Mild and efficient pentafluorophenylammonium triflate (PFPAT)-catalyzed C-acylations of enol silyl ethers or ketene silyl (Thio)acetals with acid chlorides

A pentafluorophenylammonium triflate (PFPAT) catalyst (5 mol %) successfully promoted C-acylation of enol silyl ethers with acid chloride to produce various beta-diketones (12 examples; 62-92% yield). Similarly, C-acylation of ketene silyl acetals or ketene silyl thioacetals (i.e., crossed Claisen condensation) proceeded smoothly to provide not only alpha-monoalkylated beta-keto (thio)esters but also thermodynamically unfavorable (less accessible) alpha,alpha-dialkylated beta-keto (thio)esters in good to excellent yield (38 examples; 60-92% yield).     

NaOH-catalyzed crossed Claisen condensation between ketene silyl acetals and methyl esters

We have developed a practical crossed Claisen condensation between ketene silyl acetals and methyl esters using catalytic NaOH to obtain alpha-monoalkylated beta-keto esters and inaccessible alpha,alpha-dialkylated beta-keto esters.     

Ti-crossed-Claisen condensation between carboxylic esters and acid chlorides or acids: a highly selective and general method for the preparation of various beta-keto esters

Ti-crossed-Claisen condensation between a 1:1 mixture of carboxylic esters and acid chlorides promoted by TiCl4-Bu3N-N-methylimidazole proceeded successfully to give various beta-keto esters in good yields with excellent selectivities (19 examples, approximately 48-95% yield; cross/self-selectivity = approximately 96/4-99/1). The present method was extended to the condensation between a 1:1 mixture of carboxylic acids and carboxylic esters (six examples, approximately 70-92% yield; cross/self-selectivity = approximately 91/9-99/1). To demonstrate the utility of the present two Ti-crossed-Claisen condensations, we performed a couple of efficient short-step syntheses of two natural, representative, and useful perfumes, cis-jasmone and (R)-muscone.     

A new silicon lewis acid for highly enantioselective mannich reactions of aliphatic ketone-derived hydrazones

The first general method for the highly enantioselective Mannich reaction of aliphatic ketimines is reported. A new, second generation chiral silane Lewis acid has been developed that promotes the reaction between ketone-derived hydrazones and silyl ketene acetals, providing the beta,beta-disubstituted beta-amino esters with good enantioselectivity even for the hydrazone derived from 2-butanone (methyl vs ethyl, 91% ee). Several examples are provided, including a reaction with a substituted (propanoate-derived) silyl ketene acetal.     

Lewis base activation of Lewis acids: catalytic, enantioselective addition of glycolate-derived silyl ketene acetals to aldehydes

A catalytic system involving silicon tetrachloride and a chiral, Lewis basic bisphosphoramide catalyst is effective for the addition of glycolate-derived silyl ketene acetals to aldehydes. It was found that the sense of diastereoselectivity could be modulated by changing the size of the substituents on the silyl ketene acetals. In general, the trimethylsilyl ketene acetals derived from methyl glycolates with a large protecting group on the alpha-oxygen provide enantiomerically enriched alpha,beta-dihydroxy esters with high syn-diastereoselectivity, whereas the tert-butyldimethylsilyl ketene acetals derived from bulky esters of alpha-methoxyacetic acid provide enantiomerically enriched alpha,beta-dihydroxy esters with high anti-diastereoselecitvity.     

A domino pericyclic route to polysubstituted salicylic acid derivatives: four sequential processes from enynones and ketene silyl acetals

Alkenyl alkynyl ketones and ketene silyl acetals (KSAs) undergo regioselective [2+2]-cycloaddition under thermal conditions, triggering domino pericyclic reactions en route to various poly-substituted salicylic acid derivatives.     

Powerful Claisen condensation and Claisen-aldol tandem reaction of alpha,alpha-dialkylated esters promoted by ZrCl4-iPr2NEt

Powerful Claisen ester condensations of alpha,alpha-dialkylated esters mediated by ZrCl4-iPr2NEt were performed to give the corresponding thermodynamically unfavorable alpha,alpha-dialkylated beta-ketoesters, and Claisen-aldol tandem reactions between an intermediary Zr-enolate of a alpha,alpha-dialkylated beta-ketoester and aldehydes also proceeded.     

Indium-catalyzed coupling reaction between silyl enolates and alkyl chlorides or alkyl ethers

The coupling reactions of alkyl chlorides with silyl enolates catalyzed by InBr₃, and the coupling reactions of alkyl ethers with silyl enolates catalyzed by the combined Lewis acid of InBr₃/Me₃SiBr are described. In both reaction systems, various types of silyl enolates were used to give corresponding α-alkylated esters, ketones, carboxylic acids, amides, thioesters, and aldehydes.     

Vinylcyclopropylacyl and polyeneacyl radicals. Intramolecular ketene alkyl radical additions in ring synthesis

Treatment of a variety of substituted vinylcyclopropyl selenyl esters, e.g. 11, with Bu(3)SnH-AIBN in refluxing benzene leads to the corresponding acyl radical intermediates, which undergo rearrangement and intramolecular cyclisations via their ketene alkyl radical equivalents producing cyclohexenones in 50-60% yield. By contrast, treatment of conjugated triene selenyl esters, e.g. 32, with Bu(3)SnH-AIBN produces substituted 2-cyclopentenones via intramolecular cyclisations of their ketene alkyl radical intermediates. Under the same radical-initiating conditions the selenyl esters derived from o-vinylbenzoic acid and o-vinylcinnamic acid undergo intramolecular cyclisations producing 1-indanone and 5,6-dihydrobenzocyclohepten-7-one respectively in 60-70% yields. A tandem radical cyclisation from the alpha,beta,gamma,delta-diene selenyl ester 31 provides an expeditious synthesis of the diquinane 35 in 69% yield.     

Multiple component approaches to C-glycosyl beta-amino acids by complementary one-pot Mannich-type and Reformatsky-type reactions

The development of new methods for the preparation of C-glycosyl beta-amino acid libraries with chemical and stereochemical diversity levels was investigated and the results are described herein. Two complementary one-pot three-component Mannich-type and Reformatsky-type synthetic strategies have been developed for the construction of chiral 3-amino propanoate fragments (eventually bis-substituted at C-2) directly linked to the anomeric carbon of pyranose and furanose residues. Both methods involved as the initial step the coupling of a sugar aldehyde to p-methoxybenzylamine but differed in the nucleophile (a d(2) synthon equivalent) which was successively added: a ketene silyl acetal (Mannich route) or a bromozinc enolate (Reformatsky route). Individual C-glycosyl beta-amino esters were isolated as single 3R diastereoisomers in fair to excellent yield (60-90%) and their structure assigned by NMR spectroscopy (Riguera protocol) supported by X-ray crystallography. A tentative explanation of the observed stereochemical outcome based on transition-state models is provided. A preliminary study on the synthesis of alpha,alpha-difluoro C-glycosyl beta-amino acids via a more traditional Reformatsky route is also reported.     

Direct catalytic asymmetric mannich reactions of malonates and beta-keto esters

The first catalytic asymmetric direct Mannich reaction of malonates and beta-keto esters has been developed. Malonates react with an activated N-tosyl-alpha-imino ester catalyzed by chiral tert-butyl-bisoxazoline/Cu(OTf)(2) to give the Mannich adducts in high yields and with up to 96% ee. These reactions create a chiral quaternary carbon center and it is demonstrated that this new direct Mannich reactions provides for example a new synthetic procedure for the formation of optically active beta-carboxylic ester alpha-amino acid derivatives. A series of different beta-keto esters with various ester substituents has been screened as substrates for the catalytic asymmetric direct Mannich reaction and it was found that the best results in terms of yield, diastereo- and enantioselectivity were obtained when tert-butyl esters of beta-keto esters were used as the substrate. The reaction of different beta-keto tert-butyl esters with the N-tosyl-alpha-imino ester gave the Mannich adducts in high yields, diastereo- and enantioselectivities (up to 95% ee) in the presence of chiral tert-butyl-bisoxazoline/Cu(OTf)(2) as the catalyst. To expand the synthetic utility of this direct Mannich reaction a diastereoselective decarboxylation reaction was developed for the Mannich adducts leading to a new synthetic approach to attractive optically active beta-keto alpha-amino acid derivatives. Based on the stereochemical outcome of the reactions, various approaches of the N-tosyl-alpha-imino ester to the chiral bisoxazoline/Cu(II)-substrate intermediate are discussed.     

Design of Brønsted acid-assisted chiral Brønsted acid catalyst bearing a bis(triflyl)methyl group for a Mannich-type reaction

[Structure: see text] A new Br?nsted acid-assisted chiral Br?nsted (chiral BBA) acid catalyst (1) was developed by substituting a hydroxy group of optically active 1,1'-bi(2-naphthol) with a stronger Br?nsted acidic group such as a bis(trifluoromethanesulfonyl)methyl group. The enantioselective Mannich-type reaction of ketene silyl acetals with aldimines catalyzed by (R)-1 in the presence of stoichiometric achiral proton sources gave (S)-beta-amino esters in high yield with moderate to good enantiomeric excesses.     

Gallium tribromide catalyzed coupling reaction of alkenyl ethers with ketene silyl acetals

A 'Ga'llant couple: The α-alkenylation of esters was accomplished by GaBr(3) -catalyzed coupling between alkenyl ethers and ketene silyl acetals. In this reaction system, various alkenyl ethers, including those with vinyl and substituted alkenyl groups, were applicable, and the scope of applicable ketene silyl acetals was sufficiently broad. The mechanism is also discussed.     

Two-carbon homologation of aldehydes via silyl ketene acetals. 2. Study of the stereochemical control in the formation of (E)-alkenoic acids.

The condensation of C,O,O-tris(trimethylsilyl)ketene acetal 1 with aldehydes 2 in the presence of catalytic amounts of mercuric iodide at room temperature affords syn and anti beta-trimethylsiloxy alpha-trimethylsilyl alkanoic acid silyl esters 3 in good yields. These new compounds gave, under acidic or basic conditions, E and (or) Z enoic acids 4. The paths for the formation of these alkenoic acids are discussed.     

Cationic iridium complex is a new and efficient Lewis acid catalyst for aldol and Mannich reactions

A cationic iridium complex [Ir(cod)₂]SbF₆ was found to be a new and efficient Lewis acid catalyst for Mukaiyama aldol and Mannich reactions. Aldehydes react smoothly with silyl enol ethers to give β-siloxy ketones in the presence of 0.5 mol % of [Ir(cod)₂]SbF₆. The reaction of N-alkyl arylaldimines with ketene silyl acetals in the presence of 5 mol % [Ir(cod)₂]SbF₆/P(OPh)₃ gave β-amino esters. After Mannich reaction was complete, stirring of the reaction mixture for 24 h led to cyclization to give β-lactam. The reaction of N-aryl benzaldimine with silyl enol ether derived from acetophenone gave a tetrahydroquinoline derivative as a single diastereomer.     

Termination of Mn(III)-based oxidative cyclizations by trapping with azide

The radicals formed in Mn(III)-based oxidative free-radical cyclizations of beta-keto esters and malonate esters can be trapped with sodium azide and Mn(III) to give cyclic and bicyclic azides in 30-80% yield. Reduction of the azide gives bi- and tricyclic lactams. [reaction: see text]     

Zinc- and indium-mediated ring-expansion reaction of alpha-halomethyl cyclic beta-keto esters in aqueous alcohol

Radical ring-expansion reaction of various alpha-halomethyl cyclic beta-keto esters and alpha-halomethyl benzocyclic beta-keto esters and chain-extension reaction of alpha-halomethyl beta-keto esters with zinc powder and indium powder in refluxing aqueous alcohol were carried out to generate the corresponding ring-expansion and chain-extension products. As the results indicate, it was found zinc powder was more effective than indium powder to give the corresponding ring-expanded products in quite good yields. Moreover, the addition of zinc bromide as Lewis acid showed an increase of the yields, depending on the substrates. The present reaction conditions are highly effective, simple, and environmentally friendly.     

Practical and robust method for stereoselective preparations of ketene silyl (thio)acetal derivatives and NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters

We developed an efficient, practical, and robust method for stereoselective preparations of (Z)-ketene trimethylsilyl (TMS) thioacetals from thioesters and alkyl (1Z)- or (1Z,3E)-1,3-bis(TMS)dienol ethers from alkyl β-ketoesters. The former preparation was performed by convenient procedure (LDA-TMSCl, 0-5 °C, 2.5 h), while the latter preparation involved convenient method A (2NaHMDS-2TMSCl) and cost-effective method B (NaH, NaHMDS-2TMSCl). The first catalytic NaOH-catalyzed crossed-Claisen condensation between ketene silyl acetals and methyl esters proceeded successfully to give a variety of α-monomethyl β-ketoesters and inaccessible α,α-disubstituted β-ketoesters. For further extension, a couple of Claisen-aldol tandem reactions of the obtained β-ketoester analogues utilizing TiCl₄ and TiCl₄-Bu₃N reagents smoothly proceeded with good to excellent stereoselectivity.     

An Ireland-Claisen approach to beta-alkoxy alpha-amino acids

A diastereoselective Ireland-Claisen approach to beta-alkoxy alpha-amino acid esters is reported. Amino acid esters of enol ethereal allylic alcohols undergo facile syn-selective [3,3]-sigmatropic rearrangement via silyl ketene acetals. Substrate synthesis, rearrangement development, stereoselectivity, and product elaboration are discussed.     

Rhenium-catalyzed reaction of carbonyl compounds with ketene silyl acetals

It was found that rhenium complex is an effective catalyst for the reaction of carbonyl compounds with ketene silyl acetals. A wide range of β-silyloxy esters is obtained by the treatment of carbonyl compounds with ketene silyl acetals in the presence of a catalytic amount of ReBr(CO)₅ in moderate to good yields.