Activation organocatalysis

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

An important area of organocatalysis that was also initiated in the early 1990s has been the realm of Lewis base catalysis. ° On the basis of the noninmitive activation principle of silyl bonding rehybridization, Denmark and Iseki introduced chiral and DMF variants as effective catalysts for enantioselec-... 

While the studies outlined in Eqs. (11.1)-(11.8) summarize the most important frontiers for metal-free synthesis, they also highhght a common limitation for the organocatalysis field. To date, there remain relatively few (less than 10) activation mechanisms that have been established to be amenable to organic catalysis. Accordingly, a primary objective for the advancement of the field of asymmetric organocatalysis has been the design and/or development of concepts that enable organic substrates to function as catalysts for a wide variety of new and established reactions. 

The Catalysis Concept of Enamine Activation Enamine catalysis is one of the most thoroughly investigated research areas within organocatalysis. The... 

The preparation of stereochemically-enriched compounds by asymmetric acyl transfer using chiral nucleophihc catalysts has received significant attention in recent years [1-8]. One of the most synthetically useful and probably the most studied acyl transfer reaction to date is the kinetic resolution (KR) of ec-alcohols, a class of molecules which are important building blocks for the synthesis of a plethora of natural products, chiral ligands, auxiliaries, catalysts and biologically active compounds. This research area has been in the forefront of the contemporary organocatalysis renaissance [9, 10], and has resulted in a number of attractive and practical KR protocols. 

During the past decades, the scope of Lewis acid catalysts was expanded with several organic salts. The adjustment of optimal counter anion is of significant importance, while it predetermines the nature and intensity of catalytic Lewis acid activation of the reactive species. Discovered over 100 years ago and diversely spectroscopically and computationally investigated [131-133], carbocations stiU remain seldom represented in organocatalysis, contrary to analogous of silyl salts for example. The first reported application of a carbenium salt introduced the trityl perchlorate 51 (Scheme 49) as a catalyst in the Mukaiyama aldol-type reactions and Michael transformations (Scheme 50) [134-142]. 

Hydrogen would be the simplest center element. Indeed, chiral Brpnsted acids have emerged as a new class of organocatalysis over the last few years [3-13]. The field of asymmetric Brpnsted acid catalysis can be divided into general acid catalysis and specific acid catalysis. A general acid activates its substrate (1) via hydrogen bonding (Scheme 2, a), whereas the substrate (1) of a specific acid is activated via protonation (Scheme 2, b). 

Furthermore, it may be possible to view the pharmaceutical literature as a vast library to be screened for organocatalytic, not just medidnal, activity. Many compounds that are now off-patent, or were rejected in the early stages of clinical trials, could be eminently suitable for use as organocatalysts. With the increasing importance of organocatalysis, it is foreseeable that in the future pharmaceutical companies may have to consider extending a drug s patent protection to include catalytic activity. 

Previously, a wide variety of metal-mediated asymmetric two-center catalyses based on a multifunctional catalyst concept was developed [5]. Similar to an enzyme reaction, the synergistic functions of two or more active sites in multimetallic catalysts make substrates more reactive, and control their position in the transition state so that the functional groups are proximal to each other. In order to extend this concept to asymmetric organocatalysis, two ammonium salt moieties were... 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

An enantioselective fluorination method with catalytic potential has not been realized until recently, when Takeuchi and Shibata and co-workers and the Cahard group independently demonstrated that asymmetric organocatalysis might be a suitable tool for catalytic enantioselective construction of C-F bonds [78-80]. This agent-controlled enantioselective fluorination concept, which requires the use of silyl enol ethers, 63, or active esters, e.g. 65, as starting material, is shown in Scheme 3.25. Cinchona alkaloids were found to be useful, re-usable organocata-lysts, although stoichiometric amounts were required. 

Scheme 12.19 Organocatalysis with an activated thiourea derivative (Acat/Auncat = 8 at 1 mole % in CHC13).

Activation of enones by formation of an iminium cation is an interesting strategy that has been highlighted for organocatalysis in recent publications. A similar concept has been investigated for the enantioselective Michael reaction of malo-... 

There are a growing number of asymmetric organocatalytic reactions, which are accelerated by weak interactions. This type of catalysis includes neutral host-guest complexation, or acid-base associations between catalyst and substrate. The former case is highly reminiscent of the way that many enzymes effect reactions, by bringing together reactants at an active site and without the formation of covalent bonds. The chemistry of this organocatalysis is discussed in Chapter 13. 

The goal of this handbook is to bring together all important aspects of the rapidly growing field of asymmetric organocatalysis. The authors have attempted this difficult task in order to provide some practical guidelines for all of those who wish to familiarize themselves with this new domain, and also to provide useful information to those who are contributing actively to the extraordinary evolution of this field. The book is divided into two complementary parts ... 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

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