Highly Enantioselective Catalytic Vinylogous Propargylation of Coumarins Yields a Class of Autophagy Inhibitors

Abstract

A highly enantioselective copper-catalyzed vinylogous propargylic substitution has been developed. Aromatic and aliphatic propargylic esters react smoothly with substituted coumarins under mild reaction conditions to give the desired products with excellent yields and enantioselectivities. Subsequent single-step transformations enable the synthesis of a wide range of multifunctional and diverse compounds, and allow the efficient combination of different natural product fragments. Investigation of the obtained compound collection in cell-based assays monitoring changes in phenotype led to the discovery of a novel class of autophagy inhibitors.

Iridium-catalyzed enantioselective direct vinylogous allylic alkylation of coumarins

“…This structural motif is known for its presence in antifungal agents. 23 The absolute stereochemistry of 3aa , 6 and 7 has previously been confirmed by Waldmann et al 24 and in turn established the absolute configuration of our allylated products. Finally, an olefin cross-metathesis of 3aa with methyl acrylate in the presence of Grubbs' 2 nd generation catalyst occurred smoothly to give terminally functionalized olefin 8 in 75% yield.…”

Scope and advances in the catalytic propargylic substitution reaction

“…Antonchick and Waldmann's group has carried out an asymmetric vinylogous propargylation of substituted coumarins 174 using Cu(OTf) 2 -138 catalyst system, in 2017, Scheme 78 (Path B). 108 Screening of various chiral ligands like Cl-MeO-BIPHEP, i Pr-PyBOX, Fesulphos, i Pr-PHOX along with a copper catalyst gave poor yields and insignicant enantioselectivity. Finally, (S)-138-Cu(OTf) 2 catalyst combination in DIPEA medium at À40 C gave the excellent yields and good enantioselectivity.…”

“…Antonchick and Waldmann's group has carried out an asymmetric vinylogous propargylation of substituted coumarins 174 using Cu(OTf) 2 -138 catalyst system, in 2017, Scheme 78 (Path B). 108 …”

Highly Enantioselective Catalytic Vinylogous Propargylation of Coumarins Yields a Class of Autophagy Inhibitors

“…Thecyano group in coumarins is important for formation of products.C oumarins with ester or amide groups at C3 were not reactive.T he structure as well as absolute configuration of substitution products were unambiguously established by single-crystal X-ray analysis of 3d and 4j. [17] To further demonstrate the utility of the newly developed methodology,i tw as applied in the synthesis of an aturalproduct-based compound collection (Scheme 4). Sonogashira coupling proceeded smoothly to afford 5 in 89 %y ield.…”