Reactions via Covalently Bound Intermediates

Most asymmetric catalyses are termolecular reactions. To obtain a sufficient asymmetric bias, the reactant and/or substrate must be placed in a chiral environment induced by the catalyst. Perhaps one of the most reliable mechanisms for transmitting stereochemical information is the in situ formation of reactive intermediates in which the chiral catalyst and reactant are covalently bound. Under some conditions, the inter- 

ASYMMETRIC CATALYSIS WITH PURELY ORGANIC COMPOUNDS 

Chiral catalysts also generate reactive intermediates by forming covalent bonds with substrates. A very successful example of catalysis 

SCHEME 1. Asymmetric addition of alcohols to ketenes catalyzed by chiral amines. 

ASYMMETRIC CATALYSIS WITH PURFLY ORGANIC COMPOUNDS 

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Reactions via Covalently Bound Intermediates / 323 Reactions via Hydrogen-Bonded Associates / 328... 

A catalytic cycle is composed of a series of elementary processes involving either ionic or nonionic intermediates. Formation of covalently bound species in the reaction with surface atoms may be a demanding process. In contrast to this, the formation of ionic species on the surface is a facile process. In fact, the isomerization reaction, the hydrogenation reaction, and the H2-D2 equilibration reaction via ionic intermediates such as alkyl cation, alkylallyl anion, and (H2D)+ or (HD2)+ are structure-nonrequirement type reactions, while these reactions via covalently bound intermediates are catalyzed by specific sites that fulfill the prerequisites for the formation of covalently bound species. Accordingly, the reactions via ionic intermediates are controlled by the thermodynamic activity of the protons on the surface and the proton affinity of the reactant molecules. On the other hand, the reactions via covalently bound intermediates are regulated by the structures of active sites. 

From these results, it may be concluded that the reactions that proceed through covalently bound intermediates are controlled precisely by the structures of active sites, but the reactions that occur via ionic intermediates are less affected by the structures of active sites. 

Tyr-325 (b). After release of the reducing end moiety (ROH, c) the initial state of the active site is regenerated by proton transfer via a water chain ([H20] , d) and re-binding of polysiahc acid. In total, the stmctural data allow the conclusion that the endosialidase mechanism is an SNl-type reaction, i.e., the sialic acid stereochemistry is directly inverted into the p-anomer [106]. By contrast, exosialidases form a covalently bound intermediate which is released by a water molecule thus the a2,8-linked sialic acid residue is released as a-anomer tmderlying the mutarotation towards the energetically favored p-conformation. However, no crystal structure of a non-cleavable substrate is available as yet, which would allow an unambiguous elucidation of the endosialidase mechanism [106]. 

The CP MAS NMR spectroscopy has been also extensively used for studies of proteins containing retinylidene chromophore like proteorhodopsin or bacteriorhodopsin. Bacteriorhodopsin is a protein component of purple membrane of Halobacterium salinarium.71 7 This protein contains 248 amino acids residues, forming a 7-helix bundle and a retinal chromophore covalently bound to Lys-216 via a Schiff base linkage. It is a light-driven proton pump that translocates protons from the inside to the outside of the cell. After photoisomerization of retinal, the reaction cycle is described by several intermediate states (J, K, L, M, N, O). Between L and M intermediate states, a proton transfer takes place from the protonated Schiff base to the anionic Asp85 at the central part of the protein. In the M and/or N intermediate states, the global conformational changes of the protein backbone take place. 

The remarkably versatile chemistry of PLP is due to its ability to form stable Schilf s base adducts with amino groups and to act as an effective electron sink to stabilize reaction intermediates. PLP is covalently bound to enzymes via a Schilf s base with the s-amino group of lysine in the active site. PLP exist under physiological conditions in two isomeric forms (Figure 9.2). 

Transketolase (EC 2.2.1.1) is involved in the oxidative pentose phosphate pathtvay in tvhich it catalyzes the reversible transfer of a hydroxyacetyl nucleophile bettveen a variety of sugar phosphates. The enzyme, tvhich requires thiamine diphosphate and divalent Mg as cofactors [248], is commercially available from baker s yeast and can be readily isolated from many natural or recombinant sources [249, 250]. The yeast enzyme has been structurally tvell characterized [251], including protein tvith a carbanion intermediate covalently bound to the cofactor [252]. Large-scale enzyme production has been investigated for the transketolase from Escherichia coli [253-255]. Immobilization vas sho vn to significantly increase stability against inactivation by aldehyde substrates [256]. The enzyme is quite tolerant to organic cosolvent, and preparative reactions have been performed continuously in a membrane reactor [255], vith potential in-situ product removal via borate complexation [257]. 

A steady-state kinetics study for Hod was pursued to establish the substrate binding pattern and product release, using lH-3-hydroxy-4-oxoquinoline as aromatic substrate. The reaction proceeds via a ternary complex, by an ordered-bi-bi-mechanism, in which the first to bind is the aromatic substrate then the 02 molecule, and the first to leave the enzyme-product complex is CO [359], Another related finding concerns that substrate anaerobically bound to the enzyme Qdo can easily be washed off by ultra-filtration [360] and so, the formation of a covalent acyl-enzyme intermediate seems unlikely in the... 

In solid-phase synthesis intermediates and products are bound to a solid support via a covalent linker. The linker must allow selective removal of the final product from the support, but must be stable under the reaction conditions throughout the synthesis. The advantage of a solid-phase approach is that reagents can be used in large excess to drive reactions to completion and most side products are just washed off from the solid support. However, the solid-phase implies steric constraints onto the reactions performed. The choice of method depends on the synthetic problem it is often not obvious and usually results from a reaction optimization study. 

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