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Diversity-oriented synthesis (DOS), which describes the synthesis of structurally diverse collections of small molecules, was developed, in part, to address combinatorial chemistry's shortfalls. In this paper, we hope to give an indication of what can be achieved using the DOS approach to library generation. We describe some of the most successful strategies utilized in DOS, with special focus on our own area of interest; DOS from simple, pluripotent starting materials.

The development of a novel method to attenuate bacterial virulence is reported, which is based upon the use of designed transition-state analogues to select human catalytic antibodies capable of degrading bacterial quorum-sensing molecules.

The emergence and increasing prevalence of multi-drug resistance bacterial strains represents a clear and present danger to the standard of human healthcare as we know it. The systematic study of modulating biological systems using small molecules (so-called chemical genetics) offers a potentially fruitful means of discovering critically needed new antibacterial agents. Crucial to the success of this approach is the ready availability of functionally diverse small molecule collections. In this feature article we focus upon the use of a diversity-oriented synthesis (DOS) approach for the efficient generation of such compound collections, and discuss the utility of DOS for the discovery of new antibacterial agents.

Building a better library: The synthesis of a library of natural-product-like small molecules with unprecedented scaffold diversity has been reported (see scheme; Ns = nosylate). The library represents a significant advancement in the capability of synthetic chemists to generate structurally diverse and complex small molecules in a rapid manner.

The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.

The antibacterial drug azithromycin has clinically beneficial effects at sub-inhibitory concentrations for the treatment of conditions characterized by chronic Pseudomonas aeruginosa infection, such as cystic fibrosis. These effects are, in part, the result of inhibition of bacterial biofilm formation. Herein, the efficient synthesis of azithromycin in 4 steps from erythromycin and validation of the drug's ability to inhibit biofilm formation at sub-MIC (minimum inhibitory concentration) values are reported. Furthermore, the synthesis of immobilized and biotin-tagged azithromycin analogues is described. These chemical probes were used in pull-down assays in an effort to identify azithromycin's binding partners in vivo. Results from these assays revealed, as expected, mainly ribosomal-related protein binding partners, suggesting that this is the primary target of the drug. This was further confirmed by studies using a P. aeruginosa strain containing plasmid-encoded ermC, which expresses a protein that modifies 23S rRNA and so blocks macrolide entry to the ribosome. In this strain, no biofilm inhibition was observed. This work supports the hypothesis that the sub-inhibitory effects of azithromycin are mediated through the ribosome. Moreover, the synthesis of these chemical probes, and proof of their utility, is of value in global target identification in P. aeruginosa and other species.

In the context of diversity-oriented synthesis, the exploration and optimization of the domino metathesis of decorated norbornenes allowed complex polycyclic architectures to be generated in a highly efficient and atom-economical process.

The screening of a diversity-oriented synthesis library followed by structure-activity relationship investigations have led to the discovery of an anti-MRSA agent which operates as an inhibitor of Staphylococcus aureus dihydrofolate reductase.

In the context of diversity-oriented synthesis, the exploration and optimization of the domino metathesis of decorated norbornenes allowed complex polycyclic architectures to be generated in a highly efficient and atom-economical process.

Since our emerging area article, diversity-oriented synthesis (DOS), which aims to prepare efficiently collections of skeletally diverse small molecules, has developed in the synthetic approaches it employs. This article describes three general strategies, highlighting some successful examples. The utility of DOS, in the interrogation of chemical space and in the identification of novel biologically active lead compounds, is also discussed.

Using an atropdiastereoselective oxidative biaryl coupling as the key step, the total synthesis of the ellagitannin natural product sanguiin H-5 is reported. Both organomagnesium and organozinc based metalation methodologies were used to efficiently construct the strained medium-ring core of the natural product.

Diastereomeric 2-methoxycyclopentyl analogues of a natural quorum sensing signaling molecule from Pseudomonas aeruginosa were synthesized and screened in pigment production assays with P. aeruginosa and Serratia strain ATCC39006.

Since our emerging area article, diversity-oriented synthesis (DOS), which aims to prepare efficiently collections of skeletally diverse small molecules, has developed in the synthetic approaches it employs. This article describes three general strategies, highlighting some successful examples. The utility of DOS, in the interrogation of chemical space and in the identification of novel biologically active lead compounds, is also discussed.

The search for new molecular entities in drug discovery and chemical genetic programs requires the screening of high-quality collections of structurally diverse small molecules. The design and synthesis of such collections remains a major challenge to synthetic chemists. Recent strategies and results are presented in the context of the chemical space being interrogated.

This article covers the diversity-oriented synthesis (DOS) of small molecules in order to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach useful for chemical genetics and drug discovery programmes. Nature synthesizes a rich structural diversity of small molecules, however, unfortunately, there are some disadvantages with using natural product sources for diverse small-molecule discovery. Nevertheless we have a lot to learn from nature. The efficient chemical synthesis of structural diversity (and complexity) is the aim of DOS. Highlights of this article include a discussion of nature's and synthetic chemists' strategies to obtain structural diversity and an analysis of molecular descriptors used to classify compounds. The assessment of how successful one diversity-oriented synthesis is vs another is subjective; therefore we use freely available software (www.cheminformatics.org/diversity) to assess structural diversity in any combinatorial synthesis.

A wide range of organozinc substrates may be oxidized in the presence of catalytic copper to give carbon-carbon bonds in high yield.

A wide range of organozinc substrates may be oxidized in the presence of catalytic copper to give carbon-carbon bonds in high yield.

Cell-permeable small molecules can be used to modulate protein function selectively, rapidly, reversibly, and conditionally with temporal and quantitative control in biological systems. The identification of these chemical probes can require the screening of large numbers of small molecules. With the advent of new technologies, small-molecule high-throughput screening is widely available. This Review focuses on the emerging technologies of microarray screening platforms and high-content screening formats.

The search for new molecular entities in drug discovery and chemical genetic programs requires the screening of high-quality collections of structurally diverse small molecules. The design and synthesis of such collections remains a major challenge to synthetic chemists. Recent strategies and results are presented in the context of the chemical space being interrogated.

Over the last decade or so, a wealth of research has established that bacteria communicate with one another using small molecules. These signals enable the individuals in a population to coordinate their behaviour. In the case of pathogens, this behaviour may include decisions such as when to attack a host organism or form a biofilm. Consequently, such signalling systems are excellent targets for the development of new antibacterial therapies. In this review, we assess how Gram-negative bacteria use small molecules for cell–cell communication, and discuss the main approaches that have been developed to interfere with it.

Serratia marcescens is an important cause of opportunistic human infections. Many, but not all, strains produce prodigiosin, a secondary metabolic, red-pigment antibiotic, the biosynthesis of which is directed by the pig gene cluster. Quorum sensing (QS) involves the production and detection of chemical signal molecules as a means to regulate gene expression in response to population cell density. Several strains of S. marcescens have previously been shown to possess an N-acyl-l-homoserine lactone (aHSL) QS system. This study aimed to determine the impact of introducing, by phage-mediated horizontal gene transfer, a biosynthetic gene cluster (pig) and a regulatory locus (aHSL QS) into strains lacking the respective trait. The pig cluster from S. marcescens ATCC 274 (Sma 274) was transferred to the non-pigmented strain, S. marcescens strain 12 (Sma 12). In the engineered strain, pigment was expressed and brought under the control of the recipient's native regulatory systems (aHSL QS and luxS). Moreover, transfer of the aHSL locus from Sma 12 to the non-QS Sma 274 resulted in the imposition of aHSL control onto a variety of native traits, including pigment production. In addition, during this study, the QS regulon of the clinical strain, Sma 12, was characterized, and some novel QS-regulated traits in S. marcescens were identified. The results have implications for the evolution and dissemination of biosynthetic and QS loci, illustrating the genetic modularity and ease of acquisition of these traits and the capacity of phages to act as vectors for horizontal gene transfer.

The creation of carbon-carbon and carbon-heteroatom bonds by the oxidation of organocuprates is useful in a range of challenging contexts including the formation of biaryl bonds within medium rings, diene synthesis and the coupling of tertiary carbon centres. This tutorial review introduces these applications and recent developments which have served to improve its functional group tolerance and its utility in organic synthesis.

Aryl lithium reagents formed by directed lithiation reactions undergo transmetallation with copper(I) salts to form organocuprates, which may be efficiently oxidized to yield ortho-substituted biaryls.

A biaryl banquet! Biphenyls with four ortho substituents, heteroaromatic compounds, iodinated biaryls, and medium rings containing biaryls are all readily synthesized by organocuprate oxidation. The utility of this new methodology is illustrated by the efficient synthesis of the medium-ring core of sanguiin H-5 (see scheme).

Production of virulence factors and secondary metabolites is regulated in the phytopathogen Erwinia carotovora by quorum sensing involving N-acylated homoserine lactone (AHL) signaling molecules. Non-hydrolyzable AHL analogues were synthesized and screened in vivo. The biological activity of each compound was correlated with its ability to bind Erwinia AHL receptor proteins (LuxR homologues) in vitro. There is an excellent correlation between carbapenem production in vivo and in vitro binding to CarR. However, no such correlation could be found between exoprotease production and analogue binding to EccR. Our data are consistent with the involvement of a third, as yet uncharacterized LuxR homologue.

This article covers the combinatorial synthesis of small molecules with maximal structural diversity to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach. Nature synthesises diverse small molecules, but there are disadvantages with using natural product sources. The efficient chemical synthesis of structural diversity (and complexity) is the aim of diversity-oriented synthesis, and recent progress is reviewed. Specific highlights include a discussion of strategies to obtain structural diversity and an analysis of molecular descriptors used to classify compounds. The assessment of how successful one synthesis is versus another is subjective, therefore we test-drive software to assess structural diversity in combinatorial synthesis, which is freely available via a web interface.

The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae . Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P 2 , suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer.

The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues (small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.

Bromopolystyrene beads with diameters of up to 600 microm have been derivatized completely, via bromine-magnesium exchange and interception with electrophiles, to yield high quality solid-supported reagents, scavengers and solid supports for use in diversity-oriented synthesis.

The efficient, simultaneous synthesis of structurally diverse compounds, better known as diversity-oriented synthesis (DOS), is not obvious, and remains a challenge to synthetic chemistry. This personal account details why DOS has such enormous implications for the discovery of small molecules with desired properties, such as catalysts, synthetic reagents, biological probes and new drugs, Also, I describe the evolution behind the current state-of-play of DOS.

Diversity-oriented synthesis of structurally complex and diverse small molecules can be used as the first step in a process to explore cellular and organismal pathways. The success of this process is likely going to be dependent on advances in the synthesis of small molecules having natural product-like structures in an efficient and stereoselective manner. The development, scope, and mechanism of the oxidation of organocuprates was investigated and exploited in the atropdiastereoselective synthesis of biaryl-containing medium rings (9-, 10-, and 11-membered rings). The methodology was performed on high-capacity, large polystyrene beads by metalating aryl bromides with i-PrBu(2)MgLi, followed by transmetalating with CuCN x 2LiBr and then oxidizing with 1,3-dinitrobenzene, and was used in a diversity-oriented synthesis of biaryl-containing medium rings (library total theoretical maximum 1412 members). The high capacity beads were arrayed into 384-well plates and, using a process optimized during the development of a one bead/one stock solution technology platform, converted into arrays of stock solutions, with each stock solution containing largely one compound. These stock solutions were used in numerous phenotypic and protein-binding assays. The process described outlines a pathway that we feel will contribute to a comprehensive and systematic chemical approach to exploring biology (chemical genetics).

The development of a method for the amplification of PNA tags (Svensen et al., in this issue of Chemistry & Biology) should expand the range of biological targets amenable to screening using PNA-encoded combinatorial libraries and thus facilitate the discovery of new biologically useful agents.

Two approaches have emerged for creating libraries of compounds for use in biological screening assays for drug discovery — fragment-based ligand design and diversity-oriented synthesis. Advocates of each approach discuss their favoured strategy.

Experimental Techniques and Apparatus Except as otherwise indicated, reactions were carried out under argon with dry, freshly distilled solvents. Tetrahydrofuran was distilled from sodium/benzophenone ketyl. Anhydrous 2-methyltetrahydrofuran (Aldrich, racemic) was stored over activated molecular sieves. Dichloromethane was distilled from calcium hydride. n-BuLi in hexane (Aldrich) and t-BuLi in pentane (Aldrich) were titrated with 1,10phenanthroline and anhydrous 2-butanol before use. All other reagents were purif ied in accordance with the instructions in “Purif ication of Laboratory Chemicals” or used as obtained from commercial sources. Yields refer to chromatographically and spectroscopically pure compounds. All reactions were monitored by thin layer chromatography (TLC) using glass plates precoated with E. Merck silica gel 60 F254 or aluminium oxide 60 F254. Visualization was by the quenching of UV f luorescence (λmax=254nm) or by staining with ceric ammonium molybdate or Dragendorff ’ s reagent (0.08% w/v bismuth subnitrate and 2% w/v KI in 3M aq. AcOH). Retention factors (Rf) are quoted to 0.01. Melting points were obtained using a Mel-Temp II melting point apparatus and are uncorrected. Infrared spectra were recorded either as a thin f ilm between NaCl plates or as a KBr disc on a Nicolet 5PC FT-IR spectrometer with internal referencing. Absorption maxima (νmax) are reported in wavenumbers (cm) and the following abbreviations are used: w, weak; m, medium; s, strong; br, broad. Proton magnetic resonance spectra were recorded on Varian Mercury400 (400MHz), Bruker Avance DMX500 (500MHz), and Varian Unity/Inova500 (500MHz) spectrometers. Proton assignments are supported by H-H COSY, HMQC, NOESY and GOESY spectra where necessary. Chemical shifts (δH) are quoted in ppm and are referenced to tetramethylsilane (internal). Coupling constants (J) are reported in Hertz to the nearest 0.5Hz. Data are reported as follows: chemical shift, integration, multiplicity [br, broad; s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; sept, septet; m, multiplet; or as a combination of these (e.g. dd, dt, etc.)], coupling constant(s) and assignment. Diastereotopic protons are assigned as X and X', where the ' indicates the lower f ield proton. Carbon magnetic resonance spectra were recorded on Varian Mercury400 (100MHz) and Varian Unity/Inova500 (125MHz) spectrometers. Carbon spectra assignments are supported by DEPT editing and where necessary C-H (HMQC) correlations. Chemical shifts (δC) are quoted in ppm to the nearest 0.01ppm, and are referenced to tetramethylsilane (internal). Fluorine magnetic resonance spectra (F) were recorded on a Varian Mercury300 (282MHz) spectrometer. Chemical shifts (δF) are quoted in ppm to the nearest 0.01ppm and are referenced to CF3CH2OH (external). 4

The publication of the crystal structures of a bacterial quorum sensing receptor complexed with a variety of ligands (Zou and Nair, 2009) provides a much-needed molecular rationale for the modulation of this intercellular signaling process, which may facilitate the development of new therapeutic agents.

The biomimetic synthesis of a pentacyclic alkaloid (keramaphidin B, 1), an intermediate in the biogenetic pathway to the manzamine alkaloids, has been achieved. Compound 1 was formed by an intramolecular Diels-Alder reaction of macrocycle 2 in buffer followed by reduction with NaBH

The biomimetic synthesis of a pentacyclic alkaloid (keramaphidin B, 1), an intermediate in the biogenetic pathway to the manzamine alkaloids, has been achieved. Compound 1 was formed by an intramolecular Diels-Alder reaction of macrocycle 2 in buffer followed by reduction with NaBH4. This reaction provides the first direct experimental evidence for the authors' biosynthetic hypothesis.

International audience; Improved conditions for the preparation of 17 are reported together with the synthesis of an advanced intermediate 38 en route to keramaphidin B, a plausible biogenetic precursor to the manzamines.Improved conditions for the preparation of 17 are reported together with the synthesis of an advanced intermediate 38 en route to keramaphidin B, a plausible biogenetic precursor to the manzamines.

Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved. Cheminformatic analysis of the compounds produced suggests that they reside in biologically relevant regions of chemical space and the compounds were screened for activity against two cancer cell lines.

Summary The maintenance of genomic stability relies on the spindle assembly checkpoint (SAC), which ensures accurate chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bioriented and attached to the mitotic spindle. BUB1 and BUBR1 kinases are central for this process and by interacting with Blinkin, link the SAC with the kinetochore, the macromolecular assembly that connects microtubules with centromeric DNA. Here, we identify the Blinkin motif critical for interaction with BUBR1, define the stoichiometry and affinity of the interaction, and present a 2.2 Å resolution crystal structure of the complex. The structure defines an unanticipated BUBR1 region responsible for the interaction and reveals a novel Blinkin motif that undergoes a disorder-to-order transition upon ligand binding. We also show that substitution of several BUBR1 residues engaged in binding Blinkin leads to defects in the SAC, thus providing the first molecular details of the recognition mechanism underlying kinetochore-SAC signaling., Graphical Abstract Highlights ► Molecular details of the recognition mechanism underlying kinetochore-SAC signalling ► Crystal structure of a BUBR1-Blinkin complex defines an unanticipated BUBR1 region ► A novel Blinkin motif undergoes a disorder-to-order transition upon BUBR1 binding ► Mutation of BUBR1 residues that bind Blinkin lead to an impaired mitotic checkpoint

An ideal fluorescent probe should show the strongest affinity with the relevant target (binding-selectivity) by means of a selective fluorescence change (signal-selectivity). [15]aneNO(2)S(2) (1,4-dioxa-7,13-dithia-10-azacyclopentadecane) based probes usually show high binding selectivity for Ag(+) but signal selectivity for Hg(2+), because Ag(+) can quench or silence the fluorescence. To amplify the Ag(+) binding to the greatest extent, a carbonyl group was positioned between 1,8-naphthalimide and [15]aneNO(2)S(2) which played a key role of displaying selective fluorescence enhancements with Ag(+) through increasing the oxidation potential of the fluorophore, blocking Ag(+) from sterically interacting with the naphthalimide fluorophore, and by acting as a sacrificial donor. Probe 2 can detect Ag(+) with a selective fluorescence enhancement (∼14 fold) and high affinity (K(a) = 1.64 × 10(5) M(-1)).

A carbonyl group was positioned between 1,8-naphthalimide and di-2-picolylamine (DPA) and played a key role of displaying fluorescence enhancements with heavy and transition metal (HTM) ions through increasing the oxidation potential of the fluorophore, blocking HTM ions from sterically interacting with the naphthalimide fluorophore, and by acting as a sacrificial donor.

The screening of large arrays of drug-like small-molecules was traditionally a time consuming and resource intensive task. New methodology developed within our laboratories provides an attractive low cost, 3D microarray-assisted screening platform that could be used to rapidly assay thousands of compounds. As a proof-of-principle the platform was exploited to screen a number of quorum sensing analogs. Quorum sensing is used by bacterium to initiate and spread infection; in this context its modulation may have significant clinical value. 3D microarray slides were probed with fluorescently labeled ligand-binding domains of the LuxR homolog CarR from Erwinia carotovora subsp. carotovora. The 3D microarray platform was used to discover the biologically active chloro-pyridine pharmacophore, which was validated using a fluorometric ligand binding assay and ITC. Analogs containing the chloro-pyridine pharmacophore were found to be potent inhibitors of N-acyl-homoserine-lactone (AHL) mediated quorum sensing phenotypes in Serratia (IC(50) = ∼5 μM) and Pseudomonas aeruginosa (IC(50) = 10-20 μM).

Experimental Techniques and Apparatus Except as otherwise indicated, reactions were carried out under argon with dry, freshly distilled solvents. Tetrahydrofuran was distilled from sodium/benzophenone ketyl. Anhydrous 2-methyltetrahydrofuran (Aldrich, racemic) was stored over activated molecular sieves. Dichloromethane was distilled from calcium hydride. n-BuLi in hexane (Aldrich) and t-BuLi in pentane (Aldrich) were titrated with 1,10phenanthroline and anhydrous 2-butanol before use. All other reagents were purif ied in accordance with the instructions in “Purif ication of Laboratory Chemicals” or used as obtained from commercial sources. Yields refer to chromatographically and spectroscopically pure compounds. All reactions were monitored by thin layer chromatography (TLC) using glass plates precoated with E. Merck silica gel 60 F254 or aluminium oxide 60 F254. Visualization was by the quenching of UV f luorescence (λmax=254nm) or by staining with ceric ammonium molybdate or Dragendorff ’ s reagent (0.08% w/v bismuth subnitrate and 2% w/v KI in 3M aq. AcOH). Retention factors (Rf) are quoted to 0.01. Melting points were obtained using a Mel-Temp II melting point apparatus and are uncorrected. Infrared spectra were recorded either as a thin f ilm between NaCl plates or as a KBr disc on a Nicolet 5PC FT-IR spectrometer with internal referencing. Absorption maxima (νmax) are reported in wavenumbers (cm) and the following abbreviations are used: w, weak; m, medium; s, strong; br, broad. Proton magnetic resonance spectra were recorded on Varian Mercury400 (400MHz), Bruker Avance DMX500 (500MHz), and Varian Unity/Inova500 (500MHz) spectrometers. Proton assignments are supported by H-H COSY, HMQC, NOESY and GOESY spectra where necessary. Chemical shifts (δH) are quoted in ppm and are referenced to tetramethylsilane (internal). Coupling constants (J) are reported in Hertz to the nearest 0.5Hz. Data are reported as follows: chemical shift, integration, multiplicity [br, broad; s, singlet; d, doublet; t, triplet; q, quartet; qui, quintet; sept, septet; m, multiplet; or as a combination of these (e.g. dd, dt, etc.)], coupling constant(s) and assignment. Diastereotopic protons are assigned as X and X', where the ' indicates the lower f ield proton. Carbon magnetic resonance spectra were recorded on Varian Mercury400 (100MHz) and Varian Unity/Inova500 (125MHz) spectrometers. Carbon spectra assignments are supported by DEPT editing and where necessary C-H (HMQC) correlations. Chemical shifts (δC) are quoted in ppm to the nearest 0.01ppm, and are referenced to tetramethylsilane (internal). Fluorine magnetic resonance spectra (F) were recorded on a Varian Mercury300 (282MHz) spectrometer. Chemical shifts (δF) are quoted in ppm to the nearest 0.01ppm and are referenced to CF3CH2OH (external). 4

Vinyldisiloxanes equilibrate with the corresponding silanolates under basic conditions and subsequently undergo palladium catalysed cross coupling with aryl/heteroaryl iodides and bromides.

Through the synthesis of a focused library and SAR investigations, a more potent analogue of gemmacin (discovered in a previous diversity-oriented synthesis (DOS) campaign), gemmacin B, was discovered.