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.     

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.     

Role of pseudoephedrine as chiral auxiliary in the "acetate-type" aldol reaction with chiral aldehydes; asymmetric synthesis of highly functionalized chiral building blocks

We have studied in depth the aldol reaction between acetamide enolates and chiral α-heterosubstituted aldehydes using pseudoephedrine as chiral auxiliary under double stereodifferentiation conditions, showing that high diastereoselectivities can only be achieved under the matched combination of reagents and provided that the α-heteroatom-containing substituent of the chiral aldehyde is conveniently protected. Moreover, the obtained highly functionalized aldols have been employed as very useful starting materials for the stereocontrolled preparation of other interesting compounds and chiral building blocks such as pyrrolidines, indolizidines, and densely functionalized β-hydroxy and β-amino ketones using simple and high-yielding methodologies.     

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.     

Double stereodifferentiation in the "acetate-type" aldol reaction with garner's aldehyde. Stereocontrolled synthesis of polyhydroxylated gamma-amino carbonyl compounds

[reaction: see text] The aldol reaction of acetamide enolates with protected chiral alpha-amino-beta-hydroxy aldehyde 1 (Garner's aldehyde) has been performed in a stereocontrolled way under double stereodifferentiation conditions using pseudoephedrine as the additional chiral information source attached to the enolate reagent. In addition, the obtained adduct has been transformed into other valuable chiral building blocks such as gamma-amino-beta,delta-dihydroxy acids, esters, and ketones.     

New asymmetric halo aldol reaction provides a novel approach to biologically important chiral cyclothers and cycloamines

[reaction: see text] A new asymmetric halo aldol reaction has been developed by reacting cyclopropyl carbonyl derived enolates with aldehydes. The absolute structure was unambiguously confirmed by X-ray structural analysis. Eight examples were reported with good yields and up to complete control of diastereomeric excesses. These halo aldol products have been readily cyclized in the presence of weak bases to produce chiral 2,3-disubstituted tetrahydrofuran derivatives in good yield without any observed epimerization.     

Synthetic control leading to chiral compounds

A highly diastereoselective cross aldol reaction is developed using divalent tin enolates formed from stannous trifluoromethanesulfonate and carbonyl compounds. The reaction is extended to a highly enantioselective cross aldol reaction employing chiral diamines derived from (S)-proline as ligands.     

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]     

Iron‐ and Bismuth‐Catalyzed Asymmetric Mukaiyama Aldol Reactions in Aqueous Media

We have developed asymmetric Mukaiyama aldol reactions of silicon enolates with aldehydes catalyzed by chiral Fe^II and Bi^III complexes. Although previous reactions often required relatively harsh conditions, such as strictly anhydrous conditions, very low temperatures (?78 °C), etc., the reactions reported herein proceeded in the presence of water at 0 °C. To find appropriate chiral water‐compatible Lewis acids for the Mukaiyama aldol reaction, many Lewis acids were screened in combination with chiral bipyridine L1 , which had previously been found to be a suitable chiral ligand in aqueous media. Three types of chiral catalysts that consisted of a Fe^II or Bi^III metal salt, a chiral ligand ( L1 ), and an additive have been discovered and a wide variety of substrates (silicon enolates and aldehydes) reacted to afford the desired aldol products in high yields with high diastereo‐ and enantioselectivities through an appropriate selection of one of the three catalytic systems. Mechanistic studies elucidated the coordination environments around the Fe^II and Bi^III centers and the effect of additives on the chiral catalysis. Notably, both Brønsted acids and bases worked as efficient additives in the Fe^II‐catalyzed reactions. The assumed catalytic cycle and transition states indicated important roles of water in these efficient asymmetric Mukaiyama aldol reactions in aqueous media with the broadly applicable and versatile catalytic systems.     

Diethylzinc-Mediated Cross-Coupling Reactions between Dibromoketones and Monobromo Carbonyl Compounds

A novel route to synthesize 1,4-dicarbonyl compounds is described. α,α-Dibromoketones generate zinc enolates through a diethylzinc-mediated halogen-metal exchange and react with α-bromocarbonyl compounds to furnish 1,4-dicarbonyl compounds via a second generation of zinc enolates. This cross-coupling reaction is enabled by the chemoselective formation of zinc enolates from α,α-dibromoketones in the presence of α-bromocarbonyl compounds. Chiral 1,4-dicarbonyl compounds can be obtained via the enantioselective bromination of aldehydes using a chiral secondary amine catalyst and a subsequent cross-coupling reaction between the resulting chiral α-bromoaldehydes and α,α-dibromoacetophenones.     

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.     

Highly diastereo- and enantioselective aldol reaction of methyl α-isocyanoacetate: a cooperative catalysis approach

The cooperative catalyst activity between a chiral transition-metal catalyst and an achiral organocatalyst has been identified as one of the critical asymmetric reaction optimization components in the highly diastereo- and enantioselective aldol reaction of methyl α-isocyanoacetate.     

The direct catalytic asymmetric aldol reaction of α-substituted nitroacetates with aqueous formaldehyde under base-free neutral phase-transfer conditions

Enantioselective direct aldol reaction of α-substituted nitroacetates with aqueous formaldehyde for the synthesis of α-alkyl serines has been achieved under base-free neutral phase-transfer conditions with a bifunctional chiral phase-transfer catalyst.     

1,5-asymmetric induction in boron-mediated beta-alkoxy methyl ketone aldol addition reactions

This article presents studies that illustrate beta-alkoxy methyl ketone-derived boron enolates undergo diastereoselective aldol addition to afford the 1,5-anti diol relationship. The stereochemical outcome of this reaction is documented to be general for a variety of beta-alkoxy methyl ketone analogues and aldehyde partners. The double stereodifferentiating reactions of these enolates with chiral beta-alkoxy aldehydes have also been investigated in conjunction with the possibility of controlling the absolute stereochemistry of the aldol process. With the proper selection of reaction conditions, the proximal alkoxy substituent on either the aldehyde (1,3-induction) or the enolate fragment (1,5-induction) can be employed to control facial selectivity of the aldol addition. Selection of a boron enolate ensures dominant 1,5-anti induction from the beta-alkoxy methyl ketone-derived enolate partner while negating any influence of the beta-alkoxy aldehyde substituent. Conversely, if stereochemical control from the beta-alkoxy aldehyde is desired, a Lewis acid-catalyzed enolsilane addition ensures dominant 1,3-induction from the aldehyde beta-oxygen substituent.     

Chiral N-Acetyl Selone-Promoted Aldol Reactions

The chiral oxazolidineselone functionality was found to be an excellent partner in the stereospecific acetate aldol reaction with aldehydes via the titanium enolates. Good stereocontrol was obtained as determined by NMR spectroscopy. The oxazolidineselone also provided a straightforward way to establish the stereopurity of the coupling reaction through ⁷⁷Se NMR spectroscopy.     

Development of catalytic asymmetric reactions via chiral palladium enolates

This article describes the generation of chiral palladium enolates and their application to several kinds of catalytic asymmetric reactions. Two methods to generate chiral enolates were developed using novel cationic palladium complexes 1 and 2 . In these processes, water or a hydroxo ligand on palladium metal plays an important role as a nucleophile to promote the transmetallation or as a Brønsted base to abstract an acidic α‐proton of the carbonyl group. These enolates showed sufficient reactivity with various electrophiles. Using a chiral Pd enolate as a key intermediate, highly enantioselective reactions such as catalytic aldol reactions, Mannich‐type reactions, Michael reactions, and fluorination reactions were developed. The unique structures of the palladium enolate complexes were elucidated and reaction mechanisms are proposed. © 2004 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 4: 231–242; 2004: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20017     

New Developments in Chiral Cooperative Ion Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From Protonation to Deprotonation Reactions.

This personal account summarizes our contribution to the ion pairing organocatalysis mainly by use of chiral quaternary or tertiary ammonium fluorides, aryloxides and carboxylates. Starting from an experimental observation, we were able to develop several approaches for the enantioselective protonation of silyl enolates and enol esters giving rise to chiral carbonyl compounds bearing a stereogenic center at the α‐position. Moving from protonation to deprotonation reactions, chiral ammonium ion pair catalysts were successfully applied to several asymmetric transformations such as an Henry reaction or a direct vinylogous aldol reaction to cite a few. An outlook of further possible developments in this field of research will also be discussed.     

Organocatalytic asymmetric aldol reaction of hydroxyacetone with β,γ-unsaturated α-keto esters: facile access to chiral tertiary alcohols

An efficient direct asymmetric aldol reaction between hydroxyacetone and β,γ-unsaturated α-keto esters has been successfully developed. In the presence of 9-amino-9-deoxy-epi-cinchonine and trifluoroacetic acid, the direct aldol reaction of O-protected hydroxyacetone proceeded in a highly enantioselective manner, affording the desired adducts containing a chiral tertiary alcohol in high yields and with excellent enantioselectivities. The aldol products obtained are valuable precursors for the synthesis of 2-substituted glycerol derivatives.     

Studies on the synthesis of bafilomycin A(1): stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C25) segment

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A(1) were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (gamma-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.     

1,5-Asymmetric induction in boron-mediated aldol reactions of beta-oxygenated methyl ketones

This tutorial review describes that high levels of substrate-controlled, 1,5-stereoinduction are obtained in the boron-mediated aldol reactions of beta-oxygenated methyl ketones with achiral and chiral aldehydes. Remote induction from the boron enolates gives the 1,5-anti adducts, with the enolate pi-facial selectivity critically dependent upon the nature of the beta-alkoxy protecting group. This 1,5-anti aldol methodology has been strategically employed in the total synthesis of several natural products with remarkable pharmacological activities. At present, the origin of the high level of 1,5-anti induction obtained with the boron enolates is unclear, although a model based on hydrogen bonding between the beta-alkoxy oxygen and the formyl aldehyde hydrogen has recently been proposed.