Catalysts Derived from Amino Acids

Amino acids and their derivatives represent an obvious source of chiral organic catalysts, which has been fully exploited by synthetic organic chemists [32], especially in the field of aminocatalysis, such as enantioselective catalytic processes promoted by enantiomerically pure amines [33], 

The ready availability of amino acids and their different functionalizations in the side chains allowed for a number of applications in the field of supported catalysis. While the relatively low cost of many amino acids apparently does not seem to justify the preparation of supported catalysts derived from amino acids, other reasons (as mentioned above) may drive towards the immobilization of chiral catalysts, for example to experiment with different solubilities, the easy separation of the product from the catalyst, and the catalyst s recyclability. The immobilization of these compounds on a support can also be seen as an attempt to develop a minimalist version of an enzyme, with the amino acid playing the role of the enzyme s active site and the polymer that of an oversimplified peptide backbone not directly involved in the catalytic activity [34]. It should be mentioned at this point that, in principle, amine-based catalysts offer also the possibility to be recovered by exploiting their solubility profiles in acids. 

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Silyl-protected hydroxyacetone undergoes iyn-selective cross-aldols with various aldehydes in water, using l°-3° diamine catalysts derived from amino acids and bearing a hydrophobic side-chain. Best yield, de, and ee are 94, 82, and 97%, respectively. 

An ion-pair derived from the substrate and solid NaOH forms a cation-assisted dimeric hydrophobic complex with catalyst 39c, and the deprotonated substrate occupies the apical coordination site of one of the Cu(II) ions of the complexes. Alkylation proceeds preferentially on the re-face of the enolate to produce amino acid derivatives with high enantioselectivity. However, amino ester enolates derived from amino acids other than glycine and alanine with R1 side chains are likely to hinder the re-face of enolate, resulting in a diminishing reaction rate and enantioselectivity (Table 7.5). The salen-Cu(II) complex helps to transfer the ion-pair in organic solvents, and at the same time fixes the orientation of the coordinated carbanion in the transition state which, on alkylation, releases the catalyst to continue the cycle. 

Functionalised carbenes can anchor free carbenes to the metal site, introduce hemilabil-ity, provide a means to immobilise transition metal carbene catalysts, introduce chirality, provide a chelate ligand or bridge two metal centres. NHC can be attached to carbohydrates and camphor, derived from amino acids and purines, and they can be used as organocata-lysts mimicking vitamin B1 or as weak solvent donors in lanthanide chemistry. There are many possibilities which are still only scarcely explored. 

Other Applications. Chiral oxazaborolidines derived from ephedrine have also been used in asymmetric hydroborations, and as reagents to determine the enantiomeric purity of secondary alcohols. Chiral l,3,2-oxazaborolidin-5-ones derived from amino acids have been used as asymmetric catalysts for the Diels-Alder reaction,and the aldol reaction. ... 

The same reaction has also been catalyzed by chiral oxazaborolidinones derived from amino acids and boranes. They proved to be efficient catalysts for enantioselec-tive Diels-Alder reaction [91,92]. The polymer-supported chiral oxazaborolidinones 75 were reported to be efficient catalysts [93]. These polymer-supported chiral oxaza-borolidinone ligands were prepared both by chemical modification and by the copolymerization shown in Sch. 5 [94]. The polymer-supported chiral ligands were then reacted with borane to give the oxazaborolidines which were used as catalysts in Diels-Alder reaction of cyclopentadiene with methacrolein. 

Chiral bisoxazoline ligands were initially chosen for these experiments (Eq. (13.52)). It was found that simple bisoxazoline ligands 167 derived from amino acids led to good yields but moderate selectivities of products 168 when catalytic amounts of chiral Lewis acid were used (67% ee with 20 mol % of the catalyst and 86% chemical yield). 

However, soluble metal chiral complex catalysts are better, even though ketone hydrogenation under these conditions is more difficult to run than olefin hydrogenation. Notable achievements have been made using Rh and Ru metals. Phosphine ligands are often used, which contain either an asymmetric alkyl group have the phosphorous atom as the asymmetric center, or have an axial element of chirality (atropisomerism) . Other chiral ligands commonly used are derived from amino acids, from L-hydroxyproline and from ferrocene. 

This method of asymmetric cyclopropanation using copper catalysts which are chirally modified with salicylaldimines of optically active amines has been intensively investigated and numerous modifications of the ligands have been tested24-40-43. The use of chiral amino alcohols derived from amino acids is exceptionally successful. Thus, 2-methylpropene with ethyl diazoacetate in the presence of R-7644 (Sumitomo catalyst) gives ethyl (LS)-2,2-dimethyl-1-cyclopropanecarboxylate (2) with 92% ee, on an industrial scale24. This compound is used as a precursor of cilastm, an enzyme inhibitor. 

Chiral Lewis acidic catalysts derived from -amino alcohols constitute a major field of recent development. These reagents have been used for enantioselective reduction of ketones " and for dialkylzinc... 

While primary amine organocatalysts derived from amino acids have shown very low enantioselectivities and activities in the typical aldol reactions of acetone with aldehydes. Da et al. demonstrated that the introduction of the optimal co-catalyst DNP (2,4-dinitrophenol) dramatically elevated both the activities and the enantioselectivities of these catalysts. As shown in Scheme 2.39, the combination of a primary amino acid with DNP allowed the aldol products to be obtained in moderate to high yields and excellent enantioselectivities of up to 99% ee. In addition, the scope of this methodology could... 

Rh and Ir NHC derived from amino acids such as 71 were found to be promising catalysts. Finally, Ru" complexes prepared from chiral oxazolines containing imidazol-2-ylidenes were used for ATH of acetophenone and alkyl ketones in refluxing KOH/i-PrOH. However, 72 only exhibited a moderate activity and no chiral induction. ... 

The simple primary-tertiary diamine salts can be successfully applied in the aldol reactions of a-hydroxyketones with good activity and excellent stereoselectivity. Notably, the catalyst enabled the reaction of dihydroxyacetone (DHA), a versatile C3-building block in the chemical and enzymatic synthesis of carbonhydrates. By employing either free or protected DHA, syn- or anh-diols could be selectively formed with excellent enantioselectivity (Scheme 5.7). Since enantiomers of diamine 26 and 29 are readily available, this class of chiral primary amine catalysts thus functionally mimics four types of DHA aldolases in nature [17b]. Later, simple chiral primary-tertiary diamine 27 derived from amino acid was also found to be a viable catalyst for the iyn-selective aldol reactions of hydroxyacetone and free DHA (Scheme 5.7) [18]. 

The first iminium-based asymmetric Diels-Alder reaction of a-acyloxyacrolein was realized by using a primary amine catalyst 128 derived from amino acids [62a]. The same catalyst could also be appUed to the Diels-Alder reactions of a-phthalim-idoacroleins with dienes [62b] with up to 99 1 cndo cjt -selectivity and 96% ee (Scheme 5.33). Two factors are proposed to account for the high stereocontrol n-n interaction between the phenyl group of the catalyst and the R group in the acroleins and the steric hindrance resulted from the bulky ion pair (Schane 5.33). 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

The asymmetric hydrogenation of enol esters can also be catalyzed by chiral amidophosphine phosphinite catalysts derived from chiral amino acids, but the enantioselectivity of these reactions has thus far been only moderate.35... 

B. Lygo, P. G. Wainwright, A New Class of Asymmetric Phase-Transfer Catalysts Derived from Cinchona Alkaloids - Application in the Enantioselective Synthesis of a-Amino Acids , Tetrahedron Lett., 1997, 38, 8595-8598. 

A related approach has recently been reported by Belokon and Kagan et al. These workers used chiral TADDOL-type diols, derived from tartaric acid and 2-amino-2 -hydroxy-1,1 -binaphthyl (NOBIN), as catalysts to obtain yields of up to 95% and enantioselectivity up to 93% ee [59-61], The catalytically active species seem to be the sodium salts of the diols. 

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