Asymmetric Mannich-Type Reaction Using Bis-ProPhenol Ligands

By: William Sommer, Aldrich ChemFiles 2008, 8.6, 10.

Aldrich ChemFiles 2008, 8.6, 10.

The Mannich reaction has become an essential tool for the synthesis of nitrogen-containing compounds. Trost and co-workers utilized the semi-crown ligand that they developed for asymmetric aldol reaction in an asymmetric imine-aldol reaction generating syn 1,2-amino alcohols.1 A series of hydroxyacetophenone derivatives were reacted with different glyoxalate imines in the presence of a zinc complex in THF (Scheme 2). It was noted that more electron-rich aromatic hydroxy ketones required higher catalyst loading. Good yields and selectivity were reported for the synthesis of a variety of amino alcohols. It is important to note that these imine alcohols are important synthons that can be reacted further to yield different α-hydroxyl-β-amino acids.

Scheme 2.

A recent example of the use of Bis-ProPhenol ligands is the Friedel–Crafts alkylation of pyrroles with nitroalkenes. The Friedel–Crafts reaction has been extensively studied and used for the past 100 years. Recently, several research groups focused their attention on asymmetric Friedel–Crafts alkylation with very good success.2Trost et al. reported a dinuclear zinc-bis-ProPhenol complex to efficiently catalyze the asymmetric Friedel–Crafts alkylation of unprotected pyrroles with nitroalkenes.3 The resulting products are 2-alkyl-substituted and 2,5-dialkyl-substituted pyrroles containing a chiral center at C–1 of the alkyl substituent. The significance of this transformation lies in the fact that pyrroles are relatively unstable in the acidic environment of the classical Friedel–Crafts reaction and that unprotected pyrroles can be used directly in the reaction. Furthermore, pyrroles are important motifs present in numerous natural products and medicinal reagents. The current alkylation is carried out at room temperature in THF and gives rise to moderate-to-high yields and enantioselectivities (Scheme 3).

Scheme 3.

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  1. Trost, B. M. et al. J. Am. Chem. Soc. 2003, 125, 338.
  2. (a) Bandini, M. et al. Eur. J. Org. Chem. 2006, 3527. (b) Jia, Y. X. et al. J. Org. Chem. 2006, 71, 75..
  3. Trost, B. M. et al. J. Am. Chem. Soc. 2008, 130, 2438.

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