Bronsted aldol reactions

Montmorillonite K10 was also used for aldol the reaction in water.280 Hydrates of aldehydes such as glyoxylic acid can be used directly. Thermal treatment of K10 increased the catalytic activity. The catalytic activity is attributed to the structural features of K10 and its inherent Bronsted acidity. The aldol reactions of more reactive ketene silyl acetals with reactive aldehydes proceed smoothly in water to afford the corresponding aldol products in good yields (Eq. 8.104).281... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... 

LA represents Lewis acid in the catalyst, and M represents Bren sled base. In Scheme 8-49, Bronsted base functionality in the hetero-bimetalic chiral catalyst I can deprotonate a ketone to produce the corresponding enolate II, while at the same time the Lewis acid functionality activates an aldehyde to give intermediate III. Intramolecular aldol reaction then proceeds in a chelation-controlled manner to give //-keto metal alkoxide IV. Proton exchange between the metal alkoxide moiety and an aromatic hydroxy proton or an a-proton of a ketone leads to the production of an optically active aldol product and the regeneration of the catalyst I, thus finishing the catalytic cycle. 

During our investigations of the reactions mediated by LASCs, we have found that addition of a small amount of a Bronsted acid dramatically increased the rate of the aldol reaction (Eq. 5).[191 This cooperative effect of a LASC and an added Bronsted acid was also observed in the allylation ofbenzalde-hyde with tetraallyltin in water.1201 Although, from a mechanistic point of view, little is known about the real catalytic function of scandium and proton, this cooperative effect of a Lewis acid and a Bronsted acid provides a new methodology for efficient catalytic systems in synthetic chemistry. 

The catalytic asymmetric aldol reaction has been applied to the LASC system, which uses copper bis(-dodecyl sulfate) (4b) instead of CufOTf. 1261 An example is shown in Eq. 6. In this case, a Bronsted add, such as lauric add, is necessary to obtain a good yield and enantioseledivity. This example is the first one involving Lewis acid-catalyzed asymmetric aldol reactions in water without using organic solvents. Although the yield and the selectivity are still not yet optimized, it should be noted that this appredable enantioselectivity has been attained at ambient temperature in water. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

Shibasaki et al. also developed a barium complex (BaB-M, 14, Scheme 5) for the aldol reaction of acetophenone (la), making use of the strongly basic characteristic of barium alkoxide. The catalyst was prepared from Ba(0-z-Pr)2 and BINOL monomethyl ether, and the products were obtained in excellent yield with up to 70% ee (Scheme 6) [8], Shibasaki et al. attempted to incorporate a strong Bronsted base into the catalyst and developed a lanthanide heterobime-tallic catalyst (15) possessing lithium alkoxide moieties, which promoted the aldol reaction with up to 74% ee (Scheme 6) [9]. Noyori and Shibasaki et al. reported a calcium alkoxide catalyst (16) that was prepared from Ca[N(SiMe3)2]2,... 

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],... 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

Figure 2.26 Cascade reactions requiring both strong acid and basic Bronsted sites reaction scheme and pictorial representation of tandem deprotection-aldol reaction with different acids and basic steps using a combination of Ti -montmorillonite (Ti -mont) and hydrotalcite (HT). Elaborated from the results of Kaneda et al. [219], Source adapted from Centi and Perathoner [211].

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 diastereoselectivity of the reaction was independent of the catalyst but was affected by the nature of the solvent. The threo isomer was preferentially formed in toluene, while the erythro isomer was formed in 1,2-dimethoxy-ethane. The proton-exchanged montmorillonite (H+-mont) showed similar activity and diasteroselectivity to Al3+-mont. This fact suggests that the exchangeable Al3+ cations in the montmorillonite do not function as Lewis acid sites and it is the Bronsted acid sites that are essential for catalysis of the aldol reaction. 

As a result of the preliminary examples described in Sect. 3.1 and the quest for automation techniques in solution-phase synthesis, various examples of continuous flow processes appeared in the literature lately which utilized solid-phase-bound chemical catalysts. In a simple example, Yamamoto and coworkers studied the use of super Bronsted acids loaded on polystyrene beads 5 for use in a single-pass column system (Fig. 4) [30]. It was shown that these columns are suited for the acetylation of alcohols, acetalization of carbonyl compounds, Sakurai-Hosomi allylation reactions, and Mukaiyama aldol reactions. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

For aldol reactions, typically proline-type catalysts were used. However, Palomo and coworkers reported cross-aldol reactions between unmodified aldehydes and ynals. This transformation was enabled by the cooperative action of newly designed catalyst C7, copper iodide and a Bronsted acid. In this way, remarkably high levels of diastereo- and enantioselectivily were achieved (Scheme 8.32). 

---