Hybrid Cannabinoids

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Hybrid cannabinoids, as the name indicates, were generated by combining the pharmacophoric features of classical and nonclassical cannabinoids (Fig. 3). The

Fig. 3. Evolution of hybrid cannabinoids.
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36 OH 37

Fig. 4. Novel CC/NCC hybrid ligands.

36 OH 37

Fig. 4. Novel CC/NCC hybrid ligands.

objective behind their design was to study more precisely the stereochemical requirements of the SAH pharmacophore, which was discovered during the development of NCCs. These hybrid cannabinoids had the added advantage of serving as conformationally more defined three-dimensional probes for the CB 1 and CB2 active sites than their nonclassical counterparts.

First-generation hybrid cannabinoids (34, Fig. 4) were designed to find a correlation between the stereochemistry of the SAH group (6a or 60), the chain length, and the affinity of the compounds for CBi and CB2 receptors (46,58),

~40-45% yield 6|1: 6<i = 85:15

Scheme 9. Stereoselective intramolecular oxymercuration-demercuration approach (46). Reagents and conditions: (a) Hg(OAc)2; (b) aq. NaOH; NaBHz,, «-BU4NOH.

3-(1,1-Dimethylheptyl)-12P-hydroxy-9-nor-9P-(hydroxymethyl)hexahydrocannabi-nol (34, n = 1). To a solution of 25 mg of 38 (n = 1) (0.06 mmol) in THF was added 38 mg of mercuric acetate (0.12 mmol), and the solution was stirred for 20 h at room temperature. The reaction was cooled to -78°C, and 36 mg of NaBH4 (0.94 mmol) in 1 M sodium methoxide/methanol (3 mL) was added in a single portion. The mixture was stirred at -78°C for 15 min, quenched with degassed saturated aqueous NH4Q, and allowed to warm to room temperature. The reaction was diluted with ether and washed with brine, and the aqueous phase extracted with ether. The combined ether phases were dried (MgSO4), and the solvent was evaporated to give a yellow oily solid. Elution through a short column of silica gel (EtOAc:hexane 50:50) followed by purification by HPLC (10 x 250 mm Phenomenex silica gel column, EtOAc:hexane 50:50, 1.5 mL/min, RI detection) gave 34 as a white foam (15 mg, 62% yield) with a retention time of 12 min. Chiral HPLC (1 x 25 cm Chiracel OD column, 2-propanol:hexane 10:90, 2.5 mL/min, UV detection at 254 nm) showed 34 (16.30 min retention time, 92.66%) and the enantiomer of 34 (22.71 min retention time, 4.12%), 92% ee: Rf = 0.20 (EtOAc:hexane 50:50).

whereas the second-generation hybrid cannabinoids (35-37, Fig. 4) were designed to obtain additional information on the stereochemical preferences of the SAH group with respect to its ability to interact with the CB1 and CB2 binding sites (47). A systematic study in which C6 stereochemistry and the chain length of the derivatives at this carbon were varied, revealed that the C6-P-hydroxypropyl analog had a high affinity for both CBx and CB2 receptors.

The challenge to the synthetic chemist that was posed by these structures was the control of C6 stereochemistry. An early solution to this problem involved the intramolecular oxymercuration-demercuration approach, as illustrated in Scheme 9 (46,58). Thus, the stereoselective cyclization of 38 to the tricyclic cannabinoid skeleton by means of the intramolecular oxymercuration-demercuration reaction (58,61) gave the 60-isomer predominantly (60:6a = 85:15). The enantiomers were separated by chiral high-performance liquid chromatography (HPLC) using Chiralpak OD columns. The probable

origin of this stereoselectivity has been discussed (62). Although the yield for this dihydrobenzopyran ring-forming step was modest, this approach was successfully applied to the synthesis of several SAH ligands (46). Several analogs synthesized by the above-mentioned approaches exhibited modest to good receptor affinities. Another approach is shown in Scheme 10, wherein the cyclization of 39 leads to formation of two rings of 40 and also determines the stereochemistry at carbon atoms 10a, 6a, and 6 in a single process (59). However, the reaction suffered from a low yield.

The synthesis of second-generation hybrid cannabinoids 35-37 was carried out using a modified approach as depicted in Scheme 11 (on page 130) (47).

Aldol condensation of aromatic fragment 41 and aliphatic fragment 42 (63) produced 43 (Scheme 11). Reduction of 43 with sodium borohydride followed by exposure of the resulting diastereomeric mixture of alcohols to trifluo-roacetic acid in dry chloroform at 0°C produced tricyclic alcohol 44 as an approx 1:1 mixture of C9 diastereomers. Oxidation of the diastereomers of 44 with the Dess-Martin periodinane gave ketone 45, which was converted to P-equatorial alcohol 47 by following a sequence involving the Witting-Horner-Emmonds reaction (see Subheading 3.2). Palladium-catalyzed reductive cleavage of the phenolic allyl ether function, followed by silyl ether removal, gave 35. Semihydrogenation of 35 in the presence of Lindlar's catalyst gave 36. Isomerization of an irradiated (tungsten filament lamp) solution of 36 in benzene in the presence of phenyl disulfide produced 37.

It should be noted that hybrid cannabinoids obtained by following these procedures were racemic and the enantiomers were separated by chiral HPLC using a method developed with chiral AD columns (60).

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