Thiourea Catalysis via Anion Binding

Key words

Pictet-Spengler reaction - H-bonding catalysis - anion binding - ACDC (asymmetric counteranion-directed catalysis)

Significance

Asymmetric Pictet-Spengler-type cyclizations of β-indolyl ethyl hydroxylactams 1 have been achieved in the presence of thiourea derivative 2 as chiral catalyst. Both indolizidinones (3, n = 1) and quinolizidinones (3, n = 2) are obtained in good to excellent yields and optical purities. TMSCl is required for the generation of chlorolactams 4. Plausibly thiourea catalyst 2 abstracts the chloride from 4 generating a chiral N-acyl iminium chloride-thiourea complex 5 as reactive intermediate. Subsequent cyclization in the chiral environment provided by the chiral thiourea-chloride anion complex (2×Cl^-) leads to enantiomerically enriched products.

Comment

In 2004, Taylor and Jacobsen have discovered Pictet-Spengler-type reactions, which proceed through initial acylation of imines and are promoted by thiourea catalysts of type 2 (J. Am. Chem. Soc. 2004, 126, 10558). In the present study, the Jacobsen group describes a new reaction variant and elucidates the unprecedented reaction mechanism supported by their experimental observations and the well-known anion-binding properties of (thio)ureas. Since the chiral information is exclusively provided by the chiral counteranion (2×Cl^-) during the enantiodetermining step, this study may be considered a new example of asymmetric counteranion-directed catalysis (S. Mayer, B. List Angew. Chem. Int. Ed. 2006, 45, 4193).