Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel−Crafts‐Type 1,4‐Addition: Access to Cannabidiol Analogues

Abstract The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel–Crafts‐type 1,4‐addition using a Jørgensen‐Hayashi‐like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid‐like compounds, the resorcinol formed was used to generate both ‘normal’ and ‘abnormal’ cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity.

concentrations (c) are given in units of 10 -2 g mL -1 . Temperatures are in degrees Celsius (°C). The prefixes (+) and (-) indicate the sign of the optical rotation. Correct units: deg cm 2 g -1 Melting Point: Melting points were determined on a Stuart SMP30 melting point apparatus and are uncorrected.
HPLC Profiles: HPLC analysis was determined on Agilent Technologies 1200 Series HPLC, using a ratio of HPLC grade hexanes and propan-1-ol as the eluent, using a Chiralpak AD-H, OD or AS column (0.46 cm x 25 cm) and detection by UV at 210 nm.
Catalyst V was purchased from Sigma Aldrich (CAS 1446629-74-4) as well as synthesised according to literature procedure.

Method A
To a solution of phenol/aniline in (1 equiv) in dry DMF (0.6 M) was added 4-bromo-1-butene (1.5 equiv) and K2CO3 (2 equiv). The reaction was heated to 65 °C for between 17 and 36 h, quenched with distilled water and extracted with Et2O (x2). The combined organic layers were washed with brine saturated LiCl and dried over MgSO4. The crude mixture was concentrated under reduced pressure and purified by column chromatography on silica gel.

Method B
To a solution of homologated aniline (1 equiv) in dry DCM (0.5 M) at 0 °C was added dry diisopropylamine (1.5 equiv) and acylating or sulfonylating agent (1.1 equiv). The solution was warmed to room temperature and left stirring overnight. Once all of the starting material had been consumed, the reaction was quenched with saturated NaHCO3 (aq) and extracted with DCM (x3). The combined organic layers were washed with 1 N HCl (aq) and dried over MgSO4.

Method C
To a solution of homologated aniline/phenol (1 equiv) in dry DCM (0.1 M) was added crotonaldehyde (10 equiv) and Grubbs 2 nd Generation catalyst (3 mol%). The mixture was heated to reflux for 16 h before the solvent was removed by reduced pressure and by N2. The crude mixture was purified using silica gel on column chromatography (Pentane/ Et2O).

General method for the generation of racemic products
To a solution of α,β-unsaturated aldehyde (1 equiv) in THF (0.2 M) was added p-TSA (0.5 equiv). The mixture was stirred at room temperature until consumption of starting material Once the reaction was complete, the reaction was diluted with ethyl acetate and washed with sodium bicarbonate (aq) (x2). The solution was cooled to 0 °C and diluted with methanol (0.2 M). Sodium borohydride (1.5 equiv) was added to the reaction and the reaction stirred for 1 h at 0 °C. Once all of the cyclized starting material had been consumed, the reaction was quenched with saturated ammonium chloride (aq). The layers were separated and the aqueous extracted with ethyl acetate. The organic layers were combined, washed with brine and dried over MgSO4.
See experimental within main manuscript for details of the organocatalysed reactions.
MeO O

Unsuccessful Substrates
In the interests of balance we present below the substrates that did not cyclize, or gave minimal product.