Enzymes catalyzed additions

Today, the most promising synthesis of optically active cyanohydrins, especially with respect to the enantioselectivity of the reaction, is the enzyme-catalyzed addition of hydrogen cyanide to aldehydes and ketones, respectively. 

Tunicamycin Inhibits GIcNAc-P transferase, the enzyme catalyzing addition of GIcNAc to dolichol-P, the first step in the biosynthesis of oligosaccharide-P-P-dolichol... 

From squalene, lanosterol, the first cyclic precursor, is created by a remarkable set of enzyme-catalyzed addition reactions and rearrangements that create four fused rings and seven stereocenters. 

Effenberger F, Eichhom J et al (1995) Enzyme catalyzed addition of hydrocyanic acid to substituted pivalaldehydes - a novel synthesis of (/J)-pantolactone. Tetrahedron Asymmetry 6 271-282... 

L-a-Amino Acids by Enzyme-Catalyzed Addition of Ammonia to a,/J-Unsaturated... 

In an enzyme-catalyzed addition to a carbonyl compound, only one of the enantiomers is formed. The enzyme can block one face of the carbonyl compound so that it cannot be attacked, or it can position the nucleophile so that it is able to attack the carbonyl group from only one side of the molecule. 

Section 18.15 Enzyme-Catalyzed Additions to a,/3-Unsaturated Carbonyl Compounds 773... 

The enzymatic synthesis of cyanohydrin 6 reported by the group of Ruges, demonstrates several advantages of flow over batch conditions. Toxic HCN, necessary for the enzyme catalyzed addition to aldehyde 5, was... 

Fatty acylation targets a wide range of cellular proteins which encompass kinases, GTPases, heterotrimeric G proteins, cytokines, and phosphatases (1-3). The role of fatty acylation is to regulate these proteins physicochemical properties and spatial localization in cells. In doing so, fatty acylation controls the activation and deactivation of signaling pathways. Fatty acylation involves the enzyme-catalyzed addition of 14-carbon (myristoylation) or 16-carbon (palmitoylation) fatty acid chains to cellular proteins via amide- or thioester bonds, respectively. 

A free radical ts a compound with an unpaired electron, a result of an enzyme catalyzed addition of electrons to a carb bond, with subsequent cleavage. 

In 1965 the first procedure for the asymmetrical synthesis of ethanolamines via enzyme-catalyzed addition of hydrogen cyanide to aldehydes, followed by reduction with LiAlH4 was described [47,137]. Subsequently, in order to avoid decomposition and racemization, TBS-protected cyanohydrins were used [128]. Surprisingly, quantitative deprotection by an intramolecular reductive cleavage occurred and free ethanolamines were obtained in high yields [128,131]. TBS-protected ethanolamines (with one chiral center) could be obtained by DIBAL reduction at low temperature, followed by NaBH4 reduction [124] (Scheme 14). 

Perez-Bendito, D. Silva, M. Kinetic Methods in Analytical Chemistry. Ellis Horwood Chichester, England, 1988. Additional information on the kinetics of enzyme catalyzed reactions maybe found in the following texts. 

Most of the Moco enzymes catalyze oxygen atom addition or removal from their substrates. Molybdenum usually alternates between oxidation states VI and IV. The Mo(V) state forms as an intermediate as the active site is reconstituted by coupled proton—electron transfer processes (62). The working of the Moco enzymes depends on the 0x0 chemistry of Mo (VI), Mo(V), and Mo (TV). 

Esterification. The hydroxyl groups of sugars can react with organic and inorganic acids just as other alcohols do. Both natural and synthetic carbohydrate esters are important in various apphcations (1,13). Phosphate monoesters of sugars are important in metabohc reactions. An example is the enzyme-catalyzed, reversible aldol addition between dibydroxyacetone phosphate [57-04-51 and D-ylyceraldehyde 3-phosphate [591-57-1 / to form D-fmctose 1,6-bisphosphate [488-69-7],... 

There are two distinct groups of aldolases. Type I aldolases, found in higher plants and animals, require no metal cofactor and catalyze aldol addition via Schiff base formation between the lysiae S-amino group of the enzyme and a carbonyl group of the substrate. Class II aldolases are found primarily ia microorganisms and utilize a divalent ziac to activate the electrophilic component of the reaction. The most studied aldolases are fmctose-1,6-diphosphate (FDP) enzymes from rabbit muscle, rabbit muscle adolase (RAMA), and a Zn " -containing aldolase from E. coli. In vivo these enzymes catalyze the reversible reaction of D-glyceraldehyde-3-phosphate [591-57-1] (G-3-P) and dihydroxyacetone phosphate [57-04-5] (DHAP). 

Cyanohydrin Synthesis. Another synthetically useful enzyme that catalyzes carbon—carbon bond formation is oxynitnlase (EC 4.1.2.10). This enzyme catalyzes the addition of cyanides to various aldehydes that may come either in the form of hydrogen cyanide or acetone cyanohydrin (152—158) (Fig. 7). The reaction constitutes a convenient route for the preparation of a-hydroxy acids and P-amino alcohols. Acetone cyanohydrin [75-86-5] can also be used as the cyanide carrier, and is considered to be superior since it does not involve hazardous gaseous HCN and also virtually eliminates the spontaneous nonenzymatic reaction. (R)-oxynitrilase accepts aromatic (97a,b), straight- (97c,e), and branched-chain aUphatic aldehydes, converting them to (R)-cyanohydrins in very good yields and high enantiomeric purity (Table 10). 

The enzyme-catalyzed interconversion of acetaldehyde and ethanol serves to illustrate a second important feature of prochiral relationships, that ofprochiral faces. Addition of a fourth ligand, different from the three already present, to the carbonyl carbon of acetaldehyde will produce a chiral molecule. The original molecule presents to the approaching reagent two faces which bear a mirror-image relationship to one another and are therefore enantiotopic. The two faces may be classified as re (from rectus) or si (from sinister), according to the sequence rule. If the substituents viewed from a particular face appear clockwise in order of decreasing priority, then that face is re if coimter-clockwise, then si. The re and si faces of acetaldehyde are shown below. 

In contrast to laboratory reactions, enzyme-catalyzed reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to (Z)-aconitate (usually called ris-aconitate) to give isocitrate. 

The optical purities were determined solely from the optical rotations of the (/ -cyanohydrins thus obtained. Only for (/ )-a-hydroxybcnzeneacetonitrile, available from benzaldehyde, was an optical purity determined by comparison with the natural product. Variation of the reaction conditions (pH, temperature, concentration) in water/ethanol led to no appreciable improvementsl4. The use of organic solvents that are not miscible with water, but in which the enzyme-catalyzed reaction can still take place, resulted in suppression of the spontaneous addition to a significant extent, whereas the enzyme-catalyzed formation of cyanohydrins was only slightly slower (Figure l)13. 

An example for proteases are the (3-lactamases that hydrolyse a peptide bond in the essential (3-lactam ring of penicillins, cephalosporins, carbapenems and monobac-tams and, thereby, iireversibly inactivate the diug. 13-lactamases share this mechanism with the penicillin binding proteins (PBPs), which are essential enzymes catalyzing the biosynthesis of the bacterial cell wall. In contrast to the PBPs which irreversibly bind (3-lactams to the active site serine, the analogous complex of the diug with (3-lactamases is rapidly hydrolyzed regenerating the enzyme for inactivation of additional (3-lactam molecules. 

Several cyditol derivatives of varying ring size, for example, (69)/(70), have been prepared based on an enzymatic aldolization as the initial step. Substrates carrying suitably installed C,H-acidic functional groups such as nitro, ester, phosphonate (or halogen) functionalities made use of facile intramolecular nucleophilic (or radical) cyclization reactions ensuing, or subsequent to, the enzyme-catalyzed aldol addition (Figure 10.27) [134—137]. 

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