Chiral amines dynamic kinetic resolution

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

The integration of a catalyzed kinetic enantiomer resolution and concurrent racemization is known as a dynamic kinetic resolution (DKR). This asymmetric transformation can provide a theoretical 100% yield without any requirement for enantiomer separation. Enzymes have been used most commonly as the resolving catalysts and precious metals as the racemizing catalysts. Most examples involve racemic secondary alcohols, but an increasing number of chiral amine enzyme DKRs are being reported. Reetz, in 1996, first reported the DKR of rac-2-methylbenzylamine using Candida antarctica lipase B and vinyl acetate with palladium on carbon as the racemization catalyst [20]. The reaction was carried out at 50°C over 8 days to give the (S)-amide in 99% ee and 64% yield. Rather surpris-... 

It was mentioned at the beginning of this chapter that alkaloids were among the first catalysts to be used for asymmetric hydrocyanation of aldehydes. More recent work by Tian and Deng has shown that the pseudo-enantiomeric alkaloid derivatives 5/6 and 7/8 catalyze the asymmetric addition of ethyl cyanoformate to aliphatic ketones (Scheme 6.6) [50]. It is believed that the catalytic cycle is initiated by the alkaloid tertiary amine reacting with ethyl cyanoformate to form a chiral cyanide/acylammonium ion pair, followed by addition of cyanide to the ketone and acylation of the resulting cyanoalkoxide. Potentially, the latter reaction step occurs with dynamic kinetic resolution of the cyano alkoxide intermediate... 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

An excellent example of the successful combination of chemo- and biocatalysis in a two-step cascade process is provided by the dynamic kinetic resolutions (DKR) of chiral alcohols and amines. We first suggested [6], in 1993, that (de)-hydrogenation catalysts should be capable of catalyzing the racemization of chiral alcohols and amines via a dehydrogenation/hydrogenation mechanism as shown in Fig. 9.1. 

The first example of the asymmetric synthesis of P-chiral trialkyl phosphates (12) via trialkyl phosphite, in which the keystone is dynamic kinetic resolution in the condensation of a dialkyl phosphorochloridite (13) and an alcohol by the catalytic assistance of a chiral amine has been reported (Figure 2)." 2,4-Dinitrophenol (DNP) was employed as an activating reagent with ben-zyloxy-bis-(diisopropylamino) phosphite to synthesize the cyclic phosphate derivatives (14) from a series of alkane diols HO-(CH2)n-OH (n=2-6). Included was a cyclic phosphate derivative of carbohydrate (15). The mechanism of activation by 2,4-DNP and cyclization was also described (Figure 3). ... 

The product class of enantiomerically pure amines is of considerable importance in both pharmaceutical and agrochemical applications. For instance, enantiopure aryl-alkyl amines are utilized for the synthesis of intermediates for pharmaceutically active compounds such as amphetamines and antihistamines. Several chemical as well as biotransformation methods for the asymmetric synthesis/dynamic kinetic resolution [29] or separation of enantiomers of chiral amines have been described. These are illustrated in Scheme 4.5 for (S)-a-methylbenzylamine [30]. 

List and coworkers reported an excellent approach to the enantioselective synthesis of P branched a amino phosphonates, which involved the extension of the dynamic kinetic resolution strategy (Scheme 3.53) [110] that was previously applied to the enantioselective reductive amination of a branched aldehydes by his research group (see Scheme 3.45). The method combines dynamic kinetic resolution with the parallel creation of an additional stereogenic center. They successfully accomplished the direct three component Kabachnik Fields reaction of 1 equiv each of the racemic aldehyde, p anisidine, and di(3 pentyl)phosphite in the presence of newly developed chiral phosphoric acid It. The corresponding p branched a amino phosphonates were obtained in high diastereo and enantioselectivities, especially for the aldehydes bearing a secondary alkyl group at the a position. 

A number of different groups have recently investigated the dynamic kinetic resolution of racemic chiral amines [35, 36] using an enantioselective lipase (often CAL B or Novozyme 435) in combination with a chemocatalyst that effects racemi zation of the unreactive amine enantiomer under the reaction conditions. A key issue vdth these types of DKR processes is finding conditions under which the bio and chemocatalysts can function efficiently together. The catalytic cycle for a DKR is shown in Figure 14.26 in which it is essentia] to identify methods for selective racemization of the substrate but not the product. 

Dynamic kinetic resolution (chapter 28) of 123 with (+) -di-p -toluoyltar t aric acid equilibrated the easily enolisable chiral centre and precipitated a 90% yield of the salt of the (5) -amine having 80% ee. Reduction with NaBH4 in i-PrOH was very diastereoselective giving 99 1 syn anti-124. 

M. T. Reetz, K. Schimossek, Lipase-catalyzed dynamic kinetic resolution of chiral amines use of palladium as the racemiza-tion catalyst, Chimia 1996, 50, 668. 

The first example of the asymmetric synthesis of P-chiral trialkyl phosphates (12) via trialkyl phosphite, in which the keystone is dynamic kinetic resolution in the condensation of a dialkyl phosphorochloridite (13) and an alcohol by the catalytic assistance of a chiral amine has been reported (Figure 2). ... 

Aldehydes cannot undergo direct enantioselective reduction due to the formation of an achiral product, but List s group discovered an interesting variation on this theme with the direct reductive amination of a-branched aldehydes via an efficient dynamic kinetic resolution (DKR) [56]. Under the reductive amination conditions, an a-branched aldehyde undergoes a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then have to be faster than that of the other, resulting in an enantiomerically enriched product via a dynamic kinetic resolution (Figure 15.6). TRIP once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine product in 50%... 

Andrade, L.H., Silva, A.V., and Pedrozo, E.C. (2009) First dynamic kinetic resolution of selenium-containing chiral amines catalyzed... 

The Kabachnik-Fields reaction is a three-component hydrophosphonylation of imines formed in the reaction mixture from carbonyl compounds and amines [75]. In 2008, List and coworkers reported on such a reaction catalyzed by chiral phosphoric acids that combines a dynamic kinetic resolution with the concomitant generation of a new stereogenic center (Scheme 42.30). The resolution is possible when chiral racemic aldehydes 135 are used. This is because the imine formed in the first step of the reaction is in equilibrium with its achiral enamine tautomer, thereby racemizing the starting material continuously. Since one of the two enantiomers is selectively activated by the chiral phosphoric acid catalyst, the addition of phosphite 136 affords the exclusive formation of one diastereomer. All phos-phonate products 137 were obtained with good yields and moderate to excellent diastereo- and enantioselectivity [76]. 

Very recently, Rovis et al. [20] reported the application of combined enamine and carbene catalysis in the diastereo- and enantioselective synthesis of functionalized cyclopentanones (Scheme 43.10). The authors proposed that the secondary amine catalyst was capable of epimerizmg the a-position of the intermediate aldehyde to form an equilibrium between two diastereomers. Then the chiral triazohum catalyst preferred cyclization with only one of these diastereomers to the final product. The second step of this reaction could be considered analogous to a dynamic kinetic resolution because the j0rgensen-Hayashi amine catalyst would be able to interconvert the two diastereomers. 

In 2006, Hoffmann et al. described an efficient reductive amination of racemic aldehydes via dynamic kinetic resolution (Scheme 2.10). In the presence of 5mol% Brpnsted acid 5b, a-branched aldehydes 36 condensed with amines to form two imine enantiomers XI and X3 with different reaction rates in a transfer hydrogenation reaction, which then underwent a fast racemization via an imine-enamine tautomerization and resulted in enantioenriched P-branched chiral amine products 38 [17]. 

Acyl transferase enzymes have been widely used to synthesize chiral esters, amides, alcohols, and amines. In many cases, these conversions involve kinetic resolutions of alcohols, adds, esters, amines, and amides. Of course, since each enantiomer makes up half of the racemic mixture, kinetic resolutions can provide a maximum 50% yield. This limitation can be overcome by racemizing or inverting the configuration of the unreacted substrate during the enzymatic reaction. Such a scheme is referred to as a dynamic kinetic resolution and theoretically allows complete substrate conversion to product along with 100% chemical yield of a single product enantiomer. 

Another example, from the Pfizer portfolio, of successful incorporation of biocatalysis to make functional group interconversions (FGIs) more efficient in API synthesis is in a program for a smoothened (SMO) receptor inhibitor [17], Introduction of a transaminase-catalyzed stereoselective reductive amination of a 4-piperidone 4 with concurrent dynamic kinetic resolution (DKR) gave amine 5 (Scheme 7.2), resulting in the highly efficient incorporation of two chiral centers in a single step. 

TABLE 29.2 A Variety of Chiral Amines and Amino Alcohols Produced with Asymmetric Synthesis (AS) and Dynamic Kinetic Resolution (DKR)/Deracemization (DE)... 

Dynamic Kinetic Resolution for the Synthesis of Chiral Amines... 

List et al. combined the reductive amination of an aldehyde with dynamic kinetic resolution (DKR) to obtain (3-branched chiral amines from racemic a-branched aldehydes and anilines in variable yields (39-96%) and enantio-selectivities (40-98% ee) (Scheme 32.23). °... 

Stereoselective Reductive Amination Using Chiral Ketones as Auxiliary The first report of asymmetric reductive amination using chiral ketone was published by Nugent and co-workers in 2004. The current methodology includes dynamic kinetic resolution of a racemic ketone 128 producing a chiral ketone 129,... 

Kim Y, Park J, Kim M-J. Dynamic kinetic resolution of amines and amino acids by enzyme-metal cocatalysis. Chem-CatChem 2011 3 271-277 and the following references cited therein (a) Reetz MT, Schimossek K. Lipase-Catalyzed Dynamic Kinetic Resolution of Chiral Amines Use of Palladium as the Racemization Catalyst. Chimia 1996 50 668-669. 

Blacker AJ, Stirling MJ, Page MI. Catalytic racemisation of chiral amines and application in dynamic kinetic resolution. Org. Process Res. Dev. 2007 11 642 48. 

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