Keto acid substrates, asymmetric

Synthesis of Chiral a-Amino Acids by Asymmetric Reductive Amination of Keto Acid Substrates In 2003, Rh-Deguphos catalyzed enantioselective reductive amination of a-keto acids 106 with benzylamine (BnNH2)... 

SCHEME 39.30. Asymmetric reductive amination of a-keto acid substrates 106. 

The asymmetric transamination from chiral a-amino acids 1021 and amino acid derivatives (57) (esters 86,103), amino alcohols 104 ) to carbonyl functions in prochiral substrates (58) (a-keto acids 102), a-keto esters 86,103), ketones 103b d) was described... 

Reductive amination reactions of keto acids are performed with amino acid dehydrogenases. NAD-dependent leucine dehydrogenase from Bacillus sp. is of interest for the synthesis of (S)-fert.-leucine [15-17]]. This chiral compound has found widespread application in asymmetric synthesis and as a building block of biologically active substances. The enzyme can also be used for the chemoenzy-matic preparation of (S)-hydroxy-valine [18] and unnatural hydrophobic bran-ched-chain (S)-amino acids. NAD-dependent L-phenylalanine dehydrogenase from Rhodococcus sp. [19] has been used for the synthesis of L-homophenyl-alanine ((S)-2-Amino-4-phenylbutanoic acid) [9]. These processes with water-soluble substrates and products demonstrate that the use of coenzymes must not... 

This ligand, MeO-BIPHEP (96a), has shown similar reactivities and enantioselectivities to catalysts that contain BINAP.117 Ruthenium catalysts that contain MeO-BIPHEP have been used in several asymmetric hydrogenations from bench scale to multi-ton scale, which include the large-scale preparation of a P-keto ester, an aryl ketone, allylic alcohol, and several oc,P-unsaturated carboxylic acid substrates, which are shown in Figure 12.5. 

Numerous asymmetric catalytic hydrogenations of carbon-nitrogen double bonds have been carried out. Some of the substrates used are oximes and hydrazones, but most of the reactions were carried out using Schiff s bases of ketones. a-Keto acids are precursors of a-amino acids in biosynthesis, and therefore a-keto acids have been used for the asymmetric syntheses of a-amino acids. ... 

The temperature effect could be explained by the chelation mechanism. - The Schiff s base composed of a-keto acid and optically active amine interacted with the catalyst to form a substrate-catalyst complex (14) at lower temperature at higher temperatures, the population of the unchelated structure (15) would increase as shown in Scheme 6. Asymmetric hydrogenation involving () )-a-phenylglycinate and ethyl pyruvate has also been studied. ... 

This type of reaction forming unnatural L-amino acids uses enzymes from the metabolism of proteinogenic amino acids which additionally have an unexpectedly versatile substrate specificity by also accepting highly sterically hindered a-keto acids. L-Tle and L-Npg are of growing importance because of their extended use as building blocks in pharmaceutical drugs and as chiral auxiliaries in asymmetric synthesis [114]. 

Now the asymmetric addition of the TCC 145 ester of 2-keto butyric acid (substrate strategy, see chapter 27) to the lithium derivative of 143, prepared by I/Li exchange, gave the alkoxide 144 and hence, on work up in acidic solution, the pyridone17 135. Coupling to the quinoline 134 was achieved by the same SN2-Heck sequence used in the synthesis of 124. 

The broad synthetic potential ThDP-dependent enzymes for asymmetric C-C bond formation is by far not fully exploited with the acyloin- and benzoin-condensations discussed above. On the one hand, novel branched-chain a-keto-acid decarboxylases favorably extend the limited substrate tolerance of traditirnial enzymes, such as PDC, by accepting sterically hindered a-ketoacids as dcmors [1511], On the other hand, the acceptor range may be significantly widened by using carlxMiyl compounds other than aldehydes Thus, ketones, a-ketoacids and even CO2 lead to novel types of products (Scheme 2.203). 

As mentioned in Section 29.3 asymmetric synthesis has many advantages however, the reversible reaction includes the conversion of a 2-oxo acid to an amino acid leading to equilibrium constants of -1. To overcome this unfavorable equilibrium, large amounts of amino donors can be applied, but as a consequence this leads to substrate inhibition and may complicate the purification of the desired product. Various approaches to shift the equilibrium toward the product side were developed the employment of an amino donor leading to a volatile by-product like acetone [59,60] or precipitation due to the low solubility of the product compared to the keto acid [61, 62]. Another way to remove the product, leading to a shift of the equilibrium, is the use of an ion-exchange resin or spontaneous cyclization for product removal in situ [63] or via multienz5une networks briefly described in Section 29.3.1 and extensively reviewed by Simon et al. [64]. 

In the early 1990s, Burk introduced a new series of efficient chiral bisphospholane ligands BPE and DuPhos.55,55a-55c The invention of these ligands has expanded the scope of substrates in Rh-catalyzed enantioselective hydrogenation. For example, with Rh-DuPhos or Rh-BPE as catalysts, extremely high efficiencies have been observed in the asymmetric hydrogenation of a-(acylamino)acrylic acids, enamides, enol acetates, /3-keto esters, unsaturated carboxylic acids, and itaconic acids. 

Asymmetric catalysis undertook a quantum leap with the discovery of ruthenium and rhodium catalysts based on the atropisomeric bisphosphine, BINAP (3a). These catalysts have displayed remarkable versatility and enantioselectivity in the asymmetric reduction and isomerization of a,P- and y-keto esters functionalized ketones allylic alcohols and amines oc,P-unsaturated carboxylic acids and enamides. Asymmetric transformation with these catalysts has been extensively studied and reviewed.81315 3536 The key feature of BINAP is the rigidity of the ligand during coordination on a transition metal center, which is critical during enantiofacial selection of the substrate by the catalyst. Several industrial processes currently use these technologies, whereas a number of other opportunities show potential for scale up. 

The Ni/tartaric acid/NaBr catalyst system has been extensively studied. A variety of ketone substrates have been reduced with Ni/tartaric acid/NaBr catalysts with variable enantioselectivities, but the highest (>85% ee) are obtained for the reductions of P-keto esters and P-diketones (Schemes 12.60 and 12.61).5 Asymmetric reduction of diketones results in the formation of mesa and chiral diols. The highest meso chiral diol ratio of 2 98 and enantioselectivities of 98% ee are obtained with modified Raney nickel catalysts treated by sonication.5... 

This methodology has been used to provide efficient protocols for the asymmetric allylic alkylation of p-keto esters, ketone enolates, barbituric acid derivatives, and nitroalkanes. Several natural products and analogs have been accessed using asymmetric desymmetrization of substrates with carbon nucleophiles. The palladium-catalyzed reaction of a dibenzoate with a sulfonylsuccinimide gave an advanced intermediate in the synthesis of L-showdomycin (eq 3). ... 

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