Organocatalytic concept

A literature survey of articles that focus on the use of organocatalytic concepts indicate that this area began exponential growth in 2000, and that interest in this field has continued to rapidly expand on a yearly basis ever since (Figure 11.1) As a further example of this phenomenon, the total number of organocatalysis articles for year 2004 has been overtaken in the first 6 months of 2005. 

Figure 11.1. Diagram indicating the number of articles per year focusing on the use of organocatalytic concepts.

However, the scope of organocatalytic reactions has increased in recent years through the formation of reactive intermediates generated in the presence of nucleophiles by the action of synergistic catalysis [20]. This is a powerful synthetic strategy for new reaction development that allows us to combine organometaUic chemistry and organocatalytic concepts. 

Abstract An overview of the area of organocatalytic asymmetric acyl transfer processes is presented inclnding O- andiV-acylation. The material has been ordered according to the structnral class of catalyst employed rather than reaction type with the intention to draw mechanistic parallels between the manner in which the varions reactions are accelerated by the catalysts and the concepts employed to control transfer of chiral information from the catalyst to the substrates. 

Application of an organocatalytic domino Michael addition/intramolecular aldol condensation to the preparation of a series of important heterocycles has recently received much attention [158] with methods being disclosed for the preparation of benzopyrans [159-161], thiochromenes [162-164] and dihydroquinolidines [165, 166]. The reports all use similar conditions and the independent discovery of each of these reactions shows the robust nature of the central concept. A generalised catalytic cycle which defines the principles of these reports is outlined in Fig. 10. Formation of iminium ion 102 is followed by an intermolecular Michael addition of an oxygen, sulfur or nitrogen based nucleophile (103) to give an intermediate... 

Adolfsson, H. Organocatalytic Hydride Transfers A New Concept in Asymmetric Hydrogenations. Angew. Chem. Int Ed. 2005, 44, 3340-3342. 

The Lectka group also reported an exciting development in this organocatalytic synthesis of /I-lactams - application of the concept of column asymmetric catalysis [50, 51]. This concept is based, e.g., on two jacketed columns linked together (Scheme 5.32) [50]. The top column is packed with the polymer-supported dehy-drohalogenation agent BEMP, which produces the desired ketenes, in high purity, from acid chlorides. In addition to this in-situ-formed pure ketene, an imine is... 

The required chiral sulfur ylide of type 59 is formed in a reaction with a diazo compound in the presence of an achiral metal catalyst. Subsequently, asymmetric reaction of the chiral ylide 59 with the C=N double bond of the imine proceeds diastereoselectively and enantioselectively, giving the optically active aziridine 57. The chiral sulfide catalyst released is then used for the next catalytic cycle. The cat-alytically active species in the asymmetric process is the sulfide, so this concept can also be regarded as an organocatalytic reaction. 

The asymmetric catalytic hydrophosphonylation is an attractive approach for the synthesis of optically active a-amino phosphonates [84]. The first example of this type of reaction was reported by the Shibasaki group in 1995 using heterobimetal-lie lanthanoid catalysts for the hydrophosphonylation of acyclic imines [85a]. This concept has been extended to the asymmetric synthesis of cyclic a-amino phosphonates [85b—d]. Very recently, the Jacobsen group developed the first organocatalytic asymmetric hydrophosphonylation of imines [86], In the presence of 10 mol% of thiourea-type organocatalyst 71, the reaction proceeds under formation of a-amino phosphonates 72 in high yield (up to 93%) and with enantioselectivity of up to 99% ee [86], A selected example is shown in Scheme 5.42. Di-o-nitrobenzyl phosphite 70 turned out to be the preferred nucleophile. 

Aldol reactions using a carbocation as an organocatalyst An organocatalytic aldol reaction based on a different concept was developed by the Chen group. The chiral triarylcarbenium ion 34 was used as a novel non-metallic Lewis acid catalyst in a Mukaiyama-type aldol reaction which led to enantiomerically enriched aldol products (Scheme 6.17) [67]. Although non-chiral trityl salt-mediated catalytic aldol reactions had previously been reported by Mukaiyama and co-workers [68], the construction of a suitable chiral carbenium ion remained a challenge. Optically active salts of type 34 were synthesized as Lewis acids based on a reactive carbe-... 

In summary, this organocatalytic alkylation of aldehydes and ketones is a promising route for preparation of optically active secondary and tertiary alcohols and is of general interest. Certainly, improvement of the asymmetric induction as well as applications of other nucleophiles will be the next major challenge in this field to make this synthetic concept competitive with alternative routes. 

As shown above (see also Scheme 6.87B), formation of sulfur ylides by reaction of a carbenoid with a sulfide is an efficient alternative which has also been found to be applicable to enolizable and base-sensitive aldehydes. This route, developed by the Aggarwal group, is based on use of a metal catalyst to form a carbene which subsequently reacts with the sulfide generating the sulfur ylide [200, 212, 213, 226]. Because the catalytically active species of the asymmetric process is the sulfide, this concept can be also regarded as an organocatalytic reaction. 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

Based on our organocatalytic C3+C concept for the direct synthesis of carbohydrates, we envisaged the successful development of a diastereo- and enantioselective Mannich variant that paves the way to selectively protected amino sugars and their derivatives. These amino sugars are a class of carbohydrates in which one or more hydroxyl func-... 

Several organocatalytic variants for the conjugate addition of electron-rich aromatic substrates to electron-deficient olefins have been reported in the last few years which apply the concept of activation of the electrophile by hydrogen-bonding interactions. In this context, chiral bifunctional thiourea ent-91 has been employed as an excellent promoter for the enantioselective conjugate... 

Abstract In this chapter, the asymmetric organocatalytic conjugate addition of nucleophiles to Michael acceptors is covered. This report presents an overview of the most important developments and concepts of this area of catalysis organized by the type of nucleophile involved in the process. 

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