Dynamic racemic chiral amines

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. 

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-... 

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). 

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%... 

In contrast to the facile in-situ racemization of sec-alcohols via Ru-catalysts (Schemes 3.14 and 3.17), which allows dynamic resolution, the isomerization of ot-chiral amines requires more drastic conditions. Hydrogen transfer catalyzed by Pd [283, 284], Ru [285, 286] Ni, or Co [287] is slow and requires elevated temperatures close to 100°C, which still requires the spatial separation of (metal-catalyzed) racemization from the lipase aminolysis [288]. 

In 2015, Zhao and co-workers described the first dynamic kinetic asymmetric amination of alcohols via borrowing hydrogen methodology under the cooperative catalysis of iridium complex 25 and chiral phosphoric acid 27 (Schemes 31, 32) [179]. The authors proposed that, initially, the two stereocenters in the alcohols were both racemized to ketone by the first oxidation, followed by tautomerization of the iminium intermediates 28 and 30 through enamine intermediate 29. Then, the... 

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]. 

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). °... 

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. 

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]. 

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. 

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. 

The ability of chiral CTV derivatives to racemize can be manipulated to resolve the enantiomers by dynamic thermodynamic resolution as recently illustrated by Xu and Warmuth. " Their approach is outlined in Scheme 10. A racemic mixture of the tris-aldehyde 5 is reacted with (/ ,R)-diaminocyclohexane to give an enantiomerically pure anft -cryptophane. Only the (P,P,R,R,R) isomer of the cryptophane is formed from reaction of (P)-S with the amine the (M)-5 isomer is completely inverted. Hydrolysis of the cryptophane then gives (P)-5 at >99% ee. 

As there was an amine handle for the formation of diastereomeric salts, classical resolution of to obtain CP-465,022 was also an option (Scheme 23). With the ability to thermally racemize the wrong antipode, one could envision a dynamic resolution (or, asymmetric transformation). In the presence of the appropriate chiral acid, there would be an equilibrium of the enantiomers of CP-392,110 in solution, with only the desired antipode CP-465,022 crystallizing out as the insoluble diastereomeric salt. Pfizer has developed a number of other atropisomers, and this sort of dynamic resolution has been worked out for one of those candidates. 

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]. 

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. 

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,... 

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