Synthesis of sp3-enriched medicinal chemistry-relevant fragments and studies towards the total synthesis of nimbolide

Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. Herein, we report the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events. Sp2-sp3 fragments play a vital role in fragment-based drug design (FBDD). Strategies to chemically modify them and efficiently access libraries of these compounds have been goals of the highest priority in the last decades. In this work, a series of sp2-sp3 fragments is synthesized and validated for that purpose, based on their measured physical-chemical properties. Selective C-H cyanation and allylation of these fragments is demonstrated by simple heating in presence of an appropriate hydrogen-atom transfer reagent and a radical acceptor. These conditions enable a streamlined access to covalent fragments in a single step, by direct introduction of the desired covalent binder. Preliminary results on vinylation, as well as late-stage functionalization of a drug analogue are disclosed. Nimbolide, a natural product belonging to the limonoids family, has attracted much attention thanks to its biological properties, especially against cancer cell lines. However, clinical studies still struggle to proceed due to the not fully understood metabolism and its poor pharmacokinetic properties. A flexible total synthesis would help addressing these problems by allowing access to a variety of analogues with the desired physical-chemical characteristics. The studies towards the synthesis of the two main fragments identified in our retrosynthetic analysis are here presented.