The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: Rational modifications imparting PP1 selectivity

Bioorganic and Medicinal Chemistry

Volumn 7, Issue 3, 1999, Pages 543-564

  Aggen, James B ^a   Humphrey, John M ^a,d   Gauss, Carla Maria ^a   Huang, Hsien Bin ^b   Nairn, Angus C ^c   Chamberlin, A Richard ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b TZU CHI UNIVERSITY   (Taiwan)

^c ROCKEFELLER UNIVERSITY   (United States)

^d PFIZER INC   (United States)

Author keywords

Inhibitor; Microcystin; PP1; PP2A; Selective

Indexed keywords

CYANOGINOSIN; PHOSPHOPROTEIN PHOSPHATASE 1; PHOSPHOPROTEIN PHOSPHATASE 2A; PHOSPHOPROTEIN PHOSPHATASE INHIBITOR;

CHEMICAL MODIFICATION; DRUG DESIGN; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PURIFICATION; REACTION ANALYSIS; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; REVIEW; STRUCTURE ACTIVITY RELATION;

EID: 0033018801     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0968-0896(98)00254-5     Document Type: Article

References (108)

1. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
2. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
3. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
4. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
5. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
6. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
7. For a recent review on inhibitors of PP1/PP2A, see: (a) Sheppeck, J. E.; Gauss C.-M.; Chamberlin A. R. Bioorg. Med. Chem. 1997, 5, 1739. For recent examples of the use of natural product PP1/PP2A inhibitors to study the biological processess, see: (b) Sontag, E.; Sontag, J. M.; Garcia, A. EMBO J. 1997, 16, 5662. (c) Meisinger, J.; Patel, S.; Vellody, K.; Bergstrom, R.; Benefield, J.; Lozanzo, Y.; Young, M. R. I. Cancer Lett. 1997, 111, 87. (d) Brockdorff, J.; Nielsen, M.; Dobson, P.; Geisler, C.; Ropke, C.; Svedjgaard, A., Odum, N. Tissue Antigens 1997, 49, 228. (e) Favre, B.; Turowski, P.; Hemmings, B. A. J. Biol. Chem. 1997, 272, 13856. (f) Sansom, S. C.; Stockland, J. D.; Hall, D.; Williams, B. J. Biol. Chem. 1997, 272, 9902. (g) Hernandez, M. L.; Martinez, M. J.; Lopez de Heredia, M.; Ochoa, B. Biochim. Biophys. Acta 1997, 1349, 233.
8. For reviews on the roles of PP1 and PP2A in cellular processes, see: (a) Rusnak, F.; Yu, L. A.; Mertz, P. J. Biological Inorg. Chem. 1996, 1, 388. (b) Stark, M. J. R. Yeast 1996, 12, 1647. (c) Schonthol, A. H. Seminars in Cancer Biol. 1995, 6, 239. (d) Wera, S.; Hemmings, B. A. Biochem. J. 1995, 311, 17. (e) Shenolikar, S. Annu. Rev. Cell Biol. 1994, 10, 55.
9. For reviews on the roles of PP1 and PP2A in cellular processes, see: (a) Rusnak, F.; Yu, L. A.; Mertz, P. J. Biological Inorg. Chem. 1996, 1, 388. (b) Stark, M. J. R. Yeast 1996, 12, 1647. (c) Schonthol, A. H. Seminars in Cancer Biol. 1995, 6, 239. (d) Wera, S.; Hemmings, B. A. Biochem. J. 1995, 311, 17. (e) Shenolikar, S. Annu. Rev. Cell Biol. 1994, 10, 55.
10. For reviews on the roles of PP1 and PP2A in cellular processes, see: (a) Rusnak, F.; Yu, L. A.; Mertz, P. J. Biological Inorg. Chem. 1996, 1, 388. (b) Stark, M. J. R. Yeast 1996, 12, 1647. (c) Schonthol, A. H. Seminars in Cancer Biol. 1995, 6, 239. (d) Wera, S.; Hemmings, B. A. Biochem. J. 1995, 311, 17. (e) Shenolikar, S. Annu. Rev. Cell Biol. 1994, 10, 55.
11. For reviews on the roles of PP1 and PP2A in cellular processes, see: (a) Rusnak, F.; Yu, L. A.; Mertz, P. J. Biological Inorg. Chem. 1996, 1, 388. (b) Stark, M. J. R. Yeast 1996, 12, 1647. (c) Schonthol, A. H. Seminars in Cancer Biol. 1995, 6, 239. (d) Wera, S.; Hemmings, B. A. Biochem. J. 1995, 311, 17. (e) Shenolikar, S. Annu. Rev. Cell Biol. 1994, 10, 55.
12. For reviews on the roles of PP1 and PP2A in cellular processes, see: (a) Rusnak, F.; Yu, L. A.; Mertz, P. J. Biological Inorg. Chem. 1996, 1, 388. (b) Stark, M. J. R. Yeast 1996, 12, 1647. (c) Schonthol, A. H. Seminars in Cancer Biol. 1995, 6, 239. (d) Wera, S.; Hemmings, B. A. Biochem. J. 1995, 311, 17. (e) Shenolikar, S. Annu. Rev. Cell Biol. 1994, 10, 55.
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15. For the preparation of our PP1/PP2A bound microcystin models, see: (a) Gauss, C. M.; Sheppeck, J. E.; Narin, A. C.; Chamberlin, A. R. Bioorg, Med. Chem. 1997, 5, 1751. For other recent modeling efforts in this area, see: (b) Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J. Biol. Chem. 1997, 272, 23312. (c) Bagu, J. R.; Sykes, B. D.; Craig, M. M.; Holmes, C. F. B. J. Biol. Chem. 1997, 272, 5087. (d) Gupta, V.; Ogawa, A. K.; Du, X.; Houk, K. N.; Armstrong, R. W. J. Med. Chem. 1997, 40, 3199.
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17. For the preparation of our PP1/PP2A bound microcystin models, see: (a) Gauss, C. M.; Sheppeck, J. E.; Narin, A. C.; Chamberlin, A. R. Bioorg, Med. Chem. 1997, 5, 1751. For other recent modeling efforts in this area, see: (b) Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J. Biol. Chem. 1997, 272, 23312. (c) Bagu, J. R.; Sykes, B. D.; Craig, M. M.; Holmes, C. F. B. J. Biol. Chem. 1997, 272, 5087. (d) Gupta, V.; Ogawa, A. K.; Du, X.; Houk, K. N.; Armstrong, R. W. J. Med. Chem. 1997, 40, 3199.
18. For the preparation of our PP1/PP2A bound microcystin models, see: (a) Gauss, C. M.; Sheppeck, J. E.; Narin, A. C.; Chamberlin, A. R. Bioorg, Med. Chem. 1997, 5, 1751. For other recent modeling efforts in this area, see: (b) Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J. Biol. Chem. 1997, 272, 23312. (c) Bagu, J. R.; Sykes, B. D.; Craig, M. M.; Holmes, C. F. B. J. Biol. Chem. 1997, 272, 5087. (d) Gupta, V.; Ogawa, A. K.; Du, X.; Houk, K. N.; Armstrong, R. W. J. Med. Chem. 1997, 40, 3199.
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37. 2 (only a trace amount by TLC after 30 min).
38. For some examples of bioactive compounds containing diaminoproprionic acid, see: (a) quisqualic acid: Pan, P. C.; Fang, S. D.; Tsai, C. C. Sci. Sin. (Engl. Ed.) 1976, 19, 691. (b) capreomycin: Herr, E. B. J.; Haney, M. E.; Pittenger, G. E.; Higgens, C. E. Proc. Indiana Acad. Sci. 1960, 69, 134. (c) bleomycin: Takita, T.; Muraoka, Y.; Yoshioka, T.; Fuji, A.; Maeda, K.; Umezawa, H. J. Antibiot. 1972, 25, 755. (d) anti- biotic A-19009: Van der Bann, J. L.; Barnick, J. W. F.; Bickelhaupt, F. J. Antibiot. 1983, 36, 784.
39. For some examples of bioactive compounds containing diaminoproprionic acid, see: (a) quisqualic acid: Pan, P. C.; Fang, S. D.; Tsai, C. C. Sci. Sin. (Engl. Ed.) 1976, 19, 691. (b) capreomycin: Herr, E. B. J.; Haney, M. E.; Pittenger, G. E.; Higgens, C. E. Proc. Indiana Acad. Sci. 1960, 69, 134. (c) bleomycin: Takita, T.; Muraoka, Y.; Yoshioka, T.; Fuji, A.; Maeda, K.; Umezawa, H. J. Antibiot. 1972, 25, 755. (d) anti- biotic A-19009: Van der Bann, J. L.; Barnick, J. W. F.; Bickelhaupt, F. J. Antibiot. 1983, 36, 784.
40. For some examples of bioactive compounds containing diaminoproprionic acid, see: (a) quisqualic acid: Pan, P. C.; Fang, S. D.; Tsai, C. C. Sci. Sin. (Engl. Ed.) 1976, 19, 691. (b) capreomycin: Herr, E. B. J.; Haney, M. E.; Pittenger, G. E.; Higgens, C. E. Proc. Indiana Acad. Sci. 1960, 69, 134. (c) bleomycin: Takita, T.; Muraoka, Y.; Yoshioka, T.; Fuji, A.; Maeda, K.; Umezawa, H. J. Antibiot. 1972, 25, 755. (d) anti- biotic A-19009: Van der Bann, J. L.; Barnick, J. W. F.; Bickelhaupt, F. J. Antibiot. 1983, 36, 784.
41. For some examples of bioactive compounds containing diaminoproprionic acid, see: (a) quisqualic acid: Pan, P. C.; Fang, S. D.; Tsai, C. C. Sci. Sin. (Engl. Ed.) 1976, 19, 691. (b) capreomycin: Herr, E. B. J.; Haney, M. E.; Pittenger, G. E.; Higgens, C. E. Proc. Indiana Acad. Sci. 1960, 69, 134. (c) bleomycin: Takita, T.; Muraoka, Y.; Yoshioka, T.; Fuji, A.; Maeda, K.; Umezawa, H. J. Antibiot. 1972, 25, 755. (d) anti-biotic A-19009: Van der Bann, J. L.; Barnick, J. W. F.; Bickelhaupt, F. J. Antibiot. 1983, 36, 784.
42. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
43. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
44. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
45. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
46. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
47. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
48. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
49. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
50. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
51. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
52. For a racemic synthesis via Michael addition, see: (a) Labia, R.; Morin, C. J. Org. Chem. 1986, 51, 249. For a preparation via the Curtius rearrangement, see: (b) Schirlin, D.; Altenburger, J. M. Synthesis 1995, 1351. For a preparation via the Schmidt rearrangement, see: (c) Wang, M.; Gould, S. J. J. Org. Chem. 1993, 58, 5176. For preparations via the Hoffman rearrangement, see: (d) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191. (e) Ruan, F.; Chen, K.; Itoh, K.; Sasaki, T.; Hopkins, P. B. J. Org. Chem. 1991, 56, 4347. (f) Waki, M.; Kitajima, Y.; Izumiya, N. Synthesis 1981, 266. (g) Lee, E. S.; Jurayi, J.; Cushman, M. Tetrahedron Lett. 1994, 50, 9873. (h) Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org. Chem. 1997, 62, 6918. For a preparation via a Mitsunobu reaction with serine, see: (i) Otsuka, M.; Kittaka, A.; Iimori, T.; Yamashita, H.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1985, 33, 509. For preparation via ring opening of serine lactone, see: (j) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105. (k) Ratemi, E. S.; Vederas, J. C. Tetrahedron Lett. 1994, 35, 7605.
53. The lactone 16 was prepared as per Vederas' procedure in ref 21k, with the exception that di-t-butylazodicarboxylate (DTAD) was used instead of DEAD or DMAD. DTAD is a relatively stable, crystalline solid that is convenient to use, and the byproduct from the lactonization is easier to remove from the product via chromatography.
54. 2O resulted in the disappearance of the two broad triplets at 5.80 ppm, and heating to 90°C resulted in sharpening the multiplet centered at 4.65 ppm to a pair of doublets that coupled each other with J = 12.5 Hz.
55. Abarghaz, M.; Kerbal, A.; Bourguignon, J. J. Tetrahedron Lett. 1995, 36, 6463.
56. (a) Namikoshi, M.; Rinehart, K. L.; Sakai, R. J. Org. Chem. 1990, 55, 6135.
57. (b) Meriluoto, J. A. O.; Nygard, S. E.; Dahlem, A. M.; Eriksson, J. E. Toxicon 1990, 28, 1439.
58. (c) Namikoshi, M.; Choi, B. W.; Sun, F.; Rinehart, K. L.; Evans, W. R.; Carmichael, W. W. Chem. Res. Toxicol. 1993, 6, 151.
59. (d) Gani, D.; Mehrotra, A. P. Tetrahedron Lett. 1996, 37, 6915.
60. (e) Mehrotra, A. P.; Webster, K. L.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1997, 2495.
61. (a) Moorhead, G.; MacKintosh, C.; Morrice, N.; Cohen, P. FEBS Lett. 1995, 362, 101.
62. (b) Moorhead, G.; MacKintosh, R. W.; Morrice, N.; Gallagher, T.; MacKintosh, C. FEBS Lett. 1994, 356, 46.
63. Campos, M.; Fadden, P.; Alms, G.; Qian, Z.; Haystead, T. A. J. J. Biol. Chem. 1996, 271, 28478.
64. Namikoshi, M.; Rinehart, K. L.; Sakai, R.; Stotts, R. R.; Dahlem, A. M.; Beasley, V. R.; Carmichael, W. W.; Evans, W. R. J. Org. Chem. 1992, 57, 866.
65. The occurance of a D-amino acid following an L-amino acid is known to be turn-inducing (see ref 37), and N-methylated amino acids, such as proline, in the i + 2 position of a β-turn is known to be turn stabilizing (ibid).
66. For a review on the synthesis of macrocyclic natural products of marine origin, see: Wipf, P. Chem. Rev. 1995, 95, 2115.
67. For reviews on the synthesis of cyclic peptides, see: (a) Kopple, K. D. J. Pharm. Sci. 1972, 61, 1345. (b) Wenger, R. M. Helv. Chim. Acta. 1984, 67, 502. (c) Ovichinikov, Y.; Chipens, G,; Ivanov, V. Peptides 1982; Walter de Gruyter: Berlin, 1983. (d) Meng, Q.; Hesse, M.; Springer-Verlag: Berlin, 1992. Also, see ref 17.
68. For reviews on the synthesis of cyclic peptides, see: (a) Kopple, K. D. J. Pharm. Sci. 1972, 61, 1345. (b) Wenger, R. M. Helv. Chim. Acta. 1984, 67, 502. (c) Ovichinikov, Y.; Chipens, G,; Ivanov, V. Peptides 1982; Walter de Gruyter: Berlin, 1983. (d) Meng, Q.; Hesse, M.; Springer-Verlag: Berlin, 1992. Also, see ref 17.
69. For reviews on the synthesis of cyclic peptides, see: (a) Kopple, K. D. J. Pharm. Sci. 1972, 61, 1345. (b) Wenger, R. M. Helv. Chim. Acta. 1984, 67, 502. (c) Ovichinikov, Y.; Chipens, G,; Ivanov, V. Peptides 1982; Walter de Gruyter: Berlin, 1983. (d) Meng, Q.; Hesse, M.; Springer-Verlag: Berlin, 1992. Also, see ref 17.
70. For reviews on the synthesis of cyclic peptides, see: (a) Kopple, K. D. J. Pharm. Sci. 1972, 61, 1345. (b) Wenger, R. M. Helv. Chim. Acta. 1984, 67, 502. (c) Ovichinikov, Y.; Chipens, G,; Ivanov, V. Peptides 1982; Walter de Gruyter: Berlin, 1983. (d) Meng, Q.; Hesse, M.; Springer-Verlag: Berlin, 1992. Also, see ref 17.
71. Trogen, G. B.; Annila, A.; Eriksson, J.; Kontteli, M.; Meriluoto, J.; Sethson, I.; Zdunek, J.; Edlund, U. Biochemistry 1996, 35, 3197.
72. Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem. 1985, 37, 1.
73. Maude, A. B.; Mehrotra, A. P.; Gani, D. J. Chem. Soc., Perkin Trans, 1 1997, 2513.
74. Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397.
75. Bodansky, M.; second ed.; Bodansky, M., Ed.; Springer-Verlag: New York, 1993, pp 187-189.
76. Merrifield, R. B.; Yang, C. C. J. Org. Chem. 1976, 41, 1032.
77. A single residue change at a remote position from an asparate changed the outcome from no imide observed to complete imide formation during a macrocyclization: Lender, A.; Yao, W.; Sprengeler, P. A.; Spanevello, R. A.; Furst, G. T.; Hirschmann, R.; Smith, A. B. Int. J. Peptide Protein Res. 1993, 42, 509.
78. Harris, C. M.; Kopecka, H.; Harris, T. M. J. Am Chem. Soc. 1983, 105, 6915.
79. Merrifield, R. B.; Wang, S. S.; Yang, C. C.; Kulesha, I. D.; Sonenberg, M. Int. J. Peptide Protein Res. 1974, 6, 103.
80. Several reports state that aspartate t-butyl esters gave imide formation under basic conditions: (a) Roeske, R. J. Org. Chem. 1963, 28, 1251. (b) Agarwal, K. L.; Kenner, G. W.; Sheppard, R. C. J. Chem. Soc. C 1968, 1384. (c) Wunsch, E.; Drees, F. Chem. Ber. 1966, 99, 110.
81. Several reports state that aspartate t-butyl esters gave imide formation under basic conditions: (a) Roeske, R. J. Org. Chem. 1963, 28, 1251. (b) Agarwal, K. L.; Kenner, G. W.; Sheppard, R. C. J. Chem. Soc. C 1968, 1384. (c) Wunsch, E.; Drees, F. Chem. Ber. 1966, 99, 110.
82. Several reports state that aspartate t-butyl esters gave imide formation under basic conditions: (a) Roeske, R. J. Org. Chem. 1963, 28, 1251. (b) Agarwal, K. L.; Kenner, G. W.; Sheppard, R. C. J. Chem. Soc. C 1968, 1384. (c) Wunsch, E.; Drees, F. Chem. Ber. 1966, 99, 110.
83. Humphrey, J. M.; Hart, J. A.; Bridges, R. J.; Chamberlin, A. R. J. Org. Chem. 1994, 59, 2467. The aspartate alkylation technology is an extension of the seminal observations of See- bach et al.: Seebach, D.; Wasmuth, D. Angew. Chem. Int., Ed. Engl. 1981, 20, 971. Aebi, J. D.; Seebach, D. Helv. Chim. Acta. 1985, 68, 1507.
84. Humphrey, J. M.; Hart, J. A.; Bridges, R. J.; Chamberlin, A. R. J. Org. Chem. 1994, 59, 2467. The aspartate alkylation technology is an extension of the seminal observations of See-bach et al.: Seebach, D.; Wasmuth, D. Angew. Chem. Int., Ed. Engl. 1981, 20, 971. Aebi, J. D.; Seebach, D. Helv. Chim. Acta. 1985, 68, 1507.
85. Humphrey, J. M.; Hart, J. A.; Bridges, R. J.; Chamberlin, A. R. J. Org. Chem. 1994, 59, 2467. The aspartate alkylation technology is an extension of the seminal observations of See- bach et al.: Seebach, D.; Wasmuth, D. Angew. Chem. Int., Ed. Engl. 1981, 20, 971. Aebi, J. D.; Seebach, D. Helv. Chim. Acta. 1985, 68, 1507.
86. 2, while the HCl and TsOH salts that we have had occasion to use were sufficiently soluble in DMF.
87. The higher yield obtained in synthesizing the N-methyl-glycine containing heptapeptide relative to the previous three heptapeptides likely reflects the greater excess of one component over the other used in the coupling. These coupling reactions are not optimized.
88. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
89. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
90. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
91. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
92. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
93. For reports on the effects of N-methylation on peptide conformation, see: (a) Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943. (b) Vitoux, B.; Aubry, A.; Cung, M. T.; Boussard, G.; Marraud, M. Int. J. Peptide Protein Res. 1981, 17, 469. (c) Dive, V.; Yiotakis, A.; Roumestand, C.; Gilquin, B.; Labadie, J.; Toma, F. Int. J. Peptide Protein Res. 1992, 39, 506. (d) Bean, J. W.; Kopple, K. D.; Peishoff, C. E. J. Am. Chem. Soc. 1992, 114, 5328. (e) Chalmers, D. K.; Marshall, G. R. J. Am Chem. Soc. 1995, 117, 5927. (f) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
94. During the natural product synthesis, a similar mixture of three isomers was obtained. Several alternative methods of saponification were attempted, but no improvement was found (see ref 12).
95. See the corresponding experimental section for details.
96. Laganis, E. D.; Chenard, B. L Tetrahedron Lett. 1984, 25, 5831.
97. Lui, H. W.; Auchus, R.; Walsh, C. T. J. Am. Chem. Soc. 1984, 106, 5335.
98. 2, see: (b) Gemal, A. L.; Luche, J. J. Org. Chem. 1979, 44, 4187.
99. 2, see: (b) Gemal, A. L.; Luche, J. J. Org. Chem. 1979, 44, 4187.
100. Stein, K. A.; Toogood, P. L. J. Org. Chem. 1979, 60, 8110.
101. Boland, W.; Frobl, C.; Lorenz, M. Synthesis 1991, 1049.
102. Just, G.; Grozinger, K. Synthesis 1976, 457.
103. Imai, J.; Torrence, P. F. J. Org. Chem. 1981, 46, 4015.
104. The problem of removing zinc from the product of Trocdeprotection has been encountered in peptide synthesis: Watanabe, H.; Kubota, M.; Yajima, H.; Tanaka, A.; Nakamura, M.; Kawibata, T. Chem. Pharm. Bull. 1974, 22, 1889.
105. In a survey of acidic conditions, we found that using 1 M citric acid, 1 M phosphoric acid, or 0.5 M glycine hydrochloride solutions with an equal volume of THF as the reaction medium, and using Zn/Cu couple as the reducing agent, resulted in smooth Troc removal with no problematic precipitation or zinc complexation detected.
106. Cohen, P.; Alemany, S.; Hemmings, B. A.; Resink, T. J.; Stralfors, P.; Tung, H. Y. Methods Enzymol. 1988, 159, 390.
107. Prinsep, M. R.; Caplan, F. R.; Moore, R. E.; Patterson, G. M.; Honkanen, R. E.; Boynton, A. L. Phytochemistry 1992, 31, 1247.
108. To identify which of the three isomers obtained corresponded with the starting di-ester, a small amount of each of these three materials was re-esterified using the general procedure outlined in the preparation of 2a. As with 2a, only the material that had eluted first from the reversed phase HPLC purification resulted in esterified material that was identical to the original di-ester.