Stereochemical Reassignment by Total Synthesis of an Ocular Pyridinium Bisretinoid of Retinal Pigment Epithelium Lipofuscin: iiso -A2E Is i -A2E

The stereoselective synthesis of recently discovered lipofuscin fluorophore iiso-A2E, a C3,C4-bis-polyenylpyridinium salt derived from all-trans-retinal, which has been detected in human, pig, mouse, and bovine eyes, has been completed. The Suzuki-Miyaura cross-coupling reaction and Horner-Wadsworth-Emmons condensation were the key synthetic steps for the construction of the tetraenyl and pentaenyl arms, respectively, starting from a properly functionalized pyridine-3,4-dialdehyde surrogate, followed by pyridine alkylation. Subtle changes in the ¹H NMR and ¹³C NMR spectra of the synthetic compound and natural compound suggested the structural revision of the latter, for which the C13'═C14' E isomer at the longer C3-unsaturated pentaenyl chain of the pyridinium ring was proposed. The synthesis confirmed the alternative stereostructure of the natural pigment, which should be named i-A2E, thus correcting the double bond geometry of the natural fluorophore at C13'═C14'.