Rapid Access to Compound Libraries through Flow Technology: Fully Automated Synthesis of a 3-Aminoindolizine Library via Orthogonal Diversification

A novel methodology for the synthesis of druglike heterocycle libraries has been developed through the use of flow reactor technology. The strategy employs orthogonal modification of a heterocyclic core, which is generated in situ, and was used to construct both a 25-membered library of druglike 3-aminoindolizines, and selected examples of a 100-member virtual library. This general protocol allows a broad range of acylation, alkylation and sulfonamidation reactions to be performed in conjunction with a tandem Sonogashira coupling/cycloisomerization sequence. All three synthetic steps were conducted under full automation in the flow reactor, with no handling or isolation of intermediates, to afford the desired products in good yields. This fully automated, multistep flow approach opens the way to highly efficient generation of druglike heterocyclic systems as part of a lead discovery strategy or within a lead optimization program.