On Artemisinin, Cyclopamine, D-Isocitric acid, Hyperforin, Epigenetics, Sialic Acid, and More

Dedicated to Professor Konrad Sandhoff on occasion of his 80th birthday

‘Where you fail, return, where you succeeded, say goodbye’[1]

Abstract

In this Account we present the total syntheses of artemisinin (an important antimalarial agent) and cyclopamine (the first natural inhibitor of the hedgehog signaling pathway). Furthermore, we describe the design and development of a γ-butyrolactone as an inhibitor of Gcn5 (a histone N-acetyltransferase), discuss the discovery of hyperforin and guttiferon G as the first natural products acting as inhibitors of sirtuins, and present the design of inhibitors of sialic acid biosynthesis. The biomedical background and importance are also discussed. Finally, we present the discovery and development of methods for transesterification, IBX-mediated oxidations, reduction of several functional groups with LiBH₄/Me₃SiCl, as well as a process enabling the synthesis of kilogram amounts of D-isocitric acid and its transformation to valuable chiral derivatives.

1 Artemisinin and Malaria

2 Cyclopamine and Cyclops

3 Sunflowers, Krebs Cycle, and Isocitric acid

4 Histones and N-Acetyltransferase Gcn5

5 St. John’s Wort, Hippocrates, and Sirtuins

6 Sialic Acid and Inhibitors of Its Biosynthesis

7 Transesterification

8 IBX Reloaded

9 And Finally: A Small Mistake with a Big Impact

10 Epilogue

Key words

artemisinin - cyclopamine - D-isocitric acid - hyperforin - epigenetics - sialic acid - transesterification - IBX

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