Catalytic enantioselective construction of all-carbon quaternary stereocenters: synthetic and mechanistic studies of the C-acylation of silyl ketene acetals

With the aid of an appropriate chiral catalyst, acyclic silyl ketene acetals react with anhydrides to furnish 1,3-dicarbonyl compounds that bear all-carbon quaternary stereocenters in good ee and yield. Mechanistic studies provide strong support for a catalytic cycle that involves activation of both the electrophile (anhydride --> acylpyridinium) and the nucleophile (silyl ketene acetal --> enolate).     

Mechanism of Mukaiyama-Michael Reaction of Ketene Silyl Acetal: Electron Transfer or Nucleophilic Addition?

Mechanism of Mukaiyama-Michael reaction of ketene silyl acetal has been discussed. The competition reaction employing various types of ketene silyl acetals reveals that those bearing more substituents at the beta-position react preferentially over less substituted ones. However, when ketene silyl acetals involve bulky siloxy and/or alkoxy group(s), less substituted compounds react preferentially. The Lewis acids play an important role in these reactions. Enhanced preference for the more sterically demanding Michael adducts is obtained with Bu(2)Sn(OTf)(2), SnCl(4), and Et(3)SiClO(4) in the former reaction while TiCl(4) gives the highest selectivity for the less sterically demanding products in the latter case. These results are interpreted in terms of alternative reaction mechanisms. The reaction of less bulky ketene silyl acetals are initiated by electron transfer from these compounds to a Lewis acid. On the other hand, bulkier ketene silyl acetals undergo a ubiquitous nucleophilic reaction. Such a mechanistic change is discussed based on a variety of experimental results as well as the semiempirical PM3 MO calculations.     

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.     

Experimental and theoretical studies on Mannich-type reactions of chiral non-racemic N-(benzyloxyethyl) nitrones

The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically. Aromatic nitrones showed lower reactivity that aliphatic nitrones and the addition of the silyl ketene acetal led to lower selectivities than the addition of the corresponding lithium enolate. Whereas low selectivity was obtained for the addition of the silyl ketene acetal, only one diastereomer could be detected in all cases for the addition of lithium enolate to aliphatic nitrones. The synthetic utility of the two chiral auxiliaries employed lies in the preparation of enantiomeric compounds. DFT theoretical calculations confirmed the stepwise mechanism for the addition of silyl ketene acetals to nitrones and are in good agreement with the observed experimental results.     

Photoaddition reactions of 1,2-diketones with silyl ketene acetals. formation of beta-hydroxy-gamma-ketoesters

Photochemical reactions taking place between 1,2-diketones and silyl ketene acetals and their excited state reaction mechanisms have been explored. Irradiation of benzene, acetone, or acetonitrile solutions containing 1,2-diketones and silyl ketene acetals is observed to promote formation of 1,4-dioxenes, resulting from [4 + 2]-cycloaddition, oxetanes, arising by Paterno-Buchi processes, and beta-hydroxy-gamma-ketoesters, generated by SET-promoted Claisen-type condensation. These competitive pathways leading from the excited states of the 1,2-diketones to these products are influenced by solvent polarity and the nature of the silyl ketene acetal and 1,2-diketone. The Claisen-type condensation process, following an SET desilylation pathway and predominating when the photoreactions are carried out in the polar solvent acetonitrile, represents an efficient method to prepare a variety of diversely substituted beta-hydoxy-gamma-ketoesters.     

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

The concept of Lewis base activation of Lewis acids has been reduced to practice for catalysis of the aldol reaction of silyl ketene acetals and silyl dienol ethers with aldehydes. The weakly acidic species, silicon tetrachloride (SiCl4), can be activated by binding of a strongly Lewis basic chiral phosphoramide, leading to in situ formation of a chiral Lewis acid. This species has proven to be a competent catalyst for the aldol addition of acetate-, propanoate-, and isobutyrate-derived silyl ketene acetals to conjugated and nonconjugated aldehydes. Furthermore, vinylogous aldol reactions of silyl dienol ethers are also demonstrated. The high levels of regio-, anti diastereo-, and enantioselectivity observed in these reactions can be rationalized through consideration of an open transition structure where steric interactions between the silyl cation complex and the approaching nucleophile are dominant.     

Silyl Ketene Imines: Highly Versatile Nucleophiles for Catalytic,Asymmetric Synthesis

This Minireview provides an overview on the development of silyl ketene imines and their recent applications in catalytic, enantioselective reactions. The unique structure of the ketene imine allows a diverse range of reactivity patterns and provides solutions to existing challenges in the enantioselective construction of quaternary stereogenic carbon centers and cross‐benzoin adducts. A variety of reactions for which silyl ketene imines have been applied are presented with an overall goal of inspiring new uses for these underutilized nucleophiles.     

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.     

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).     

alpha-thiocyanation of carbonyl and beta-dicarbonyl compounds using (dichloroiodo)benzene-lead(II) thiocyanate

The combination reagent (dichloroiodo)benzene and lead(II) thiocyanate in dichloromethane effects oxidation of various enol silyl ethers, ketene silyl acetals, and beta-dicarbonyl compounds, thereby providing an efficient and convenient method for alpha-thiocyanation of carbonyl and beta-dicarbonyl compounds.     

Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of β,γ‐Unsaturated Nitriles

Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr₃ and Me₃SiBr is described. Kinetic studies have revealed that an indium catalyst and Me₃SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction.     

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.     

Comparison between electron transfer and nucleophilic reactivities of ketene silyl acetals with cationic electrophiles

The products and kinetics for the reactions of ketone silyl acetals with a series of p-methoxy-substituted trityl cations have been examined, and they are compared with those of outer-sphere electron transfer reactions from 10,10'-dimethyl-9,9', 10, 10'- tetrahydro-9,9'-biacridine [(AcrH)2] to the same series of trityl cations as well as other electron acceptors. The C-C bond formation in the reaction of beta,beta-dimethyl-substituted ketene silyl acetal (1: (Me2C=C(OMe)OSiMe3) with trityl cation salt (Ph3C+ClO4-) takes place between 1 and the carbon of para-positon of phenyl group of Ph3C+, whereas a much less sterically hindered ketene silyl acetal (3: H2C=C(OEt)OSiEt3) reacts with Ph3C+ at the central carbon of Ph3C+. The kinetic comparison indicates that the nucleophilic reactivities of ketene silyl acetals are well correlated with the electron transfer reactivities provided that the steric demand at the reaction center for the C-C bond formation remains constant.     

Reductive aminopropylation of ketene silyl (thio)acetals leading to the synthesis of δ-amino esters

In the presence of silica gel or titanium tetrachloride, ketene silyl acetals or ketene silyl thioacetals underwent 1,4-addition with α,β unsaturated aldimines which possess a large triphenylmethyl group at the imino nitrogens followed by reduction with sodium cyanoborohydride to give aminopropylated products, δ-amino esters, in good yields.     

Aminoboranes as "compatible" iminium ion generators in aminative C-C bond formations

Aminoboranes have been shown to be highly efficient and mild iminium ion generators in the Mannich-type aminative coupling of aldehydes with silyl ketene acetals. By using aminoboranes bearing bulky amino groups, such as a diisopropylamino group, free secondary amines can be successfully used as the amino component in a three-component Mannich reaction with aldehydes and silyl ketene acetals.     

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.     

Enantioselective addition of ketene silyl acetals to nitrones catalyzed by chiral titanium complexes. Synthesis of optically active beta-amino acids

A chiral titanium complex, Ti(O-i-Pr)(4)/BINOL/tert-butylcatechol, catalyzes enantioselective addition reaction of ketene silyl acetals to nitrones to give optically active beta-amino acid derivatives which are biologically active compounds and useful synthetic intermediates of natural products and pharmaceuticals such as beta-lactam antibiotics. The combined process of catalytic oxidation of secondary amines and enantioselective carbon-carbon bond formation of nitrones thus obtained with ketene silyl acetals provides a useful two-step method for the synthesis of optically active beta-amino acid derivatives and related nitrogen compounds.     

Catalytic enantioselective aldol reaction to ketones

An enantioselective aldol reaction between ketones and ketene silyl acetals is described using CuF-chiral phosphine as a catalyst. The key for high enantioselectivity was the development of a novel ligand derived from Taniaphos combined with the unique accelerative effect of PhBF3K. These conditions are applicable to various substrates such as aromatic, aliphatic, and heteroaromatic ketones. In the case of substituted nucleophiles, the reaction proceeds well. The diastereoselectivity is independent of ketene silyl acetal geometry. This is the first example of a catalytic enantio- and diastereoselective aldol reaction to ketones using ketene silyl acetals.     

One-pot enol silane formation-Mukaiyama aldol reactions: Crossed aldehyde-aldehyde coupling,thioester substrates,and reactions in ester solvents

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a trialkylamine base promote both in situ enol silane/silyl ketene acetal formation and Mukaiyama aldol addition reactions between a variety of reaction partners in a single reaction flask. Isolation of the required enol silane or silyl ketene acetal is not necessary. For example, crossed aldol reactions between α-disubstituted aldehydes and non-enolizable aldehydes yield β-hydroxy aldehydes in good yield. In a related reaction, the common laboratory solvent ethyl acetate functions as both an enolate precursor and a green reaction solvent. When thioesters are employed as enolate precursors, high yields for additions to non-enolizable aldehydes are routinely observed.     

Highly enantioselective Mannich reactions with α-aryl silyl ketene acetals and imines

Mannich reactions with chiral silicon Lewis acid activated acylhydrazones and α-aryl silyl ketene acetals and α-aryl,α-alkyl silyl ketene imines proceed efficiently and with good to excellent levels of both diastereoselectivity and enantioselectivity. The reactions provide access to α-aryl,β-hydrazido esters and α-aryl,α-alkyl,β-hydrazido nitriles, which are valuable analogs of β-amino acids.