Dynamic kinetic asymmetric racemization

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... 

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. 

This methodology has been expanded to geranyl methyl carbonate for the synthesis of the vitamin E nucleus, and to tiglyl methyl carbonate for the synthesis of (—)-calanolide A and B. In the latter example, the anthracenyldiamine -based ligand was required for optimum selectivity. The synthesis of (—)-aflatoxin B lactone utilizes a dynamic kinetic asymmetric transformation, whereby a suitably functionalized phenol reacts with a racemic 5-acyloxy-2-(5//)-furanone to provide a single product in 89% yield. One final example of phenol as a nucleophile is for the deracemization of Baylis-Hillman adducts." ... 

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). ... 

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). 

Chiral adduct 265, prepared by Pd-catalyzed dynamic kinetic asymmetric arylation of MBH adduct, has been subjected to a reductive Heck-type cyclization to give diastereomers of the dihydrobenzofuran derivative 266 (in an 8.3 1 ratio major one depicted) in 72% yield without any racemization (Scheme 4.85). ... 

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. 

Recently, some elegant work was reported on the preparation of chiral ortho-substituted phenol derivatives through intramolecular chirahty transfer by Trost et al. [64]. Chiral substrate 78 was prepared in excellent enantiomeric excess from phenol and racemic aUyUc carbonate through asymmetric O-aUylation with dynamic kinetic asymmetric transformation. They showed that a europium(lll) tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate) Eu(fod)3-catalyzed rearrangement proceeds at 50 °C to give product 79 with complete chirahty transfer. 

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... 

In 2015, Zhao and co-workers described the first dynamic kinetic asymmetric amination of alcohols via borrowing hydrogen methodology under the cooperative catalysis of iridium complex 25 and chiral phosphoric acid 27 (Schemes 31, 32) [179]. The authors proposed that, initially, the two stereocenters in the alcohols were both racemized to ketone by the first oxidation, followed by tautomerization of the iminium intermediates 28 and 30 through enamine intermediate 29. Then, the... 

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. 

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. 

In 2009, Parsons and Johnson reported the synthesis of enantio-enriched tetrahydrofurans via a dynamic kinetic asymmetric cycloaddition of racemic cyclopropanes with aldehydes under the influence of a chiral Lewis acid as illustrated in Scheme 10.40 and Table 10.13 [38]. 

Trost and Jiang recently reported on an asymmetric allylic alkylation for the synthesis of the quaternary center of the cyclopentyl core of viridenomycin 158 (Scheme 13.42). Palladium-catalyzed dynamic kinetic asymmetric transformation of racemic isoprene monoepoxide with ketoester 155 furnishes lactol 156 in 71% yield as a mixture of diastereo-mers. The alkylation was performed with chiral ligand 148... 

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).

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]. 

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

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