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Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755. 2. Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435. Biological Activity:

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Presentation on theme: "Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, 5755. 2. Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435. Biological Activity:"— Presentation transcript:

1 Amphidinolide A Isolation: 1. Kobayashi, J. et al. Tetrahedron Lett. 1986, 27, Kobayashi, J. et al. J. Nat. Prod. 1991, 54, Biological Activity: L1210 murine leukemia cells human epidermoid carcinoma KB cells rabbit skeletal muscle actomysion ATPase Kobayashi, J. et al. J. Nat. Prod. 1991, 54, 1435.

2 Amphidinolide A: Pattenden’s Retrosynthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511. For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

3 Amphidinolide A: Trost’s Retrosynthesis Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421.

4 Amphidinolide A: Our Retrosynthesis Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844.

5 Synthesis of Fragment A

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7 Synthesis of Fragment C

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9 Coupling of Fragments C and D For an example synthesis of Fragment D see: Thibonnet, J. et. al. Tetrahedron Lett. 1998, 39, 4277.

10 Chelation Controlled Additions

11

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13 Elaboration of the AB Subunit

14 For leading Red-Sil references see: (a) Reed-Mundell, J. J.; Nadkarni, D. V.; Kunz, J. M., Jr.; Fry, C. W.; Fry, J. L. Chem. Mater. 1995, 7, (b) Kini, A. D.; Nadkarni, D. V.; Fry, J. L. Tetrahedron Lett. 1994, 35, (c) Fry, J. L.; Nadkarni, D. V. U. S. Patent 5,281,440, 1994.

15 The Union

16 The RCM Note: Employing the bis-phosphine catalysts solely affords the methyl ketone See: Hoye, T. R.; Zhao, H. Org. Lett. 1999, 1,

17 High Yielding Highly Selective RCM is possible

18 The Total Synthesis of Amphidinolide A?

19 Presumed Amphidinolide A Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844. Possible Reasons for the Discrepancy: (1) We screwed up. (2) Trace contamination affecting NMR data. (3) Misidentification of natural product. Spectroscopic data inconsistent with those of the natural product! 35 steps from article of commerce with a longest linear sequence of 23 steps from L-(-)-ephedrine.

20 Presumed Amphidinolide A Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844. Possible Reasons for the Discrepancy: (1) We screwed up. (2) Trace contamination affecting NMR data. (3) Misidentification of natural product. Spectroscopic data inconsistent with those of the natural product! 35 steps from article of commerce with a longest linear sequence of 23 steps from L-(-)-ephedrine.

21 Amphidinolide A: Pattenden’s Retrosynthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511. For Stille Reaction Review See: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic Reactions 1997, 50, 1–652.

22 Pattenden’s Epoxide Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511.

23 Pattenden’s Epoxide Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511.

24 Pattenden’s Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511.

25 Pattenden’s Synthesis Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41, 508–511.

26 Amphidinolide A: Trost’s Retrosynthesis Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420– % 58%

27 Presumed Amphidinolide A: Trost’s Syntheses Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028–5029. Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420– isomers

28 Presumed Amphidinolide A: Trost’s Syntheses Trost, B. M.; Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028–5029. Trost, B. M.; Chisholm, J. D.; Wrobleski, S. J.; Jung, M. J. Am. Chem. Soc. 2002, 124, 12420–12421.

29 Amphidinolide A: Another Possibility? Maleczka, R. E., Jr.; Terrell, L. R.; Geng, F.; Ward, J. S., III Org. Lett. 2002, 4, 2841–2844. Ishiyama, H.; Nakamura, Y.; Kobayashi, J. Tetrahedron 2006,62, 166–170. Trost, B. M.; et al. J. Am. Chem. Soc. 2005, 126, 13589–13610.


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