Diverging DOS strategy using an allene-containing tryptophan scaffold and a library design that maximizes biologically relevant chemical space while minimizing the number of compounds

ACS Combinatorial Science

Volumn 13, Issue 2, 2011, Pages 166-174

  Painter, Thomas O ^a   Wang, Lirong ^a   Majumder, Supriyo ^a   Xie, Xiang Qun ^a   Brummond, Kay M ^a  

^a UNIVERSITY OF PITTSBURGH   (United States)

Author keywords

Allene; Allene yne; BCUT; Chemical space; Cyclocarbonylation; Cycloisomerization; Microwave assisted; MLSMR; Pauson Khand; Pictet Spengler; Rhodium(I) catalyzed; Tanimoto; Tetrahydro carboline; Thermal 2 + 2 cycloaddition; Tryptophan; Virtual library

Indexed keywords

ALKADIENE; ALLENE; TRYPTOPHAN;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; COMBINATORIAL CHEMISTRY; CYCLIZATION; DRUG DESIGN; METHODOLOGY; MOLECULAR LIBRARY;

ALKADIENES; COMBINATORIAL CHEMISTRY TECHNIQUES; CYCLIZATION; DRUG DESIGN; MOLECULAR STRUCTURE; SMALL MOLECULE LIBRARIES; TRYPTOPHAN;

EID: 79955380437     PISSN: 21568952     EISSN: None     Source Type: Journal    
DOI: 10.1021/co100052s     Document Type: Article

References (32)

1. Tan, D. S. Diversity-Oriented Synthesis: Exploring the Intersections Between Chemistry and Biology. Nat. Chem. Biol. 2005, 1, 74-84.
2. Dandapani, S.; Marcaurelle, L. A. Current Strategies for Diversity-Oriented Synthesis. Curr. Opin. Chem. Biol. 2010, 14, 362-370.
3. A scaffold analysis of the 24 million compounds in the Chemical Abstracts (CAS) database reveals that half of the compounds can be described by a mere 143 molecular frameworks, see: Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F., III; Schenck, R. J.; Trippe, A. J. Structural Diversity of Organic Chemistry. A Scaffold Analysis of the CAS Registry. J. Org. Chem. 2008, 73, 4443-4451. (Pubitemid 351842458)
4. When screening libraries of compounds for biological activity, increasing the occupation of distinct chemical space increases the likelihood of finding biological activity for a wider range of biological targets, see: Sauer, W. H. B.; Schwarz, M. K. Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity. J. Chem. Inf. Comput. Sci. 2003, 43, 987-1003.
5. For recent work demonstrating the rapid preparation of over eighty distinct scaffolds, see: Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds. Angew. Chem., Int. Ed. 2009, 48, 104-109.
6. For a recent review of this build/couple/pair strategy, see: Nielsen, T. E.; Schreiber, S. L. Towards the Optimal Screening Collection: A Synthesis Strategy. Angew. Chem., Int. Ed. 2008, 47, 48-56.
7. Brummond, K. M.; Mitasev, B. Allenes and Transition Metals: A Diverging Approach to Heterocycles. Org. Lett. 2004, 6, 2245-2248. (Pubitemid 38918710)
8. For an example of a library generated using this diverging DOS strategy, see: Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.; Twining, L. A.; Mitasev, B.; Brummond, K. M. Solution-Phase Synthesis of a Tricyclic Pyrrole-2-Carboxamide Discovery Library Applying a Stetter-Paal-Knorr Reaction Sequence. J. Comb. Chem. 2006, 8, 368-380. (Pubitemid 43798302)
9. Carbocyclization approaches using alkene and enyne metathesis to prepare functionalized heterocycles is common, but less so for other transition metal catalyzed processes. For a leading references, see: Ben-Othman, R.; Othman, M.; Coste, S.; Decroix, B. One-Pot Enyne Metathesis/Diels - Alder Reaction for the Construction of Highly Functionalized Novel Polycyclic Aza-Compounds. Tetrahedron 2008, 64, 559.
10. For a recent review of indole-containing natural products: Kawasaki, T.; Higuchi, K. Simple Indole Alkaloids and Those with Nonrearranged Monoterpenoid Unit. Nat. Prod. Rep. 2005, 22, 761.
11. O'Connor, S. E.; Maresh, J. Chemistry and Biology of Monoterpene Indole Alkaloid Biosynthesis. Nat. Prod. Rep. 2006, 23, 532.
12. Rottmann, M.; McNamara, C.; Yeung, B. K. S.; Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N. V.; Tan, J.; Cohen, S. B.; Spencer, K. R.; Gonzalez-Paez, G. E.; Lakshminarayana, S. B.; Goh, A.; Suwanarusk, R.; Jegla, T.; Schmitt, E. K.; Beck, H.-P.; Brun, R.; Nosten, F.; Renia, L.; Dartois, V.; Keller, T. H.; Fidock, D. A.; Winzeler, E. A.; Diangana, T. T. Spiroindolones, A Potent Compound Class for the Treatment of Malaria. Science 2010, 329, 1175-1180.
13. For leading references, see: Brummond, K. M.; Davis, M.; Huang, C. Rh(I)-Catalyzed Cyclocarbonylation of Allenol Esters to Prepare Acetoxy 4-Alkylidene Cyclopent-3-en-2-ones. J. Org. Chem. 2009, 74, 8314-8320.
14. Chen, D.; Brummond, K. M. Microwave-Assisted Intramolecular [2 + 2] Allenic Cycloaddition Reaction for the Rapid Assembly of Bicyclo[4.2.0]octa-1, 6-dienes and Bicyclo[5.2.0]nona-1, 7-dienes. Org. Lett. 2005, 7, 3473-3475. (Pubitemid 41186809)
15. Brummond, K. M.; Tantillo, D. J. Differentiating Mechanistic Possibilities for the Thermal Intramolecular [2 + 2] Cycloaddition of Allene-ynes. J. Am. Chem. Soc. 2010, 132, 11952-11966.
16. Brummond, K. M.; Wan, H.; Kent, J. L. An Intramolecular Allenic [2 + 2 + 1] Cycloaddition. J. Org. Chem. 1998, 63, 6535.
17. For the design and synthesis of a 3, 4-dehydroproline amide discovery library, see: Werner, S.; Kasi, D.; Brummond, K. M. Design and Synthesis of a 3, 4-Dehydroproline Amide Discovery Library. J. Comb. Chem. 2007, 9, 677-683 and PubChem SID #'s 8143029-8143143.
18. (a) Dieter, R. K.; Yu, H. Synthesis of 3-Pyrrolines, Annulated 3-Pyrrolines, and Pyrroles from α-Amino Allenes. Org. Lett. 2001, 3, 3855-3858. (Pubitemid 33625484)
19. 3-Pyrrolines. J. Org. Chem. 2005, 70, 2109-2119. (Pubitemid 40395146)
20. (c) Dieter, R. K.; Chen, N.; Gore, V. K. Reaction of α-(N- Carbamoyl)alkylcuprates with Enantioenriched Propargyl Electrophiles: Synthesis of Enantioenriched 3-Pyrrolines. J. Org. Chem. 2006, 71, 8755-8760. (Pubitemid 44721946)
21. 3-Pyrrolines via a Ag(I)-Catalyzed Cyclization of Amino Acid Derived Allenes. Synlett 2006, 3100-3104. (Pubitemid 44800013)
22. For a review on the silver-catalyzed allenic cycloisomerization reaction please see: Alvarez-Corral, M.; Munoz-Dorado, M.; Rodriguez-Garcia, I. Chem. Rev. 2008, 108, 3174-3198.
23. in-Boc-Tryptophan Derivatives. J. Chem. Soc., Chem. Commun. 1984, 1699-1700.
24. Castelhano, A.; Horne, S.; Taylor, G.; Billedeu, R.; Krantz, A. Synthesis of α-Amino Acids with β, γ-Unsaturated Side Chains. Tetrahedron 1988, 44, 5451-5466.
25. Brummond, K. M.; Curran, D. P.; Mitasev, B.; Fischer, S. Heterocyclic α-Alkylidene Cyclopentenones Obtained via a Pauson-Khand Reaction of Amino Acid Derived Allenynes. A Scope and Limitation Study Directed Toward the Preparation of a Tricyclic Pyrrole Library. J. Org. Chem. 2005, 70, 1745-1753. (Pubitemid 40300137)
26. For a review of the Pictet-Spengler reaction please, see: Cox, E. D.; Cook, J. M. The Pictet-Spengler Condensation: A New Direction for an Old Reaction. Chem. Rev. 1995, 95, 1797-1842.
27. Brummond, K. M.; Painter, T. O.; Probst, D. A.; Mitasev, B. Rhodium(I)-Catalyzed Allenic Carbocyclization Reaction Affording δ- and ε-Lactams. Org. Lett. 2007, 9, 347-349.
28. Ungemach, F.; DiPierro, M.; Weber, R.; Cook, J.M. Stereospecific Synthesis of Trans-1,3-Disubstituted-1,2,3,4-Tetrahydro-β-Carbolines. J. Org. Chem. 1981, 46, 164-168.
29. Casnati, G.; Dossena, A.; Pochini, A. Electrophilic Substitution in Indoles: Direct Attack at the 2-Position of 3-Alkylindoles. Tetrahedron Lett. 1972, 5277.
30. For a selected example, see: Blaser, G.; Sanderson, J. M.; Batsanov, A. S.; Howard, J. A. K. The Facile Synthesis of a Series of Trytophan Derivatives. Tetrahedron Lett. 2008, 49, 2795-2798.
31. Xie, X.-Q. C.; Chen, J. Z. Data Mining a Small Molecule Drug Screening Representative Subset from NIH PubChem. J. Chem. Inf. Model. 2008, 48, 465-475.
32. Of the databases that our compounds could be compared to, the NIH Molecular Repository was selected because this will be the physical location of the compounds. NIH Molecular Repository (http://mlsmr.glpg.com/MLSMR-HomePage).