Halogenation enzyme-catalyzed

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]. 

Novel approach for optically pure alcohol from racemic compounds is the use of dehalogenases.24 For example, L-2-halo acid dehalogenase Pseudomonas putida was used for the synthesis of D-3-chlorolactic acid from racemic 2,3-dichloropropionic acid (Figure 23(a)).24ad The enzyme catalyzed hydrolytic release of halogen from 2-halocarboxylic acids and produces 2-hydroxy acids with inversion of the configuration. L-2-Halo acid dehalogenase acted on the L-isomer of 2-halo acids and produces D-2-hydroxy acid with an excellent enantioselectivity. 

The only type of halogenating enzymes known until 1997 were peroxidases and perhydrolases which catalyze the formation of carbon halogen bonds using halide ions, hydrogen peroxide and an organic substrate activated for electrophilic attack. 

Oxidative transformations, as noted above, are more likely to be induced by enzyme-catalyzed processes in biota or photoinduced reactions in the atmosphere or in water. Consequently, this analysis will focus on reductions. The carbon of halogenated aliphatic compounds shows a high positive oxidation state (Table 7.1) and thus these compounds would be candidates for reduction. Since these compounds have been used extensively and may be released into the environment, it is useful to assess the significance of these transformation processes. 

Figure 1.59 Formation of hypochlorous acid from FAD-4o -OOH (a) mechanism of tryptophan chlorination (b) catalyzed by tryptophan 7-halogenase and (c) catalyzed by halogenating enzyme RebH.

The same considerations are applicable to acylates of type 11, where short-chain acetates or propionates are the preferred acyl moieties. Increasing the carbonyl reactivity of the substrate ester by adding electron-withdrawing substituents such as halogen (leading to a-haloacetates) is a frequently used method to enhance the reaction rate in enzyme-catalyzed ester hydrolysis [188]. 

Unfortunately, direct epoxidation of alkenes by metal-free haloperoxidases led to racemic epoxides [1331, 1332]. Since the reaction only takes place in the presence of a short-chain carboxylic acid (e.g., acetate or propionate), it is believed to proceed via an enzymatically generated peroxycarboxylic acid, which subsequently oxidizes the alkene without the aid of the enzyme. This mechanism has a close analogy to the lipase-catalyzed epoxidation of alkenes (Sect 3.1.5) and halogenation reactions catalyzed by haloperoxidases (Sect. 2.7.1), where enzyme catalysis is only involved in the formation of a reactive intermediate, which in turn converts the substrate in a spontaneous (nonenzymatic) foUowup reaction. 

The individual enzymes are called chloro-, bromo-, and iodoperoxidase. The name reflects the smallest halide ion that they can oxidize, in correlation to the corresponding redox potential. Bearing in mind their unique position as halogenating enzymes and the large variety of structurally different halometabolites produced by them, it is not surprising that the majority of haloperoxidases are characterized by a low product selectivity and wide substrate tolerance. As a consequence, any asymmetric induction observed in haloperoxidase-catalyzed reactions is usually low. 

The presence of the halc en in these and in other haloge-nated natural products has a strong effect on their properties, and their biosynthetic origin was a scientific puzzle of longstanding. What are the biolc ical halogenating agents, what enzymes catalyze the halogenation, and how do they do it Recent studies have unlocked the answers to some of these questions. 

Several more enzyme-catalyzed reactions, including a second halogenation... 

The high-valent iron-oxo sites of nonheme iron enzymes catalyze a variety of reactions (halogenation and hydroxylation of alkanes, desaturation and cyclization, electrophilic aromatic substitution, and cis-dihydroxylation of olefins) [lb]. Most of these (and other) reactions have also been achieved and studied with model systems [Ic, 2a-c]. With the bispidine complexes, we have primarily concentrated on olefin epoxidation and dihydroxylation, alkane hydroxylation and halogenation, and sulfoxidation and demethylation processes. The focus in these studies so far has been on a thorough analysis of the reaction mechanisms rather than the substrate scope and catalyst optimization. 

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