Efficient Synthesis of Cannabigerol, Grifolin, and Piperogalin via Alumina-Promoted Allylation

Abstract

The synthesis of three phenolic natural products has been accomplished with unprecedented efficiency using a new alumina-promoted regioselective aromatic allylation reaction. Cannabigerol and grifolin were prepared in one step from the inexpensive 5-alkyl-resorcinols olivetol and orcinol. Piperogalin was synthesized, for the first time, via two sequential allylations of orcinol with geraniol and prenol.

Syntheses of Amorfrutins and Derivatives via Tandem Diels–Alder and Anionic Cascade Approaches

“…Flash column chromatography on silica using a gradient of 0–30% EtOAc in hexanes afforded 30 (39.0 mg, 81%) as an off-white solid. NMR spectroscopic data were identical to those reported previously …”

“…Alternatively, careful treatment of 27d with concentrated aqueous sodium sulfide has been reported to allow hydrolysis to CBGA ( 5 ), providing access to CBG and CBGA in four steps from dimedone . While short synthetic approaches to CBG have been described from the condensation of geraniol and olivetol, additional undesired regioisomers and bis-geranylated products have been reported. , …”

Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa

“…ZnCl 2 did not yield greater productivity. Experiments with PTSA and Al 2 O 3 showed much lower efficacy when compared to the previous reports. − However, BF 3 ·OEt 2 significantly improved the yield of CBG-C 5 ( 2a ). The reaction efficiency with BF 3 ·OEt 2 increased after careful consideration of several parameters; the substrate geraniol ( 20 ) should be added precisely dropwise for an extended time of at least 1 h to the dissolved mixture of olivetol ( 1a ) and BF 3 ·OEt 2 in chloroform in the presence of MgSO 4 as a dehydrating agent (Table ; entries 2.6–8).…”

“… a Literature reports for CBG-C 5 ( 2a ): (i) PTSA, CH 2 Cl 2 , 10 °C, 5 h, 52%; (ii) BF 3 · OEt 2 , CHCl 3 , 10 °C, 3 h, 40%; (iii) anh. Al 2 O 3 , 1,2-dichlorethane, reflux, 4 h, 67% …”

“…Cannabigerol and Its Analogues. Cannabigerol (CBG or CBG-C 5 , 2a) was the first natural phytocannabinoid synthesized in 1964 by Gaoni and Mechoulam 17 via C−C allylation between olivetol (1a) and geraniol (20) in the presence of PTSA (p-toluenesulfonic acid) . Besides CBG-C 5 , this reaction had various byproducts, such as 10a (referred to as an "abnormal" CBG-C 5 isomer) and by dual-coupled 2,6digeranyl-olivetol (11a) (Scheme 2).…”