Amino acid-derived catalysts reduction

Recently, Borner and coworkers described an efficient Rh-deguphos catalyst for the reductive amination of a-keto acids with benzyl amine. E.e.-values up to 98% were obtained for the reaction of phenyl pyruvic acid and PhCH2COCOOH (entry 4.9), albeit with often incomplete conversion and low TOFs. Similar results were also obtained for several other a-keto acids, and also with ligands such as norphos and chiraphos. An interesting variant for the preparation of a-amino acid derivatives is the one-pot preparation of aromatic a-(N-cyclohexyla-mino) amides from the corresponding aryl iodide, cyclohexylamine under a H2/ CO atmosphere catalyzed by Pd-duphos or Pd-Trost ligands [50]. Yields and ee-values were in the order of 30-50% and 90 >99%, respectively, and a catalyst loading of around 4% was necessary. 

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... 

Whichever catalyst system is used to prepare an a-amino acid derivative at scale, the cost of the ligand can play a major economical role, often more than the metal. The cost of the catalyst can be offset by large substrate-to-catalysts ratios that can be improved by recycles and fast reactions. However, because metal hydride species are invariably involved in the catalytic cycle, recycles usually mean reuse in a short time span. The conclusion is that expensive ligands must be extremely good at the desired reduction. This is particularly true with amino acid derivatives because almost all are crystalline and offer the possibility of enantioenrichment during the purification process. Thus, high ee s may not be required in the reduction itself. In many cases, the synthesis of the substrate is the difficult part of the synthesis. This problem has been highlighted in the synthesis of [3-amino acids (see Section 2.6). 

Figure4.1 Formamides derived from cyclic amino acids as catalysts forthe asymmetric reduction of imines.

Reduction of p-enamides can provide straightforward access to p-amino acids. It was demonstrated that the Me-DuPhos-Rh catalysts are very effective for hydrogenation of a series of ( )-p-enamides 22 to afford the desired p-amino acid derivatives 23 with high enantioselectivities (Scheme 9.23). In addition, the Me-and Et-FerroTANE-Rh catalysts hydrogenate ( )-p-enamides with high enantioselectivities (>98%) and rates. Unfortunately, neither catalyst system was able to reduce the corresponding (Z)-p-enamides with the same high level of absolute stereocontrol. °... 

Friedel-Crafts alkylations of arenes with mesylates, benzyl or allyl alcohols, aldehyde/diol combinations (reductive alkylation), 1,3-dienes, or alkenes in an ionic liquid are also effectively catalyzed by Sc(OTf)3. Sc(OTf)3 works as an efficient catalyst for the condensation reaction of trimethylhydroquinone with isophytol to afford a-tocopherol. 2-Aminoalkylation of phenols with a-iminoacetates (or glyoxylate/amine) is catalyzed by Sc(OTf)3 to produce amino acid derivatives. The Sc(OTf)3-catalyzed alkylations of indoles with a-hydroxy esters, aziri-dines, acetals, and aldehydes have been utilized as key steps of total syntheses as exemplified in eq 15. ... 

The corresponding (3-formyl functionalized amino acid derivatives are obtained in high yields and stereoselectivity. The reaction is readily performed on a multigram scale, and the catalyst loading can be decreased to 10 mol%. The proline-catalyzed cross-Mannich-type reactions to other preformed imines is also possible [41]. In this context, reduction of the aldehyde moiety is usually required to increase the stability of the Mannich adducts, and the corresponding amino alcohols are isolated in high yields and with >99% ee in several cases (Scheme 4.8) [41, 42]. Thus, the transformation can be viewed as a regiospecific asymmetric synthesis of 3-amino-l-ols. It is noteworthy that proline is also able to catalyze the one-pot... 

In the presence of diazo compounds 9, enynes 10 containing a fluorinated amino acid moiety could be transformed into fluorinated alkenyl bicyclo[4.1.0]heptane amino acid derivatives 11 using Cp (Cl)Ru(COD) as the precatalyst (Scheme 5.5) [12], In this process, the in situ-generated catalyst from ruthenium complex and diazo compound completely inhibits RCM of enyne to the profit of cascade alkenyl-ation/cyclopropanation. The Cp (Cl)Ru moiety in ruthenacyclobutane is believed to favor reductive elimination versus expected alkene metathesis. 

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

Catalytic Enantioselective Reduction of Ketones. An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most developed is the oxazaborolidine 18, which is derived from the amino acid proline.148 The enantiomer is also available. These catalysts are called the CBS-oxazaborolidines. 

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