3,4-Dihydroxyacetaldehyde (DOPAL) when injected into rat brain results in neuronal cell death that is more selective for cells in the substantia nigra (cells which are primarily dopamine producing cells). Despite the significance of DOPAL, it is not commercially available and must be synthesized. There are several published methods, but they all share one common problem. DOPAL is very unstable and difficult to isolate and work with. In 1998, Li et al, reported a synthesis, however, that required four steps, three chromatographic separations, and proceeded with an overall yield of about 4%. Therefore, considerable effort to produce DOPAL in a higher yield would be of interest. In an effort to mitigate these problems, we have directed our attention toward the synthesis of DOPAL via two routes with the goal of simplifying the synthetic process by shortening the route and eliminating the chromatography. First, a Wittig reaction that utilizes methoxymethyltriphenylphosphonium chloride, LDA and piperonal in tetrahydrofuran resulted in an excellent yield of a mixture of the E and Z isometric vinyl ethers. Subsequent, aqueous hydrolysis of the E/Z mixture with sulfuric acid afforded 2-(3,4-methylene-dioxypheny1)-2-methoxyethene. After attempting numerous deprotection strategies for removal of the methylenedioxy group proved unsatisfactory, the development of a new condition employing phosphorus pentachloride was developed that removed the methylenedioxy group giving rise to DOPAL in ~40% yield. Second, we synthesized the title compound based on a pinacol-pinacolone type mechanism for the rearrangement in one-step by using perchloric acid. Due to the risks associated with perchloric acid (explosive when heated), we found a safer alternative using phosphoric acid as an alternative preparation for DOPAL from commercially available epinephrine (adrenaline). Finally, biological studies utilized western blot analysis to determine the effects of dopamine (DA), DOPAL, and dihydroxyphenylacetic acid (DOPAC) on oligomerization of α-synuclein. This presynaptic neuronal protein is linked to the pathologies presented in Parkinson’s disease. DOPAL was shown to potently oligeromerize the protein by its poor gel migration patterns compared to DA and DOPAC. An A53T mutation of α-synuclein showed even more oligomerization than wild type, indicating that individuals with this mutation may be increasingly susceptible to aggregation.

Syntheses of a biochemically important aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic dopamine metabolite in vivo: implications for parkinson's disease pathogenesis

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.