Total synthesis of (±)- and (-)-actinophyllic acid

Journal of the American Chemical Society

Volumn 132, Issue 13, 2010, Pages 4894-4906

  Martin, Connor L ^a   Overman, Larry E ^a   Rohde, Jason M ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b IRONWOOD PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTINOPHYLLIC ACID; DIRECT SEQUENCE; ENANTIOSELECTIVE REDUCTION; ENANTIOSELECTIVE TOTAL SYNTHESIS; HOMOALLYL AMINE; MALONATES; ONE STEP; OXIDATIVE CYCLIZATION; PARAFORMALDEHYDES; RING SYSTEMS; TOTAL SYNTHESIS; UNSATURATED KETONES;

ACETAL RESINS; AMINO ACIDS; BIOCHEMISTRY; KETONES; ORGANIC ACIDS; REACTION INTERMEDIATES;

SYNTHESIS (CHEMICAL);

ACTINOPHYLLIC ACID; CHLORIDE; INDOLE ALKALOID; PARAFORMALDEHYDE; UNCLASSIFIED DRUG;

ARTICLE; BIOSYNTHESIS; CATALYST; CHEMICAL REACTION; CYCLIZATION; DRUG SYNTHESIS; ENANTIOSELECTIVITY; MANNICH REACTION; CHEMICAL STRUCTURE; CHEMISTRY; STEREOISOMERISM; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

CRYSTALLOGRAPHY, X-RAY; INDOLE ALKALOIDS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; STEREOISOMERISM;

EID: 77950806076     PISSN: 00027863     EISSN: 15205126     Source Type: Journal    
DOI: 10.1021/ja100178u     Document Type: Article

References (124)

1. Cesarman-Maus, G. and Hajjar, K. A. Br. J. Hamaetol. 2005, 129, 307 - 321
2. For reviews of the role of TAFIa in fibrinolysis, see: Leurs, J. and Hendriks, D. Thromb. Haemost. 2005, 94, 471 487
3. Willemse, J. L. and Hendriks, D. F. Front. Biosci. 2007, 12, 1973 1987
4. For a review of small molecule inhibitors of TAFIa, see: Bunnage, M. E. and Owen, D. R. Curr. Opin. Drug Discovery Dev. 2008, 11, 480 - 486
5. Also known as carboxypeptidase U or plasma carboxypeptidase B
6. Carroll, A. R., Hyde, E., Smith, J., Quinn, R. J., Guymer, G., and Forster, P. I. J. Org. Chem. 2005, 70, 1096 - 1099
7. This ring system is named differently in Chemical Abstracts: 2,3,3a,4,8,12c-hexahydro-4-hydroxy-1,4,7-[1]propanyl[3]ylidene-1 H -pyrrolo[2-,3-:6,7]oxocino[4,5- b ]indole-7(6 H)-carboxylic acid.
8. Taniguchi, T., Martin, C. L., Monde, K., Nakanishi, K., Berova, N., and Overman, L. E. J. Nat. Prod. 2009, 72, 430 - 432
9. Martin, C. L., Overman, L. E., and Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 7568 - 7569
10. For progress toward the total synthesis of actinophyllic acid by a different approach, see: Vaswani, R. G., Day, J. J., and Wood, J. L. Org. Lett. 2009, 11, 4532 - 4535
11. Overman, L. E., Humphreys, P. G., and Welmaker, G. S. Org. React. 2010, 75
12. Overman, L. E. Tetrahedron 2009, 65, 6432 - 6446
13. Brüggemann, M., McDonald, A. I., Overman, L. E., Rosen, M. D., Schwink, L., and Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284 - 15285
14. Grob, C. A., Kunz, W., and Marbet, P. R. Tetrahedron Lett. 1973, 16, 2613 - 2616
15. The Monoterpene Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds; Wiley: New York, 1983; Vol. 25,- Part 4.
16. For representative examples of syntheses of the hexahydro-1,5-methano-1 H -azocino[4,3- b ]indole ring system, see: Jackson, A., Wilson, N. D. V., Gaskell, A. J., and Joule, J. A. J. Chem. Soc. C 1969, 19, 2738 2747
17. Büchi, G., Gould, S. J., and Näf, F. J. Am. Chem. Soc. 1971, 93, 2492 2501
18. Grierson, D. S., Harris, M., and Husson, H.-P. Tetrahedron 1983, 39, 3683 3694
19. Magnus, P., Sear, N. L., Kim, C. S., and Vicker, N. J. Org. Chem. 1992, 57, 70 78
20. Gràcia, J., Casamitjana, N., Bonjoch, J., and Bosch, J. J. Org. Chem. 1994, 59, 3939 3951
21. Micouin, L., Diez, A., Castells, J., López, D., Rubiralta, M., Quirion, J.-C., and Husson, H.-P. Tetrahedron Lett. 1995, 36, 1693 1696
22. Blechert, S., Knier, R., Schroers, H., and Wirth, T. Synthesis 1995, 592 604
23. Saito, M., Kawamura, M., Hiroya, K., and Ogasawara, K. Chem. Commun. 1997, 765 766
24. Amat, M., Hadida, S., Pshenichnyi, G., and Bosch, J. J. Org. Chem. 1997, 62, 3158 3175
25. Ergün, Y., Patir, S., and Okay, G. J. Heterocycl. Chem. 2002, 39, 315 - 317
26. Jiricek, J. and Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534 3538
27. Ishikura, M., Takahashi, N., Takahashi, H., and Yanada, K. Heterocycles 2005, 66, 45 50
28. Uludag, N., Hkelek, T., and Patir, S. J. Heterocycl. Chem 2006, 43, 585 591
29. Bennasar, M.-L., Roca, T., and García-Díaz, D. J. Org. Chem. 2008, 73, 9033 - 9039
30. For a review that covers the synthesis of uleine alkaloids, see: Alvarez, M. and Joule, J. A. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2001; Vol. 57, pp 247 - 258.
31. Our motivations for pursuing such potentially high-risk strategies are discussed briefly in ref 9b.
32. Bennasar, M.-L., Alvarez, M., Lavilla, R., Zulaica, E., and Bosch, J. J. Org. Chem. 1990, 55, 1156 - 1168
33. Bosch, J. and Bennasar, M.-L. Synlett 1995, 587 - 596
34. For reviews, see: Bennasar, M.-L., Lavilla, R., Alvarez, M., and Bosch, J. Heterocycles 1988, 27, 789 - 824 Comins, D. L. and Joseph, S. P. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates. In Advances in Nitrogen Heterocycles; Moody, C. J., Ed.; JAI: Greenwich, CT, 1996; Vol. 2, pp 251 - 294.
35. Mahboobi, S. and Bernauer, K. Helv. Chim. Acta 1988, 71, 2034 - 2041
36. Indole-2-malonate 19 contains variable amounts (8-94%) of the indolin-2-ylidene tautomer i depending upon the method employed to purify this intermediate. Purification by recrystallization gives the indole tautomer predominantly, whereas purification by column chromatography gives i as the major tautomer. (18) For simplicity, these structures are depicted only in their indole form. In cases where we have examined the issue, we have not observed differences in reaction outcome depending upon tautomer composition.
37. as of indole and dimethyl malonate are 21.0 and 15.9, respectively: Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456 - 463 Arnett, E. M., Maroldo, S. G., Schilling, S. L., and Harrelson, J. A. J. Am. Chem. Soc. 1984, 106, 6759 - 6767
38. Akiba, K., Nishihara, Y., and Wada, M. Tetrahedron Lett. 1983, 24, 5269 - 5272
39. Corey, E. J. and Tian, Y. Org. Lett. 2005, 7, 5535 - 5537
40. Shi, Y. Acc. Chem. Res. 2004, 37, 488 - 496
41. Ivanoff, D. and Spassoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76 - 78
42. For a recent historical summary and leading references, see: Richter, J. M., Whitefield, B. W., Maimone, T. J., Lin, D. W., Castroviejo, M. P., and Baran, P. S J. Am. Chem. Soc. 2007, 129, 12857 - 12869 For a brief review, see: Csák, A. G. and Plumet, J. Chem. Soc. Rev. 2001, 30, 313 - 320
43. Ito, Y., Konoike, T., Harada, T., and Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487 1493
44. Kobayashi, Y., Taguchi, T., and Morikawa, T. Tetrahedron Lett. 1978, 19, 3555 3556
45. Kobayashi, Y., Taguchi, T., Morikawa, T., Tokuno, E., and Sekiguchi, S. Chem. Pharm. Bull. 1980, 28, 262 - 267
46. Chung, S. K. and Dunn, L. B., Jr. J. Org. Chem. 1983, 48, 1125 1127
47. Babler, J. H. and Sarussi, S. J. J. Org. Chem. 1987, 52, 3462 - 3464
48. Kawabata, T., Sumi, K., and Hiyama, T. J. Am. Chem. Soc. 1989, 111, 6843 - 6845
49. Kawabata, T., Minami, T., and Hiyama, T. J. Org. Chem. 1992, 57, 1864 - 1873
50. For an early example, see Hendrickson, J. B., Rees, R., and Gschke, R. Proc. Chem. Soc. 1962, 383
51. Paquette, L. A., Snow, R. A., Muthard, J. L., and Cynkowski, T. J. Am. Chem. Soc. 1978, 100, 1600 1602
52. Ramig, K., Kuzemko, M. A., McNamara, K., and Cohen, T. J. Org. Chem. 1992, 57, 1968 1969
53. Cohen, T., McNamara, K., Kuzemko, M. A., Ramig, K., Landi, J. J., Jr., and Dong, Y. Tetrahedron 1993, 49, 7931 7942
54. Baran, P. S., Guerrero, C. A., Ambhaikar, N. B., and Hafensteiner, B. D. Angew. Chem., Int. Ed. 2005, 44, 606 609
55. Baran, P. S., Hafensteiner, B. D., Ambhaikar, N. B., Guerrero, C. A., and Gallagher, J. D. J. Am. Chem. Soc. 2006, 128, 8678 - 8693
56. The major byproduct under these conditions is 2-oxindole.
57. This procedure is a modification of Hecks procedure for transfer hydrogenation with triethylammonium formate. For the original procedure, see: Weir, J. R., Patel, B. A., and Heck, R. F. J. Org. Chem. 1980, 45, 4926 - 4931
58. 3 as a promotor in the catalytic hydrogenation of nitroarenes, see: Baumeister, P., Blaser, H.-U., and Studer, M. Catal. Lett. 1997, 49, 219 - 222
59. Brosius, A. D., Overman, L. E., and Schwink, L. J. Am. Chem. Soc. 1999, 121, 700 - 709
60. For the closest precedent of which we are aware, see: Whitlock, C. R. and Cava, M. P. Tetrahedron Lett. 1994, 35, 371 - 374
61. For the use of this oxidant in phenolic couplings, see: Tobinaga, S. and Kotani, E. J. Am. Chem. Soc. 1972, 94, 309 310
62. 3 in DMF for oxidative coupling of enolates, see, inter alia Frazier, R. H. and Harlow, R. L. J. Org. Chem. 1980, 45, 5408 5411
63. Paquette, L. A., Bzowej, E. I., Branan, B. M., and Stanton, K. J. J. Org. Chem. 1995, 60, 7277 - 7283 Poupart, M.-A. and Paquette, L. A. Tetrahedron Lett. 1988, 29, 269 - 272 and refs 29b and 29c
64. Crystallographic data for this compound were deposited at the Cambridge Crystallographic Data Centre: CCDC 701592; CCDC 759087.
65. Johnson, F. Chem. Rev. 1968, 68, 375 - 413
66. Deuteration experiments showed that the malonate and α-methylene had been deprotonated. However, because of rapid exchange of the indole hydrogen under all the quenching conditions that we examined, no information about the fate of the indole hydrogen was obtained.
67. This dimer is formed in 18% yield in cyclizations carried out at a substrate concentration of 0.08 M.
68. See the Supporting Information for more details. Investigations into the mechanism of the oxidative cyclization of intermediate 35, which hopefully will clarify the origin of this unexpected trend, are currently underway.
69. Imamoto, T., Takiyama, N., Nakamura, K., Hatajima, T., and Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392 - 4398
70. The α-epimer, rac-46a, provided single crystals from methanol, allowing its constitution and relative configuration to be confirmed by X-ray analysis; however, diffraction data from these crystals was of insufficient quality to refine to high precision.
71. Schlosser, M. and Coffinet, D. Synthesis 1971, 380 - 381 We prepared monomeric formaldehyde by an improved procedure, see
72. Schlosser, M., Jenny, T., and Guggisberg, Y. Synlett 1990, 704
73. 1H NMR spectra corresponding to hydroxymethylene fragments and on the basis of LRMS data.
74. Comparable yields for this transformation were obtained when the pure α-epimer, rac-46a, was used or when a 1:1 mixture of α and β epimers of rac-46 was employed.
75. The prediction would be the same if lithium was not chelated to the indole nitrogen.
76. The natural sample of actinophyllic acid (1) degraded sometime after its isolation and bioassay. The concentration reported for the optical rotation of natural (-)-actinophyllic acid is incorrect in ref 4; it should be (0.05 M); the low reported rotation could be the result of the low solubility of this zwitterionic amino acid or that the natural sample started to degrade prior to analysis. Personal communications from Professor Tony Carroll, Griffith University, Gold Coast Campus, Australia.
77. The β-epimer, rac-45b, crystallized from an aqueous solution of this mixture of carboxylic acid epimers. The relative configuration of this sample was established by single-crystal X-ray analysis; crystallographic data for this compound were deposited at the Cambridge Crystallographic Data Centre: CCDC 752916.
78. Several other conditions that employed LiCl or TMEDA additives or potassium diisopropylamide as the base were also examined. In no case was actinophyllic acid the major product of this aldol reaction.
79. A complex mixture of byproducts was formed; products arising from competitive addition of the organometallic reagent to the methyl ester of the lactone product rac-41 were isolated, but they did not account for the entire mass balance of the reaction. In contrast to rac-37, complete consumption of keto diester rac-36 was not possible when 2.5 equiv of vinylmagnesium bromide were used.
80. This partial quench resulted in slightly improved yields, but it is not crucial.
81. Dunn, T. B., Ellis, J. M., Kofink, C, C., Manning, J. R., and Overman, L. E. Org. Lett. 2009, 11, 5658 - 5661
82. For a review of the complexation of lanthanides with various functional groups, see: Cockerill, A. F., Davies, G. L. O., Harden, R. C., and Rackham, D. M. Chem. Rev. 1973, 73, 553 - 588 and references cited therein
83. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226 - 2227 For Luche reduction of a lactone having a β ester substituent, see
84. Kusama, H., Mori, T., Mitani, I., Kashima, H., and Kuwajima, I. Tetrahedron Lett. 1997, 38, 4129 - 4132
85. Because of the limited solubility of hydrochloride salt rac-54 in acetonitrile, the solvent was a mixture of acetonitrile and water.
86. The absolute configurations of the structures depicted in eq 4 were established later in our studies.
87. For some representative examples, see: Doyle, A. G. and Jacobsen, E. N. Chem. Rev. 2007, 107, 5713 - 5743
88. Uraguchi, D., Sorimachi, K., and Terada, M. J. Am. Chem. Soc. 2004, 126, 11804 11805
89. Terada, M. and Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292 293
90. Terada, M., Machioka, K., and Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553 2556
91. Terada, M. and Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354-6355
92. Okitsu, O., Suzuki, R., and Kobayashi, S. J. Org. Chem. 2001, 66, 809-823
93. Okitsu, O., Suzuki, R., and Kobayashi, S. Synlett 2000, 989-990
94. Piperidine derivatives 57 were prepared from commercially available 1-(tert -butoxycarbonyl)-1,4,5,6-tetrahydropyridine using procedures similar to those employed by Kobayashi to prepare the related compounds in the benzyloxycarbonyl series; see the Supporting Information for details. (59) Neat samples of diol 57a decomposed shortly after being concentrated but could be stored for months in solution at 20 °C. In contrast to the report of Kobayashi and coworkers, (59) we found diacetate 57d to be sufficiently stable to be a viable synthetic intermediate.
95. The trans configuration of indole piperidine 59 was determined by X-ray analysis of N -sulfonyl derivative ii.
96. (3 S)-1-(Benzyloxycarbonyl)-2,3-diacetoxypiperidine has been prepared enantioselectively by Kobayashi and co-workers in six steps from a commercially available precursor. (59a)
97. Sharpless asymmetric dihydroxylation of this alkene is reported to give the cis -diol product in only 40% ee. See: Sukemoto, S., Oshige, M., Sato, M., Mimura, K., Nishioka, H., Abe, H., Harayama, T., and Takeuchi, Y. Synthesis 2008, 3081-3087
98. Shu, L., Wang, P., Gan, Y., and Shi, Y. Org. Lett. 2003, 5, 293-296
99. Enantiomeric excesses were determined by enantioselective HPLC analysis of the dibenzoate derivative.
100. Larrow, J. F. and Jacobsen, E. N. Org. Synth. 1998, 75, 1-11
101. Jacobsen, E. N., Zhang, W., Muci, A. R., Ecker, J. R., and Deng, L. J. Am. Chem. Soc. 1991, 113, 7063-7064
102. Palucki, M., Pospisil, P. J., Zhang, W., and Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 9333-9334
103. Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247-4250
104. Brown, S. P., Brochu, M. P., Sinz, C. J., and MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808-10809
105. Lee, B. H., Miller, M. J., Prody, C. A., and Neilands, J. B. J. Med. Chem. 1985, 28, 317-323
106. Aldehyde 62 cyclizes upon silica gel chromatography or upon storage for a few days as a solution in benzene at 25 °C to give 2-hydroxy-1-(tert -butoxycarbonyl)piperidine (64).
107. Nahm, S. and Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818
108. The use of a non-basic organometallic reagent was essential to suppress lactam formation.
109. Ohkuma, T., Koizumi, M., Muiz, K., Hilt, G., Kabuto, C., and Noyori, R. J. Am. Chem. Soc. 2002, 124, 6508-6509 Careful control of reaction time was necessary to avoid over-hydrogenation.
110. The R absolute configuration of allylic alcohol 67 was determined by Mosher ester analysis: Dale, J. A. and Mosher, H. S J. Am. Chem. Soc. 1973, 95, 512 519
111. Hoye, T. R., Jeffrey, C. S., and Shao, F. Nature Protocols 2007, 2, 2451-2458
112. Enantiomeric excess was determined by enantioselective HPLC analysis of the benzoate derivative.
113. To isolate 58 in good yield, it was essential to use a NaF workup; see: Yamamoto, H. and Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186-4194
114. Mancuso, A. J., Huang, S.-L., and Swern, D. J. Org. Chem. 1978, 43, 2480-2482 It was essential to remove triethylamine prior to concentration of the crude reaction mixture to prevent deterioration of the enantiopurity of this product.
115. The yield of enantiopure (-)- 1 undoubtedly can be increased, as no attempt was made to optimize the recrystallization of intermediate (+)- 54.
116. Massiot, G, Boumendjel, A., Nuzillard, J.-M., Richard, B., Le Men-Olivier, L., David, B., and Hadi, H. A. Phytochemistry 1992, 31, 1078 - 1079
117. Koyama, K., Hirasawa, Y., Zaima, K., Hoe, T. C., Chan, K.-L., and Morita, H. Bioorg. Med. Chem. 2008, 16, 6483 - 6488
118. At the experimental level, little is known about the biosynthesis of monoterpene indole alkaloids that lack the normal tryptophan side chain and have only one-carbon linking the β-carbon of the indole and the basic nitrogen, (83) particularly for natural products having the uleine skeleton. (84)
119. Kutney, J. P., Nelson, V. R., and Wigfield, D. C. J. Am. Chem. Soc. 1969, 91, 4278 - 4279
120. Kutney, J. P., Nelson, V. R., and Wigfield, D. C. J. Am. Chem. Soc. 1969, 91, 4279-4280
121. For reviews, see: Kutney, J. P. Heterocycles 1976, 4, 429 - 451 Herbert, R. B. Structural and Biosynthetic Relationships. In The Monoterpene Indole Alkaloids; Saxton, J. E., Ed.; The Chemistry of Heterocyclic Compounds; Wiley: New York, 1983; Vol. 25,- Part 4, Chapter I, pp 13 - 14.
122. The laboratory formation of the " nor " alkaloid vallesamine from stemmadenine by a Polonovski fragmentation (86) is the basis of most biosynthetic proposals for the synthesis of uleine-type alkaloids. (81, 84b)
123. Scott, A, I., Yeh, C.-L., and Greenslade, D. J. Chem. Soc., Chem. Commun. 1978, 947 - 948
124. Scott, A, I., Yeh, C.-L., and Greenslade, D. J. Chem. Soc., Chem. Commun. 1978, 947 - 948 Ahond, A., Cavé, A., Kan-Fan, C., Langlois, Y., and Potier, P. Chem. Commun. 1970, 517