1. Kirk W. Shimkin Total Synthesis Spring 2012
Total Synthesis of Prostaglandins F2α and E2 as the naturally occurring forms
Corey, et al. JACS, 1970, 92, 398
Kirk W. Shimkin
Total Synthesis Spring 2012

2. Elias J. Corey Born in Methuen, MA in 1928 (age 83)
Birth name is actually Matthew, mother
changed it to Elias to honor his father who
died shortly after his birth.
B.A , MIT
PhD , MIT (age 22)
Made full professor at university of Illinois in 1956 (at age 27!)
1959-present: Professor of chemistry at Harvard university
Focuses on synthetic organic chemistry because of “its intrinsic beauty and its great relevance to human health.”
Over 1000 publications, in 2002 was recognized as “Most cited author in chemistry” by ACS
Awards and Honors:
National Medal of Science (1988)
Nobel prize in chemistry (1990)
Priestley Medal (2004)

3. Corey, Cont.
Known For:
Pyridinium Chlorochromate (PCC, aka the Corey-Suggs reagent)
t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), methoxyethoxymethyl (MEM) protecting groups
Corey-Bakshi-Shibata enantioselective reduction
Corey-Fuchs reaction
Corey-Kim reaction
Corey-Winter olefin synthesis
Corey-House synthesis
Corey-Johnson-Chaykovsky reaction
Corey-Seebach reaction
Total synthesis of ginkolide A and B, Lactacystin, Ecteinascidin 743, Salinosporamide A, prostaglandins, among many others.
Development of retrosynthetic analysis
Claims to have inspired the inception of the Woodward-Hoffman rules in a 1964 conversation with Robert Woodward.

4. Prostaglandins Naturally occurring hormones found in all animal cells
Lipid compounds derived from fatty acids
All contain 20 carbons, 5-membered ring
First isolated from seminal fluid in 1935 (Ulf von Euler), but is actually produced by various types of cells
Regulate contraction and relaxation of smooth muscle tissues (one of many functions)
Sune K. Bergstrom, John R. Vane, and Bengt I. Samuelsson won nobel prize in Physiology and Medicine in 1982 for their research on prostandins
Prostaglandin I2

5. Prostaglandin F2α Marketed as dinoprost and enzaprost
Used to induce labor; as an abortifacient
4 contiguous stereocenters

6. Retrosynthesis/ strategy

7. Synthesis
Product of first reaction is unstable, isomerizes at temperatures above 0°C
Copper catalyst is necessary to speed up reaction so it can proceed below 0°C without isomerization of starting material

8. Enantioselectivity: ephedrine resolution
Proof of Conformation

9. Synthesis cont.

10. Completing the synthesis

11. Conclusion
First stereospecific synthesis of Prostaglandin F2α and E2 completed
Bicycloheptane strategy used to set relative stereochemistry at 3 stereogenic centers
Ephedrine resolution provides enantiopure intermediate for enantiospecific synthesis
Main precursor can be made in roughly 50% yield from enantiopure cyclopentene intermediate.

12. Questions?