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. 2022 Jun 10;24(22):4040-4045.
doi: 10.1021/acs.orglett.2c01486. Epub 2022 Jun 2.

Isothiourea-Catalyzed Enantioselective Michael Addition of Malonates to α,β-Unsaturated Aryl Esters

Jiufeng Wu  1 , Claire M Young  1 , Amy A Watts  1 , Alexandra M Z Slawin  1 , Gregory R Boyce  2 , Michael Bühl  1 , Andrew D Smith  1
Affiliations

Isothiourea-Catalyzed Enantioselective Michael Addition of Malonates to α,β-Unsaturated Aryl Esters

Jiufeng Wu et al. Org Lett. .

Abstract

An enantioselective Michael addition of malonates to α,β-unsaturated para-nitrophenyl esters was achieved using the Lewis basic isothiourea HyperBTM, giving excellent levels of product enantioselectivity (up to >99:1 enantiomeric ratio) in good yields and with complete regioselectivity (>20:1 regioselectivity ratio) in the presence of alternative (phenyl ketone and ethyl ester) Michael acceptors. Density functional theory calculations indicate that N-acylation is rate-limiting. This constitutes a rare example of a highly enantioselective addition of simple, readily available malonates to α,β-unsaturated esters.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Selected Examples of Chiral Amine-Catalyzed Michael Reaction/Cyclization Cascades with Malonate Derivatives and Comparison to This Work
Scheme 2
Scheme 2. Scope and Limitations of Dimethyl Malonate Addition to α,β-Unsaturated Esters
(2R,3S)-HyperBTM was used, and the product has the opposite absolute configuration to that shown. All yields are isolated yields after purification by column chromatography. Enantiomeric ratios are determined by HPLC analysis on a chiral stationary phase. PNP, p-nitrophenyl; TCP, 2,4,6-trichlorophenyl.
Scheme 3
Scheme 3. Scope and Limitations of the Addition of Nucleophiles to β-Trifluoromethyl α,β-Unsaturated PNP Ester
(2R,3S)-HyperBTM was used, and the product has the opposite absolute configuration to that shown. In MeCN, and 10% diisopropylethyl amine was added. Complete in 5 h. Complete in 3 h. All yields are isolated yields after purification by column chromatography. Enantiomeric ratios are determined by HPLC analysis on a chiral stationary phase.
Scheme 4
Scheme 4. Proposed Catalytic Cycle [M06-2X/6-31G(d,p)/IEFPCM Optimized]: TS to (S)-Product Enantiomer
See this image and copyright information in PMC

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