A Concise Synthesis of (+)-Artemisinin

CHEM635

Yinzhi FangGroup 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.

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(+)-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

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Some Highlights

1.Zinc enolate alkylation

2.Unconventional [4+2] reaction

3.Singlet Oxygen Oxidation

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Zinc enolate alkylation

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

Singlet Oxygen Oxidation

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Proposed Mechanism

OH

CH3H3CO OTIPS

CH3

CH3

O1O2

OH

CH3

H3CO OTIPS

CH3

CH3

O

OO

OH

CH3

H3CO OTIPS

CH3

CH3

O

O

O

OH

CH3H3CO OTIPS

CH3

O

H

H3C

H

OO

OH

CH3

H3CO OTIPS

CH3

CH3

O

O

O

perepoxide

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Conclusion

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