MacMillan Imidazolidinone OrganoCatalysts™

Chemfiles Volume 6 Article 4

Developed by Professor David MacMillan at Caltech, imidazolidinonebased organocatalysts are designed to serve as general catalysts for a myriad of asymmetric transformations. The first highly enantioselective organocatalytic Diels–Alder reaction using a chiral organocatalyst (569763) was reported in his pioneering work in 2000 (Scheme 6).1 The activated iminium ion, formed through condensation of the imidazolidinone and an α,β-unsaturated aldehyde, reacted with various dienes to give [4+2] cycloadducts in excellent yields and enantioselectivities.

Scheme 6.

Other organocatalytic transformations such as 1,3-dipolar cycloadditions, 2 Friedel–Crafts alkylations,3 α-chlorinations,4 α-fluorinations,5 and intramolecular Michael reactions6 using MacMillan’s organocatalyst technology (569763) were reported, all proceeding with impressive levels of enantioselectivity (Scheme 7).

Scheme 7.

Having established iminium and enamine catalysis using organocatalyst (569763), MacMillan found an optimized structure in organocatalyst (663107) for the Friedel–Crafts alkylation of indoles (Scheme 8)7, which are known to be privileged structures in drug discovery. See ChemFiles Vol. 4 No. 8, Indoles (US) or Vol. 4 Supplement II (Europe).

Scheme 8.

MacMillan later demonstrated the synthetic utility of this concept in the total synthesis of (–)-flustramine B, a biologically active alkaloid bearing a pyrroloindoline architecture. The fused ring system was cleanly assembled with the aid of imidazolidinone organocatalyst (663107) (Scheme 9).8

Scheme 9.

Imitating nature’s stereoselective enzymatic transfer hydrogenation with NADH cofactor, MacMillan’s variant used the combination of organocatalyst (661902) and Hantzsch ester (127220) to reduce simple α,β-unsaturated aldehydes in a highly enantioselective manner (Table 1).9

Table 1.

In sharp contrast to metal-mediated hydrogenations, the E/Z geometry of the enal substrates did not have a significant influence on the outcome of the absolute configuration of the newly created stereocenter. In an elegant organocascade reaction, MacMillan showed that both LUMO-lowering iminium- and HOMO-raising enamine catalysis could coexist without deleterious catalyst–catalyst interactions by substrate activation in an orthogonal mode, hence leading to highly enantioenriched products with increased structural complexity in just one step. Using both organocatalytic transfer hydrogenation (Hantzsch ester, (120227) and α-halogenation methodologies (N-fluorobenzenesulfonimide, (392715), the formal addition of HF to α,β-unsaturated aldehydes could be achieved with very high levels of enantio- and diastereoselectivity (Scheme 10 . Various examples have been reported.10

Scheme 10.

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  1. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243.
  2. Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874.
  3. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4379.
  4. Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108.
  5. Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826.
  6. Fonseca, M. H.; List, B. Angew. Chem. Int. Ed. 2004, 43, 3958.
  7. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172.
  8. Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Nat. Acad. Sci. USA 2004, 101, 5482.
  9. Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32.
  10. Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051.

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