Total synthesis of ingenol

Journal of the American Chemical Society

Volumn 126, Issue 50, 2004, Pages 16300-16301

  Nickel, Andrew ^a   Maruyama, Toru ^a   Tang, Haifeng ^a   Murphy, Prescott D ^a   Greene, Blake ^a   Yusuff, Naeem ^a   Wood, John L ^a  

^a YALE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INGENOL;

ARTICLE; CATALYST; DRUG STRUCTURE; RING CLOSING METATHESIS; RING OPENING; STEREOCHEMISTRY; SYNTHESIS;

ALLYL COMPOUNDS; DITERPENES; MODELS, MOLECULAR; SULFONES;

EID: 11444258937     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja044123l     Document Type: Article

References (28)

1. Initial isolation and characterization: (a) Hecker, E. Cancer Res. 1968, 28, 2338-2349. (b) Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 11, 4075-4078.
2. Initial isolation and characterization: (a) Hecker, E. Cancer Res. 1968, 28, 2338-2349. (b) Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. Tetrahedron Lett. 1970, 11, 4075-4078.
3. For a review on in/out isomerism, see: Alder, R. W.; East, S. P. Chem. Rev. 1996, 96, 2097-2111.
4. See Blañco-Molina, M.; Tron, G. C.; Macho, A.; Lucena, C.; Calzado, M. A.; Munoz, E.; Appendino, G. Chem. Biol. 2001, 8, 767-778 and references therein.
5. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
6. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
7. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
8. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
9. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
10. There have been two previous total syntheses: (a) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124, 9726-9728. (b) Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-1500. For a formal total synthesis, see: (c) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802-7808. For successful construction of the ingenane "inside-outside" skeleton, see: (d) Funk, R. L.; Olmstead, T. A.; Parvez, M.; Stallman, J. B. J. Am. Chem. Soc. 1993, 58, 5873-5875. (e) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett. 2001, 3, 1563-1566. (f) Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799-801.
11. Prepared as a single enantiomer in five steps from commercially available 3-carene: Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298-3300.
12. Prepared in an analagous manner to 3. See Supporting Information.
13. The conversion of 5 to 6 required the Hoveyda modified second generation Grubbs catalyst for acceptable yields. See: Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168-8179.
14. Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526-5528.
15. Disanayaka, B. W.; Weedon, A. C. Synthesis 1983, 952.
16. 2O, DIBAL, or L-selectride, none of the desired syn diol was detected.
17. Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26, 387-399.
18. For recent reviews, see: (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595-1615. (b) Clennan, E. L. Tetrahedron 2000, 56, 9151-9179.
19. For recent reviews, see: (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595-1615. (b) Clennan, E. L. Tetrahedron 2000, 56, 9151-9179.
20. 2, hv, and either rose bengal, TPP, or methylene blue in suitable solvents.
21. A similar epoxide-opening approach also proved unsuccessful for the Kuwajima group. See ref 4b.
22. Sulfones 22 and 23 were isolated as a 1:1 mixture. For a leading reference of the isomerizion of α,β-unsaturated sulfones to β,γ-unsaturated sulfones, see: (a) O'Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840-3846. For recent examples of one-pot epoxide-opening/isomerization of β,γ-epoxysulfones, see: (b) Trost, B. M.; Acemoglu, M. Tetrahedron Lett. 1989, 30, 1495-1498. (c) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 2861-2864. (d) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619-622.
23. Sulfones 22 and 23 were isolated as a 1:1 mixture. For a leading reference of the isomerizion of α,β-unsaturated sulfones to β,γ-unsaturated sulfones, see: (a) O'Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840-3846. For recent examples of one-pot epoxide-opening/isomerization of β,γ-epoxysulfones, see: (b) Trost, B. M.; Acemoglu, M. Tetrahedron Lett. 1989, 30, 1495-1498. (c) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 2861-2864. (d) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619-622.
24. Sulfones 22 and 23 were isolated as a 1:1 mixture. For a leading reference of the isomerizion of α,β-unsaturated sulfones to β,γ-unsaturated sulfones, see: (a) O'Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840-3846. For recent examples of one-pot epoxide-opening/isomerization of β,γ-epoxysulfones, see: (b) Trost, B. M.; Acemoglu, M. Tetrahedron Lett. 1989, 30, 1495-1498. (c) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 2861-2864. (d) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619-622.
25. Sulfones 22 and 23 were isolated as a 1:1 mixture. For a leading reference of the isomerizion of α,β-unsaturated sulfones to β,γ-unsaturated sulfones, see: (a) O'Connor, D. E.; Lyness, W. I. J. Am. Chem. Soc. 1964, 86, 3840-3846. For recent examples of one-pot epoxide-opening/isomerization of β,γ-epoxysulfones, see: (b) Trost, B. M.; Acemoglu, M. Tetrahedron Lett. 1989, 30, 1495-1498. (c) Lee, S. W.; Fuchs, P. L. Tetrahedron Lett. 1991, 32, 2861-2864. (d) Ohtani, Y.; Shinada, T.; Ohfune, Y. Synlett 2003, 619-622.
26. 20-Deoxyingenol (24) is a natural product: (a) Uemura, D.; Ohwaki, H.; Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 15, 2527-2528. The intermediate 3,4-O-isopropylidene of 24 is a previously reported natural product derivative: (b) Gotta, H.; Adolf, W.; Opferkuch, H. J.; Hecker, E. Z. Naturforsch. 1984, 39b, 683-694. This is the first total synthesis of 24, and its first structural confirmation by X-ray crystallographic analysis.
27. 20-Deoxyingenol (24) is a natural product: (a) Uemura, D.; Ohwaki, H.; Hirata, Y.; Chen, Y.-P.; Hsu, H.-Y. Tetrahedron Lett. 1974, 15, 2527-2528. The intermediate 3,4-O-isopropylidene of 24 is a previously reported natural product derivative: (b) Gotta, H.; Adolf, W.; Opferkuch, H. J.; Hecker, E. Z. Naturforsch. 1984, 39b, 683-694. This is the first total synthesis of 24, and its first structural confirmation by X-ray crystallographic analysis.
28. Chromatographically and spectroscopically identical to an authentic sample (Sigma).