A library of spirooxindoles based on a stereoselective three-component coupling reaction

Journal of the American Chemical Society

Volumn 126, Issue 49, 2004, Pages 16077-16086

  Lo, Michael M C ^a   Neumann, Christopher S ^a   Nagayama, Satoshi ^a   Perlstein, Ethan O ^a   Schreiber, Stuart L ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

ACYLATION; CELLS; POLYMERIZATION; PROTEINS; YEAST;

CELL CIRCUITRY; SPIROOXINDOLES; SPLIT-FOOL SYNTHESIS; STEREOSELECTIVITY; THREE-COMPONENT COUPLING REACTIONS;

STEREOCHEMISTRY;

GAMMA LACTAM DERIVATIVE; LATRUNCULIN B; LEWIS ACID; OXINDOLE; SPIROOXINDOLE DERIVATIVE; UNCLASSIFIED DRUG;

ACTIN POLYMERIZATION; ACYLATION; ARTICLE; BINOMIAL DISTRIBUTION; CHEMICAL GENETICS; CONTROLLED STUDY; NONHUMAN; SONOGASHIRA REACTION; STEREOCHEMISTRY; SYNTHESIS; YEAST CELL;

ALDEHYDES; ALKYNES; COMBINATORIAL CHEMISTRY TECHNIQUES; INDOLES; LACTAMS; MAGNETIC RESONANCE SPECTROSCOPY; SPIRO COMPOUNDS; STEREOISOMERISM;

EID: 10344242467     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja045089d     Document Type: Article

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25. Some examples include: (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624-9634. (b) Tandem aza[4 + 2]-cycloaddition/allylboration: Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. Chem.-Eur. J. 2003, 9, 466-474. (c) Addition of organoboronic acids to in situ generated imines: Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (d) 1,3-Dipoiar cycloaddition: Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. (e) Passerini reaction: Frey, R.; Galbraith, S. G.; Gueifi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-1538. (f) Propargylamine synthesis: Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (g) aza-Baylis-Hillman reaction: Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
26. Some examples include: (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624-9634. (b) Tandem aza[4 + 2]-cycloaddition/allylboration: Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. Chem.-Eur. J. 2003, 9, 466-474. (c) Addition of organoboronic acids to in situ generated imines: Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (d) 1,3-Dipoiar cycloaddition: Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. (e) Passerini reaction: Frey, R.; Galbraith, S. G.; Gueifi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-1538. (f) Propargylamine synthesis: Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (g) aza-Baylis-Hillman reaction: Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
27. Some examples include: (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624-9634. (b) Tandem aza[4 + 2]-cycloaddition/allylboration: Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. Chem.-Eur. J. 2003, 9, 466-474. (c) Addition of organoboronic acids to in situ generated imines: Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (d) 1,3-Dipoiar cycloaddition: Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. (e) Passerini reaction: Frey, R.; Galbraith, S. G.; Gueifi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-1538. (f) Propargylamine synthesis: Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (g) aza-Baylis-Hillman reaction: Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
28. Some examples include: (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624-9634. (b) Tandem aza[4 + 2]-cycloaddition/allylboration: Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. Chem.-Eur. J. 2003, 9, 466-474. (c) Addition of organoboronic acids to in situ generated imines: Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (d) 1,3-Dipoiar cycloaddition: Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. (e) Passerini reaction: Frey, R.; Galbraith, S. G.; Gueifi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-1538. (f) Propargylamine synthesis: Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (g) aza-Baylis-Hillman reaction: Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
29. Some examples include: (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624-9634. (b) Tandem aza[4 + 2]-cycloaddition/allylboration: Touré, B. B.; Hoveyda, H. R.; Tailor, J.; Ulaczyk-Lesanko, A.; Hall, D. G. Chem.-Eur. J. 2003, 9, 466-474. (c) Addition of organoboronic acids to in situ generated imines: Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-446. (d) 1,3-Dipoiar cycloaddition: Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. (e) Passerini reaction: Frey, R.; Galbraith, S. G.; Gueifi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-1538. (f) Propargylamine synthesis: Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766. (g) aza-Baylis-Hillman reaction: Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
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49. Both enantiomers of Boc-protected Williams' chiral auxiliary 1 are commercially available.
50. 3. Strong Lewis acids cleave the silicon linker on the macrobead and, thus, were not examined.
51. Other amine bases that were examined include 2,6-lutidine, 2,6-di-tert-butyl-4-methylpyridine, diisopropylethylamine, and 2,2′-bipyridine.
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57. We have installed other esters (e.g., methyl, ethyl, ferf-butyl, benzyl, p-methoxybenzyl) in the 3-CR product and explored their corresponding deprotection methods, but none show the desired reactivity.
58. We could have conceivably used the more potent palladium catalysts that are based on bulky phosphines/carbenes to lower the catalyst loading. (For a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.) However, in the library synthesis, electrophoric tags that contain multiple aryl chlorides are used for encoding, and it is quite likely that these tags would be activated as well.
59. A case study was presented by Silicycle, a company that markets silica-bound metal scavengers. http://www.silicycle.com/html/english/products/ product_line.php?cat_id=15 (accessed August 2004).
60. Amberlite resins have been coated with glyoxal bis(thiosemicarbazone) to extract metal ions such as Hg(II), Pd(II), Cu(II), Cd(II), and Pb(II) from aqueous solutions. See: Hoshi, S.; Fujisawa, H.; Nakamura, K.; Nakata, S.; Uto, M.; Akatsuka, K. Talanta 1994, 41, 503-507.
61. Analyzed by ICP-MS (West Coast Analytical Labs, CA).
62. (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate.
63. In one model study, a spirooxindole was treated with 3-methoxybenzoyl chloride to give the acylated product in high yield. Although the product can be cleaved from macrobeads and characterized, it appears prone to hydrolysis upon prolonged storage as a 10 mM solution in DMSO. Hence, we excluded acid chlorides from further studies.
64. N,N-(Dimethylamino)pyridine.
65. The aldehydes were loaded on 500-600 μm polystyrene beads at a level of 150-200 nmol per bead.
66. After the "skip" step in Sonogashira coupling, the allyl ester remained intact. Thus, amidation is not possible, and only one library member was generated.
67. Based on the nature of the reaction, a percent loss was assigned to estimate bead loss or breakage during the reaction.
68. For accounts of the development of chemical-encoding strategy, see: (a) Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10922-10926. (b) Nestler, H. P.; Bartlett, P. A.; Still, W. C. J. Org. Chem. 1994, 59, 4723-4724.
69. For accounts of the development of chemical-encoding strategy, see: (a) Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10922-10926. (b) Nestler, H. P.; Bartlett, P. A.; Still, W. C. J. Org. Chem. 1994, 59, 4723-4724.
70. For details regarding the operation of chemical encoding, see: (a) Blackwell, H. E.; Pérez, L.; Schreiber, S. L. Angew. Chem., Int. Ed. 2001, 40, 3421-3425. (b) Reference 3a.
71. 1H NMR analysis depends on the reliability of the reactions involved and the nature of the products.
72. The flowchart depicting the realized library is provided in the Supporting Information.
73. Dolle, R. E.; Guo, J.; O'Brien, L.; Jin, Y.; Piznik, M.; Bowman, K. J.; Li, W.; Egan, W. J.; Cavallaro, C. L.; Roughton, A. L.; Zhao, Q.; Reader, J. C.; Orlowski, M.; Jacob-Samuel, B.; DiIanni Carroll, C. J. Comb. Chem. 2000, 716-731.
74. The multiplicative finite population correction factor for the confidence limit is given as √((N - n)/(N - l)), where N is the number of beads in the whole library and n is the number of beads in the sample. The factor is greater than 0.99 and hence approximated by 1.
75. Intercooled Stata 8.0 for Macintosh; Stata Corporation: College Station, TX, 2003.
76. 4 value of 0.6, we cannot assign a definite value of either 0 or 1. We therefore report the total number of pure compounds as a range and calculate the lower limit in each case.
77. The average of the two lower limits from 40 pure compounds (80.4%) and 41 pure compounds (83.3%).
78. For a listing of libraries available for screening at the ICG, see http://iccb.med.harvard.edu/chemistry/compound_libraries/libraries_available. htm (accessed August 2004).
79. McPherson, O. M.; Koehler, A. K. Broad Institute, Cambridge, MA. Unpublished work.
80. Lipinski, C. A.; Lombarde, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug Delivery Rev. 1997, 23, 3-25.
81. For a general review on screening, see: (a) Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116-125. For examples of chemical genetic modifier screens, see: (b) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, J. M.-C.; Schreiber, S. L. Chem. Biol. 2003, 10, 397-410. (c) Butcher, R. A.; Schreiber, S. L. Chem. Biol. 2003, 10, 521-531. (d) Haggarty, S. J.; Koeller, K. M.; Kau, T. R.; Silver, P. A.; Roberge, M.; Schreiber, S. L. Chem. Biol. 2003, 10, 1267-1279. (e) Huang, J.; Zhu H.; Haggarty, S. J.; Spring, D. R.; Snyder, M.; Schreiber, S. L. Submitted for publication.
82. For a general review on screening, see: (a) Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116-125. For examples of chemical genetic modifier screens, see: (b) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, J. M.-C.; Schreiber, S. L. Chem. Biol. 2003, 10, 397-410. (c) Butcher, R. A.; Schreiber, S. L. Chem. Biol. 2003, 10, 521-531. (d) Haggarty, S. J.; Koeller, K. M.; Kau, T. R.; Silver, P. A.; Roberge, M.; Schreiber, S. L. Chem. Biol. 2003, 10, 1267-1279. (e) Huang, J.; Zhu H.; Haggarty, S. J.; Spring, D. R.; Snyder, M.; Schreiber, S. L. Submitted for publication.
83. For a general review on screening, see: (a) Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116-125. For examples of chemical genetic modifier screens, see: (b) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, J. M.-C.; Schreiber, S. L. Chem. Biol. 2003, 10, 397-410. (c) Butcher, R. A.; Schreiber, S. L. Chem. Biol. 2003, 10, 521-531. (d) Haggarty, S. J.; Koeller, K. M.; Kau, T. R.; Silver, P. A.; Roberge, M.; Schreiber, S. L. Chem. Biol. 2003, 10, 1267-1279. (e) Huang, J.; Zhu H.; Haggarty, S. J.; Spring, D. R.; Snyder, M.; Schreiber, S. L. Submitted for publication.
84. For a general review on screening, see: (a) Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116-125. For examples of chemical genetic modifier screens, see: (b) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, J. M.-C.; Schreiber, S. L. Chem. Biol. 2003, 10, 397-410. (c) Butcher, R. A.; Schreiber, S. L. Chem. Biol. 2003, 10, 521-531. (d) Haggarty, S. J.; Koeller, K. M.; Kau, T. R.; Silver, P. A.; Roberge, M.; Schreiber, S. L. Chem. Biol. 2003, 10, 1267-1279. (e) Huang, J.; Zhu H.; Haggarty, S. J.; Spring, D. R.; Snyder, M.; Schreiber, S. L. Submitted for publication.
85. For a general review on screening, see: (a) Stockwell, B. R. Nat. Rev. Genet. 2000, 1, 116-125. For examples of chemical genetic modifier screens, see: (b) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, J. M.-C.; Schreiber, S. L. Chem. Biol. 2003, 10, 397-410. (c) Butcher, R. A.; Schreiber, S. L. Chem. Biol. 2003, 10, 521-531. (d) Haggarty, S. J.; Koeller, K. M.; Kau, T. R.; Silver, P. A.; Roberge, M.; Schreiber, S. L. Chem. Biol. 2003, 10, 1267-1279. (e) Huang, J.; Zhu H.; Haggarty, S. J.; Spring, D. R.; Snyder, M.; Schreiber, S. L. Submitted for publication.
86. Detailed procedures for the high-throughput assay and corresponding follow-up assays are available in the Supporting Information.
87. Spector, I.; Shochet, N. R.; Kashman, Y.; Groweiss, A. Science 1983, 219, 493-495.
88. Peterson, J. R.; Mitchison, T. J. Chem. Biol. 2002, 9, 1275-1285.
89. See Supporting Information for the structures of these positives.
90. Effective concentration that produces 50% of the maximum possible response for the small molecule.
91. 50 value 8 μM.