P-keto esters a-substituted

Scheme 6.81 Transformation of one adduct prepared from the 64-catalyzed asymmetric addition of a-substituted P-keto esters to di-tert-butyl azodicarboxylate (a-hydrazination) into the corresponding oxazolidinone amino acid derivative.

The enzyme-catalyzed regio- and enantioselective reduction of a- and/or y-alkyl-substituted p,5-diketo ester derivatives would enable the simultaneous introduction of up to four stereogenic centers into the molecule by two consecutive reduction steps through dynamic kinetic resolution with a theoretical maximum yield of 100%. Although the dynamic kinetic resolution of a-substituted P-keto esters by chemical [14] or biocatalytic [15] reduction has proven broad applicability in stereoselective synthesis, the corresponding dynamic kinetic resolution of 2-substituted 1,3-diketones is rarely found in the literature [16]. 

Highly stereoselective hydrogenation of racemic a-substituted P-keto esters via dynamic kinetic resolution [14,17] has been reported. Hydrogenation of a racemic a-amidomethyl substrate with the (-)-DTBM-SEGPHOS/Ru catalyst resulted in the 2S,3R alcohol in 99.4% ee (syn anti=99.3 0.7) (Scheme 22) [36]. The product was a key compound for an industrial synthesis of carbapenem antibi-... 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

Dynamic kinetic resolution can occur for a-substituted P-keto esters with epimerizable substituents provided that racemization of the antipodes 32 and 33 is rapid with respect to the Ru(BINAP)-catalyzed reduction, thereby potentially allowing the formation of a single diastereo-isomer (Scheme 12.9). Deuterium labeling experiments have confirmed the rapid equilibrium of... 

The reduction of imines/enamines 10j-10n/36j-36n generated from p keto esters can be regarded as an interesting method for the preparation of p amino acids. This approach has been extended to the reduction ofthe imines/enamines derived from a substituted P keto esters 37 (Scheme 4.4). In this case, the fast enamine imine equilibration 38 39 is the key point since imines 39 are chiral but racemic, so that... 

Two stereogenic centers are established on allylation of a-substituted P-keto esters and cyanoacetic esters with secondary cinnamyl acetates. The reaction is directed toward a regio-selective and diastereoselective pathway when o-diphenylphosphinobenzoic acid is used as a hgand. ... 

Owing to the importance of optically active amino acid derivatives and the lack of successful systems for catalytic asymmetric CDC reactions of glycine derivatives with p-keto esters, Wang and co orkers embarked on the study of enantioselective CDC reactions of secondary and tertiary amines for the synthesis of optically active a-alkyl a-amino acids. In the presence of a catalytic amount of Cu(OTf)2 and BOX ligand L2 as the chiral catalyst, in combination with DDQ as the stoichiometric oxidant, the reactions of glycine esters 47 with a-substituted p-keto esters 48 underwent smoothly to afford the desired products 49 in satisfactory yields, moderate dr and excellent ee (Scheme 2.17). 

Scheme 4.41 Arylation of a-substituted p-keto esters using aryllead triacetates...

Scheme 1.56 Michael additions of malonate and a-substituted P-keto esters to nitroalkenes catalysed by bifunctional amine-thioureas.

Historically, this term was applied for the first time by Noyori [2], in the case of a ruthenium-catalyzed hydrogenation of a-substituted-P-keto esters. According to Noyori and his coworkers, even when the racemization constant k ac is the same as the rate constant of the fast reacting enantiomer, good enantioselectivities and quantitative conversions can be obtained [3]. An efficient DKR process can also be obtained when krac is higher than the rate constant of the reduction of the slow reacting enantiomer (krac > fesiow)-... 

Acyclic a-Substituted-P-Keto Esters and 2-Substituted-1,3-Diketones I 313... 

Acyclic a-Substituted-p-Keto Esters and 2-Substituted-l, 3-Diketones... 

As it is known, through the DKR of a-substituted P-keto esters by chemical [29] or biocatalytical reduction [la], two stereogenic centers are simultaneously introduced into the molecule in a theoretical maximum yield of 100%. This methodology was extended in order to introduce more stereogenic centers by consecutive reduction steps. 

In 2000, the group of Stewart in Florida reported the asymmetric synthesis of P-hydroxy esters and a-alkyl-P-hydroxy esters by recombinant E. cdi expressing enzymes from baker s yeast [32]. In all cases, a single diastereomer was produced (Scheme 12.15). Both strains yielded the syn-(3S)-alcohols 20a, 21a, 23a, and 28a, with high ee values and in moderate chemical yields. When racemic a-substituted P-keto esters 20, 21, 23, and 28 were employed as substrates, DKRs resulted in almost complete conversion of the substrate, due to facile racemization at the a-position. 

Recently, it has been shown that the BY-mediated reduction of a-substituted p-keto esters led to the reduction of the carbonyl group with high stereospecificity at low pH values, whereas at higher pH values cleavage of the C—C bond is observed. Thus, 250 gave at pH = 4 251 and 252 each of 99% e.e. with a syn anti ratio of 10 1, whereas at pH = 7 a 1 1 ratio was observed and the e.e. values were significantly lower. Finally, at pH = 8 a cleavage of the C—C bond with more than 75% formation of benzoic acid (229) was observed [361]. 

---