1. Last Chem 125 Lecture 4/29/09 Projected material This material is for the exclusive use of Chem 125 students at Yale and may not be copied or distributed further. It is not readily understood without reference to notes from the lecture.

2. Chapter 22 whatever RC O H substitution at  -C

3. Ester Enolate (sec. 22.7B p. 1087) C nucleophile ** **

4.  -Halogenation (sec. 22.3 p. 1057-1060)

6. Aldol (sec. 22.4 pp. 1063-1067) ,  -unsaturated carbonyl

7. Aldol (sec. 22.4 pp. 1063-1067) ,  -unsaturated carbonyl

8. Hydrocinnamaldehyde Starting Material for “Clamshell” Synthesis (Cf. p. 1068) ,  -unsaturated carbonyl  Aldol H acetaldehyde H Cinnamaldehyde (prepared by this method in 1884) Ph-CH 2 -CH 2 -CHO H 2 / cat (see frame 13)

9. “Claisen” or “Acetoacetic Ester” Condensation (pp. 1072-1075) substitution at ester Why not use OH - ? Equilibrium position?

10. Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083)

11. Biological Claisen X = SR = coA (sec. 22.6, pp. 1081-1083)

12. Addn. to Conjugated Systems II  -Unsaturated Carbonyl: C=O p. 1100

13. Addn. to Conjugated Systems III  -Unsaturated Carbonyl: C=C Sec. 22.9 pp. 1100-1101 O via ?

14. 1,4 addn enol  ketone Addn. to Conjugated Systems IV  -Unsaturated Carbonyl: Conjugate sec. 22.8 pp.1092-1095 “1,4” “Conjugate” Addition or “Michael”

15. Addn. to Conjugated Systems IV  -Unsaturated Carbonyl: Conjugate sec. 22.10 pp. 1101-1103

16. sec. 22.10 pp. 1101-1103 PhMgBr 1,4 (96%) PhLi 1,2 (75%) CuI (cat) 1,4 RCuLi 1,4 Addn. to Conjugated Systems IV  -Unsaturated Carbonyl: Conjugate LORE

17. Cortisone from Fieser & Fieser, Advanced Organic Chemistry, Reinhold (1961) 1943 100 mg from 100 lbs. beef adrenal glands

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

19. "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 Zn Why lose the top OH not one of these? H + hemiaceta l Diels-Alder via enolate OH allylic rearrangement known and readily available + + CH 3 CO Zn : +2+2 CH 3 CO 2 -

20. D? C O CH 3 H "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 p. 1098 Robinson annulation Robinson and Woodward after an MIT seminar on the Robinson annulation (photo J.D. Roberts, 1951) Protecting C=C

21. O C CH 3 H H B "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

22. 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!

23. 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

24. "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

25. "Total" Synthesis Woodward (1951) CH 3 H D? O O 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 (luck) base -H 2 O I O O-O- O O H / resolved (1909 method) / H 2 -cat -IO 3 - pericyclic H 2) CH 2 =N 2 hydrolyze acetal new “acetal” reduces ketone not ester CH 3

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

27. But What Was the Yield? Intellectual Problem Solved. Sequential (40 steps @ 80%) 0.01% yield Convergent (4x9 steps + 2) 9% yield 9 9 9 9 A B C D P E F

28. 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

29. Cortisone Synthesis (Practical) Pregnancy hormone ~1955 $0.48/gm Abundant in a Mexican yam Russell Marker

30. 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, p. 1335) with ~100 co-workers including…

31. 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.

32. 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

33. E7389 being developed commercially for breast cancer by Eisai Pharmaceutical Active Fragment of Halichondrin B "Simplified" Version of Active Fragment is Drug Candidate E7389 ~ 100,000 configurational isomers!

34. 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)

35. Good Luck on the Final Exam Review at Class Time Friday