Exploring Polyene Construction Tactics for the Total Synthesis of Ocular Pyridinium Bisretinoids of Lipofuscin A2E and pdA2E

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.