Mitsonobu reaction of cannabidiol. Synthesis of water-soluble cannabidiol derivatives

Mitsunobu reactions of cannabidiol (CBD) as the acid component and primary alcohols, for example benzyl, allyl, propargyl and methyl glycolate as the alcohol component gave the corresponding bis-alkylated CBD derivatives which were also obtained by alkylating CBD with the corresponding alkyl bromides. Alkylation of CBD with methyl bromoacetate followed by saponification of the two ester moieties and neutralization of the di-carboxylic acid afforded a water-soluble CBD bis-acetate bis-potassium salt


Introduction
Cannabidiol (CBD) is a phenolic monoterpene which is, beside the psychotropic tetrahydrocannabinol (THC), one of the major constituents among the more than 113 cannabinoids found in the resin from hemp (cannabis sativa). 1 Although not psychoactive itself, CBD reduces the effect of THC on the nervous system by binding agonistically to the cannabinoid receptors CB1 and CB2 and inhibiting them in an allosteric fashion. 2,3Pure CBD isolate is also used for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients two years of age and older. 4Through CBD's binding affinity for other G protein-coupled receptors, such as GPR18, 55, 119, 5HT1A, and TRPV2, it may be of pharmaceutical importance for the treatment of numerous medical conditions, like for instance, arthritis, cancer and diabetes. 5,6Unfortunately, a significant hurdle for the medical application of CBD and other cannabinoids is the high lipophilicity of these compounds and thus, their poor water solubility.In an effort to overcome the poor water solubility of CBD and other cannabinoids, suspensions of CBD nanoparticles 7 or micellar systems 8 were developed.Other groups have described various procedures to solubilize CBD in water by, for example, deprotonating the phenolic alcohol groups in the resorcinol moiety of CBD.However, only CBD concentrations up to 78 mg/l could be achieved this way and the deprotonated CBD species were extremely sensitive toward oxidation, resulting in dark tar-like material. 9In this paper we describe the chemical synthesis of a CBD derivative which is highly water soluble.Furthermore, a hitherto not described Mitsunobu protocol for modification of CBD is presented as well. 10BD was first isolated in 1940 from cannabis sativa by Adams, Hunt and Clark 11 and from cannabis indica by Jacob and Todd. 12Its structure was proven and its stereochemistry unambiguously assigned by Mechoulam and Shvo in 1963. 13The configuration of naturally occurring CBD and CBD-analogues has since been confirmed multiple times by several enantioselective total syntheses. 146][17][18][19] In general, two major types of chemical modifications of CBD had been described so far: modifications of the monoterpene ring or of the resorcinol moiety.For the latter modification, mainly the hydroxyl groups were either alkylated or acylated by various reagents and we are pursuing this modification avenue as well.

Results and Discussion
For the preparation of O-alkylated CBD derivatives (alkyl-CBD-ethers) we compared the classical alkylation of phenolic hydroxyls with alkyl bromides with a Mitsunobu protocol with the corresponding alcohols in which the phenolic hydroxyl groups of CBD act as the acid component.1][22][23][24] However, to the best of our knowledge, no Mitsunobu reaction of cannabinoids has been described so far.Thus, we reacted CBD (1) with bromides 2 and K2CO3 in DMF, and with primary alcohols 3 using a Mitsunobu protocol to give alkylated CBD derivatives 4 (Scheme 1).Table 1 shows the results.
In general, alkylations of CBD with alkyl bromides 2 proceeded smoothly affording the corresponding alkylated derivatives 4 in 63-99% yield (table 1).In case of propargyl bromide (2c) the medium yield was likely due to the instability of propargyl bromide.With the exception of methyl glycolate (3d) (table 1, entry 4), all primary alcohols 3 gave comparable yields of alkylated CBD derivatives 4 under Mitsunobu conditions.For the failure of the Mitsunobu reaction of 3d we do not have any reasonable explanation.
Attempts to react  9 -tetrahydrocannabinol ( 9 -THC) with benzyl alcohol (3a) under Mitsunobu conditions (Ph3P, DIAD, THF, 20°C) failed.No alkylated THC could be detected.In contrast, smooth alkylation of CBD occurred when it was reacted with 3a.Most likely, the failure of the Mitsunobu reaction of THC is due to the different acidities of THC and CBD.The pKa of CBD is approximately 8.0-8.3 9 while the pKa of THC is 10.6. 25herefore, THC is not acidic enough for acting as the acid component in a Mitsunobu condensation.Whether more basic phosphane reagents or other azodicarboxylates enable THC to participate in a Mitsunobu reaction needs to be tested in the future.

Scheme 1. Reaction of CBD with alkyl bromides (method A) and with primary alcohol under Mitsunobu conditions (method B)
.
For the synthesis of water-soluble CBD-derivatives we planned to attach a carboxylic acid to CBD which allows to form an anionic species and thus, increase the water solubility.For that purpose, we chose bisacetate derivative 4d.Since for mainly practical reasons, like for instance reaction conditions and purification procedures, classical alkylations of CBD with alkylbromides were regarded as being superior to a Mitsunobu protocol we reacted 41 g of CBD (1) with methyl bromoacetate (2d) under the conditions of method A in scheme 1 to obtain CBD derivative 4d in virtually quantitative yield (scheme 2).A similar mono ethyl acetate of CBD had been described in a patent but no experimental details were given. 17Next, CBD di-ester 4d was saponified with ethanolic KOH to give the free di-acid 5 (99%).Quantitative deprotonation of the latter with an equimolar amount of KOH finally gave the di-potassium salt 6 which is highly soluble in water up to 60% by weight.

Conclusions
We could show that cannabidiol (CBD) functions in Mitsunobu reactions as the acid component affording upon reaction with primary alcohols the corresponding bis-alkylated cannabidiols.The same products can be obtained by O-alkylation of CBD with alkyl bromides.The bis-hydroxycarbonylmethylated CBD derivative forms highly water-soluble potassium salts.No Mitsunobu reaction takes place with  9 -tetrahydrocannabinol.

General Procedure Method A
A suspension of CBD (1) (1 mol equivalent), alkyl bromide (2) (3 mol equivalents) and K2CO3 (3 mol equivalents) in DMF was vigorously stirred under an atmosphere of nitrogen at room temperature for 16 h.The mixture was filtered through a glass filter and the filtrate was concentrated in vacuo.The residue was dissolved in ethyl acetate and the resulting solution was washed 3 times with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo.If necessary, the product 4 was purified by chromatography with mixtures of petrol ether and ethyl acetate on silica gel.

General Procedure Method B
A solution of CBD (1) (1 mol equivalent), alcohol 3 (2 mol equivalents) and Ph3P (2 mol equivalents) in THF was stirred under nitrogen at 0°C for 0.5 h.Diisopropyl azodicarboxylate (2 mol equivalents) was added and stirring was continued at room temperature until TLC (petrol ether/ethyl acetate 3/1) revealed complete consumption of the starting material.The solution was concentrated in vacuo, the residue re-dissolved in dichloromethane, washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated again.The residue was chromatographed with mixtures of petrol ether and ethyl acetate to afford 4.