One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.

Alastair Nimmo; Kevin Kasten; George White; Julia Roeterdink; Aidan McKay; David Bradford Cordes; Andrew David Smith

doi:10.3390/molecules29153635

One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.

Alastair Nimmo, Kevin Kasten, George White, Julia Roeterdink, Aidan McKay, David Bradford Cordes, Andrew David Smith^*

^*Corresponding author for this work

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

Abstract

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and ox-indole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereoselectivity (up to >95:5 dr and >99:1 er).

Original language	English
Article number	3635
Number of pages	16
Journal	Molecules
Volume	29
Issue number	15
DOIs	https://doi.org/10.3390/molecules29153635
Publication status	Published - 31 Jul 2024

Keywords

Malamides
Organocatalysis
Isothiourea
Lactone ring-opening
Oxindole ring-opening
Asymmetric synthesis
[2+2] cycloaddition

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10.3390/molecules29153635Licence: CC BY

Nimmo-2024-One-pot-access-Molecules-29-03635-CCBY
Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Final published version, 521 KBLicence: CC BY

https://www.mdpi.com/1420-3049/29/15/3635Licence: CC BY

1 Finished
1 Active

Allan Watson Programme Grant: Boron: Beyond the Reagent
Watson, A. J. B. (PI), Morris, R. E. (CoI), Smith, A. D. (CoI) & Zysman-Colman, E. (CoI)
UK Research and Innovation
1/05/23 → 30/04/28
Project: Standard
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

One-pot Access to Functionalised Malamides via Organocata-lytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-opening (dataset)
Smith, A. D. (Creator), Kasten, K. (Owner), Nimmo, A. (Owner), Cordes, D. B. (Owner), McKay, A. (Owner), Roeterdink, J. (Creator) & White, G. (Creator), University of St Andrews, 9 Aug 2024
DOI: 10.17630/c2137162-53d3-4722-bc51-ae2ee579ce61
Dataset

File

Cite this

@article{c0bbe3ad2c9c4b42bdc834aa24f13b7d,

title = "One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.",

abstract = "Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and ox-indole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereoselectivity (up to >95:5 dr and >99:1 er).",

keywords = "Malamides, Organocatalysis, Isothiourea, Lactone ring-opening, Oxindole ring-opening, Asymmetric synthesis, [2+2] cycloaddition",

author = "Alastair Nimmo and Kevin Kasten and George White and Julia Roeterdink and Aidan McKay and Cordes, {David Bradford} and Smith, {Andrew David}",

note = "Funding: The research leading to these results has received funding from the EPSRC (K.K., EP/T023643/1) and the EaSI-CAT centre for Doctoral Training (A.J.N.). A.D.S. and K.K. thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.",

year = "2024",

month = jul,

day = "31",

doi = "10.3390/molecules29153635",

language = "English",

volume = "29",

journal = "Molecules",

issn = "1420-3049",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "15",

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TY - JOUR

T1 - One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.

AU - Nimmo, Alastair

AU - Kasten, Kevin

AU - White, George

AU - Roeterdink, Julia

AU - McKay, Aidan

AU - Cordes, David Bradford

AU - Smith, Andrew David

N1 - Funding: The research leading to these results has received funding from the EPSRC (K.K., EP/T023643/1) and the EaSI-CAT centre for Doctoral Training (A.J.N.). A.D.S. and K.K. thank the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support.

PY - 2024/7/31

Y1 - 2024/7/31

N2 - Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and ox-indole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereoselectivity (up to >95:5 dr and >99:1 er).

AB - Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and ox-indole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereoselectivity (up to >95:5 dr and >99:1 er).

KW - Malamides

KW - Organocatalysis

KW - Isothiourea

KW - Lactone ring-opening

KW - Oxindole ring-opening

KW - Asymmetric synthesis

KW - [2+2] cycloaddition

U2 - 10.3390/molecules29153635

DO - 10.3390/molecules29153635

M3 - Article

SN - 1420-3049

VL - 29

JO - Molecules

JF - Molecules

IS - 15

M1 - 3635

ER -

One-pot access to functionalised malamides via organocatalytic enantioselective formation of spirocyclic β-lactone-oxindoles and double ring-opening.

Abstract

Keywords

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Projects

Allan Watson Programme Grant: Boron: Beyond the Reagent

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

Datasets

One-pot Access to Functionalised Malamides via Organocata-lytic Enantioselective Formation of Spirocyclic β-Lactone-Oxindoles and Double Ring-opening (dataset)

Cite this