Ni‐Catalyzed Regio‐ and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5‐Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis

• Published in: Angewandte Chemie International Edition Vol. 62; no. 50; pp. e202314865 - n/a
• Main Authors: Ghorai, Debasish, Garcia‐Roca, Aleria, Tóth, Balázs L., Benet‐Buchholz, Jordi, Kleij, Arjan W.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 11.12.2023; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Allylic Compounds; Asymmetric Synthesis; Bimetals; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; Coupling; Dienes; Enantiomers; Intermediates; Mechanistic Analysis; Nickel; Physical Sciences; Quaternary Stereocenters; Science & Technology; Allylic Compounds; 1,3-DIENES; COMPLEXES; C-C BONDS; OXIDATIVE ADDITION; REDUCTIVE ELIMINATION; HYDROALLYLATION; ALCOHOLS; STEREOCENTERS; CONSTRUCTION; Asymmetric Synthesis; Nickel; Quaternary Stereocenters; Mechanistic Analysis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202314865

Asymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio‐ and enantioselective synthesis of chiral 1,5‐dienes featuring quaternary stereocenters is reported via nickel‐promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo‐ and E‐selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)‐allyl intermediates empowering a unique formal bimetallic cross‐electrophile manifold in two separate kinetic regimes. A reductive cross‐electrophile coupling of allylic carbonates under Ni‐catalysis provides access to unique 1,5‐dienes featuring a quaternary stereogenic center under high chemo‐, regio‐, diastereo‐ and enantio‐control. Mechanistic studies align well with a catalytic cycle based on a Ni(0)/Ni(II) couple with a crucial role for divalent Zn boosting the overall kinetics and selectivity while favoring a key bimetallic C−C bond formation.