Chapter 17, Problem 51DSP

Epoxide Rearrangements and the NIH Shift

This passage is about two seemingly unrelated aspects of epoxides:

epoxide rearrangements

arene oxides

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.

Epoxide rearrangements

In some epoxide ring-opening reactions $\text{C-O}$ bond cleavage is accompanied by the development of enough carbocation character at carbon $\left({}^{\text{+δ}}\text{C-O}\right)$ to allow rearrangement to occur. These reactions are typically promoted by protonation of the epoxide oxygen or by its coordination to Lewis acids such as boron trifluoride $\left({\text{BF}}_3\right)$ and aluminum chloride $\left({\text{AlCl}}_3\right)$.

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 $\text{-}$ 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 $\text{16}$

Descriptive Passage and Interpretive Problems) and takes place under similar conditions.

Arene Oxides

Aromatic rings are normally inert to the customary reagents that convert alkenes to epoxides, but

arene oxides have been synthesized in the laboratory, often by indirect methods. Their chemical

reactivity resembles that of other epoxides.

The most striking thing about arene oxides is their involvement in biological processes. Enzymes

In the liver oxidize aromatic hydrocarbons to arene oxides, which then react with biological nucleophiles to give compounds used in subsequent reactions or to aid elimination of the arene oxide from the body. Some arene oxides, especially those from polycyclic aromatic hydrocarbons, are carcinogenic and react with nitrogen nucleophiles of DNA to induce mutations $\left(\text{Section 12}\text{.6}\right)$.

The NIH shift

Although hydroxylation of phenylalanine to tyrosine looks like a typical electrophilic aromatic sub stitution, scientists at the U.S. National Institutes of Health discovered that the biochemical pathway combines epoxidation of the benzene ring followed by epoxide ring opening with rearrangement. This rearrangement, which is the biochemical analog of the pinacol $\text{-}$ type reactions described earlier, is known as the “NIH shift.”

The hormones serotonin and melatonin are biosynthesized from tryptophan by a series of

reactions, including one that involves an NIH shift.

What is the most likely structure for tryptophan?