Total Synthesis Heroes

1. Total Synthesis Heroes Nobel Prize winners: Hermann Emil Fischer (1902,sugar and purine ) Fritz Haber (1918,ammonia, Haber-Bosch process) Heinrich Otto Wieland,(1927, bile acids) Adolf Otto Reinhold Windaus(1928, cholesterol, vitamin D3) Hans Fischer (1930, Haemin) Paul Karrer  Walter Haworth (1937, vitamins.) Richard Kuhn(1938, carotenoids and vitamins) Otto Paul Hermann Diels/Kurt Alder(1950, diene synthesis) Vincent du Vigneaud,(1955 cyclic peptide, oxytocin)Robert Robinson (1947, Tropinone)    Robert Burns Woodward (1965) Elias James Corey (1990)

2. Pre-WorldWarII Era, The Woodward Era, The Corey Era, The1990s. Total Synthesis Heroes The birth of total synthesis- Urea Isolated in 1773 from human urine (hence the name) by Hilaire M. Rouelle Synthesized in 1828 by Friedrich Wöhler F. Wöhler, Ann. Phys. Chem. 1828, 12, 253.

3. Pre-WorldWarII Era, Total Synthesis in the Nineteenth Century Total Synthesis Heroes Indigo Baeyer (1878) Glucose Fischer, 1890 Acetic Acid Kolbe, 1845 Alizarin Graebeand Liebermann (1869) H. Kolbe, Ann. Chem. Pharm. 1845, 54, 145. E. Fischer, Ber. Dtsch. Chem. Ges. 1890, 23, 799 Baeyer, Ber. Dtsch. Chem. Ges. 1878, 11, 1296; C. Graebe, C. Liebermann, Ber. Dtsch. Chem. Ges. 1869, 2, 332

4. Pre-World War II Era, Total Synthesis in the Twentieth Century (Pre-Woodward Era) Total Synthesis Heroes Haemin H. Fischer,1929 Tropinone Robert Robinson (1917) a-terpineol (Perkin, 1904) (R)- (left) and (S)-camphor Komppa, 1903; Perkin, 1904 W. H. Perkin, J. Chem. Soc. 1904, 85, 654 R. Robinson, J. Chem. Soc. 1917, 111, 762 Willstätter, Ber. Dtsch. Chem. Ges. 1901, 34, and 3163 H. Fischer, K. Zeile, Justus Liebigs Ann. Chem. 1929, 468, 98.

5. Total Synthesis-WoodwardEra Robert Burns Woodward April 10, 1917 – July 8, 1979 Active in Total synthesis from 1940’s-1980’s

6. Total Synthesis-WoodwardEra Pre-Woodward Era. –Painstaking breakthroughs in the determination of structure were achieved, not by single chemists but by large research groups. The Nobel Prize recipients, Heinrich Wieland (1877 – 1957) and Adolf Windaus (1876 – 1959) owed their reputations to prodigious chemical degradation of the steroids and related bile acids to simpler fragments for derivation and identification by using only elemental analysis and melting-point measurements. In those days, synthesis (from the Greek word, the process of putting together) was more destructive than constructive!

7. Total Synthesis-WoodwardEra However, the final experimental proof of structure, then, IR and elemental analysis, and amusingly on a simple melting point of the synthetic material mixed with the natural material, which then showed no melting-point depression when compared to that of the two separate samples R. B. Woodward, “The Structure of Strychnine”, J. Am. Chem. Soc. 1947, 69, 2250. J. H. Robertson, “The Crystal Structure of Strychnine Hydrobromide”, ActaCrystallogr. 1951, 4, 270 – 275. R. B. Woodward, “The Total Synthesis of Strychnine,” J. Am. Chem. Soc. 1954, 76, 4749 – 4751. A. F. Peerdeman, “The Absolute Configuration of Natural Strychnine”, ActaCrystallogr. 1956, 824. In time(1950’s), this distinct order of synthesis before structure analysis reversed, as X-ray crystallography became the work-horse for even more audacious complex structures

8. Total Synthesis-WoodwardEra K. C. Nicolaou, Phil S. Baran, Angew. Chem. Int. Ed. 2000, 39, 44

9. Total Synthesis-The Corey Era Mostly ative 1960’s-1990’s and still active now two distinctive elements: 1).Retrosynthetic analysis 2). new synthetic methods

10. Total Synthesis-The Corey Era Gilbert Stork Albert Eschenmoser vitamin B12 Corrins Colchicine Sir D. H. R. Barton  Nobel Prize (with Odd Hassel) for "contributions to the development of the concept of conformation and its application in chemistry."

11. Total Synthesis-The Corey Era MarcfortineB B. M. Trost FK506 Amos B. Smith III Stuart Schreiber

12. Total Synthesis-The Corey Era YoshitoKishi(1966) TohruFukuyama(1978) Samuel J. Danishefsky (1963) Albert Padwa(1963) Calicheamicin Samuel J. Danishefsky Vinblastine Palytoxin(1994) Albert Padwa Platensimycin Philip Magnus Cyanocycline A  HalichondrinB(1992)

13. Total Synthesis-The Corey Era Manzamine Jeffrey D. Winkler, Stephen Martin Masako Nakagawa Brevetoxins 1995 by K. C. Nicolaou Cyclosporin Roland M. Wenger  Samuel J. Danishefsky Nicolaou, 3/20, 2000 Tohru Fukuyama, 5/15,2000 Matthew D. Shair, 6/2, 2000 Danishefsky, 8/ 22, 2000 Taxol Robert A. Holton, K. C. Nicolaou,SamuelJ. Danishefsky Resiniferatoxin Wender, P. A

14. Total Synthesis-The1990s Era John Porco(1999) Peter Wipf Hexacyclinol John Porco James J. La Clair Scott Rychnovsky

15. Total Synthesis-The 2000s Era (+)-saxitoxin Justin Du Bois Mo Movassaghi Johnson, J. S. Erik Sorensen

16. Total Synthesis-The present Era Coming last…..

17. Total Synthesis-Woodward Robert Burns Woodward April 10, 1917 – July 8, 1979 Active in Total synthesis from 1940’s-1980’s

18. 1933, he entered the Massachusetts Institute of Technology (MIT), 1934 fall term，excluded for formal studies badly( but neglected ) 1935 fall term MIT readmitted him； 1936 he had received the Bachelor of Science degree. 1937 MIT awarded him the doctorate(20 years old), when his classmates were still graduating with their bachelor's degrees. 1953 National Academy of Sciences, (age of 36!) 1965 The Nobel Prize in Chemistry 1965: "for his outstanding achievements in the art of organic synthesis” 1969 Woodward and Hoffmann: Frontier orbital symmetry could explain the important stereochemicalselectivities in concerted reaction. 1979 Died. 1981 Roald Hoffmann and Kenichi Fukui received the Nobel Prize in chemistry for discovering the rules governing the course of chemical reaction. If Bob had lived, he would surely have shared in this award. Robert Burns Woodward authored or coauthored 196 publications

19. Nature is full of organic substances - a large and highly diverse array of chemical compounds that contain the basic element carbon. Building, or synthesizing, organic substances using chemical methods is important in both scientific and industrial contexts. Synthesis often entails complicated, multistep processes. Robert Woodward mastered these processes. Robert Burns Woodward ---The Nobel Prize in Chemistry 1965committee

20. Robert Burns Woodward Early work：Ultraviolet spectroscopy in the elucidation of the structure Woodward's rules, also known as Woodward–Fieser rules (for Louis Fieser) wavelength of maximum diene absorption Base value for acyclic diene： 217nm homoannular with both double bonds contained in one ring heteroannular with two double bonds distributed between two rings.

21. Robert Burns Woodward Woodward's rules, extension to wavelength of maximum Conj. carbonyl absorption

22. Robert Burns Woodward Later work and its impact： During the late 1940s, Woodward synthesized many complex natural products including quinine, cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, cephalosporin, and colchicine.With these, Woodward opened up a new era of synthesis, sometimes called the 'Woodwardian era' in which he showed that natural products could be synthesized by careful applications of the principles of physical organic chemistry, and by meticulous planning. Nobel Laureate Derek Barton said: The most brilliant analysis ever done on a structural puzzle was surely the solution (1953) of the terramycin problem. It was a problem of great industrial importance, and hence many able chemists had performed an enormous amountof work trying to determine the structure. There seemed to be too much data to resolve the problem, because a significant number of observations, although experimentally correct, were very misleading. Woodward took a large piece of cardboard, wrote on it all the facts and, by thought alone, deduced the correct structure for terramycin. Nobody else could have done that at the time.

23. Robert Burns Woodward Later work and its impact： 1965 The Nobel Prize in Chemistry 1965: "for his outstanding achievements in the art of organic synthesis” 1981 Roald Hoffmann and Kenichi Fukui received the Nobel Prize in chemistry for discovering the rules governing the course of chemical reaction. If Bob had lived, he would surely have shared in this award….. In the early 1950s, Woodward, along with the British chemist Geoffrey Wilkinson, then at Harvard, postulated a novel structure for ferrocene, a compound consisting of a combination of an organic molecule with iron. This marked the beginning of the field of transition metal organometallic chemistrywhich grew into an industrially very significant field.Wilkinson won the Nobel Prize for this work in 1973, along with Ernst Otto Fischer. Some historians think that Woodward should have shared this prize along with Wilkinson. Wilkinson's catalyst RhCl(PPh3)3 + RCHO → RhCl(CO)(PPh3)2 + RH + PPh3

24. Robert Burns Woodward Mentors: Norris served as President of the American Chemical Society from 1925 to 1926 and as Vice-President of the International Union of Pure and Applied Chemistry from 1925 to 1928.  The James Flack Norris Award is named in his honour

25. Robert Burns Woodward

26. Robert Burns Woodward Best-known students include： YoshitoKishi (Harvard), (TohruFukuyama, Stuart L. Schreiber, Yoshihisa Kobayashi, Alison J. Frontier Stuart Schreiber (Harvard):(John Louis Wood, Daniel Romo, Scott D. Rychnovsky, Amir H. Hoveyda, John A. Porco, Jr., Timothy F. Jamison, Matthew D. Shair) William R. Roush (Scripps-Florida),  Peter Yates(Harvard) (Samuel J. Danishefsky) Steven A. Benner (UF), Christopher S. Foote(UCLA), Kendall Houk (UCLA), porphyrin chemist Kevin M. Smith, Ronald Breslow (Columbia University), Ian Fleming, (University of Cambridge Ian Paterson) Henry  N. C. Wong(黃乃正Zhen Yang) andDavid Dolphin (UBC). Robert M. Williams (Colorado State),

27. “I teach all the time so that I don’t have to teach formal courses.” He taught in the laboratory, in seminars, and via lectures Robert Burns Woodward “one could attack difficult problems without a clear idea of their outcome, but with confidence that intelligence and effort would solve them”