Efficient Total Synthesis of Bilirubin IXα from Butyrolactone

Fapu Chen, Yage Chen, Zhanglong Luo, Feng Pan, Xiliang Zhao, Jun Zhou, Rui Chen, Moris S. Eisen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalOrganic Process Research and Development
DOIs
StateAccepted/In press - 2024

Keywords

  • bilirubin
  • biliverdin
  • butyrolactone
  • synthesis

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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