A Direct Synthesis of 3,5‐Dibromo‐O‐methyl‐L‐tyrosine

Abstract

A simple and efficient synthesis of 3,5‐dibromo‐O‐methyl‐L‐tyrosine is described by direct bromination of commercial O‐methyl‐L‐tyrosine with bromine in aqueous hydrochloric acid. MO calculations are presented to explain a difference in the degree of substitution of O‐methyl‐L‐tyrosine in different solvents.

Keywords:

• Bromotyrosine metabolite
• 3,5‐Dibromo‐O‐methyl‐L‐tyrosine
• Bromination
• Synthesis

Notes

^aAll calculations of tyrosine derivatives were carried out for their gauche conformers in which the carbonyl group is directed towards the plane containing the phenyl ring. They have been found to be more stable and have higher HOMO energies than the corresponding trans conformers in which the carbonyl group is directed away from the ring plane. For example, the gauche conformer of 1A is 1.7 kcal/mol more stable than its trans conformer at the HF/6‐31G* level. The HOMO energies of gauche and trans conformers of 1A are respectively −0.316 and −0.326 hartrees at the HF/6‐31G* level. The higher HOMO energies may be mediated by strong through‐space effect arising from the high‐energy carboxylate group, although the nodal patterns of the HOMO orbitals are relatively unaffected by conformational changes in substituent as reported in recent literature.

^bThe ratio of form A and B is approximately 17/83 based on Henderson‐Haselbalch equation and pH value of 1 in acetic (pH = 2.21).

^cThe HOMO energies of 1A and 1B are respectively −0.316 and −0.430 hartrees at the HF/6‐31G* level.

^dThe energy barrier between 1A and 4A is 85.0 kcal/mol, while between 2A and 5A is 124.5 kcal/mol.

^eThe energy barrier between 1B and 4B is 32.4 kcal/mol, while between 2B and 5B is 38.1 kcal/mol.