Lewis base catalyzed aldol additions of chiral trichlorosilyl enolates and silyl enol ethers

[structures: see text] The consequences of double diastereodifferentiation in chiral Lewis base catalyzed aldol additions using chiral enoxysilanes derived from lactate, 3-hydroxyisobutyrate, and 3-hydroxybutyrate have been investigated. Trichlorosilyl enolates derived from the chiral methyl and ethyl ketones were subjected to aldolization in the presence of phosphoramides, and the intrinsic selectivity of these enolates and the external stereoinduction from chiral catalyst were studied. In the reactions with the lactate derived enolate, the strong internal stereoinduction dominated the stereochemical outcome of the aldol addition. For the 3-hydroxyisobutyrate- and 3-hydroxybutyrate derived enolates, the catalyst-controlled diastereoselectivities were observed, and the resident stereogenic centers exerted marginal influence. The corresponding trimethylsilyl enol ethers were employed in SiCl4/bisphosphoramide catalyzed aldol additions, and the effect of double diastereodifferentiation was also investigated. The overall diastereoselection of the process was again controlled by the strong external influence of the catalyst.     

The effects of a remote stereogenic center in the Lewis base catalyzed aldol additions of chiral trichlorosilyl enolates

Chiral trichlorosilyl enolates bearing a remote stereogenic center were employed in the phosphoramide-catalyzed aldol reaction. The additions of the methyl ketone enolates proceeded with only moderate diastereoselectivities. The addition of the Z-enolate to various aldehydes selectively produced the syn relative diastereomers. In both cases, the effect of the beta-silyloxy stereogenic center was modest, and the internal diastereoselection was mainly controlled by the catalyst. [reaction: see text]     

Diastereoselective protonation of enolates of chiral Schiff bases

Diastereoselective protonation of potassium enolates of chiral Schiff bases prepared from racemic α-amino esters and 2-hydroxypinan-3-one afforded, after mild cleavage of the imine function, optically active α-amino esters.     

Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates

Methods for the preparation of geometrically defined enoxy(trichlorosilanes) derived from ethyl ketone enolates have been developed. The addition of enoxy(trichlorosilanes) (trichlorosilyl enolates) to aldehydes proceeds with good yields in the presence of catalytic amounts of chiral phosphoramides. The reaction of Z-trichlorosilyl enolates to aryl aldehydes affords aldol products with good to excellent diastereo- and enantioselectivities. Phosphoramide-catalyzed aldol additions lacked substrate generality providing modest selectivities with unsaturated and aliphatic aldehydes. In all cases, the phosphoramide-catalyzed aldol addition of E-trichlorosilyl enolates to aldehydes provided good yields with moderate to good stereoselectivities.     

Chiral phosphoramide-catalyzed aldol additions of ketone trichlorosilyl enolates. Mechanistic aspects

The mechanism of the catalytic, enantioselective addition of trichlorosilyl enolates to aldehydes has been investigated. Kinetic studies using ReactIR and rapid injection NMR (RINMR) spectroscopy have confirmed the simultaneous operation of dual mechanistic pathways involving either one or two phosphoramides bound to a siliconium ion organizational center. This mechanistic dichotomy was initially postulated on the basis of catalyst loading studies and nonlinear effects studies. This duality explains the difference in reactivity and stereoselectivity of various classes of phosphoramides. Determination of Arrhenius activation parameters revealed that aldol addition occurs through the reversible albeit unfavorable formation of an activated complex, and natural-abundance 13C NMR kinetic isotope effect (KIE) studies have determined that the turnover limiting step is the aldol addition. A thorough examination of a range of phosphoramides has established empirical structure-activity selectivity relationships. In addition, the effects of catalyst loading, rate of addition, solvents, and additives have been studied and together allow the formulation of a unified mechanistic picture for the aldol addition.     

Asymmetric synthesis of beta-hydroxy amino acids via aldol reactions catalyzed by chiral ammonium salts

The Cinchona alkaloid derived chiral ammonium salt developed by Park and Jew functions as an effective catalyst for the synthesis of beta-hydroxy alpha-amino acids via asymmetric aldol reactions under homogeneous conditions. The syn diastereomers are obtained in good ee, and aryl-substituted aliphatic aldehydes are the best substrates for the reaction. These results represent the highest ee's obtained to date in direct aldol reactions of glycine equivalents catalyzed by inexpensive, readily prepared chiral ammonium salts.     

Titanium enolates of thiazolidinethione chiral auxiliaries: versatile tools for asymmetric aldol additions

[formula: see text] Asymmetric aldol additions using chlorotitanium enolates of thiazolidinethione propionates proceed with high diastereoselectivity for the "Evans" or "non-Evans" syn product depending on the nature and amount of the base used. With (-)-sparteine as the base, selectivities of 97:3 to > 99:1 were obtained for the Evans syn products with 2 equivalents of base and for the non-Evans syn when 1 equiv of base was employed. The thiazolidinethione auxiliaries are easily removed, and the aldol adducts can be readily transformed to various functional groups. Even direct reduction to the aldehyde with diisobutylaluminum hydride is possible.     

Diastereoselective aldol condensations of tin enolates with aldehydes

The reaction of tin enolates of cyclohexanone or propiophenone with benzaldehyde at ?78°C gives predominately the $\text{threo}$ aldol diastereomer.     

Diastereofacial selectivity via aldol reactions using ethyl dithioacetate and ethyl dithiopropionate enolates

The lithium enolate of ethyl dithioacetate reacts with α-methyl aldehydes to yield the aldol products in which the $\text{syn}$ configuration in the positions β and γ to the thiocarbonyl of the product is favored over the $\text{anti}$ configuration. This selectivity is solvent-dependent, and is enhanced at lower temperatures. In most cases, $\text{syn:anti}$ product ratios obtained under these conditions varied from 57:43 to >99:1, depending upon the structure of the α-methyl aldehyde. When the lithium enolate of ethyl dithiopropionate was allowed to react with α-methyl aldehydes, only two out of the four possible diastereomers were detected in the product mixtures.     

First asymmetric Abramov-type phosphonylation of aldehydes with trialkyl phosphites catalyzed by chiral Lewis bases

Chiral phosphine oxides (Lewis bases) catalyze silicon tetrachloride-mediated, enantioselective phosphonylation of aldehydes with trialkyl phosphites (Abramov-type reaction), which leads to optically active α-hydroxyphosphonates with moderate enantioselectivities. ³¹P NMR analysis of the phosphonylation of benzaldehyde with triethyl phosphite supports the assumed reaction mechanism.     

Concerning the diastereofacial selectivity of aldol reactions of chiral methyl ketone enolates: Evidence for remote chelation in the bafilomycin aldol reaction

Evidence is presented that the aldol reactions of the lithium enolates of 4 and 7 proceed preferentially by way of chelated transition structure 19.     

Diastereoselective aldol reactions of enolates generated from vicinally substituted trimethylsilylmethyl cyclopropyl ketones

[reaction: see text] Vicinally substituted trimethylsilylmethyl cyclopropyl ketones undergo facile desilylative ring opening with Lewis acids under mild conditions. The enolates, thus generated, undergo aldol addition with aldehydes and ketones. The diastereoselectivity of the reaction with aldehydes depends on the nature of the Lewis acid used. The resulting aldol product is easily converted into a substituted tetrahydrofuran derivative.     

Chemoselective aldol reaction of silyl enolates catalyzed by MgI(2) etherate

Mukaiyama-type aldol coupling of typical silyl enolates 2-4 with aryl or vinyl aldehydes and acetals was realized in the presence of 1-5 mol % of MgI(2) etherate (1) in a mild, efficient, and highly chemoselective manner. Iodide counterion, weakly coordinating peripheral ethereal ligands (Et(2)O) of Mg(II), and a noncoordinating reaction media (i.e. CH(2)Cl(2)) are among the critical factors for the unique reactivity of this catalytic system. [reaction: see text]     

Enantioselective aldol reaction mediated by chiral lithium amide bases

Highly enantioselective aldol reaction mediated by chiral lithium amide bases was achieved between some methylketones and aldehydes     

Asymmetric Diels-Alder reaction catalyzed by chiral bases

Anthrone has been found to react with N-methyl maleimide in the presence of catalytic amounts of various chiral β-amino alcohols. The optically active cycloadduct 3a has been obtained in excellent yield. Several features of the reaction have been studied.     

Chiral boron enolate aldol additions to chiral aldehydes

We have examined the double-diastereodifferentiating aldol addition reactions of chiral enolborinate 1a with chiral aldehydes leading to the corresponding aldol adducts with excellent levels of 1,5-anti diastereoselection.     

Stereoselective aldol additions of titanium enolates of N-acetyl-4-isopropyl-thiazolidinethione

The addition of chlorotitanium enolates of N-acetyl isopropyl thiazolidine-2-thione to aldehydes was investigated. The stereoselectivity of the aldol products was controlled by the number of equivalents of base added. The syn aldol product was obtained preferentially when 2 equiv of Lewis acid and 1 equiv of base were employed. The anti aldol product was obtained preferentially when 1 equiv of Lewis acid and 2 equiv of base were employed for unsaturated aldehydes. Unexpected results were found with hindered aldehydes when 2 equiv of base were employed.     

Diastereoselective aldol additions to alpha-amino-beta-silyloxy aldehydes. Divergent synthesis of aminodiols

A divergent protocol for substrate-controlled diastereoselective synthesis of aminodiols has been developed using nucleophilic Mukaiyama aldol additions to alpha-amino-beta-silyloxy aldehydes. The merged stereochemical impact on the diastereoselectivity of the polar alpha- and beta-substituents is highlighted. [reaction: see text]