The Mukaiyama Aldol Reaction: 40 Years of Continuous Development

A directed cross‐aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross‐aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross‐aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.     

Chiral phosphine oxide BINAPO as a Lewis base catalyst for asymmetric allylation and aldol reaction of trichlorosilyl compounds

Chiral phosphine oxide BINAPO, which was readily prepared from chiral phosphine BINAP, exhibited good catalytic activities in the reaction of trichlorosilyl compounds via hypervalent silicate intermediates. The allylation of aldehydes with allyltrichlorosilanes in the presence of a catalytic amount of BINAPO gave the allylated adducts in good enantioselectivities (up to 79% ee) wherein a combination of diisopropylethylamine and tetrabutylammonium iodide as additives was crucial to accelerate the catalytic cycle. ³¹P NMR analysis of the phosphine oxide suggested that the amine promoted the dissociation of phosphine oxide from silicon atom. BINAPO also promoted the enantioselective aldol reaction of aldehydes with trichlorosilyl enol ethers in the presence of diisopropylethylamine as an additive to afford the corresponding aldol adducts in high diastereo- and enantioselectivities (up to syn/anti=1/25, 96% ee (anti)).     

Kinetic Analysis of the Divergence of Reaction Pathways in the Chiral Lewis Base Promoted Aldol Additions of Trichlorosilyl Enol Ethers: A Rapid‐Injection NMR Study

The aldol addition reaction of trichlorosilyl enol ethers and aldehydes with and without chiral Lewis base catalysts has been kinetically analyzed. The uncatalyzed reactions display classic first‐order dependence on each component. The reactions catalyzed by bulky chiral phosphoramide 5 were examined by ReactIR and exhibited first‐order dependence on the catalyst. To examine the kinetic behavior of the reaction catalyzed by phosphoramide 4 , a Rapid‐Injection (RI) NMR apparatus was constructed and employed to allow rapid in‐situ mixing and monitoring of the reaction course. The aldol addition catalyzed by 4 displayed second‐order dependence on phosphoramide, thus providing direct evidence that two catalyzed pathways (with complimentary stereochemical consequences) exist that depend on phosphoramide structure and concentration. Arrhenius activation parameters for all three reactions showed striking characteristics of negligible enthalpies and extremely high entropies of activation. Comparison of these values was precluded by the existence of complex preequilibria in the catalyzed process.     

Gold-catalyzed hydrosilyloxylation driving tandem aldol and mannich reactions

The chemoselective formation of an enolate from alkyne in the presence of a carbonyl and imine group was realized, which constructed a variety of structural motifs under exceedingly mild reaction conditions in a tandem process. Reaction driving tandem hydrosilyloxylation/aldol reactions was achieved through the formation of enol silyl ethers catalytically generated in situ from readily available alkynes. These reactions were expanded to obtain β-amino enol silyl ethers in good yields via the tandem hydrosilyloxylation/isomerization/Mannich reaction.     

Novel enantioselective direct aldol-type reaction promoted by a chiral phosphine oxide as an organocatalyst

Chiral phosphine oxide successfully catalyzed the direct aldol-type reactions of cyclohexanone derivatives and benzaldehyde derivatives in high stereoselectivities. The reaction mechanism involves the in situ formation of trichlorosilyl enol ethers. The present reaction could be extended to the cross-aldol reactions between two aldehydes.     

Lewis base catalyzed Mannich-type reactions between trimethylsilyl enol ethers and aldimines

Lewis base catalyzed Mannich-type reaction between trimethylsilyl enol ethers and N-tosylaldimines is described. Nitrogen anions generated from amides or imides such as lithium benzamide or potassium phthalimide are found to be effective Lewis base catalysts in DMF at room temperature to afford the corresponding beta-amino carbonyl compounds in good to high yields; the oxygen anion generated from carboxylic acids such as lithium acetate was also found to be effective in dry DMF. The above-mentioned lithium acetate-catalyzed Mannich-type reaction between aldimines and various trimethylsilyl (TMS) enol ethers such as silyl ketene acetal proceeded smoothly even in water-containing DMF. Then, Lewis base catalyzed three-component Mannich-type reactions of TMS enol ether, tosylamide, and aromatic aldehyde having electron-withdrawing group such as p-nitrobenzaldehyde were investigated. The reaction proceeded smoothly to afford the corresponding beta-amino ester in good yield. Further, ammonium carboxylates such as tetrabutyl ammonium acetate or tetrabutyl ammonium benzoate were found to be more effective Lewis base catalysts in the above-mentioned Mannich-type reaction. The synthesis proceeded in various solvents at lower temperatures. The reaction between aldimines and TMS enol ethers generated from thioester and various ketones such as propiophenone or cyclohexanone also proceeded smoothly to afford the corresponding beta-amino carbonyl compounds in high yields with good to high anti-selectivities.     

Scope and limitations of chiral B-

A new chiral oxazaborolidine catalyst was prepared in situ from 3, 5-bis(trifluoromethyl)phenylboron dichloride and N-(p-toluenesulfonyl)-(S)-tryptophan. This catalyst is much more active than Corey's original catalyst for the Mukaiyama aldol reaction of aldehydes with silyl enol ethers. The observed syn selectivities and re-face attack of silyl enol ethers on carbonyl carbon of aldehydes imply that the extended-transition state model is applicable.     

Enantioselective aldol reactions of trichlorosilyl enol ethers catalyzed by chiral N,N-dioxides and monodentate N-oxides

Chiral N,N^′-dioxides and monodentate N-oxides were employed as catalysts in catalytic, enantioselective aldol reactions of trichlorosilyl enol ethers. The reactions of acyclic enol ethers using N,N^′-dioxides resulted in the anti-adducts from (E)-enol ethers and the syn-adducts from (Z)-enol ethers. The reactions of cyclic (E)-enol ethers using N,N^′-dioxides gave the anti-adducts, whereas monodentate N-oxides predominantly gave the syn-adducts.     

Unexpected ambidoselectivity in crossed-aldol reactions of α-oxy aldehyde trichlorosilyl enolates

The ambido-, stereo- and enantioselectivity of the phosphoramide-promoted aldol reactions of α-oxy aldehyde trichlorosilyl enolates with benzaldehyde has been investigated. Analysis of the products from α-tert-butyldimethylsilyloxy α-deuterioacetaldehyde trichlorosilyl enolate confirmed that this 1,2-bis-silyloxyethene derivative reacted as a tert-butyldimethylsilyl enolate rather than trichlorosilyl enolate in the aldol reaction with very high ambidoselectivity. The phosphoramide-coordinated trichlorosilyl group acted as an organizing center for the aldol reaction. From the aldol process, excellent anti-diastereoselectivity could be achieved. The enantioselectivity remained moderate to low for both anti- and syn-diastereomer with a wide range of phosphoramide catalysts. α-Triisopropylsilyloxy, phenoxy and benzyloxy acetaldehyde trichlorosilyl enolates also reacted in a similar fashion with benzaldehyde to give aldol products with varying degrees of selectivities.     

Zn(pybox)-complex-catalyzed asymmetric aqueous Mukaiyama-aldol reactions

Catalytic asymmetric aldol reactions in aqueous media have been developed using chiral zinc complex. The aldol products have been obtained in high yields, high diastereocontrol, and good level of enantioselectivity. Various aromatic and alpha,beta-unsaturated aldehydes and silyl enol ethers derived from ketones can be employed in this reaction to provide the aldol adducts in good to high yield. The elaborated catalytic system has been found as selective for aliphatic aldehydes as well.     

Oxovanadium(V)-Catalyzed Deoxygenative Coupling Reaction of Alcohols with Trimethylsilyl Enol Ethers in the Presence of MS3A

Oxovanadium(V)-catalyzed deoxygenative coupling reaction of allyl alcohols with trimethylsilyl enol ethers was demonstrated to afford γ,δ-unsaturated carbonyl compounds in one-step. The catalytic deoxygenative coupling reaction of allyl alcohols proceeded smoothly with both aromatic and aliphatic trimethylsilyl enol ethers. This catalytic deoxygenative coupling system could be applied to the deoxygenative coupling reaction of benzyl alcohols with trimethylsilyl enol ethers, providing the corresponding carbonyl compounds. Furthermore, a gram-scale catalytic synthesis of the γ,δ-unsaturated carbonyl compound was successfully performed to validate the scalability of this catalytic deoxygenative coupling reaction.     

Trichlorosilyl triflate for enantioselective direct-type aldol reaction with chiral phosphine oxide

Trichlorosilyl triflate, in the presence of a chiral Lewis base catalyst, provides an effective method for the enantioselective direct-type aldol reaction of aldehydes and ketones. A chiral Lewis base induces both the production and activation of trichlorosilyl enol ether, yielding an aldol product in good yield and with high diastereo- and enantioselectivities.     

Catalytic asymmetric aldol reactions in aqueous media using chiral bis-pyridino-18-crown-6-rare earth metal triflate complexes

Catalytic asymmetric aldol reactions in aqueous media have been developed using Pr(OTf)(3) and chiral bis-pyridino-18-crown-6 1. In the asymmetric aldol reaction using rare earth metal triflates (RE(OTf)(3)) and 1, slight changes in the ionic diameters of the metal cations greatly affected the diastereo- and enantioselectivities of the products. The substituents (MeO, Br) at the 4-position of the pyridine rings of the crown ether did not significantly affect the selectivities in the asymmetric aldol reaction, although they affected the binding ability of the crown ether with RE cations and the catalytic activity of Pr(OTf)(3)-crown ether complexes. From X-ray structures of RE(NO(3))(3)-crown ether complexes, it was found that they had similar structures regardless of the RE cations and the crown ethers used. Accordingly, the binding ability of the crown ether with the RE cation and the catalytic activity of the complex are important for attaining high selectivity in the asymmetric aldol reaction. Various aromatic and alpha,beta-unsaturated aldehydes and silyl enol ethers derived from ketones and a thioester can be employed in the catalytic asymmetric aldol reactions using Pr(OTf)(3) and 1, to provide the aldol adducts in good to high yields and stereoselectivities. In the case using the silyl enol ether derived from the thioester, 2,6-di-tert-butylpyridine significantly improved the yields of the aldol adducts.     

Construction of quaternary carbon centers by a base-catalyzed enantioselective aldol reaction and related reactions of trimethoxysilyl enol ethers

The aldol reactions of trimethoxysilyl enol ethers catalyzed by lithium binaphtholate were found to be powerful tools for the construction of quaternary asymmetric carbon centers. The stereoselectivities were greatly affected by the presence of water. Trimethoxysilyl enol ether derived from a cyclic ketone, such as cyclohexanone, was used as a substrate to obtain the anti-adduct preferentially under anhydrous conditions; by contrast, the syn-adduct was preferentially obtained under aqueous conditions with high stereoselectivity. The aldol-Tishchenko reaction of a trimethoxysilyl enol ether derived from acyclic ketones proceeded to give monoacyl 1,3-diol derivatives in high enantioselectivities.     

1-Phenylthio-3-vinyl-3-cyclohexenol, a new reagent for bis-annelation of silyl enol ethers

1-Phenylthio-3-vinyl-cyclohex-1-en-3-ol (2) has been synthesized and investigated as a new bis-annelation reagent for silyl enol ethers. Reagent 2 can be synthesized by a Grignard reaction of vinyl magnesium bromide with 3-phenylthiocyclohexenone. The reaction with silyl enol ethers takes place under Lewis acid catalysis and generally proceeds in good yields. The resulting phenylthiodienes can be hydrolyzed to enones, which have been cyclized in a homologous aldol reaction to polycyclic compounds.     

Catalytic,asymmetric Mannich-type reactions of N-acylimino esters: reactivity,diastereo- and enantioselectivity,and application to synthesis of N-acylated amino acid derivatives

In the presence of a catalytic amount of Cu(OTf)(2)-chiral diamine 3e complex, N-acylimino esters reacted with silyl enol ethers to afford the corresponding Mannich-type adducts in high yields with high enantioselectivities. A wide variety of silyl enol ethers derived from ketones, as well as esters and thioesters, reacted smoothly. In the reactions of alpha-substituted silyl enol ethers (alpha-methyl or benzyloxy), the desired syn-adducts were obtained in high yields with high diastereo- and enantioselectivities. Several intermediates for the synthesis of biologically important compounds were prepared using this novel catalytic asymmetric Mannich-type reaction, and at the same time, absolute and relative stereochemical assignments were made. In addition, it has been revealed that alkyl vinyl ethers reacted with N-acylimino esters in the presence of a catalytic amount of the Cu(II) catalyst to give the corresponding Mannich-type adducts in high yields with high enantioselectivities. This is the first example of catalytic asymmetric Mannich-type reactions with alkyl vinyl ethers. The reaction mechanism, structure of chiral catalyst-electrophile complexes, and transition states of these catalytic asymmetric reactions were assumed based on X-ray crystallographic analysis of the Cu(II)-chiral amine complex, PM3 calculations, and FT-IR analyses, etc. Finally, (1R,3R)-N-(3-hydroxy-1-hydroxymethyl-3-phenylpropyl)dodecanamide (HPA-12, 1), a new inhibitor of ceramide trafficking from endoplasmic reticulum to the site of sphingomyerin (SM) synthesis, has been synthesized efficiently using the present Mannich-type reaction as a key step. The synthesis involved three steps (two-pot), and total yield was 82.9%.     

Mesoporous aluminosilicate-catalyzed Mukaiyama aldol reaction of aldehydes and acetals

A mesoporous aluminosilicate (Al-MCM-41) was found to be an effective heterogeneous catalyst for the reaction of both aldehydes and acetals with silyl enol ethers or ketene silyl acetals to give the corresponding aldol adducts in moderate to high yields. The remarkable high catalytic activity of Al-MCM-41 over amorphous silica-alumina and aluminum-free mesoporous silicate was observed in the reaction. The solid acid catalyst could be recovered easily by filtration and the recovered catalyst was reusable in the same reactions without a significant loss of catalytic activity.     

Reduction of carbonyl compounds via hydrosilylation : I. Hydrosilylation of carbonyl compounds catalyzed by tris(triphenylphosphine)chlororhodium

The hydrosilylation of various carbonyl compounds such as simple aldehydes, simple ketones, α,β-unsaturated carbonyl compounds, α-diketones, acyl cyanides and ketones having an electron-withdrawing group on the α-carbon using tris(triphenylphosphine)chlororhodium as a catalyst is described. Solvolysis of these silyl ethers and silyl enol ethers afforded the corresponding reduced products. The hydrosilylation of α,β-unsaturated carbonyl compounds was found to proceed by 1,4-addition. An oxidative adduct of triethylsilane to the rhodium-(I) complex was obtained as a reaction intermediate. The structure of the adduct was discussed on the basis of its IR and far-IR spectra.     

Tris(pentafluorophenyl)silyl enol ethers: synthesis and aldol reactions

Silyl enol ethers bearing three pentafluorophenyl groups at the silicon atom are described. These compounds undergo uncatalyzed aldol reactions with aliphatic, α,β-unsaturated, and aromatic aldehydes. The observed reactivity is analyzed in terms of the Lewis acidity of the silyl fragment.     

A carbocationic route to 3-substituted 1,4-cycloheptadienes

The Lewis acid catalysed reaction of 5-chloro-1, 3-cycloheptadiene 4 with silyl enol ethers yields -cycloheptadienyl substituted carbonyl compounds in high yield. Since 4 is easily prepared from cycloheptatriene, and the cycloheptadienyl cation 3 is preferably attacked at 3-position, this reaction opens an efficient access to 3-substituted 1,4-cycloheptadienes.