Chiral amplification enantioselectivity

There are a number of examples of enantioselective catalysis with a zinc catalyst. The use of zinc as a catalyst in the Diels-Alder reaction of (R,R)-4,6-dibenzofurandiyl-2,2 -bis(4-phenylox-azoline) with cyclopentadiene shows high enantioselectivity. Chiral amplification is observed in the... 

These schemes have been frequently suggested [105-107] as possible mechanisms to achieve the chirally pure starting point for prebiotic molecular evolution toward our present homochiral biopolymers. Demonstrably successftd amplification mechanisms are the spontaneous resolution of enantiomeric mixtures under race-mizing conditions, [509 lattice-controlled solid-state asymmetric reactions, [108] and other autocatalytic processes. [103, 104] Other experimentally successful mechanisms that have been proposed for chirality amplification are those involving kinetic resolutions [109] enantioselective occlusions of enantiomers on opposite crystal faces, [110] and lyotropic liquid crystals. [Ill] These systems are interesting in themselves but are not of direct prebiotic relevance because of their limited scope and the specialized experimental conditions needed for their implementation. 

The enantioselective incorporation of these amino acids into the serine octamers represents an example of chiral transmission to elementary biomolecules and a possible way of chirality amplification on primitive earth. 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

Amplification of Chirality. Perhaps the most striking of the nonclas-sical aspects that emerge from the enantioselective alkylation is the phenomenon illustrated in Scheme 22 (3, 14, 16, 20k, 40). A prominent nonlinear relation that allows for catalytic chiral amplification exists between the enantiomeric purity of the chiral auxiliary and the enantiomeric purity of the methylation or ethylation product (Scheme 23). Typically, when benzaldehyde and diethylzinc react in the presence of 8 mol % of (-)-DAIB of only 15% ee [(-) (+) = 57.5 42.5], the S ethylation product is obtained in 95% ee. This enantiomeric excess is close to that obtained with enantiomerically pure (—)-DAIB (98%). Evidently, chiral and achiral catalyst systems compete in the same reaction. The extent of the chiral amplification is influenced by many factors including the concentration of dialkylzincs, benzaldehyde, and chiral... 

Their most detailed investigations focused on the Heck cyclization of iodide 18.1c to form oxindole 17.3a (Scheme 8G.18) [38a,b]. A chiral-amplification study [47] established that the catalytically active species is a monomeric Pd-BINAP complex, a conclusion also corroborated by NMR studies by Amatore and co-workers [42d,43], In addition, two possibilities for the enantioselective step of the neutral pathway were easily eliminated [38a], Oxidative addition was precluded as the enantioselective step, because iodides cyclize with very different enantioselectivities in the presence of Ag(I) salts. A scenario where migratory insertion is reversible and [l-hydridc elimination is the enantioselective step was also ruled out, because this is not consistent with the dependence of enantioselectivity on the geometry of the double bond of the cyclization precursor. 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

We have given kinetic insight into a number of experimental features of the Soai reaction. It was shown that chiral amplification and mirror-symmetry breaking are driven by a reaction network that contains enantioselective autocatalysis and mutual inhibition as the essential ingredients. In this sense, the Soai reaction moves the early concepts of Frank forward into experimental reality. Taking into account the formation of isopropylzinc alkoxide dimers, an evaluation of the parameter space in which amplification and symmetrybreaking are observed indicates that the heterochiral dimers display a higher thermodynamic stability and have to be formed faster than the homochiral ones. The necessity of such sensitive interplay may explain why such reactions systems are so scarce. 

Enantioselective Addition of Organozinc Compounds to Carbonyl Compounds Chiral Amplification... 

In summary, chiral Br0nsted acids have been used to protonate prochiral intermediates that were photochemically produced. Optimization of the chiral amino alcohols and the conditions led to excellent enantioselectivities of up to 91% ee employing only 0.1 equivalent of chiral inductor with respect to the substrate. These results demonstrate that the desirable goal of chiral amplification can be reached with chiral templates. The asymmetric induction varies strongly for different substrates, and therefore the general applicability as a synthetic tool seems to be limited. 

Noyori and coworkers [110] have shown that these reactions involve a binu-clear zinc complex ( 2.5.1). Chirality transfer takes place from the Zn binuclear assembly 6.34. The aldehyde is coordinated to ZnA, and the repulsion between the R group located on ZnA and the R substituent of the aldehyde is the key interaction in determining the structure of the complex. The transferred R group is located on the other zinc atom (Zng) (Figure 6.32). The approach depicted in 634 results in the enantioselective formation of an (S)-alcohol from the (-)-enantiomer of 13 [110,253,1170], This process is subject to chirality amplification ( 2.5.1). 

In a one-pot synthetic method for chiral 2,2-disubstituted oxetanes, a sequential addition reaction of a sulfur ylide to ketones and intermediate epoxides was promoted by the heterobimetallic catalyst LaLi3tris(binaphthoxide) (LLB). Chiral amplification was observed in the second reaction and was the key to affording the desired oxetanes with excellent enantioselectivity (Scheme 14). 

Schiaffino, L. Ercolani, G. Amplification of Chirality and Enantioselectivity in the Asymmetric Autocatalytic Soai Reaction. Chem. Phys. Chem. 2009,10, 2508-2515. 

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

Gagne and coworkers utilized this combination to discover enantioselec-tive receptors for (-)-adenosine [12]. A racemic dipeptide hydrazone [( )-pro-aib] generated a stereochemically diverse DCL of n-mer. The dimers were composed of two chiral (DD/LL) and one achiral isomer (DL), the four trimers (DDD, LLL, DDL, and LLD), the tetramers of four chiral and two achiral isomers, etc. Two techniques were used to measure the enan-tio-imbalance that was caused by the enantioselective binding of the chiral analyte to the enantiomeric receptors (Fig. 5.11). Since the unperturbed library is optically inactive, the optical enrichment of each library component could be measured by a combined HPLC optical rotation detection scheme (laser polarimeter, LP). LP detection differentiated unselective binding (amplification but not optical enrichment) from enantioselective recognition of the analyte (amplification and optical enrichment). In this manner the LL dimer (SS) of the dipeptide was amplified and identified as the enantioselective match for (-)-adenosine. 

We describe highly enantioselective asymmetric autocatalysis with amplification of chirality and asymmetric autocatalysis initiated by chiral triggers. Asymmetric autocatalysis correlates between the origin of chirality and the homochirality of organic compounds. We also describe spontaneous absolute asymmetric synthesis in combination with asymmetric autocatalysis. 

Relatively few syntheses of chiral allenes are known that exploit amplification of chirality by the catalytic enantioselective synthetic approach in which the chiral catalyst is used in a substoichiometric amount. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

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