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

## TL;DR

Scientists synthesized specific forms of a compound found in eye cells and studied how they form structures.

## Contribution

A new enantiopure synthesis method for pyridinium bisretinoids with hexahydrobenzofuran structures is developed.

## Key findings

- Enantiopure pyridinium bisretinoids were synthesized using a key HWE condensation reaction.
- Aggregation behavior of the synthesized compounds was observed via nanoprecipitation.
- Spherical aggregates formed by (5′R,8′R)-L-trans-hexahydrobenzofuran-A2E were confirmed using TEM.

## Abstract

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.