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
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.- 1948, MIT
• PhD.- 1951, 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)
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.
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
Prostaglandin F2α
• Marketed as dinoprost and enzaprost
• Used to induce labor; as an abortifacient
• 4 contiguous stereocenters
Retrosynthesis/ strategy
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
Enantioselectivity: ephedrine
resolution
Proof of Conformation
Synthesis cont.
Completing the synthesis
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.
Questions?