DKR methodology

This nitrilase dynamic kinetic resolution (DKR) methodology depends on the availability of highly enantioselective biocatalysts that generate a minimum amount of amide. This latter issue may seem trivial and has long been disregarded somewhat, but reports of modest amounts of amide co-products date back to the early days of nitrilase enzymology. Only recently has the subject come under more intense scrutiny [3-5] and has a relationship with the stereochemistry of the nitrile been demonstrated [3, 5]. Hence, we set out to investigate the enantiomer and chemical selectivity of nitrilases in the hydrolysis of a representative set of cyanohydrins. 

Although the enzymatic DKR methodology has been exhaustively applied to different secondary alcohols through enzymatic hydrolysis or transesterification, relatively few examples are known in the case of amines, probably because this type of DKR implies the formation of imino compounds as intermediates, which are less stable than carbonyl compounds.However, in the last few... 

Scheme 4.13 Synthesis of ataxotere precursor using a DKR methodology with ADHs.

The Backvall group applied the amine DKR methodology to the synthesis of nor-sertraline [67] (Scheme 5.45), which is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. In the first step, the DKR of racemic amine rac-29 was performed with CAL-B (Novozym 435) and dimeric Ru catalyst 12 to obtain the enantiomeric amide (R)-30 (99% ee). The (R)-amide was converted via several chemical steps to tiie target (99% ee) with an overall 28% 5deld. 

Nanda et al. applied an alcohol DKR methodology to the total synthesis of a natural product, stagonolide-C, which exhibited antibacterial and antifungal activities (Scheme 5.47) [69]. In this synthesis, the DKRs of two monoprotected diols rac-33 and rac-36 were performed with CAL-B (Novozym 435) and Ru catalyst 5, followed by... 

The coupling of enzyme-catalyzed resolution with metal-catalyzed racemization constitutes a powerful DKR methodology for the synthesis of enantioenriched alcohols, amines, and amino acids. In many cases, the metalloenzymatic DKRs provide high yields and excellent enantiopurities, both approaching 100%, and thus provide useful alternatives to the chemical catalytic asymmetric reactions employing transition metals (complexes) or organocatalysts. The wider applications of a metalloenzymatic DKR method, however, are often limited by the low activity, narrow substrate specificity, or modest enantioselectivity of the enzyme employed. The low activities of metal-based catalysts, particularly in the racemization of amines and amino acids, also limit the wider applications of DKR. It is expected that fm-ther efforts to overcome these limitations with the developments of new enzyme-metal combinations will make the metalloenzymatic DKR more attractive as a tool for asymmetric synthesis in the future. 

This highly efficient DKR methodology was applied to the synthesis of the selective serotonin reuptake inhibitor, norsertraline (Scheme 1.4), which is used to treat depression. For the application of enzymatic dynamic kinetic resolution in stereoselective synthesis, see chapter 57. 

The amino motif is ubiquitous in nature and can usually be found in the structure of innumerable natural and synthetic bioactive compounds. In fact, it is estimated that around 20% of drugs contain at least one amine chiral center. The DKR methodology has also been successfully applied to chiral amines, " although some years later than for alcohols. 

Several reports on DKR of cyanohydrins have been developed using this methodology The unstable nature of cyanohydrins allows continuous racemization through reversible elimination/addition of HCN under basic conditions. The lipase-catalyzed KR in the presence of an acyl donor yields cyanohydrin acetates, which are not racemized under the reaction conditions. 

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

It should be mentioned that the great majority of dynamic kinetic resolutions reported so far are carried out in organic solvents, whereas all cyclic deracemizations are conducted in aqueous media. Therefore, formally, this latter methodology would not fit the scope of this book, which is focused on the synthetic uses of enzymes in non-aqueous media. However, to fully present and discuss the applications and potentials of chemoenzymatic deracemization processes for the synthesis of enantiopure compounds, chemoenzymatic cyclic de-racemizations will also be briefly treated in this chapter, as well as a small number of other examples of enzymatic DKR performed in water. 

The same methodology was also applied to the DKR of (5-hydroxyesters. In the latter case, the reaction was carried out in tandem with an aldol reaction and the P-hydroxyester formed, after neutralization, underwent DKR using the immobilized lipase from Candida antarctica and a ruthenium catalyst [8]. 

This particular methodology has been used extensively for the DKR of a wide variety of structurally related /3-keto-esters to give /3-hydroxy-esters, such as rac-75 yielding (S,S)-76 (equation 10) " " and rac-77 yielding (R,R)-79 (equation 11) ", with excellent diastereo- and enantioselectivities. The diastereoselectivity can be influenced using reagent control. 

Extensive studies have been carried out on nucleophilic substitution of a-halocarboxylic acid derivatives containing a chiral auxiliary in the carboxylic moiety. Racemisation of the labile chiral centre in the a-position to the carbonyl—induced by additives such as polar solvents, bases or halide salts—allows a high asymmetric induction through a DKR process to be obtained. This methodology has been recently recognised as a powerful synthetic method for asymmetric syntheses of a-heteroatom-substituted carboxylic acid derivatives. 

As an example, ferf-butyl (45)-l-methyl-2-oxoimidazolidine-4-carboxylate was used by Nunami and colleagues as a chiral auxiliary for DKR of a-bromo-carboxylic acids. In this case, the nucleophile was a malonic ester enolate and the role of the polarity of the solvent (hexamethylphosphoramide, HMPA) was demonstrated (Scheme 1.2). The alkylated products were further easily converted to chiral a-alkylsuccinic acid derivatives and chiral jS-amino acid derivatives. Moreover, these authors showed that this methodology could be extended to other nucleophiles such as amines." Therefore, the reaction of a diastereomeric mixture of tert-bvAy (45)-l-methyl-2-oxoimidazolidine-4-carb-oxylate with potassium phthalimide predominantly afforded fcrf-butyl (45)-1-methyl-3-((25)-2-(phthaloylamino)propionyl)-2-oxoimidazolidine-4-carboxylate in 90% yield and 94% diastereomeric excess (de). The successive removal of the chiral auxiliary afforded A-phthaloyl-L-alanine. 

The incorporation of unnatural amino acids into peptides to enhance their metabolic stability and activity is an area of major interest in peptidomimetic chemistry. In order to accomplish this goal. Park and colleagues have developed nucleophilic substitutions of a-bromo amides derived from L-amino acids in the presence of amine nucleophiles on the basis of DKR processes. Whereas moderate stereoselectivities were obtained when using benzylamine as the nucleophile, the nucleophilic substitution reactions of various a-bromo amides with the more sterically demanding secondary amine nucleophile, dibenzylamine, allowed the stereoselectivity of the reactions to be increased remarkably. This methodology provided, in the presence of tetra-n-butyl-ammonium iodide (TBAI) and TEA, the corresponding dipeptide analogues in up to 98% yield and 98% de (Scheme 1.15). 

In 2006, Lassaletta s group had extended the scope of the DKR transfer hydrogenation methodology to a variety of cyclic a-haloketones, offering an... 

The scope of the ruthenium-catalysed asymmetric transfer hydrogenation methodology was very recently extended to a-alkyl-substituted )S-ketoamides by Limanto et Indeed, the first enantio- and diastereoselective synthesis of various syn a-alkyl-substituted jS-hydroxyamides via highly efficient Ru-cata-lysed hydrogenation through DKR of the corresponding ) -ketoamides has been successfully demonstrated. As shown in Scheme 2.31, excellent diastereo-and enantioselectivities of up to 98% de and > 99% ee, respectively, were observed when the process was performed in CH2CI2 or toluene as the solvent. 

In 1995, a practical route to fosfomydn was described by Noyori s group based on a very efficient DKR of j9-ketophosphonates, as shown in Scheme 2.33. This methodology was extended to the hydrogenation of a-amido -ketophospho-nates, which provided the corresponding yu-a-amido ) -hydroxy phosphonates in excellent diastereo- and enantioselectivities, as shown in Scheme 2.33. ... 

In 2003, Trost s group developed the Pd-catalysed DKR of y-acyloxy-butenolides and apphed this methodology to the first enantioselective total synthesis of ( )-aflatoxins B2a and Bi, as shown in Scheme 2.53. This methodology was also apphed to the total synthesis of (-I- )-brefeldin... 

Nickel, one of abundant and cheap base transition metals, has attracted a great deal of attention in catalytic organic synthesis. In this context, a new practical methodology to prepare enantiopure 1,2-hydrazinoalcohols based on a dia-stereoselective Ni(ii)-catalysed Michael addition step followed by stereoselective reduction of the keto function has been reported. In this process, a DKR was involved during the reduction of chiral a-hydrazino-jS-ketoacid derivatives (Scheme 2.67). ... 

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