Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution of Tetra‐substituted Morpholinone and Benzoxazinone Lactols DOI Creative Commons
Haoxiang Zhu, Alejandro Manchado, Abdikani Omar Farah

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(37)

Published: May 7, 2024

Abstract The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) tetra‐substituted lactols is a recognised synthetic challenge. In this manuscript, highly enantioselective isothiourea‐catalysed DKR morpholinone and benzoxazinone‐derived reported. scope limitations methodology have been developed, with high enantioselectivity good excellent yields (up 89 %, 99 : 1 er) observed across broad range substrate derivatives incorporating substitution at N(4) C(2), di‐ spirocyclic C(5) C(6), as well benzannulation (>35 examples in total). process amenable scale‐up on g laboratory scale. factors leading selectivity probed through computation, an N−C=O⋅⋅⋅isothiouronium interaction identified key producing ester products enantioenriched form.

Language: Английский

Enantioselective Synthesis of Tetra‐substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution DOI Creative Commons
Shubham Agrawal, Pankaj Kumar Majhi, Alister S. Goodfellow

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(37)

Published: May 7, 2024

Abstract A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2 S ,3 R )‐HyperBTM (5 mol %) as catalyst, scope limitations this methodology have been extensively probed, with high enantioselectivity good to excellent yields observed (>40 examples, up 99 %, : 1 er). Substitution aromatic core within skeleton, well aliphatic substitution at C(3), readily tolerated. diverse range anhydrides, including those from bioactive pharmaceutically relevant acids, can also be used. The in DKR process has probed computationally, a key substrate heteroatom donor O⋅⋅⋅acyl‐isothiouronium interaction identified through DFT analysis necessary enantiodiscrimination.

Language: Английский

Citations

5
Rational Design of Bifunctional Imidazoles as Acyl Transfer Catalysts: Dynamic Kinetic Resolution of 5-Hydroxy-furanones/3-Hydroxy-phthalides DOI

Meng Shan,

Yongmei Yu,

Shuping Yang

et al.

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

A new class of chiral bifunctional imidazole catalysts has been designed and synthesized, utilizing economical amino alcohols as precursors, significantly expanding the diversity N-1 position catalysts. These exhibit excellent substrate activation stereoselectivity control have successfully employed in asymmetric acylation 5-hydroxy-furanones/3-hydroxy-phthalides through dynamic kinetic resolution, producing a series furanone phthalide analogues featuring quaternary stereocenter. This reaction exhibits reactivity enantioselectivity, wide range applicability, requires low catalyst loading, can be readily converted into valuable building blocks. Moreover, DFT calculations revealed detailed mechanism demonstrated that weak N-H···O C-H···O interactions between are key factors affecting stereoselectivity.

Language: Английский

Citations

0
Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution of Tetra‐substituted Morpholinone and Benzoxazinone Lactols DOI Creative Commons
Haoxiang Zhu, Alejandro Manchado, Abdikani Omar Farah

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(37)

Published: May 7, 2024

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, highly enantioselective isothiourea-catalysed DKR morpholinone and benzoxazinone-derived reported. scope limitations methodology have been developed, with high enantioselectivity good excellent yields (up 89 %, 99 : 1 er) observed across broad range substrate derivatives incorporating substitution at N(4) C(2), di- spirocyclic C(5) C(6), as well benzannulation (>35 examples in total). process amenable scale-up on g laboratory scale. factors leading selectivity probed through computation, an N-C=O⋅⋅⋅isothiouronium interaction identified key producing ester products enantioenriched form.

Language: Английский

Citations

3
Carbene‐Catalyzed Asymmetric Acetalization to Access Chiral 3‐Aryloxyphthalides DOI
Chengli Mou, Guangping Liang, Haiyan Xu

et al.

Chemistry - An Asian Journal, Journal Year: 2025, Volume and Issue: unknown

Published: May 16, 2025

Abstract Chiral acetals, particularly aryloxyacetals, are pivotal intermediates in organic synthesis, pharmaceuticals, and natural product synthesis. Aryloxyacetals have been utilized as chiral aldehyde equivalents the total synthesis of biologically significant products. However, achieving high enantiocontrol aryloxyphthalides remains a challenge due to side reactions racemic formation. Herein, we report novel N ‐heterocyclic carbene (NHC)‐catalyzed enantioselective from phthalaldehyde phenols. Our methodology demonstrates broad substrate scope, providing up 98% enantioselectivity with excellent yields. This strategy offers practical solution for aryloxyphthalides, expanding utility acetals asymmetric The development optically pure may further benefit complex products containing phthalide moieties.

Language: Английский

Citations

0
Enantioselective Synthesis of Tetra‐substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution DOI Creative Commons
Shubham Agrawal, Pankaj Kumar Majhi, Alister S. Goodfellow

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(37)

Published: May 7, 2024

Abstract A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2 S ,3 R )‐HyperBTM (5 mol %) as catalyst, scope limitations this methodology have been extensively probed, with high enantioselectivity good to excellent yields observed (>40 examples, up 99 %, : 1 er). Substitution aromatic core within skeleton, well aliphatic substitution at C(3), readily tolerated. diverse range anhydrides, including those from bioactive pharmaceutically relevant acids, can also be used. The in DKR process has probed computationally, a key substrate heteroatom donor O⋅⋅⋅acyl‐isothiouronium interaction identified through DFT analysis necessary enantiodiscrimination.

Language: Английский

Citations

0
Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution of Tetra‐substituted Morpholinone and Benzoxazinone Lactols DOI Creative Commons
Haoxiang Zhu, Alejandro Manchado, Abdikani Omar Farah

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(37)

Published: May 7, 2024

Abstract The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) tetra‐substituted lactols is a recognised synthetic challenge. In this manuscript, highly enantioselective isothiourea‐catalysed DKR morpholinone and benzoxazinone‐derived reported. scope limitations methodology have been developed, with high enantioselectivity good excellent yields (up 89 %, 99 : 1 er) observed across broad range substrate derivatives incorporating substitution at N(4) C(2), di‐ spirocyclic C(5) C(6), as well benzannulation (>35 examples in total). process amenable scale‐up on g laboratory scale. factors leading selectivity probed through computation, an N−C=O⋅⋅⋅isothiouronium interaction identified key producing ester products enantioenriched form.

Language: Английский

Citations

0