Aldol reactions Subject

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

Mixed condensations of esters are subject to the same general restrictions as outlined for mixed aldol reactions (Section 2.1.2). One reactant must act preferentially as the acceptor and another as the nucleophile for good yields to be obtained. Combinations that work best involve one ester that cannot form an enolate but is relatively reactive as an electrophile. Esters of aromatic acids, formic acid, and oxalic acid are especially useful. Some examples of mixed ester condensations are shown in Section C of Scheme 2.14. Entries 9 and 10 show diethyl oxalate as the acceptor, and aromatic esters function as acceptors in Entries 11 and 12. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

Glyceraldehyde (2,3-dihydroxypropanal), acetol, and dihydroxyace-tone form 1-5% of biacetyl and a number of other products, including pyrocatechol and 33, after exposure to aqueous alkali at 300°. Such trioses as glyceraldehyde and dihydroxyacetone have been shown to form various hexoses by aldol reaction. Aldolization, followed by retro-aldoliza-tion, is undoubtedly a major consideration when three-, four-, and five-carbon sugars are subjected to elevated temperatures. Differences in thermolysis products, partially quantitative, are noticeable at 100°, but, at temperatures near 300°, it is quite difficult, if not impossible, to determine if the starting material was a triose, a tetrose, or a pentose. 

Why is only one of these products formed To understand this, you must recognize that aldol reactions are reversible and therefore are subject to equilibrium rather than kinetic control (Section 10-4A). Although the formation of 10 is mechanistically reasonable, it is not reasonable on thermodynamic grounds. Indeed, while the overall A/7° (for the vapor) calculated from bond energies is —4 kcal mole 1 for the formation of the aldol, it is +20.4 kcal mole-1 for the formation of 1Q.2 Therefore, the reaction is overwhelmingly in favor of the aldol as the more stable of the two possible products. 

Metal template syntheses of complexes incorporating the p-amino imine fragment have been introduced by Curtis as a result of his discovery that tris(l,2-diaminoethane)nickel(II) perchlorate reacted slowly with acetone to yield the macrocyclic complexes (40) and (41) (equation 8).81-83 In this macrocyclic structure the bridging group is diacetone amine imine, arising from the aldol condensation of two acetone molecules. This reaction is widely general, in the same way that the aldol reaction is, and can be applied to many types of amine complexes. The subject has been reviewed in detail with respect to macrocyclic complexes by Curtis.84... 

Hydrogen bond-promoted asymmetric aldol reactions and related processes represent an emerging facet of asymmetric proton-catalyzed reactions, with the first examples appearing in 2005. Nonetheless, given their importance, these reactions have been the subject of investigation in several laboratories, and numerous advances have already been recorded. The substrate scope of such reactions already encompasses the use of enamines, silyl ketene acetals and vinylogous silyl ketene acetals as nucleophiles, and nitrosobenzene and aldehydes as electrophiles. 

After mercury(II)-assisted hydrolysis of the thioenol ether, aldehyde 3 was obtained. This was then subjected to the critical vinylogous aldol reaction needed to complete the carbon backbone of the natural product. The latter process furnished a 3.5 1 mixture of the y to ot addition products. The stereoselectivity observed in the installation of the C(5)-hydroxyl (natural product numbering) was only 2 1. Fortunately, the predominant isomer was the desired product 2. In retrospect, it can be seen that the level of selectivity attained conformed to the predictions of the Still model.4... 

A specially interesting case of the blocked carbonyl compound is the lactone or cyclic ester. Open-chain esters do not give aldol reactions they prefer a different reaction that is the subject of the next chapter. But lactones are in some ways quite like ketones and give unsaturated carbonyl products under basic catalysis. Enolization is unambiguous because the ester oxygen atom blocks enolization on one side. 

The aldol reaction is one of the most fundamental tools in organic chemistry, and it still remains an open field for new ideas and developments504-509. Among the many reviews dedicated to this subject, the reader should refer, for a more referenced survey, to Heathcock7,11 and more recently to Braun s articles510 devoted specifically to the preformed metal enolates of group I—II. The Mannich reaction (the aza-equivalent of the aldol reaction) is a subject on its own and will be only partially treated here. 

N-Acetylneuraminic acid aldolase (NeuAc aldolase) is commercially available and has been the subject of much attention [49]. NeuAc aldolase catalyzes the aldol reaction between pyruvate and mannose or mannose derivatives. The enzyme activates the donor as its enamine, similar to the Type I aldolase described above (Scheme 5.21). The enzyme has been used for the synthesis of aza sugars and var-... 

This encouraged us to proceed to elaborate the D ring of aspidospermidine. Ketone 51 was subjected to aldol reaction, and the aldol... 

The ring-strain-released aldol reaction was described in detail by Denmark and was subjected to asymmetric reaction by use of enoxysilacyclobutanes attached to chiral auxiliaries (Sch. 65) [106]. 

Imines and their derivatives could be used in an analogous way to aldehydes, ketones, or their derivatives this subject has been reviewed [79]. A competition experiment between an aldimine and the corresponding aldehyde in the addition to an enol silyl ether under titanium catalysis revealed that the former is less reactive than the latter (Eq. 14) [80]. In other words, TiCU works as a selective aldehyde activator, enabling chemoselective aldol reaction in the presence of the corresponding imine. (A,0)-Acetals could be considered as the equivalent of imines, because they react with enol silyl ethers in the presence of a titanium salt to give /5-amino carbonyl compounds, as shown in Eqs (15) [81] and (16) [79,82]. 

The C27-C35 segment 238 was prepared from 32 (O Scheme 30), which is the synthetic intermediate of erythronolide A. Oxidative cleavage of 32 gave aldehyde 251, which was subjected to aldol reaction with TBDMS-enol ether and TiCl4 to provide 252. Hydrolysis of thioester and deacetalization with TFA were accompanied by furanose-to-p)ranose interconversion and... 

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