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Total Synthesis of Prostaglandins F2

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 WoodwardHoffman 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 F2
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 0C
Copper catalyst is necessary to speed up reaction so it can
proceed below 0C without isomerization of starting material

Enantioselectivity: ephedrine
resolution

Proof of Conformation

Synthesis cont.

Completing the synthesis

Conclusion
First stereospecific synthesis of Prostaglandin F 2
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?