Dynamic kinetic asymmetric catalysts

A DYKAT (dynamic kinetic asymmetric transformation) approach has been taken to de novo synthesis of triketide- and deoxy-sugars from racemic /i-hydroxyal-dehydes.119 Using proline as catalyst, the process involves continuous amino acid-mediated racemization of the acceptor /3-hydroxyaldehydc in combination with direct... 

One of the routes leading to P-stereogenic phosphines is electrophilic substim-tion at the phosphorus atom of secondary phosphines, as a result of asymmetric catalysis in which a catalyst activates a phosphorus nucleophile or a carbon electrophile, creating an asymmetric environment, i.e., creating preference for one of Si or Re face sides at the reactive center [103-113]. Upon reaction with chiral metal complexes, racemic secondary phosphines are converted into diaste-reomeric metal-phosphide complexes A or B, which interconvert rapidly through the inversion at phosphorus. If the equilibrium A B is faster than the reaction of A or B with an electrophile E, then P-stereogenic phosphines 196, in which pyramidal inversion is slow, can be formed enantioselectively. The product ratio in this dynamic kinetic asymmetric transformation depends both on and on the rate constants ks and (Scheme 63). 

Cycloaddition of cyclopropanes to aldehydes leads to the formation of tetrahydrofurans derivatives, whose enantiomeric form can be obtained either by using enantioenriched cyclopropane substrates or by a dynamic kinetic asymmetric transformation. In this regard, Johnson et al. reported a dynamic kinetic asymmetric [3 -I- 2] cycloaddition of racemic cyclopropanes 63 for the enantioselective synthesis of tetrahydrofurans 64. In this study, the magnesium catalyst can promote the ring opening of the racemic cyclopropane and catalyses the reaction of one of the ring-opened enantiomers with the aldehydes (Scheme 3.19). 

In 1999, Trost and Toste introduced the concept of dynamic kinetic asymmetric transformation (DYKAT) which is frequently referred to as DKR, since it involves the equilibration of diastereomeric intermediates generated from the racemic substrates. This concept allows for the transformation of both enantiomers of a racemic substrate in a highly enantio-enriched product. As an example. Trust s group has demonstrated that exposing butadiene monoepoxide and phthalimide to a catalyst formed in situ from a 7i-allylpalladium chloride dimer and a chiral ligand led to the corresponding chiral phthalimide... 

Among asymmetric version of barium-catalyzed aldol reactions, the direct aldol reaction of y3,y-unsaturated esters with aldehydes is promising due to the DYKAT (dynamic kinetic asymmetric transformation). Shibasaki and coworkers (147) established an optimized catalyst system for the DYKAT involving aldol/retro-aldol reaction, that a Ba(0-iPr)2/BIN0L mixture gave excellent enan-tioinduction and conversion (Scheme 32). a-Alkylidene-y3-hydroxy esters were obtained under proton-transfer conditions via DYKAT in 87-99% ee. 

Scheme 16.14 Dynamic kinetic asymmetric transformation of propargyi esters with a chiral bis(HBHC)-digold catalyst.

Kejrwords Dynamic kinetic asymmetric transformation (DYKAT) Dynamic kinetic resolution (DKR) Hydrogenation Imine reduction Ketone reduction Mechanism of carbonyl reduction Mechanism of imine reduction Mechanism of dUiydrogen activation Ruthenium catalysis Shvo s catalyst Transfer hydrogenation... 

The Shvo catalyst 1 was successfully used in the transfer hydrogenation of 1,3-diones to the corresponding 1,3-diols with isopropanol as the hydrogen donor (2) [36, 37], This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlIli preferentially gives the aUyUc alcohol [36]. Also piperidine-3,5-diones were efficiently reduced to the corresptMiding diols by isopropanol using 1 as catalyst [37], and these diols were subsequently used in dynamic kinetic asymmetric transformatimis (DYKATs) to provide stereodefined 3,5-disubstituted piperidines [36, 37],... 

Considering the rapid growth of asymmetric construction of oxindoles, Sun et al. recently reported their assembly of chiral spirooxindoles by combining secondary amine and palladium catalysis in a cascade reaction [55]. The reaction was initiated by the reversible Michael addition of 3-substituted oxindole to enal, which was followed by a metal/organic-cocatalyzed carbocyclization of the aUcyne tether (Scheme 9.60). Similar to the aforementioned dynamic kinetic asymmetric transformations, this chemistry highlighted the cooperative effects of the two catalysts in the same reaction vessel, while either catalyst could not solely promote the overall reaction, and unsatisfactory results were observed when this reaction was conducted in a two-step mode. 

With a racemic mixture of the secondary Grignard reagent, asymmetric cross-coupling with chiral catalysts creates a stereogenic center on the nucleophile. Using (iS,S)-chiraphos as ligand, the facile interconversion between the two enantiomers of a-phenethylmagnesium bromide allows the formation of the allylated product in 87% yield and 58% ee by a dynamic kinetic asymmetric transformation (Eq. 8E.28) [207]. 

Asymmetric synthesis can refer to any process which accesses homochiral products. We will focus on asymmetric synthesis from racemic or prochiral starting materials in the presence of an enantioselective catalyst (enzyme). There are four general methodologies commonly applied kinetic resolution, dynamic kinetic resolution, deracemization and... 

Pellissier, H., Recent developments in dynamic kinetic resolution. Tetrahedron, 2008, 64, 1563-1601 Turner, N.J., Enzyme catalysed deracemisation and dynamic kinetic resolution reactions. Curr. Opin. Chem. Biol., 2004, 8, 114-119 Gmber, C.C., Lavandera, I., Faber, K. and Kroutil, W., From a racemate to a single enantiomer deracemisation by stereoinversion. Adv. Synth. Catal., 2006, 348, 1789-1805 Pellissier, H., Dynamic kinetic resolution. Tetrahedron, 2003, 59, 8291-8327 Pmnies, O. and Backvall, J.-E., Combination of enzymes and metal catalysts. A powerful approach in asymmetric catalysis. Chem. Rev., 2003, 103, 3247-3261. 

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. 

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. 

Makino, K., Hiroki, Y. and Hamada, Y. Dynamic Kinetic Resolution Catalyzed by Ir Axially Chiral Phosphine Catalyst Asymmetric S3mthesis of anti-Aromatic -Hydroxy-ot-amino Acid Esters. J. Am. Chem. Soc. 2005, 127, 5784—5785. 

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-... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

As described above, the catalyst comprising RuC12 complex with a strong base is effective for the asymmetric hydrogenation through dynamic kinetic resolution. However, it is not suitable for static kinetic resolution of racemic a-substi-tuted ketones because of the basic conditions. The newly devised frans-RuHfri1-BH4)[(R)-XylBINAP][(S,S)-DPEN] without any additional base allows one to... 

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