Aldol reactions, synthetic applications

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

Enantiomencally pure (+)- and (-)-diphenylethylenediamines have recently been used for highly stereoselective Dlels-Alder, aldol,8 allylation,9 osmylation,10 and epoxidafion11 reactions. Other synthetic applications involve enantioselective Michael addition12 and asymmetric hydrogenation.13... 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

The aldol reaction is probably one of the most important reactions in organic synthesis. In many industrially important hydroformylation processes selfcondensation of aldehydes is observed. Sometimes this consecutive reaction is favored as in the production of 2-ethyl hexanol. But synthetic applications of tandem hydroformylation/aldol reactions seem to be limited due regiose-lectivity problems of a mixed aldol reaction (Scheme 28). However, various tandem hydroformylation/intramolecular mixed aldol reactions have been described. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Superheated and supercritical water are used in several applications. Supercritical water is most often used in the destruction of organic wastes, including some chemical warfare agents, as an alternative to incineration (Katritzky et al., 1996 Sherman et al., 1998). Recent reports describe the use of both forms as a solvent and as a reactant in synthetic chemistry (Katritzky et al., 1996 An et al., 1997). Some of the reactions investigated include metal-mediated alkyne cyclizations, Pd-catalyzed al-kene arylations, aldol reactions, the Fischer indole synthesis, and hydrolysis reactions. Waterborne coatings and the destruction of wastes in supercritical water are fully... 

Asymmetric C-C bond formation is the most important and most challenging problem in synthetic organic chemistry. In Nature, such reactions are facilitated by lyases, which catalyze the addition of carbonucleophiles to C=0 double bonds in a manner that is classified mechanistically as an aldol addition [1]. Most enzymes that have been investigated lately for synthetic applications include aldolases from carbohydrate, amino acid, or sialic acid metabolism [1, 2]. Because enzymes are active on unprotected substrates under very mild conditions and with high chemo-, regio-, and stereoselectivity, aldolases and related enzymes hold particularly high potential for the synthesis of polyfunctionalized products that are otherwise difficult to prepare and to handle by conventional chemical methods. 

A most important property of enolate anions, at least as far as synthesis is concerned, is their excellent nucleophilicity, which enables them to add to double bonds and to participate in nucleophilic substitution. When the addition is to a carbonyl double bond, it is called an aldol addition (Equation 17-4). Additions of enolate anions to carbon-carbon double bonds usually are classified as Michael additions (Equation 17-5), and these are discussed in Sections 17-5B and 18-9D. The principles of SN nucleophilic reactions of enolate anions (Equation 17-6) will be considered in Section 17-4, and their synthetic applications in detail in Chapter 18. 

An asymmetric C-C coupling, one of the most important and challenging problems in synthetic organic chemistry, seems to be most appropriate for the creation of a complete set of diastereomers because of the applicability of a convergent, combinatorial strategy [38-40]. In Nature, such reactions are facilitated by lyases which catalyze the (usually reversible) addition of carbo-nucleophiles to C=0 double bonds, in a manner mechanistically most often categorized as aldol and Claisen additions or acyloin reactions [41], The most frequent reaction type is the aldol reaction, and some 30 lyases of the aldol type ( aldolases ) have been identified so far [42], of which the majority are involved in carbohydrate, amino acid, or hydroxy acid metabolism. This review will focus on the current state of development of this type of enzyme and will outline the scope and limitations for their preparative application in asymmetric synthesis. 

The aldol reaction is well established in organic chemistry as a remarkably useful synthetic tool, providing access to p-hydroxycarbonyl compounds and related building blocks. Intensive efforts have raised this classic process to a highly enantioselective transformation employing only catalytic amounts of chiral promoters, as reviewed in the previous section (Chap. 29.1). While some effective applications have been reported, most of the methodologies necessarily involve the preformation of latent enolates 2, such as ketene silyl acetals, using... 

The mechanism, stereoselectivity, and synthetic applications of the nitrile aldol reaction have been reviewed.75... 

The substrate range scope and limitations Promising prospects for synthetic applications of the proline-catalyzed aldol reaction in the future were opened up by experimental studies of the range of substrates by the List [69, 70a, 73] and Barbas [71] groups. The reaction proceeds well when aromatic aldehydes are used as starting materials - enantioselectivity is 60 to 77% ee and yields are up to 94% (Scheme 6.19) [69, 70], The direct L-proline-catalyzed aldol reaction proceeds very efficiently when isobutyraldehyde is used as substrate - the product, (R)-38d, has been obtained in very good yield (97%) and with high enantioselectivity (96% ee). 

More effort was therefore invested in the application of synthetic methodologies for these alkaloids and some straightforward chemo-enzymatic approaches were recently developed [150]. An enzyme-catalysed aldol reaction was again a crucial step in that synthetic route and is strongly reminiscent of Wong s research strategy relating to the chemo-enzymatic synthesis of pyrrolizidines mentioned earlier. 

This procedure illustrates a general method for preparing a wide range of spirocyclohexenones and hence spirocyclohexadienones. A number of intramolecular and intermolecular reactions are known to give spirodi-enones however, these methods have limited synthetic application.2 This procedure is superior3 to that developed by Bordwell and Wellman,4 for side reactions such as aldol condensation of the aldehyde and polymerization of methyl vinyl ketone are avoided. These spirodienones are useful intermediates in the synthesis of paracyclophanes.5 6... 

The aldol reaction is of central importance to synthetic organic chemistry in carbon skeletal elaboration. Furthermore it generates at least one and often two new stereogenic centers. Since an abundance of natural aldolases have now been identified and characterized, interest in the application of aldolases as catalysts in synthetic organic chemistry continues to increase. However, despite the potential synthetic utility of aldolase chemistry, the lyase class of enzymes is still underutilized. In contrast, the oxido-reductase and hydrolase class of enzymes have demonstrated substantial synthetic utility and are the two most utilized class of biocatalysts. 

The reaction of 2-(trimethylsilyloxy)thiophene with carbon nucleophiles has been discussed in CHEC-II(1996) <1996CHEC-II(2)491>. Several recent publications have reported the isolation of the initial aldol from the reaction of 2-(trimethylsilyloxy)thiophene with aldehydes. The reaction and its synthetic applications have been reviewed several times <19958607, 1999SL1333, 2000CSR109>. 

Recently, a lot of attention has been focused on enantioselective aldol condensations using organoboron compounds. But in this review, only related literature has been cited, as the major purpose of the review is to present synthetic applications of organoboranes obtained by the hydroboration reaction of carbon-carbon multiple bonds. 

Furthermore, the carbanion also may be added to a carbonyl group of another molecule, with formation of a new CC bond. Synthetic applications are the aldol condensation and the diacetonealcohol condensation. The acid strength of CH bonds in alpha position to COO-, COOR, or CN groups is extremely low (p > 20) and condensation reactions of the corresponding anions must be carried out in the absence of water (Claisen, Perkin, and Knoevenagel condensations). 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

Products with low enantiomeric purity are obtained by direct application of this chemistry to unsubstituted acetate esters. However, aldol reactions of f-butyl bromoacetate mediated by (5) afford synthetically useful bromohydrins (6) with high selectivities (eq 8). h These may be reductively dehalogenated or converted to a variety of compounds by way of the derived epoxides. 

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