Small Ring Building Blocks for Medicinal Chemistry

Cross-coupling reactions have become ubiquitous in synthesis and are essential in enabling the expansion of building block libraries, which has notably had a positive impact on the synthesis of pharmaceuticals with a high sp² carbon ratio. Unfortunately, reviews of clinical trial data has shown drug candidates with high planarity were more likely to fail.¹⁾ It was speculated that the planarity of compounds caused unpredictable and undesirable bioavailability and toxicity owing to their insolubility. This pitfall has demonstrated the importance of sp³ character in drug candidates and its needed emphasis. Spiro type building blocks comprised of an oxetane and azetidine (1,2)^2,3) are bioisosteres of morpholine and piperazine respectively. The related bicyclo[1.1.1]pentane or cubane (3,4,5)^4,5) are bioisosteres of benzene rings. The introduction of these unique functionalities from selected building blocks are expected to assist in the introduce more sp³ carbon character to drug candidates while still retaining paralleled biological properties to their bioisosteres, lending to improved solubility and increase 3-dimensionality.