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Multistep Syntheses

  • Francis A. Carey
  • Richard J. Sundberg
Part of the Advanced Organic Chemistry book series (AOC)

Abstract

The reactions which have been discussed to this point provide the tools for synthesis of organic compounds. When the synthetic target is a relatively complex molecule, a sequence of such reactions that would lead to the desired product must be devised. At the present time, syntheses requiring 15–20 steps are common, and many that are even longer have been developed. In the planning and execution of such multistep syntheses, an important consideration is the compatibility of the functional groups that are already present in the molecule with the reaction conditions required for subsequent steps. It is frequently necessary to modify a functional group in order to prevent interference with some reaction in the synthetic sequence. One way to do this is by use of a protective group. A protective group is some derivative that can be put in place, and then subsequently removed, in order to prevent such problems. For example, alcohols are often protected as trisubstituted silyl ethers and aldehydes as acetals. The silyl group replaces the labile proton of the hydroxyl group, and the acetal group prevents unwanted nucleophilic additions at an aldehyde.

Keywords

Chiral Center Protective Group Chiral Auxiliary Synthetic Sequence Synthetic Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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General References

Protective Groups

  1. T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1981.Google Scholar
  2. J. F. W. McOmie (ed.), Protective Groups in Organic Chemistry, Plenum, New York, 1973.Google Scholar

Synthetic Equivalent Groups

  1. T. A. Hase (ed.), Umpoled Synthons, Wiley-Interscience, New York, 1987.Google Scholar
  2. D. Lednicer, Adv. Org. Chem. Methods Results 8, 179 (1972).Google Scholar
  3. D. Seebach, Angew. Chem. Int. Ed. Engl. 18, 239 (1979).CrossRefGoogle Scholar

Synthetic Analysis and Planning

  1. E. J. Corey and X.-M. Cheng, The Logic of Chemical Synthesis, Wiley, New York, 1989.Google Scholar
  2. J.-H. Fuhrop and G. Penzlin, Organic Synthesis: Concepts, Methods and Starting Materials, Verlag Chemie, Weinheim, 1983.Google Scholar
  3. T. Lindberg, Strategies and Tactics in Organic Synthesis, Academic Press, New York, 1984.Google Scholar
  4. S. Warren, Designing Organic Syntheses, A Programmed Introduction to the Synthon Approach, Wiley, New York, 1978.Google Scholar
  5. S. Warren, Organic Synthesis: The Disconnection Approach, Wiley, New York, 1982.Google Scholar

Stereoselective Synthesis

  1. J. W. ApSimon, Tetrahedron 35, 2797 (1979).CrossRefGoogle Scholar
  2. P. A. Bartlett, Tetrahedron 36, 3 (1980).CrossRefGoogle Scholar
  3. G. M. Coppola and H. F. Schuster, Asymmetric Synthesis, Wiley-Interscience, New York, 1987.Google Scholar
  4. B. Fraser-Reid and R. C. Anderson, Fortschr. Chem. Org. Naturstoffe 39, 1 (1980).CrossRefGoogle Scholar
  5. S. Hanessian, Total Synthesis of Natural Products, the Chiron Approach, Pergamon, New York, 1983.Google Scholar
  6. Y. Izumi and A. Tai, Stereodifferentiating Reactions, Academic Press, New York, 1977.Google Scholar
  7. H. B. Kagan and J. C. Fiaud, Top. Stereochem. 10, 175 (1977).CrossRefGoogle Scholar
  8. H. S. Mosher and J. D. Morrison, Asymmetric Organic Reactions, Second Edition, American Chemical Society, Washington, D.C., 1976.Google Scholar
  9. S. Nogradi, Stereoselective Syntheses, Verlag Chemie, Weinheim, 1987.Google Scholar

Description of Total Syntheses

  1. N. Anand, J. S. Bindra, and S. Ranganathan, Art in Organic Synthesis, Second Edition, Wiley-Interscience, New York, 1988.Google Scholar
  2. J. Apsimon (ed.), The Total Synthesis of Natural Products, Vols. 1-7, Wiley-Interscience, New York, 1973–1988.Google Scholar
  3. J. S. Bindra and R. Bindra, Creativity in Organic Synthesis, Academic Press, New York, 1975.Google Scholar
  4. S. Danishefsky and S. E. Danishefsky, Progress in Total Synthesis, Meredith, New York, 1971.Google Scholar
  5. I. Fleming, Selected Organic Syntheses, Wiley-Interscience, New York, 1973.Google Scholar
  6. 1a.
    E. J. Corey, J.-L. Gras, and P. Ulrich, Tetrahedron Lett., 809 (1976).Google Scholar
  7. b.
    K. C. Nicolaou, S. P. Seitz, and M. R. Pavia, J. Am. Chem. Soc. 103, 1222 (1981).CrossRefGoogle Scholar
  8. c.
    E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc. 94, 6190 (1972).CrossRefGoogle Scholar
  9. d-f.
    H. H. Meyer, Justus Liebigs Ann. Chem., 732 (1977).Google Scholar
  10. 2a.
    M. Miyashita, A. Yoshikoshi, and P. A. Grieco, J. Org. Chem. 42, 3772 (1977).CrossRefGoogle Scholar
  11. b.
    E. J. Corey, L. O. Wiegel, D. Floyd, and M. G. Bock, J. Am. Chem. Soc 100, 2916 (1978).CrossRefGoogle Scholar
  12. c.
    A. M. Felix, E. P. Heimer, T. J. Lambros, C. Tzougraki, and J. Meienhofer, J. Org. Chem. 43, 4194 (1978).CrossRefGoogle Scholar
  13. d.
    P. N. Confalone, G. Pizzolato, E. G. Baggiolini, D. Lollar, and M. R. Uskokovic, J. Am. Chem. Soc. 97, 5936 (1975).CrossRefGoogle Scholar
  14. e.
    A. B. Foster, J. Lehmann, and M. Stacey, J. Chem. Soc, 4649 (1961).Google Scholar
  15. 3a.
    D. M. Simonovic, A. S. Rao, and S. C. Bhattacharyya, Tetrahedron 19, 1061 (1963).CrossRefGoogle Scholar
  16. b.
    R. E. Ireland and L. N. Mander, J. Org. Chem. 32, 689 (1967).CrossRefGoogle Scholar
  17. c.
    G. Büchi, W. D. MacLeod, Jr., and J. Padilla, J. Am. Chem. Soc. 86, 4438 (1964).CrossRefGoogle Scholar
  18. d.
    P. Doyle, I. R. Maclean, W. Parker, and R. A. Raphael, Proc. Chem. Soc, 239 (1963).Google Scholar
  19. e.
    J. C. Sheehan and K. R. Henry-Logan, J. Am. Chem. Soc 84, 2983 (1962).CrossRefGoogle Scholar
  20. f.
    E. J. Corey, M. Ohno, R. B. Mitra, and P. A. Vatakencherry, J. Am. Chem. Soc 86, 478 (1964).CrossRefGoogle Scholar
  21. 4a.
    B. ElAmin, G. M. Anantharamaiah, G. P. Royer, and G. E. Means, J. Org. Chem. 44, 3442 (1979).CrossRefGoogle Scholar
  22. b.
    B. Moreay, S. Lavielle, and A. Marquet, Tetrahedron Lett., 2591 (1977); B. C. Laguzza and B. Ganem, Tetrahedron Lett., 1483 (1981).Google Scholar
  23. c.
    J. I. Seeman, Synthesis, 498 (1977); D. Spitzner, Synthesis, 242 (1977).Google Scholar
  24. d.
    H. J. Anderson and J. K. Groves, Tetrahedron Lett., 3165 (1971).Google Scholar
  25. 5a.
    T. Hylton and V. Boekelheide, J. Am. Chem. Soc 90, 6987 (1968).CrossRefGoogle Scholar
  26. b.
    B. W. Erickson, Org. Synth. 53, 189 (1973).Google Scholar
  27. c.
    H. Paulsen, V. Sinnwell, and P. Stadler, Angew. Dhem. Int. Ed. Engl. 11, 149 (1972).CrossRefGoogle Scholar
  28. d.
    S. Torii, K. Uneyama, and M. Isihara, J. Org. Chem. 39, 3645 (1974).CrossRefGoogle Scholar
  29. e.
    J. A. Marshall and A. E. Greene, J. Org. Chem. 36, 2035 (1971).CrossRefGoogle Scholar
  30. f.
    E. Leete, M. R. Chedekel, and G. B. Bodem, J. Org. Chem. 37, 4465 (1972).CrossRefGoogle Scholar
  31. g.
    H. Yamamoto and H. L. Sham, J. Am. Chem. Soc. 101, 1609 (1979).CrossRefGoogle Scholar
  32. h.
    K. Deuchert, U. Hertenstein, S. Hünig, and G. Wehner, Chem. her. 112, 2045 (1979).Google Scholar
  33. i.
    T. Takahashi, K. Kitamura, and J. Tsuji, Tetrahedron Lett. 24, 4695 (1983).CrossRefGoogle Scholar
  34. 6a.
    S. Danishefsky and T. Kitahara, J. Am. Chem. Soc. 96, 7807 (1974).CrossRefGoogle Scholar
  35. b.
    P. S. Wharton, C. E. Sundin, D. W. Johnson, and H. C. Kluender, J. Org. Chem. 37, 34 (1972).CrossRefGoogle Scholar
  36. c.
    E. J. Corey, B. W. Erickson, and R. Noyori, J. Am. Chem. Soc 93, 1724 (1971).CrossRefGoogle Scholar
  37. d.
    R. E. Ireland and J. A. Marshall, J. Org. Chem. 27, 1615 (1962).CrossRefGoogle Scholar
  38. e.
    W. S. Johnson, T. J. Brocksom, P. Loew, D. H. Rich, L. Werthemann, R. A. Arnold, T. Li, and D. J. Faulkner, J. Am. Chem. Soc. 92, 4463 (1970).CrossRefGoogle Scholar
  39. f.
    L. Birladeanu, T. Hanafusa, and S. Winstein, J. Am. Chem. Soc. 88, 2315 (1966); T. Hanafusa, L. Birladeanu, and S. Winstein, J. Am. Chem. Soc 87, 3510 (1965).CrossRefGoogle Scholar
  40. 7a.
    A. B. Smith III and W. C. Agosta, J. Am. Chem. Soc. 96, 3289 (1974).CrossRefGoogle Scholar
  41. b.
    R. S. Cooke and U. H. Andrews, J. Am. Chem. Soc 96, 2974 (1974).CrossRefGoogle Scholar
  42. c.
    L. A. Hulshof and H. Wynberg, J. Am. Chem. Soc 96, 2191 (1974).CrossRefGoogle Scholar
  43. d.
    S. D. Burke, C. W. Murtiashaw, M. S. Dike, S. M. S. Strickland, and J. O. Saunders, J. Org. Cyem. 46, 2400 (1981).CrossRefGoogle Scholar
  44. e.
    K. C. Nicolaou, M. R. Pavia, and S. P. Seitz, J. Am. Chem. Soc. 103, 1224 (1981).CrossRefGoogle Scholar
  45. 8a.
    E. M. Acton, R. N. Goerner, H. S. Uh, K. J. Ryan, D. W. Henry, C. E. Cass, and G. A. LePage, J. Med. Chem. 22, 518 (1979).CrossRefGoogle Scholar
  46. b.
    E. G. Gros, Carbohydr. Res. 2, 56 (1966).CrossRefGoogle Scholar
  47. c.
    S. Hanessian and G. Rancourt, Can. J. Chem. 55, 1111 (1977).CrossRefGoogle Scholar
  48. d.
    R. R. Schmidt and A. Gohl, Chem. Ber. 112, 1689 (1979).CrossRefGoogle Scholar
  49. 9a.
    S. F. Martin and T. Chou, J. Org. Chem. 43, 1027 (1978).CrossRefGoogle Scholar
  50. b.
    W. C. Still and M.-Y. Tsai, J. Am. Chem. Soc. 102, 3654 (1980).CrossRefGoogle Scholar
  51. c.
    J. C. Bottaro and G. A. Berchtold, J. Org. Chem. 45, 1176 (1980).CrossRefGoogle Scholar
  52. d.
    A. S. Kende and T. P. Demuth, Tetrahedron Lett., 715 (1980).Google Scholar
  53. e.
    J. A. Marshall and P. G. M. Wuts, J. Org. Chem. 43, 1086 (1978).CrossRefGoogle Scholar
  54. 10a.
    R. Bonjouklian and R. A. Rüden, J. Org. Chem. 42, 4095 (1977).CrossRefGoogle Scholar
  55. b.
    L. A. Paquette, R. E. Moerck, B. Harirchian, and P. D. Magnus, J. Am. Chem. Soc 100, 1597 (1978).CrossRefGoogle Scholar
  56. c.
    P. S. Wharton, C. E. Sundin, D. W. Johnson, and H. C. Kluender, J. Org. Chem. 37, 34 (1972).CrossRefGoogle Scholar
  57. d.
    S. Danishefsky, T. Kitahara, C. F. Yan, and J. Morris, J. Am. Chem. Soc 101, 6996 (1979).CrossRefGoogle Scholar
  58. e.
    B. M. Trost, J. Ippen, and W. C. Vladuchick, J. Am. Chem. Soc. 99, 8116 (1977).CrossRefGoogle Scholar
  59. 11a.
    E. J. Corey, E. J. Trybulski, L. S. Melvin, Jr., K. C. Nicolaou, J. A. Secrist, R. Lett, P. W. Sheldrake, J. R. Falck, D. J. Brunelle, M. F. Haslanger, S. Kim, and S. Yoo, J. Am. Chem. Soc 100, 4618 (1978).CrossRefGoogle Scholar
  60. b.
    K. G. Paul, F. Johnson, and D. Favara, J. Am. Chem. Soc. 98, 1285 (1976).CrossRefGoogle Scholar
  61. c.
    P.N. Confalone, G. Pizzolato, E. G. Baggiolini, D. Lollar, and M. R. Uskokovic, J. Am. Chem. Soc. 97, 5936 (1975).CrossRefGoogle Scholar
  62. d.
    E. Baer, J. M. Grosheintz, and H. O. L. Fischer, J. Am. Chem. Soc. 61, 2607 (1939).CrossRefGoogle Scholar
  63. e.
    J. L. Coke and A. B. Richon, J. Org. Chem. 41, 3516 (1976).CrossRefGoogle Scholar
  64. f.
    J. R. Dyer, W. E. McGonigal, and K. C. Rice, J. Am. Chem. Soc. 87, 654 (1965).CrossRefGoogle Scholar
  65. g.
    E. J. Corey and S. Nozoe, J. Am. Chem. Soc. 85, 3527 (1963).CrossRefGoogle Scholar
  66. h.
    R. Jacobson, R. J. Taylor, H. J. Williams, and L. R. Smith, J. Org. Chem. 47, 3140 (1982).CrossRefGoogle Scholar
  67. 12a.
    R. B. Miller and E. S. Behare, J. Am. Chem. Soc. 96, 8102 (1974).CrossRefGoogle Scholar
  68. b.
    S. Iwaki, S. Marumo, T. Saito, M. Yamada, and K. Katagiri, J. Am. Chem. Soc. 96, 7842 (1974).CrossRefGoogle Scholar
  69. c.
    G. Büchi, W. Hofheinz, and J. V. Paukstelis, J. Am. Chem. Soc. 91, 6473 (1969).CrossRefGoogle Scholar
  70. d.
    M. Brown, J. Org. Chem. 33, 162 (1968).CrossRefGoogle Scholar
  71. e.
    E. J. Corey, R. B. Mitra, and H. Uda, J. Am. Chem. Soc. 86, 485 (1964).CrossRefGoogle Scholar
  72. 13a.
    I. Fleming, Selected Organic Syntheses, Wiley, London, 1973, pp. 3-6; J. E. McMurry and J. Melton, J. Am. Chem. Soc. 93, 5309 (1971).Google Scholar
  73. b.
    R. M. Coates and J. E. Shaw, J. Am. Chem. Soc. 92, 5657 (1970).CrossRefGoogle Scholar
  74. c.
    T. F. Buckley III and H. Rapoport, J. Am. Chem. 102, 3056 (1980).CrossRefGoogle Scholar
  75. d.
    D. A. Evans, A. M. Golob, N. S. Mandel, and G. S. Mandel, J. Am. Chem. Soc. 100, 8170 (1978).CrossRefGoogle Scholar
  76. e.
    E. J. Corey and R. D. Balanson, J. Am. Chem. Soc. 96, 6516 (1974).CrossRefGoogle Scholar
  77. f.
    J. L. Herrmann, M. H. Berger, and R. H. Schlessinger, J. Am. Chem. Soc. 95, 7923 (1973).CrossRefGoogle Scholar
  78. g.
    R. F. Romanet and R. H. Schlessinger, J. Am. Chem. Soc. 96, 3701 (1974); R. A. LeMahieu, M. Carson, and R. W. Kierstead, J. Org. Chem. 33, 3660 (1968); G. Büchi, D. Minster, and J. C. F. Young, J. Am. Chem. Soc. 93, 4319 (1971).CrossRefGoogle Scholar
  79. h.
    J. H. Babler, D. O. Olsen, and W. H. Arnold, J. Org. Chem. 39, 1656 (1974); R. J. Crawford, W. F. Erman, and C. D. Broaddus, J. Am. Chem. Soc. 94, 4298 (1972).CrossRefGoogle Scholar
  80. i.
    C. S. Subramanian, P. J. Thomas, V. R. Mamdapur, and M. S. Chandra, J. Chem. Soc, Perkin Trans. 1, 2346 (1979).Google Scholar
  81. j.
    S. Hanessian and R. Frenette, Tetrahedron Lett., 3391 (1979).Google Scholar
  82. k.
    E. Piers, R. W. Britton, and W. de Waal, J. Am. Chem. Soc. 93, 5113 (1971); K. J. Schmalzl and R. N. Mirrington, Tetrahedron Lett., 3219 (1970); N. Fukamiya, M. Kato, and A. Yoshikoshi, J. Chem. Soc, Chem. Commun., 1120 (1971); G. Frater, Helv. Chim. Acta 57, pp172 (1974); K. Yamada, Y. Kyotani, S. Manabe, and M. Suzuki, Tetrahedron 35, 93 (1979); M. E. Jung, C. A. McCombs, Y. Takeda, and Y. G. Pan, J. Am. Chem. Soc. 103, 6677 (1981); S. C. Welch, J. M. Gruber, and P. A. Morrison, J. Org. Chem. 50, pp2676 (1985); S. C. Welch, C. Chou, J. M. Gruber, and J. M. Assercq, J. Org. Chem. 50, 2668 (1985); H. Hagaiwara, A. Okano, and H. Uda, J. Chem. Soc, Chem. Commun., 1047 (1985); G. Stork and N. H. Baird, Tetrahedron Lett. 26, 5927 (1985).CrossRefGoogle Scholar
  83. l.
    E. J. Corey and R. H. Wollenberg, Tetrahedron Lett., 4705 (1976); R. Baudouy, P. Crabbe, A. E. Greene, C. LeDrain, and A. F. Orr, Tetrahedron Lett., 2973 (1977); A. E. Greene, C. LeDrian, and P. Crabbe, J. Am. Chem. Soc 102, 7583 (1980); P. A. Bartlett and F. R. Green, J. Am. Chem. Soc 100, 4858 (1978); T. Kitahara, K. Mori, and M. Matsui, Tetrahedron Lett., 3021 (1979); Y. Köksal, P. Raddatz, and E. Winterfeldt, Angew. Chem. Int. Ed. Engl. 19, pp472 (1980); K. H. Marx, P. Raddatz, and E. Winterfeldt, Justus Liebigs Ann. Chem., 474 (1984); C. LeDrain and A. E. Green, J. Am. Chem. Soc 104, 5473 (1982); T. Kitahara and K. Mori, Tetrahedron 40, 2935 (1984); K. Nakatani and S. Isoe, Tetrahedron Lett. 26, 2209 (1985); B. M. Trost and S. M. Mignani, Tetrahedron Lett. 27, pp4137 (1986); B. M. Trost, J. Lunch, P. Renault, and D. H. Steinman, J. Am. Chem. Soc. 108, 284 (1986).CrossRefGoogle Scholar
  84. m.
    S. Danishefsky, M. Hirama, K. Gombatz, T. Harayam, E. Berman, and P. F. Schuda, J. Am. Chem. Soc 101, 7020 (1979); W. H. Parsons, R. H. Schlessinger, and M. L. Quesada, J. Am. Chem. Soc 102, 889 (1980); S. D. Burke, C. W. Murtiashaw, J. O. Saunders, and M. S. Dike, J. Am. Chem. Soc. 104, 872 (1982); L. A. Paquette, G. D. Amis, and H. Schostarez, J. Am. Chem. Soc. 104, 6646 (1982); M. C. Pirrung and S. A. Thompson, J. Org. Chem. 53, 227 (1988); T. Ohtsuka, H. Shirahama, and T. Matsumoto, Tetrahedron Lett. 21, 3851 (1983); D. E. Cane and P. J. Thomas, J. Am. Chem. Soc. 106, 5295 (1984); D. F. Taber and J. L. Schuchardt, J. Am. Chem. Soc 107, 5289 (1985).CrossRefGoogle Scholar
  85. 14a.
    R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. Soc. 98, 2568 (1976).Google Scholar
  86. b.
    W. A. Kleschick, C. T. Buse, and C. H. Heathcock, J. Am. Chem. Soc. 99, 247 (1977); P. Fellmann and J. E. Dubois, Tetrahedron 34, 1349 (1978).CrossRefGoogle Scholar
  87. c.
    B. M. Trost, S. A. Godleski, and J. P. Genet, J. Am. Chem. Soc. 100, 3930 (1978).CrossRefGoogle Scholar
  88. d.
    M. Mousseron, M. Mousseron, J. Neyrolles, and Y. Beziat, Bull. Chim. Soc. Fr., 1483 (1963); Y. Beziat and M. Mousseron-Canet, Bull. Chim. Soc. Fr., 1187 (1968).Google Scholar
  89. e.
    G. Stork and V. Nair, J. Am. Chem. Soc. 101, 1315 (1979).CrossRefGoogle Scholar
  90. 15a.
    R. D. Cooper, V. B. Jigajimmi, and R. H. Wightman, Tetrahedron Lett. 25, 5215 (1984).CrossRefGoogle Scholar
  91. b.
    C. E. Adams, F. J. Walker, and K. B. Sharpless, J. Org. Chem. 50, 420 (1985).CrossRefGoogle Scholar
  92. c.
    G. Grethe, J. Sereno, T. H. Williams, and M. R. Uskokovic, J. Org. Chem. 48, 5315 (1983).CrossRefGoogle Scholar
  93. 16a.
    H. Ahlbrect, G. Bonnet, D. Enders, and G. Zimmermann, Tetrahedron Lett., 3175 (1980).Google Scholar
  94. b.
    A. I. Meyers, G. Knaus, K. Kamata, and M. E. Ford, J. Am. Chem. Soc. 98, 567 (1976).CrossRefGoogle Scholar
  95. c.
    S. Hashimoto and K. Koga, Tetrahedron Lett., 573 (1978).Google Scholar
  96. d.
    A. I. Meyers and J. Slade, J. Org. Chem. 45, 2785 (1980).CrossRefGoogle Scholar
  97. e.
    S. Terashima, M. Hayashi, and K. Koga, Tetrahedron Lett., 2733 (1980).Google Scholar
  98. f.
    B. M. Trost, D. O’Krongly, and J. L. Balletire, J. Am. Chem. Soc. 102, 7595 (1980).CrossRefGoogle Scholar
  99. g.
    A. I. Meyers, R. K. Smith, and C. E. Whitten, J. Org. Chem. 44, 2250 (1979).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Francis A. Carey
    • 1
  • Richard J. Sundberg
    • 1
  1. 1.University of VirginiaCharlottesvilleUSA

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