Direct, Stereodivergent, and Catalytic Michael Additions of Thioimides to α,β‐Unsaturated Aldehydes – Total Synthesis of Tapentadol

• Published in: Angewandte Chemie International Edition 2024-03, Vol.63 (12), p.e202319308-n/a
• Main Authors: Galeote, Oriol, Kennington, Stuart C. D., Benedito, Gabriela, Fraedrich, Lena, Davies‐Howe, Evan, Costa, Anna M., Romea, Pedro, Urpí, Fèlix, Aullón, Gabriel, Font‐Bardia, Mercè, Puigjaner, Cristina
• Format: Article
• Language: English
• Subjects: Aldehydes; asymmetric catalysis; Asymmetric synthesis; Bioactive compounds; Biological activity; Enantiomers; Michael addition; Nickel; nickel complexes; stereodivergent synthesis; Stereoisomerism; Stereoisomers; Synthesis; tapentadol
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202319308

Direct and stereodivergent Michael additions of N‐acyl 1,3‐thiazinane‐2‐thiones to α,β‐unsaturated aldehydes catalyzed by chiral nickel(II) complexes are reported. The reactions proceed with a remarkable regio‐, diastereo‐, and enantioselectivity, so access to any of the four potential Michael stereoisomers is granted through the appropriate choice of the chiral ligand of the nickel(II) complex. Simple removal of the heterocyclic scaffold furnishes a wide array of either syn or anti enantiomerically pure derivatives, which can be exploited for the asymmetric synthesis of biologically active compounds, as demonstrated in a new approach to tapentadol. In turn, a mechanism, based on theoretical calculations, is proposed to account for the stereochemical outcome of these transformations. The direct, triisopropy silyl triflate (TIPSOTf)‐mediated, regioselective and stereodivergent Michael additions of thioimides to α,β‐unsaturated aldehydes catalyzed by chiral nickel complexes give any of the potential syn and anti diastereomers, at will, with good to high yields. The resultant adducts can be easily transformed into a wide array of enantiomerically pure intermediates ready to participate in the asymmetric synthesis of biologically active compounds.