1. Chemistry 125: Lecture 75 April 29, 2011 Review: Synthesis of Cortisone, a Natural Product This For copyright notice see final page of this file

2. Cortisone based on Fieser & Fieser Advanced Organic Chemistry Reinhold (1961) pp. 594-599 O O CH 3 H H H OH CO CH 2 OH Louis F. Fieser (1899-1977)

3. Mikael Häggström

4. Steroid work was awarded four Nobel Prizes between 1927 and 1950. Closely related work earned another three between 1965 and 1975. The awards in 1927 and 1928 were for determining the structure. wrong

5. http://nobelprize.org

6. Philip Hench Nobel Address http://nobelprize.org

7. Philip Hench Nobel Address http://nobelprize.org

8. Reichstein Tadeus Reichstein Nobel Address Fishhook to Extract Ketones : H 2 N-NH-C-CH 2 -N(CH 3 ) 3 O + H 2 N-NH-R + EtO-C-CH 2 -N(CH 3 ) 3 O + EtO-C-CH 2 -Cl O Cl-C-CH 2 -Cl O HO-C-CH 3 O H 2 NNH 2 EtOHP/Cl 2 N(CH 3 ) 3 http://nobelprize.org Cf Lect 6511 slide 3

9. 5 were Previously Known Cortisol (hydrocortisone) 11 17 29 Steroids from Adrenal Cortex http://nobelprize.org

10. O O CH 3 H H H OH CO CH 2 OH 11 http://nobelprize.org

11. Woodward "Total" Synthesis (1951) O O CH 3 H H H OH CO CH 2 OH

12. "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH LiAlH 4 reduction D? C O CH 3 O CH 3 O H D? C O CH 3 O CH 3 O H OH D? C CH 3 O CH 3 H OH D? C O CH 3 H H + /H 2 O OH D? C CH 3 O CH 3 H OH CH 3 C O CH 3 O O H H OH - H H + + D? C O CH 3 H Ac 2 O Why lose the top OH not one of these? hemiaceta l Diels-Alder via enolate OH allylic rearrangement known and readily available + + CH 3 CO Zn : +2+2 CH 3 CO 2 - H+H+ cis trans Zn “handle” for B “handle” for 11 C=O “handle” to modify D Redox Analysis

13. "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH D? C O CH 3 H O O D? C CH 3 H H B OsO 4 O D? C CH 3 H H B OH O D? C CH 3 H H B O O H + O=C(CH 3 ) 2 (ketal) O D? C CH 3 H H B O O H 2 / Pd enolate - - - “Michael” (1,4 or conjugate) addition aldol Robinson annulation Protecting C=C “handle” for A “handle” for 11 C=O protection for D?

14. "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH O D? C CH 3 H H B O O Abbreviate Ring D (while we work on A) O C CH 3 H H B

15. Protect the more reactive  position "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH O C CH 3 H H B O C H H B N(CH 3 )Ph H O C CH 3 H H B N(CH 3 )Ph H N CH 3 C - - OH - (catalytic) N C C B O CH 3 H H O conjugate addition H-N(CH 3 )Ph O B H OCH 3 O B H O O B H OH O N(CH 3 )Ph - - : like aldol   -unsaturated ketone (also an enamine) like Claisen HH  H H "vinylogous”  H LORE! ready for aldol to A closer to 11 C=O Robinson? MVK

16. H + Protect the more reactive  position "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH O C CH 3 H H B O C H H B N(CH 3 )Ph H O C CH 3 H H B N(CH 3 )Ph H N CH 3 C - OH - (catalytic) N C OH - (strong) H 2 O O N C CH 3 H H B C O O CH 3 MgBr H+H+ C B O CH 3 H H O C H H B O O conjugate addition A? - O N(CH 3 )PhH lose HO H + + + H + H + H CH 3 enolate

17. "Total" Synthesis Woodward (1951) CH 3 O C B O H H D? O O A aldol C D B A O O CH 3 H H H OH CO CH 2 OH now work on D A all set

18. "Total" Synthesis Woodward (1951) C D B A O O CH 3 H H H OH CO CH 2 OH CH 3 H D? OH H+H+ H2OH2O CH 3 H O H O H H D? O O I H H O O-O- O Formal (or "Relay") This conversion was known from previous cortisone studies! 1) K 2 Cr 2 O 7 O B A C-OH CH 3 H D O H C BH 4 - C CH 3 H D! O aldol base -H 2 O I O O-O- O O H / resolved (1909 method) -IO 3 - pericyclic H 2) CH 2 =N 2 hydrolyze acetal new “acetal” reduces ketone not ester CH 3 not (luck) precipitated 3  from 90% EtOH by natural “digitonin” D? O O

19. J. Am. Chem. Soc. H 2 Pd 1) NaBH 4 2) Ac 2 O 4 5 67 8 O O H

20. But What Was the Yield? Intellectual/Artistic Problem Solved Sequential (39 steps @ 80%) 0.01% yield Convergent 9 9 9 9 A B C D Product E F (4x9 steps + 2) 9% yield

21. Cortisone Synthesis (Practical) Choose an appropriate, readily available starting material. properly methylated tetracyclic carbon skeleton with proper stereochemistry at key positions and functional groups at or near some of the proper positions but from ox bile 1946-49 Merck made 1 kg cortisone from 600 kg of this bile acid ? Br ? ? O 1949 Merck $200/gm

22. Cortisone Synthesis (Practical) Pregnancy hormone ~1955 $0.48/gm Abundant in a Mexican yam Russell Marker (1943) 10 tons 3 kg ($250,000)

23. 1954 Strychnine Synthesis Photos courtesy M. Saunders “Woodward’s style is polished showing an insight and sense of proportion that afford him strong convictions, and a well developed dramatic sense.” Bartlett, Westheimer, Büchi (1969) Nobel (1965) "for his outstanding achievements in the art of organic synthesis”.

24. Vitamin B 12 (1973) Albert Eschenmoser ETH Zurich Robert Burns Woodward (1917-1979) Harvard During this work RBW discovered control of stereochemistry by orbital symmetry (pericyclic reactions) with ~100 co-workers including… V. Kisakürek H.C.A. M. Saunders

25. postdoctoral Woodward collaborator Yoshito Kishi (instructor Nagoya Univ.) WOODWARD, PURE APPL CHEM 25: 283 (1971) Kishi joined and then succeeded Woodward as professor at Harvard.

26. Palytoxin 62 Stereogenic Centers 42 Functional Groups Protected 8 Different Ways Convergent from 8 Pieces Kishi et al. 1994 10 20 stereoisomers 7 E/Z Double Bonds C 123 H 213 NO 53

27. The FDA approved Eribulin for metastatic breast cancer on November 15, 2010 Active Fragment of Halichondrin B "Simplified" Version of Active Fragment is Drug Candidate E7389 ~ 100,000 configurational isomers!

28. Friedrich Wöhler (1800-1882) Organic Synthesis has come a long way from urea. "Perhaps you still remember the experiment I carried out in that fortunate time when I was working with you, in which I found that whenever one tries to react cyanic acid with ammonia a crystalline substance appears which is inert, behaving neither like cyanate nor like ammonia." To Berzelius (1828)

29. Thanks & Credits T. R. Williams G. C. Maxfield P. D. Bartlett L. F. Fieser J. B. Conant T. W. Richards W. Ostwald E. P. Kohler I. Remsen R. Fittig K. Schmid J. LiebigF. Woehler J. J. Berzelius J. L. Gay-Lussac C. L. Berthollet “a tall, thin man with a small head, a strong nose, ice-gray hair, and a thin beard”

32. Connecticut Science Teachers Association

43. Good Luck on the Final Exam Review at Class Time Monday in 110 SCL

44.  April 29, 2011 Copyright © J. M. McBride 2011. Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0