Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. For recent reviews on the enantioselective organocatalytic Michael reaction, see

    2. Parella R.; Jakkampudi S.; Zhao J. C.-G. Recent Applications of Asymmetric Organocatalytic Methods in Total Synthesis. ChemistrySelect 2021, 6, 2252–2280. 10.1002/slct.202004196. - DOI
    3. Scheffler U.; Mahrwald R. Recent Advances in Organocatalytic Methods for Asymmetric C–C Bond Formation. Chem.—Eur. J. 2013, 19, 14346–14396. 10.1002/chem.201301996. - DOI - PubMed
    4. Zhang Y.; Wang W. Recent Advances in Organocatalytic Asymmetric Michael Reactions. Catal. Sci. Technol. 2012, 2, 42–53. 10.1039/C1CY00334H. - DOI
    1. Allgäuer D. S.; Jangra H.; Asahara H.; Li Z.; Chen Q.; Zipse H.; Ofial A. R.; Mayr H. Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors. J. Am. Chem. Soc. 2017, 139 (38), 13318–13329. 10.1021/jacs.7b05106. - DOI - PubMed
    1. Gatzenmeier T.; Kaib P. S. J.; Lingnau J. B.; Goddard R.; List B. The Catalytic Asymmetric Mukaiyama-Michael Reaction of Silyl Ketene Acetals with α,β-Unsaturated Methyl Esters. Angew. Chem., Int. Ed. 2018, 57, 2464–2468. 10.1002/anie.201712088. - DOI - PubMed
    1. Shu C.; Liu H.; Slawin A. M. Z.; Carpenter-Warren C.; Smith A. D. Isothiourea-Catalysed Enantioselective Michael Addition of N-Heterocyclic Pronucleophiles to α,β-Unsaturated Aryl Esters. Chem. Sci. 2020, 11, 241–247. 10.1039/C9SC04303A. - DOI - PMC - PubMed
    1. Takaya Y.; Senda T.; Kurushima H.; Ogasawara M.; Hayashi T. Rhodium-catalyzed Asymmetric 1,4-Addition of Arylboron Reagents to α,β-Unsaturated Esters. Tetrahedron: Asymmetry 1999, 10, 4047–4056. 10.1016/S0957-4166(99)00417-6. - DOI
    2. Sakuma S.; Sakai M.; Itooka R.; Miyaura N. Asymmetric Conjugate 1,4-Addition of Arylboronic Acids to α,β-Unsaturated Esters Catalyzed by Rhodium(I)/(S)-Binap. J. Org. Chem. 2000, 65, 5951–5955. 10.1021/jo0002184. - DOI - PubMed