General organocatalytic reactions

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

The catalytic asymmetric epoxidation of a,p-unsaturated aldehydes has also been an important challenge in iminium catalysis and for chemical synthesis in general. More recently, Jprgensen and coworkers have developed an asymmetric organocatalytic approach to ot, (3-epoxy aldehydes using pyrrolidine catalyst 20 and H2O2 as the stoichiometric oxidant. The reaction appears to be extremely general and will likely receive wide attention from the chemical synthesis community (Scheme 11.6b). 

Consequently, the processes most relevant to the topic of this chapter, that is, hydrogen bonds in organocatalytic transition states, are (i) transition state stabilization by pure hydrogen bonding (without full proton transfer), and (ii) general Bronsted-acid/Bronsted-based catalyzed reactions which are initiated by hydrogen bonding but move further to distinct proton transfer. 

Even considering only the example of the proline family of aldol catalysts, it is dear that there will soon be hundreds of cases of organocatalysts described in the literature. Direct, organocatalytic aldol reactions do not yet have the generality of traditional stoichiometric methods, which can offer predictable results for a wide variety of substrates. However, companies already offer to screen substrates against panels of up to 200 enzymes to find the optimum biocatalyst for a reaction, and the same approach could be applied to identify rapidly the best organocatalyst for a process. 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

Oxidation reactions - notably alkene epoxidations - were some of the first asymmetric organocatalytic processes to develop into generally useful synthetic methods applicable to a range of substrates [1], This chapter surveys these reactions, with emphasis placed on the most practical and general. Some recent, very useful oxidation reactions involving a-oxidation of carbonyl compounds are covered elsewhere (see Chapter 2). 

General Procedure for Organocatalytic Sulfenylation-Amination Reaction Sequence [102] (p. 114)... 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

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