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. 2019 Oct 23;11(1):241-247.
doi: 10.1039/c9sc04303a.

Isothiourea-catalysed enantioselective Michael addition of N-heterocyclic pronucleophiles to α,β-unsaturated aryl esters

Chang Shu  1 , Honglei Liu  1 , Alexandra M Z Slawin  1 , Cameron Carpenter-Warren  1 , Andrew D Smith  1
Affiliations

Isothiourea-catalysed enantioselective Michael addition of N-heterocyclic pronucleophiles to α,β-unsaturated aryl esters

Chang Shu et al. Chem Sci. .

Abstract

The isothiourea-catalysed enantioselective Michael addition of 3-aryloxindole and 4-substituted-dihydropyrazol-3-one pronucleophiles to α,β-unsaturated p-nitrophenyl esters is reported. This process generates products containing two contiguous stereocentres, one quaternary, in good yields and excellent enantioselectivities (>30 examples, up to > 95 : 5 dr and 99 : 1 er). This protocol harnesses the multifunctional ability of p-nitrophenoxide to promote effective catalysis. In contrast to previous methodologies using tertiary amine Lewis bases, in which the pronucleophile was used as the solvent, this work allows bespoke pronucleophiles to be used in stoichiometric quantities.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Enantioselective Michael addition to α,β-unsaturated esters.
Fig. 1
Fig. 1. Screening of pronucleophiles. Isolated overall yields given; dr determined by 1H NMR spectroscopic analysis of crude mixture; er determined by chiral HPLC analysis of purified products and refers to er of major diastereoisomer.
Fig. 2
Fig. 2. (A–E) Scope and limitations: 3-aryloxindole pronucleophiles and α,β-unsaturated aryl esters.a Isolated overall yields given; dr determined by 1H NMR spectroscopic analysis of crude mixture; er determined by chiral HPLC analysis.b Reaction carried out at −40 °C.
Scheme 2
Scheme 2. Gram-scale experiment.
Scheme 3
Scheme 3. Proposed mechanism for the reaction.
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