Concise, scalable and enantioselective total synthesis of prostaglandins

• Published in: Nature chemistry 2021-07, Vol.13 (7), p.692-697
• Main Authors: Zhang, Fuhao, Zeng, Jingwen, Gao, Mohan, Wang, Linzhou, Chen, Gen-Qiang, Lu, Yixin, Zhang, Xumu
• Format: Article
• Language: English
• Subjects: 639/638/403/933; 639/638/403/977; 639/638/549/933; 639/638/549/972; Analytical Chemistry; Biochemistry; Catalysis; Chemical synthesis; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Divergence; Drugs; Enantiomers; Hydrogenation; Inorganic Chemistry; Intermediates; Isomerization; Organic Chemistry; Physical Chemistry; Prostaglandins; Rhodium; Selectivity
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-021-00706-1

Prostaglandins are among the most important natural isolates owing to their broad range of bioactivities and unique structures. However, current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Here, we report a practicability-oriented synthetic strategy for the enantioselective and divergent synthesis of prostaglandins. In this approach, the multiply substituted five-membered rings in prostaglandins were constructed via the key enyne cycloisomerization with excellent selectivity (>20:1 d.r., 98% e.e.). The crucial chiral centre on the scaffold of the prostaglandins was installed using the asymmetric hydrogenation method (up to 98% yield and 98% e.e.). From our versatile common intermediates, a series of prostaglandins and related drugs could be produced in two steps, and fluprostenol could be prepared on a 20-gram scale. Current methods for the synthesis of prostaglandins suffer from low yields and lengthy steps. Now, a strategy for their enantioselective synthesis has been developed with rhodium-catalysed enyne cycloisomerization as the key step. This concise route was scaled up, enabling the preparation of fluprostenol on a 20-gram scale.