DOI: 10.1002/asia.

201901179 Minireview

Synthetic Strategies for ( )-Cannabidiol and Its Structural Analogs

Byunghyuck Jung,*[b] Jungkyu K. Lee,[c] Jungnam Kim,[a] Eunhye K. Kang,[a]
Sang Yeong Han,[a] Hee-Yoon Lee,[a] and Insung S. Choi*[a]

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Abstract: ( )-Cannabidiol (( )-CBD), a non-psychoactive some drawbacks, such as poor quality control along with
phytocannabinoid from Cannabis, and its structural analogs purification difficulty. Chemical-synthetic strategies for ( )-
have received growing attention in recent years because of CBD could tackle these issues, and, additionally, generate
their potential therapeutic benefits, including neuroprotec- novel ( )-CBD analogs that exhibit advanced biological ac-
tive, anti-epileptic, anti-inflammatory, anxiolytic, and anti- tivities. This review concisely summarizes the historic and
cancer properties. ( )-CBD and its analogs have been ob- recent milestones in the synthetic strategies for ( )-CBD and
tained mainly based on extraction from the natural source; its analogs.
however, the conventional extraction-based methods have

1. Introduction dicative of any abuse or dependence potential in a pre-review

report in 2017.[13] In addition to epilepsy,[14] ( )-CBD anecdotal-
Epilepsy, one of the major neurological disorders, causes the ly–if not clinically–shows potential therapeutic benefits in vari-
patients to experience chronic, repetitive, and severe seizures, ous healthcare applications including autism,[15–17] inflamma-
resulting in sudden death.[1, 2] It is the fourth leading disease in tion,[18, 19] cancer,[20] and neurodegenerative diseases.[21–23] The
the neurological disorders, for example, affecting approximate- unpurified Cannabis extract is a mixture of hundreds of natural
ly 65 million people worldwide, 2.2 millions in the USA, 6 mil- products, and more than 500 compounds have been identified,
lions in Europe, and 120 000 in Korea.[3, 4] Its annual incidence is including ( )-CBD (1) and ( )-trans-D9-tetrahydrocannabinol
67.8 per 100 000 persons.[5] Its national prevalence seems to be (( )-trans-D9-THC, 2) (Figure 1).[24] In the view of structural and
linked to the national wealth; more than 80 percent of the epi-
lepsy patients are the residents in the developing countries,
and the occurrence rate in the developing countries is at least
twice as high as that in the developed countries.[3] Although
more than 20 drugs are available on the market for epilepsy
treatment, they are mostly anti-seizure drugs and not effective
for one-third of the epilepsy patients.[6] The insufficient anti-
seizure capability and severe side effects of the current anti-
Figure 1. Structure of ( )-cannabidiol (( )-CBD, 1) and ( )-trans-D9-THC (2).
seizure drugs have led healthcare researchers to look for new
types of remedies.[7–9] In 2018, the use of a Cannabis extract
was approved, as a treatment of epileptic seizures associated biological features, phytocannabinoids could be classified into
with the Lennox–Gastaut or Dravet syndrome in patients two categories: ( )-CBD and its analogs; ( )-trans-D9-THC and
2 years of age and older, by the US Food and Drug Administra- its analogs. ( )-trans-D9-THC, the main cause of psychoactive
tion (FDA).[10, 11] The active ingredient of this prescription medi- effects of Cannabis, has a hexahydro-6H-benzo[c]chromene
cine, Epidiolex , by GW Pharmaceuticals is a purified Cannabis- core (violet color, 3) and exhibits high binding affinity for the
derived ( )-cannabidiol (( )-CBD, 2-[(1R,6R)-3-methyl-6-prop-1- endocannabinoid receptors (CB1 receptor: abundant in brain;
en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol).[12] CB2 receptor: abundant in immune cells).[25, 26] The chemical
( )-CBD is a chiral terpenophenolic phytocannabinoid with- synthesis of ( )-trans-D9-THC and its analogs bearing the ben-
out psychoactive effects. Accordingly, the World Health Organi- zo[c]chromene motif has extensively been investigated over
zation (WHO) announced that ( )-CBD exhibited no effects in- last half-century,[27] and a seminal review on their synthesis has
recently been reported by Carreira et al.[24] On the other hand,
[a] J. Kim, E. K. Kang, S. Y. Han, Prof. H.-Y. Lee, Prof. I. S. Choi ( )-CBD does not contain the benzo[c]chromene motif, and is
Department of Chemistry
structurally composed of three major parts: i.e., limonene
KAIST
Daejeon 34141 (Korea) (green), resorcinol (blue), and C4’-alkyl chain (red) parts
E-mail: ischoi@kaist.ac.kr (Figure 2; yellow circle). It is reported that ( )-CBD does not
[b] Prof. B. Jung bind to the orthosteric sites of the CB1 and CB2 endocannabi-
School of Undergraduate Studies noid receptors.[28] ( )-CBD and its analogs of the three structur-
DGIST
al parts have been synthesized chemically by many groups,
Daegu 42988 (Korea)
E-mail: byunghyuck.jung@dgist.ac.kr but a panoptic article of their syntheses has not yet been re-
[c] Prof. J. K. Lee ported.[29]
Department of Chemistry ( )-CBD and its structural analogs, like other phytocannabi-
Green-Nano Materials Research Center noids, have generally been obtained by the purification and
Kyungpook National University
isolation from a Cannabis extract, yet challenging due to the
Daegu 41566 (Korea)
structural, physical, and chemical similarities among the phyto-
The ORCID identification number(s) for the author(s) of this article can be
found under: cannabinoids.[30] Therefore, chemical synthesis has its own ad-
https://doi.org/10.1002/asia.201901179. vantages, considering practical difficulties in purification and

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they found that the direct p-TsCl treatment of the compound 5

as a form of crude mixture, which was generated by addition
of lithiated olivetol dimethyl ether (4) to citral A (geranial), led
to racemic cannabidiol dimethyl ether (()-CBDD, ()-8). In
their reaction Scheme, tosylation of allyl alcohol (5) with p-TsCl
under the basic condition generated the corresponding tosy-
late, and the liberation of the tosylate ion led to the formation

Byunghyuck Jung is a professor at the School

of Undergraduate Studies of DGIST, Korea. He
received his B.S., M.S., and Ph.D. degrees from
KAIST (with Prof. Sung Ho Kang). After his
postdoctoral research at Boston College (with
Prof. Amir H. Hoveyda), he joined the faculty
at DGIST in 2014. His research interests in-
clude organic chemistry, organometallics, and
total synthesis of natural products.

Figure 2. Classification of ( )-CBD analogs.

consistent quality control (QC). For example, the absolute and

Jungkyu K. Lee is a professor of chemistry at
relative chemical compositions in the Cannabis extracts are dif- Kyungpook National University (KNU). He re-
ferent from-strain-to-strain and from-harvest-to-harvest, ceived his Ph.D. at Stanford University (with
making the QC for pharmaceutical grade practically difficult Prof. Zhenan Bao). After his postdoctoral re-
and costly marketwise. Moreover, synthetic strategies would search at Massachusetts Institute of Technolo-
gy (with Prof. Hadley D. Sikes), he joined the
lead to the generation of new ( )-CBD analogs, the medical faculty at KNU in 2012. His research interests
properties of which are not attainable with natural ones. In include organic chemistry and polymer
this review, we focus on the synthetic strategies applied to chemistry.
produce racemic or enantio-pure CBD and the recent achieve-
ments in the synthesis of ( )-CBD analogs. Specifically, we clas-
sified the ( )-CBD analogs mainly into one of the three sub-
groups-C4’, resorcinol, and limonene analogs-based on our
structural classification of ( )-CBD (Figure 2). Hee-Yoon Lee is a professor of chemistry at
KAIST, and director of the Directorate for
Basic Research in Sci. & Eng. (NRF Korea).
2. CBD Synthesis After completing his B.S. and M.S. degrees
(with Prof. Eun Lee) at Seoul National Univer-
Since Adams et al. elucidated the molecular structure of ( )- sity, and his Ph.D. degree (with Prof. Paul A.
CBD in 1940,[31] various synthetic strategies to CBD have been Wender) at Stanford University, he worked as
a postdoctoral researcher (with Prof. Gilbert
reported,[32] including Mechoulam and Gaoni’s first synthesis of Stork) at Columbia University. His current re-
racemic ()-CBD from citral A (Scheme 1).[33] In the studies, search interest is organic synthesis and chem-
ical biology.

Insung S. Choi is a professor of chemistry and

of bio and brain engineering at KAIST, and di-
rector of the Center for Cell-Encapsulation Re-
search (Creative Research Initiative). After
completing his B.S. and M.S. degrees (with
Prof. Eun Lee) at Seoul National University,
and his Ph.D. degree (with Prof. George M.
Whitesides) at Harvard University, he worked
as a postdoctoral researcher (with Prof.
Robert Langer) at MIT. His current research in-
terest is cytospace.

Scheme 1. First total synthesis of ()-CBD by Mechoulam and Gaoni. p-

TsCl = para-toluenesulfonyl chloride.

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of allyl cation (6). Ring formation by the electrophilic attack of

p electrons allowed for the generation of tertiary carbocation
(7), and the successive elimination of proton produced a mix-
ture of the desired Hofmann’s alkene 8 (()-CBDD) and Zait-
sev’s alkene 9. The nucleophilic demethylation of ()-CBDD
with methyl Grignard reagent at 160 8C afforded the racemic
CBD (()-1). It is to note that the demethylation step, requiring
harsh reaction conditions (e.g., temperature up to 200 8C), still
remains to improve even more than 50 years after the first
report. Mechoulam and Gaoni’s synthesis, the first total synthe-
sis of ()-CBD, could be classified into a (partially) biomimetic
approach to CBD, by considering that the biogenetic pathway
to ( )-CBD also involves the cyclization step (Scheme 2);[34, 35]
while the allyl-benzyl cation, triggering the cyclization to CBD,
is generated by the oxidative removal of a hydride by flavin
adenine dinucleotide (FAD) associated with cannabidiolic acid
(CBDA) synthase at the enzymatic level, the cation generation
in the Mechoulam and Gaoni’s synthesis is acidic, involving sol-
volysis of the toslylate.

Scheme 3. First stereoselective synthesis of ( )-CBD by Petrzilka et al.

Scheme 2. Biogenesis of ( )-CBD (1).

Petrzilka et al. attempted the direct, stereoselective synthesis

of ( )-CBD by using the electrophilic aromatic substitution re-
action of olivetol (18) with optically pure D-2,8-menthadien-1-
ol (14), based on the retrosynthetic disconnection of the C C
Scheme 4. Stereoselective synthesis of ( )-CBDD (8) by SN2’ reaction.
bond between the resorcinol and limonene moieties
(Scheme 3).[36] The key to their stereoselective synthesis was
the synthesis of enantiomerically enriched D-2,8-menthadien- desired ( )-CBDD was obtained in the 78 % yield. In this syn-
1-ol (14), which could be readily available from (+)-(R)-limo- thetic Scheme, the substrate-controlled, high regio- and diaste-
nene.[37] The treatment of the compound 14 with N,N-dime- reoselectivities were observed: it was proposed that, between
thylformamide dineopentylacetal enabled the formation of the two potential reaction sites (C1 and C3), the attack at the C1
acetal (15), which was subsequently transformed to alkoxyimi- site was not feasible due to the steric hindrance of the tertiary
nium ion (16). The release of N,N-dimethylformamide (DMF) carbon center, and the bulky isopropenyl substituent at the C4
generated the desired allyl cation (17). The electrophilic aro- carbon blocked the a-face of the ring to favor the anti-addi-
matic substitution of olivetol (18), having two reactive sites, tion of the diaryl cuprate to minimize the steric hindrance be-
yielded a mixture of three products including ( )-CBD: 25 % of tween the cuprate and isopropenyl units. Although they high-
( )-CBD, 35 % of ( )-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-olive- lighted that their report was the first example of Lewis acid-
tol (19, abnormal CBD), and 5 % of ( )-2,4-disubstituted olive- catalyzed SN2’ substitution with homocuprate R2CuBr, the reac-
tol (20), along with 30 % recovery of olivetol.[38] tion should be considered to be BF3-mediated, not BF3-cata-
To tackle the issue of poor regioselectivity in the Petrzilka’s lyzed, because the 3.5 equivalents of BF3·OEt2 were used. ( )-
method (site #1 vs. site #2 in Scheme 3), Rickards and Ronne- CBD could be readily obtained by demethylation of ( )-CBDM,
berg utilized a BF3-catalyzed regioselective and diastereoselec- as shown in Scheme 1.
tive synthesis of ( )-CBDD (( )-8), as shown in Scheme 4.[39] Similarly, Kobayashi et al. utilized the coupling reaction be-
While diaryl cuprate itself, generated from the reaction of CuBr tween a-iodo enone (25) and olivetol dimethyl ether cyano-
with lithiated olivetol dimethyl ether, was not reactive enough cuprate complex (26), produced from the reaction of CuCN
to accomplish the SN2’ reaction with allyl acetate (21), the ad- with lithiated olivetol dimethyl ether, for the synthesis of ( )-
dition of a 3.5 equivalents of BF3·OEt2 was found to make the CBD (Scheme 5).[40] For the synthesis of the compound 25, they
SN2’ reaction proceed very smoothly even at 78 8C, and the initially examined the Ni-catalyzed allylation with lithium iso-

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alkenyl groups in place of the isopropenyl moiety of the opti-

cally pure terpineol (14). On the other hand, Kobayashi et al.
proposed that this obstacle could be overcome by the addi-
tion of various alkenyl-metal reagents to cyclohexenyl monoa-
cetate (22) in the presence of the Ni catalyst, which will be dis-
cussed in detail in the limonene-analog section.
Leahy et al. have recently reported a synthetic strategy for a
scalable production of enantiopure ( )-CBD by combining
three well-recognized reactions:[27b] Corey–Bakshi–Shibata
(CBS) reduction of ketones,[43] stereospecific Ireland–Claisen re-
arrangement,[44] and Ru-catalyzed ring-closing metathesis
(RCM) (Scheme 6).[45] Their key idea for the installation of chiral

Scheme 5. SN2 and 1,4-addition approach by Kobayashi et al. TMEDA = tetra-

methylethylenediamine, DBHQ = 2,5-di-tert-butylhydroquinone, py = pyri-
dine, and THF = tetrahydrofuran.

propenyl borate (23 a), but the attempted reaction resulted in

poor site selectivity (SN2:SN2’ = 67:33).[41] However, the use of
alkenyl Grignard reagent (23 b) with a catalytic amount of
CuCN and 15 equivalents of MgCl2, instead of the combination
of Ni catalyst and TMEDA ligand, transformed the allyl acetate
(22) to the desired SN2 product (24) with better site-selectivity
(SN2:SN2’ = 86:14), which was improved further to 94:6 of regio-
selectivity by the use of a zinc reagent (23 c) with NiCl2(PPh3)2
as a catalyst and TMEDA as a ligand. The compound 25 was
then formed, from the compound 24, by Jones oxidation and Scheme 6. Leahy’s synthetic strategy for ( )-CBD. DCC = N,N’-dicyclohexyl-
iodination, and the subsequent 1,4-addition reaction, in the carbodiimide, DMAP = 4-dimethylaminopyridine, KHMDS = potassium bis(tri-
methylsilyl)amide, and TMSCl = chlorotrimethylsilane.
presence of BF3·OEt2, led to the compound 27 as a diastereo-
meric mixture at the a position. The mixture was transformed
to enol phosphate (28) via the reductive formation of magnesi-
um enolate, using a Grignard reagent, followed by quenching centers was the enantioselective reduction of the enone (29)
with ClP(O)(OEt)2, which underwent the Ni-catalyzed Kumada and the stereospecific Ireland–Claisen rearrangement of the
coupling reaction with MeMgCl.[42] The demethylation of result- compound 33. The a,b-unsaturated enone (29) was prepared
ing ( )-CBDD led to the generation of ( )-CBD. by formylation of olivetol dimethyl ether and successive aldol
The advantage of the Kobayashi’s method, compared with condensation with acetone. Use of the CBS oxazaborolidine
the Petrizilka’s one, is presented in Figure 3. In the Petrizilka’s (30) led to the formation of the allyl alcohol (31) with moder-
method, it was difficult to generally apply the reaction to the ate enantioselectivity (77 %ee), but this degree of enantiopurity
synthesis of ( )-CBD analogs, especially those bearing longer proved suitable for the synthesis of enantiopure ( )-CBD
owing to the feasibility of recrystallization of the carboxylic
acid (34) after the Ireland–Claisen rearrangement. The conver-
sion of the acid (34) to methyl ketone (35) with MeLi and suc-
cessive RCM afforded the methyl cyclohexenyl ketone (36),
which was converted to ( )-CBD through the Wittig olefination
with Ph3P = CH2 and MeMgI-mediated demethylation. They
also used an enzymatic method for the enantioselective syn-
thesis of the allyl alcohol (31): the enzymatic kinetic resolution
of racemic allyl alcohols,[46] prepared from NaBH4 reduction of
the compound 29, proceeded smoothly in the presence of Sa-
Figure 3. Kobayashi’s strategy for the synthesis of ( )-CBD analogs bearing vinase 12T and vinyl butyrate, and the saponification of the
longer alkenyl groups. corresponding ester allowed for the formation of the enantio-

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enriched compound 31 (> 98 %ee) in the modest overall yield

(38 %).
ent-CBD ((+)-1), the mirror image of naturally occurring ( )-
CBD, has also been synthesized, and its pharmacological prop-
erties were evaluated (Scheme 7).[47] The Luche reduction of
( )-p-mentha-1,8-diene-3-one (38), in the presence of CeCl3,
led to the formation of D-1,8-menthadien-3-ol (39) in the 85 %
Scheme 8. Synthesis of nor-cannabidiol(CBD-C4, 42). p-TsOH = para-toluene-
yield. While the BF3-mediated condensation of the com-
sulfonic acid.
pound 39 with olivetol (18) generated the cyclized ent-trans-
D9-THC ((+)-2) predominantly, a modified method, which used
BF3·OEt2 absorbed on basic alumina (Al2O3), allowed for the for- pound 14 with Brønsted acid produced the allyl cation inter-
mation of ent-CBD in the 44 % yield. In contrast to ( )-CBD, mediate (17), and electrophilic aromatic substitution of 5-bu-
the therapeutic benefits of ent-CBD has not yet been report- tylbenzene-1,3-diol (49) with the compound 17 led to the for-
ed.[12] mation of nor-cannabidiol (42) in the 32 % yield.
Synthetic C4’ analogs of ( )-CBD have been designed and
executed for achieving better potency, safety, and permeability,
as a neuroprotective drug, than ( )-CBD.[12] For example, the
compound 43, having the N-acetyl azetidine moiety, showed
better pharmacological performance:[51] the EC50 value of
2,000 nm (EC50 of ( )-CBD: 40 mm) and 400-fold-enhanced in
vitro safety for hippocampal neurons. The synthesis of the
compound 43 was started with the compound 50 (Scheme 9).

Scheme 7. Synthesis of ent-CBD ((+)-1) from ( )-p-mentha-1,8-diene-3-one

(38).

3. C4’ Analogs
( )-CBD bears n-pentyl group at its C4’ position, and several
natural and synthetic molecules that have the CBD core struc-
ture with different C4’-alkyl chains have been reported
(Figure 4). For example, in the Cannabis extract, cannabidiorcol
(CBD-C1, 40), cannabidivarin (CBDV, 41), and nor-cannabidiol Scheme 9. Synthesis of the compound 43. TFA = trifluoroacetic acid, Boc = -
tert-butyloxycarbonyl, and Ac = acetyl.
(CBD-C4, 42) structurally differ from ( )-CBD only by the
length of the C4’-alkyl chain. This subtle difference in the struc-
ture changed the bioactivities, and CBDV is reported to exhibit
the promising anticonvulsant and antiepileptic effects without The N-acetyl azetidine moiety at the C4’ position was installed
any harmful side effects.[48, 49] Cannazza et al. have recently re- by the Wittig reaction of benzyl phosphonium salt (51) and
ported the synthesis of nor-cannabidiol (42) in a similar way to azetidinone (52), and the subsequent conventional reactions,
the Petrizilka’s method (Scheme 8).[50] Treatment of the com- such as Pd-catalyzed hydrogenation, acid (TFA)-mediated Boc-
deprotection, N-acetylation, and BBr3-mediated demethylation.
The resulting N-acetyl azetidine-bearing resorcinol (56) was
then simply coupled with optically pure terpenol (14) under
Lewis-acid catalyzed conditions to form the desired C2-alkyla-
tion product (43) in a modest yield (13 %) along with C4-alkyla-
tion product (57).
The ( )-CBD analogs with the lipophilic 1’,1’-dimethylheptyl
(DMH) chain (46–48 in Figure 4) were synthesized by Hanuš
et al. (Scheme 10).[46, 52] In addition to the DMH-CBD (46), they
synthesized 7-OH-DMH-CBD (47) and 7-COOH-DMH-CBD (48).
These DMH-CBD analogs showed unique and better bioactivi-
ties than ( )-CBD;[53, 54] it is to note that the replacement of the
pentyl chain of ( )-trans-D9-THC (2) by the DMH chain was
Figure 4. Representative C4’-alkyl chain analogs of ( )-CBD. also found to be more biologically active than ( )-trans-D9-

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4. Resorcinol Analogs
In this section, we deal with the ( )-CBD analogs that have the
modifications at others than the C4’ position of the resorcinol
moiety of ( )-CBD (Figure 5). This type of structural analogs
also could be found in nature, exemplified by cannabidiolic
acid (CBDA, 64) and cannabidivarinic acid (CBDVA-C3, 65) from
the Cannabis extracts.[57] As shown in Scheme 2, the biogenesis
of ( )-CBD includes the decarboxylation of CBDA (13), as an in-
termediate, from cannabigerolic acid (CBGA, 12) by CBDA
enzyme.

Scheme 10. Synthesis of ( )-CBD analogues, 46–48, bearing the C4’-DMH

moiety. m-CPBA = meta-chloroperoxybenzoic acid, py = pyridine,
Ac2O = acetic anhydride, and TMSBr = bromotrimethylsilane.

THC in psychoactivity.[55] For the synthesis of DMH-CBD ana-

logs, racemic isopiperitenol (39), not enantiopure terpinol, was Figure 5. Representative ( )-CBD analogs with modified resorcinol.
utilized as a coupling partner for resorcinol analogs
(Scheme 10): the reaction between BF3·OEt2 and isopiperitenol
allowed for the generation of an electrophilic allyl cation, Halogenated ( )-CBD analogs (66–72) were synthesized di-
which reacted with the resorcinol DMH analogue, resulting in rectly from ( )-CBD by Yamamoto’s protocol (Scheme 11).[58, 59]
the generation of DMH-CBD (46) in the 55 % yield as a major
product due to steric hindrance of the DMH group. The methyl
ether formation of DMH-CBD under basic conditions and m-
CPBA-mediated epoxidation enabled the formation of the oxir-
ane (59) at the more substituted alkene of the compound 46
in the 67 % yield. The sterically hindered base (methylmagnesi-
um-N-cyclohexylisoprylamide) converted the epoxide (59) into
the allyl alcohol, and the successive acetylation of the hydroxyl
group afforded the allyl acetate (60), which was then used for
the formation of the compounds 47 and 48. In the synthesis of Scheme 11. Synthesis of mono- or di-halogenated ( )-CBD analogs.
7-OH-DMH-CBD (47), the allylic substitution reaction (SN2’-
manner) of the compound 60 with TMSBr and subsequent
substitution reaction (SN2-manner) with tetrabutylammonium For direct halogenation of ( )-CBD, N-halopyridinium triflates
acetate led to the compound 61 in the 83 % yield. Saponifica- (75 a–c) were used. In this reaction Scheme, the control over
tion of the compound 61 and disconnection of methyl ether substitution degree was problematic from the synthetic point
linkage with Grignard reagent produced 7-OH-DMH-CBD (47). of view, generating a mixture of mono- and di-substituted CBD
For the synthesis of 7-COOH-DMH-CBD (48), triacetate (62) was analogs. Among the structural analogs synthesized, the mono-
prepared by simple deprotection/protection of -OH group of fluorinated ( )-CBD (66) displayed the most promising results
the compound 60. The SN2’ reaction of the compound 62 with in the mice behavior assays and showed better potency than
TMSBr generated the corresponding allyl bromide, which was ( )-CBD in the induction of antinociceptive effects.[59] The re-
oxidized with potassium chromate to form the aldehyde (63) gioisomers of ( )-CBD, such as the compounds 19 and 73 in
in 27 % overall yield. The Pinnick oxidation of the com- Figure 5, were also synthesized with olivetol and orcinol, re-
pound 63 and subsequent NaBH4 reduction of the two acetate spectively, by Petrizilka et al., who used the synthetic method
moieties generated 7-COOH-DMH-CBD (48) in the 79 % yield,[56] shown in Scheme 3. Kassiou et al. used the same strategy for
which showed strong anti-inflammatory and immunosuppres- the synthesis of desoxy-CBD (74) with m-pentylphenol.[37a] It
sive effects.[54] has recently been reported that the compound 19 (Abn-CBD)
acts as a nonretinoid inhibitor of cellular retinol-binding pro-
tein 1 (CRBP1).[60]

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The in vitro aerobic oxidation of ( )-CBD, first reported by

Mechoulam et al., led to the formation of hydroxyquinone (76)
in low yield (5–10 %),[61a] and the yield could be improved
slightly (to 20 %) by lowering reaction temperature (0 8C from
22 8C, Scheme 12 a).[61b] Interestingly, the compound 76 was re-

Scheme 13. Synthesis of the compounds 79 and 8 from 3,9-dibromocam-

phor (83). DMSO = dimethylsulfoxide, DIBAL-H = diisobutylaluminum hy-
dride, MsCl = methanesulfonyl chloride, and py = pyridine.

generated vinyl phosphate (86), and the subsequent reductive

cleavage of C-OPO(OEt)2 bond generated CBDM.[65] For the syn-
thesis of the compound 8, the ketone in the compound 84
was reduced by DIBAL-H to the secondary alcohol, which was
Scheme 12. (a) Aerobic transformation of ( )-CBD into hydroxyquinone (76).
mesylated to yield the compound 85. Na-naphthalenide-medi-
(b) Amine-bearing quinone-CBD analogs, 77 and 78. SIBX = stabilized 2-io-
doxybenzoic acid. ated Grob-type fragmentation of the C1–C7 bond in the com-
pound 85 then allowed for the formation of CBDD (8). Other
phenolic ether analogs, such as the compounds 80–82 in
ported to show high potency in reducing the growth of Figure 6, were reported to have noticeable biological activities,
human colon carcinoma HT-29 cells, and the quinone moiety although their synthetic steps are not disclosed.[66, 67]
was found to be essential for the anti-proliferative activity For other examples of the resorcinol analogs of ( )-CBD,
against diverse cancer cell lines.[60] The structural analogs of Mechoulam et al. reported the synthesis and applications of
the compound 76 with 3’-amine substituents (77 and 78 in ( )-CBD diacetate (87) (Scheme 14).[68] ( )-CBD diacetate, syn-
Scheme 12 b) were claimed to have a neuroprotective activity. thesized by simple acetylation of ( )-CBD, could be converted
Especially, the compound 78 has received the orphan drug into 6-oxo-CBD diacetate (88) with sodium chromate in the
status by FDA in the USA and EMA in Europe as an experimen- 36 % yield. On the other hand, selenium oxide oxidation of the
tal treatment for scleroderma, and a formulation of the com- compound 87, followed by acetylation, allowed for the regio-
pound 78 is currently under clinical studies for multiple sclero- selective formation of AcO-protected allylic alcohol (89) with
sis.[62] The aminoquinone (77 or 78) was synthesized by the the C-10 oxdiation in the 12 % yield.
treatment of ( )-CBD with stabilized 2-iodoxybenzoic acid
(SIBX) and successive trapping with n-pentylamine for the
compound 77 or benzylamine for the compound 78.[63]
Other analogs in this section include the ( )-CBD analogs
with phenolic protective-groups (Figure 6). For example, can-
nabidiol monomethyl ether (CBDM, 79) occurs naturally, and
its chemical synthesis from 3,9-dibromocamphor (83) has been
reported by Alibizati and Vaillancourt (Scheme 13).[64] In the re-
actions, the coupling of the compound 83 with the aryl-lithium
cuprate led to the arylation at a-carbon with high endo-selec-
tivity (almost single endo isomer), presumably because of the
steric bulkiness of the dimethyl olivetol moiety; with the steri-
cally less-demanding phenyl moiety (LiCu(Ph)2), the stereose-
Scheme 14. Regioselective oxidation of ( )-CBD diacetate (87) for the for-
lectivity (endo/exo) decreased to 4.5/1. The fragmentation of mation of the compounds 88 and 89. Ac2O = acetic anhydride, and py = pyr-
the C1–C7 camphor bond of the compound 84 with Na-naph- idine.
thalenide and in situ trapping with diethylchlorophosphate
5. Limonene Analogs
Cannabigerol (CBG, 90), a minor component in the Cannabis
extract, has a unique structural feature–the opened cyclohex-
enyl moiety (Figure 7).[69] It displays the antibacterial, antide-
pressant, and anti-inflammatory activities.[57b, d, 70] Sesquicanna-
Figure 6. Representative resorcinol-OH alkylated ( )-CBD analogs. bigerol (91) is another minor constituent of natural cannabi-

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Figure 7. ( )-CBD analogs with modified limonene moieties.

Scheme 16. Synthesis of cannabinodiol (94) by Lousberg et al.

noids with the additional terpenyl moiety to CBG (90), and its
affinity at CB2 is 5-fold higher than CBG.[71] On the other hand,
7-OH-CBD (92) and 7-COOH-CBD (93) are the examples of rep- nodiol (94) (Scheme 17).[78] Specifically, the Ru-catalyzed
resentative metabolites of ( )-CBD in numerous species includ- [2+2+2] cyclotrimerization of diyne (105) with propargyltrime-
ing human, with structural similarity of 7-OH-DMH-CBD (47) thylsilane under microwave irradiation generated the tricyclic
and 7-COOH-DMH-CBD (48) in Figure 4.[72] The first conversion compound (106) as a single isomer (88 %).[79] The com-
step of ( )-CBD in the human body is the CYP450-enzymatic pound 105 was prepared by simple SN2 reaction of phenolic
hydroxylation at the C-7 position to yield 7-OH-CBD. Although
7-OH-CBD is the first metabolite of ( )-CBD, it is found in the
low concentration, and 7-COOH-CBD is the most abundant
among the metabolites. Mechoulam et al. reported the synthe-
sis of 7-OH-CBD and 7-COOH-CBD from ( )-CBD by a similar
synthetic strategy to that for DMH-CBD analogs shown in
Scheme 10 (Scheme 15).[73]

Scheme 17. Synthesis of cannabinodiol (94) through Ru-catalyzed cyclotri-

merization route. TMS = trimethylsilyl, Cp = cyclopentadienyl, TBAF = tetra-n-
butylammonium fluoride, PCC = pyridinium chlorochromate, MsCl = metha-
nesulfonyl chloride, and TEA = triethylamine.
Scheme 15. Synthesis of the compounds 92/93 with the same strategy for
the compounds 47/48 by Mechoulam et al.

compound (104) with TMS-protected propargyl bromide and

Nature provides other limonene analogs (Figure 7): for ex- subsequent conversion of benzaldehyde into phenylacetylene
ample, cannabinodiol (94) and cannabinodivarin (95), from the with lithium salt of trimethylsilyldiazomethane (TMSCHN2). It is
flower of Lebanese hashish, have a benzene ring instead of the to note that the cyclotrimerization reaction was fast (in
cyclohexene ring of ( )-CBD.[74] The synthesis of the two aro- 10 min), highly efficient, and regioselective. They found that
matic analogs of ( )-CBD have been reported by Lousberg[75] the TMS group in the compound 105 was crucial for the ob-
and Deiters.[76] Lousberg et al. synthesized a tricyclic ring com- served efficiency and selectivity: for example, the use of the
pound (101) by the POCl3-assisted condensation of ethyl 5- unprotected terminal alkyne (  H, instead of  TMS)
methylcyclohexanone-2-carboxylate (100) with olivetol (18) in led to the 7:3 mixture of regioisomers (yield: 61 %). The TMS
the 57 % yield (Scheme 16).[77] The treatment of 7,8,9,10-tetra- removal for the compound 106 occurred rapidly with tetrabu-
hydro-6-dibenzopyrone (101) with sulfur and 1,2-dichloro-4,5- tylammonium fluoride (TBAF) under 2-min microwave irradia-
dicyanoquinone (DDQ) furnished the desired aromatized com- tion, and PCC oxidation and deprotection yielded the com-
pound (102) in the 61 % yield. The cyclic ester in the com- pound 108. The treatment of the compound 108 with methyl
pound 102 was then cleaved by the nucleophilic addition of Grignard reagent led to the formation of the corresponding
methyl Grignard reagent, and the dehydration of tertiary alco- triol, and the subsequent mesylation under basic conditions al-
hol in (103) generated cannabinodiol (94) in 9 % of two-step lowed for the formation of the dehydrated product (109) in
yield. the 61 % overall yield. Finally, methyl-lithium-mediated deme-
Dieters and Teske applied a [2+2+2] cyclotrimerization strat- sylation led to the synthesis of cannabinodiol (94) in the 72 %
egy for the tricyclic ring formation in the synthesis of cannabi- yield.

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8,9-Dihydrocannabidiol (96), also known as H2CBD, has the

structural difference from ( )-CBD only by the saturated exocy-
clic C=C bond in the limonene moiety. Despite this subtle dif-
ference, H2CBD, an unnatural CBD analog, is reported to have
several interesting characteristics compared with ( )-CBD.[80] In
addition to the comparable anticonvulsant effect as seen in
the positive control of ( )-CBD, H2CBD has the inhibitory
effect on cytochrome P450 and the antioxidant activity by in-
hibiting the production of reactive oxygen intermediates, nitric
oxide, and tumor necrosis factor in murine macrophage.[81] In
the structural point of view, the saturated exocyclic C C
double bond provides no pathway for the conversion from Scheme 19. Synthesis of the compounds 97 and 98. Ac2O = acetic anhy-
H2CBD to psychoactive THC, while the chemical conversion of dride, and py = pyridine.
( )-CBD to ( )-trans-D9-THC is attainable.[82] Another advant-
age of H2CBD (and other synthetic ( )-CBD analogs in general)
would be that it is purely synthetic compound and, thus, free terpenoid skeleton, which is thought to be generated bioge-
from problems in the uncontrolled Cannabis cultivation and netically by the intramolecular aldolization of ring-cleaved ke-
compound extraction (e.g., heavy water usage and use of pes- toaldehyde precursor.[87] Biological studies showed that ( )-
ticides/herbicides).[83] H2CBD was initially synthesized by the cannabimovone had little binding affinity for the CB1 and CB2
terpenylation of olivetol (18) with the allyl cation derived by p- receptors, but displayed significant activity for ionotropic re-
TsOH treatment of a-phellandrene (110),[84] and the reaction ceptors (TRPs, especially the TRPV1). Its total synthesis was re-
conditions were optimized further to generate ()-H2CBD (()- ported by Echavarren et al., who used a coupling-first-and-ma-
96) in higher yield (71 %) (Scheme 18).[80] Their reaction strat- nipulation-later strategy (Scheme 20).[88] One of the coupling
egy made the gram-scale synthesis feasible, and it was also an- partners (119) was synthesized from methyl (S)-(+)-3-hydroxyl-
ticipated that the single-step synthesis from food-grade a- butyrate (116) by diastereoselective alkylation of lithium eno-
phellandrene and olivetol would bring practicality to the late (98:2 diastereoselectivity), followed by silyl protection,
chemical synthesis. DIBAL reduction, Swern oxidation,[89] and Ohira-Bestmann ho-
mologation.[90] The Pd-catalyzed C C bond formation[91] under-
went smoothly, and the cationic AuI-catalyzed cycloisomeriza-
tion of the compound 121 yielded the desired cyclopentene
(123), presumably through the generation of Au-carbene com-

Scheme 18. Synthesis of H2CBD (96). p-TsOH = para-toluenesulfonic acid.

The major structural difference of the compounds 97 and 98

from 7-OH-CBD (92) is the isopropyl substituent, instead of the
isopropenyl group at the C6 position (Figure 7). Their chemical
synthesis, developed by Kozela et al.,[85] was started with
Adams’ hydrogenation of ( )-CBD to furnish the hydrogenated
compound (112) in the 97 % yield (Scheme 19). Simple acetyla-
tion of the compound 112 afforded the formation of the diace-
tate (113) in the quantitative yield. Treatment of the diacetate
with SeO2 under reflux condition underwent the Alder–Ene re-
action at two available allylic positions (purple and green), and
a mixture of allyl alcohols was obtained in the 54 % yield.[86]
Due to the difficulty of separating the compounds 114 and
115, the next step was performed without purification: the
mixture was reduced by NaBH4 to form the isolable triol mix-
tures of the desired triol (97) (30 %) and the isomer (60 %). Di-
ethylaminosulfur trifluoride (DAST) transformed the com- Scheme 20. First total synthesis of ( )-cannabimovone (99) by Echavarren
et al. LDA = lithium diisopropylamide, TBSCl = tert-butyldimethylsilyl chloride,
pound 97 into the compound 98 in the 50 % yield.[59]
DBU = 1,8-diazabicylo[5.4.0]undec-7-ene, DIBAL-H = diisobutylaluminum hy-
( )-Cannabimovone (99 in Figure 7) is one of the recently dride, AllocCl = allyl chloroformate, TMEDA = tetramethylethylenediamine,
isolated phytocannabinoids from Cannabis, with a rearranged DMP = Dess–Martin periodinane, and BnSH = benzyl mercaptan.

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plex as an intermediate and the proton elimination.[92] They ob-

served that the solvent played a deterministic role in the AuI-
catalyzed reaction. For example, the use of CH2Cl2, instead of
DMSO, exclusively formed a fused bicyclic ring (127), and the
use of methanol as a solvent led to the addition product (128)
(Scheme 21).[88] Subsequent conventional manipulations with
the compound 127 or 128 also generated ( )-cannabimovone.

Scheme 22. Synthesis of the ( )-CBD analogs, the compounds 129–132.

Piv = trimethylacetyl, DMH = 1,1-dimethylheptyl, Ac2O = acetic anhydride,
and py = pyridine.
Scheme 21. Solvent-dependent AuI-catalyzed cycloisomerization of the com-
pound 121.
ment of the compound 130 with sodium borohydride under
reflux condition furnished the hydrolyzed diol (131). The com-
pound 132, a fluorinated ( )-CBD analog, was synthesized by
6. Other Analogs
Breuer et al. (Scheme 22 c).[59] Acetylation of ( )-CBD and sub-
In this section, we deal with the ( )-CBD analogs that belong sequent Alder-Ene reaction with SeO2 generated 10-hydroxy-
to two subgroups or more in our classification (among the C4’, CBD diacetate (139), the treatment of which with diethylami-
resorcinol, and limonene analogs) (Figure 8). The synthetic ana- nosulfur trifluoride (DAST) at 0 8C for 15 min afforded the allyl
logs to ( )-CBD in this section have mostly been designed and fluoride (132) in the 19 % yield. The compound 132 displayed
synthesized for the pharmaceutical purposes. For example, the the potency of anxiolytic, antidepressant, antipsychotic and an-
compound 129, a promising agonist for the CB2 endocannabi- ticompulsive effects.[59]
noid receptor and CB2-like receptors present in peripheral Berber et al. used optically pure ( )-a-phellandrene (( )-
nerve terminals,[52] was synthesized by Hanuš and his co-work- 110) for the electrophilic aromatic substitution of 3,5-dimethyl-
ers.[47a, 93] Structurally, The compound 129 has a pinene moiety, phenol (140), and the resulting compounds (141 and 142)
instead of cyclohexene moiety of ( )-CBD, and the condensa- were hydrogenated (Scheme 23).[95] The hydrogenation, in the
tion of 4-hydroxymyrtenyl pivalate (137) with 5-(1,1-dimethyl- presence of Adams’ catalyst, saturated the endocyclic C C
heptyl)-resorcinol (58) under acidic conditions furnished the double bond in the limonene moiety, generating the com-
diol (138), the methylation and LiAlH4 reduction of which led pound 133 with 74 %de or the compound 134 as a single
to the compound 129 (Scheme 22 a). The compound 131, isomer. The compounds showed the atropisomeric characteris-
showing anti-inflammatory activity, was synthesized as shown tics, because the rotation of the C3-C1’ bond led to the P- or M-
in Scheme 22 b.[94] The diacetate (115) was prepared by the Ko- form (bottom in Scheme 23). In the atropisomerism, the P-form
zela’s method, and the two-step oxidation of the com- was observed to be dominant, presumably because of more
pound 115 gave the conjugate carboxylic acid (130). Treat-

Scheme 23. Synthesis of the compounds 133 and 134, and their atropiso-
merism. p-TsOH = para-toluenesulfonic acid, Ac2O = acetic anhydride, and
Figure 8. Double-modified ( )-CBD analogs. py = pyridine.

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severe steric hindrance between the C2-Haxial and C6’-methyl 7. Conclusion

substituents than the C2-Haxial and C2’-OH (or OAc). Instead of
-OAc, they also introduced -OPiv or -OMe to the C2’ position, Preclinical and clinical investigations have increasingly suggest-
but the introduction of the -OPiv or -OMe group decreased ed the potential therapeutic effects of ( )-CBD and its structur-
the P/M ratio, compared with the -OH group. al analogs, and the critical demand lies in full mechanistic elu-
Nature also provides the other examples of ( )-CBD analogs cidation of their biological activities and pharmacological ac-
for the category of this section. Ferruginene C (135), from Rho- tions, not to mention the production of high-quality, pure ( )-
dodendron ferrugineum, and linderatin (136), from Lindera um- CBD compounds in a consistent and reliable fashion, because
bellate, are the natural products, which have the opposite ste- the molecular targets for biological activities have not been
reochemistry to ( )-CBD.[96] Ferruginene C shows the cytotoxic- identified clearly.[21b, 100]
ity in the HL-60 cancer cell-line (IC50: 13.7 mm) and binds In this review, we discussed the synthetic strategies to ( )-
weakly to the CB2 and TPRV1 receptors, while no biological cannabidiol (( )-CBD) and its structural analogs (natural and
data of linderatin has been reported. There is the sole example synthetic ones) by categorizing the analogs based on the
of the synthesis of linderatin,[84] and there have been no report three structural moieties of ( )-CBD: limonene, resorcinol, and
on the synthesis of ferruginene C. C4’ alkyl moieties. These synthetic strategies would promote
(+)-Machaeridiols (143–145 in Scheme 24) are another natu- the design and synthesis of chemical tools for molecular target
rally occurring ( )-CBD analogs, isolated from the stem bark of identification as well as drug development. Economical synthe-
the Amazonian liana Machaerium multiflorum Spruce.[97] Their sis of natural and synthetic ( )-CBD analogs also would elimi-
noticeable structural difference from ( )-CBD is the presence nate the cultivation-derived problems (such as use of pesti-
of styrene or benzofuran group at the C4’ position. In addition, cides and microbial/fungal contamination in any uncontrolled
the cyclohexyl ring is fully saturated, and their stereochemistry cultivation) as well as extraction-associated problems (e.g.,
is the opposite to that of ( )-CBD. No synthetic reports are abuse of the extracts including THC). We anticipate that the
found for (+)-machaeridiol B and C, but the total synthesis of synthetic applications of more efficient and atom-economical
(+)-machaeridiol A (143) was made by She et al. strategies, including state-of-the-art C H activation, could pro-
(Scheme 24).[98] The addition of aryl cyanocuprate (147) to the vide a flexible and versatile toolbox for the advanced synthesis
compound 146 afforded the a-arylated ketone (148) with high of ( )-CBD and its structural analogs.
regioselectivity and stereoselectivity after acidic work-up. Rou-
tine reaction steps, such as TBDMS protection, LiAlH4 reduc-
tion, and Barton–McCombie deoxygenation,[99] led to the com- Acknowledgements
pound 150. Because the Barton–McCombie deoxygenation did
not proceed well for the deprotected 150, the mesylation, fol- This work was supported by Cannabis Medical, Inc.
lowed by LiAlH4 reduction, was applied for the synthesis of the
deoxygenated product (151). The MOM deprotection with
AlCl3 and NaI in CH3CN/CH2Cl2 (2:1) at 0 8C afforded (+)-ma-
Conflict of interest
chaeridiol A (143).
The authors declare no conflict of interest.

Keywords: ( )-cannabidiol · cannabidiol analogs · hemp

plant · medical marijuana · therapeutic effects

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MINIREVIEW
By chemical synthesis: Non-psychoac- Byunghyuck Jung,* Jungkyu K. Lee,
tive ( )-cannabidiol (( )-CBD) has re- Jungnam Kim, Eunhye K. Kang,
cently attracted a great deal of atten- Sang Yeong Han, Hee-Yoon Lee,
tion for its therapeutic potential. Chemi- Insung S. Choi*
cal synthesis of ( )-CBD and its structur-
&& – &&
al analogs would contribute to detailed
mechanistic studies on their biological Synthetic Strategies for ( )-
actions as well as to market production. Cannabidiol and Its Structural Analogs

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