Scope, Limitations and Mechanistic Analysis of the HyperBTM‐Catalyzed Acylative Kinetic Resolution of Tertiary Heterocyclic Alcohols

• Published in: European journal of organic chemistry 2022-01, Vol.2022 (1), p.n/a
• Main Authors: Smith, Samuel M., Greenhalgh, Mark D., Feoktistova, Taisiia, Walden, Daniel M., Taylor, James E., Cordes, David B., Slawin, Alexandra M. Z., Cheong, Paul Ha‐Yeon, Smith, Andrew D.
• Format: Article
• Language: English
• Subjects: Acyl transfer; Acylation; Alcohol; Alcohols; Enantioselectivity; Kinetic resolution; Lewis base; Organocatalysis; Reaction mechanisms; Substitutes; Tertiary alcohol
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202101111

The full scope and limitations of the catalytic acylative kinetic resolution of a range of tertiary heterocyclic alcohols (78 examples, s up to >200) is reported under operationally‐simple conditions, using low loadings of a commercially available Lewis basic isothiourea catalyst, HyperBTM (generally 1 mol %). The protocol is highly effective for the kinetic resolution of 3‐substituted 3‐hydroxyoxindole and α‐substituted α‐hydroxylactam derivatives bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. The full power of this methodology has been showcased through the synthesis of highly enantioenriched biologically‐active target compounds in both enantiomeric forms. To provide further insight into the reaction mechanism, a detailed kinetic analysis of this Lewis base‐catalyzed acylation of tertiary alcohols is reported using the variable time normalization analysis (VTNA) method. The isothiourea HyperBTM catalyzes the acylative kinetic resolution of a wide range of tertiary heterocyclic alcohols under mild conditions with high selectivity. The synthetic utility of the methodology has been demonstrated with the preparation of two bioactive targets. Kinetic analysis reveals a fractional reaction order with respect to the alcohol concentration.