Dynamic kinetic resolution amines

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]. 

Scheme 7.19 Dynamic kinetic resolution of primary amines.

The procedure constitutes the first known example of a chemoenzymatic dynamic kinetic resolution of a secondary amine. The operational simplicity of the procedure is exemplified by the mild conditions, air-stable reagents and low catalyst loading. 

Stirling, M., Blacker J. and Page M.I., Chemoenzymatic dynamic kinetic resolution of secondary amines. Tetrahedron Lett., 2007, 48, 1247. 

Dynamic Kinetic Resolution of Primary Amines with a Recyclable Palladium Nanocatalyst (Pd/A10(0H)) for Racemization... 

The complete transformation of a racemic mixture into a single enantiomer is one of the challenging goals in asymmetric synthesis. We have developed metal-enzyme combinations for the dynamic kinetic resolution (DKR) of racemic primary amines. This procedure employs a heterogeneous palladium catalyst, Pd/A10(0H), as the racemization catalyst, Candida antarctica lipase B immobilized on acrylic resin (CAL-B) as the resolution catalyst and ethyl acetate or methoxymethylacetate as the acyl donor. Benzylic and aliphatic primary amines and one amino acid amide have been efficiently resolved with good yields (85—99 %) and high optical purities (97—99 %). The racemization catalyst was recyclable and could be reused for the DKR without activity loss at least 10 times. 

Dynamic Kinetic Resolution of Amines Involving Biocatalysis and In Situ Free-radical-mediated Racemization... 

Dynamic kinetic resolution enables the limit of 50 % theoretical yield of kinetic resolution to be overcome. The application of lipase-catalyzed enzymatic resolution with in situ thiyl radical-mediated racemization enables the dynamic kinetic resolution of non-benzylic amines to be obtained. This protocol leads to (/f)-amides with high enantioselectivities. It can be applied either to the conversion of racemic mixtures or to the inversion of (5)-enantiomers. 

Gastaldi, S., Escoubet, S., Vanthuyne, N., Gil, G. and Bertrand, M.P., Dynamic kinetic resolution of amines involving biocatalysis and in situ free radical mediated racemization. Org. Lett., 2007, 9, 837-839. 

The reversibility of hydrogen transfer reactions has been exploited for the racemi-zation of alcohols and amines. By coupling the racemization process with an enantioselective enzyme-catalyzed acylation reaction, it has been possible to achieve dynamic kinetic resolution reactions. The combination of lipases or... 

Scheme 32 Dynamic kinetic resolution of racemic aryloxy epoxides with amine using the catalysts 77...

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

A prominent example of chemoenzymatic catalysis in bio-organic chemistry is the dynamic kinetic resolution (DKR) of secondary alcohols (Scheme 9) [94, 95] and amines [96-99], In this process, a lipase is employed as an enantioselective acylation catalyst, and a metal-based catalyst ensures continuous racemization of the unreactive enantiomer. 

Compared to the chemo-catalyzed kinetic resolution of alcohols, there are few reports of similar reactions for amines. Building on other work, one elegant example from Berkessel uses bifunctional organocatalysts to enantioselectively hydrolyze a racemic azlactone, and the dynamic kinetic resolution (DKR) is achieved by in-situ acid-catalyzed racemization of the azlactone under mild conditions to give product N-acylarnino esters in, for example, 72% ee and 96% conversion with phenylalanine [6]. 

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-... 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

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... 

Dynamic kinetic resolutions of secondary alcohols and amines have been achieved by the combination of biocatalysts with metal catalysts.12 For example, a metal catalyst was used to racemize the substrate, phenylethanol, and a lipase was used for the enantioselective esterification as shown in Figure 12. The yield was improved from 50% in kinetic resolution without racemization of the substrate to 100% with metal catalyzed racemization. 

At the onset of this study, we hypothesized that under our reductive amination conditions an a-branched aldehyde substrate would undergo 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 (Scheme 15 for reviews, see Noyori et al. 1995 Ward 1995 Caddick and Jenkins 1996 Stecher and Faber 1997 Huerta et al. 2001 Perllissier 2003). 

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). 

In general the hydrolysis of amides is performed as a kinetic resolution and not as a dynamic kinetic resolution. It is applied industrially [96] but in most cases the industrial kinetic resolution of amines, as performed for instance by BASF, is an acylation of racemic amines [38], rather than the hydrolysis of racemic amides. For the acylation of amines many different acyl donors [27] and enzymes can be used, including lipases (or a review see [97]). 

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. 

Another important difference between (dynamic) kinetic resolution of alcohols and amines is the ease with which the acylated product, an ester and an amide, respectively, is hydrolyzed. This is necessary in order to recover the substrate enantiomer which has undergone acylation. Ester hydrolysis is generally a facile process but amide hydrolysis, in contrast, is often not trivial. For example, in the BASF process [28] for amine resolution by lipase-catalyzed acylation the amide product is hydrolyzed using NaOH in aq. ethylene glycol at 150 °C (Fig. 9.18). In the case of phenethylamine this does not present a problem but it will obviously lead to problems with a variety of amines containing other functional groups. 

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