Efficient Total Synthesis of Bilirubin IXα from Butyrolactone

Bilirubin, a yellow
pigment formed during the heme breakdown in
the red blood cells, plays a central role in the physiological processes
of vertebrates. It is the main component of Bovis Calculus (Bezoar),
one of East Asia’s most valuable and often-used medicinal materials.
Although the significance of bilirubin in human health has been extensively
studied, its chemical synthesis has remained a challenging endeavor.
This paper presents an efficient total synthesis of bilirubin on a
33 g scale in a minimum number of steps from inexpensive starting
materials under very mild conditions. The synthetic route featured
11 steps from butyrolactone, resulting in 19% overall yield with 98.8%
purity. The convergent synthesis overcomes limitations such as difficult
chromatographic separation, high toxicity of selenium compounds, expensive
rhodium catalysts, and isomerization byproducts. This new synthetic
pathway makes it possible to industrially produce bilirubin on a large
scale. The methine bridge configuration in the ring systems AB and
CD was assigned as a Z-syn-periplanar conformer,
as corroborated by single-crystal X-ray studies.