Organocatalyzed Aldol Reactions

Abstract

The use of catalytic enantioselective methods to perform an aldol reaction provides a direct entry for the synthesis of chiral compounds and is probably the most attractive way to achieve this goal with high control of the chemo-, regio-, diastereo-, and enantioselectivity. The application of biochemical methods based on enzyme aldolases or antibodies, which are discussed in other chapters, avoid the use of preformed enolates or their equivalents for enhancing the global atom efficiency of the process [1] for which the narrow substrate scope is a major drawback. The discovery of methodologies to carry out the enantioselective direct aldol reaction [2] has eluded the production of stoichiometric by-products increasing the substrate scope. This task could be accomplished by using small molecules as catalysts, such as metal complexes (which are covered along this book) and organic molecules, also known as organocatalysts [3]. The growth of this last research area and the direct aldol reaction are closely linked [4], with the report on the use of (S)-proline as catalyst for the intermolecular aldol [5] definitely being the push for the development of the organocatalytic methods as a competitive methodology for the synthesis of chiral compounds.In a strict sense, an organocatalyzed reaction is a process in which all the involved reagents and catalysis are purely organic compounds of low-molecular weight, excluding boron-and silicon-containing derivatives. However, in some cases, the presence of a silyl group only plays a steric role and therefore can also be considered as an organocatalyzed process. Also, if the organocatalyst involved in a reaction is immobilized in a polymer, a dendrimer, or even an inorganic material that serves only as a support to facilitate its recovery [6], it could still be considered as an organocatalyst, although those types of derivatives have been scarcely used in the natural product synthesis and therefore will be excluded from this chapter. Therefore, a comprehensive overview of the direct aldol reaction [7], emphasizing the reactivity, scope, selectivity, and limitations of the methodology and giving several examples of their application to the synthesis of biologically active compounds, is discussed in this chapter.

Highly enantioselective asymmetric direct aldol reaction promoted by aziridine amides constructed on chiral terpene scaffold

“…Stereoselective direct aldol reaction is a very useful and commonly applied tool for the synthesis of various chiral organic junctions . Among various catalysts, proline, its differently modified amides, and other various amine‐functionalized compounds are the most frequent examples of chiral promotors for asymmetric aldol reaction.…”

“…[2][3][4] Stereoselective direct aldol reaction is a very useful and commonly applied tool for the synthesis of various chiral organic junctions. [5][6][7][8] Among various catalysts, proline, 9 its differently modified amides, [10][11][12][13] and other various aminefunctionalized compounds 14,15 are the most frequent examples of chiral promotors for asymmetric aldol reaction. This type of organic reaction is traditionally performed under anhydrous conditions; however, the number of reports describing the asymmetric aldol condensation in the presence of water is still growing in the chemical literature.…”

Novel L-threonine-based ionic liquid supported organocatalyst for asymmetric syn-aldol reaction: activity and recyclability design

“…[1][2][3] One of the most important organocatalytic reactions is the asymmetric aldol reaction, which occur in Nature and is widely used in chemical research for enantioselective formation of the carbon-carbon bonds in organic compounds. 4 As a rule, major products of aldol reactions catalyzed by secondary amines have anti-configuration [5][6][7] whereas synaldols, which are key structural fragments of carbohydrates, are formed in aldolase-catalyzed enzymatic aldol reactions. [8][9] Some of these native catalysts (aldolases of type II) have a peptide structure with primary amino acid fragments as active sites.…”

Pursuing Chemical Efficiency by Using Supported Organocatalysts for Asymmetric Reactions under Aqueous Conditions

“…Both are active in water in a very selective way but with a limitation in the substrate scope. The use of small organic molecules to perform this reaction [30][31][32][33][34][35][36] gave the definitive boost for the development of organocatalysis, L-proline (1) and its derivatives being the most used systems to carry out this transformation in an intra- [37][38][39][40][41][42] or intermolecular fashion [43,45]. Although the use of this type of catalysts has several advantages, such as the atom economy enhancement, the use of mild reaction conditions and, more important, the lack of contamination with toxic metals of the final product, generally these organocatalytic systems are used in high loadings (from 10 to 30 mol%) and show their efficiencies in high polar solvents such as DMSO or DMF.…”