Towards a Library of Chromene Cannabinoids: A Combinatorial Approach on Solid Supports

Abstract

A novel solid-phase synthesis towards classical cannabinoids is presented. Starting from immobilized salicylaldehydes the desired THC-analogous tricycles are obtained in four atom-economic steps including cleavage. The reagents of the employed reactions (domino oxa-Michael-aldol, Wittig, and Diels-Alder) can be varied easily, providing the basis for a combinatorial approach. Overall yields range from 20-60%.

Key words

cannabinoids - combinatorial chemistry - domino reactions - heterocycles - solid phase synthesis

References

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8

General Procedure for Immobilization
DHP-resin 9 (6 g, 0.99 mmol/g) was dried overnight at 100 ˚C, then suspended in a mixture of DCE-toluene (42/18 mL) under nitrogen. Then, 4- or 6-HSA (4.15 g, 30.0 mmol) and PPTS (2.26 g, 9.00 mmol) were added and the mixture agitated at 55 ˚C overnight. Afterwards, the resin was filtered, washed (CH₂Cl₂, 2 ¥ H₂O and DMF, 2 ¥ H₂O and THF, 3 ¥ MeOH and CH₂Cl₂, 4 ¥ CH₂Cl₂; with 20 mL/g resin each), and dried under vacuum.

9

General Procedure for Cleavage
Resin (200 mg) were suspended in a 1:1 mixture of EtOH-DCE (4 mL). Then PPTS (100 mg, 0.40 mmol) was added, and the mixture was agitated at 70 ˚C overnight. The resin was separated by filtration, washed with EtOAc (25 mL), and the filtrate concentrated. The crude product was diluted with EtOAc (15 mL) and H₂O (10 mL). The organic layer was separated and the aqueous one extracted twice with EtOAc (15 mL). The combined organic phases were dried (MgSO₄) and concentrated under reduced pressure. After Diels-Alder reactions the crude product was additionally purified by flash chromatography to separate endo- and exo-diastereomers.

10

For procedures see Supporting Information.

15

General Procedure for DOMA Condensation
Resin (1.00 g) was suspended in 1,4-dioxane (10 mL) in a 20 mL vial. Nitrogen was bubbled through for a few minutes, before addition of K₂CO₃ (552 mg, 4.0 mmol) and the Michael acceptor (6.0 mmol). The vial was closed and agitated at 80 ˚C for 4 d. After the second day another portion of the Michael acceptor (1.0 mmol) was added. At the end of the reaction, the resin was filtered, washed (as described above), and dried under vacuum. The procedure was repeated a second time if remaining starting material was detected after cleavage.

16

General Procedure for Wittig Reaction
Methyl triphenylphosphonium bromide (1.79 g, 5.0 mmol) was suspended in anhydrous THF (14 mL) under nitrogen and cooled to -25 ˚C. n-BuLi (3.1 mL, 5.0 mmol, 1.6 M solution in hexanes) was added (yellow color) and the mixture stirred for 2 h (-25 ˚C up to r.t.). Afterwards, it was cooled to -35 ˚C and added to the resin (1.65 g), which was previously suspended in anhydrous THF (12 mL), also cooled to -35 ˚C. The reaction was allowed to warm up to r.t. and agitated overnight. It was quenched with H₂O (2 mL), washed (as described above), and dried under vacuum.

17

General Procedure for Diels-Alder Reaction
The resin (500 mg) was dried overnight at 90 ˚C. It was suspended in toluene (5 mL) in a vial and nitrogen was bubbled through for 10 min. The dienophile (5.0 mmol) was added, the vial closed, and the reaction agitated at 80 ˚C for 2 d. The resin was filtered, washed (as described above), and dried under vacuum before being cleaved.
Analytical Data for Compound 18bb
IR (ATR, platinum): 3329, 2978, 2937, 2248, 1622, 1589, 1506, 1456, 1310, 1296, 1160, 1139, 1121 cm^-¹. ^¹H NMR (250 MHz, acetone-d ₆): δ = 1.39 (s, 3 H, CH₃), 1.43 (s, 3 H, CH₃), 1.84-2.01 (m, 1 H, CH₂), 2.08-2.27 (m, 3 H, CH₂), 3.00 (ddd, J = 11.5, 9.1, 3.1 Hz, 1 H, NCCH), 3.73 (br dd, J = 9.1, 2.2 Hz, 1 H, CH), 5.80-5.88 (m, 1 H, =CH), 6.28 (d, J = 2.5 Hz, 1 H, Ar_mH), 6.47 (dd, J = 8.5, 2.5 Hz, 1 H, Ar_mH), 7.51 (d, J = 8.5 Hz, 1 H, Ar_mH), 8.32 (s, 1 H, OH) ppm. ^¹³C NMR (125 MHz, acetone-d ₆): δ = 25.0, 27.6, 28.28, 28.34, 32.4, 37.3, 79.2, 106.2, 110.3, 117.7, 121.7, 125.1, 128.2, 139.6, 156.6, 159.4 ppm. MS (EI, 70 eV): m/z (%) = 255 (43) [M⁺], 187 (100), 174 (27), 173 (29). HRMS (EI): [M⁺] calcd for C₁₆H₁₇NO₂: 255.1259; found: 255.1258. Structure verified by 2D NMR.