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.    

Scheme 1

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).

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

Scheme 3

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

Scheme 4

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

Scheme 5

References

1. Ahrendt KA, Borths CJ, MacMillan DWC. 2000. New Strategies for Organic Catalysis:  The First Highly Enantioselective Organocatalytic Diels?Alder Reaction. J. Am. Chem. Soc.. 122(17):4243-4244. https://doi.org/10.1021/ja000092s

2. Jen WS, Wiener JJM, MacMillan DWC. 2000. New Strategies for Organic Catalysis:  The First Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition. J. Am. Chem. Soc.. 122(40):9874-9875. https://doi.org/10.1021/ja005517p

3. Paras NA, MacMillan DWC. 2001. New Strategies in Organic Catalysis:  The First Enantioselective Organocatalytic Friedel?Crafts Alkylation. J. Am. Chem. Soc.. 123(18):4370-4371. https://doi.org/10.1021/ja015717g

4. Beeson TD, MacMillan DWC. 2005. Enantioselective Organocatalytic ?-Fluorination of Aldehydes. J. Am. Chem. Soc.. 127(24):8826-8828. https://doi.org/10.1021/ja051805f

5. Hechavarria Fonseca MT, List B. 2004. Catalytic Asymmetric Intramolecular Michael Reaction of Aldehydes. Angew. Chem. Int. Ed.. 43(30):3958-3960. https://doi.org/10.1002/anie.200460578

6. Austin JF, MacMillan DWC. 2002. Enantioselective Organocatalytic Indole Alkylations. Design of a New and Highly Effective Chiral Amine for Iminium Catalysis. J. Am. Chem. Soc.. 124(7):1172-1173. https://doi.org/10.1021/ja017255c

7. Austin JF, Kim S, Sinz CJ, Xiao W, MacMillan DWC. 2004. Enantioselective organocatalytic construction of pyrroloindolines by a cascade addition–cyclization strategy: Synthesis of (–)-flustramine B. Proc. Natl. Acad. Sci. U.S.A.. 101(15):5482-5487. https://doi.org/10.1073/pnas.0308177101

8. Yetra SR, Schmitt N, Tambar UK. Catalytic photochemical enantioselective α-alkylation with pyridinium salts. Chem. Sci.. 14(3):586-592. https://doi.org/10.1039/d2sc05654b