Catalyst catalytic aldol reaction

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Aldol reactions using a carbocation as an organocatalyst An organocatalytic aldol reaction based on a different concept was developed by the Chen group. The chiral triarylcarbenium ion 34 was used as a novel non-metallic Lewis acid catalyst in a Mukaiyama-type aldol reaction which led to enantiomerically enriched aldol products (Scheme 6.17) [67]. Although non-chiral trityl salt-mediated catalytic aldol reactions had previously been reported by Mukaiyama and co-workers [68], the construction of a suitable chiral carbenium ion remained a challenge. Optically active salts of type 34 were synthesized as Lewis acids based on a reactive carbe-... 

It is worth noting that, in a similar manner to enzymatic conversions with type I or II aldolases, a direct asymmetric aldol reaction was achieved when L-proline was used as catalyst. Accordingly, the use of enol derivatives of the ketone component is not necessary, i.e. ketones (acting as donors) can be used directly without previous modification [72]. So far, most asymmetric catalytic aldol reactions with... 

In addition to the many intermolecular asymmetric (organo)catalytic aldol reactions, analogous intramolecular syntheses are also possible. In this connection it is worthy of note that the first example of an asymmetric catalytic aldol reaction was an intramolecular reaction using an organic molecule, L-proline, as chiral catalyst. This reaction - which will be discussed in more detail below - is the so-called Hajos-Parrish-Eder-Sauer-Wiechert reaction [97-101], which was discovered as early as the beginning of the 1970s. 

The asymmetric catalytic aldol reaction of silyl allenolates ICH=C=CR2OSiMe3 with aldehydes R CHO has been achieved by Li et al. by using N-C3F7CO oxazaborolidine as the catalyst [43], The fluoroacyl group of the catalyst was found to be crucial for control of enantioselectivity. The reaction provides the first enantioselective approach to / -halo Baylis-Hillman-type adducts. 

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]. 

Chiral amines (both primary and secondary amines) and amino acids have been used as catalysts for aldol reactions, Mannich-type reactions, and other reactions that proceed through enamine intermediates. An enamine-based catalytic cycle is shown in Scheme 2.1. The catalytic cycle includes formation of an iminium intermediate between a donor carbonyl compound and the amine-containing catalyst, the formation of an enamine intermediate from the iminium, C-C bond forma-... 

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C2 symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93]. 

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. 

Enantiomerically pure boron-based Lewis acids have also been used successfully in catalytic aldol reactions. Corey s catalyst (7.10a) provides good enantioselectivity with ketone-derived silyl enol ethers, including compound (7.11). Other oxazaborolidine complexes (7.13) derived from a,a-disubstituted a-amino acids give particularly high enantioselectivity, especially with the disubstituted ketene... 

Yamamoto s CAB catalysts (7.16) (see Section 8.1) have also been used in catalytic aldol reactions. This reaction is stereoconvergent as either geometry of silyl enol ether (7.18) affords syn selectivity in the product (7.19) indicating that the reaction proceeds via an open anticHnal transition state with the minimum of steric interactions between the aldehyde substituent and a-substituent of the enol ether, as depicted in Figure 7.2. ... 

Trost has described very efficient and versatile bimetallic zinc catalyst 10 generated in situ from diethyl zinc and a chiral Ugand derived from proline and p-cresol (Scheme 10) [46], For example, this complex can promote catalytic aldol reactions with high enantiomeric excess. The role of two proximal zinc species is for one of them to form the enolate and for the second one to function as a Lewis acid to activate the aldehyde. 

It is difficult to summarize all the progress of the homogeneous catalytic aldol reaction due to the space limitations. With representative or selected examples, this article focuses on those efforts in homogeneous catalysis and will be discussed with selected examples according to the different types of catalysts il) transition metals based Lewis acids, such as palladium, copper, iron, etc (2)... 

Transition metal catalyzed aldol reactions are attractive methods due to their high catalytic activity, privileged chelation effects of controlling stereoselectivity, and mild or neutral reaction conditions. Except group 5-7, most of transition metals have been shown as efficient catalyst in homogeneous aldol reactions with variants of substrates. Thus and correspondingly, the catalytic aldol reactions will be emphasized herein with representative transition metal based complexes in group 4 and 8-11. 

Scandium trifiate was found to be an effective catalyst for the aldol reactions of silyl enol ethers with aldehydes in aqueous solvent/micellar systems (205). While the reactions proceeded sluggishly in water, remarkable enhancement of the reactivity was observed in the presence of a small amount of a surfactant (206). In related asymmetric version, scandium trifiate (Sc(OTf)3) catalyzed asymmetric aldol of formaldehyde (hydroxymethylation) could be conducted with highly enantioselectively in the presence of chiral bipyridine based ligand (Scheme 53) (207). A significant progress was also made by Feng and co-workers recently a C-2-symmetric iV,iV -dioxide-Sc(III) complex has been developed to asymmetric catalytic aldol reaction of a-ketoesters and diazoacetate... 

Mukaiyama Aldol and Related Processes. The Carreira group has developed an asymmetric catalytic aldol reaction that involves addition of a silyl dienolate to an aldehyde partner in the presence of a chiral catalyst generated in situ from (S)-Tol-BINAP, Cu(OTf)2, and TBAT, e.g., eq... 

Hayashi and co-workers applied the asymmetric direct aldol reaction for the synthesis of chiral building block 75 for (+)-cytotrienin A 76," which is a microbial antitumor secondary metabolite. The diol 75 was synthesized with high enantioselectivity by means of the organo-catalytic aldol reaction of furfural 55 and propanal 39 in the presence of a catalytic amount of 4-acyloxy proline 74 (Scheme 27.13). The original procedure, i.e., with proline as a catalyst, was not effective for large-scale synthesis of 75 because of low yield and low diastereoselec-tivity. Total synthesis of (+)-cytotrienin A 76 was achieved in another 32 steps from diol 75. 

One of the earliest examples of an asymmetric catalytic aldol reaction in which the enolate component is generated in situ in the presence of an aldehyde is to be found in the pioneering work by Hayashi and Ito. In 1986, these investigators reported enantioselective addition reactions of a-isocyanoacetate to aldehydes catalyzed by chiral gold complexes (Scheme 4.23 see also Scheme 4.3) [18, 40). Several features of the catalyst and the process are important to note (1) the isocyanoester is a C-H acid (pfC 13), which is significantly further acidified upon its chelation to the Au center, (2) the presence of the tertiary amine in the ligand likely assists the enolization event, and (3) turnover of the... 

In 1991, Yamamoto reported a simple catalyst for aldol reactions consisting of a chiral (acyloxy)borane (CAB) complex of tartrate-derived ligands (241, Scheme 4.28) [120-122]. This work, along with that of Mukaiyama and Kobayashi, stunningly showed that remarkably simple complexes for catalytic enantioselective aldol addition reactions could be identified. Both enantiomers of the catalyst are readily accessible from the enantiomers of tartaric acid. The syn aldol adducts were observed to be preferentially formed regardless of the enolate geometry (242 vs. 244) with high levels of enantios-... 

It turned out that the dodecylsulfate surfactants Co(DS)i Ni(DS)2, Cu(DS)2 and Zn(DS)2 containing catalytically active counterions are extremely potent catalysts for the Diels-Alder reaction between 5.1 and 5.2 (see Scheme 5.1). The physical properties of these micelles have been described in the literature and a small number of catalytic studies have been reported. The influence of Cu(DS)2 micelles on the kinetics of quenching of a photoexcited species has been investigated. Interestingly, Kobayashi recently employed surfactants in scandium triflate catalysed aldol reactions". Robinson et al. have demonshuted that the interaction between metal ions and ligand at the surface of dodecylsulfate micelles can be extremely efficient. ... 

Mercaptals, CH2CH(SR)2, are formed in a like manner by the addition of mercaptans. The formation of acetals by noncatalytic vapor-phase reactions of acetaldehyde and various alcohols at 35°C has been reported (67). Butadiene [106-99-0] can be made by the reaction of acetaldehyde and ethyl alcohol at temperatures above 300°C over a tantala—siUca catalyst (68). Aldol and crotonaldehyde are beheved to be intermediates. Butyl acetate [123-86-4] has been prepared by the catalytic reaction of acetaldehyde with 1-butanol [71-36-3] at 300°C (69). 

On the other hand, carbonyl condensation reactions require only a catalytic amount of a relatively weak base rather than a full equivalent so that a small amount of enolate ion is generated in the presence of unreacted carbonyl compound. Once a condensation has occurred, the basic catalyst is regenerated. To carry out an aldol reaction on propanal, for instance, we might dissolve the aldehyde in methanol, add 0.05 equivalent of sodium methoxide, and then warm the mixture to give the aldol product. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

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