Exploring Chemical Space: Recent Advances in Chemistry

  • Yung-Sing WongEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 800)


Recent advances and concepts for exploring chemical space are highlighted in this chapter and show how the synthetic chemical world meets the demand of making large and relevant collection of new molecules for analyzing the biological world more closely.

Key words

Chemical space Multicomponent reactions Biology-oriented synthesis Diversity-oriented synthesis Divergent selectivity 


  1. 1.
    Dobson CM (2004) Chemical space and biology. Nature 432:824–828PubMedCrossRefGoogle Scholar
  2. 2.
    Lipinski C, Hopkins A (2004) Navigating chemical space for biology and medicine. Nature 432:855–861PubMedCrossRefGoogle Scholar
  3. 3.
    Paolini GV, Shapland RHB, van Hoorn WP et al (2006) Global mapping of pharmacological space. Nat Biotechnol 24:805–815PubMedCrossRefGoogle Scholar
  4. 4.
    Reymond J-L, van Deursen R, Blum LC et al (2010) Chemical space as a source for new drugs. Med Chem Comm 1:30–38CrossRefGoogle Scholar
  5. 5.
    Lipinski CA, Lombardo F, Dominy BW et al (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25CrossRefGoogle Scholar
  6. 6.
    Putta S, Beroza P (2007) Shape of things: computer modelling of molecular shape in drug discovery. Curr Top Med Chem 7:1514–1524PubMedCrossRefGoogle Scholar
  7. 7.
    Nicholls A, McGaughey GB, Sheridan RP et al (2010) Molecular Shape and Medicinal Chemistry: A Perspective. J Med Chem 53:3862–3886PubMedCrossRefGoogle Scholar
  8. 8.
    Sauer WHB, Schwarz MK (2003) Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity. J Chem Inf Comput Sci 43:987–1003PubMedCrossRefGoogle Scholar
  9. 9.
    Lovering F, Bikker J, Humblet C (2009) Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J Med Chem 52:6752–6756PubMedCrossRefGoogle Scholar
  10. 10.
    Clemons PA, Bodycombe NE, Carrinski HA et al (2010) Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc Natl Acad Sci USA 107:18787–18792PubMedCrossRefGoogle Scholar
  11. 11.
    Cooper TWJ, Campbell IB, Macdonald, SJF (2010) Factors Determining the Selection of Organic Reactions by Medicinal Chemists and the Use of These Reactions in Arrays (Small Focused Libraries). Angew Chem Int Ed 49: 8082–8091CrossRefGoogle Scholar
  12. 12.
    Hopkins AL, Bickerton GR (2010) Drug discovery. Know your chemical space. Nat Chem Biol 6:482–483PubMedCrossRefGoogle Scholar
  13. 13.
    Burke MD, Schreiber SL (2004) A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed 43:46–58CrossRefGoogle Scholar
  14. 14.
    Jacoby E, Mozzarelli A (2009) Chemogenomic strategies to expand the bioactive chemical space. Curr Med Chem 16:4374–4381PubMedCrossRefGoogle Scholar
  15. 15.
    Dandapani S, Marcaurelle LA (2010) Grand Challenge Commentary: Accessing new chemical space for ‘undruggable’ targets. Nat Chem Biol 6:861–863PubMedCrossRefGoogle Scholar
  16. 16.
    Pulici M, Cervi G, Martina K et al (2003) Use of multicomponent, domino, and other one-pot syntheses on solid phase: Powerful tools for the generation of libraries of diverse and complex compounds. Comb Chem High Throughput Screen 6:693–727PubMedGoogle Scholar
  17. 17.
    Ulaczyk-Lesanko A, Hall DG (2005) Wanted: New multicomponent reactions for generating libraries of polycyclic natural products. Curr Opin Chem Biol 9:266–276PubMedCrossRefGoogle Scholar
  18. 18.
    Sunderhaus JD, Martin SF (2009) Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. Chem Eur J 15:1300–1308PubMedCrossRefGoogle Scholar
  19. 19.
    Toure BB, Hall DG (2009) Natural Product Synthesis Using Multicomponent Reaction Strategies. Chem Rev 109:4439–4486PubMedCrossRefGoogle Scholar
  20. 20.
    Biggs-Houck JE, Younai A, Shaw JT (2010) Recent advances in multicomponent reactions for diversity-oriented synthesis. Curr Opin Chem Biol 14:371–382PubMedCrossRefGoogle Scholar
  21. 21.
    Ramon DJ, Yus M (2005) Asymmetric multicomponent reactions (AMCRs): The new frontier, Angew Chem Int Ed 44:1602–1634CrossRefGoogle Scholar
  22. 22.
    Panek JS, Yang M, Xu F (1992) Diastereoselective additions of chiral (E)-crotylsilanes to in situ generated oxonium ions: a direct asymmetric synthesis of functionalized homoallylic ethers. J Org Chem 57:5790–5792CrossRefGoogle Scholar
  23. 23.
    Pospisil J, Kumamoto T, Marko IE (2006) Highly diastereoselective silyl-modified sakurai multicomponent reaction. Angew Chem Int Ed 45:3357–3360CrossRefGoogle Scholar
  24. 24.
    Lipomi DJ, Panek JS (2005) Three-Component, Room Temperature Crotylation Catalyzed by Solid-Supported Bronsted Acid: Enantioselective Synthesis of Homoallylic Carbamates. Org Lett 7:4701–4704PubMedCrossRefGoogle Scholar
  25. 25.
    Petasis NA, Zavialov IA (1998) Highly Stereocontrolled One-Step Synthesis of anti-beta -Amino Alcohols from Organoboronic Acids, Amines, and alpha -Hydroxy Aldehydes. J Am Chem Soc 120:11798–11799CrossRefGoogle Scholar
  26. 26.
    Candeias NR, Montalbano F, Cal PMSD et al (2010) Boronic Acids and Esters in the Petasis-Borono Mannich Multicomponent Reaction. Chem Rev 110:6169–6193PubMedCrossRefGoogle Scholar
  27. 27.
    Kappe CO (2000) Recent Advances in the Biginelli Dihydropyrimidine Synthesis. New Tricks from an Old Dog. Acc Chem Res 33:879–888PubMedCrossRefGoogle Scholar
  28. 28.
    Chen X-H, Xu X-Y, Liu H et al (2006) Highly Enantioselective Organocatalytic Biginelli Reaction. J Am Chem Soc 128:14802–14803PubMedCrossRefGoogle Scholar
  29. 29.
    Doemling A (2006) Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem Rev 106:17–89CrossRefGoogle Scholar
  30. 30.
    Andreana PR, Liu CC, Schreiber SL (2004) Stereochemical Control of the Passerini Reaction. Org Lett 6:4231–4233PubMedCrossRefGoogle Scholar
  31. 31.
    Wang S-X, Wang M-X, Wang D-X et al (2008) Catalytic enantioselective Passerini three-component reaction. Angew Chem Int Ed 47:388–391CrossRefGoogle Scholar
  32. 32.
    Lou S, Schaus SE (2008) Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols. J Am Chem Soc 130:6922–6923PubMedCrossRefGoogle Scholar
  33. 33.
    Gommermann N, Koradin C, Polborn K et al (2003) Enantioselective, copper(I)-catalyzed three-component reaction for the preparation of propargylamines. Angew Chem Int Ed 42:5763–5766CrossRefGoogle Scholar
  34. 34.
    Carlone A, Cabrera S, Marigo M et al (2007) A new approach for an organocatalytic multicomponent domino asymmetric reaction. Angew Chem Int Ed 46:1101–1104CrossRefGoogle Scholar
  35. 35.
    Grondal C, Jeanty M, Enders D (2010) Organocatalytic cascade reactions as a new tool in total synthesis. Nat Chem 2:167–178PubMedCrossRefGoogle Scholar
  36. 36.
    Enders D, Huettl MRM, Grondal C et al (2006) Control of four stereocenters in a triple cascade organocatalytic reaction. Nature 441:861–863PubMedCrossRefGoogle Scholar
  37. 37.
    Bon RS, Waldmann H (2010) Bioactivity-Guided Navigation of Chemical Space. Acc Chem Res 43:1103–1114PubMedCrossRefGoogle Scholar
  38. 38.
    Koch MA, Schuffenhauer A, Scheck M et al (2005) Charting biologically relevant chemical space: A structural classification of natural products (SCONP), Proc Natl Acad Sci USA 102:17272–17277PubMedCrossRefGoogle Scholar
  39. 39.
    Schuffenhauer A, Ertl P, Roggo S et al (2007) The Scaffold Tree - Visualization of the Scaffold Universe by Hierarchical Scaffold Classification, J Chem Inf Model 47:47–58PubMedCrossRefGoogle Scholar
  40. 40.
    Feher M, Schmidt JM (2003) Property distributions: differences between drugs, natural products and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43:218–227PubMedCrossRefGoogle Scholar
  41. 41.
    Reayi A, Arya P (2005) Natural product-like chemical space: search for chemical dissectors of macromolecular interactions. Curr Opin Chem Biol 9:240–247PubMedCrossRefGoogle Scholar
  42. 42.
    Kumar K, Waldmann H (2009) Synthesis of natural product inspired compound collections. Angew Chem Int Ed 48:3224–3242CrossRefGoogle Scholar
  43. 43.
    Lessmann T, Leuenberger MG, Menninger S et al (2007) Natural Product-Derived Modulators of Cell Cycle Progression and Viral Entry by Enantioselective Oxa Diels-Alder Reactions on the Solid Phase. Chem Biol 14:443–451PubMedCrossRefGoogle Scholar
  44. 44.
    Antonchick AP, Gerding-Reimers C, Catarinella M et al (2010) Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products. Nat Chem 2:735–740PubMedCrossRefGoogle Scholar
  45. 45.
    Tan DS (2005) Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nat Chem Biol 1:74–84PubMedCrossRefGoogle Scholar
  46. 46.
    Thomas GL, Wyatt EE, Spring DR (2006) Enriching chemical space with diversity-oriented synthesis. Curr Opin Drug Discov Develop 9:700–712Google Scholar
  47. 47.
    Peuchmaur M, Wong Y-S (2008) Expanding the chemical space in practice: diversity-oriented synthesis. Comb Chem High Throughput Screen 11:587–601PubMedCrossRefGoogle Scholar
  48. 48.
    Dandapani S, Marcaurelle LA (2010) Current strategies for diversity-oriented synthesis. Curr Opin Chem Biol 14:362–370PubMedCrossRefGoogle Scholar
  49. 49.
    Biggs-Houck JE, Younai A, Shaw JT (2010) Recent advances in multicomponent reactions for diversity-oriented synthesis. Curr Opin Chem Biol 14:371–382PubMedCrossRefGoogle Scholar
  50. 50.
    Kumagai N, Muncipinto G, Schreiber SL (2006) Short synthesis of skeletally and stereochemically diverse small molecules by coupling Petasis condensation reactions to cyclization reactions. Angew Chem Int Ed 45:3635–3638CrossRefGoogle Scholar
  51. 51.
    Schaus JV, Jain N, Panek JS (2000) Asymmetric synthesis of homoallylic amines and functionalized pyrrolidines via direct amino-crotylation of in situ generated imines. Tetrahedron 56:10263–10274CrossRefGoogle Scholar
  52. 52.
    Flamme EM, Roush WR (2002) Enantioselective Synthesis of 1,5-anti- and 1,5-syn-Diols Using a Highly Diastereoselective One-Pot Double Allylboration Reaction Sequence. J Am Chem Soc 124:13644–13645PubMedCrossRefGoogle Scholar
  53. 53.
    Westermann B, Ayaz M, van Berkel SS (2010) Enantiodivergent Organocascade Reactions. Angew Chem Int Ed 49:846–849Google Scholar
  54. 54.
    Simmons B, Walji AM, MacMillan DWC (2009) Cycle-Specific Organocascade Catalysis: Application to Olefin Hydroamination, Hydro-oxidation, and Amino-oxidation, and to Natural Product Synthesis. Angew Chem Int Ed 48:4349–4353CrossRefGoogle Scholar
  55. 55.
    Sunderhaus JD, Martin SF (2009) Applications of multicomponent reactions to the synthesis of diverse heterocyclic scaffolds. Chem Eur J 15:1300–1308PubMedCrossRefGoogle Scholar
  56. 56.
    Di Micco S, Vitale R, Pellecchia M et al (2009) Identification of Lead Compounds as Antagonists of Protein Bcl-xL with a Diversity-Oriented Multidisciplinary Approach. J Med Chem 52:7856–7867PubMedCrossRefGoogle Scholar
  57. 57.
    Muncipinto G, Kaya T, Wilson JA et al (2010) Expanding Stereochemical and Skeletal Diversity Using Petasis Reactions and 1,3-Dipolar Cycloadditions. Org Lett 12:5230–5233PubMedCrossRefGoogle Scholar
  58. 58.
    Marcaurelle LA, Comer E, Dandapani S et al (2010) An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors. J Am Chem Soc 132:16962–16976PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Département de Pharmacochimie MoléculaireUJF-Université Grenoble 1GrenobleFrance

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