Total Synthesis of Prostaglandins F2α and E2 as the naturally occurring forms

Kirk W. ShimkinTotal Synthesis Spring 2012

Corey, et al. JACS, 1970, 92, 398

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?