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?