Catalyst Bronsted base asymmetric

Shibasaki and co-workers reported an elegant asymmetric total synthesis of 11-deoxy-PGFic 19 using the Al-Li bis(binaphthoxide) complex (ALB) 21 [15], a member of a novel class of heterobimetallic chiral catalysts showing dual behavior as both a Bronsted base and a Lewis acid (Scheme 12.5) [16]. 

Shibasaki and coworkers have conducted extensive research on the use of hetero-bimetallic complexes as catalysts for asymmetric synthesis [11]. The reactions are catalyzed by heterobimetallic complexes that function as both a Lewis acid and a Bronsted base. Among these, LaLi3tris(binaphthoxide) catalyst 1 (LLB) was proven to be an effective catalyst in direct asymmetric aldol reactions (Fig. 1) [12]. On the basis of this research, Shibasaki et al. reported the first report of a direct catalytic asymmetric Mannich reaction [13],... 

Recently, Liu has developed a Bronsted acid activated trifunctional organocatalyst, based on the BINAP scaffold, that was used for the first time to catalyze aza MBH reactions between N tosylimines and MVK with fast reaction rates and good enantioselectivity at room temperature. This trifunctional catalyst containing a Lewis base, a Bronsted base and a Bronsted acid, required add activation to confer its enantioselectivity and rate improvement for both electron rich and electron deficient imine substrates. The role of the amino Lewis base of 27 was investigated and found to be the activity switch in response to an acid additive. The counterion of the acid additive was found to influence not only the excess ratio but also the sense of asymmetric induction (Scheme 13.23) [36]. 

The use of alkali metal-containing, heterobimetallic lanthanoid complexes as catalysts in asymmetric synthesis is reviewed. This new and innovative type of chiral catalyst, which was recently developed by Shibasaki et al., contains a Lewis acid as well as a Bronsted base moiety, thereupon showing a similar mechanistic effect as observed in enzyme chemistry. The heterobimetallic complexes have been successfully applied as highly stereoinducing catalysts in many different types of asymmetric reactions, including the stereoselective formation of C-C, C-O, and C-P bonds. 

All of the above methods introduce the aryl group during the enantiodetermining step. An alternative strategy would be to already have the aryl group in place and to generate the tertiary stereocentre via an asymmetric protonation of an enolate complex. This was first reahsed by the pioneering work of Yamamoto in this area with the use of Lewis acid assisted chiral Bronsted acid (LBA) catalysts in the enantioselective synthesis of a-aryl cyclohexanones ((2), Scheme 4.34). Initially developed with the use of stoichiometric quantities of a BlNOL-SnCLi catalyst for the asymmetric protonation of silyl enol ethers, [63] the extensive development of this reaction has resulted in a catalytic variant with an achiral proton donor [64] and expansion of the scope to include tertiary a-aryl carboxylic acids. [65] Further improvement was made with the development of a metal free IV-triflyl thiophos-phoramide BINOL derived proton source (126) [66] and more recently a Lewis base-tolerant chiral LBA [67]. 

Fine-tuning of the substrate and reaction conditions is also critical for the asymmetric F-C alkylation of electron-rich aromatic compounds with functionalized aldehydes, ketones and imines. Both the regioselectivity and enantioselectivity of these alkylation reactions can be mediated through use of a complexing chiral catalyst. The catalyst may be either a Lewis or Bronsted base. 

The postulated catalytic cycle of the asymmetric epoxidation reaction is shown in Figure 13.10. A lanthanide metal alkoxide moiety changes to a rare earth metal-peroxide through proton exchange (I). In this step, lanthanide metal alkoxide moiety functions as a Bronsted base. The rare earth metal-BINOL complex also functions as a Lewis acid to activate electron-deficient olefins through monoden-tate coordination (II). Enantioselective 1,4-addition of rare earth metal-peroxide gives intermediate enolate (III), followed by epoxide formation to regenerate the catalyst (IV). 

Nature s aldolases use combinations of acids and bases in their active sites to accomplish direct asymmetric aldolization of unmodified carbonyl compounds. Aldolases are distinguished by their enolization mode - Class I aldolases use the Lewis base catalysis of a primary amino group and Class II aldolases use the Lewis acid catalysis of a Zinc(II) cofactor. To accomplish enolization under essentially neutral, aqueous conditions, these enzymes decrease the pKa of the carbonyl donor (typically a ketone) by converting it into a cationic species, either an iminium ion (5) or an oxonium ion (8). A relatively weak Bronsted base co-catalyst then generates the nucleophilic species, an enamine- (6) or a zinc enolate (9), via deprotonation (Scheme 4.2). 

In 2007, Ooi and coworkers introduced chiral tetraaminophosphonium salts as a new class of Bronsted acids [166]. Similar to the guanidine/guanidinium case, these tetraaminophosphonium salts act as Bronsted bases in their neutral/ deprotonated (triaminoiminophosphorane) form, while they can also be used as mono-functional Bronsted acids in their protonated, phosphonium form. Phos-phonium salt 67, when neutralized in situ with KO Bu, was shown to be a highly effective catalyst in the enantioselective Henry reaction of nitroalkanes with various aromatic and aliphatic aldehydes (Scheme 10.65). The same strategy was further applied to the catalytic asymmetric Henry reaction of ynals [167] and hydrophosphonylation of ynones (Scheme 10.66) [168]. Brfunctional catalysis using this scaffold were also obtained using the carboxylate salts of tetraaminophosphoniums in the direct Mannich reaction of sulfonyl imines with azlactones (Scheme 10.67) [169]. 

The focus of organocatalytic Bronsted bases will continue to evolve towards catalysts that can more efficiently activate reaction systems that may seem feasible in theory yet, in practice, encounter energy barriers that prevent the desired yields and selectivity. Our evolving knowledge of the asymmetric organocatalytic field, complemented by computational resources, can offer new avenues of exploration towards rational design of new scaffolds. 

Tetraaminophosphonium carboxylates and phenoxides have also been developed as chiral Bronsted base catalysts for asymmetric Mannich reachons and conjugate addihons [6c, 33]. These catalysts recognized and achvated the nucleophiles through the hydrogen-bonding network (Scheme 14.10). 

Nucleophilic or Bronsted base catalysts have been used in a range of asymmetric transformations, many of which have been catalysed by... 

The synthetic utility of the bifunctional catalysts in various organic transformations with chiral cyclohexane-diamine derived thioureas was established through the works of Jacobsen, Takemoto, Johnston, Li, Wang, and Tsogoeva. In the last decade, asymmetric conjugate-type reactions have become popular with cinchona alkaloid derived thioureas. The next section presents non-traditional asymmetric reactions of nitroolefins, enones, imines, and cycloadditions to highlight the role of chiral Bronsted base derived thiourea catalysts. 

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