Organocatalyzed Highly Enantioselective Aldol Reaction of Aldehydes for Synthesis of (R)‐Pantolactone

Abstract

This work demonstrates that a tert-leucine-derived 2-phenolic anilide is the efficient organocatalyst to catalyze the asymmetric cross-aldol reaction of glyoxylate and alkyl aldehydes in high yield and enantioselectivity at room temperature. As compared to the reported simple primary amino acids, the 2-phenolic anilide can produce two hydrogen bonds from its phenolic hydroxy and amide groups with aldehyde moiety of ethyl glyoxylate, greatly enhancing the electrophilicity of ethyl glyoxylate and effectively increasing the asymmetric induction of the aldol reaction. Additionally, the large side group-bearing tert-leucine is also essential to high enantioselectivity. The reaction was successfully performed on 50 mmol scale with no decrease in the yield and enantioselectivity, showing potential for the chemical production of the pharmaceutical intermediate (R)-pantolactone with high yield and enantiopurity in an eco-friendly method.

Highly asymmetric aldol reaction of isatins and ketones catalyzed by chiral bifunctional primary-amine organocatalyst on water

“…Such catalysts are also highly soluble and catalytically active in organic solvents, as previously reported. 13 Primary amine catalysts B–E bearing alternative side groups were prepared from valine, leucine, isoleucine, and phenylalanine, respectively. These catalysts also exhibited excellent catalytic activities, with 3a being formed in high yields (94–96%) and diastereoselectivities (>98 : 2 dr).…”

Asymmetric Synthesis of Pantolactone: Recent Advances

“…Reproduced from ref. [95] Scheme 34. Aldol reaction between aldehydes and its synthetic application for synthesis of D-PL and it's analogs.…”

“…Moreover, in 2021, our group successfully developed an effective organocatalyst 108 based on 2-phenolaniline and tertleucine for the asymmetric aldol reaction between isobutyraldehyde and glyoxylate, which afforded D-PL precursors ent-5 aent-5 e (Scheme 33). [95] During this process, the catalyst loading was maintained at 10 mol%, and no additive was required. It was also possible to scale up the aldol reaction to 50 mmol without any loss in the asymmetric catalytic efficiency.…”