Team:Georgia State/CBGAsynthesis
PROJECT
The olivetol synthesis route from “A Simple and Practical Synthesis of Olivetol by Antonino Focella, Sidney Teitel, and Arnold Brossi” entails reacting an alpha, beta unsaturated ketone with dimethyl malonate in a Michael reaction which was subsequently aromatized and decarbomethoxylated in bromine. Materials and Methods • 3-nonen-2-one • Sodium methoxide • Anhydrous methanol • Dimethyl malonate • Bromine • DMF Methyl 6-n-Pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-l-carboxylate (2) In 230 mL of anhydrous methanol with 32.4 g (0.60 mol) of sodium methoxide and 90 g (0.68 mol) of dimethyl malonate, add 75 g (0.48 mol) of 90% pure 3-nonen-2-one portionwise. The reaction mixture was then refluxed for 3 hours in nitrogen gas. The solvent was distilled under reduced pressure and the residue dissolved in 350 mL of water. The slurry of white crystals and the almost clear solution was extracted with 3 X 80 mL of CHCl3,the aqueous acidified to pH 4 with concentrated HCl and the white precipitate allowed to stand overnight and filtered. The crystals were dried at 50 "C under high vacuum for 5 h t C J yield 106.5g (92%)of 2, mp 96-98 "C. An analytical sample prepared from heptane gave mp 98-100 "C; IR (CHC13):3180, 3270-2500 (OH), 1740, 1710 (C=O ester), 1600 cm-' (C=O and C=C); NMR (CDC13):6 0.90 (CH3), 1.33 (4CHz),5.50 (-CH=), 9.23 (OH). Anal. Calcd for C13H2004: C, 64.98; H, 8.39. Found: C, 65.01; H, 8.40. l-n-Pentyl-3,5-dihydroxybenzene, Olivetol To an ice cooled solution of 58.4 g (0.24; mol) of 2 dissolved in 115 mL of dimethylformamide was added dropwise with stirring a solution of 37.9g (0.23 mol) of bromine dissolved in 60 mL of dimethylformamide. At the end of the addition (ca.90min) the reaction mixture was slowly heated to 80 "C during which time the evolution of carbon dioxide became quite vigorous. The reaction was maintained at this temperature until the gas evolution had ceased and was then heated to 160"C and held at this temperature for 10 h. The DMF was removed under reduced pressure and the residue treated with 80 mL of water. The mixture was extracted with 2 X 250 mL of ether and the ether solution washed with water, 2 X 80 mL of a 10% solution of sodium bisulfite, 2 X 80 mL of a 10%solution of acetic acid, and then again with water. The ether solution was dried (Na2S04) and the solvent removed under reduced pressure to give 46.8 g of a viscous oil. The oil was distilled through a 12 in. Vigreux column (314 in. diameter)to give 30.3 g (69.3%)of 3,95%pure by VPC. An analytical sample recrystallized from ether gave: mp 85-86 "C; IR (CHC13)3150 (OH), 1790,1710(C=O ester), 1600cm-' (C=O, C=Cj; NMR (CDC13):6 Anal. Calcd for C15H2204: C, 67.13; H, 9.02. Found: C, 67.28; H, 9.25 Materials & Methods • alpha-resorcylic acid • Potassium Carbonate • Benzyl chloride • DMF • LAH • Pyridinium chlorchromate Materials & Methods • Butyl magnesium bromide (Made from butyl bromine and magnesium) • P-toluene sulfonic acid • Dean and Stark Apparatus From Anand and Ranjan’s 1983 paper: _-resorcylic acid(3,5-dihydroxybenzoic acid was benzylated with potassium carbonate and benzyl chloride in DMF to give benzyl 3,5- bis(benzyloxy) benzoate (3) in 97% yield. Lithium aluminum hydride reduction of the benzyl ester followed by oxidation of the resulting alcohol with pyridinium chlorochromate afforded 3,5-bis(benzyloxy)benzaldehyde. Grignard reaction of butyl magnesium bromide on the aldehyde furnished the alcohol. Refluxing with p-toluenesulfonic acid in benzene under Dean and Stark apparatus followed by hydrogenation of the resulting product with 10% Pd/C at room temperature afforded olivetol in 55% overall yield (3) : Benzyl 3,5 – Bis (benzyloxy) benzoate :Prepared by refluxing by refluxing and stirring a mixture of -resorcylic acid (20g; 0.129 mol), DMF (150 ml), K2CO3(107.64 g, 0.78 mol) and benzyl chloride (98.28 g, 0.78 mol). Evaporation of solvent and crystallization of the residue with benzene-hexane afforded (3) (4) : 3,5-Bis (benzyloxy) benzyl Alcohol: 54 grams (0.12 mol) was reducedwith lithium aluminum hydride (9.12 g, 2 mol) in dry ether. It was decomposed with 5% HCl. Removal of the solvent followed by crystallization from benzene-hexane gave the alcohol. (5) : To a stirred mixture of pyridinium chlorochromate (40 g) sodium acetate (3g) in anhydrous dichloromethane was added (4) (38 g, 0.118 mol). Stir for 1 hour and dilute with with 80 mL of dry ether and the dichloromethane-ether layer was decanted. Residue was washed with dry ether and pushed through a silica gel column. Removal of the solvent followed by recrystallization of with benzene- hexane furnished aldehyde. (6) : To a solution of butylmagnesium bromide (prepared from 30.14 g of butyl bromide and 5.76 of magnesium) in an anhydrous ether was added (5) [35 g, 0.11 mol) in anhydrous ether was added the aldehyde in anhydrous ether under N2 at 0oC while stirring. Stirred at room temperature for 2 hr, then decomposed with 5% H2SO4. Organic layer was separated and theaqueous layer extracted with ether. Combined organic layer was washed with brine and stripped off the solvent and the residue was crystalized from acetone-hexane. Olivetol: A solution of 6 and 0.6 g of para-toluenesulfonic acid (0.6g) in 350 benzene was refluxed in Dean and Stark Apparatus until no more water separated. It was washed with Sodium bicarbonate and brine solution. Solvent was evaporated and the residue dissolved in ethanol (300 mL). Hydrogenated with 1 gram of 10% Pd/C. After filtration, the solvent was evaporated to have a thick residue which was distilled under vacuum to procure olivetol. • Olivetol • Geraniol • Chloroform • P-toluenesulfonic acid • Sodium bicarbonate • Silica gel column • Benzene Materials and Methods C.1:1. Synthesis of 2-[ (2E)-3, 7-dimethylocta-2, 6-dienyl] -5-pentyl-benzene-l , 3-diol (Cannabigerol (CBG)) [0124] Geraniol (3g, 0.0194 mol) and olivetol (2 g, 0.0111 mol) were dissolved in 400 mL of chloroform containing 80 mg of p-toluenesulfonic acid as catalyst and the reaction mixture was stirred at room temperature for 12 h in the dark. After 12 hours, the reaction mixture was washed with saturated sodium bicarbonate (400 mL) and then with H20 (400 mL). The chloroform layer was concentrated at 40 C under reduced pressure, and the residue obtained was chromatographed on a 2.0 cm x 25 cm silica gel column using benzene (1000 mL) as the eluent to give 1.4 g (0.00442 mol)(39.9percent) CBG as product. [0125] Alternatively crude CBG was purified as follows. To a 250 mL beaker was added 7.25 g crude CBG and 50 mL benzene. The flask was swirled to dissolve the CBG and 50 g silica gel was added, along with a stir bar. The solution was stirred overnight, and then poured into a 44 cm x 2.75 cm column. The column was eluted with 300 mL benzene. The eluent, approximately 70 mL fractions were assayed for CBG. Fractions 1, 2, and 3 (-230 mL) that contained CBG were combined and the solvent removed under pressure to give 6.464 g residue containing >80 percent CBG, having a purity suitable for use in the next synthetic step. [0126] In one embodiment, crude CBG was purified by mixing 7.25 g crude CBG residue with a slurry of silica gel (50 mL), in a 250ml Beaker. This mixture was slowly agitated for 1 hour and then vacuum filtered using a fine mesh filter paper. The filter cake was washed with 250 ml benzene until a clear filtrate was obtained. The solvent from the filtrate was removed under reduced pressure to give 6.567 g of a residue having > 80percent CBG Selective Carboxylation of Resorcinols In a typical experiment, 1 mM was heated at 120o Celsius for 3 hour with a 2M-solution (1.5ml) of MMC in DMF. After acidification with dilute HCl, followed by ether extraction and purification by preparative t.l.c.
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