Enantiopure Pyridinium Bisretinoids of Ocular Lipofuscin with Hexahydrobenzofuran Structure: Total Synthesis and Structure-Dependent Aggregated Morphology.

Oxidized photoproducts of pyridinium bisretinoid A2E, including the mono- and bishexahydrobenzofurans, which have been isolated from lipofuscin in the retinal pigment epithelium (RPE) cells of human eyes, have been synthesized in enantiopure form using as key step a Horner-Wadsworth-Emmons (HWE) condensation reaction of pyridinecarbaldehydes and enantiopure cyclohexene oxide pentadienylphosphonates. The synthesis of the trienylcyclohexene oxide branch on the shorter arm (S) of the pyridine ring was followed by a diastereoselective rearrangement to the hexahydrobenzofurandienyl substituent under acidic conditions. In contrast, the construction of the polyenic long arm (L) of the pyridine ring by HWE condensation evolved to the formation of diastereomeric hexahydrobenzofurantrienyl substituents in an unselective rearrangement. The alternative and more straightforward bidirectional HWE condensation of the cyclohexene oxide pentadienylphosphonates with 4-formylpyridine-2-butenal afforded a more complex mixture of products, from which the bishexahydrobenzofurans together with the 11-cis double bond isomer and a rearrangement product in S were also characterized. DFT studies on model systems provided a mechanistic rationale for these transformations. The pyridinium bisretinoid hexahydrobenzofurans underwent aggregation upon nanoprecipitation using methanol/water solvent mixtures, and (5'R,8'R)-L-trans-hexahydrobenzofuran-A2E (9a) was shown by TEM to form spherical aggregates.