazine Derivatives Enabled C‐Glycosylation

“…[4] Meanwhile, lower yield and high cost of iodination step and complicated operation employed in the conversion from 3 to 5 compromised the value of this route. Recently, List et al reported an organocatalytic approach to this type of C-glycoside, [5] from non-halogenated compound 1. This remarkable regioselectivity on electrophile 1 indicated the pi-basicity on C-9, which is used during the halogenation of 1.…”

N-Cyano-2,2′-biphenyldicarboimide as a Cyanation Reagent for Co(III)-Catalyzed C–H Cyanation of Indoles in Ionic Liquids

“…In order to prove the synthesis effectiveness of this Co-catalyzed cyanation reaction, the cyano group can be converted into other functional groups to synthesize some important compounds, as shown in Scheme . For example, product 3ab could be used to synthesize the precursors of the unnatural nucleobase fragment seen in Remdesivir, − a marketed drug licensed for the treatment of COVID-19, and compared it with the route in the literature, and the experimental results are shown in the SI for details. This structural motif is also present in a variety of other approved and experimental drugs …”