Aldol condensation catalytic, enantioselective

Finally, another possibility is to design enantioselective syntheses by using external chiral auxiliaries either in catalytic or in stoichiometric quantities [21], Since these strategies are nowadays of great interest in organic synthesis, we will consider here some of the most recent results achieved in enantioselective aldol condensations, as well as in the asymmetric epoxidation and hydroxylation of olefmic double bonds. 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

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... 

On the basis of a catalytic system previously developed by the same group, Nicholls and collaborators [51] reported the preparation of an imprinted polymer for enantioselective formation of a C-C bond with properties of a metallo-enzyme aldolase type II. Polymers were imprinted using the two enantiomers of a 1,3-diketone, the (l.S, 35,45)-(75), and the corresponding (l/ ,3/ ,4/ )-(75), together with two 4-vinyl-pyridine held in place by a Co(II). The cross-aldol condensation... 

Keywords Catalytic antibody. Hapten, Enantiofacial, Enantioselective, Diels-Alder cycloaddition, Cationic reactions, Aldol condensation. Disfavored cyclization... 

This review covers the catalytic literature on condensation reactions to form ketones, by various routes. The focus is on newer developments from the past 15 years, although some older references are included to put the new work in context. Decarboxylative condensations of carboxylic acids and aldehydes, multistep aldol transformations, and condensations based on other functional groups such as boronic acids are considered. The composition of successful catalysts and the important process considerations are discussed. The treatment excludes enantioselective aldehyde and ketone additions requiring stoichiometric amounts of enol silyl ethers (Mukaiyama reaction) or other silyl enolates, and aldol condensations catalyzed by enzymes (aldolases) or catalytic antibodies with aldolase activity. It also excludes condensations catalyzed at ambient conditions or below by aqueous base. Recent reviews on these topics are those of Machajewski and Wong, Shibasaki and Sasai, and Lawrence. " The enzymatic condensations produce mainly polyhydroxyketones. The Mukaiyama and similar reactions require a Lewis acid or Lewis base as catalyst, and the protecting silyl ether or other group must be subsequently removed. However, in some recent work the silane concentrations have been reduced to catalytic amounts (or even zero) this work is discussed. 

Shibasaki published an elegant catalytic asymmetric synthesis of bedaquiline (1) in 2010. At first, a site-selechve aldol condensation between 33 and 34 produced enone 35 after dehydration. A catalyhc enantioselective proton migration of 35 to 36 was achieved using optimized conditions in quantitative yield and 88% ee. The next catalytic diastereoselective allylation using 37 was also optimized to convert 36 to diastereomer 38 in quanhtahve yield and 14 1 dr. 

In 2013, another intramolecular hydrosilojqrlation was combined with a Mukaiyama aldol condensation by Gong et al. in an enantioselective relay catalytic cascade. This domino reaction occurred between atylacetylene silanols and glyoxylates and was induced by a combination of an achiral gold catalyst and a chiral N-triflyl phosphoramide. As shown in Scheme 7.37,... 

Certainly a major advance in synthetic chemistry during the 1980s was the development of methods for enantioselective synthesis. We have increased the level of attention to stereochemistry in the discussion of many reactions. In areas in which new stereoselective methods have been well developed, such as in aldol condensations, hydroboration, catalytic reduction, and epoxidation, we discuss these methods. 

List documented another approach to effect catalytic enantioselective Pic-tet-Spengler reactions, using chiral phosphoric acids derived from BINOL [40-42, 133] (Equation 13) [134]. Treatment of substituted tryptamine 173 with aldehyde 174 in the presence of chiral Bronsted acid 175 afforded adduct 176 in 98% yield and 96% ee. List suggested that the operation of the Thorpe-lngold effect was critical for these systems. Thus, in the absence of geminal diester substitution (cf 177), aldol condensation to give 178 was observed exclusively. 

The methodology of the catalytic asymmetric aldol reaction has been further extended to the aldol-type condensation of (isocyanomethyl)phosphonates (12) with aldehydes, providing a useful method for the synthesis of optically active (l-aminoalkyl)phosphonic acids, which are a class of biologically interesting phosphorous analogs of a-amino acids (Scheme 8B1.6) [21,22], Higher enantioselectivity and reactivity are obtained with diphenyl ester 12b than with diethyl ester 12a (Table 8B1.6). 

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

Asymmetric Aldol-Type Reaction. CAB complex (2) is an excellent catalyst for the Mukaiyama condensation of simple achiral enol silyl ethers of ketones with various aldehydes. The CAB-catalyzed aldol process allows the formation of adducts in a highly diastereo- and enantioselective manner (up to 96% ee) under mild reaction conditions (eqs 4 and 5). The reactions are catalytic 20 mol % of catalyst is sufficient for efficient conversion, and the chiral auxiliary can be recovered and reused. 

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 10-20 mol % of 2, R = 3,5-(CF3)2C6H3, prepared from 3,5-bis(trifluoromethyl)phenyl-boronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol % 2, R = o-PhOCgH4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 % ee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). 

The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of la were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, la has poor Lewis acidity for activation of aldehydes in Mukaiyama s original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of 11-cat-alyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. 

It catalyses the aminolysis of epoxides in an extraordinarily efficient manner in aprotic solvents (e.g. toluene, CH2CI2) with complete trans stereoselectivity and high regioselectivity [Chini et al. Tetrahedron Lett 35 433 1994], It also catalyses the trans addition of indole (at position 3) to epoxides (e.g. to phenoxymetltyloxirane) in >50% yields at 60° (42 hours) under pressure (10 Kbar) and was successfully applied for an enantioselective synthesis of (+)-diolmycin A2 [Kotsuki Tetrahedron Lett 37 3727 799(5]. Of the ten lanthanide triflates, Yb(OTf)3 gave the highest yields (> 90%, see above) of condensation products by catalytically activating formaldehyde, and a variety of aldehydes, in hydroformylations and aldol reactions, respectively, with trimethylsilyl enol-ethers in THF at room temperature. All the lanthanide triflates can be recovered from these reactions for re-use. [Kobayashi Hachiya J Org Chem 59 3590 1994.]... 

General reviews include the direct aldol/" aldoi and related processes,the Zimmerman-Traxler TS model used to explain the stereochemistry of the aldoi condensation,catalysis of direct asymmetric aldols by prolinamides versus prolinef/zioamides, " " the catalytic asymmetric aldoi reaction in aqueous media (considering both organometallic and organocatalytic approaches), " the use of BINAP oxide in enantioselective direct aldols,and the use of metal enolates as synthons. " ... 

Carbonyl groups are also activated by Lewis acids to participate in various condensation reactions. One of the most important of these is the Mukaiyama aldol reaction. The first version of this in the 1970s (Figure 23.9) was not catalytic, but catalytic versions and enantioselective variants were quickly developed. The advantage of the process is that a crossed-aldol reaction is achieved without any risk of self-condensation of either component, and reaction conditions are exceptionally mild. However, the starting silyl enol ether does need to be prepared. Some examples are shown in Figure 23.10. The first reaction is one on which many common catalysts... 

The Darzens condensation is an old methodology for the construction of a,p-epoxy carbonyl compounds 49 with control of two formed stereogenic centers. This reaction includes an aldol reaction (C-C bond formation), which normally requires stoichiometric amounts of base to achieve good yields. Only phase transfer catalysts, usually chiral ammonium halides have shown to be efQdent to perform this transformation in a catalytic and enantioselective form. 

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