Merger of Visible Light‐Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α‐Alkylation of Aldehydes

• Published in: Advanced synthesis & catalysis Vol. 365; no. 10; pp. 1660 - 1670
• Main Authors: Molnár, Márk, Kappe, C. Oliver, Ötvös, Sándor B.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 23.05.2023; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Aldehydes; Alkylation; Asymmetric synthesis; Asymmetry; Catalysts; Chemical reactions; Chemistry; Chemistry, Applied; Chemistry, Organic; Continuous flow; Enantiomers; Optimization; Organocatalysis; Photochemistry; Photoredox catalysis; Physical Sciences; Science & Technology; α-Alkylation; ACID; PHOTOCATALYSIS; CASCADE; Organocatalysis; IMINIUM; Continuous flow; PHOTOREDOX CATALYSIS; Asymmetric synthesis; PHOTOCHEMICAL ACTIVITY; TRANSITION-METAL; ASYMMETRIC ALKYLATION; alpha-Alkylation; Photochemistry; α-Alkylation
• ISSN: 1615-4150; 1615-4169
• DOI: 10.1002/adsc.202300289

The electron donor‐acceptor complex‐enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α‐alkylated aldehydes without an external photoredox catalyst. The photosensitizer‐free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α‐alkylation of aldehydes based on the synergistic combination of visible light‐driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer‐free enantioselective α‐alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α‐alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.