Recent advances in multicomponent reactions for diversity-oriented synthesis

Biggs‐Houck, James E.; Younai, Ashkaan; Shaw, Jared T.

doi:10.1016/j.cbpa.2010.03.003

Cited by 491 publications

(213 citation statements)

References 81 publications

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“…Th is generally means the use of a known methodology that has a literature precedent. In addition, reactions that are capable of rapidly assembling complex molecular skeletons and generating complex functionalization motifs, such as pericyclic, cascade, multicomponent 58 and tandem reactions, are particularly valuable 35 . Folding-type DOS processes typically exploit the remarkable utility of ring-closing metathesis to generate complex molecular scaff olds from much simpler substrates 9,35,57 .…”

Section: Dos and Synthetic Methodologymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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Biologically active molecules can be identifi ed through the screening of small-molecule libraries. Defi ciencies in current compound collections are evidenced by the continuing decline in drugdiscovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an effi cient manner. Recent years have witnessed signifi cant achievements in the fi eld, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.S mall molecular mass chemical entities (so-called small molecules) have always been of interest in chemistry and biology because of their ability to exert powerful eff ects on the functions of macromolecules that comprise living systems 1 -3 . Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry (wherein molecules are sought to chemically modify disease states) and chemical genetics (wherein molecules are used as ' probes ' to study biological systems 3 -8 . Such chemical modulators are most commonly identifi ed by screening collections or ' libraries ' of small molecules. However, a crucial consideration is what compounds to use 3,9,10 . A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration. Th e effi cient creation of functionally diverse small-molecule collections presents a formidable challenge.Traditionally, when a specifi c biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3,9,11 . Th e selection criteria are dramatically complicated if the subsequent screening is ' unbiased ' ; that is, when the precise nature of the biological target is unknown (for example, in a random drug-discovery screen) 4,3,12 . In such situations, the structural features required in the small molecules cannot be defi ned a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specifi c biological target (or family of related targets) is not logical, whereas the random screening of many such ' focused ' collections can be extremely time and cost demanding.In general, the identifi cation of biologically active small molecules may be aided by screening functionally diverse compound libraries (that is, libraries that display a broad range of biological activities), as it has been argued that a greater sample of the bioactive chemical universe (that is, of all bioactive molecules) increases the chance of identifying a compound with the desired properties 3,10,13,14 . As a corollary, ...

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Section: Dos and Synthetic Methodologymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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“…Indeed, the easy access to a wide variety of starting materials, comparably mild reaction conditions and the wide spectrum of attainable products place such reactions at the heart of many combinatorial approaches and also form the bedrock for the generation of small product libraries. 1,2 In pharmaceutical chemistry, isocyanide based MCRs (IMCRs), such as the Ugi and Passerini reactions, are of particular interest as they allow the synthesis of peptidomimetic compounds, i.e. compounds which 'resemble' natural, peptide like substances.…”

Section: Introductionmentioning

confidence: 99%

Sulfur, selenium and tellurium pseudopeptides: Synthesis and biological evaluation

Shaaban

Sasse

Burkholz

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Typical variable building blocks include amines, aldehydes, ketoesters, isocyanides, etc, as seen in the Hantszch (11), Biginelli (12) and Ugi-type (13) MCRs. It can be argued that these processes and others that meet both of these criteria are the most powerful MCRs because they will generate maximum complexity with minimal effort (14). We discovered a mechanistically distinct four-component reaction (4CR, Fig.…”

mentioning

confidence: 99%

Ammonia synthons for the multicomponent assembly of complex γ-lactams

Tan

Martin

Fettinger

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The synthesis of γ-lactams that are unsubstituted at the 1-position (nitrogen) as well as their subsequent N -functionalization is reported. A recently discovered four-component reaction (4CR) is employed with either an ammonia precursor or a protected form of ammonia that can be deprotected in a subsequent synthetic step. These methods represent the first multicomponent assembly of complex lactam structures that are unsubstituted at nitrogen. In addition, two methods for the introduction of nitrogen substituents that are not possible through the original 4CR are reported. X-ray crystallographic analysis of representative structures reveals conformational changes in the core structure that will enable future deployment of this chemistry in the design and synthesis of diverse collections of lactams suitable for the discovery of new biological probes.

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Recent advances in multicomponent reactions for diversity-oriented synthesis

Cited by 491 publications

References 81 publications

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Sulfur, selenium and tellurium pseudopeptides: Synthesis and biological evaluation

Ammonia synthons for the multicomponent assembly of complex γ-lactams

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