Synthesis of challenging 6-functionalized 1-oxaspiro[3.3]heptanes – New scaffolds for drug discovery

A decagram-scale synthesis of seven new building blocks of 1-oxaspiro[3.3]heptane family is described. This general approach requires 6 to 13 operationally simple steps starting from commercially available and inexpensive 3-oxocyclobutane-1-carboxylic acid. Expedient synthetic routes enable the straightforward access to these novel modules. Finally, the generation of virtual combinatorial library using the LLAMA software showed that building blocks described here demonstrated the high propensity to populate the lead-like chemical space. Like pigeons delivering letters, the newly 1-oxaspiro[3.3]heptane family scaffolds could deliver their functionality to drug-like compounds that are expected to be important in drug discovery and design.