Copper-Catalyzed Chemoselective and Enantioselective Friedel–Crafts 1,2-Addition of Pyrrole with β,γ-Unsaturated α-Ketoesters

Abstract

A Friedel-Crafts alkylation of pyrrole was developed to afford the β,γ-unsaturated α-hydroxy esters bearing a quaternary stereogenic center with good enantioselectivities and yields. This protocol represents the first report of 1,2-addition of Friedel-Crafts alkylation of pyrrole to β,γ-unsaturated α-ketoesters.

Recent Advances in Metal‐ and Organocatalyzed Asymmetric Functionalization of Pyrroles

“…As evident from experimental results and their previous mechanism (see Scheme 26) [85] a stereochemical model was proposed by the authors which mainly involves the bifunctional mode of activation between the catalyst and the substrates (Scheme 32). Generally, the dinuclear dimeric water-soluble copper complex was generated in situ from CuBr 2 and L14 which in turn dissociated into the monomers in situ and involves the coordination with the substrates.…”

“…These results represent the first enantioselective 1,2-addition of pyrroles to β,γ-unsaturated αketoesters (Scheme 26). [85] With the help of 10 mol% of CuBr 2 and 10 mol% of L10 as the catalyst complex, the Friedel-Crafts adduct 68 bearing quaternary chiral centers were obtained in good yield and enantioselectivity. With substrates bearing two distinct electrophilic sites, this reaction displayed remarkable regioselectivity as only the product of 1,2-addition could be obtained.…”

“…Consequently, a stereochemical model was projected to realized this direct alkylation of the pyrrole ring to the Re-face of the β,γ-unsaturated α-ketoesters via TS-68 (Scheme 26). [85]…”

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…Pyrroles could readily react with various electrophilic reagents bearing prochiral centers to give enantiomerically enriched pyrrole derivatives, taking advantage of the electron-rich aromatic rings. In 2017, the Wang group reported a copper catalyzed asymmetry 1,2-addition reaction of β,γ -unsaturated α -ketoesters 1d with pyrrole, as opposite to the previous 1,4-addition ( Scheme 5 B) ( Sun et al., 2017 ). The desired products 44 were obtained in moderate to good yields (33–77%) with excellent enantioselectivities (75–90% ee), under the catalysis of copper-complex.…”

New Application of β,γ-Unsaturated α-Ketoesters in Asymmetric Catalysis

“…图式 36 β,γ-不饱和 α-酮酸酯的不对称炔基化反应 Scheme 36 Catalytic asymmetric conjugate alkynylation of β,γ-unsaturated α-ketoester 在过去已经有了比较系统的报道 [46～49] , 所以近年来相 关文献相对较少. 2017 年, 汪志勇课题组 [50] 报道了 CuBr 2 与手性小分子 C36 络合物催化的 β,γ-不饱和 α-酮 酸酯中羰基与吡咯 83 的不对称 Friedel-Crafts 反应 (Scheme 37), 获得了中等收率(33%～77%)和高对映选 择性(75%～90% ee), 实现了吡咯与 β,γ-不饱和 α-酮酸酯 中羰基的 1,2-加成, 但是在最优条件下, 当使用 N-甲基 保护的吡咯作为底物时反应不能发生.…”