Polyprenylpyridinols. Synthesis of Piericidin Analogues

Piericidin A, isolated from S. mobaraensis, is a specific antagonist of coenzyme Q. Its unusual structure consists of a 2,3-dimethoxy-5-methyl-4-pyridinol nucleus with a polyunsaturated side chain at C-6. We have prepared this nucleus and attached conventional polyprenyl side chains for structure-activity studies on coenzyme Q inhibitors. To prepare the nucleus, 3-methoxyacetylamino-2-methylacrylonitrile was cyclized to a 4-amino-2-pyridone which trimethyloxonium fluoroborate converted to the 4-amino-2,3-dimethoxypyridine. Bromination of the acylated amine formed the 6-bromo derivative in which the 4-amino was then replaced by hydroxy and the latter blocked by conversion to its benzyl ether with a benzylisourea. Transmetalation now gave the 6-lithio compound which was coupled with various prenyl bromides, leading to introduction of all trans polyprenyl side chains. The final 4-pyridinols were formed on selective debenzylation with butyl mercaptide. All the polyprenylpyridinols inhibited coenzyme Q electron transport to some extent, with the farnesyl analogue having the same activity as piericidin A.