A Concise Synthesis of Artemisinin CHEM 635 Yinzhi

A Concise Synthesis of (+)-Artemisinin CHEM 635 Yinzhi Fang Group C February 26, 2013 Chunyin Zhu and Silas P. Cook J. Am. Chem. Soc. , 2012, 134 (33), pp 13577– 13579

Silas P. Cook • • Education: B. A. Reed College (1999); Ph. D. Columbia University (2006) Supervisor: Samuel J. Danishefsky; Postdoctoral Fellow Harvard University (2006 -2008) Eric Jacobsen; • In 2009, Silas began his independent appointment in the Chemistry Department at Indiana University, Bloomington. 1

(+)-Artemisinin • • also known as Qinghaosu (Chinese: 青蒿素), and its derivatives are a group of drugs that possess the most rapid action of all current drugs against Plasmodium falciparum malaria The starting compound artemisinin is isolated from the plant Artemisia annua, sweet wormwood, a herb employed in Chinese traditional medicine. Recent advances in flow chemistry and photochemistry have highlighted an efficient method for the synthesis of artemisinin from its more plentiful biosynthetic precursor artemisinic acid, which is reduced to dihydroartemisinic acid before reacting it with singlet oxygen —Wiki 2

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Some Highlights 1. Zinc enolate alkylation 2. Unconventional [4+2] reaction 3. Singlet Oxygen Oxidation 4

Zinc enolate alkylation Jarugamilli, G. K. ; Zhu, C. ; Cook, S. P. Eur. J. Org. Chem. 2012, 1712– 1715. 5

Singlet Oxygen Oxidation 6

Proposed Mechanism 7

Conclusion A cost-e�ective total synthesis of (+)-artemisinin has been achieved on a gram scale from a widely available, inexpensive starting material, cyclohexenone. 8