Proline metal complexes

Corma and coworkers tested a number of rhodium and other transition metal complexes with ligands based on proline (Fig. 29.23). These authors reported ee-values of 54—90% for the hydrogenation of dehydroamino acid derivatives with a catalyst prepared from ligand 38 [51]. With ligand 39, an ee-value of 34% was recorded for the hydrogenation of ethyl acetamidocinnamate 10 [52]. 

Enantiomerically pure 3-amino alcohols which are important intermediates for many bioactive compounds can be directly synthesized by the ARO reaction of readily accessible racemic and meso epoxides with appropriate amines. Indeed, some simple and multifunctional p-amino alcohols have been obtained using this strategy by the promotion of chiral BINOL [30-32,88,89], salen [35,52], bipyridine [33,40,90-94] and proline-A,JV-dioxide based metal complexes [95]. However, none of these systems demonstrated the recyclability of the precious chiral catalyst. 

The development of chiral peptide-based metal catalysts has also been studied. The group of Gilbertson has synthesized several phosphine-modified amino adds and incorporated two of them into short peptide sequences.[45J,71 They demonstrated the formation of several metal complexes, in particular Rh complexes, and reported their structure as well as their ability to catalyze enantioselectively certain hydrogenation reactions.[481 While the enantioselectivities observed are modest so far, optimization through combinatorial synthesis will probably lead to useful catalysts. The synthesis of the sulfide protected form of both Fmoc- and Boc-dicyclohexylphosphinoserine 49 and -diphenylphosphinoserine 50 has been reported, in addition to diphenylphosphino-L-proline 51 (Scheme 14).[49 To show their compatibility with solid-phase peptide synthesis, they were incorporated into hydrophobic peptides, such as dodecapeptide 53, using the standard Fmoc protocol (Scheme 15).[451 For better results, the phosphine-modified amino acid 50 was coupled as a Fmoc-protected dipeptide 56, rather than the usual Fmoc derivative 52.[471 As an illustrative example, the synthesis of diphe-nylphosphinoserine 52 is depicted in Scheme 16J45 ... 

Many relatively specific reagents, particularly a variety of metal complexes, have been developed as an aid to the isolation of individual amino acids. An example is provided by the isolation of L-proline from a gelatine hydrolysate using the chromium complex ammonium rhodanilate ammonium dianiline-... 

The as)rmmetric proline-catalyzed intramolecular aldol cyclization, known as the Hajos-Par-rish-Eder-Sauer-Wiechert reaction [106,107], was discovered in the 1970s [108,109,110,111]. This reaction, together with the discovery of nonproteinogenic metal complex-catalyzed direct asymmetric aldol reactions (see also Sect 5.5.1) [112,113,114], led to the development by List and co-workers [115,116] of the first proline-catalyzed intermolecular aldol reaction. Under these conditions, the reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used. For example, acetone reacts with several aldehydes in dimethylsulfoxide (DMSO) to give the corresponding aldol in good yields and enantiomeric excesses (ee) (O Scheme 17) [117]. 

Another method used for recycling TSOSs consists in using the so-called supported ionic liquid phase (SILP) [44-49], The general principle is using an OS with a trialkoxysilane moiety that can be grafted covalently to a particle of silica. The particle, now coated with onium salt, has a special affinity for other onium salts, especially ILs. ILs can therefore get immobilized on a solid particle and subsequently be used for immobilizing other reagents (transition metal complexes, proline, etc.). This method has recently been reviewed and employs mostly non-functional ILs, so it won t be explained in more detail [44-49] (Fig. 17). 

Proline is a stable, nontoxic, cyclic, secondary pyrrolidine-based amino acid with an increased pK value. Thus, proline is a chiral bidentate compound that can form catalytically active metal complexes (Melchiorre et al. 2008). Bidentate means that proline has not only one tooth but also a second one to bite and react. The greatest difference to other amino acids is a Lewis-base type catalysis that facilitates iminium and enamine-based reactions. It is especially noteworthy that cross-aldol condensations of unprotected glycoladehyde and racemic glyceralde-hyde in the presence of catalytic amounts of the Zn-(proline)2 gave a mixture of pentoses and hexoses (Kofoed et al. 2004). Again, proline seems to play the decisive role. The conditions are prebiotic the reaction proceeded in water for seven days at room temperature. It is remarkable that the pentose products contained ribose (34%), lyxose (32%), arabinose (21%), and xylose (12%) and that all are stable under the conditions. Thus, the diastereomeric and enantiomeric selection observed support the idea that amino acids have been the source of chirality for prebiotic sugar synthesis. 

Figure 5.1 Reactivity modes for proline eatalysis. (a) bifunctional acid/base catalysis (b) iminium catalysis (c) metal-complexes and (d) enamine catalysis.

A cyclo-nonapeptide, isolated from linseed by Kaufmann and Tobschirbel [48] which also prevents the uptake of phalloidin (and other substances) by hepatocytes, cyclolinopeptide A, shows a certain similarity with AA in its amino acid sequence (Fig. 20) but does not form alkali-metal complexes. With the accumulation of aromatic amino acids between proline residues as an active region in mind, Kessler et al. designed some smaller cyclopeptides of which one, c(D-ProPhePheProPhePhe), exhibited somewhat stronger protection and a second less related one, called 008, showed even better protection of liver cells against phalloidin than antamanide [49]. 

Still higher resolution factors were found in systems in which a diastereomeric metal complex is responsible for chiral recognition. Thus, on Cu(L-proline)2 dissolved in the mobile phase (in HPLC), the enantiomers of valine were resolved with a = 4.8 at room temperature (AAG = —0.95 Kcal) [19] Davankov [28] has reported for proline on N-n-heptyl-L-hydroxyproline a = 10.9 (AAG = -1.4 Kcal). 

The development of new efficient catalytic reactions lies at the heart of the synthesis of enantioenriched biologically active molecules. Until recently, the use of transition metal complexes and enzymes were the main chaimels to achieve this goal (see [1] and references therein). While early reports hinted at the possibilities of future, the first report of a highly enantioselective reaction catalyzed by proline in 1971 helped focus attention on the great potential of... 

The principle of this method depends on the formation of a reversible diastereomeric complex between amino acid enantiomers and chiral addends, by coordination to metal, hydrogen bonding, or ion—ion mutual action, in the presence of metal ion if necessary. L-Proline (60), T.-phenylalanine (61),... 

Metal ion complexes. These classic CSPs were developed independently by Davankov and Bernauer in the late 1960s. In a typical implementation, copper (II) is complexed with L-proline moieties bound to the surface of a porous polymer support such as a Merrifield resin [28-30]. They only separate well a limited number of racemates such as amino acids, amino alcohols, and hydroxy acids. 

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