Search

In this feature article we discuss the construction of biaryl-containingmedium-sized rings by organocuprate oxidation and the applicationof this chemistry in the synthesis of members of the ellagitanninfamily of natural products. A concise and efficient total synthesisof the ellagitannin sanguiin H-5 is highlighted. Studies towardsthe synthesis of elaeocarpusin are also presented. 1 Introduction 2 Results and Discussion 2.1 Total Synthesis of Sanguiin H-5 2.2 Studies towards the Total Synthesis of Elaeocarpusin 2.2.1 Towards Elaeocarpusin: Organocuprate Oxidation 2.2.2 Towards Elaeocarpusin: A Double Esterification Approach 3 Conclusions

The synthesis of bacterial quorum-sensing regulator N-(3-oxohexanoyl)-L-homoserine lactone (OHHL) and biotin-tagged OHHL is reported. The latter will be applied to developing a general method to address the 'target identification problem' in chemical genetics.

Antibacterial drugs have played an essential role in the global increase in quality of life and life expectancy. However, these gains are at serious risk owing to bacterial drug resistance by so-called “superbugs”, such as methicillin-resistant Staphylococcus aureus (MRSA). The discovery of new antibiotics with novel modes of action is vital to tackle the threat of multidrug-resistant bacteria. Traditionally, antibiotics have been discovered from natural sources; however, there are many disadvantages to using extracts (e.g. limited availability, bioactive constituent identification, and complex analogue synthesis). These problems have led to a complementary approach of synthesizing structurally diverse, natural-product-like small molecules directly and efficiently, an approach known as diversity-oriented synthesis (DOS). Whereas compound collections of a common scaffold decorated with diverse building blocks have been synthesized efficiently, there are limited examples of the synthesis of small molecules with a high degree of skeletal diversity (usually by a build–couple–pair strategy). Previously, we have used a diazoacetate starting unit to mimic nature8s divergent synthetic strategy with acetyl CoA (by a pluripotent functional-group strategy) to synthesize compounds with natural-product scaffolds (e.g. cocaine and warfarin). Herein, we report the use of a solid-supported phosphonate unit to synthesize 242 drug-like compounds based on 18 natural-product-like scaffolds in two to five steps and their use in discovering a new structural class of antibiotic with anti-MRSA activity. The solid-supported phosphonate 1 (Scheme 1) was identified as an attractive DOS starting unit for three key reasons. First, the reactive phosphonate functionality permits the stereoselective formation of a,b-unsaturated acyl imidazolidinones (2) that could be used to generate enantioselectively a wide range of scaffolds that can be diversified further. Second, the imidazolidinone linker not only enables twopoint binding of chiral catalysts but also permits divergent cleavage of the exocyclic acyl group (hydrolysis, reduction, esterification, and amide formation). Thirdly, immobilization of 1 on a silyl polystyrene support simplified reaction optimization and work-up procedures in the multistep parallel synthesis (total of over 1000 individual steps), thereby allowing the efficient production of milligram quantities of 242 compounds without the requirement for automation equipment. In the first step of the diversity-oriented synthesis, 1 was treated with aldehyde building blocks (aryl, heteroaryl, and alkyl; see the Supporting Information) to deliver twelve a,bunsaturated acyl imidazolidinones (2). The second steps of the solid-supported synthesis exploited three catalytic, enantioselective, divergent reaction pathways (Scheme 1): 1) [2+3] cycloaddition (reaction b, ee 60–65%, de 7899%), 2) dihydroxylation (reaction c, ee 88–91%), and 3) [4+2] cycloaddition (reaction d, ee 89–98%, de 74– 74%). Similar selectivities were observed when repeating the reactions in solution with a triisopropylsilyl-protected linker (as opposed to the diisopropylpolystyrene group; see the Supporting Information). The reactions were also conducted with achiral catalysts to give racemic products, which were used for the later steps of the synthesis. This procedure enabled the diversity-oriented synthesis to be streamlined to half the size, yet permitted the enantioselective synthesis of hits during the structure–activity relationship stages of this [*] Dr. G. L. Thomas, R. J. Spandl, F. G. Glansdorp, Dr. M. Ladlow, Dr. D. R. Spring Department of Chemistry, University of Cambridge Lensfield Road, Cambridge, CB2 1EW (UK) Fax: (+44) 1223-336362 E-mail: drspring@ch.cam.ac.uk Homepage: http://www-spring.ch.cam.ac.uk/

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.

1.1 Introduction 1 1.2 Exploring Chemical Space 2 1.3 Sources of Skeletally Diverse Small Molecules 3 1.4 Enriching Chemical Space Using DOS 4 1.5 The Subjective Nature of ‘Diversity’ 4 1.6 Differing Strategies Towards Similar Goals 5 1.6.1 DOS based on privileged scaffolds 5 1.6.2 DOS from simple starting materials 6 1.7 Generating Skeletal Diversity 6 1.7.1 Strategy 1: Pluripotent Functional Groups 7 1.7.3 Strategy 3: Folding Pathways 10 1.8 DOS and Solid-Phase Organic Synthesis 10 1.8.1 An Overview of Linkage Cleavage Strategies 11 1.8.2 Diversity Linkers; A Summary Of The Approaches Used 11 1.9 Conclusion 12 1.9 References 13

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 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.

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.

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.

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.

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.