Chiral Phosphoric Acids

Aldrich ChemFiles 2007, 7.9, 11.

Aldrich ChemFiles 2007, 7.9, 11.

BINOL-derived phosphoric acids are capable of catalyzing a range of interesting processes of which nucleophilic addition reactions to imine substrates are particularly noteworthy. List and coworkers reported1 a direct Pictet-Spengler reaction with a range of aldehydes using organocatalyst (R)-TRIP (689890) to form isoquinolines in high yields and enantiomeric excess (Scheme 1). A geminally disubstituted tryptamine is needed, but this limitation does not significantly affect the utility of this process.

Scheme 1

An enantioselective reductive amination has been reported by several research groups.2 Rueping first reported that phosphoric acid 674605 catalyzed the reduction of an imine with a Hantzsch ester in good enantiomeric excess (Scheme 2, top). List reported an improvement to this method using (689890) and highlighted the ability to perform a one-pot process from aldehyde to amine in enantiomeric excesses up to 92% (Scheme 2, bottom).

Scheme 2

MacMillan finally reported a one-pot, direct, reductive amination with broad substrate scope that enables the effective reductive amination of a range of methyl ketones and aryl amines (Scheme 3).3 It is even possible to obtain good enantiomeric excess with 2-butanone where the silylated phosphoric acid MacMillan TiPSY catalyst (674745) can distinguish between a methyl group and an ethyl group, delivering the product in high enantiomeric excess.

Scheme 3

Recently, List reported an elegant, highly enantioselective cascade reaction.4 The synthesis of pharmaceutically relevant 3-substituted cyclohexylamines from 2,6-diketones via an aldolizationdehydration- conjugate reduction-reductive amination cascade that is catalyzed by the chiral Brønsted acid (R)-TRIP (689890) and accelerated by the achiral amine substrate, which is ultimately incorporated into the product (Scheme 4).

Scheme 4

Antilla and co-workers reported on the use of VAPOL derived phosphoric acid derivative (675512) in the addition of sulfonamides to Boc-protected aryl imines, giving rise to protected aminals in excellent enantioselectivities (Scheme 5).5

Scheme 5

The aza-Diels-Alder reaction of aldimines with Danishefsky’s diene to afford piperidinone derivatives proceeded with high enantioselectivity using (R)-TRIP (689890). Addition of acetic acid improved both reactivity and enantioselectivity (Scheme 6).6

Scheme 6

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  1. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
  2. (a) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424.
  3. Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
  4. Zhou, J.; List, B. J. Am. Chem. Soc. 2007, 129, 7498.
  5. Gerald, B.; Rowland, G. B.; Zhang, H.; Rowland, E. B.; Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2005, 127, 15696.
  6. Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2006, 141.

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