Synthesis of the nakanishi ring-locked retinoid

Abstract

An optimized synthetic route to prepare ring-locked retinoid 1a has been developed. We fully describe a purification protocol that provides isomerically pure 1a in support of on-going proof of concept studies for the development of therapeutic agents to treat human ADRP. Additionally, we have found that isomerically pure 1a can be stored in amber vials under argon at -20°C for use over time (up to six months) without degradation. Thus, enabling 1a to be an accessible and valuable biological tool.

Figure 1

Ring-locked retinoid derivative of 11-cis-retinal.

Scheme 1

Reagents and conditions: (a) (i) NBS, ACHN, benzene, reflux, 2 h, and 34%; (ii) KOAc, TBAB, THF/H₂O, r.t., 4 days, and 17%; (b) NaH, (EtO)₂P(O)CH(CH₃)CN, THF, 0°C to r.t., and 20 h; (c) isomer separation by SiO₂ column chromatography, E 33%, and Z 17%; (d) K₂CO₃, MeOH, r.t., 1.5 h, and 99%; (e) TBSCl, imidazole, DMAP, CH₂Cl₂, r.t., 1 h, and 80%; (f) DIBAL-H, Et₂O, −78°C to 0°C, 2 h, and 96%.

Scheme 2

Reagents and conditions: (a) KOtBu, 18-crown-6, CH₂Cl₂, r.t., 5 h, and 35%; (b) (i) TBAF, THF, 0°C, and 4.5 h; (ii) MnO₂, CH₂Cl₂, −20°C to 0°C, 2 h, and 47%; (c) NaH, (EtO)₂P(O)CH₂CN, THF, r.t., 3 h, and 99%; (d) (i) DIBAL-H, Et₂O, −78°C to r.t., and 30 min; (ii) SiO₂ gel, ether, and E/Z 96%.

Figure 2

Key NOEs used to establish the geometry of the tetra-substituted double bond corresponding to the double bond between C9 and C10 of 1.

Figure 3

Isomerization between 1a and 1b under normal atmospheric conditions as monitored by HPLC (AUC at 310 nm). Note that samples stored in amber glass vial show no appreciable degradation or isomerization up to 18 h under argon at room temperature.