Methods for the Synthesis of Cannabinergic Ligands

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Ganesh A. Thakur, Spyros P. Nikas, Richard I. Duclos, Jr., and Alexandros Makriyannis


During the last decade, numerous cannabinergic ligands with high affinity and selectivity profiles for cannabinoid receptors (CB1 and CB2) emerged from rigorously pursued structure-activity relationship studies. This chapter focuses on the synthetic aspects of key cannabi-noid receptor probes representing the different classes of cannabinergic ligands that encompasses classical cannabinoids (CCs) including some covalent binding derivatives, nonclassical cannabinoids (NCCs), hybrid cannabinoids, aminoalkylindoles (AAIs), diarylpyrazoles, and the endocannabinoids.

Key Words: Cannabinoid, CBi, CB2, aminoalkylindole, diarylpyrazole, endocannabinoid.

1. Introduction

The long history of worldwide self-medication by a mixture of cannabinoids present in Cannabis sativa generated the first wave of interest among synthetic and medicinal chemists in conjunction with the co-developments of modern separation, spectroscopic, and synthetic methods during the last half century. The identification of the family of C21 tricyclic cannabinoids led to the chi-rospecific partial syntheses of these classical cannabinoids from more readily available monoterpenes, and to the total syntheses of these plant constituents, as well as an expanding list of cannabimimetic compounds. However, only a few efficacious drugs, which include Marinol (Dronabinol, (-)-A9-THC from Roxane Labs), Cesamet (Nabilone, developed by Eli Lilly) and Sativex (A9-THC and cannabidiol, developed by GW Pharmaceuticals), have resulted. Cannabinoid synthesis has seen a renewed wave of interest with the discovery and cloning of the CB1 and CB2 cannabinoid receptors and the characterizations of the two endogenous cannabinoid ligands N-arachidonoylethanolamine

From: Methods in Molecular Medicine: Marijuana and Cannabinoid Research: Methods and Protocols Edited by: E. S. Onaivi © Humana Press Inc., Totowa, NJ

(AEA; anandamide) and 2-arachidonoylglycerol (2-AG). The synthesis and evaluation of ligands for the two cannabinoid receptors thus now includes six general classes of compounds. The first class is the classical cannabinoids (CCs), which have the benzopyran ABC-tricyclic framework. The second class of cannabinergic ligands was initially developed at Pfizer and includes both AC bicyclic and ACD-tricyclic compounds lacking the pyran B-ring, characteristic of the classical cannabinoids. A third class of analogs is a hybrid cannabinoid class (CC/NCC hybrid) combining the ABC-tricyclic structural framework of the classical cannabinoids with the additional chiral center at C6 in the B-ring. The fourth chemical class of cannabinoid receptor ligands is the aminoalkyl indoles, initially developed at Sterling Winthrop, of which WIN55,212-2 is perhaps the benchmark compound. The fifth chemical class of ligands is the diarylpyrazoles. This class includes the highly CBi-selective SR141716A (Rimonabant) from Sanofi, which has currently passed phase III clinical trials for the treatment of obesity and smoking cessation, as well as the highly CB2-selective SR144528 from Sanofi. The sixth class of cannabinoid receptor lig-ands includes the endogenous lipids AEA, 2-AG, noladin ether, as well as their synthetic analogs. While the preponderance of the literature relates to the classical cannabinoids, this discussion of the chemical methods and selected synthetic approaches is a more balanced discussion covering the six classes of CB1 and CB2 receptor ligands and covalent binding probes.

Discovery of the endocannabinoids and the biochemical systems involved in their inactivation, namely fatty acid amide hydrolase (FAAH) and monoglyc-eride lipase (MAGL), as well as the anandamide transporter (AT) system, has also prompted the synthesis of several substrates capable of modulating the endocannabinoid system. Ligands for FAAH, MAGL, and compounds targeting the AT system will not be discussed, however.

2. Materials

Standard laboratory practices and procedures were followed. Eye protection and a functioning fume hood, glassware, magnetic and mechanical stirrers, chro-matography columns and column materials, rotary evaporator, and vacuum pump were required. Chemicals for syntheses were either commercially available or synthesized by following the standard reported procedures. Compounds were routinely checked by solution nuclear magnetic resonance spectroscopy (NMR) and other appropriate spectroscopic and analytical methods.

3. Synthesis of Cannabinoid Receptor Ligands: Approaches and Methods 3.1. Classical Cannabinoids and Covalent Binding Probes

The medicinal advantages of marijuana have been recognized for many centuries, but it was the characterization and synthesis (1) of its major active prin-

Structure Nabilone

AM708 Nabilone

Fig. 1. Structures of representative classical cannabinoids.

AM708 Nabilone

Fig. 1. Structures of representative classical cannabinoids.

ciple, (-)-A9-tetrahydrocannabinol ((-)-A9-THC, 1, Fig. 1) that began a new era for synthetic cannabinoids as pharmacological agents. The active constituents of the Cannabis plant, as well as numerous synthetic analogs, are the stereo-specific (-)-enantiomers, i.e., the (6aK,10aft)-configuration, of THC (Fig. 1).

(-)- A9-THC (1) and its A8-isomer (2, Fig. 1) are the first members of a class of canabinergic ligands referred to as classical cannabinoids. In general, these are ABC-tricyclic terpenoid compounds bearing a benzopyran moiety. Many CC analogs have been synthesized and evaluated pharmacologically and biochemically (for reviews, see refs. 2-8). Structure-activity relationship (SAR) studies recognize four pharmacophores within the cannabinoid prototype: a phenolic hydroxyl (PH), a lipophilic alkyl side chain (SC), a northern aliphatic hydroxyl (NAH), and a southern aliphatic hydroxyl (SAH). The first two are encompassed in the plant-derived cannabinoids, while all four pharmacophores are represented in some of the synthetic non-classical cannabinoids developed by Pfizer (e.g., 27, Fig. 2).

Syntheses of (-)-A9-THC have utilized the acid-catalyzed condensation of olivetol (9, Scheme 1) with suitable chiral monoterpenes, such as (+)-cis- or trans-p-mentha-2,8-dien-1-ol (9,10), (+)-trans-2-carene epoxide (11,12), p-mentha-2-ene-1,8-diol (13,14), and (-)-cis- or trans-verbenol (15). Other successful approaches to A9-THCs are also known (16-21), but a problem common to these methods is created by the fact that a variety of by-products results. "Normal" and "abnormal" THCs, bis-adducts, open-chain intermediates, starting materials, degradation products as well as double-bond isomers complicate work-up procedures and purifications. Although an improved method has

Fig. 2. Representative nonclassical cannabinoids.
Scheme 1. Syntheses of (-)-A9-THC.

recently been reported (14), the most popular syntheses of (-)-A9-THC employ either (+)-cis- or trans-p-mentha-2,8-dien-1-ol (7, Scheme 1) or (-)-trans- or cis-verbenol (8, Scheme 1). Neither method avoids double-bond isomerization of the thermodynamically less stable (-)-A9-THC to the more stable (-)-A8-iso-

Scheme 2. Single-step synthesis of (-)-A9-THC (10). Reagents and conditions: (a) MgSO4, BF3-Et2O, CH2CI2, 0°C, 1.5 h, 31%.

(-)-trans-A9-THC (1). A mixture of 2.88 g (16.0 mmol) of olivetol (9), 2.45 g (16.1 mmol) of (+)-cis/trans-p-mentha-2,8-dien-1-ol (7), and 2 g of anhydrous magnesium sulfate was stirred with 100 mL of methylene chloride under a N2 atmosphere. After cooling in an ice bath, 1 mL of freshly distilled BF3-Et2O was added. The mixture was stirred for 1.5 h at 0°C, and 5 g of anhydrous sodium bicarbonate was added. Stirring continued until the color faded, and the reaction mixture was then filtered and evaporated to give a colorless gum (5 g). On the basis of gas-liquid chromatography it contained 50% A9-THC. One half of this material was chromatographed on 150 g of Florisil (100-200 mesh) packed in a 1 in x 3 ft column in petroleum ether (30-40°C). It was eluted with petroleum ether followed by graded mixtures up to 2:98 of ethyl ether:petroleum ether. Fractions containing pure 1 (TLC) were combined and evaporated to give 0.77 g (31%) of (-)-A9-THC.

mer. Addition of hydrogen chloride to the double bond of (-)-A8-THC, followed by phenolate-anion-assisted dehydrochlorination leads to (-)-A9-THC.

Razdan and coworkers (10) have reported a modification of the Petrzilka (9) cannabinoid synthesis. Thus, condensation of olivetol with (+)-cis- or trans-p-mentha-2,8-dien-1-ol in the presence of boron trifluoride-etherate and anhydrous magnesium sulfate at 0°C yielded (-)-A9-THC, and practically no A8-iso-mer was formed (Scheme 2). This modification represents a useful direct route to (-)-A9-THCs, (-)-A9-tetrahydrocannabivarins, and their regiospecifically deuterated analogs (22-24). It was recently reported that the synthesis of a (-)-A9-THC derivative was accomplished without the presence of a drying agent by keeping the reaction temperature at 0°C (25).

(-)-A8-THC has a pharmacological profile similar to (-)-A9-THC and has been used as a template since the early days of cannabinoid structure-activity correlations because of its greater chemical stability. In general, syntheses of (-)-A8-THC congeners does not differ from those reported for (-)-A9-THC, involving condensation of a resorcinol with a suitable chiral monoterpene, which affords the (6aft,10aft)-configuration. However, the initially formed (-)-A9-THC is subsequently allowed to isomerize to (-)-A8-THC. Over the years, numerous (-)-A8-THC analogs were synthesized and tested, providing substantial information

Scheme 3. Synthesis of a representative (-)-A8-THC analog (34). Reagents and conditions: (a) (Me3Si)2N-K+, Br(CH2)4Br, THF, 0°C, 17 min, 88%; (b) DIBAL-H, CH2Cl2, -78°C, 1 h, 87%; (c) Br- Ph3P+-(CH2^CH3, (Me3Si)2N-K+, THF, 10°C, 1.5 h, 96%; (d) H2, 10% Pd/C, AcOEt, room temperature, overnight, 95%; (e) BBr3, CH2Cl2, -78 to -20°C, 5 d, 90%; (f) (+)-ds/irans-p-mentha-2,8-dien-1-ol, p-TSA, C6H6, 10 to 20°C, 1 h, 85%; (g) BF3-Et2O, CH2CI2, 0°C to room temperature, 7 h, 79%.

1-(3,5-Dimethoxyphenyl)cyclopentanecarbonitrile (12). To a solution of 11 (2.0 g, 11.3 mmol) in dry tetrahydrofuran (THF) (99 mL) at 0°C, under an argon atmosphere, was added potassium bis(trimethylsilyl)amide (6.77 g, 34.0 mmol). The mixture was stirred at the same temperature for 3 min, and then a solution of 1,4-dibromobutane (2.7 g, 12.5 mmol) in dry THF (14 mL) was added over a period of 10 min. Following the addition, the reaction was stirred for 5 min at 0°C and then quenched by the addition of saturated aqueous NH4CL The mixture was diluted with EtOAc, the organic layer separated, and the aqueous phase was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and the solvent evaporated under reduced pressure to give an oily residue. Purification by flash column chromatography (diethyl ether:petro-leum ether 30:70) afforded 2.3 g (88% yield) of the compound 12 as a colorless oil.

(-)-2-[3-(3,4-irans-p-Menthadien-(1,8))-yl]-5-(1-hexylcyclopentyl)resorcinol (14). To a solution of 13 (571 mg, 2.18 mmol) in dry benzene (22 mL) at 10°C under an argon atmosphere was added p-toluenesulfonic acid (79 mg, 0.42 mmol) followed by the addition of a solution of (+)-ds/irans-p-mentha-2,8-dien-1-ol (464 mg, 3.05 mmol) in dry benzene (6 mL). The reaction mixture was stirred at 10-20°C for 1 h, at which time thin-layer chromatography (TLC) indicated the complete consumption of starting material. The reaction mixture was diluted with diethyl ether, and the ether solution was washed with saturated NaHCO3 solution, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (diethyl ether:petroleum ether 7:93) afforded 736 mg (85% yield) of the title compound 14 as colorless viscous oil.

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15 16 17

Scheme 4. Synthesis of (-)-11-hydroxydimethylheptyl-A8-THC. Reagents and conditions: (a) BF3-Et2O, CH2Q2; (b) LiAlH^,, THF.

15 16 17

Scheme 4. Synthesis of (-)-11-hydroxydimethylheptyl-A8-THC. Reagents and conditions: (a) BF3-Et2O, CH2Q2; (b) LiAlH^,, THF.

about the phenolic hydroxyl (PH) and the lipophilic side chain (SC) pharmacophores (2-7,26,27). The latter has been recognized as the most critical pharmacophore group. Variation of the n-pentyl group of natural cannabinoids can lead to wide variations in potency and selectivity. Optimal activity is obtained with a seven or eight carbon length substituted with 1',1'- or 1',2'-dimethyl groups, as was first demonstrated by Adams (28-30). More recent studies have focused on novel side chains bearing 1',1'-cyclic moieties (31-34). One of the most successful compounds to result from this work was the C1'-cyclopentyl analog 3 (Fig. 1), chosen here to represent the side-chain-modified (-)-A8-tetrahydrocannabinols. The one-pot cyclobisalkylation of 11 to give cyclopen-tane carbonitrile 12, the terpenylation of resorcinol 13 with (+)-cis/trans-p-men-tha-2,8-dien-1-ol, and the cyclization of the cannabidiol intermediate 14 in which the initially formed (-)-A9-THC derivative is converted to the respective (-)-A8-isomer are the key steps leading to 3 (Scheme 3).

Structural modifications of the tetrahydrocannabinol framework identified one further pharmacophore: a northern aliphatic hydroxyl (NAH) at the C-9 or C-11 position of the classical cannabinoids. Thus, introduction of a hydroxyl group at the C-11 position in tetrahydrocannabinols (e.g., (-)-11-hydroxydi-methylheptyl-A8-THC, 17, Scheme 4) leads to significant enhancement in affin-

(6aR)-(trans)-3-(1-Hexylcyclopentyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol (3). To a solution of 14 (601 mg, 1.52 mmol) in anhydrous CH2Cl2 (43 mL) at 0°C under an argon atmosphere was added boron trifluoride-ether-ate (1.32 mL 10.6 mmol). Following the addition, the mixture was stirred at 0°C for 1 h and then at room temperature for 7 h. The reaction was quenched by the addition of saturated NaHCO3 solution, and the volatiles were removed under reduced pressure. The crude residue was diluted with EtOAc, and the organic layer was washed with water, brine, and dried over MgSOzi. Solvent evaporation and purification by flash column chromatography on silica gel (diethyl ether:petroleum ether 6:94) afforded 476 mg (79% yield) of the title compound 3 as white foam.

ity and potency for CBi and CB2 (35,36). This is also the case for the hexahy-drocannabinols (HHC, e.g., 5, Fig. 1) in which the C-ring is fully saturated. Based on the relative configuration at the C-9 position, hexahydrocannabinol encompasses two types of isomers (9a and 9P). Although both isomers are biologically active, the P-epimers in which the C-9 hydroxyl or hydroxymethyl group is equatorial (e.g., 5) have been shown to be more potent than the a-axial counterparts (37-39).

In general, synthesis of 11-hydroxy-A8-THC derivatives (e.g., 17, Scheme 4) follows a strategy used for the preparation of (-)-A8-THCs. Thus, verbenol (8, Scheme 1) is replaced by optically active 4-hydroxymyrtenyl pivalate (15, Scheme 4) in a Lewis-acid-catalyzed condensation with the appropriate resor-cinol (15,30,40-42).

For example, the highly potent (-)-11-hydroxydimethylheptyl-A8-THC (17) was synthesized following this method and has served as a template for the design of the high affinity covalent binding probes 19 and 4 (Scheme 5). Development of these ligands was directed at obtaining information on the receptor-binding domain. The electrophilic isothiocyanato group (NCS) targets nucleophilic amino acid residues such as lysine, histidine, and cysteine at or near the active site, and the photoactivatable aliphatic azido group (N3) is capable of labeling amino acid residues at the active site via a highly reactive nitrene intermediate. Both probes were shown to successfully label the cannabinoid receptors (43). The C-7' bromo analog 18 is the starting point for the synthesis of 19 and 4. Thus, displacement of the bromide in 18 by tetramethylguanidini-um azide (TMGA) led to C-7' azide 19, which was converted to the respective isothiocyanate 4 by the triphenylphosphine/carbon disulfide method (41).

Introduction of the more potent equatorial hydroxymethyl group for the hexahydrocannabinol series can be accomplished either by catalytic hydrogenation of the A8-double bond followed by chromatographic separation of the resulting mixture of isomers (44) or preferably, by utilizing a Wittig-Horner-Emmons process starting from the appropriate keto-precursor (38,45-47). The synthesis of the analog 5, a representative hexahydrocannabinol derivative, is shown in Scheme 6. Protection of the free phenolic hydroxyl in 20 followed by Wittig olefination using (methoxymethylene)triphenylphosphorane produced a mixture of methyl enol ethers, which were hydrolyzed to aldehyde diastere-omers 21 and 22. Epimerization (38,45-48) gave the thermodynamically more stable equatorial aldehyde 22. This was followed by carbonyl reduction and deprotection of the phenolic hydroxyl to give 5.

It is also known that presence of a C-9 carbonyl group significantly enhances cannabinergic activity (49). Thus, nabilone (6) (developed at Eli Lilly) represents a successful modification at the northern end of the tricyclic ABC-cannabinoid. This ligand was synthesized (50) from the corresponding

Scheme 5. Synthesis of representative covalent probes for cannabinoid receptors (41). Reagents and conditions: (a) TMGA, CHCL, reflux, overnight, 92%; (b) CS2, PPh3, THF, room temperature, 3 d, 73%.

(-)-11-Hydroxy-7'-azido-1',1'-dimethylheptyl-A8-THC (19). A solution of 11-hydroxy-7' -bromo-1',1'-dimethylheptyl-A8-THC (18) (138.2 mg, 0.297 mmol) in 10 mL of dry chloroform was added dropwise to a solution of TMGA (94 mg, 0.594 mmol) in 5 mL of dry chloroform at 0°C under nitrogen. The resulting mixture was allowed to reach room temperature and refluxed overnight. Subsequently, the solvent was removed under a flow of nitrogen, and ethyl ether was added until no more precipitate was formed. The precipitate was filtered out, and the filtrate was dried over sodium sulfate. Removal of the solvent yielded 124.8 mg of crude product, which was purified by column chromatography (ethyl ether:petroleum ether 70:30). The desired product (19), 117.3 mg (light yellow oil), was obtained in 92% yield.

(-)-11-Hydroxy-7'-isothiocyanato-1' ,1'-dimethylheptyl-A8-THC (4). (-)-11 -Hydroxy-7'-azido-1',1' -dimethylheptyl-A8-THC (19) (100 mg, 0.23 mmol) and carbon disulfide (0.4 mL, 6.6 mmol) were dissolved in 10 mL of anhydrous THF. The mixture was stirred at room temperature, and triphenylphosphine (92 mg, 0.35 mmol) was added. After 3 d, the solvent was evaporated under vacuum, and the residue was purified by column chromatography (ethyl ether:petroleum ether 70:30). After purification 74.4 mg of 4 (white solid) was obtained in 73% yield.

resorcinol 16 and either of the acetates 23 or 24 (Scheme 7), which were in turn obtained from commercially available (1^,5^)-(+)-nopinone in two steps (46,50,51). Coupling of 16 with 23 or 24 in the presence of p-toluenesulfon-ic acid afforded the key intermediate 25 (50). A useful modification of this method was reported later (46). Norpinanone 25 was then treated with stannic chloride in chloroform at room temperature to give ketone 6 not free from its respective ds-isomer. However, nabilone (6) was purified by column chro-

Scheme 6. Synthesis of 3-hept-1-ynyl-11-hydroxyhexahydrocannabinol (45). Reagents and conditions: (a) i-BuCC^SiCl, imidazole, DMF, 25°C, 92%; (b) Ph3P=CHOMe, PhH, 70°C, 1.5 h; (c) Cl3CCOOH, CH2Cl2/H2O, 25°C; (d) K2CO3, EtOH, 25°C, 85% (three steps); (e) NaBH4, EtOH, 0°C; (f) «-Bu4NF, THF, 0°C, 95% (two steps).

Aldehyde 22. (Methoxymethyl)triphenylphosphonium chloride (247 mg, 0.72 mmol) was suspended in 6 mL of dry benzene. Sodium tert-amylate (1.24 M in benzene, 0.58 mL, 0.72 mmol), from NaH and tert-amyl alcohol, was added, and the reaction mixture was stirred for 5 min at 25°C. The TBS derivative of ketone 20 (107 mg, 0.24 mmol) was dissolved in the minimum amount of benzene and transferred to the solution of the ylide via cannula. The reaction mixture was stirred at 70°C for 1.5 h. Quenching with saturated aqueous NH4Cl, dilution with ether, and extraction with 3 x 10 mL of ethyl ether produced an organic phase, which was washed with brine, dried (MgSO4), and evaporated. The residue was dissolved in 16 mL of dichloromethane, 155 mg (0.9 mmol) of wet trichloroacetic acid was added, and the mixture was stirred at 25°C for 30 min. The reaction was quenched with saturated aqueous NaHCO3:brine 50:50, and the mixture was diluted with dichloromethane. The aqueous phase was extracted with 3 x 20 mL of dichloromethane, and the combined organic extract was washed with brine, dried (MgSO4), and evaporated. The residue, which consisted of a mixture of aldehydes 21 and 22, was dissolved in 10 mL of ethanol and added to 71 mg (0.54 mmol) of powdered potassium carbonate suspended in 10 mL of ethanol. The heterogeneous mixture was stirred at 25°C for 4 h. Then the reaction was quenched with saturated aqueous NaH2PO4 and the mixture diluted with ether. The aqueous phase was extracted with 4 x 20 mL of ether. The combined organic extracts were dried (MgSO4), evaporated, and purified by flash column chromatography (ethyl acetate:hexane 5:95) to produce 94 mg (85% overall yield) of 22 as an oil.

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Diol 5. Aldehyde 22 (45 mg, 0.124 mmol) was dissolved in 1.5 mL of EtOH and cooled to 0°C. A solution of 11 mg (0.289 mmol) of NaBH4 dissolved in 0.5 mL of EtOH was added via cannula. The reaction mixture was stirred at 0°C for 30 min, the reaction quenched with water, and the mixture diluted with ether. The aqueous phase was extracted twice with ether, and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated, and the crude product was dissolved in 3 mL of THF and cooled to 0°C. Tetrabutylammonium fluoride (48 mg, 0.188 mmol) in 0.7 mL of THF was added, the mixture was stirred at 0°C for 45 min, and then the reaction was quenched with water. Ether was added (5 mL), and the aqueous phase was extracted with 2 x 10 mL of ether. The combined organic extracts were washed with brine, dried (MgSO4), evaporated, and purified by flash chromatography (ethyl acetate:hexane 35:65) to produce 34 mg of 5 (95% overall yield) as an oil.

Scheme 7. Synthesis of nabilone (50). Reagents and conditions: (a) p-TSA-H2O, CHCL, room temperature, 4 h, 70%; (b) SnCl,, CHCL, room temperature, 16 h, 82%.

(+)-4-[4-(1,1-Dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone (25). A mixture of 1.19 g (5 mmol) of either 23 or 24, 1.18 g (5 mmol) of 16, and 0.95 g (5 mmol) of p-TSA-H2O in 50 mL of CHCl3 was permitted to stand at room temperature for 4 h. Ether was added, and the organic extracts were washed with 10% aqueous NaHCO3, water, dried over Na2SO4, and concentrated to give a semicrystalline residue. The residue was triturated with 25 mL of n-hexane and filtered to provide 1.30 g (70% yield) of 25 as a white, crystalline solid.

(-)-irans-3-(1,1-Dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one (6, nabilone). To a solution of 372 mg (1 mmol) of 25 in 25 mL of CHC13 was added 1.0 mL of SnCL,. The resulting mixture was stirred at room temperature for 16 h and then poured onto ice and extracted with Et2O. The organic extracts were combined, washed with 2 N HCl, water, 5% aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated to afford 378 mg of a foam. Chromatography (Woelm activity II, silica gel; benzene) yielded 305 mg (82% yield) of 6 and 55 mg (14% yield) of its corresponding ds-isomer.

32 33


Scheme 8. Synthesis of CP-47,497 (54). Reagents and conditions: (a) MeBr, NaOH, DMSO/H2O, 98%; (b) DIBAL-H, THF, 99%; (c) Ph3P=CH(CH2)sCH3, DMSO, 57%; (d) Pd/C, H2, EtOH, 78%; (e) Br2, CCI4,100%; (f) KH, PhCH2Br, DMF, 100%; (g) Mg, CuI, 2-cyclohexen-1-one, THF, 79%; (h) NaBH4, MeOH, 51% of 32 and 12% of 33; (i) Pd/C, EtOH, H2, 77%.

3-[2-(Benzyloxy)-4-(1,1-dimethylheptyl)phenyl]cyclohexanone (31). A solution of 30 (75.0 g, 0.193 mol) in 200 mL of THF was slowly added to 70-80 mesh Mg (9.25 g, 0.386 mol). The resultant mixture was refluxed for 20 min and then cooled to -18°C. CuI (1.84 g, 9.7 mmol) was added, and stirring was continued for 10 min. To the resultant mixture was slowly added a solution of 2-cyclohexen-1-one (18.5 g, 0.193 mol) in 40 mL of THF at such a rate that the reaction temperature was maintained at < -3°C with NaCl-ice cooling. The reaction was stirred an additional 30 min, and then added to 500 mL of 2 N HCl and 2 L of ice water. The quenched reaction was extracted with 3 x 500 mL portions of ether. The combined extracts were washed with 2 x 100 mL of water and with 2 x 100 mL of saturated aqueous NaCl, dried (MgSO4), and evaporated to give an oil. The oil was purified via column chromatography on 1.6 kg of silica gel (ethyl ether:cyclohexane 20:80) to yield 62.5 g (79%) of 31 as an oil.

(cis)- and (ira«s)-3-[2-(Benzyloxy)-4-(1,1-dimethylheptyl)phenyl] cyclohexanol (32 and 33). To a -40°C solution of 31 (4.30 g, 0.106 mol) in 500 mL of MeOH and 15 mL of THF was added NaBH4 (8.05 g, 0.212 mol). The reaction mixture was stirred for 1 h at -40°C, allowed to warm to -10°C, and then quenched by the addition of 100 mL

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of saturated aqueous NaCl. The quenched reaction was diluted with 1.5 L of H2O and extracted with 3 x 450 mL portions of Et2O. The combined extracts were washed with 3 x 100 mL of H2O and with 2 x 200 mL of saturated aqueous NaCl, dried (MgSO4), and evaporated to give an oil. The oil was purified via column chromatography on 400 g of silica gel (ethyl ether:cyclohexane 20:80) to yield, in order of elution, 5.0 g of 33 (12%) as an oil and 22.2 g of 32 (51%) as a solid.

(ris)-3-[4-(1,1-Dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (26, CP-47,497). A mixture of 32 (2.20 g, 5.39 mmol), NaHCO3 (12 g), and 10% Pd/C (2.0 g) in 100 mL of EtOH was stirred under 1 atm of H2 for 2 h. The reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated to give a solid. The solid was recrys-tallized from hexane to yield 1.32 g (77%) of 26.

matography. It should be mentioned that in closely related systems, a clean and rapid cyclization resulted when trimethylsilyl triflate was used in place of stannic chloride (45).

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