Chiral Phosphoric Acid Catalyzed Desymmetrization of Cyclopentendiones via Friedel–Crafts Conjugate Addition of Indolizines

Abstract

An organocatalytic highly diastero-and enantioselective Friedel−Crafts conjugate addition of indolizines to prochiral cyclopentenediones has been successfully developed. This desymmetric transformation provides a direct access to the desired indolizine-substituted cyclopentanediones in yields of 62−91% and excellent stereoselectivities. The utility of the approach was demonstrated by diverse late-stage functionalizations through reduction or oxidation. Importantly, the direct sp 2 C−H functionalization with nitromethane in one-pot process resulted in the indolizine-linked axially chiral styrene bearing a remote chiral center.

Indolizine: A Promising Framework for Developing a Diverse Array of C−H Functionalized Hybrids

“…Ni et al [55] . developed a methodology for the conjugate addition of indolizines to cyclopentadiones (74) .…”

“…The Me, Et, and OMe groups were well tolerated at the indolizines and afforded moderate yield of the desired product. Further various electron-donating as well as -withdrawing groups were well tolerated at the aryl ring of 2-phenylindolizines Ni et al [55] developed a methodology for the conjugate addition of indolizines to cyclopentadiones (74). To define the optimized conditions, cyclopentene-1,3-dione (74) and indolizine (1) were utilised as substrates, and their reaction was attempted in DCM using CPA (5 mol%) as catalyst.…”

Formal [5 + 2] cycloaddition of ortho-indolizinyl anilines with cyclopentenediones: access to planar indolizine-fused azepines

“…12 Our group recently realized a chiral phosphoric acid (CPA)-catalyzed desymmetrization of prochiral cyclopentene-1,3-diones via direct Friedel–Crafts conjugate addition of indolizines. 13 As part of our ongoing interest in the functionalization of indolizines, herein we wish to disclose a formal [5 + 2] cycloaddition of ortho -indolizinyl anilines and cyclopentene-1,3-diones. With a Brønsted acid (BA) as the catalyst, a tandem reaction involving Friedel–Crafts addition, oxidation and Schiff-base condensation processes occurred, which resulted in polycyclic indolizine-fused azepines under mild conditions (Scheme 1c).…”

Chiral Phosphoric Acid-Catalyzed Asymmetric Friedel–Crafts Addition of Indolizine to Cyclic N-Sulfonyl Imine

“…Recently, List and co-workers demonstrated the first organocatalyzed asymmetric conjugate addition of indolizines to enones with the use of a chiral phosphoric acid (Scheme a) . Similar strategy was employed by Song to develop a highly diastereoselective desymmetrization of cyclopentadienones (Scheme b) and the same group has recently reported the atroposelective functionalization of indolizines (Scheme c) . Despite these efforts, alternate electrophilic functionalities to access chiral indolizines have rarely been explored .…”