In medicinal chemistry, bioisosteres are functional groups and scaffolds that display similar characteristics and can be replaced to modulate the physicochemical properties of drug candidates. Indeed, many properties such as solubility, metabolic stability and bioactivity can be improved through a bioisosteric replacement. The substitution of a building block for another one with similar features should not alter the overall molecular architecture of the drug candidate nor compromising target engagement, assuring that both compounds work through the same mechanism of action and display the same key interactions with proteins, enzymes or receptors within biological complex systems. This concept can be exploited in medicinal chemistry upon an appropriate bioisosteric replacement: the shape and function of a drug can be preserved, while improving other important properties.
Among the different scaffolds, aromatic moieties are ubiquitous in bioactive compounds with the phenyl ring being present in nearly half of the small molecule marketed drugs. This is essentially due to the availability of efficient methods for the construction
of Csp2-Csp2 bonds in comparison with the incorporation of saturated skeletons. Nevertheless, in recent years, an increasing interest in rigid sp3-hybridized scaffolds has been observed in medicinal chemistry since they provide tridimensionality and well-defined exit vectors that give access to novel unexplored chemical space, leading to a higher success in drug discovery programs. Specifically, some polycyclic bridged skeletons have been identified as suitable saturated bioisosteres of aromatic rings which represent the common two-dimensional, flat moieties that are routinely employed in the drug discovery process. Additionally, few of them display a stereogenic center in their structure, being chiral skeletons. Thus, an additional level of complexity is involved in their synthesis, requiring a stereocontrolled transformation to obtain only one of the enantiomers. Moreover, since two enantiomers of a drug candidate can display completely different biological properties, new methodologies that enable precise control over stereochemistry are critically needed.
Thus, this research project aimed at designing novel enantioselective methodologies for the synthesis of phenyl bioisosteres, enabling unprecedented approaches to obtain sp3-hybridized drug analogues with improved properties. Specifically, the construction of 1,5-, and 1,3-bicyclo[2.1.1]hexanes (BCHs) would be highly desirable. Indeed, these frameworks appear as perfect candidates to serve as appropriate mimics for ortho- and meta-benzene bioisosteres, giving access to highly demanded enantioenriched building blocks of immediate relevance to pharmaceutical research.
