A general synthetic entry to Strychnos alkaloids of the curan type via a common 3a-(2-nitrophenyl)hexahydroindol-4-one intermediate. Total syntheses of (±)- and (-)-tubifolidine, (±)-akuammicine, (±)-19,20-dihydroakuammicine, (±)-norfluorocurarine, (±)-echitamidine, and (±)-20-epilochneridine

Journal of the American Chemical Society

Volumn 119, Issue 31, 1997, Pages 7230-7240

  Bonjoch, Josep ^a   Solé, Daniel ^a   García Rubio, Silvina ^a   Bosch, Joan ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

19,20 DIHYDROAKUAMMICINE; AKUAMMICINE; ALKALOID; INDOLE ALKALOID; TUBIFOLIDINE; UNCLASSIFIED DRUG;

ARTICLE; CHIRALITY; DRUG SYNTHESIS; IN VITRO STUDY; METHODOLOGY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REACTION ANALYSIS; STEREOCHEMISTRY;

STRYCHNOS;

EID: 0030840651     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja970347a     Document Type: Article

References (112)

1. For preliminary accounts of parts of this work, see: (a) Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115 2064-2065. (b) Solé, D.; Bonjoch, J.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017-11018. (c) Solé, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194-4195. (d) Solé, D.; Bonjoch, J.; García-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron Lett. 1996, 37, 5213-5216.
2. For preliminary accounts of parts of this work, see: (a) Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115 2064-2065. (b) Solé, D.; Bonjoch, J.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017-11018. (c) Solé, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194-4195. (d) Solé, D.; Bonjoch, J.; García-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron Lett. 1996, 37, 5213-5216.
3. For preliminary accounts of parts of this work, see: (a) Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115 2064-2065. (b) Solé, D.; Bonjoch, J.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017-11018. (c) Solé, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194-4195. (d) Solé, D.; Bonjoch, J.; García-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron Lett. 1996, 37, 5213-5216.
4. For preliminary accounts of parts of this work, see: (a) Bonjoch, J.; Sole, D.; Bosch, J. J. Am. Chem. Soc. 1993, 115 2064-2065. (b) Solé, D.; Bonjoch, J.; Bosch, J. J. Am. Chem. Soc. 1995, 117, 11017-11018. (c) Solé, D.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1996, 61, 4194-4195. (d) Solé, D.; Bonjoch, J.; García-Rubio, S.; Suriol, R.; Bosch, J. Tetrahedron Lett. 1996, 37, 5213-5216.
5. Reviews: (a) Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocylic Compounds, Taylor, E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4, pp 279-355. (b) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell, G. A.; Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
6. Reviews: (a) Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocylic Compounds, Taylor, E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4, pp 279-355. (b) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell, G. A.; Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
7. Reviews: (a) Sapi, J.; Massiot, G. In Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed. In The Chemistry of Heterocylic Compounds, Taylor, E. C., Ed.; Wiley: New York, 1994; Supplement to Vol. 25, Part 4, pp 279-355. (b) Bosch, J.; Bonjoch, J.; Amat, M. In The Alkaloids; Cordell, G. A.; Ed.; Academic Press: New York, 1996; Vol. 48, pp 75-189.
8. 4
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11. 8
12. (a) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker, H. U.; Schenker, K. J. Am. Chem. Soc. 1954, 76, 4749-4751. Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger A.; Daeniker, H. U.; Schenker, K. Tetrahedron 1963, 19, 247-288.
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31. (a) Formation of C-20/C-21 bond: Kuehne, M. E.; Xu, F.; Brook, C. S. J. Org. Chem. 1994, 59, 7803-7806.
32. (b) Formation of C-15/C-20 bond: Kuehne, M. E.; Wang, T.; Seraphin, D. J. Org. Chem. 1996, 61, 7873-7881. See also ref 8b.
33. 1
34. (b) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W., Jr.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966-3977. See also ref 8c.
35. Solé, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996, 52, 4013-4028.
36. Grierson, D. Org. React. 1990, 39, 85-295.
37. 3CN, although with a lower stereoselectivity (2:1 cis/trans ratio).
38. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011-1013.
39. Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem. 1984, 49, 2081-2082.
40. Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React. 1995, 47, 315-552.
41. Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. J. Am. Chem. Soc. 1985, 107, 173-179.
42. This epimer could give access to the alstogustine alkaloid series, although this possibility was not explored.
43. (a) Isolation and structural elucidation: Kump, W. G.; Patel, M. B.; Rowson, J. M.; Schmid, H. Helv. Chim. Acta 1964, 47, 1497-1503.
44. (b) NMR data: ref 10.
45. (c) Previous syntheses: refs 9a,e and 10.
46. Gutierrez, C. G.; Stringham, R. A.; Nitasaka, T.; Glasscock, K. G. J. Org. Chem. 1980, 45, 3393-3395.
47. 3SnH. For the use of 2-nitrophenyl derivatives as precursors of the indoline nucleus in alkaloid synthesis, see inter alia: Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641-2643. Heathcock, C. H.; Norman, M. H.; Dickman, D. A.; J. Org. Chem. 1990, 55, 798-811. Mittendorf, J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1990, 46, 4049-4062.
48. 3SnH. For the use of 2-nitrophenyl derivatives as precursors of the indoline nucleus in alkaloid synthesis, see inter alia: Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641-2643. Heathcock, C. H.; Norman, M. H.; Dickman, D. A.; J. Org. Chem. 1990, 55, 798-811. Mittendorf, J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1990, 46, 4049-4062.
49. 3SnH. For the use of 2-nitrophenyl derivatives as precursors of the indoline nucleus in alkaloid synthesis, see inter alia: Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem. Pharm. Bull. 1982, 30, 2641-2643. Heathcock, C. H.; Norman, M. H.; Dickman, D. A.; J. Org. Chem. 1990, 55, 798-811. Mittendorf, J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1990, 46, 4049-4062.
50. 14b for the methoxycarbonylation of azatricyclic derivatives that differ from 27 in the substituent on the aromatic ring and makes evident that the nitro group is the cause of the different behavior. For an unusual reaction of nitro ketone 27 under basic conditions, see: Solé, D.; Parés, A.; Bonjoch, J. Tetrahedron 1994, 50, 9769-9774.
51. 3) or neutral conditions afforded appreciable amounts of the corresponding carbinolamine.
52. (a) Isolation and structural elucidation: Goodson, J. A. J. Chem. Soc. 1932, 2626. Djerassi, C.; Nakagawa, Y.; Budzikiewicz, H.; Wilson, J. M.; LeMen, J., Poisson, J.; Janot. M.-M. Tetrahedron Lett. 1962, 653-659. Zèches, M.; Ravao, T.; Richard, B.; Massiot, G.; LeMen-Olivier, L.; Guilhem, J., Pascard, C.; Tetrahedron Lett. 1984, 25, 659-662.
53. (a) Isolation and structural elucidation: Goodson, J. A. J. Chem. Soc. 1932, 2626. Djerassi, C.; Nakagawa, Y.; Budzikiewicz, H.; Wilson, J. M.; LeMen, J., Poisson, J.; Janot. M.-M. Tetrahedron Lett. 1962, 653-659. Zèches, M.; Ravao, T.; Richard, B.; Massiot, G.; LeMen-Olivier, L.; Guilhem, J., Pascard, C.; Tetrahedron Lett. 1984, 25, 659-662.
54. (a) Isolation and structural elucidation: Goodson, J. A. J. Chem. Soc. 1932, 2626. Djerassi, C.; Nakagawa, Y.; Budzikiewicz, H.; Wilson, J. M.; LeMen, J., Poisson, J.; Janot. M.-M. Tetrahedron Lett. 1962, 653-659. Zèches, M.; Ravao, T.; Richard, B.; Massiot, G.; LeMen-Olivier, L.; Guilhem, J., Pascard, C.; Tetrahedron Lett. 1984, 25, 659-662.
55. (b) NMR data: Keawpradub, N.; Takayama, H.; Aimi, N.; Sakai, S. Phytochemistry 1994, 37, 1745-1749.
56. 11b
57. (a) Solé, D.; Cancho, Y.; Llebaria, A.; Moretó, J. M.; Delgado, A. J. Am. Chem. Soc. 1994, 116, 12133-12134.
58. (b) Solé, D.; Cancho, Y.; Llebaria, A.; Moretó, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895-5904.
59. Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc. 1993, 115, 3030-3031.
60. Previous syntheses: (a) Takano, S.; Hirama, M.; Ogasawara, K. Tetrahedron Lett. 1982, 23, 881-884. (b) Hugel, G.; Lévy, J. Tetrahedron Lett. 1993, 34, 633-634. See also refs 9d, 14b, and 30.
61. Previous syntheses: (a) Takano, S.; Hirama, M.; Ogasawara, K. Tetrahedron Lett. 1982, 23, 881-884. (b) Hugel, G.; Lévy, J. Tetrahedron Lett. 1993, 34, 633-634. See also refs 9d, 14b, and 30.
62. 2-promoted cyclization. For a related example where an alkylnickel intermediate generated in such a process is protonated during the workup, see: Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 1807-1810.
63. For the use of this photoisomerization in the synthesis of Strychnos alkaloids, see: Gràcia, J.; Casamitjana, N.; Bonjoch, J.; Bosch, J. J. Org. Chem. 1994, 59, 3939-3951. See also ref 10.
64. (a) Isolation of (±)-akuammicine (ψ-akuammicine): Edwards, P. N.; Smith, G. F. Proc. Chem. Soc. (London) 1960, 215.
65. (b) Isolation and structural elucidation of (-)-akuammicine: Aghoramurthy, K.; Robinson, R. Tetrahedron 1957, 1, 172-173. Edwards, P. N.; Smith, G. F. J. Chem. Soc. 1961, 152-156
66. (b) Isolation and structural elucidation of (-)-akuammicine: Aghoramurthy, K.; Robinson, R. Tetrahedron 1957, 1, 172-173. Edwards, P. N.; Smith, G. F. J. Chem. Soc. 1961, 152-156
67. (c) NMR data: Hu, W.-L.; Zhu, J.-P.; Hesse, M. Planta Med. 1989, 55, 463-466. See also refs 13a.
68. (d) Synthesis: ref 12, 13a, and 14b.
69. 3, DMF, 50-60 °C) of dehydrotubifoline 32 to the N-formyl derivative 34 has been previously reported (no yield indicated): see ref 14b.
70. Lenz, G. R. Synthesis 1978, 489-518.
71. (a) Isolation of (±)-norfluorocurarine: Rakhimov, D. A.; Malikov, V. M.; Yusunov, C. Y. Khim. Prir. Soedin 1969, 5, 461-462; Chem. Abstr. 1970, 72, 67165n.
72. (a) Isolation of (±)-norfluorocurarine: Rakhimov, D. A.; Malikov, V. M.; Yusunov, C. Y. Khim. Prir. Soedin 1969, 5, 461-462; Chem. Abstr. 1970, 72, 67165n.
73. (b) Isolation and structural elucidation of (-)-norfluorocurarine. Stauffacher, D. Helv. Chim. Acta 1961, 44, 2006-2015.
74. (c) NMR data: Clivio, P.; Richard, B.; Deverre, J.-R.; Sevenet, T.; Zeches, M.; Le Men-Oliver, L. Phytochemistry 1991, 30, 3785-3792.
75. (d) For the only previous synthesis of racemic norfluorocurarine, see ref 9d.
76. Atta-ur-Rahman; Habib-ur-Rehman; Ahmad, Y.; Fatima, K.; Badar, Y. Planta Med. 1987, 53, 256-259.
77. For a previous synthesis, see: Smith, G. F.; Wróbel, J. T. J. Chem. Soc. 1960, 792-795.
78. 2] have been well-characterized: del Rosario, R.; Sthul, L. S. Organometallics 1986, 5, 1260-1262. del Rosario, R.; Sthul, L. S. J. Am. Chem. Soc. 1984, 106, 1160-1161. Moreover, cyanonickelate(0) species have been postulated as intermediates in some reductions with cyanonickel complexes: Bingham, D.; Burnett, M. G. J. Chem. Soc. (A) 1971, 1782.
79. 2] have been well-characterized: del Rosario, R.; Sthul, L. S. Organometallics 1986, 5, 1260-1262. del Rosario, R.; Sthul, L. S. J. Am. Chem. Soc. 1984, 106, 1160-1161. Moreover, cyanonickelate(0) species have been postulated as intermediates in some reductions with cyanonickel complexes: Bingham, D.; Burnett, M. G. J. Chem. Soc. (A) 1971, 1782.
80. 2] have been well-characterized: del Rosario, R.; Sthul, L. S. Organometallics 1986, 5, 1260-1262. del Rosario, R.; Sthul, L. S. J. Am. Chem. Soc. 1984, 106, 1160-1161. Moreover, cyanonickelate(0) species have been postulated as intermediates in some reductions with cyanonickel complexes: Bingham, D.; Burnett, M. G. J. Chem. Soc. (A) 1971, 1782.
81. 2-, the redox potential of Ni decreases in the presence of cyanide ions.
82. 2 in the presence of LiCN/DMF is in agreement with this interpretation.
83. Octahydropyrrolo[2,3-d]carbazoles are valuable intermediates in the synthesis of Aspidosperma and ibophyllidine alkaloids: (a) Benchekroun-Mounir, N.; Dugat, D.; Gramain, J.-C; Husson, H.-P. J. Org. Chem. 1993, 58, 6457-6465. (b) Kuehne, M. E.; Pitner, J. B. J. Org. Chem. 1989, 54, 4553-4569.
84. Octahydropyrrolo[2,3-d]carbazoles are valuable intermediates in the synthesis of Aspidosperma and ibophyllidine alkaloids: (a) Benchekroun-Mounir, N.; Dugat, D.; Gramain, J.-C; Husson, H.-P. J. Org. Chem. 1993, 58, 6457-6465. (b) Kuehne, M. E.; Pitner, J. B. J. Org. Chem. 1989, 54, 4553-4569.
85. Delgado, A.; Llebaria, A.; Camps, F.; Moretó, J. M. Tetrahedron Lett. 1994, 35, 4011-4014.
86. Heck, R. F. Vinyl Substitution with Organopalladium Intermediates. In Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: New York, 1991; Vol. 4, pp 833-863.
87. Grigg, R.; Santhakumar, S.; Sridharan, V. Tetrahedron Lett. 1993, 34, 3163-3164.
88. Formation of 44 requires the protolysis of the transient alkylpalladium intermediate: Benhaddou, R.; Czernecki, S.; Ville, G. J. Org. Chem. 1992, 57, 4612-4616.
89. The pyrrolidine ring is formed by a 1,5-hydrogen shift from the initially formed vinylic radical, followed by a 5-exo-trig cyclization of the resulting allylic radical: Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem. Commun. 1988, 81-82.
90. Langkopf, E.; Schinzer, D. Chem. Rev. 1995, 95, 1375-1408.
91. Klaver, W. J.; Moolenaar, M. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1988, 44, 3805-3818.
92. Solé, D.; García-Rubio, S.; Bosch, J.; Bonjoch, J. Heterocycles 1996, 43, 2415-2424.
93. For model studies from 3-vinylidenepiperidines, see ref 51. Although allenes have received extensive application in the synthesis of natural products, they have mainly been used as precursors of carbonyl groups: (a) Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Red. Trav. Chim. Pays-Bas 1986, 105, 299-306. (b) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588-2595.
94. For model studies from 3-vinylidenepiperidines, see ref 51. Although allenes have received extensive application in the synthesis of natural products, they have mainly been used as precursors of carbonyl groups: (a) Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Red. Trav. Chim. Pays-Bas 1986, 105, 299-306. (b) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc. 1989, 111, 2588-2595.
95. a-ethyltubifolidine was isolated as the major product (20%).
96. (a) Isolation and structural elucidation: ref 23a.
97. (b) NMR data and Previous synthesis: ref 10. See also ref 11a.
98. Schuster, H. E.; Coppola, G. M. Allenes in Organic Synthesis; Wiley: New York, 1984; Chapter 3.
99. Mitchell, T. N.; Schneider, U. J. Organomet. Chem. 1991, 405, 195-199.
100. Hydroboration of allene 47 with 9-borabicyclo[3.3.1]nonane (Brown, H. C.; Liotta, R.; Kramer, G. W. J. Am. Chem. Soc. 1979, 101, 2966-2979) did not give satisfactory results because the initially formed allylborane reacted with the ketone group.
101. Ueno, Y.; Sano, H.; Okawara, M. Synthesis 1980, 1011-1013.
102. (a) Isolation and structural elucidation: Lathuillière, P.; Olivier, L.; Lévy, J.; Le Men, J. Ann. Pharm. Fr. 1966, 24, 547-549.
103. 13C NMR data and hemisynthesis from akuammicine: Mirand, C.; Masiot, G.; Le Men-Olivier, L.; Lévy, J. Tetrahedron Lett. 1982, 23, 1257-1258.
104. For a recent synthesis of (-)-tubifolidine and (-)-19,20-dihydroakuammicine following the methodology reported in ref 9f, see: Amat, M.; Coll, M.-D.; Bosch, J.; Espinosa, E.; Molins, E. Tetrahedron: Asymmetry 1997, 8, 935-948.
105. 15 led to considerable amounts of 52 (four diastereomers). Its formation can be rationalized as outlined in the following scheme, taking into account that the hydride reduction of the iminium intermediate A is slower than in the N-methyl series as a consequence of the larger size of the N-substituent.
106. Octahydroindolone (-)-51 is in a preferred conformation that locates the 3a-aryl group in equatorial disposition with respect to the carbocyclic ring. A related 3a-aryloctahydroindolone (aryl = 3,4-methylenedioxyphenyl) possessing the same relative stereochemistry as (-)-51 exists in a preferred conformation in which the aryl group is axial: Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745-749. For the conformational behavior of 3a-aryloctahydroindoles, see: Bonjoch, J.; Solé, D.; Cuesta, X. Heterocycles 1997, 45, 315-322. See also ref 15.
107. Octahydroindolone (-)-51 is in a preferred conformation that locates the 3a-aryl group in equatorial disposition with respect to the carbocyclic ring. A related 3a-aryloctahydroindolone (aryl = 3,4-methylenedioxyphenyl) possessing the same relative stereochemistry as (-)-51 exists in a preferred conformation in which the aryl group is axial: Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745-749. For the conformational behavior of 3a-aryloctahydroindoles, see: Bonjoch, J.; Solé, D.; Cuesta, X. Heterocycles 1997, 45, 315-322. See also ref 15.
108. 13C NMR data of N-(α-chloroethoxycarbonyl) octahydroindoles a hyphen is used to indicate that the spectra are complex due to the existence of diastereoisomers and rotamers.
109. When the THF used had been kept with Na, appreciable amounts of the corresponding α-chloro ketone were formed: see Supporting Information.
110. 2 gave the same result.
111. In some runs, tricycles 25 and 26 (3:1 ratio) were obtained together with the alkylated product. These compounds were formed during purification by column chromatography. All attempts to take advantage of this spontaneous cyclization resulted in failure.
112. In some runs, the corresponding carbonate was formed as a minor byproduct: see Supporting Information.