Introduction
HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from (1R,5S)-myrtenol by a group led by Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action. HU-210 has a binding affinity of 0.061nM at CB1 and 0.52nM at CB2 in cloned human cannabinoid receptors. Compared to Delta-9-THC of 40.7nM at CB1. HU-210 is the (–)-1,1-dimethylheptyl analog of 11-hydroxy- Δ8- tetrahydrocannabinol; in some references it is called 1,1-dimethylheptyl- 11-hydroxytetrahydrocannabinol. The abbreviation "HU" stands for Hebrew University.
Resorcinol (8) was identified as a key intermediate to be reacted with both enantiomers of 4-hydroxy-myrtenyl pivalate (9) forming the desired THC-like structural frameworks. Synthesis of the key fluorinated building block (8) proved to be challenging. In fact, a number of unsuccessful approaches to (8). The synthesis of 8 started with the methylation of commercially available (3,5-dimethoxyphenyl)acetonitrile (1), that afforded the α,α-dimethylnitrile (2) in excellent yield. Subsequent hydride reduction of (2) afforded the aldehyde (2), which was subjected to a Wittig olefination with the yield generated from the phosphonium salt (5) that yielded the unsaturated substance (6) as a single isomer, presumably having (Z)-geometry. The CvC bond of (6) was then hydrogenated (Pd/C, H 2 , in EtOAc) to give compound (7) in quantitative yield. Treatment of (7) with MeMgI at 170 °C provided the demethylated alcohol (8) in very good yield. The synthesis of (−)-(R, R)-HU-210 was achieved from commercially available (−)-(1R)-myrtenol (≥95% ee) that was transformed into 4-hydroxymyrtenyl pivalate (9) using the method of Zahalka and Huffman. Finally, reduction with LiAlH4 gave the target compound (−)-(R, R)-HU-210. Since the source of chirality in the syntheses are the two 4-hydroxymyrtenyl pivalate enantiomers, (9), the ee of the two final compounds reflected the ee of the commercially available starting materials. The enantiomeric purity of the cannabinoid mimics was confirmed by analytical chiral HPLC. Subsequently, (−)-(R, R)-HU-210 were purified by semi-preparative chiral HPLC in order to obtain high-purity (>99% ee) single enantiomers for the pharmacological assays.
Resorcinol (8) was identified as a key intermediate to be reacted with both enantiomers of 4-hydroxy-myrtenyl pivalate (9) forming the desired THC-like structural frameworks. Synthesis of the key fluorinated building block (8) proved to be challenging. In fact, a number of unsuccessful approaches to (8). The synthesis of 8 started with the methylation of commercially available (3,5-dimethoxyphenyl)acetonitrile (1), that afforded the α,α-dimethylnitrile (2) in excellent yield. Subsequent hydride reduction of (2) afforded the aldehyde (2), which was subjected to a Wittig olefination with the yield generated from the phosphonium salt (5) that yielded the unsaturated substance (6) as a single isomer, presumably having (Z)-geometry. The CvC bond of (6) was then hydrogenated (Pd/C, H 2 , in EtOAc) to give compound (7) in quantitative yield. Treatment of (7) with MeMgI at 170 °C provided the demethylated alcohol (8) in very good yield. The synthesis of (−)-(R, R)-HU-210 was achieved from commercially available (−)-(1R)-myrtenol (≥95% ee) that was transformed into 4-hydroxymyrtenyl pivalate (9) using the method of Zahalka and Huffman. Finally, reduction with LiAlH4 gave the target compound (−)-(R, R)-HU-210. Since the source of chirality in the syntheses are the two 4-hydroxymyrtenyl pivalate enantiomers, (9), the ee of the two final compounds reflected the ee of the commercially available starting materials. The enantiomeric purity of the cannabinoid mimics was confirmed by analytical chiral HPLC. Subsequently, (−)-(R, R)-HU-210 were purified by semi-preparative chiral HPLC in order to obtain high-purity (>99% ee) single enantiomers for the pharmacological assays.
Equipment and glassware:
- 100 mL, 250 mL, 500 mL Round bottom flasks (RBF);
- 50 ml Pear shaped flask;
- Retort stand and clamp for securing apparatus;
- Magnetic stirrer with heater;
- 100 mL x3; 50 mL x2 Beakers;
- 500 mL Separatory funnel;
- 100 mL Drip funnel;
- Dewar bath;
- Water bath;
- Solid CO2 (Dry Ice);
- Vacuum source;
- Glass rod and spatula;
- Rotovap machine;
- Plastic or glass syringe;
- Erlenmeyer flask 150-200 mL x2;
- Reflux condenser;
- Flash chromatography kit;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Laboratory grade thermometer (-50 °C to 200 °C) with flask adapter;
- ~10 L Nitrogen (N2) or argonn (Ar) balloon (1 atm);
- Hydrogen gas (H2) source;
- Laboratory scale (0.001-100 g is suitable) [depends on synthesis load].
Reagents:
- Sodium hydride (NaH) 60% in mineral oil, 677 mg, 16.9 mmol;
- Dimethylformamide (DMF) 10.0 mL;
- 2-(3,5-dimethoxyphenyl)acetonitrile (1) 1.0 g, 5.64 mmol;
- Iodomethane (CH3I) 1.1 mL, 16.9 mmol;
- Ammonium chloride (NH4Cl) aqueous solution (25.0 mL);
- Diethyl ether (Et2O) 363 mL;
- Sodium sulfate (Na2SO4) or Magnesium sulfate (MgSO4) ~150 g;
- Dichloromethane (DCM) 115.0 mL;
- DIBALH (C₈H₁₉Al) 1 M solution in hexane, 14.75 mL, 14.75 mmol;
- Sodium tartrate 10% solution in water, 20 mL;
- Ethyl acetate (EtOAc) 1070 mL;
- Distilled water ~1 L;
- Sodium chloride (NaCl) ~100 g;
- Hexane ~650 mL;
- 5-bromopentane (4) 3.134 mL, 16.6 mmol;
- Ethanole (EtOH) 35 mL;
- Triphenylphosphine (Ph3P) 4.35 g, 16.6 mmol;
- Potassium carbonate (K2CO3) 2.30 g, 16.6 mmol;
- Toluene 35 mL;
- Tetrahydrofuran (THF) 179 mL;
- Pd/C 10% 139 mg;
- Methylmagnesium iodide (MeMgI) 3 M in Et2O, 8.0 mL, 24.0 mmol;
- Pivalate ester (9) 48 mg, 0.19 mmol;
- Boron trifluoride etherate (BF3·OEt2) 0.12 mL, 1.0 mmol;
- Lithium aluminium hydride (LiAlH4) 15.3 mg, 0.39 mmol.
Boiling Point: 485.51 at 760 mm Hg;
Melting Point: 205.83 °C;
Molecular Weight: 386.576 g/mol;
Density: 1.0±0.1 g/mL;
CAS Number: 112830-95-2.
Precursor synthesis
2-(3,5-Dimethoxyphenyl)-2-methylpropanenitrile (2)To a stirred suspension of sodium hydride (60% in mineral oil, 677 mg, 16.9 mmol, 3 eq.) in dry DMF (5.0 mL) at 0 °C was added drop-wise a solution of commercially available 2-(3,5-dimethoxyphenyl)acetonitrile (1) (1.0 g, 5.64 mmol, 1 eq.) and iodomethane (1.1 mL, 16.9 mmol, 3 eq.) in dry DMF (5.0 mL). The reaction temperature rose to 25 °C over a 15-min period and stirring was continued for 2 h in a 100 mL round bottom flask. The reaction mixture was quenched with a saturated aqueous NH4Cl solution (5.0 mL) and diluted with diethyl ether (10 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (3×10 mL). The combined organic layer was washed with water and brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 8:2) to give compound (2) (1.1 g, 98%) as a colorless oil.
2-(3,5-Dimethoxyphenyl)-2-methylpropanal (3)
To a solution of (2) (1.21 g, 5.90 mmol, 1 eq.) in dry DCM (50.0 mL) at −78 °C (in Dewar bath with dry ice) was added DIBALH (1 M solution in hexane, 14.75 mL, 14.75 mmol, 2.5 eq.) (C₈H₁₉Al) in 250 mL round bottom flask. The reaction mixture was stirred at the same temperature for 1 h and then quenched by drop-wise addition of potassium sodium tartrate (10% solution in water, 20 mL). The resulting mixture was warmed to room temperature, stirred vigorously for 1 h, and then diluted with EtOAc (20 mL). The organic phase was separated, and the aqueous phase extracted with EtOAc (3×50 mL). The combined organic layer was washed with water and brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 8:2) to give aldehyde (3) (1.14 g, 93%) as a colorless oil.
5-(Bromotriphenyl-λ5-phosphanyl)pentane (5)
To a solution of commercially available 5-bromopentane (4) (3.134 mL, 16.6 mmol, 1 eq.) in EtOH (35 mL) was added triphenylphosphine (4.35 g, 16.6 mmol, 1 eq.) and K2CO3 (2.30 g, 16.6 mmol, 1 eq.) and the mixture was heated at reflux overnight in 250 mL round bottom flask. The solvent was evaporated under reduced pressure, the crude product was dissolved in toluene (35 mL) and the mixture was stirred vigorously at 100 °C for 5 min. The mixture was allowed to cool down to r.t. and the crystallized phosphonium salt (5) (74%) was collected by filtration as a white crystalline solid.
To a solution of commercially available 5-bromopentane (4) (3.134 mL, 16.6 mmol, 1 eq.) in EtOH (35 mL) was added triphenylphosphine (4.35 g, 16.6 mmol, 1 eq.) and K2CO3 (2.30 g, 16.6 mmol, 1 eq.) and the mixture was heated at reflux overnight in 250 mL round bottom flask. The solvent was evaporated under reduced pressure, the crude product was dissolved in toluene (35 mL) and the mixture was stirred vigorously at 100 °C for 5 min. The mixture was allowed to cool down to r.t. and the crystallized phosphonium salt (5) (74%) was collected by filtration as a white crystalline solid.
(5Z)-7-(3,5-Dimethoxyphenyl)-7-methyloct-5-en (6)
To a suspension of phosphonium salt (5) (27.3 mmol, 5 eq.) in dry THF (130 mL) at 0 °C was added drop-wise LiHMDS (LiN[(CH₃)₃Si]₂) (1 M in THF, 27.3 mL, 27.3 mmol, 5 eq.) in 500 mL round bottom flask. The mixture was warmed to 10 °C and stirred for 30 min to ensure complete formation of the orange ylide. A solution of aldehyde (3) (1.1 g, 5.46 mmol, 1 eq.) in THF (15 mL) was added drop-wise to the resulting slurry at the same temperature. The reaction was stirred overnight at room temperature. The mixture was quenched by addition of saturated aqueous NH4Cl (10 mL). The organic layer was separated, and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 7:3) to give the alkene (6) (92%, single diastereoisomer) as a colorless oil.
To a suspension of phosphonium salt (5) (27.3 mmol, 5 eq.) in dry THF (130 mL) at 0 °C was added drop-wise LiHMDS (LiN[(CH₃)₃Si]₂) (1 M in THF, 27.3 mL, 27.3 mmol, 5 eq.) in 500 mL round bottom flask. The mixture was warmed to 10 °C and stirred for 30 min to ensure complete formation of the orange ylide. A solution of aldehyde (3) (1.1 g, 5.46 mmol, 1 eq.) in THF (15 mL) was added drop-wise to the resulting slurry at the same temperature. The reaction was stirred overnight at room temperature. The mixture was quenched by addition of saturated aqueous NH4Cl (10 mL). The organic layer was separated, and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 7:3) to give the alkene (6) (92%, single diastereoisomer) as a colorless oil.
7-(3,5-Dimethoxyphenyl)-7-methyloctan (7)
To a solution of (6) (5.0 mmol, 1 eq.) in EtOAc (200 mL) was added 10% Pd/C (139 mg), and the resulting suspension was stirred vigorously under hydrogen atmosphere overnight at room temperature in 500 mL RBF. The catalyst was removed by filtration through Celite and the filtrate was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 6:4) to give the hydrogenated compound (7) (quantitative yield) as a colorless oil.
5-(2-methyloctan-2-yl)benzene-1,3-diol (8)
To a solution of compound (7) (1.20 mmol, 1 eq.) in dry Et2O (5.0 mL) and dry THF (0.4 mL) MeMgI (3 M in Et2O, 8.0 mL, 24.0 mmol, 20 eq.) was added at 0 °C in 100 mL RBF. The slurry was heated to 100 °C under reduced pressure, then the residue was heated to 170 °C for 1 h under a flux of nitrogen. The cooled reaction mixture was quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (5×20 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product (8) was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give the alcohol (8) (70%) as a waxy white solid.
Product synthesis
[(6aR,10aR)-3-(2-methyloctan-2-yl)-1-hydroxy-6,6-dimethyl-6H,6aH,7H,10H,10aH-benzo[c]isochromen-9-yl]methyl 2,2-dimethylpropanoate (10)
To a solution of resorcinol (8) (0.19 mmol, 1 eq.) and pivalate ester (9) (48 mg, 0.19 mmol, 1 eq.) in dry DCM (65 mL) at −20 °C was added BF3·OEt2 (0.12 mL, 1.0 mmol, 5.3 eq.) in 250 mL RBF. The mixture was allowed to warm up to room temperature and then stirred for 2 h. The mixture was carefully washed with brine, over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 9:1) to give compound (10) (55%) as a waxy white solid.
To a solution of resorcinol (8) (0.19 mmol, 1 eq.) and pivalate ester (9) (48 mg, 0.19 mmol, 1 eq.) in dry DCM (65 mL) at −20 °C was added BF3·OEt2 (0.12 mL, 1.0 mmol, 5.3 eq.) in 250 mL RBF. The mixture was allowed to warm up to room temperature and then stirred for 2 h. The mixture was carefully washed with brine, over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 9:1) to give compound (10) (55%) as a waxy white solid.
(−)-(R,R)-HU-210 (11)
A solution of the protected ester (10) (0.098 mmol, 1 eq.) in dry THF (1.0 ml) was added drop-wise to a suspension of LiAlH4 (15.3 mg, 0.39 mmol, 4 eq.) in THF (1.0 mL) at 0 °C in 50 ml pear shaped flask. The reaction mixture was stirred for 2 h and allowed to warm to room temperature. The reaction was quenched with water (2 mL) and extracted with ether (2×5 mL). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexane/EtOAc 8:2) to give the final compound (−)-(R, R)-HU-210 (11) (50%, ee 97%) as a hygroscopic white solid. The final product was subsequently purified by a chiral HPLC (see the Experimental for details) in order to obtain (−)-(R, R)-HU-210 enantiomerically pure (ee 100%).
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