In the last 15-20 years, the medicinal chemistry community has been seeking to introduce more sp3 character in the design of new bioactive compounds. This stems out from the observation that, despites millions of flat aromatic molecules could be made and have been made using palladium-catalyzed chemistry, the chemical space covered and results of screening did not quite match the effort. More three-dimensional character, more conformational restriction etc. would allow - with the help of rational design and chemoinformatics - to reah our goal faster. However, the addition of one more dimension to the equation meant more chemical space coverage but also A LOT more complexity in the design and synthesis of suitable building blocks. The design of efficient methodologies is therefore strongly needed.<br/>We will describe new synthetic strategies that have been designed and optimized to grant access to a large variety of small conformationally-restricted molecules, such as spirocycles and bicyclo[1.1.1]pentanes, but also other cage motifs such as cubanes and bicyclo[x.y.z]alkanes. Examples of how we made some of them accessible on large scale will be given. We will also showcase our efforts to design late-stage functionalization strategies that will facilitate the introduction of such motif in more complex structures and facilitate the exploration of isosteric switches.

Conformationally-restricted motifs as bioisosteres for aromatics: Playground for new methods development

2019 Fall National Meeting

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