Kinetic Asymmetric Transformations

DyKAT reaction pathways involving epimerization. The (R)- and (S)-substrates and products are S , Sj, P , and Pj.The chiral catalyst is cat.  

DyKAT of racemic phosphine to generate a tertiary P-chirogenic phosphine. 

Proposed mechanism of the DyKAT, where inversion of phosphorus is faster than reductive elimination. 

Desymmetrization of Achiral Dienes via Cataiytic Asymmetric Hydrosilylation 

Desymmetrization of dienes by cataiytic asymmetric hydrosilylation. Oxidation of the product provides a valuable 1,3-diol. 

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The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

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]. 

Steinreiber, J., Schurmann, M., Wolberg, M. et al. (2007) Overcoming thermodynamic and kinetic limitations of aldolase-catalyzed reactions by applying multienzymatic dynamic kinetic asymmetric transformations. Ange-wandte Chemie International Edition. 46, 1624-1626. 

Trost, B.M. and Andersen, N.G., Utilization of molybdenum- and palladium-catalysed dynamic kinetic asymmetric transformations for the preparation of tertiary and quaternary stereogenic centers a concise synthesis of tipranavir, J. Am. Chem. Soc., 2002, 124, 14320-14321. 

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-... 

Dynamic kinetic asymmetric transformation Dynamic kinetic resolution... 

Silylated amino acid esters have been prepared by a dynamic kinetic asymmetric transformation of this type. Slow addition (by syringe pump) of (R,R) DPEC maintained insertion slow relative to interconversion and afforded the silyl-substituted amino acid esters in Eq. 36 with ee values of 80, 68, and 83%. The ester 38c (R=TMS) was too base-sensitive to permit removal of the chiral diol, but transesterification of the other /J-hydroxyethyl esters 38 to the corresponding methyl esters was straightforward [22]. 

It would be preferable to carry out a dynamic kinetic asymmetric transformation on a zirconaaziridine without having to add the inserting reagent slowly. The fact that the enantiomers of 2i interconvert rapidly makes it possible to carry out such a transformation at maximum de (64% with R,R-DPEC) without having to use a syringe pump for addition of the optically active carbonate. 

Zirconaaziridines, which can be prepared in a few steps from commercially available starting materials, have polar Zr-C bonds that permit the insertion of many electrophilic reagents (C=0, C=N) as well as alkynes (C=C) and alkenes (C=C). Appropriate substituents on their ring carbons make zirconaaziridines chiral and raise the possibility of their use in asymmetric synthesis. The lability of their chiral centers distinguishes zirconaaziridines from other organo-metallic reagents and makes it possible for them to undergo dynamic kinetic asymmetric transformations . 

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. 

Later work has shown that a dynamic kinetic asymmetric transformation could be obtained if the acetates were converted into carbonate groups. With the tetra(2,2,2-trichloroethyl) carbonate derivative, reactions with carbon and nitrogen nucleophiles gave exclusively the monosubstituted products in high yield (61-95%) and excellent enantiomeric excesses (95-99%). However, car-boxylate nucleophiles afforded the disubstituted products in high yield and enantiomeric excess (eq 7). This allowed an efficient synthesis of D-myo-inositol-l,4,5-trisphosphate to be devised. 

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." ... 

Notable were highly enantioselective additions of N-phosphonyl imines with dialkyl zinc or hydroxyketones and a one-pot reaction of alkynylzirconocenes with alkynyl phosphazenes and zinc carbenoids to give single isomer cyclopropylphosphonamides. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. Other interesting reports cover the use of phosphoramidates for the synthesis of allylic amines as well as the first example of C-P cleavage of a-aminophosphono acids using periodate. 

The current review is of necessity selective. Over the two year period covered, there has been impressive advances in several areas of P(V) chemistry. For example, biological aspects of quinquevalent phosphorus acids chemistry continue to increase in importance. A wide variety of natural and unnatural phosphates including inositols, lipids, some carbohydrates and their phospho-nates, phosphinates and fluorinated analogues has been synthesized. Special attention has been paid to the synthesis of phosphorus analogues of all types of amino acids and some peptides. Numerous investigations of phosphate ester hydrolysis and related reactions continue to be reported. Interest in approaches to easier detoxification of insecticides continues. A number of new and improved stereoselective synthetic procedures have been elaborated. The importance of enantioselective and dynamic kinetic asymmetric transformations is illustrated in many publications. 

Scheme 4.15 Dynamic kinetic asymmetric transformation with p-chloro-phenyl acetate (PCPA) as acyl donor (CALB Candida antarctica lipase B).

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). 

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. 

Trost BM, Toste FD (1999) Palladium-Catalyzed Kinetic and Dynamic Kinetic Asymmetric Transformation of 5-Acyloxy-2-(5H)-furanone. Enantioselective Synthesis of (-)-Aflatoxin B Lactone. J Am Chem Soc 121 3543... 

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