The document summarizes the formal synthesis of (−)-clavosolide A, a natural product with a highly functionalized 16-membered macrocyclic structure containing 14 stereocenters. The synthesis involved initial retrosynthetic analyses, exploration of various reaction strategies reported in literature for constructing key structural motifs, and development of a revised retrosynthetic route involving D-malic acid as the starting material. Key steps included preparation of an auxiliary, aldehyde synthesis, lactone formation, and generation of the C9 diastereomeric monomer.

1. Target Oriented Synthesis via Oxocarbenium Cations: The Formal Synthesis of ( − )-Clavosolide A Jesse D. Carrick, Ph.D. The University of Alabama

2. The Importance of Natural Products Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod. 2003 , 66, 1022. KEY: B = Biological (peptidic > 45 residues) N = Natural product ND = Natural product derivative (usually semisynthetic) S = Completely synthetic compound S* = Completely synthetic compound (natural product pharmacophore) V = Vaccine ~90% of pharmaceuticals are natural products, derivatives, or purely synthetic by design Origin of Drug Indication Total B N ND S S* V antibacterial 90 9 61 19 1 anticancer 79 12 9 21 25 10 2 antihypertensive 75 1 40 34 antiinflammatory 50 1 13 36 antiviral 35 2 1 8 24 antiulcer 32 1 1 12 18 antithrombotic 28 13 1 5 7 2 antifungal 24 1 2 21 antidiabetic 23 12 1 2 7 1 antidepressant 21 19 2 hormone 20 10 10 Ca 2+ metabolism 17 8 9 antiallergic 15 1 3 11 Totals 868 91 40 209 386 131 11

3. Public Health Relevance http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/102008/500221/article.pdf

4. Complementary C -Glycosides via Oxocarbenium Cations Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982 , 104, 4976.

5. (−)-Clavosolide A (a) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002 , 65, 386-388. (b) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.; Boyd, M. R. J. Nat. Prod. 2002 , 65, 1303. (c) http://www.robertosozzani.it/Walea/Varie/spugna01.shtml

7. Willis Synthesis Original communication: Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding, J. R.; Willis, C. L. Chem. Commun. 2005, 40, 5097-5099. Also see: Barry, C. S.; Elsworth, J. D.; Seden, P. T.; Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett. 2006 , 8, 3319-3322.

8. Lee Synthesis Original communication: Son, J. B.; Kim, S. N.; Kim, N. Y. and D. H. Lee Org. Lett. 2006 , 8, 661-664. Addition and correction: Lee, H. D.; Kim, N. Y.; Kim, S. N.; Son, J. B. Org. Lett. 2006 , 8, 3411-3413.

9. Smith Synthesis Simov, V.; Smith, A. B. III Org. Lett. 2006 , 8, 3315-3318.

10. Chakraborty Synthesis Original communication: Chakraborty, K. T.; Reddy, R. V. Tetrahedron Lett. 2006 , 2099-2101. Completion of the Total Synthesis: Chakraborty, T. K.; Reddy, V. R.; Chattopadhyay, A. K. Tetrahedron Lett. 2006 , 7435-7438. An alternate synthesis of the aglycon monomer was described by: Yakambram, P.; Puranik, V.; Gurjar, M. Tetrahedron Lett. 2006 , 22, 3781.

11. Initial Retrosynthetic Analysis

12. Initial Retrosynthetic Analysis

13. Initial Efforts (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997 , 119, 7883-7884. (b) Gopinath, R.; Patel, B. K. Org. Lett. 2000 , 2, 4177-4180. (c) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997 , 62, 6974-6977. (d) Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983 , 105, 2487-2489. (e) Anwar, S.; Davis, A. P. Tetrahedron 1988 , 44, 3761-3770.

14. 1,5- anti Aldol Ketone Synthesis (a) Ong, B. S. Tetrahedron Lett. 1980 , 21, 4225-4228. Chan, T. H.; Brook, M. A.; Chally, T. Synthesis 1983 , 203-205. (b) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc. Chem. Comm. 1987 , 1625-1627. (c) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993 , 115, 11446-11459. Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1998 , 110, 2506-2526. (d) Willis, C. L. Tetrahedron Lett. 1999 , 40, 4093-4096.

15. 1,5- anti Aldol Ketone Synthesis

16. 1,5- anti Aldol Ketone Synthesis (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000 , 122, 12003-12004. (b) Trost, B. M., Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001 , 123, 3367-3368. (c) Trost, B. M.; Fettes, A.; Shireman, B. J. J. Am. Chem. Soc. 2004 , 126, 2660-2661. (d) Bercich, M. D.; Cambie, R. C.; Rutledge, P. S. Aust. J. Chem. 1999 , 52, 851-859. (e) Danishefsky, S. J.; Harvey, D. F.; Quallich, G.; Uang, B. J. J. Org. Chem. 1984 , 49, 393-395. (f) Danishefsky, S. J. Uang, B. J.; Quallich, G. J. Am. Chem. Soc. 1985 , 107, 1285-1293.

17. Revised Retrosynthetic Analysis

18. Revised Route from D -Malic Acid (a) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003 , 5, 1147-1150. (b) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997 , 62, 6974-6977. (c) Smith, A.B., III; Chen, S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997 , 119, 10935-10946. (d) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1998 , 110, 2506-2526.

19. Revised Route from D -Malic Acid (a) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003 , 5, 1147-1150. (b) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997 , 62, 6974-6977. (c) Smith, A.B., III; Chen, S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997 , 119, 10935-10946. (d) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1998 , 110, 2506-2526.

20. Revised Route from D -Malic Acid (a) Sneddon, H. F.; Gaunt, M. J.; Ley, S. V. Org. Lett. 2003 , 5, 1147-1150. (b) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997 , 62, 6974-6977. (c) Smith, A.B., III; Chen, S.-Y.; Nelson, F. C.; Reichert, J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1997 , 119, 10935-10946. (d) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1998 , 110, 2506-2526.

21. Revised Route from D -Malic Acid

22. Revised Retrosynthetic Analysis

23. Preparation of the Phillips Auxiliary Guz, N. R.; Phillips, A. J. Org. Lett. 2002 , 4, 2253-2256.

24. Aldehyde Synthesis (a) Guz, N. R.; Phillips, A. J. Org. Lett. 2002 , 4, 2253-2256. (b) Crimmins, , M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc. 1997 , 119, 7883-4. (c) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981 , 22, 3815-3818. (d) Sibi, M. P. Org. Prep. Proced. Int. 1993 , 25, 15-40. (e) Mentzel, M.; Hoffman, H. M. R. J. Prakt. Chem. 1997 , 339, 517-524. (f) Singh, J.; Satyamurthi, N.; Aidhen, I. S. J. Prakt. Chem. 2000 , 342, 340-347. (g) Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003 , 7, 967-993. (h) Charette, A.; Label, H. J. Org. Chem. 1995 , 60, 2966. (i) Evans, D. A.; Trenkle, W. C.; Zhang, J.; Burch, J. D. Org. Lett. 2005 , 7, 3335-3338.

25. Lactone Synthesis (a) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Komiyama, K.; Omura, S. J. Am. Chem. Soc. 1996 , 118, 8308-8315. (b) Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1996 , 118, 8316-8328. (c) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004 , 6, 525-528. (d) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993 , 115, 11446-11459. (e) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1998 , 110, 2506-2526. (f) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987 , 28, 6141-6144. (g) Damon, R. E.; Coppola, G. M. Tetrahedron Lett. 1990 , 31, 2849-2852.

26. Exploration of Protection Conditions

27. Mitsunobu Inversion Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006 , 106, 911-930.

28. Mitsunobu Inversion Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006 , 106, 911-930.

29. Kishi Lactone Alkylation/Reduction (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982 , 104, 4976. (b) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005 , 46, 2021. (c) Ding, F.; Jennings, M. P. Org. Lett. 2005 , 7, 2321. (d) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007 , 48, 5177-5180. (e) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007 , 72 , 6621-6623. (f) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006 , 71, 7911-7914.

30. C 9 Diastereomer Monomer Synthesis (a) Lindgren, B. O.; Nilsson, T. Acta Chemica Scandinavica 1973 , 27, 888-90. (b) Bal, B. S.; Childers, W. E., Jr., Pinnick, H. W. Tetrahedron 1981 , 37, 2091-6. (c) Overman, L. E.; Paone, D. V. J. Am. Chem. Soc. 2001 , 123, 9465-7.

31. Deja Vu

32. β - C - Glycoside Oxidation/Reduction

33. Hemi -Ketal Oxidation/Reduction

34. Early C 9 Inversion

35. Correct C 9 Aldehyde Synthesis

36. Correct C 9 Lactone Synthesis

37. Exploration of Protection Conditions

38. Kishi Lactone Alkylation/Reduction (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982 , 104, 4976. (b) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005 , 46, 2021. (c) Ding, F.; Jennings, M. P. Org. Lett. 2005 , 7, 2321. (d) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007 , 48, 5177-5180. (e) Solorio, D. M.; Jennings, M. P. J. Org. Chem. 2007 , 72 , 6621-6623. (f) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006 , 71, 7911-7914.

39. Monomer Completion Paquette, L. A.; Barriault, L.; Pissarnitski, D.; Johnston, J. N. J. Am. Chem. Soc. 2000 , 122, 629-631.

40. Formal Synthesis Completion 1. Carrick, J. D.; Jennings, M. P. Org. Lett. 2009 , 11, 769-772.

41. (−)-Lasonolide A Oxocarbenium (a) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007 , 48, 5177-5180. Also see: (b) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006 , 47, 939-942. Lett. 2007 , 48, 5177-5180.

42. (−)-Dactylolide Oxocarbenium Ding, F.; Jennings, M. P. Org. Lett. 2005 , 7, 2321-2324.

43. (−)-Clavosolide A: Mismatched Case?

47. Supplementary Information

48. Brown Allylboration Transition State (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983 , 105, 2092-2093. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986 , 108, 5919-5923. (c) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991 , 56, 401-404.

49. Evans Aldol Transition States Evans, D. A. J. Am. Chem. Soc. 1981 , 103, 2876. Also see: Evans, D. A. J. Am. Chem. Soc. 1981 , 103, 3099.

50. Transition State Equilibria Crimmins, M. T. J. Am. Chem. Soc. 1997 , 119, 7883-7884.

51. Proposed Transition State

52. Initial Acetate Aldol Endeavors (a) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000 , 122, 12003-12004. (b) Trost, B. M., Ito, H.; Silcoff, E. R. J. Am. Chem. Soc. 2001 , 123, 3367-3368. (c) Trost, B. M.; Fettes, A.; Shireman, B. J. J. Am. Chem. Soc. 2004 , 126, 2660-2661. (d) Bercich, M. D.; Cambie, R. C.; Rutledge, P. S. Aust. J. Chem. 1999 , 52, 851-859. (e) Danishefsky, S. J.; Harvey, D. F.; Quallich, G.; Uang, B. J. J. Org. Chem. 1984 , 49, 393-395. (f) Danishefsky, S. J. Uang, B. J.; Quallich, G. J. Am. Chem. Soc. 1985 , 107, 1285-1293.

53. Trost Dicoordinate Zinc Reagent

54. Initial Acetate Aldol Endeavors (a) Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J. Org. Chem. 2000 , 65, 1702-1706. (b) Wessjohann, L.; Gabriel, T. J. Org. Chem. 1997 , 62, 3772-3774. (c) Gabriel, T.; Wesjohann, L. Tetrahedron Lett. 1997 , 38, 1363-1366. (d) Wipf, P.; Uto, Y.; Yoshimura, S. Chem. Eur. J. 2002 , 8, 1670-1681.

55. Intramolecular Silyl Allylation Reetz, M. T.; Jung, A.; Bolm, C. Tetrahedron. 1988 , 44, 3889-3898.

56. Intramolecular Silyl Allylation Reetz, M. T.; Jung, A.; Bolm, C. Tetrahedron. 1988 , 44, 3889-3898.

57. Intramolecular Hydrosilylation

58. A Logical Extension