ArPNO-catalyzed acylative kinetic resolution of tertiary alcohols: access to 3-hydroxy-3-substituted oxindoles

Yang, Min; Gao, Yuwei; Xie, Ming‐Sheng; Guo, Hai‐Ming

doi:10.1039/d2ob01205g

“…Spivey and co-workers were the first to report the preparation of chiral DMAP- N -oxides, featuring oxygen as the nucleophilic site, for the application of enantioselective N -sulfonylation . Afterward, our research group reported the utilization of chiral 3-substituted DMAP- N -oxides, 2-substituted DMAP- N -oxides, and 4-aryl-pyridine- N -oxide (ArPNO) as acyl transfer catalysts . Therefore, we assume that such chiral pyridine- N -oxides might be applied as acyl transfer catalysts for the desymmetrization of meso -1,2-diols via acylation.…”

Section: Introductionmentioning

confidence: 99%

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides

Lian,

Li,

Tian

et al. 2023

J. Org. Chem.

0

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Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

Westwood,

Omar Farah,

Wise

et al. 2024

Angewandte Chemie

0

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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 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, 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 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.

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Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

Westwood,

Omar Farah,

Wise

et al. 2024

Angew Chem Int Ed

0

View full text Add to dashboard Cite

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 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, 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 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.

show abstract

ArPNO-catalyzed acylative kinetic resolution of tertiary alcohols: access to 3-hydroxy-3-substituted oxindoles

Abstract: Bifunctional chiral 4-aryl-pyridine-N-oxides (ArPNO) were reported for the acylative kinetic resolution of 3-hydroxy-3-substituted oxindoles，where the oxygen acts as the nucleophilic site. Using less sterically hindered acetic anhydride, both the recovered...

Cited by 3 publications

References 38 publications

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides

Reversal of Enantioselectivity for the Desymmetrization of meso-1,2-Diols Catalyzed by Pyridine-N-oxides

Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

Isothiourea‐Catalysed Acylative Kinetic Resolution of Tertiary Pyrazolone Alcohols

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