Catalysts aldol additions, catalytic asymmetric

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... 

The studies summarized above clearly bear testimony to the significance of Zr-based chiral catalysts in the important field of catalytic asymmetric synthesis. Chiral zircono-cenes promote unique reactions such as enantioselective alkene alkylations, processes that are not effectively catalyzed by any other chiral catalyst class. More recently, since about 1996, an impressive body of work has appeared that involves non-metallocene Zr catalysts. These chiral complexes are readily prepared (often in situ), easily modified, and effect a wide range of enantioselective C—C bond-forming reactions in an efficient manner (e. g. imine alkylations, Mannich reactions, aldol additions). 

Lewis acids as water-stable catalysts have been developed. Metal salts, such as rare earth metal triflates, can be used in aldol reactions of aldehydes with silyl enolates in aqueous media. These salts can be recovered after the reactions and reused. Furthermore, surfactant-aided Lewis acid catalysis, which can be used for aldol reactions in water without using any organic solvents, has been also developed. These reaction systems have been applied successfully to catalytic asymmetric aldol reactions in aqueous media. In addition, the surfactant-aided Lewis acid catalysis for Mannich-type reactions in water has been disclosed. These investigations are expected to contribute to the decrease of the use of harmful organic solvents in chemical processes, leading to environmentally friendly green chemistry. 

LLB, KHMDS (0.9 equiv to LLB) and H20 (1 equiv to LLB), which presumably forms a heteropolymetallic complex (LLB-ID, was found to be a superior catalyst for the direct catalytic asymmetric aldol reaction giving 49 in 89 % yield and 79 % ee (using 8 mol% of LLB). We employed this method to generate KOH in situ because of its insolubility in THE The use of KO-t-Bu instead of KHMDS gave a similar result, indicating that HMDS dose not play a key role. Interestingly, further addition of H20 (1 equiv with respect to LLB) resulted in the formation of 49 in 83 % yield and higher ee. The powder obtained from the cata-... 

Until then, only heterogeneous catalyst had been successful. However, in the mid-1980s, the work of Ito et al. led to an outstanding discovery in a catalytic asymmetric aldol reaction. In this case, enantioselectivity was given by a chiral ferrocene diphosphine ligand, with a carbon nucleophile addition to a carbonyl... 

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

Aldol additions to methyl pyruvate by silyl ketene thioacetals have been shown to proceed in high yield and with excellent asymmetric induction (Eq. 28). This process is an uncommon example of catalytic, asymmetric aldol additions to ketones, providing access to synthetically useful compounds. The remarkable ability of the catalyst to differentiate between subtle steric differences of substituents flanking a 1,2-diketone has been elegantly demonstrated in highly enantioselective additions to 2,3-pentane-dione (Eq. 29). Tlie aldol adduct of 5-ferr-butyl thiopropionate derived silyl ketene acetal afforded 2,3-anh-aldol adduct (>99 1 antilsyn) in 98 % ee and 97 3 chemoselec-tivity for the methyl ketone. 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

Several of the aldol products obtained were readily converted to their corresponding esters by Baeyer-Villiger oxidation. These results also are summarized in Table 16. Ester 66 was further transformed into key epothilone A intermediate 69 and also a key synthetic intermediate 70 for bryostatin 7. What is the mechanism of these direct catalytic asymmetric aldol reactions using LLB-II It is apparent that self-assembly of LLB and KOH occms, because of the formation of a variety of aldol products in high ee and yields. In addition, the NMR and LDI-TOF(-i-)MS spectra of LLB KOH show the occurrence of rapid exchange between Li and K. We have already found that LPB[LaK3tris(binaphthoxide)] itself is not a useful catalyst for aldol reactions, and that the complexes LPB KOH or LPB LiOH give rise to much less satisfactory results. 

A possible way to induce enantioselectivity in the aldol reaction is to empioy a chirai catalyst. M. Shibasaki and coworkers developed a bifunctional catalyst, (S)-LLB (L=lanthanum LB=lithium binaphthoxide), which could be successfully applied in direct catalytic asymmetric aldol reactions. An improved version of this catalyst derived from (S)-LLB by the addition of water and KOH was utilized in the formal total synthesis of fostriecin. ... 

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. 

This concept of Lewis base catalysis has been widely developed by Denmark and coworkers in the asymmetric aldol additions of trichlorosilyl enolates on aldehydes. These reactions were shown to be highly susceptible to acceleration by catalytic quantities of chiral phosphoramides [69-77]. In particular, a phos-phoramide derived from (S,S)-stilbenediamine was remarkably effective not only in accelerating the reaction but also in modulating the diastereoselectivity and in providing the aldol addition products in good to excellent enantioselec-tivity. For example, trichlorosilyl enolate 61 reacts with benzaldehyde in very high enantio- and diastereoselectivity with 10 mol% of phosphoramide 62 in favor of the anti diastereomer (antifsyn 60/1). The catalyzed aldol reaction depends on the bulkiness and loading of the catalyst. On the other hand, the hindered phosphoramide (S,S)-63 afforded the syn aldol product in excellent diastereoselectivity (anti syn 1/97) but with modest enantioselectivity. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

The rapid evolution of catalytic reaction methods for enantioselective aldol additions affords newer processes that are increasingly practical in their execution for a broad range of substrates prescribing minuscule amounts of catalyst. However, when compared to other catalytic asymmetric processes such as hydrogenation, dihydroxylation, and epoxidation it is evident that there is much room for further optimization. Without doubt, discovery and innovation in this area of C-C bond-forming reactions will lead to the development of catalysts and processes indispensable to the synthesis of optically active, stereochemically complex structures with applications in materials science and medicine. 

A series of reports by Mukaiyama and coworkers have highlighted the ability of triarylmethyl cations to function as promoters for the aldol addition reaction of enol silanes and aldehydes [27a, 27b, 27c, 27d, 27e, 27f, 27g, 90]. Subsequent studies by Denmark have provided the mechanistic and conceptual groundwork for the design of catalytic strategies utihzing 1-phenyldibenzosuberyl perchlorate 237 and triflate 238 salts as novel carbon-based Lewis acid catalysts for asymmetric aldol addition reactions [73]. 

In our illustration of the graphical manipulations of data using reaction progress kinetic analysis, we will make use of the example of a model reaction, the intermolecnlar aldol reaction between acetone 1 and aldehyde 2 to form the aldol addition product 3, mediated by proline 4, as shown in Scheme 27.1. The demonstration by List, Lemer, and Barbas in 2000 that proline mediates intermolecular aldol reactions with a high degree of asymmetric induction heralded a revolution in the field of organocatalysis, encompassing the discovery of new catalysts and new catalytic transformations." ... 

In all of the examples considered so far, the chiral element has been employed in stoichiometric quantities. Ultimately, it would be desirable to require only a small investment from the chirality pool. This is only possible if the chiral species responsible for enantioselectivity is catalytic. It is worth stating explicitly that, in order to achieve asymmetric induction with a chiral catalyst, the catalyzed reaction must proceed faster than the uncatalyzed reaction. One example of an asymmetric aldol addition that has been studied is variations of the Mukaiyama aldol reaction [110] whereby silyl enol ethers react with aldehydes with the aid of a chiral Lewis acid. These reactions proceed via open transition structures such as those shown in Figure... 

The aldol reaction and related processes have been of considerable importance in organic synthesis. The control of syn/anti diastereoselectivity, enantioselectivity and chemoselectivity has now reached impressive levels. The use of catalysts is a relatively recent addition to the story of the aldol reaction. One of the most common approaches to the development of a catalytic asymmetric aldol reaction is based on the use of enantiomerically pure Lewis acids in the reaction of silyl enol ethers with aldehydes and ketones (the Mukaiyama reaction) and variants of this process have been developed for the synthesis of both syn and anti aldol adducts. A typical catalytic cycle is represented in Figure 7.1, where aldehyde (7.01) coordinates to the catalytic Lewis acid, which encourages addition of the silyl enol ether (7.02). Release of the Lewis acid affords the aldol product, often as the silyl ether (7.03). 

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