In recent years the pharmaceutical industry has benefited from the advances made in fragment‐based drug discovery (FBDD) with more than 30 fragment‐derived drugs currently marketed or progressing through clinical trials. The success of fragment‐based drug discovery is entirely dependent upon the composition of the fragment screening libraries used. Heterocycles are prevalent within marketed drugs due to the role they play in providing binding interactions; consequently, heterocyclic fragments are important components of FBDD libraries. Current screening libraries are dominated by flat, sp2‐rich compounds, primarily owing to their synthetic tractability, despite the superior physicochemical properties displayed by more three‐dimensional scaffolds. Herein, we report step‐efficient routes to a number of biologically relevant, fragment‐like heterocyclic spirocycles. The use of both electron‐deficient and electron‐rich 2‐atom donors was explored in complexity‐generating [3+2]‐cycloadditions to furnish products in 3 steps from commercially available starting materials. The resulting compounds were primed for further fragment elaboration through the inclusion of synthetic handles from the outset of the syntheses.

Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.

We describe semi-syntheses of the 11-hydroxyrotenoids sumatrol (1) and villosinol (2), starting from rotenone (5), using an oxime-directed C11-H functionalisation approach. Thus, rotenone (5) was converted into rotenone oxime (6), which gave dimeric palladacycle 7 following reaction with Na2PdCl4·3H2O. Controlled, divergent, oxidation of palladacycle 7 with either Pb(OAc)4 or K2Cr2O7 afforded the 11-acetoxylated intermediates 9 and 13, respectively, which were transformed into sumatrol (1) and villosinol (2).

Communicable and non-communicable diseases are prevalent worldwide. Whilst treatments and cures exist for several of these, for many more they are either ineffective or non-existent. Cancer, malaria and antibiotic resistance are some representative examples of conditions that cause huge burdens on worldwide healthcare. However, despite research and development investment being higher than ever, the biomedical community struggles to provide effective solutions for such devastating diseases. This can be attributed to the inability to identify appropriate targets to modulate the disease, the lack of suitable compounds to interact with identified targets, or the failure of compounds to pass through clinical trials. In such a situation, the question remains as to where the problem fundamentally lies and how to address it. This chapter will analyse the importance of screening

A simple, high yielding and scalable synthesis for diastereoselective access to privileged fused bicyclic heteroaromatic scaffolds.