Macmillan Imidazolidinone Organocatalysts

Metal-free Asymmetric Catalysis

Developed by Professor David MacMillan at Caltech, imidazolidinone-based OrganoCatalysts are designed to serve as general catalysts for a variety of asymmetric transformations. The first highly enantioselective organocatalytic Diels-Alder reaction using (5S)-2,2,3-trimethyl-5-phenylmethyl-4-imidazolidinone monohydrochloride was reported by MacMillan in his pioneering work in 2000 (Scheme 1).¹ The activated iminium ion, formed through condensation of the imidazolidinone and an α,β-unsaturated aldehyde, underwent reaction with various dienes to yield [4+2]-cycloadducts in excellent yields and enantioselectivities.    

Other organocatalytic transformations such as 1,3-dipolar cycloadditions,² Friedel-Crafts alkylations,³ α-chlorinations,³ α-fluorinations,⁴ and intramolecular Michael reactions⁵ were reported using MacMillan’s Imidazolidinone OrganoCatalysts, all proceeding with high levels of enantioselectivity (Scheme 2).

MacMillan found an optimized structure in (2S,5S)-(−)-2-tert-butyl-3-methyl-5-benzyl-4-imidazolidinone for the Friedel-Crafts alkylation of indoles (Scheme 3). ^5,6

The synthetic utility of this concept was later demonstrated in the total synthesis of (–)-flustramine B, a biologically active pyrroloindoline-containing alkaloid (Scheme 4).⁷

More recently, a photochemical enantioselective α-alkylation protocol has been developed and applied to the total synthesis of (−)-enterolactone and (−)-enterodiol. The reaction proceeds in the presence of visible light and in the absence of a photocatalyst via a light-activated charge-transfer complex. (Scheme 5).⁸