Epoxide Rearrangements and the NIH Shift

This passage is about two seemingly unrelated aspects of epoxides  

These two topics merge in an important biological transformation in which neither the reactant nor the product is an epoxide—the conversion of the amino acid phenylalanine to tyrosine. 

In some epoxide ring-opening reactions C—O bond cleavage is accompanied by the development of enough carbocation character at carbon —O) to allow rearrangement to occur. These reac- 

As positive charge develops on the ring carbon, one of the groups on the adjacent carbon migrates to it. This migration is assisted by electron-pair donation from oxygen. It is likely that all of this occurs in the same transition state. Subsequent deprotonation gives an aldehyde or ketone as the isolated product. 

Overall, the reaction resembles the pinacol rearrangement of vicinal diols (see the Chapter 15 Descriptive Passage and Interpretive Problems) and takes place under similar conditions. 

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Descriptive Passage and Interpretive Problems 16 Epoxide Rearrangements and the NIH Shift 721... 

For more on this reaction, see Descriptive Passage and interpretive Probiems 16 Epoxide Rearrangements and the NiH Shift. 

The microsomal mixed-function oxidase system containing multiple forms of cytochrome P-450 is the catalytic site for the initial oxidation of BaP. The primary products are the 2,3-, 4,5-, 7,8-, and 9,10-epoxide. The 4,5-epoxide has been isolated, while the formation of the other epoxides was demonstrated indirectly (757, 754, 236, 415, 428, 482, 505, 506). Primary oxidation at the 6 position results in formation of the unstable 6-hydroxy-BaP which is further oxidized by way of the 6-oxo radical to the 1,6-, 3,6-, and 6,12-quinones 290, 291, 350, 351). The major phenolic metabolite of BaP is 3-hydroxy-BaP lesser amounts of 1-, 7-, and 9-hydroxy-BaP are also formed. These phenols are produced at least partially by nonenzymatic rearrangement of the epoxides (the NIH shift 85, 93, 164, 236, 272, 416, 422, 424, 428, 482, 505, 506). 

A side chain migration to the ortho position takes place in this rearrangement and this has been referred to as the NIH shift (296). However, this mechanism was questioned because the reaction still worked with phenyl-pyruvic acid (no p-OH). A more likely mechanism would be the involvement of a transition metal ion to form first a peracid which would then undergo an oxene mechanism via an epoxide intermediate ... 

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