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CH402: Synthetic Chemistry I (Organic) Professor Martin Wills. synthetic approaches to complex target organic molecules Structure of course (7 lectures)

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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  -arylpropionic acids, menthol, zaragozic acid, statins. 1

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 Classics in Total Synthesis II, K. C. Nicolaou and E. J. Sorensen, VCH Molecules that changed the world, K. C. Nicolaou and T. Montagnon, Wiley-VCH, The Logic of Chemical Synthesis, E. J. Corey and X.-M. Cheng, Wiley-VCH, S. Warren and P. Wyatt, Organic Synthesis: The Disconnection Approach, Wiley, 2 nd Edn 2008 and the associated workbook, 2 nd Edition Catalysis in Asymmetric Synthesis’ by V. Caprio and J. M. J. Williams, Wiley, 2010 (2 nd 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. 2

3 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 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. 3 Please note that not all reagents/solvents/conditions are given for each step. In most cases only the main reagent or reagents are shown.

4 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 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 6 Palytoxin - toxic marine natural product. Synthesised by Kishi in "Synthesis of Palytoxin from Palytoxin Carboxylic-Acid". E. M. Suh and Y. Kishi, J. Am. Chem. Soc. 1994, 116 (24): 11205– "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 7 Palytoxin – the power of protecting groups. A list of protecting groups follows in a couple of slides, along with removal methods.

8 8 Eribulin – an anticancer drug which arose from the related halichondrin synthesis: 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– 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,

9 OTMS=OSi(Me) 3 OTBS= OSi(Me) 2 tBu (also called OTBDMS) OTPS=OSi(Ph) 2 tBu (also called OTBDPS) OTIPS=)Si(iPr) 3 Silyl group are added using R 3 SiCl + amine base, removed using fluoride e.g. HF or (Bu) 4 NF (TBAF). TMS can be removed with mild acid. OPMB=CH 2 C 6 H 4 p(OMe) (paramethoxybenzyl) OBn = OCH 2 Ph (benzyl). Above are added using ArCH 2 Br + base, Bn removed by H 2 /Pd and PMB by using DDQ (dichlorodicyanoquinone). OTHP=Otetrahydropyran; added using THPOH and acid, removed with H 2 O/acid. OBz= OCOPh (benzoyl) and OAc (acetate): added using anhydride or acid chloride, removed with H 2 O/acid. NtBoc; add with Boc 2 O, remove with acid (CF 3 CO 2 H), NZ = N(CO)OCH 2 Ph, add with chloride, remove by hydrogenation. NFMoc; add via chloride, remove with base. Commonly used protecting groups:

10 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. Synthesised by Woodward and Eschenmoser, et al (and over 100 students and researchers. R. B. Woodward, Pure & Appl. Chem. 1973, 33, 145, A. Eschenmoser and C. E. Winter, Science 1977, 196, (and other references). R B Woodward (Harvard) Albert Eschenmoser ETH Zurich

11 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 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,

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

14 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,

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

16 16 Azadirachtin – dealing with sensitive functionality.

17 17 Azadirachtin – Decalin construction.

18 18 Azadirachtin – synthesis completion.

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

20 20 Sir Robert Robinson. Nobel Prize PhD Manchester 1910, Sydney , Manchester , Director of Research at the British Dyestuffs Corporation , StAndrews , Manchester , London , Oxford 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. Tropinone: A classic synthesis.

21 21 Features in MT course CH408 Colchicine; Deceptively simple but actually very challenging. BBC Science news 12 th 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).

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

23 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 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,

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

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

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

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

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

30 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,

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

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

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

34 34 Epothilones - This to be the focus of Section 3. Discussed in MT course for binding - metathesis And structural variation but not synthesis. 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 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.

35 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,

36 36 Epothilones – metathesis approach.

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

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

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

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

41 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 42 Avermectin – Hanessian route. Professor Stephen Hanessian (Univeristy of Montreal). S. Hanessian, A. Ugolini, D. Debé, P. J. Hodges and C. André, J. Am. Chem. Soc. 1986, 108,

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

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

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

46 46 Amphotericin B; Carrerira synthesis of polyol structure: A. M. Szpilman, D. M. Cereghette, N. R. Wurtz, J. M. Manthorpe and E. M. Carreira, Angew. Chem. Int. Ed. 2008, 47, The key step is conversion of A to B. A B

47 47 Amphotericin B; Krische iterative polyol synthesis:

48 48 S. B. Han, A. Hassan, I. S. Kim and M. J. Krische, J. Am. Chem. Soc. 2010, 132, Amphotericin B; Krische iterative polyol synthesis: Michael Krische University of Texas at Austin. Key step is conversion of A to B. AB

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

50 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,

51 51 Ginkgolide B. E J Corey (Harvard) Alleviates asthma symptoms (and other medicinal properties) E. J. Corey, M. C. Kang, M. C. Desai, A. K. Ghosh and I. N. Houpis J. Am. Chem. Soc., 1988, 110, 649–651

52 52 Taxol – selected for close analysis. Features in MT course, Including biosynthesis, Semisynthesis and binding. Nicolaou route: Key step is conversion of A to B. ‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34, A B

53 53 Taxol – Nicolaou route. Key steps are conversion of A to B, and of C to D. A CD B

54 Taken from: ‘The Conquest of Taxol’, K. C. Nicolaou and R. K. Guy, Angew. Chem. Int. Ed. 1995, 34,

55 55 Taxol - Holton route. R. A. Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P.D. Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentle and J. W. Liu, J. Am. Chem. Soc. 1994, 116, Professor Robert Holton, Florida State University. Key step is conversion of A to B. A B

56 56 Taxol - An approach to the CD ring by G Audran et al. 2008: P. Bremond, G. Audran and H. Monti, J. Org. Chem. 2008, 73, Key steps are conversion of A to B and C to D. A D B C

57 57 6) The use of cycloadditions in complex molecule synthesis, which may include FR182877, estrone, platensimycin, progesterone, daphniphyllum alkaloids, abyssomicin C. Cholesterol biosynthesis and statins etc in MT course with discussion of biosynthesis.

58 58 Estrone – Vollhardt synthesis. K. Peter Vollhardt, Berkeley. K. Peter C. Vollhardt, Angew. Chem. Int. Ed. 1984, 23,

59 59 Progesterone – W. S. Johnson, W. S. Johnson, M. B. Gravestock and B. E. McCarry, "Acetylenic bond participation in biogenetic-like olefinic cyclizations. II. Synthesis of dl-progesterone". J. Am. Chem. Soc. 1971, 93, 4332–4. William Summer Johnson (Stanford)

60 60 Estrone, progesterone - Pattenden approach. Professor Gerry Pattenden, Nottingham. A. Batsanov, L. Chen, G. B. Gill and G. Pattenden J. Chem. Soc., Perkin Trans. 1, 1996,

61 61 Endiandric acids: K. C. Nicolaou’s research group achieved a direct synthesis of endiandric acid A in the laboratory. This was achieved by the reduction of the two alkyne groups in the molecule below by Lindlar catalyst (cis- alkenes are formed selectively) which then formed the product upon heating in toluene. A pretty impressive ‘one-pot’ reaction. K. C. Nicolaou, N. A. Petasis and R. E. Zipkin, J. Am. Chem. Soc. 1982, 104,

62 62 Further applications of Diels-Alder reactions - alkaloid synthesis: R. Kartika and R. E. Taylor, Richard Chemtracts 2006, 19,

63 63 Daphniphyllum alkaloids. G. A. Wallace and C. H. Heathcock, "Further Studies of the Daphniphyllum Alkaloid Polycyclization Cascade," J. Org. Chem. 2001, 66,

64 64 FR – selected for close analysis. Sorensen Approach – inspired by biosynthetic route: Eric Sorensen Princeton University D. A. Vosberg, C. D. Vandewall and E. J. Sorensen,. J. Am. Chem. Soc. 2002, 124, Key step is from A to B. A B

65 65 FR – anticancer Compound, selected for close analysis. Evans Approach (to (-) enantiomer) Different (Suzuki) coupling step between fragments but same cyclisation approach: D. A. Evans and J. T. Starr, Angew. Chem. Int. Ed , 41, Key step is from A to B. A B

66 66 Abyssomicin C – selected for close analysis. Again a Diels-Alder approach by Sorensen. This compound inhibits growth of gram positive bacteria including MRSA and the vancomycin resistant strain. It blocks an early stage in the biosynthesis of tetrahydrofolate – a process important to bacteria but not humans. C. W. Zapf, B. A. Harrison, C. Drahl and S. J. Sorenson, Angew. Chem. Int. Ed , 44, Key step is from A to B. A B

67 67 Abyssomicin C – synthesis completion. Key step is from A to B. A B

68 68 Abyssomicin C – synthesis by Nicolaou. Approach depends on early synthesis of bicyclic part then coupling to aldehyde, and a metathesis: K. C. Nicolaou and S. T. Harrison. J. Am. Chem. Soc. 2007, 129, Key step is from A to B. A B

69 69 7) Enantioselective strategies which may include biotin,  -arylpropionic acids, menthol, zaragozic acid, statins (nb statins and zaragozic acids mentioned in MT course).

70 70 A total synthesis of Biotin.. E. G. Baggiolini, H. L. Lee, G. Pizzolato, M. R. Uskoković, J. Am. Chem. Soc. 1982, 104, 6460.

71 71  -Arylpropionic acids Several classes of asymmetric catalysts can do this.

72 72 Zaragozic acid synthesis – key asymmetric dihydroxylations.

73 73 Zaragozic acid synthesis – continued. Reference: a) K. C. Nicolaou. E. W. Yue, Y. Naniwa, F. DeRiccardis, A. Nadin, J. E. Leresche. S. LaGreca. Z. Yang, Angew. Chem. Int. Ed. 1994, 33, b) K. C. Nicolaou, A. Nadin, J. E. Leresche, S. LaCreca, T. Tsuri. E. W. Yue, Z. Yang, Angew. Chem. Int. Ed. 1994,

74 74 Menthol is prepared through an ene reaction: This uses a mild Lewis acid. The chirality of the product comes entirely from the single chiral centre of the starting material, itself made by an asymmetric isomerisation reaction. This method was developed by Takasago, developed in collaboration with R. Noyori – BASF have a similar strategy. S.-I. Inoue, H. Takaya, K. Tani, S. Otsuka, T. Saito and R. Noyori, J. Am. Chem. Soc. 1990, 112, 4897.

75 75 Statins - selected for closer attention.

76 76 Synthetic approaches to statins; An early approach to compactin from M. Hirama and M. Uei. M. Hirama and M. Uei, J. Am. Chem. Soc. 1982, 104,

77 77 Hirama and Uei, J. Am. Chem. Soc. 1982, 104, Last steps include i) deprotection of the OBn to OH, then oxidation, ii) deprotection iii) cyclisation to the lactone Key steps is from A to B and B to C. BC A

78 78 Synthetic approaches (+)-dihydrocompactin where remote stereocontrol is achieved. T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, Key step is from A to B. A B

79 79 Synthetic approaches (+)-dihydrocompactin – completion of synthesis. T. Sammakia, D. J. Johns, G. Kim and M. A. Berliner, J. Am. Chem. Soc. 2005, 127, Key step is from A to B. A B

80 80 Statins - An approach to a subunit involving organocatalysis and a metathesis. J. Robichaud and F. Tremblay, Org. Lett. 2006, 8, Key step is from A to B. A B


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