CH402: Synthetic Chemistry I (Organic) Professor Martin Wills.

1. CH402: Synthetic Chemistry I (Organic) Professor Martin Wills. synthetic approaches to complex target organic molecules Structure of course (7 lectures) (underlined/red text indicates the molecule on which the course will focus, and the examinable/workshop material), there is one handout and one set of notes on the course with links to references: 1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and extreme targets which may include palytoxin, vitamin B12, brevitoxin, azadirachtin, vancomycin. 2) Early classics of total synthesis in organic chemistry, which may include colchicine, morphine, strychnine, thienamycin and penicillin. 3) Lessons learnt from the synthesis of small important organic molecules which may include hirsutene, periplanone B, epothilones and prostaglandins. 4) Molecules with a high degree of functionality, which may include avermectin, erythromycin, amphotericin B, strychnine. 5) Construction of highly complex structures which may include ginkgolide B, calicheamycin, taxol. 6) The use of cycloadditions in complex molecule synthesis, which may include FR182877/abyssomicin C, estrone, platensimycin, progesterone, daphniphylline alkaloids. 7) Enantioselective strategies which may include biotin a-arylpropionic acids, menthol, zaragozic acid, statins.

2. CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills. synthetic approaches to complex target organic molecules Recommended reading (not essential but if you want to learn more or check anything): Classics in Total Synthesis; K. C. Nicolaou and E. J. Sorensen, Wiley-VCH 1996. Classics in Total Synthesis II, K. C. Nicolaou and E. J. Sorensen, VCH 2003. Molecules that changed the world, K. C. Nicolaou and T. Montagnon, Wiley-VCH, 2008. The Logic of Chemical Synthesis, E. J. Corey and X.-M. Cheng, Wiley-VCH, 1995. S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach, Wiley, 2nd Edn 2008 and the associated workbook, 2nd Edition 2009. Catalysis in Asymmetric Synthesis’ by V. Caprio and J. M. J. Williams, Wiley, 2010 (2nd Edition). In addition, other annual reviews of progress frequently appear in review journals. For more detailed reviews of particular areas, you can search the web of knowledge or Scifinder Scholar for comprehensive literature surveys.

3. CH402: Synthetic Chemistry I (Organic), lectures 1-7; Professor Martin Wills. Specific requirements and structure of the course: 15 CATS is equivalent to around 150 study hours. There are 10 lectures of 1 h each, three workshops (1h, 2h, 2h) and a piece of assessed work which would be expected to take 15-20 hours of work. The remaining time is for self-study around the subject. For the M. Wills section of the course, a number of key references will be provided on the seven molecules selected for detailed study. These seven molecules and the associated references represent the main material for the workshops and for the examinable material. Key references will be provided for each of the seven targets in bold, and these papers should be treated as examinable material however - you do not have to learn the content by heart but should ensure that you understand the reasons for the choice of strategy and the main mechanisms, particularly with respect to the key steps indicated for each synthesis. The assessed task will involve writing an essay about the analysis of a complex synthesis (which will not be one of the seven highlighted earlier). Further information about this will be distributed early in the course. Please note that not all reagents/solvents/conditions are given for each step. In most cases only the KEY reagent is shown. 3

4. 1) Introduction to strategy, disconnections, retrosynthesis, protecting groups and extreme targets which may include palytoxin, vitamin B12, brevetoxin, azadirachtin, vancomycin. Recap: disconnections, synthons, FGIs and reagents. But remember there are no ‘rules’ – the only limit is your imagination!

5. Examples of ‘extreme targets’ which have been prepared by total synthesis. Palytoxin is too big to fit on this slide – see the next slide!.

6. Palytoxin - toxic marine natural product. Synthesised by Kishi in 1994. "Synthesis of Palytoxin from Palytoxin Carboxylic-Acid". E. M. Suh and Y. Kishi, J. Am. Chem. Soc. 1994,116 (24): 11205–11206. "Total Synthesis of Palytoxin Carboxylic-Acid and Palytoxin Amide". R. W. Armstrong, J. M. Beau, Y. Kishi et al.J. Am. Chem. Soc. 1989, 111, 7530–7533.

7. Palytoxin – the power of protecting groups. A list of protecting groups follows in a couple of slides, along with removal methods.

8. Eribulin – an anticancer drug which arose from the related halichondrin synthesis: Conclusion of total synthesis: T. D. Aicher, K. R. Buszek, F. G. Fang, C. J. Forsyth, S. Ho Jung, Y. Kishi, M. C. Matelich, P. M. Scola, D. M. Spero and S. K. Yoon, J. Am. Chem. Soc. 1992, 114, 3162-3164. D. S. Kim, C. G. Dong, J. T. Kim, H. Guo, J. Huang, P. S. Tiseni and Y. Kishi, "New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach". J. Am. Chem. Soc. 2009, 131, 15636–15641.

9. Commonly used protecting groups: OTMS=OSi(Me)3 OTBS= OSi(Me)2tBu (also called OTBDMS) OTPS=OSi(Ph)2tBu (also called OTBDPS) OTIPS=)Si(iPr)3 Silyl group are added using R3SiCl + amine base, removed using fluoride e.g. HF or (Bu)4NF (TBAF). TMS can be removed with mild acid. OPMB=CH2C6H4p(OMe) (paramethoxybenzyl) OBn = OCH2Ph (benzyl). Above are added using ArCH2Br + base, Bn removed by H2/Pd and PMB by using DDQ (dichlorodicyanoquinone). OTHP=Otetrahydropyran; added using THPOH and acid, removed with H2O/acid. OBz= OCOPh (benzoyl) and OAc (acetate): added using anhydride or acid chloride, removed with H2O/acid. NtBoc; add with Boc2O, remove with acid (CF3CO2H), NZ = N(CO)OCH2Ph, add with chloride, remove by hydrogenation. NFMoc; add via chloride, remove with base.

10. Vitamin B12 – strategic construction of large units. A very large target can soon be broken down into smaller ones if a convergent strategy is used. Albert Eschenmoser ETH Zurich Synthesised by Woodward and Eschenmoser, et al. 1973 (and over 100 students and researchers. R. B. Woodward, Pure & Appl. Chem. 1973, 33, 145, A. Eschenmoser and C. E. Winter, Science 1977, 196, 1410. (and other references). R B Woodward (Harvard)

11. Brevetoxin B – a marine neurotoxin (‘red tide’ algae blooms) multiple coupling steps for ring construction – some examples. You’d be expect to know, or be able to work out, the mechanisms of the reactions.

12. Brevetoxin B – multiple coupling steps for ring construction; synthesis completion. Note what a variety of cyclisation methods can be used. Professor K. C. Nicolaou, Scripps Research Institute (California). Reference: ‘The Total Synthesis of Brevetoxin B: A Twelve-Year Odyssey in Organic Synthesis’ K. C. Nicolaou, Angew. Chem. Int. Ed. 1996, 35, 588-607.

13. Vancomycin – aromatic ether coupling strategies. Professor David Evans, Harvard. Vancomycin is a powerful antibiotic which inhibits the formation of cell walls by binding to terminal peptide chains.

14. Vancomycin – aromatic ether coupling strategies. Total Syntheses of Vancomycin and Eremomycin Aglycons, D. A. Evans, M. R. Wood, B. W. Trotter, T. I. Richardson, J. C. Barrow, J. L. Katz, Angew. Chem. Int. Ed. 1998, 19, 2700-2704.

15. Azadirachtin – dealing with sensitive functionality. Selected for closer focus. ‘The Azadirachtin Story, by G. E. Veitch, A. Boyer and S. V. Ley, Angew. Chem. Int. Ed. 2008, 47, 9402-9429. Prepared by S. V. Ley and Colleagues in 2007.

16. Azadirachtin – dealing with sensitive functionality. 16

17. Azadirachtin – Decalin construction. 17

18. Azadirachtin – synthesis completion. 18

19. 2) Early classics of total synthesis in organic chemistry, which may include colchicine, morphine, strychnine, thienamycin and penicillin.

20. Tropinone: A classic synthesis. Sir Robert Robinson. Nobel Prize 1947. PhD Manchester 1910, Sydney 1912-1915, Manchester 1915-1920, Director of Research at the British Dyestuffs Corporation 1920-21, StAndrews 1921-1922, Manchester 1922-1928, London 1928-1930, Oxford 1930-1955. Birch, A. J. (1993). "Investigating a Scientific Legend: the Tropinone Synthesis of Sir Robert Robinson, F.R.S". Notes and Records of the Royal Society of London, 1993, 47, 277–296.

21. Colchicine; Deceptively simple but actually very challenging. BBC Science news 12th Sept 2011: ‘The native British Autumn crocus, is recorded in early herbal guides as a treatment for inflammation. This is because it contains the potent chemical colchicine, which is known to have medicinal properties, including anti-cancer effects.’ (reporting on anew drug delivery method). Features in MT course CH408

22. Colchicine Total synthesis of colchicine in comparison: By: Graening, Timm; Schmalz, Hans-Guenther , Angew Chem Int Ed. 2004, 43, 3230-3256.

23. Synthesis of Penicillins and related antibiotics. John S Sheehan From Time Magazine, March 1957; ‘After nine years of dogged work, Chemist John C. Sheehan of M.I.T. announced last week that he had discovered a practical method of synthesizing penicillin V.’ The synthesis would not compete with microbiological methods for Pencillin, but allows analogues to be made.

24. Morphine and related alkaloids. Professor Barry Trost (Stanford). "Enantioselective Synthesis of (-)-Codeine and (-)-Morphine", Trost, B.M.; Tang, W. J. Am. Chem. Soc. 2002, 124, 14542.

25. Strychnine – selected for closer analysis. Key step here is the transformation Of A to B. L Overman S. D. Knight, L. E. Overman and G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293–9294 .

26. Key steps are from A to C (via B). Shibasaki synthesis of strychnine T. Ohshira, Y. Xu, R. Takita, S. Shimizu, D. Zhong and M. Shibasaki, J. Am. Chem. Soc, 2002, 124, 14546-14547.

27. Strychnine synthesis by Vanderwal, 2011. 27 D. B. C. Martin and C. D. Vanderwal, Chemical Science, 2011, 2, 649-651.

28. Key steps are from A to C and from D to E. Strychnine synthesis by Andrade, 2010. G. Sirasani, T. Paul, W. Dougherty Jr., S. Kassel and R. B Andrade, J. Org. Chem. 2010, 75, 3529-3532. 28

29. 3) Lessons learnt from the synthesis of small important organic molecules which may include hirsutene, periplanone B, epothilones and prostaglandins.

30. Intramolecular epoxide opening reactions • The synthesis of Grandisol, the pheromone of the male cotton boll weevil, and closely-related compounds, has been achieved in a very concise synthesis using a key epoxide-opening step. The high level of ring strain provides a means for the synthesis of similarly strained targets: I. Petschen, A. Parrilla, M. P. Bosch, C. Amela, A. A. Botar, F. Camps and A. Guerrero, Chem. Eur. J. 1999, 11, 3299-3309 30

31. Hirsutene – radical cyclisation approach by Curran. • D. P. Curran and D. M. Rakiewicz, Tetrahedron 1985, 41, 3943-58. • D. P. Curran and D. M. Rakiewicz, Donna M, J. Am. Chem. Soc. 1985, 107, 1448-9.

32. Periplanone B. – approach by Still. W. C. Still, J. Am. Chem. Soc. 1979, 101, 2493-2495. M. A. Adams, K. Nakanishi, W. C. Still, E. V. Arnold, J. Clardy, C. J. Persoons, J. Am. Chem. Soc. 1979, 101, 2495- 2498.

33. Prostaglandins – approach by Corey. E. J. Corey, N. M. Weinshenker, T. K. Schaaf J. Am. Chem. Soc. 1969, 91, 5675-5677. This process has been significantly developed by Corey since the initial report.

34. Discussed in MT course for binding - metathesis And structural variation but not synthesis. Epothilones - This to be the focus of Section 3. First isolated in early 1990s from soil bacterium Sorangium cellusum and found to possess antfungal activity. In 1993, they were found to possess antitumour activity in a screen run by MSD. Epothilone B was even more active than taxol and share the same binding site on tubulin. First synthesised in 1996-7. Can be prepared by fermentation processes. Tubulin is a polymeric, tube-shaped protein which for the ‘mititic spindle when cells divide – this controls the correct separation of DNA into the daughter cells. Like Taxol, epothilones bind to the tubulin in the microtubules and interfere with their operation, thus preventing mitosis. Like many anticancer drugs, epothilones are highly cytotoxic. More information on biological action in M. Tosin’s CH408 course. 34

35. Epothilones – synthetic strategies. Semisynthesis represents A viable approach to new analogues. The majority are made by derivatisation. Note the amide version too. Key review: J. Mulzer, K.-H. Altmann, Höfle, R. Müller and K. Prantz, COMPTES RENDUS CHIMIE.  2008, 11, 1336-1368. 35

36. Epothilones – metathesis approach. 36

37. Epothilones – alkyne metathesis approach. Key steps are the conversion of A to B, and B to C A B C 37

38. Epothilones – Aldol approach. Prof Samuel Danishefsky, Columbia University and the Memorial Sloan-Kettering Cancer Center (New York) Key step is conversion of A to B. A B 38

39. Epothilones – lactonisation approach. B A Key step is the Aldol reaction from A to B. 39

40. 4) Molecules with a high degree of functionality, which may include avermectin, erythromycin, amphotericin B and strychnine (covered in part 2).

41. Avermectins - retrosynthesis. First discovered when a scientist notice a healthy patch of grass on a golf course! Analysis of the sample produced a bacteria which produced the Avermectins. These act as insecticides and as treatment for internal and external parasites in livestock. Almost no toxicity to humans.

42. Avermectin – Hanessian route. Professor Stephen Hanessian (University of Montreal). S. Hanessian, A. Ugolini, D. Debé, P. J. Hodges and C. André, J. Am. Chem. Soc. 1986, 108, 2776-2778.

43. Amphotericin B – focus of this section. Key disconnections and approach.

44. Key step is the Wadsworth-Emmons reaction. Amphotericin B – focus of this section. Nicolaou approach. First step;- Sharpless asymmetric epoxidation. K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S. Li, D. P. Paphatjis and T. K. Chakraborty, J. Am. Chem. Soc. 1988, 110, 4672-4685. (the completion is described in the two papers which follow this).

45. Amphotericin B completion of the synthesis. Key step is the Intramolecular cyclisation reaction of A to B. A B

46. Amphotericin B; Krische iterative polyol synthesis: 46

47. Amphotericin B; Krische iterative polyol synthesis: Key step is conversion of A to B. B A Michael Krische University of Texas at Austin. See Xin Gao, Sang Kook Woo, and Michael J. KrischeJ. Am. Chem. Soc. 2013, vol 123, 4223-4226 for a synthesis of 6-deoxyerythronolide B in just14 steps. S. B. Han, A. Hassan, I. S. Kim and M. J. Krische, J. Am. Chem. Soc. 2010, 132, 15559-15561. 47

48. Deoxyerythronolide B; Krischesynthesis in just 14 steps: See Xin Gao, Sang Kook Woo, and Michael J. KrischeJ. Am. Chem. Soc. 2013, 123, 4223-4226 48

49. 5) Construction of highly complex structures which may include ginkgolide B, calicheamycin, taxol. Ginkgo tree in Kew gardens. Features in MT course, Including biosynthesis, Semisynthesis and binding.

50. Calicheamycin – intramolecular cyclisation. Chemistry and Biology of Natural and Designed Enediynes, K.C. Nicolaou, A.L. Smith, E.W. Yue, Proc. Natl. Acad. Sci. USA 1993,90, 5881-5888.