Dynamic kinetic resolution reductive amination

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 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... 

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). 

List and coworkers developed an excellent approach to synthesize p branched amines in optically active forms by combining the enamine and reductive amination processes (Scheme 3.45) [96]. The reductive amination of unsymmetrically a,a disubstituted aldehydes and aniline derivatives proceeded through a tautomerization between imine and enamine forms. Dynamic kinetic resolution occurred under the... 

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. 

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. 

List et al. have achieved catalytic reductive amination of a-branched aldehydes for the first time. -Substituted amines were obtained with good to excellent ees by use of (41e) (5 mol%) via dynamic kinetic resolution (Scheme 2.99) [174]. 

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]. 

Like amine oxidases, one can also combine amino add dehydrogenases with in situ chemical reduction, a transaminase, or an amino add dehydrogenase to effect dynamic kinetic resolutions of amino adds. Details of these more complex processes are desaibed in the appropriate later chapters. 

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. 

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). °... 

Hoffmann S, Nicoletti M, List B. Catalytic asymmetric reductive amination of aldehydes via dynamic kinetic resolution. J. Am. Chem. Soc. 2006 128 13074-13075. 

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,... 

List and coworkers developed an excellent application of this method to a dynamic kinetic resolution approach (Scheme 11.12) [23]. In the presence of phosphoric acid catalyst la and 39, the reductive amination of racemic a,a-disubstituted aldehydes 46andpara-anisidine (17) proceeded through a tautomerization between enamine 48 and imine 49. The essential point of this protocol is that the hydrogenation of (R)-49 proceeded more rapidly than that of (S)-49 to give P-branched amine 47 in 87% yield with 96% ee. 

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