Asymmetric aldol reactions lewis base activation

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely />-hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

Compared to the great variety of Lewis acid catalysts for the catalytic asymmetric aldol reaction the field of nucleophilic (Lewis base) catalysts is less explored. This strategy involves the transient activation of the latent enolate equivalent via Lewis base coordination to the silyl enol ether (Scheme 9) [3], For instance the tri-chlorosilyl enol ether 50 is able to expand its valency at the silicon atom from four to five and six. It reacts with an aldehyde (51), proceeding through a closed Zimmerman-Traxler-like transition state (54), to give 53 after quenching with saturated aqueous NaHCO, [16]. 

The concept of Lewis base activation of Lewis acids was developed by Denmark, and it takes advantage of the fact that the Lewis acidity of silicon is increased when the coordination sphere is enlarged. If chiral Lewis bases are provided, here chiral phosphoramides and bisphosphoramide, SiCl can be efficiently employed in asymmetric Mukaiyama aldol reactions. The Lewis base activation can be performed on trichlorosilyl enolates (24), which can be generated in situ by mercury-mediated trans-silylalion of a TMS silyl enol ether (18) in the presence of SiCl. Generation of the hypervalent silicon species produces a more Lewis acidic silicon moiety, which acts to coordinate and activate the aldehyde that has to be brought to reaction (Scheme 2.128) [48]. 

The asymmetric catalysis of aldol reactions with chiral Lewis bases is an important method to form C-C bonds [130-139], The emergence of Lewis base-activated Lewis acid catalysis is pioneered by the Denmark group [140-142], They used a variety of chiral phosphoramides as catalysts for the enantioselective intermolecular aldol reactions (Scheme 7,20),... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Optically active l,l -binaphthols are among the most important chiral ligands of a variety of metal species. Binaphthol-aluminum complexes have been used as chiral Lewis acid catalysts. The l,T-binaphthyl-based chiral ligands owe their success in a variety of asymmetric reactions to the chiral cavity they create around the metal center [107,108]. In contrast with the wide use of these binaphthyls, the polymer-supported variety has been less popular. The optically active and sterically regular poly(l,l -bi-naphthyls) 96 have been prepared by nickel-catalyzed dehalogenating polycondensation of dibromide monomer 95 (Sch. 7) [109] and used to prepare the polybinaphthyl aluminum(III) catalyst 97 this had much greater catalytic activity than the corresponding monomeric catalyst when used in the Mukaiyama aldol reaction (Eq. 29). Unfortunately no enantioselectivity was observed in the aldol reaction. 

Recent developments in the field have also identified novel mechanistic pathways for the development of catalytic, asymmetric aldol processes. Thus in addition to Lewis acid catalysts that mediate the Mukaiyama aldol addition by electrophilic activation of the aldehyde reactant, metal complexes that lead to enolate activation by the formation of a metalloenolate have been documented. Additionally, a new class of Lewis-base-catalyzed addition reactions is now available for the asymmetric aldol addition reaction. 

Sinou and co-workers [73] studied the influence of different surfactants on the palladium-catalyzed asymmetric alkylation of l,3-diphenyl-2-propenyl acetate with dimethyl malonate in presence of potassium carbonate as base and non-water-soluble chiral ligands. Best results in activity and enatioselectivity (> 90% ee) were observed with 2,2 -bis(diphenylphosphino)-l,l -binaphthyl (BINAP) as ligand and cetyltrimethylammonium hydrogen sulfate as surfactant in aqueous medium. Water-stable Lewis acids as catalysts for aldol reactions were developed by Kobayashi and co-workers [74]. An acceleration of the reaction was indicated in presence of SDS as anionic surfactants. An additional promotion could be observed by combination of Lewis acid and surfactant (LASCs = Lewis acid-surfactant-combined catalysts) as shown in Eq. (3). Surfactant the anion of dodecanesulfonic acid. 

In conclusion, chiral heterobimetallic lanthanoid compexes LnMB, which were recently developed by Shibasaki et al., are highly efficient catalysts in stereoselective synthesis. This new and innovative type of chiral catalyst contains a Lewis acid as well as a Bronsted base moiety and shows a similar mechanistic effect as observed in enzyme chemistry. A broad variety of asymmetric transformations were carried out using this catalysts, including asymmetric C-C bond formations like the nitroaldol reaction, direct aldol reaction, Michael addition and Diels-Alder reaction, as well as C-0 bond formations (epoxidation of enones). Thereupon, asymmetric C-P bond formation can also be realized as has been successfully shown in case of the asymmetric hydrophosphonylation of aldehydes and imines. It is noteworthy that all above-mentioned reactions proceed with high stereoselectivity, resulting in the formation of the desired optically active products in high to excellent optical purity. 

The majority of metal-based Lewis acid catalysts used in the HDA reaction are moisture sensitive and are thus usually prepared in situ. The stable and storable zirconium-BINOL Lewis acids developed by Kobayashi and coworkers, effective in the aldol reaction (see Section 7.1) can also be used as asymmetric catalysts in the HDA reaction of aliphatic and aromatic aldehydes with dioxygenated dienes. Metal-free catalytic asymmetric HDA reactions have been developed, utilising enantiomerically pure protic molecules that activate the aldehyde component by hydrogen bonding to the carbonyl group. Rawal and coworkers have achieved up... 

Other chiral zinc based Lewis acid, such as zinc(II) complex with pybox, showed good stability in aqueous media and gave syn-adducts in moderate to excellent catalytic activity and enantioselectivity for asymmetric Mukaiyama aldol reactions (113,114). A simple combination of Lewis acidic zinc salt (Zn(OTf)2) and organocatalyst is also shown to be effective catalysts for the direct aldol reaction of acetone and aldehydes in the presence of water (115). 

A versatile y-vinylogous aldol reaction of a dioxinone-derived silyl enol ether, by enolate activation with an appropriate Lewis base, has been developed. Using chi- ral 2-(methylsulfinyl)benzaldehyde, adduct (69) has been obtained in high de and ee. 0 This 1,4-asymmetric induction features a dual role for the sulfinyl group chiral inductor and activator of a silyloxydiene. 

With the current emphasis on enantioselective synthesis, it is not surprising that numerous, highly successful asymmetric versions of aldol reaction have been developed. Noncatalytic methods involve the use of stoichiometric amounts of a chiral auxiliary in diastereoselective aldol reactions. Small-molecule-catalyzed aldol reactions typically would involve the use of a chiral Lewis acid for aldehyde activation or a chiral Lewis base for donor... 

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