Dynamic kinetic asymmetric transformation DYKAT

A dynamic kinetic asymmetric transformation (DYKAT) of racemic vinyl aziridine 347 yielded the enantiopure imidazolidinone 348 (Scheme 90) <20050L823>. This transformation was the initial step in a total synthesis of (+)-pseudodistomin D. 

Ins(l,4,5)P3. A number of phosphates, e.g. (37), which act as inositol monophosphatase inhibitors have been synthesised from the l,6-epoxy-4-benzyloxycyc-lohexan-2-ol (36)7" Conduritol derivatives (39) are useful synthetic building blocks. However, the enantioselective palladium-catalysed allyl alkylation and similar reactions of (38) are complex due to C2 symmetry. It has now been reported that dynamic kinetic asymmetric transformation (DYKAT) of racemic... 

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). ... 

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. 

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... 

Langlois JB, Alexakis A (2010) Copper-catalyzed asymmetric allylic alkylation of racemic cyclic substrates application of dynamic kinetic asymmetric transformation (DYKAT). Adv Synth Catal 352 447-457... 

Perhaps the most important mechanistic implication of all is the very fact that the allylpalladium complexes can interconvert via n-G-n equilibration. This enables chiral racemic material to be transformed into products of enantiopurity through a dynamic kinetic asymmetric transformation (DYKAT). This powerful strategy has facilitated the construction of numerous complex, asymmetric molecules from simple racemic starting materials. Dynamic kinetic asymmetric transformations are extremely rare in other asymmetric reactions, highlighting the importance of the AAA reaction. 

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... 

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 enzyme-catalyzed kinetic asymmetric transformation (KAT) of a diastereomeric 1 1 syn anti mixture is limited to a maximum theoretical yield of 25% of one enantiomer. This important drawback has been overcome by the combination of the actions of a ruthenium complex and a lipase in a dynamic kinetic asymmetric transformation (DYKAT), the desymmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates, implying different equilibration rates of the stereoisomers. Thus, this strategy allows the preparation of optically active diols, widely employed in organic and medicinal chemistry, as they are an important source of chiral auxiliaries and ligands and they can be easily employed as precursors of much other functionality. 

Martin-Matute, B., Edin, M., and Backvall, J.-E. (2006). Highly efficient synthesis of enan-tiopure diacetylated C-2-symmetric diols by ruthenium- and enzyme-catalyzed dynamic kinetic asymmetric transformation (DYKAT). Chem. Eur.., 12,6053-6061. 

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. 

From 1 Steinreiber, K. Faber, H. Griengl, De-racemization of enantiomers versus de-epimerization of diastereomers-classification of dynamic kinetic asymmetric transformations (DYKAT), Chemistry 14 (2008) 8060. Copyright 2008 Wiley). 

Fig. 8.33 DYKAT of 1,3-diols via lipase-catalyzed acyl-transfer in combination with Ru-catalyzed epimerization of hydroxyl groups. G=chiral carbon, convertible for equilibration and acyl migration, but not for the irreversible step H=chiral carbon, convertible for equilibration, acyl migration and the irreversible step l=chiral carbon, convertible for acyl migration, stable chirality. (From J. Steinreiber, K. Faber, H. Griengl, De-racemization of enantiomers versus de-epimerization of diastereomers-chssification of dynamic kinetic asymmetric transformations (DYKAT), Chemistry 14 (2(X)8), 8060. Copyright 2008 Wiley).

Dynamic kinetic asymmetric transformation (DYKAT) is a somewhat different from DKR, since it involves the metal-catalyzed equihbration of diastereomeric but not enantiomeric intermediates. 

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