Alternative tactics for polyene construction have been explored for the total synthesis of lipofuscin fluorophores A2E and pentadienyl-extended analog pdA2E, starting from properly functionalized pyridines. The bidirectional acyclic cross-metathesis (ACM) reaction of a C2-dienyl,C4-vinylpyridine with an excess of a conjugated tetraene unexpectedly afforded a C2-dienyl,C4-tetraenylpyridine with extended conjugation at just one of the branches. Although the stepwise process involving N-alkylation and a second ACM of the resulting pyridinium ion with the same tetraene generated A2E, the inconsistent results of the last ACM led to completing the skeleton using instead a Horner–Wadsworth–Emmons (HWE) condensation reaction of the C2-pentadienal-functionalized pyridine with a trienylphosphonate. The ACM proceeded even in lower yields in this case, thus showing the limitations of ACM for polyene synthesis. As an alternative, the C4-tetraenyl- and C4-hexaenylpyridine branches present in A2E and pdA2E were constructed by a Suzuki–Miyaura cross-coupling of a pyridine alkenylboronate and a trienyl- or a pentaenyl iodide, respectively, while extending the common C2-pentaenyl arms by a HWE reaction. Pyridine alkylation completed the synthesis of the lipofuscin fluorophores and confirmed the stereostructure of pdA2E, namely, the double-bond geometries and the relative location of the longer unsaturated chain on the pyridinium ring.
Vidal et al. (Mon,) studied this question.