Stereodivergent access to 5–6–5, 5–6–6, and 5–6–7 fused tricyclic indolizidine cores via ring-size-dependent fragmentation of overbred intermediates

Abstract

We report a stereodivergent strategy for constructing 5–6–5, 5–6–6, and the underexplored 5–6–7 fused tricyclic nitrogen frameworks from a common rigid precursor. A Pd-catalyzed allylation followed by an acid-mediated intramolecular aza-Michael cyclization reveals a ring-size-dependent stereochemical switch: the six-membered series (n = 2) afford the thermodynamic trans isomer, whereas the seven-membered series (n = 3) favor the cis isomer, while the five-membered system (n = 1) furnishes exclusively the cis product. These rigid overbred intermediates undergo efficient strain-release fragmentation to furnish functionalized fused indolizidine cores relevant to alkaloids such as gephyrotoxin, calyciphylline-type alkaloids, and plakinamine I.