Metallophosphite‐Induced Nucleophilic Acylation of α,β‐Unsaturated Amides: Facilitated Catalysis by a Diastereoselective Retro [1,4] Brook Rearrangement

Abstract

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...

Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts

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Asymmetric nucleophilic catalysis has been extensively studied over the last several decades and plays an increasingly important role in modern asymmetric synthesis. [2,3] We recently introduced the chiral ammonium betaine 1 as a new, yet intriguing structural motif as an organic molecular catalyst. In this respect, an anionic molecule could function as a potentially more nucleophilic catalyst for initiating the reaction, compared to the commonly utilized electronically neutral molecules, but it generates a rather stable intermediate bearing no charge (see below).

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“…Hence, research toward exploiting the reactivity of anionic molecules for the development of a new type of nucleophilic catalysis, that is, enantioselective ionic nucleophilic catalysis, has met with limited success. [2,3] We recently introduced the chiral ammonium betaine 1 as a new, yet intriguing structural motif as an organic molecular catalyst. [4,5] The basic character of its anionic site (aryloxylate) and the hydrogen-bonding capability of its conjugate acid (arylhydroxide) appeared to be the key features for realizing highly enantioselective Mannich-type reactions.…”

Towards Tartaric‐Acid‐Derived Asymmetric Organocatalysts

“…Johnson’s group later on expanded this methodology to asymmetric acylations of α,β-unsaturated amides and to the C-acylation of nitrones 44. Notably, the addition of acylsilanes 97 to α,β-unsaturated amides 99 (Scheme 27) proceeded with moderate enantioselectivity only when the standard TADDOL-derived phosphite 96b was used 44a.…”

“…Notably, the addition of acylsilanes 97 to α,β-unsaturated amides 99 (Scheme 27) proceeded with moderate enantioselectivity only when the standard TADDOL-derived phosphite 96b was used 44a. Incorporation of an additional element of chirality in the ketal part of the catalyst (compound 100 ), however, resulted in a significantly improved enantioselectivity for a broad scope of different Michael acceptors (Scheme 27 – upper reaction) 44b.…”