The indolizidine alkaloids are a large and functionally diverse family of natural products containing a characteristic [4.3.0]-azabicyclononane motif. As a result of their value in the pharmaceutical and biotechnology industries, new high-yielding, rapid, and stereoselective synthetic pathways are in constant demand. This work aims to develop a six-step procedure to obtain fully functionalized indolizidines from L-Pyroglutamic acid and an allylic alcohol using the Ireland–Claisen rearrangement and Ring-closing Metathesis as key transformations. The Ireland–Claisen rearrangement allows for the stereospecific rearrangement of pyroglutamate esters where Z-enolate formation is governed by a dianionic chelate complex. N-allylation and subsequent Ring-closing Metathesis gives rise to a fused bicyclic precursor to the indolizidine core. Functionalization of the core via reduction, oxidation, or alkylation will install different functionality to generate a library of potentially bioactive compounds. Utilizing enantioenriched allylic pyroglutamate esters enables the enantioselective synthesis of indolizidines where readily-generated C–O stereochemistry is translated to C–C stereochemistry by the Ireland–Claisen rearrangement.

Synthesis of indolizidines from L-pyroglutamic acid using the Ireland–Claisen rearrangement and ring-closing metathesis

2019 Spring National Meeting

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