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Funding: Engineering and Physical Sciences Research Council (Grant Number(s): EP/E03795X/1, EP/S019359/1). Mechanistic studies of the triazolium ion‐catalyzed intramolecular Stetter reaction using initial rates analysis in NEt3/NEt3. HCl buffered methanol showed the reaction to be first order in catalyst and zero order in aldehyde over a broad range of aldehyde concentrations. The observed reaction rate is higher for catalysts bearing N‐aryl substituents with electron‐withdrawing groups. A concurrent, NHC‐independent substrate isomerization was also observed and found to demonstrate a first order dependence on aldehyde concentration. The reported data are consistent with deprotonation to form the Breslow intermediate being turnover‐limiting in this process. Publisher PDF

Herein, we describe the enantioselective construction of the 12-membered macrocyclic pyrrole core 4 of marineosin A in 5.1% overall yield from (S)-propylene oxide. The route features a key Stetter reaction to install a 1,4-diketone, which is then subjected to Paal-Knorr pyrrole synthesis and ring closing metathesis (RCM) to afford macrocycle 4. A divergence point in the synthetic scheme also enabled access to a highly functionalized spiroaminal model system 8 via an acid-mediated hydroxyketoamide cyclization strategy.

α,β-Unsaturated 1-acyl-1H-pyrroles are employed as enabling units for the construction of 1,4-dicarbonyl systems using the organocatalytic Stetter reaction. The enhanced electrophilicity of the 1-acyl-1H-pyrrole unit allows for the catalytic construction of fused and non-fused pyranones from aliphatic aldehydes, is compatible with aromatic aldehydes, and also facilitates an intermolecular variant of the reaction involving both aromatic and aliphatic aldehydes.

On the basis of Breslow's mechanism for benzoin condensation, a model asymmetric Stetter reaction has been investigated using DFT methods. In contrast to the concerted benzoin condensation, after formation of the Breslow intermediate the Stetter reaction is found to be a two-step process in which the rate-determining C–C coupling of the Breslow intermediate and the Michael acceptor precedes final proton transfer. In addition, the enolamine is found to play a significant role in the stereochemistry of the product, with the energy difference between stereoisomers of this intermediate reflected throughout the remainder of the reaction sequence. Consequently, electronic and steric control of the stereochemistry of this intermediate should directly enhance the ee values of the product. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

N-Aryl-substituted imidazoles 14b, 15b and thiazoles 17−22, 25 were prepared which contain a stereogenic axis and which can occur as atropisomers. The imidazolium salts 15b could be obtained from 2-isopropylaniline (12b) and diacetyl (11) in three steps (19% yield) whereas the synthesis of their tert-butyl analogues failed. The meso-isomer meso-15b prevailed (dr = 90/10). The chiral thiazolium salts rac-17 (53% yield) and rac-22 (49% yield) were prepared in two steps from 2-tert-butylaniline (12a). The enantiomerically pure thiazolium salt 19 was obtained from α-bromomenthone (23) and the aniline 12a (27% overall yield). In contrast to the imidazolium salts 15b, the thiazolium salts proved to be suitable catalysts in the benzoin condensation of benzaldehyde (1 2) and in the intramolecular Stetter reaction of the α,β-unsaturated ester 9a. The best results obtained with catalyst 19 (20 mol %) were 85% yield of product 2 (40% ee) and 75% yield of product 10a (50% ee). The stereogenic axis of catalyst 19 is not configurationally stable in the catalytically active carbene intermediate 28. The catalyst is recovered as a mixture of diastereomeric atropisomers 19 and 26 in a ratio of 70:30 to 75:25. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)