Enantioselective synthesis of 4,5-disubstituted pyrrolidin-2-one derivatives with two stereocenters on the basis of Mich
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Enantioselective synthesis of 4,5-disubstituted pyrrolidin-2-one derivatives with two stereocenters on the basis of Michael adducts Natalja Orlova1*, Maxim Vorona1, Vladislavs Baskevics1, Marina Petrova1, Sergey Belyakov1, Helena Kazoka1, Ruslan Muhamadejev1, Grigory Veinberg1* 1
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia; e-mail: veinberg @osi.lv Submitted February 3, 2020 Accepted after revision March 30, 2020
Published in Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(8), 997–1009
The addition of malonates to trans-β-alkyl-β-nitrostyrenes in the presence of chiral Mg2+ bisoxazoline complex and Ni2+ and Co2+ bis((S,S)- or (R,R)-N,N'-dibenzylcyclohexane-1,2-diamine) complexes resulted in the formation of Michael adducts with two stereocenters which were used as key precursors for the preparation of potentially biologically active enantiopure 4,5-disubstituted pyrrolidin2-one derivatives. Keywords: chiral Mg2+, Ni2+, and Co2+ complexes, 4,5-disubstituted pyrrolidin-2-ones, Michael adduct, asymmetric catalysis.
were obtained by the resolution of racemic molecules or by asymmetric synthesis in the presence of chiral catalysts.1–5 The addition of a vicinal chiral center to the carbon skeleton of 2-pyrrolidinones 5–8 doubled the number of possible chiral enantiomers. The synthetic problems that arose during their preparation were also successfully solved by the usage of chiral catalysts, resulting in the formation of a pair of diastereoisomeric adducts usually as a mixture of syn and anti isomers suitable for their conversion into the target products.6–8 A similar approach was developed for clausenamide 8 with three chiral centers in pyrrolidin2-one heterocycle.9 In general, the majority of published data devoted to this problem have focused on the preparation of type I–IV adducts with one or two chiral centers that were successfully used as precursors in the preparation of monoor disubstituted linear or cyclic GABA analogs with potential pharmaceutical application (Fig. 2).
According to structure–activity relationships, the biological and pharmacological effectiveness of chiral γ-aminobutyric acid (GABA) and its cyclic pyrrolidin-2-one derivatives at the molecular level depends on the configuration of substituents providing optimal interaction with an appropriate receptor. Identification of stereoisomer with such properties usually involves the development of synthetic methodology suitable for the preparation of all possible isomers and their comparable biological testing. It explains the constant interest in the search for efficient chiral catalysts for the preparation of chiral Michael adducts and their subsequent conversion into biologically active compounds. The above-mentioned conditions fully apply to investigations aimed at the synthesis of chiral drugs and biologically active compounds 1–8 on the basis of linear and cyclic GABA derivatives (Fig. 1). In the case of drugs 1–4 with one chiral center, their individual R- or S-enantiomers 0009-3122/20/56(8)-0997©2020 Spri
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