Hydroxylation of Unsaturated or Aromatic Compounds and the NIH Shift

Epoxides are the first reaction products when monooxygenases attack C=C bonds. In the case of aromatic substrates the epoxides are very unstable and may be further transformed by the reactions shown in Fig. 19. 

Pathway I leads via the addition of water to a dihydrodiol, which can either be dehydrogenated to a dihydroxy derivative (D 21.5), or may be transformed to monohydroxylated compounds with the elimination of water. 

Pathway II leads directly to the monohydroxylated compounds. The epoxide is opened by an electrophilic agent, e.g., a proton and the formed cationic intermediate stabilizes with the elimination of a proton (see transformation of squalene epoxide, D 6.4). 

Pathway III shows the degradation of the epoxide by compounds containing an SH-group, e.g., glutathione (D 23). Thioethers are formed with or without elimination of water. 

A shift of constituents may occur in pathway II. This shift was observed first by scientists of the National Institute of Health and thus is termed the NIH-shift . Some reactions which are accompanied by an NIH-shift are the hydroxy-lations of L-tryptophan (Fig. 254), L-phenylalanine (Fig. 266) and cinnamic acid (Fig. 294). During formation of 5-hydroxy-L-tryptophan, a hydrogen atom is shifted from position 5 to position 4 and during formation of L-tyrosine or p-coumaric acid the hydrogen atom of position 4 is shifted to the equivalent positions 3 and 5 (Fig. 20). 

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