Lewis base catalyzed, enantioselective aldol addition of methyl trichlorosilyl ketene acetal to ketones

The catalytic enantioselective addition of an acetate enolate equivalent to ketones is described. Methyl trichlorosilyl ketene acetal reacts with a wide range of ketones in the presence of pyridine N-oxide to afford the aldol addition products in excellent yields. Chiral 2,2'-pyridyl bis-N-oxides bearing various substituents at the 3,3'- and 6,6'-positions also provide excellent yields of the aldol products with variable enantioselectivities ranging from 94/6 er for aromatic ketones to nearly racemic for aliphatic ketones. An X-ray crystal structure of the complex between a catalyst and silicon tetrachloride (((P)-(R,R)-19.SiCl(4))) has been obtained. Extensive computational analysis provides a stereochemical rationale for the observed trends in enantioselectivities.     

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.     

Lewis base activation of lewis acids. Addition of silyl ketene acetals to aldehydes

The weak Lewis acid silicon tetrachloride can be activated by catalytic amounts of the chiral bisphosphoramide (R,R)-3 to form a highly reactive, chiral trichlorosilyl cation which is an extremely effective promoter of aldol addition reactions between aldehydes and silyl ketene acetals. The tert-butyldimethylsilyl ketene acetal of methyl acetate adds nearly instantaneously to aromatic and olefinic aldehydes as well as aliphatic aldehydes (albeit more slowly) with excellent enantioselectivity. The homologous tert-butyldimethylsilyl ketene acetal of tert-butyl propanoate adds with nearly exclusive anti diastereoselectivity to a similar range of aldehydes also with excellent enantioselectivity. The origin of the slower reaction rate with aliphatic aldehydes is revealed to be the formation of chlorosilyl ether adducts.     

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)).     

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.     

Biheteroaromatic diphosphine oxides-catalyzed stereoselective direct aldol reactions

A highly stereoselective direct aldol condensation of ketones to aromatic aldehydes was realized; the trichlorosilyl enolether generated in situ in the presence of tetrachlorosilane is activated by catalytic amounts of an enantiomerically pure biheteroaromatic phosphine oxide to react with aldehydes, coordinated as well as activated by the chiral cationic hypervalent silicon species. This Lewis acid-mediated Lewis base-catalyzed transformation allowed, starting from two carbonyl compounds, to directly synthesize β-hydroxy ketones generally with high anti stereoselectivity and up to 93% ee for the anti isomer.     

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.     

Enantioselective Aldol Reactions Catalyzed by Chiral Phosphine Oxides

The development of enantioselective aldol reactions catalyzed by chiral phosphine oxides is described. The aldol reactions presented herein do not require the prior preparation of the masked enol ethers from carbonyl compounds as aldol donors. The reactions proceed through a trichlorosilyl enol ether intermediate, formed in situ from carbonyl compounds, which then acts as the aldol donor. Phosphine oxides activate the trichlorosilyl enol ethers to afford the aldol adducts with high stereoselectivities. This procedure was used to realize a directed cross‐aldol reaction between ketones and two types of double aldol reactions (a reaction at one/two α position(s) of a carbonyl group) with high diastereo‐ and enantioselectivities.     

Diastereoselective aldol additions of chiral beta-hydroxy ethyl ketone enolates catalyzed by Lewis bases

The trichlorosilyl enolates derived from chiral ethyl ketones bearing a beta-hydroxyl group and an alpha-stereogenic center were employed in the phosphoramide-catalyzed aldol reaction. The addition of Z-enolates to achiral aldehydes produced aldol products in good yields and high syn relative diastereoselectivities. The internal diastereoselectivity is controlled by the catalyst configuration, allowing for selective formation of either syn diastereomer. [reaction: see text]     

Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions.

Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with commercially available chiral cyclic secondary amines as catalysts. Structure-based catalyst screening identified L-proline and 5,5-dimethyl thiazolidinium-4-carboxylate (DMTC) as the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding aldol products with high regio-, diastereo-, and enantioselectivities. Reactions employing hydroxyacetone as an aldol donor provide anti-1,2-diols as the major product with ee values up to >99%. The reactions are assumed to proceed via a metal-free Zimmerman-Traxler-type transition state and involve an enamine intermediate. The observed stereochemistry of the products is in accordance with the proposed transition state. Further supporting evidence is provided by the lack of nonlinear effects. The reactions tolerate a small amount of water (<4 vol %), do not require inert reaction conditions and preformed enolate equivalents, and can be conveniently performed at room temperature in various solvents. In addition, reaction conditions that facilitate catalyst recovery as well as immobilization are described. Finally, mechanistically related addition reactions such as ketone additions to imines (Mannich-type reactions) and to nitro-olefins and alpha,beta-unsaturated diesters (Michael-type reactions) have also been developed.     

Diastereo- and Enantioselective Reductive Aldol Addition of Vinyl Ketones via Catalytic Hydrogenation

An overview of studies on hydrogenative reductive aldol addition is presented. By simply hydrogenating enones in the presence of aldehydes at ambient temperature and pressure, aldol adducts are generated under neutral conditions in the absence of any stoichiometric byproducts. Using cationic rhodium complexes modified by tri(2-furyl)phosphine, highly syn-diastereoselective reductive aldol additions of vinyl ketones are achieved. Finally, using novel monodentate TADDOL-like phosphonite ligands, the first highly diastereo- and enantioselective reductive aldol couplings of vinyl ketones were devised. These studies, along with other works from our laboratory, demonstrate that organometallics arising transiently in the course of catalytic hydrogenation offer byproduct-free alternatives to preformed organometallic reagents employed in classical carbonyl addition processes.     

Catalytic enantioselective alkylative aldol reaction: efficient multicomponent assembly of dialkylzincs, allenic esters, and ketones toward highly functionalized delta-lactones with tetrasubstituted chiral centers

A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized delta-lactones were produced in the presence of a catalytic amount of the Cu(OAc)2-DIFLUORPHOS complex through three-component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs two C-C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkylcopper species to an allenic ester produced highly active copper enolate in situ, and the successive asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The addition of MS4A and Lewis base (Ph2S=O, DMSO, or HMPA) is important for obtaining a high yield, with suppression of the undesired alpha-addition pathway. Control/crossover experiments suggest that the addition of a Lewis base facilitated the retro-aldol reaction of the alpha-adducts (proofreading effect). The ketone and copper enolate generated through the retro-aldol reaction were converted to the desired lactone through the gamma-aldol pathway, which was trapped by irreversible lactone formation.     

Organocatalytic asymmetric direct aldol reactions of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones

The organocatalytic asymmetric direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones in the presence of a catalytic amount of (S)-5-(pyrrolidin-2-yl)-1H-tetrazole in dichloroethane at 40 °C proceeds smoothly to produce (R)-4,4,4-trifluoro-1-aryl-3-hydroxy-1-butanones in high yields with up to 90% ee.     

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]     

Enantioselective reductive aldol reaction using tertiary amine as hydride donor

An efficient method was developed for the enantioselective reductive aldol reaction of α,β-unsaturated ketones with aldehydes in the presence of a Lewis base catalyst; conjugate reduction using a tertiary amine and trichlorosilyl triflate, followed by an aldol reaction with BINAP dioxide (BINAPO) as an organocatalyst, gave the corresponding product in high yield with high stereoselectivity.     

L-脯氨酸催化下甲基酮和1-芳基-2,2,2-三氟乙酮的不对称Aldol反应

Direct asymmetric aldol addition of methyl ketones to 2,2,2-trifluoro-1-phenylethanone and its ring-substituted derivatives was achieved using L-proline as a chiral promoter. Various optically active β-trifluoromethyl-β-hydroxy ketones were obtained in almost quantitative yields with moderate enantioselectivities up to 64 % ee.     

Direct asymmetric aldol reactions inspired by two types of natural aldolases: water-compatible organocatalysts and Zn(II) complexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.     

Catalytic Enantioselective Direct Aldol Addition of Aryl Ketones to α-Fluorinated Ketones

The catalytic enantioselective synthesis of α-fluorinated chiral tertiary alcohols from (hetero)aryl methyl ketones is described. The use of a bifunctional iminophosphorane (BIMP) superbase was found to facilitate direct aldol addition by providing the strong Brønsted basicity required for rapid aryl enolate formation. The new synthetic protocol is easy to perform and tolerates a broad range of functionalities and heterocycles with high enantioselectivity (up to >99:1 e.r.). Multi-gram scalability has been demonstrated along with catalyst recovery and recycling. ¹H NMR studies identified a 1400-fold rate enhancement under BIMP catalysis, compared to the prior state-of-the-art catalytic system. The utility of the aldol products has been highlighted with the synthesis of various enantioenriched building blocks and heterocycles, including 1,3-aminoalcohol, 1,3-diol, oxetane, and isoxazoline derivatives.     

Dramatic ligand effect in catalytic asymmetric reductive aldol reaction of allenic esters to ketones

A general catalytic asymmetric reductive aldol reaction of allenic esters to ketones is described. Two distinct constitutional isomers were selectively produced depending on the reaction conditions. A combination of CuOAc/(R)-DTBM-SEGPHOS/PCy3 as the catalyst predominantly produced gamma-cis-products in high yield with excellent enantioselectivity (up to 99% ee). The reaction was applicable to both aromatic and aliphatic ketones, including unsaturated ketones. On the other hand, CuF-Taniaphos complexes produced alpha-aldol products with high diastereo- and enantioselectivity (up to 84% ee). The new Taniaphos derivative L3, containing di(3,5-xylyl)phosphine and morpholine units, produced optimum results in the alpha-selective reaction. The products are versatile chiral building blocks in organic synthesis. Furthermore, the basic reaction pattern (i.e., conjugate addition-aldol reaction) was extended to a catalytic enantioselective alkylative aldol reaction to ketones using dialkylzinc reagents as the initiator.     

Current progress in the asymmetric aldol addition reaction

Control of stereochemistry during aldol addition reactions has attracted considerable interest over the years as the aldol reaction is one of the most fundamental tools for the construction of new carbon-carbon bonds. Several strategies have been implemented whereby eventually any single possible stereoisomeric aldol product can be accessed by choosing the appropriate procedure. With earlier methods, stoichiometric quantities of chiral reagents were required for efficient asymmetric induction, with the auxiliary most often attached covalently to the substrate carbonyl. Lewis acid catalyzed addition reactions of silyl enolates to aldehydes (Mukaiyama reaction) later opened the way for catalytic asymmetric induction. In the last few years, both chiral metal complexes and small chiral organic molecules have been found to catalyse the direct aldol addition of unmodified ketones to aldehydes with relatively high chemical and stereochemical efficiency. These techniques along with the more recent developments in the area are discussed in this tutorial review.