Isothiourea-catalysed acylative dynamic kinetic resolution of tetra-substituted morpholinone and benzoxazinone lactols

Haoxiang Zhu; Alejandro Manchado; Abikani Omar  Farah; Aidan McKay; David Bradford Cordes; Paul Ha-Yeon  Cheong; Kevin Kasten; Andrew David Smith

doi:10.1002/anie.202402908

Isothiourea-catalysed acylative dynamic kinetic resolution of tetra-substituted morpholinone and benzoxazinone lactols

Haoxiang Zhu, Alejandro Manchado, Abikani Omar Farah, Aidan McKay, David Bradford Cordes, Paul Ha-Yeon Cheong^*, Kevin Kasten^*, Andrew David Smith^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

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

Original language	English
Article number	e202402908
Number of pages	10
Journal	Angewandte Chemie International Edition
Volume	63
Issue number	37
Early online date	6 Aug 2024
DOIs	https://doi.org/10.1002/anie.202402908
Publication status	Published - 9 Sept 2024

Keywords

Isothiourea
Dynamic kinetic resolution
Tetra-substituted morpholinone lactol
Acyclation
Enanioselective

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Zhu_2024_AC_Isothiourea‐catalysed-acylative-dynamic-kinetic-resolution_CC
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Final published version, 26.7 MBLicence: CC BY

Exploiting Chalcogen Bonding and Non: Exploiting Chalcogen Bonding and Non-Covalent Interactions in Isochalcogenourea Catalysis: Catalyst Preparation, Mechanistic Studies and Applications
Smith, A. D. (PI)
1/11/20 → 31/10/23
Project: Standard

data underpinning "Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols"
Smith, A. D. (Creator), Zhu, H. (Creator), Manchado, A. (Creator), McKay, A. (Creator), Cordes, D. B. (Creator), Kasten, K. (Creator), Ha-Yeon Cheong, P. (Creator) & Farah, A. (Creator), University of St Andrews, 26 Jan 2024
DOI: 10.17630/be31964f-f256-4aeb-92cc-5598add7e635
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title = "Isothiourea-catalysed acylative dynamic kinetic resolution of tetra-substituted morpholinone and benzoxazinone lactols",

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

keywords = "Isothiourea, Dynamic kinetic resolution, Tetra-substituted morpholinone lactol, Acyclation, Enanioselective",

author = "Haoxiang Zhu and Alejandro Manchado and Farah, {Abikani Omar} and Aidan McKay and Cordes, {David Bradford} and Cheong, {Paul Ha-Yeon} and Kevin Kasten and Smith, {Andrew David}",

note = "Funding: The research leading to these results has received funding from the CSC St Andrews Scheme (PhD Scholarship to H.Z.), and the EPSRC (K.K., EP/T023643/1). The authors thank the University of Salamanca, the Spanish Government and European Union for a Margarita Salas grant (Orden UNI/551/2021, A.M.). P.H.-Y.C. and A. O. F gratefully acknowledge financial support from the Bert and Emelyn Christensen and the Stone Family of OSU. A.O.F. acknowledges the Larry W. Martin & Joyce B. O'Neill Endowed Fellowship of OSU. A.O.F. and P.H.-Y.C. acknowledge computing infrastructure in part provided by the National Science Foundation (NSF) CHE-1352663 and NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (CHE-1102637).",

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doi = "10.1002/anie.202402908",

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T1 - Isothiourea-catalysed acylative dynamic kinetic resolution of tetra-substituted morpholinone and benzoxazinone lactols

AU - Zhu, Haoxiang

AU - Manchado, Alejandro

AU - Farah, Abikani Omar

AU - McKay, Aidan

AU - Cordes, David Bradford

AU - Cheong, Paul Ha-Yeon

AU - Kasten, Kevin

AU - Smith, Andrew David

N1 - Funding: The research leading to these results has received funding from the CSC St Andrews Scheme (PhD Scholarship to H.Z.), and the EPSRC (K.K., EP/T023643/1). The authors thank the University of Salamanca, the Spanish Government and European Union for a Margarita Salas grant (Orden UNI/551/2021, A.M.). P.H.-Y.C. and A. O. F gratefully acknowledge financial support from the Bert and Emelyn Christensen and the Stone Family of OSU. A.O.F. acknowledges the Larry W. Martin & Joyce B. O'Neill Endowed Fellowship of OSU. A.O.F. and P.H.-Y.C. acknowledge computing infrastructure in part provided by the National Science Foundation (NSF) CHE-1352663 and NSF Phase-2 CCI, Center for Sustainable Materials Chemistry (CHE-1102637).

PY - 2024/9/9

Y1 - 2024/9/9

N2 - The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N−C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

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

KW - Isothiourea

KW - Dynamic kinetic resolution

KW - Tetra-substituted morpholinone lactol

KW - Acyclation

KW - Enanioselective

U2 - 10.1002/anie.202402908

DO - 10.1002/anie.202402908

M3 - Article

SN - 1433-7851

VL - 63

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 37

M1 - e202402908

ER -

Isothiourea-catalysed acylative dynamic kinetic resolution of tetra-substituted morpholinone and benzoxazinone lactols

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Keywords

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Exploiting Chalcogen Bonding and Non: Exploiting Chalcogen Bonding and Non-Covalent Interactions in Isochalcogenourea Catalysis: Catalyst Preparation, Mechanistic Studies and Applications

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data underpinning "Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols"

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