A short synthesis of (±)-cherylline dimethyl ether

Summary A synthesis of (±)-cherylline dimethyl ether is reported. The key steps involved are Michael-type addition, radical azidonation of an aldehyde, Curtius rearrangement, and reduction of an isocyanate intermediate followed by Pictet–Spengler cyclization.


Introduction
Aryl-1,2,3,4-tetrahydroisoquinolines have attracted much attention from the synthetic community owing to the potential biological activities of this class of compounds and their increasing medicinal interest. Among these heterobicyclic compounds cherylline (1) (Figure 1), a rare phenolic 4-phenyltetrahydroisoquinoline alkaloid, and its dimethyl ether 5 (Scheme 1). Their structures are unique among the Amaryllidaceae alkaloids [1,2] and they have long been fascinating targets for organic chemists as witnessed by a number of articles dealing with biogenesis, isolation, characterization and synthesis. Cherylline (1) and latifine (2) are the two 4-aryltetrahydroisoquinoline alkaloids isolated from Amaryllidaceae plants. Apart from their natural occurence, 4-aryltetrahydroisoquinolines are of interest due to various pharmacological activities [3]. For example, nomifensine (3) [3] and dichlofensine (4) [4] exhibit CNS activity and inhibit serotonin and dopamine uptake mechanisms.
The key steps involved are Michael addition, radical azidonation of aldehydes [18], Curtius rearrangement, and reduction of an isocyanate intermediate followed by Pictet-Spengler cyclization.

Results and Discussion
Our retrosynthetic analysis of (±)-cherylline dimethyl ether (5) is depicted in Scheme 1. It can be anticipated that 5 could be constructed via a Pictet-Spengler ring annulation from amine 6 which, in turn, could be obtained by reduction of the corresponding isocyanate. The required isocyanate would arise from the aldehyde 7 via radical azidonation followed by Curtius reaction. Lastly, aldehyde 7 could be assembled by Michael addition of 1,2-dimethoxybenzene to p-methoxycinnamonitrile.
In short, we have devised a short and efficient method for the synthesis of (±)-cherylline dimethyl ether. The simple and facile nature of this tetrahydroisoquinoline synthesis should allow the construction of a wide variety of interesting and useful analogous molecules.

Materials and Instruments
All solvents and reagents were purchased from the suppliers and used without further purification. All non-aqueous reactions were performed in dry glassware under an atmosphere of dry nitrogen. Organic solutions were concentrated under reduced pressure. Thin layer chromatography was performed on Merck precoated Silica-gel 60F 254 plates. 1 H and 13 C NMR spectra were recorded in DMSO-d 6 and CDCl 3 using 400 MHz, on a Varian Gemini 400 MHz FT NMR spectrometer. The chemical shifts were reported in δ ppm relative to TMS. The IR spectra were recorded in the solid state as KBr dispersion using Perkin Elmer FT-IR spectrophotometer. The mass spectra were recorded on Shimadzu LCMS-QP 800 LC-MS and AB-4000 Q-trap LC-MS/MS. Melting points were obtained by using the open capillary method and are uncorrected.