The Basics of Diversity‐Oriented Synthesis

In this chapter, the underlying ideas behind diversity-oriented synthesis are introduced. The relationship between diversity-oriented synthesis and combinatorial chemistry is discussed, and the rationale behind the use of diversity-oriented synthesis as a tool for the discovery of biologically active molecules is explained. Common synthetic strategies for the efficient generation of structurally diverse compound collections are then introduced. In the second part of the chapter we discuss recent examples of diversity-oriented syntheses, with examples taken from our own research and from the wider community. These examples seek to illustrate the imaginative ways in which the various synthetic strategies have been implemented and to represent the current state of the art in diversity-oriented synthesis.

[1]  David R Spring,et al.  Is synthesis the main hurdle for the generation of diversity in compound libraries for screening? , 2009, Expert opinion on drug discovery.

[2]  Stuart L. Schreiber,et al.  Gold(I)-Catalyzed Coupling Reactions for the Synthesis of Diverse Small Molecules Using the Build/Couple/Pair Strategy , 2009, Journal of the American Chemical Society.

[3]  Andreas Bender,et al.  Diversity-oriented synthesis; a spectrum of approaches and results. , 2008, Organic & biomolecular chemistry.

[4]  Suzanne Fergus,et al.  Skeletal diversity construction via a branching synthetic strategy. , 2006, Chemical communications.

[5]  Stephen J Haggarty,et al.  The principle of complementarity: chemical versus biological space. , 2005, Current opinion in chemical biology.

[6]  Stuart L. Schreiber,et al.  Stereoselective Synthesis of over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays , 1998 .

[7]  David R Spring,et al.  Chemical genetics to chemical genomics: small molecules offer big insights. , 2005, Chemical Society reviews.

[8]  Stuart L. Schreiber,et al.  Skeletally Diverse Small Molecules Using a Build/Couple/Pair Strategy , 2009, Organic letters.

[9]  Victoria Gilman,et al.  HAND JIVE: Summer researchers—deaf and hearing—at James Madison put a twist on hands-on learning , 2004 .

[10]  Martin Stahl,et al.  Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. , 2003, Journal of medicinal chemistry.

[11]  Stuart L. Schreiber,et al.  Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays , 2002, Nature.

[12]  W. Patrick Walters,et al.  A guide to drug discovery: Designing screens: how to make your hits a hit , 2003, Nature Reviews Drug Discovery.

[13]  Jared T. Shaw,et al.  Synthesis of diverse lactam carboxamides leading to the discovery of a new transcription-factor inhibitor. , 2007, Angewandte Chemie.

[14]  Stuart L Schreiber,et al.  A planning strategy for diversity-oriented synthesis. , 2004, Angewandte Chemie.

[15]  Stuart L Schreiber,et al.  Small molecules: the missing link in the central dogma , 2005, Nature chemical biology.

[16]  Stuart L Schreiber,et al.  Discovery of an inhibitor of a transcription factor using small molecule microarrays and diversity-oriented synthesis. , 2003, Journal of the American Chemical Society.

[17]  A. Hopkins,et al.  Navigating chemical space for biology and medicine , 2004, Nature.

[18]  P. Bartlett,et al.  Synthetic strategies in combinatorial chemistry. , 1997, Current opinion in chemical biology.

[19]  David R Spring,et al.  Gemmacin B: bringing diversity back into focus. , 2008, Organic & biomolecular chemistry.

[20]  William Lewis,et al.  Synthesis of natural-product-like scaffolds in unprecedented efficiency via a 12-fold branching pathway , 2011 .

[21]  David R Spring,et al.  Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. , 2010, Nature communications.

[22]  David R Spring,et al.  Diversity-oriented synthesis. , 2009, Chemical record.

[23]  D. Young,et al.  Accessing skeletal diversity using catalyst control: formation of n and n + 1 macrocyclic triazole rings. , 2009, Organic letters.

[24]  Giovanni Muncipinto,et al.  Short synthesis of skeletally and stereochemically diverse small molecules by coupling petasis condensation reactions to cyclization reactions. , 2006, Angewandte Chemie.

[25]  David R Spring,et al.  Exploiting domino enyne metathesis mechanisms for skeletal diversity generation. , 2008, Chemical communications.

[26]  Wolfgang H. B. Sauer,et al.  Molecular Shape Diversity of Combinatorial Libraries: A Prerequisite for Broad Bioactivity , 2003, J. Chem. Inf. Comput. Sci..

[27]  Stuart L Schreiber,et al.  Generating Diverse Skeletons of Small Molecules Combinatorially , 2003, Science.

[28]  Stuart L. Schreiber,et al.  Stereochemical and Skeletal Diversity Arising from Amino Propargylic Alcohols , 2010, Organic letters.

[29]  Andreas Bender,et al.  The discovery of antibacterial agents using diversity-oriented synthesis. , 2009, Chemical communications.

[30]  J. Andrew Grant,et al.  Small Molecule Shape-Fingerprints , 2005, J. Chem. Inf. Model..

[31]  Craig W Lindsley,et al.  Application of combinatorial chemistry science on modern drug discovery. , 2008, Journal of combinatorial chemistry.

[32]  Alan L Harvey,et al.  Natural products as a screening resource. , 2007, Current opinion in chemical biology.

[33]  David R Spring,et al.  Diversity-oriented synthesis; a challenge for synthetic chemists. , 2003, Organic & biomolecular chemistry.

[34]  A. Bender,et al.  Diversity-oriented synthesis of macrocyclic peptidomimetics , 2011, Proceedings of the National Academy of Sciences.

[35]  Andreas Bender,et al.  Anti-MRSA agent discovery using diversity-oriented synthesis. , 2008, Angewandte Chemie.

[36]  J. Porco,et al.  An approach to skeletal diversity using functional group pairing of multifunctional scaffolds. , 2007, Organic letters.

[37]  S. Schreiber,et al.  Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. , 2000, Organic letters.

[38]  S. Schreiber,et al.  Target-oriented and diversity-oriented organic synthesis in drug discovery. , 2000, Science.

[39]  Tudor I. Oprea,et al.  Chemography: the Art of Navigating in Chemical Space , 2000 .

[40]  Stuart L. Schreiber,et al.  Organic chemistry: Molecular diversity by design , 2009, Nature.

[41]  Anang A Shelat,et al.  Scaffold composition and biological relevance of screening libraries. , 2007, Nature chemical biology.

[42]  Derek S. Tan,et al.  Diversity-oriented synthesis: exploring the intersections between chemistry and biology , 2005, Nature chemical biology.

[43]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[44]  David R Spring,et al.  Identification of an anti-MRSA dihydrofolate reductase inhibitor from a diversity-oriented synthesis. , 2008, Chemical communications.

[45]  G. Schneider,et al.  The State of the Art of Chemical Biology , 2009, Chembiochem : a European journal of chemical biology.

[46]  Adam Nelson,et al.  Synthesis of Natural-Product-Like Molecules with Over Eighty Distinct Scaffolds** , 2008, Angewandte Chemie.

[47]  Kieron M. G. O'Connell,et al.  Diversity-oriented synthesis of bicyclic and tricyclic alkaloids. , 2010, Chemical communications.

[48]  D. Seebach,et al.  Alkylation of amino acids without loss of the optical activity: preparation of .alpha.-substituted proline derivatives. A case of self-reproduction of chirality , 1983 .

[49]  Peter Schneider,et al.  Iclaprim, a novel diaminopyrimidine with potent activity on trimethoprim sensitive and resistant bacteria. , 2003, Bioorganic & medicinal chemistry letters.

[50]  Stuart L Schreiber,et al.  Towards the optimal screening collection: a synthesis strategy. , 2008, Angewandte Chemie.

[51]  P. Hanson,et al.  "Click, click, cyclize": a DOS approach to sultams utilizing vinyl sulfonamide linchpins. , 2009, Organic letters.

[52]  P. Clemons,et al.  Route to three-dimensional fragments using diversity-oriented synthesis , 2011, Proceedings of the National Academy of Sciences.

[53]  B. Stockwell.  Chemical genetics: ligand-based discovery of gene function , 2000, Nature Reviews Genetics.

[54]  A. Bender,et al.  Assessment of structural diversity in combinatorial synthesis. , 2005, Current opinion in chemical biology.

[55]  Tudor I. Oprea,et al.  Chemical space navigation in lead discovery. , 2002, Current opinion in chemical biology.

[56]  M. Congreve,et al.  A 'rule of three' for fragment-based lead discovery? , 2003, Drug discovery today.

[57]  Stu Borman.  RESCUING COMBICHEM: Diversity-oriented synthesis aims to pick up where traditional combinatorial chemistry left off , 2004 .

[58]  C. Dobson.  Chemical space and biology , 2004, Nature.

[59]  J. Vederas,et al.  Drug Discovery and Natural Products: End of an Era or an Endless Frontier? , 2009, Science.

[60]  A. Mann,et al.  1,3-STEREOCONTROL WITH BROMOALLENES. SYNTHESIS OF N-BOC-ADDA, THE UNIQUE AMINO ACID PRESENT IN SEVERAL INHIBITORS OF SERINE/THREONINE PHOSPHATASES , 1996 .