Pd-Catalyzed Regioselective Asymmetric Addition Reaction of Unprotected Pyrimidines to Alkoxyallene

Abstract

Catalytic asymmetric synthesis of N-heterocyclic glycosides free of protecting and directing groups is reported. The key reaction is highlighted by the atom-efficient and regioselective addition of unprotected pyrimidines to highly functionalized alkoxyallene. Numerous acyclic and cyclic N-heterocyclic glycosides are accessed with minimal formation of organic byproducts. The synthetic utility of the reaction is demonstrated by the first catalytic asymmetric synthesis of anticancer pharmaceutical (-)-Tegafur and stereoselective synthesis of an oxepane nucleoside derivative.

Stereoselective Construction of N,O– and O,O‐Acetals by Pd‐catalyzed Addition of Heteroatoms to Alkoxyallene

“…Most of their synthetic methods are based on the alkylation of iminium and oxocarbenium ions generated in situ from their precursors, with poor stereoselectivity in most cases. Recently, an eminent Korean synthetic organic chemist Young Ho Rhee succeeded a conceptually new method as stereoselective construction of N , O – and O , O ‐acetals by Pd‐catalyzed addition of heteroatoms to alkoxyallene …”

“…The p‐ toluenesulfonyl (Ts)‐protected allylic amines and allylic alcohols ( 1a or 1b ) were added to alkoxyallenes ( 2 ) in the presence of the chiral Pd‐catalyst consisted of either L1 or L2 to yield N , O – and O , O ‐acetals ( 3a or 3b ) with high stereoselectivity. This reaction has a wide scope of the alkyl substrates (R’) shown in the Scheme . In most cases the substrate cyclopropoxyallene was the best for the reaction of Ts‐protected allylic amines and allylic alcohols with the chiral catalyst with either L1 or L2 in quantitative yield with more than 92% ee .…”

Recent progress in non-native nucleic acid modifications

“…Inspired by earlier work for palladium-catalyzed synthesis of acyclic amido ethers 46 , Trost and coworkers developed a method for synthesis of nucleoside analogues via novel chiral diamidophosphite ligands (Fig 2c ). 38 Most of their efforts focused on the synthesis of 5 to 12-membered rings containing oxygen and nitrogen with pyrimidines at the anomeric position.…”

Synthesis of Chiral Acyclic Pyrimidine Nucleosides with a Sulfur‐Containing Side Chain via Enantioselective Tandem Conjugate Addition/Protonation

“…Therefore, it is of great importance to develop more effective synthetic methods to construct chiral pyrimidine acyclic nucleosides. In 2017, the Rhee group developed a Pd‐catalyzed regioselective asymmetric addition reaction of unprotected pyrimidines to alkoxyallenes, affording diverse chiral pyrimidine acyclic nucleosides with excellent yields (Scheme a) . Recently, our group reported a Rh‐catalyzed regioselective asymmetric allylation of pyrimidines with racemic allylic carbonates.…”