Dynamic chiral amines

The Catalysis Concept of Iminium Activation In 2000, the MacMillan laboratory disclosed a new strategy for asymmetric synthesis based on the capacity of chiral amines to function as enantioselective catalysts for a range of transformations that traditionally use Lewis acids. This catalytic concept was founded on the mechanistic postulate that the reversible formation of iminium ions from a,p-unsaturated aldehydes and amines [Eq. (11.10)] might emulate the equilibrium dynamics and 7i-orbital electronics that are inherent to Lewis acid catalysis [i.e., lowest unoccupied molecular orbital (LUMO)-lowering activation] [Eq. (11.9)] ... 

Dynamic Resolution of Chiral Amine Pharmaceuticals Turning Waste Isomers into Useful 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-... 

I 13 Dynamic Resolution of Chiral Amine Pharmaceuticals Turning Waste Isomers into Useful Product Table 13.3 Enantiomer ratios at different stages of the (IS, 4S)-sertraline mandelate process. 

The macromolecular helicity induced in poly(phenylacetylene)s 28-30 (Fig. 14) upon complexation with chiral amines is dynamic in nature, and therefore, the ICD due to the helical chirality immediately disappears when exposed to a stronger acid such as trifluoroacetic acid. However, during the intensive exploration of the helicity induction and chirality amplification mechanism of the poly(phenylacetylene)s, such an induced helical chirality of 28-30 by an optically active amine such as (R)-39 has been found to be maintained, namely memorized , when the chiral amine is completely removed and replaced by various achiral amines, for example, 71 and 72 for 28 and diamines such as ethylenediamine for 29 and 30 in... 

A cast film of 28 also responded to the chirality of liquid and solid chiral amines, and exhibited an ICD in the UV-visible region. The observed Cotton effect patterns were similar to those of 28 induced by the chiral amines in solution [147]. These methods are more convenient and practically feasible to sense the chirality of chiral amines than the solution method, and may be applicable to other dynamic helical polyacetylenes. 

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). 

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]. 

P chiral amines are not included in this review, but we remind the reader that List has extended his TRIP/p anisidine system to an elegant dynamic kinetic reductive amination protocol for a branched aldehydes, which provides p chiral amines [18]. A computational investigation of the stereochemical pathway for p chiral amine formation has been reported on and is noteworthy [19]. 

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. 

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%... 

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]. 

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

Palladium and chiral amine co-catalyzed enantioselective dynamic cascade reaction of simple starting materials leads to the synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter (Scheme 6.14) [16]. 

Ma, G., Afewerki, S., Deiana, L., Palo-Nieto, C., Liu, L., Sun, J., Ibrahem, I., Cordova, A. (2013). A palladium/chiral amine co-catalyzed enantioselective dynamic cascade reaction synthesis of polysubstituted carbocycles with a quaternary carbon stereocenter. Ange-wandte Chemie International Edition, 52, 6050-6054. 

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]. 

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