Amino acids organocatalyst

L-Proline is commercially available in bulk quantities and represents an economically attractive amino acid organocatalyst. (D-Proline is commercially available, too.)... 

The IL medium is most beneficially appUed for asymmetric reactions promoted by hydrophilic amino acid organocatalysts, in particular proline. Amino acids, being poorly soluble in hydrocarbon or ether solvents, are not washed out to the organic phase during products isolation, which allows the catalyst-IL system... 

In the organocatalytic 1,3-dipoIar cycloadditions between A,A -cyclic azomethine imines and acrolein, either exo- or cnrio-cycloadducts could be selectively synthesized with the enantiomerically enriched form by using structurally similar amino acid organocatalysts [17]. Suga et al. have... 

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

When it comes to the development of an organocatalyst, the most thoroughly documented case is proline - an amino acid which can catalyze the asymmetric... 

The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96... 

A new, metal-free protocol involving (heteroaryl)oxazoline catalysts for the enantioselective reduction of aromatic ketones (up to 94% ee) and ketimines (up to 87% ee) with trichlorosilane has been developed. The reaction is characterized by an unusual, long-ranging chiral induction.The enantiodifferentiation is presumed to be aided by aromatic interactions between the catalyst and the substrate.360 Asymmetric reduction of A-arylketimines with trichlorosilane is catalysed by A-methyl-L-amino acid-derived Lewis-basic organocatalysts with high enantioselectivity (up to 92% ee) 61... 

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. 

A 3D-structure of the substrate-catalyst complex, which was supported by molecular modeling, revealed that the large group of the imine is directed away from the catalyst. This complex of the catalyst with the Z imine, and a solution structure of the organocatalyst, are shown in Figure 5.1 [12]. This explains the broad substrate tolerance which is independent of steric or electronic properties. A further important hypothesis is that addition of HCN occurs over the diaminocyclohexane framework in 10a this led to the prediction that a more bulky amino acid/amide portion should give a further improved catalyst. This conclusion led to (model-driven) optimization which resulted in the improved and highly enantioselective Strecker catalyst 10b (for preparative results with this catalyst see Scheme 5.8 and related text) [12]. 

In addition to proline, other types of organocatalyst have been found to catalyze the Mannich-type reaction efficiently. The Jacobsen group developed an elegant and highly enantioselective route to N-Boc-/i-amino acid esters via nucleophilic ad-... 

The Jacobsen group have also focused on optimization of the organocatalyst, and the design of new, simpler catalysts [37], by systematic variation of each modular component of the catalyst, for example the salicylaldimine, diamine, amino acid, and amide. A new catalyst was found, a simple amino acid derivative 42 with less than half the molecular weight and fewer stereogenic centers than the thiourea catalyst 41. In the presence of this organocatalyst 42, benzaldimine was converted into the corresponding //-phenylalanine derivative (R)-40a with 100% conversion and 94% ee (Scheme 5.24) [37]. 

Diels-Alder and hetero-Diels-Alder Reactions Using a-Amino Acid Derivatives as Organocatalysts... 

For a recent review on amino acids and peptides as asymmetric organocatalysts see E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481-2495. 

Researchers at Degussa AG focused on an alternative means towards commercial application of the Julia-Colonna epoxidation [41]. Successful development was based on design of a continuous process in a chemzyme membrane reactor (CMR reactor). In this the epoxide and unconverted chalcone and oxidation reagent pass through the membrane whereas the polymer-enlarged organocatalyst is retained in the reactor by means of a nanofiltration membrane. The equipment used for this type of continuous epoxidation reaction is shown in Scheme 14.5 [41]. The chemzyme membrane reactor is based on the same continuous process concept as the efficient enzyme membrane reactor, which is already used for enzymatic a-amino acid resolution on an industrial scale at a production level of hundreds of tons per year [42]. 

The asymmetric catalytic Strecker reaction is an elegant means of synthesis of optically active a-amino acids. The Jacobsen group developed optimized organocata-lysts [21, 44-48], optically active urea or thiourea derivatives, which were found to be the most efficient type of catalyst yet for asymmetric hydrocyanation of imines (see also Section 5.1 on the hydrocyanation of imines). Because of its high efficiency, Jacobsen hydrocyanation technology has already been used commercially at Rodia ChiRex [49]. The concept of the reaction is shown in Scheme 14.7. In the presence of a catalytic amount (2 mol%) of the readily available organocatalyst... 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

L-Proline is perhaps the most well-known organocatalyst. Although the natural L-form is normally used, proline is available in both enantiomeric forms [57], this being somewhat of an asset when compared to enzymatic catalysis [58], Proline is the only natural amino acid to exhibit genuine secondary amine functionality thus, the nitrogen atom has a higher p Ka than other amino acids and so features an enhanced nucleophilicity compared to the other amino acids. Hence, proline is able to act as a nucleophile, in particular with carbonyl compounds or Michael acceptors, to form either an iminium ion or enamine. In these reactions, the carboxylic function of the amino acid acts as a Bronsted acid, rendering the proline a bifunctional catalyst. 

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