A multifunctional catalyst that stereoselectively assembles prodrugs

Abstract

The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.

Stereoselective Synthesis of Sofosbuvir through Nucleoside Phosphorylation Controlled by Kinetic Resolution

“…Although this procedure was very efficient, it could be considered to be less atom economical and step economical than catalytic procedures that, starting from 2 , do not use protection at OH‐3′ , , . However, all the published syntheses of compound 2 ,, which use commercially available lactone 17 as the starting material (Scheme ), require the use of protective groups.…”

“…The protective groups of 22 are removed with ammonia in MeOH, and finally the 4‐benzoylcytosine is transformed into uracil with hot acetic acid to give nucleoside 2 (Scheme , reactions inside the red frame). Compound 2 may then be transformed into Sofosbuvir ( 1 ) in a single step by selective phosphorylation at OH‐5′ (as shown in Scheme ) ― a seven‐step synthetic procedure overall, starting from 17 . Consequently, as protection of the OH group is required for nucleobase insertion, we decided to also introduce our different protective groups at the 3′‐ and 5′‐OH groups of lactone 17 ; compound 23 was obtained in 67 % yield (Scheme ).…”

“…Finally, a group of Merck scientists recently described the use of a chiral catalyst for the stereoselective assembly of ProTide nucleosides starting from the stereochemically unstable isopropyl‐2‐{[chloro(phenoxy)‐phosphoryl]amino}propanoate (Scheme ). Using the unprotected nucleoside, a tailor‐made enantiomerically pure catalyst is required to reach a high level of regio‐ and stereoselectivity …”

Enantioselective γ‐Addition of Pyrazole and Imidazole Heterocycles to Allenoates Catalyzed by Chiral Phosphine

“…[1] Moreover,p yrazole and imidazole derivatives are also an important scaffold in asymmetric synthesis. [3] Specially,organocatalysts have been used to generate the b-heteroaryl adducts in good results. [3] Specially,organocatalysts have been used to generate the b-heteroaryl adducts in good results.…”

Enantioselective γ‐Addition of Pyrazole and Imidazole Heterocycles to Allenoates Catalyzed by Chiral Phosphine

“…[2] Therefore,areliable and diversifiable functionalization with such embedded motifs represents ah ighly important goal, which would find broad application in asymmetric catalytic reactions. [3] Specially,organocatalysts have been used to generate the b-heteroaryl adducts in good results. [4] Recently,t he N-allylation of nitrogen-containing heterocycles catalyzed by chiral transition-metal has emerged as an attractive strategy to prepare multifunctional compounds.…”