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Yassir EL-AZIZI Literature meeting A. Charette group 15 Feb. 2005

Statins Family: Cholesterol-Lowering Drugs. Yassir EL-AZIZI Literature meeting A. Charette group 15 Feb. 2005. Statins Family: Cholesterol-Lowering Drugs. Statin drugs constituted 6% of the total annual sale of the top 200 drugs in 1999 , worth $125 billion in the USA.

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Yassir EL-AZIZI Literature meeting A. Charette group 15 Feb. 2005

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  1. Statins Family: Cholesterol-Lowering Drugs Yassir EL-AZIZI Literature meeting A. Charette group 15 Feb. 2005

  2. Statins Family: Cholesterol-Lowering Drugs • Statin drugs constituted 6% of the total annual sale of the top 200 drugs in 1999, worth $125 billion in the USA. MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, 2004, 82, Number 24, 47-62

  3. Statins Family: Cholesterol-Lowering Drugs OUTLINE • Introduction • Cholesterol biosynthesis • The missing members of the family • Merck reduction of complexity of natural statins • Synthetic Statins • Exemple of industrail synthesis: Lescol

  4. Statins Family: Cholesterol-Lowering Drugs

  5. Statins : Natural and Natural-like structures

  6. Statins : Natural and Natural-like structures common main polyketide portion hexahydro naphthalene ring system ‘…the mechanism involved in the control of endogenous cholesterol levels by statins makes these molecules suitable for therapeutic use…, Different types of statins are currently available: the natural statins obtained directly by fermentation, and the semi-synthetic and synthetic statins . Cerivastatin, a fully synthesized statin approved in the United States in 1997, has been employed until the recent withdrawal from the market. ’ * Mini review Manzoni* M, Rollini M., ‘Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs’,Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-64.

  7. Statins Family: Cholesterol-Lowering Drugs OUTLINE • Introduction • Cholesterol biosynthesis • The missing members of the family • Merck reduction of complexity of natural statins • Synthetic Statins • Exemple of industrail synthesis: Lescol

  8. The Mevanolate Pathway: Cholesterol Biogenesis The biosynthesis of cholesterol and isoprenoids (a group of compounds responsible for cell fluidity and cell proliferation) 5-pyrophosphomevalonate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene 2,3-oxidosqualene

  9. Natural statins Manzoni M, Rollini M., ‘Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs’,Appl. Microbiol. Biotechnol. 2002 Apr.;58(5):555-564.

  10. Statins Family: Cholesterol-Lowering Drugs OUTLINE • Introduction and problematic • Cholesterol biosynthesis • The missing members of the family • Merck reduction of complexity of natural statins • Synthetic Statins • Exemple of industrail synthesis: Lescol

  11. Total synthesis of natural and natural-like statins common main polyketide portion Hexahydro or Octahydro naphthalene ring system Hexaline or octaline

  12. Synthetic statins, The missing members of the family… • Synthetic studies • Danishefsky, S.; Kerwin, J. F., Jr.; Kobayashi, S. J. Am. Chem. Soc. 1982, 204, 358. • Funk, R. L.; Zeller, W. E. J. Org. Chem. 1982,47, 180. • Deutsch, E. A.; Snider, B.B. J. Org. Chem. 1982, 47, 2682. • Prugh, J. D.; Deana, A. A. Tetrhedron Lett. 1982,23, 281. • Yang, Y.-L.; Falck, J. R. Tetrahedron Lett. 1982, 23,4305. • Heathcock, C. H.; Taschner, M. J.; R a n , T.; Thomas, J. A.; Hadley, C. R.; Popjak, G. Tetrahedron Lett. 1982, 23,4747. • Lee, T.-J.; Holtz, W. J.; Smith, R. L. J. Org. Chem. 1982,47,4750. MERCK • Anderson, P. C.; Clive, D. L. J.; Evans, C. F. Tetrahedron Lett. 1983, 24, 1373. • Kuo, C. H.; Patchett, A. A,; Wendler, N. L. J. Org. Chem. 1983, 48, 1991. • Deutsch, E. A,; Snider, B. B.Tetrahedron Lett. 1983, 24, 3701. • Funk, R. L.; Mossman, C. J.; Zeller, W. E. Tetrahedron Lett. 1984, 25, 1655. • Majewski, M.; Clive, D. L. J.; Anderson, P. C. Tetrahedron Lett. 1984, 25, 2101. • Prasad, K.; Repic,O. Tetrahedron Lett. 1984,25, 2435. NOVARTIS • R a n , T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1984, 49, 3994. • Rosen, T.; Taschner, M. J.; Heathcock, C. H. J. Org. Chem. 1985, 50, 1190. • Burke, S. D.; Saunders, J. 0.; Oplinger, J. A.; Murtiashaw, C. W. Tetrahedron Lett. 1985, 26, 1131. • Guindon, Y.; Yoakim, C.; Bernstein, M. A,; Morton, H. E. Tetrahedron Lett. 1985, 26, 1185. • Kozikowski, A. P.; Li, C.3. J. Org. Chem. 1985, 50, 778. Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.

  13. Deutsh and Sinder approach to Hexaline system Deutsch, E. A.; Snider, B. B.,J.Org. Chem. 1982, 47, 2682.

  14. Heatcock approach to the Octaline system, Total synthesis of (+) Dihydromevinolin Re Face of the dienophile Hecker,S.; Heathcock, C. H.J. Am. Chem. Soc. 1986, 108, 45861.

  15. Heatcock approach to Octaline system, Total synthesis of (+) Dihydromevinolin

  16. Heatcock approach to Octaline system Review: Rosen, Terry; Heathcock, Clayton H.. ‘The synthesis of mevinic acids’. Tetrahedron (1986), 42(18), 4909-51.

  17. Statins Family: Cholesterol-Lowering Drugs OUTLINE • Introduction and problematic • Cholesterol biosynthesis (what can we learn from a biochemical process?) • The missing members of the family • Merck reduction of complexity of natural statins • Synthetic Statins • Exemple of industrail synthesis: Lescol

  18. Semi- synthetic statins, Modifications of Lovastatin • New drug design approaches are geared towards making lovastatin analogs that will have longer interaction with the enzyme –increase duration of drug occupancy of active site. • Structural modification: (Lee, et. al. 1982, Merck & Co) • Structural modification and simplification: (Hoffman*, Stokker**, et. al. 1985, Merck & Co) • suppression of the hexahydro-naphtaline system • Progress toward the introduction of the (3 ,5-Disubstituted [ l, l’-biphenyl] system

  19. Synthetic statins, Hoffman- Stokker Modifications I Hoffman, Stokker et al, J. Med. Chem. 1986, 28, 347-358

  20. Synthetic statins, Hoffman- Stokker Modifications II Hoffman, Stokker, J. Med. Chem. 1986,29, 170-181

  21. Statins Family: Cholesterol-Lowering Drugs OUTLINE • Introduction and problematic • Cholesterol biosynthesis (what can we learn from a biochemical process?) • The missing members of the family • Merck reduction of complexity of natural statins • Synthetic Statins • Exemple of industrail synthesis: Lescol

  22. Semi- synthetic statins

  23. Statins Family: Common side chain

  24. Statins side chain, H. C. Brown approach • Yields: • Allylboration with (-)-B-allyldiisopinacocamphenylborane 71-76% • Esterification 80% • RCM up to 84% • Epoxydation 86% • 1,3-reduction of the epoxyde 87% • (Miyashita conditions,ee up to 92%, 99% after recrystallization) • ‘It is believed that this reduction proceeds via the formation of PhSeH’ (a) M. Venkat Ram Reddy, Herbert C. Brown*, P. Veeraraghavan Ramachandran*, J. Organomet. Chem. 624 (2001) 239–243. (b)P. Veeraraghavan Ramachandran*, Kamlesh J. Padiya, Vivek Rauniyar, M. Venkat Ram Reddy, Herbert C. Brown*, J. Fluorine Chem. 125 (2004) 615–620.

  25. Regioselective 1,3 reduction of epoxyde M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikishi, Tetahedron, 53, 12469

  26. Statins Family: Common side chain

  27. Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach • Arun K. Ghosh* and Hui Lei, ‘Chelation-Controlled Reduction: Stereoselective Formation of syn-1,3-Diols and Synthesis of Compactin and Mevinolin Lactone’, J. Org. Chem., 2002, 67, 8783-8788. • Narasaka*, K.; Pai, F., Tetrahedron 1984, 40, 2223. • (c) Chen, K.-M.; Hardtmann, G. E.; Prasad*, K.; Repic*, O.; Shapiro, M., Tetrahedron Lett. 1987, 28, 155. (Novartis) • ,

  28. Statins side chain, Narasaka(84), Prasad(87), Ghosh(2002) approach • Arun K. Ghosh* and Hui Lei, ,J. Org. Chem., 2002, 67, 8783-8788. • ,

  29. Statins Family: Common side chain

  30. Statins side chain, Via IodolactonizationSubstarte controlled (a) Stanislav Ràdl,* Jan Stach and Josef Hajicek, Tetrahedron Letters, 43 (2002) 2087–2090 (b) Butler, D. E.; Deering, C. F.; Millar, A.; Nanninga, T. N.; Roth, B. D. (Warner-Lambert Co.) US Patent 5,245,047.

  31. Reagent Controlled Iodolactonizations are rare… Haas, J.; Piguel, S.; Wirth*, T. Org. Lett. 2002, 2, 297 – 300. Wang, M.; Gao*, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J. Org. Chem. 2004, 69, 2874 – 2876.

  32. Reagent Controlled Iodolactonizations are rare… Kang, S. H.; Lee, S. B.; Park, C. H. J. Am. Chem. Soc. 2003, 125, 15748 – 15749.

  33. Statins Family: Common side chain

  34. Statins side chain, Other methods… O. Repic. K. Prasad, Org. Pro. R&D, 2001, 5, 519

  35. Statins Family: Common side chain

  36. Stereoselective synthesis vs. traditional chemistry ‘Despite the unrelenting pace of research in catalytic asymmetric chemistry, relatively few catalytic enantioselective processes are currently operated on a commercial scale. Until more bio- and chemocatalytic chiral routes are developed that are robust and cost-effective for large-scale production, the bulk of optically pure compounds will have to be prepared through traditional chemistry, including conventional syntheses based on chiral substrates or stoichiometric chiral induction and separations, such as chromatographic resolutions’. MAUREEN ROUHI MAUREEN ROUHI, ‘CHIRAL CHEMISTRY’, C&EN News, June 14, 2004, Volume 82, Number 24, p. 47-62

  37. Statins side chain, Chemo-Enzymatic approach DERA After 15 h, product isolated in 96% yield (98.5%ee), 619 g.L-1d-1. Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365

  38. Statins side chain, Chemo-Enzymatic approach Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365

  39. Statins side chain, Chemo-Enzymatic approach (α-Chymotrypsine-BioFac) Highly scalable process (400g in one batch) R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)

  40. Statins side chain, Chemo-Enzymatic approach PLE: Pig liver esterase ‘This so called ‘aza’-W ittig reaction, which proceeds via an imine intermediate is promoted by a phosphine reagent and a weak, sterically hindered acid’. R. Öhrlein R. Öhrlein*, G. Baisch, Adv. Synth. Catal., 2003, 345, 713 -715 (CIBA)

  41. Statins side chain, Chemo-Enzymatic approach DERA Michael Muller, Angew. Chem. Int. Ed., 2005, 44, 362 –365

  42. Statins side chain, Total- Enzymatic approach ~‘Absolute’ stereo control >99.9% ee, >96.6% de (a) Junjie Liu, Che-Chang Hsu and Chi-Huey Wong* , Tetrahedron Letters, 45 (2004) 2439–2441. Scripps RI, La Jolla. 10 dec 2003 (Early work since 1994) (b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.14 Nov. 2003

  43. Statins side chain, Total -Enzymatic approach (b) W. A. Greenberg*, A. Varvak, S. R. Hanson, K. Wong, H. Huang, P. Chen, and M. J. Burk*, PNAS, April 20, 2004 vol. 101 no. 16,5788–5793. Diversa Co.

  44. Statins side chain, Direct Cross Aldol approach Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799

  45. Statins side chain, Direct Cross Aldol approach Alan B. Northrup and David W. C. MacMillan*, J. Am. Chem. Soc. 2002, 124, 6798-6799

  46. Statins side chain, Direct Aldol approach Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154

  47. Statins side chain, Direct Aldol approach Alan B. Northrup, Ian K. Mangion, Frank Hettche, and David W. C. MacMillan* ,Angew. Chem. Int. Ed. 2004, 43, 2152 –2154

  48. Statins side chain, Direct Aldol approach (…) Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579

  49. Statins side chain, Direct Aldol approach (…) Review: S. Saito*, H. Yamamoto*, Acc. Chem. Res. 2004, 37, 570-579

  50. Houk/ List Model for Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions… Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475 – 2479.

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