Dynamic kinetic asymmetric process

A classical approach to driving the unfavorable equilibrium of an enzymatic process is to couple it to another, irreversible enzymatic process. Griengl and coworkers have applied this concept to asymmetric synthesis of 1,2-amino alcohols with a threonine aldolase [24] (Figure 6.7). While the equilibrium in threonine aldolase reactions typically does not favor the synthetic direction, and the bond formation leads to nearly equal amounts of two diastereomers, coupling the aldolase reaction with a selective tyrosine decarboxylase leads to irreversible formation of aryl amino alcohols in reasonable enantiomeric excess via a dynamic kinetic asymmetric transformation. A one-pot, two-enzyme asymmetric synthesis of amino alcohols, including noradrenaline and octopamine, from readily available starting materials was developed [25]. 

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... 

Trost and coworkers have shown that Baylis-Hillman adducts can be efficiently derace-mized by Pd2dba3-CHCl3 catalyzed reaction of the corresponding carbonates 55 with phenols 56 in the presence of chiral C2-symmetric P,N-ligands (Scheme 11) [44], The strategy follows a dynamic kinetic asymmetric transformation process via jr-allyl palladium chemis-... 

One good example of the application of this technology is in the AAA reaction of a racemic vinyl epoxide. The epoxide undergoes a dynamic kinetic asymmetric transformation (DYKAT) by reaction with p-methoxybenzyl alcohol, the standard ligand, and a palladium source. The product is obtained in 69% yield and 98% e.e. After further manipulations a key building block for the nonpeptidic protease inhibitor tipranavir was produced. Coupling of this intermediate with a synthon obtained using a molybdenum-catalyzed DYKAT process led to an advanced intermediate in a total synthesis of tipranavir (Scheme 20.14). ... 

An advantage of this process is that it is possible to circumvent the racemiza-tion step if the unwanted isomer can be made to undergo spontaneous in situ racemization under the reaction conditions. In such a dynamic kinetic resolution process, a theoretical yield of 100% is possible as in asymmetric synthesis. Another example is the production of (/ )-phenylglycine. 

Aryl alcohols are competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic MBH derivatives. As an extension of this strategy, the palladium-catalyzed intramolecular DYKAT of MBH adducts was further explored. As shown in Scheme 4.96, reactions were carried out in dioxane at 25 °C with chiral ligand affording 300 in up to 45% yields and 98% ee via a highly selective kinetic resolution interestingly, when reactions were performed at 80 °C, up to 94% yield with 91% ee of 300 was obtained by the DYKAT process. 

This fundamental experiment has strong implications on related catalyst-controlled Mizoroki-Heck cyclizations of precursors of this type. As axial chirality in 113 sets the stereochemistry in 114, enantioinduction was rationalized to arise from a dynamic kinetic resolution of (at elevated temperature) rapidly interconverting enanhomers of 113 in the oxidative addition step, rather than in the alkene coordination-migratory insertion event. Such a dynamic kinetic resolution process has been previously proposed by Stephenson et al. within their mechanistic study regarding the conformations of helically chiral 2-iodoanilides in intramolecular asymmetric Mizoroki-Heck reactions [72],... 

In 2007, Griengl et al. developed the synthesis of chiral aromatic 1,2-amino alcohols on the basis of a bienzymatic dynamic kinetic asymmetric transformation process.The reaction occurred between a benzaldehyde derivative and glycine in the presence of L-threonine aldolase from Pseudomonas putida and L-tyrosine decarbmylase from either Enterococcus faecalis or two genes from Enterococcus faecium. The best results were obtained for the production of (5 )-octopamine (99%, ee = 81%), and (5 )-noradrenaline (76%, ee = 79%), as shown in Scheme 4.16. 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

The substrate is a mixture of four stereoisomers (a diastereomeric mixture of enantiomeric pairs), which could be converted into only one stereoisomer of the product. These processes are called dynamic kinetic asymmetric transformations (DYKATs), and they will be addressed in section 1.2. 

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... 

Figure 2b shows the other extreme, whereby the rate of epimerization is fast relative to the rate of substitution. In this case, Curtin-Hammett kinetics apply, and the product ratio is determined by AAG. In the specific case of organolithium enantiomers that are rendered diastereomeric by virtue of an external chiral ligand, such a process may be termed a dynamic kinetic resolution. Both of these processes are also known by the more general term asymmetric transformation One should be careful to restrict the term resolution to a separation (either physical or dynamic) of enantiomers. An asymmetric transformation may also afford dynamic separation of equilibrating diastereomers, but such a process is not a resolution. "... 

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. 

The first strategy involves discrimination between enantiotopic leaving groups (Type A). In the second approach, two enantiomers of a racemic substrate converge into a meso-n-al y complex wherein preferential attack of the nucleophile at one of either allylic termini leads to asymmetric induction, a process that may be referred to as a dynamic kinetic enantioselective transformation (Type B). The third requires differentiation between two enantiotopic transition... 

A tandem 1,4-addition-Meerwein-Ponndorf-Verley (MPV) reduction allows the reduction of a, /i-unsaturated ketones with excellent ee and in good yield using a camphor-based thiol as reductant.274 The 1,4-addition is reversible and the high ee stems from the subsequent 1,7-hydride shift the overall process is thus one of dynamic kinetic resolution. A crossover experiment demonstrated that the shift is intramolecular. Subsequent reductive desulfurization yielded fiilly saturated compounds in an impressive overall asymmetric reductive technique with apparently wide general applicability. 

Huerta FF, Minidis ABE, Backvall JE (2001) Racemisation in asymmetric synthesis. Dynamic kinetic resolution and related processes in enzyme and metal catalysis. Chem Soc Rev 30 321-331... 

Numerous biotranformation processes for fhe synthesis of amino acids have been described and for fhe purpose of this chapter, we have restricted the discussion to fhe unnatural amino acids fhat are not accessible by fermentation. For this class of amino acids, commercialized biotranformations are either based on asymmetric synthesis starting from a prochiral compound or on (dynamic) kinetic resolutions of a racemate. As an illustration the published processes for (R)- and (S)-tert-leucine are outlined in Scheme 4.4. Both stereoisomers of tert-leucine have been used for fhe synfhesis of peptides that serve as protease inhibitors acting against viral infections (e.g. Hepatitis C, HIV), bacterial infections, autoimmune diseases and cancer [27]. This particular amino acid is versatile in fhese applications since fhe tert-butyl moiety provides resistance against endogenous proteases and can enhance the binding affinity of fhe peptide to fhe target protease. 

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