anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients

Abstract

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters

“…This new KR procedure was also applied in continuous flow using apolymer-supported isothiourea catalyst to resolve acyclictertiary alcohols with good to excellent selectivity.B ased on mechanistic control reaction, and previous computational studies,i ti sp roposed that stabilization and enantiodiscrimination within the acylation transition-state structure originates through maximization of aC =O•••isothiouronium interaction between the ahydroxy ester substrate and acylatedc atalyst. Although not demonstrated in this manuscript, the known derivatization [25] of structurally related products with conservation of er should allow access to further tertiary-alcohol-containing motifs using this method. [26] Figure 3.…”

Recent Advances in Continuous‐Flow Enantioselective Catalysis

“…This has been applied to the synthesis of drug intermediated 35 (Scheme b). The solvent effect on the Nd/Na heterobimetallic catalyst was further studied in 2018 . Different solvents (THF, 2‐Me‐THF) have a significant difference both on the reaction rate and the stereoselectivity.…”

Recent Progress in the Asymmetric Syntheses of α‐Heterofunctionalized (Masked) α‐ and β‐Amino Acid Derivatives

“…The asymmetric synthesis of α‐chalcogenated β‐amino acids can be achieved by a variety of different strategies, [ 43–64 ] as outlined in the following chapters.…”