Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

Abstract: The development of methods for the selective acylative kinetic resolution (KR) of tertiary alcohols is a recognised synthetic challenge with relatively few successful substrate classes reported to date. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative KR of tertiary pyrazolone alcohols is reported. The scope and limitations of this methodology have been developed, with high selectivity observed across a broad range of substrate derivatives incorporating varying substitution at N (2)‐, C (4)‐ and C (5)‐, as well as bicyclic constraints within the pyrazolone scaffold (30 examples, selectivity factors (s) typically >100) at generally low catalyst loadings (1 mol %). The application of this KR method to tertiary alcohols derived directly from a natural product (geraniol), alongside pharmaceutically relevant drug compounds (indomethacin, gemfibrozil and probenecid), with high efficiency (s >100) is also described. The KR process is readily amenable to scale up using bench grade solvents and reagents, with effective resolution on a 50 g (0.22 mol) scale demonstrated. The key structural motif leading to excellent selectivity in this KR process has been probed through computation, with an NC=O⋅⋅⋅isothiouronium interaction from substrate to acylated catalyst observed within the favoured transition state. Similarly, the effect of C (5)‐aryl substitution that leads to reduced experimental selectivity is probed, with a competitive π–isothiouronium interaction identified as leading to reduced selectivity.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols ; day:30 ; month:10 ; year:2024 ; extent:9 ; Angewandte Chemie / International edition. International edition ; (30.10.2024) (gesamt 9)

Contributors, Places and Time

• Creator: Westwood, Matthew T. ; Omar Farah, Abdikani ; Wise, Henry B. ; Sinfield, Mike ; Robichon, Camille ; Prindl, Martha I. ; Cordes, David B. ; Ha‐Yeong Cheong, Paul ; Smith, Andrew D.

Further information

• DOI: 10.1002/anie.202407983
• URN: urn:nbn:de:101:1-2410301359232.986531340633
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:25 AM CEST