The l-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate additions of acyl silanes to α,β-unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a variety of N,N-dimethyl acrylamide derivatives in the presence of the lithium salt of 6b. In many instances the α-silyl-γ-ketoamide product undergoes facile enantioenrichment (to 97-99% ee) upon recrystallization. Desilylation with HF·pyr affords the formal Stetter addition products. BaeyerVilliger oxidation of the desilylated γ-ketoamides affords useful ester products. An X-ray diffraction study of 6b reveals that the isopropyl group of the menthone ketal influences the position of the synpseudoaxial phenyl group in the TADDOL structure. Through a crossover experiment, the silicon migration step in the reaction mechanism is shown to be strictly intramolecular.

Nucleophilic acylation of enones and enoates catalyzed by cyanide ions or heterazolium carbenes, commonly known as the Stetter reaction, is a useful method for the synthesis of 1,4-dicarbonyl compounds. [1] The key feature of this reaction is the carbonyl-polarity reversal initiated by the addition of a cyanide ion or a heterazolium carbene to an aldehyde facilitating subsequent 1,4-addition to an a,b-unsaturated carbonyl compound. Although this reaction has proven fruitful with a variety of acceptors, its success has been largely limited to aryl or unsubstituted [2] substrates. Acceptors bearing a b-alkyl group normally give the 1,4-addition product in 30-40 % yield, [3] and achieving enantioselectivity in the intermolecular Stetter reaction has also proven to be difficult. [4] Herein, we provide a strategy to address both of these issues through metallophosphite-catalyzed acylations of a,b-unsaturated amides. These reactions are enabled by an unusual [1,2] Brook rearrangement/conjugate addition/retro [1,4] Brook rearrangement sequence that proceeds with good anti diastereoselectivity and allows access to a range of stable a-silyl-g-ketoamides (Scheme 1).Acyl silanes are effective aldehyde surrogates that confer unique advantages in umpolung reactions. The acyl anion equivalent formed on nucleophilic addition and subsequent [1,2] Brook rearrangement [5,6] undergoes addition to a number of electrophiles. Degl Innocenti et al. found that the 1,4-addition of benzoyl trimethylsilane to cyclohexenone can be catalyzed by cyanide ions, [7] whereas Scheidt and coworkers recently described the successful conjugate addition of acyl silanes to unsaturated esters and ketones by using thiazolium carbene catalysis. [8,9] The substrate scope of the latter process mirrors the classic Stetter reaction, and conjugate acceptors bearing a b-alkyl substituent have not been reported. Metallophosphites [10,11] can be considered as an alternative to cyanide ions and thiazolium carbenes, and they have recently been described as carbonyl-umpolung catalysts in the context of a new enantioselective crossbenzoin reaction. [12] We projected that this catalysis concept might be applicable to alkene electrophiles as well.The conjugate addition of acyl silanes (benzoyl trimethylsilane, benzoyl triethylsilane, and benzoyl dimethylphenylsilane) to Michael acceptors (ethyl crotonate, methyl cinnamate, and cyclohexenone) catalyzed by the Enders phosphite 5 was initially examined. Potassium hydride gave the best reactivity of the bases screened in these reactions; however, few reactions provided appreciable quantities of the desired acylation product. The 1 H NMR spectra of the reactions typically revealed incorporation of the phosphite in the acyl silane/acceptor adduct, thus indicating that the proposed cycle was initiated but not completed. Exposure of the reaction mixture to tetrabutylammonium fluoride (TBAF) afforded the desired g-ketoester. Ethyl crotonate provided the best yields of the acceptors screened, but even under optimized condition...

Nucleophilic acylation of enones and enoates catalyzed by cyanide ions or heterazolium carbenes, commonly known as the Stetter reaction, is a useful method for the synthesis of 1,4-dicarbonyl compounds.[1] The key feature of this reaction is the carbonyl-polarity reversal initiated by the addition of a cyanide ion or a heterazolium carbene to an aldehyde facilitating subsequent 1,4-addition to an a,b-unsaturated carbonyl compound. Although this reaction has proven fruitful with a variety of acceptors, its success has been largely limited to aryl or unsubstituted [2] substrates. Acceptors bearing a b-alkyl group normally give the 1,4-addition product in 30-40 % yield, [3] and achieving enantioselectivity in the intermolecular Stetter reaction has also proven to be difficult.[4] Herein, we provide a strategy to address both of these issues through metallophosphite-catalyzed acylations of a,b-unsaturated amides. These reactions are enabled by an unusual [1,2] Brook rearrangement/conjugate addition/retro [1,4] Brook rearrangement sequence that proceeds with good anti diastereoselectivity and allows access to a range of stable a-silyl-g-ketoamides (Scheme 1).Acyl silanes are effective aldehyde surrogates that confer unique advantages in umpolung reactions. The acyl anion equivalent formed on nucleophilic addition and subsequent [1,2] Brook rearrangement [5,6] undergoes addition to a number of electrophiles. DeglInnocenti et al. found that the 1,4-addition of benzoyl trimethylsilane to cyclohexenone can be catalyzed by cyanide ions, [7] whereas Scheidt and coworkers recently described the successful conjugate addition of acyl silanes to unsaturated esters and ketones by using thiazolium carbene catalysis. [8,9] The substrate scope of the latter process mirrors the classic Stetter reaction, and conjugate acceptors bearing a b-alkyl substituent have not been reported. Metallophosphites [10,11] can be considered as an alternative to cyanide ions and thiazolium carbenes, and they have recently been described as carbonyl-umpolung catalysts in the context of a new enantioselective crossbenzoin reaction.[12] We projected that this catalysis concept might be applicable to alkene electrophiles as well.The conjugate addition of acyl silanes (benzoyl trimethylsilane, benzoyl triethylsilane, and benzoyl dimethylphenylsilane) to Michael acceptors (ethyl crotonate, methyl cinnamate, and cyclohexenone) catalyzed by the Enders phosphite 5 was initially examined. Potassium hydride gave the best reactivity of the bases screened in these reactions; however, few reactions provided appreciable quantities of the desired acylation product. The 1 H NMR spectra of the reactions typically revealed incorporation of the phosphite in the acyl silane/acceptor adduct, thus indicating that the proposed cycle was initiated but not completed. Exposure of the reaction mixture to tetrabutylammonium fluoride (TBAF) afforded the desired g-ketoester. Ethyl crotonate provided the best yields of the acceptors screened, but even under optimized conditions thes...

No abstract

2005 Carboxylic amides Q 0490Metallophosphite-Induced Nucleophilic Acylation of α,β-Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement.-Synthetically interesting α-silyl-γ-ketoamides of type (IV) are formed with high to moderate anti-selectivity by conjugate addition of a variety of acylsilanes to unsaturated amides. Desilylation of the diastereomeric product mixtures affords γ-ketoamides.-(NAHM, M. R.; LINGHU, X.; POTNICK, J. R.; YATEES, C. M.; WHITE, P. S.; JOHNSON*, J. S.; Angew.