Enantioselective Synthesis of Polycyclic Coumarin Derivatives Catalyzed by anin SituFormed Primary Amine-Imine Catalyst

Abstract

A facile in situ formed primary amine-imine organocatalyst was developed in the asymmetric Michael addition of substituted 4-hydroxycoumarins to cyclic enones. A series of optically active polycyclic coumarin derivatives were obtained in high yields with excellent enantioselectivities up to 97% ee.Coumarin derivatives are distributed in a large number of natural products and are commonly used as versatile intermediates in natural product synthesis. 1 Modification of this class of compound has been of great interest to chemists due to their various biological activities to antimalarial, anticoagulant, and anti-HIV activities, etc. 2 Although most of coumarin derivatives are currently prescribed as the racemate, activity and metabolism are markedly dissimilar for the two enantiomers. 3 Therefore, efficient asymmetric syntheses of coumarins are of longstanding interest. 4 Organocatalysis has proven itself a valuable strategy in the preparation of the synthesis of optically active coumarins 5 since Jørgensen reported a onestep synthesis of enantiomerically pure warfarin in 2003. 6 They presented the first example of an imidazolidine organocatalyst promoted asymmetric Michael reaction of coumarin and R,β-unsaturated ketones. 7 Chin and Chen

Catalytic methods of creation and functionalization of the coumarin skeleton

“…4-Hydroxycoumarins under organocatalysis conditions interact effectively with α,β-unsaturated ketones [68,69] in the presence of chiral ethylenediimine catalysts.…”

Asymmetric Organocatalysis at the Service of Medicinal Chemistry

“…Subsequent efforts with simple primary diamine catalysts were directed [103] at improving the practical applicability of this reaction and included the discovery that the catalyst loading of phenylenediamine XX could be lowered by exploiting a combination of Lewis (lithium perchlorate) and Brønsted (acetic acid) acid cocatalysts in the reaction (entry 3) and that water as reaction medium under ultrasound activation [104] provided a fast protocol allowing the isolation of warfarin in essentially enantiopure form by simple filtration of the reaction mixture (entry 4). Variations in the phenylenediamine motif by functionalization of one of the amines have also been reported and include the monoamine XXI , generated in situ by acidic hydrolysis from a corresponding diimine [105], and the monophosphonamide XXII [106]. …”

Metal-mediated aminocatalysis provides mild conditions: Enantioselective Michael addition mediated by primary amino catalysts and alkali-metal ions

“…The eluent consisted of 80% hexanes and 20% isopropanol. The enantiomers of the chiral compounds were identified by reference spectra of racemates and literature data [23]. …”

“…The mixture was subjected to column chromatography without quenching, and all yields were determined as isolated yields. The ee’s were established by chiral HPLC according to racemic standards and literature data [23]. …”

“…The detector wavelength was 254 nm. t R = 12.0 min (minor, ( S )-enantiomer) and 13.3 min (major, ( R )-enantiomer [23]. …”