Short and Protecting-Group-Free Approach to the (-)-Δ8-THC-Motif: Synthesis of THC-Analogues, (-)-Machaeriol B and (-)-Machaeriol D

Article abstract of DOI:10.1021/acs.orglett.8b01005

Friedel-Crafts alkylation of resorcinols with (S)-cis-verbenol and subsequent cyclization allows the construction of the tetrahydrodibenzopyran core of (-)-δ⁸-THC which is also found in other natural products in one step. Using a benzofuryl sub

Full text of DOI:10.1021/acs.orglett.8b01005

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Short and Protecting-Group-Free Approach to the (−)‑Δ8‑THC-Motif:
Synthesis of THC-Analogues, (−)-Machaeriol B and (−)-Machaeriol D
Grete Hoffmann and Armido Studer*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstrasse 40, 48149 Munster, Germany
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* Supporting Information
ABSTRACT: Friedel−Crafts alkylation of resorcinols with
(S)-cis-verbenol and subsequent cyclization allows the
construction of the tetrahydrodibenzopyran core of (−)-Δ8-
THC which is also found in other natural products in one step.
Using a benzofuryl substituted resorcinol, followed by
diastereoselective hydroboration and oxidative or reductive
workup, directly provides (−)-machaeriol B and D in 42% and
43% overall yields. Bromoresorcinol as a coupling partner
delivers Br−THC that can be applied for late-stage
diversification by Suzuki−Miyaura cross-coupling to readily
access (−)-Δ8-THC analogues.
he tetrahydrodibenzopyran motif is found in many natural
Machaerium multiflorum spruce (Fabaceae), an Amazonian liana
found in Peru.10,11 (+)-Machaeriol B exhibits potent in vitro
antimalarial activity against Plasmodium falciparum W2 clones
and antibacterial properties against methicillin resistant Staph-
ylococcus aureus.11
T
products such as tetrahydrocannabinols (THC) and
machaeriols. (−)-Δ9-THC and its double bond isomer
(−)-Δ8-THC (Figure 1) are isolated from Cannabis sativa L.,1
To explore the full potential of this interesting structural class
with respect to its pharmacology, short and efficient methods
enabling the synthesis of natural and unnatural THCs and
machaeriol derivatives are demanded. Along these lines, Trost,
Zhou, Brase, Carreira, Leahy, and others have developed elegant
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syntheses.12 Some approaches toward (−)-Δ9-THC and
(−)-Δ8-THC are based on the condensation of resorcinols
with natural terpenoids such as (+)-trans-2-carenepoxide,
(+)-chrysanthenol, (+)-menthadienol, or others.13 In their
pioneering 1967 work, R. Mechoulam, P. Braun, and Y. Gaoni
described the reaction of S-(cis)-verbenol and olivetol, both
commercially available, with catalytic BF3·OEt2 to directly deliver
(−)-Δ8-THC in 35% yield (Scheme 1A).13d This cascade likely
proceeds via regio- and diastereoselective Friedel−Crafts
alkylation to give intermediate A. Protonation of A and
subsequent cleavage of the strained four-membered ring in B
lead to the tertiary cation C, that finally cyclizes via C−O bond
formation with the phenolic OH-group to give (−)-Δ8-THC.
Inspired by this straightforward one-step synthesis, we
questioned whether this sequence is also applicable to resorcinol
derivatives other than olivetol and planned to use that strategy
for the construction of the hexahydrodibenzopyran core 2 of
(−)-machaeriol B and D (Scheme 1B). Diastereoselective
hydroboration of 2 followed by either oxidative or reductive
workup, as shown before on the corresponding methyl ether,14
Figure 1. Structures of the natural products (−)-Δ9-THC, (−)-Δ8-
THC, and (+)-machaeriol A−D.
and they have been used for recreational and therapeutic
purposes.2 THCs interact with cannabinoid receptors CB1 and
CB23,4 which are expressed in the brain/central nervous system
(CB1) and in cells of the immune system (CB2).5,6 Since CBs are
involved in neurogenesis, metabolism, immune-system activity,
and reproduction, they represent key drug targets for the
treatment of a number of diseases.7 Notably, (−)-Δ9-THC is
meanwhile found in the drug market under the name Marinol or
Sativex.8 Importantly, unnatural THC-analogues with the pentyl
side chain replaced by other substituents have shown even
increased receptor affinity and pharmacological potency.9
The structure of (+)-machaeriols A, B, C, D is based on the
same THC core motif; however, their side chains and absolute
stereochemistry differ. They have been isolated from the bark of
Received: March 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (A) Friedel−Crafts Alkylation and Subsequent
Cyclization of (S)-cis-Verbenol and Olivetol to (−)-Δ8-
THC;13d (B) Retrosynthesis of (−)-Machaeriol B and D
Scheme 2. Synthesis of (−)-Machaeriol B and (−)-Machaeriol
D
should directly lead to (−)-machaeriol B and D without the need
for any protecting-group strategy.
We commenced our studies by reinvestigating the Friedel−
Crafts-type alkylation and subsequent cyclization of (S)-cis-
verbenol and olivetol. Extensive experimentation revealed that
the highest yield is achieved in CH2Cl2 using 2 equiv of HBF4·
OEt2 for 2 h at −78 °C followed by 1 h of stirring at room
temperature to give (−)-Δ8-THC in 54% isolated yield at 1
mmol scale (see Supporting Information (SI)). Note that the
NMR yield was significantly higher (69%), and product loss
during purification could not be fully prevented.
These optimized reaction conditions were then tested for the
synthesis of machaeriols. The required benzofuryl substituted
resorcinol 1 was readily obtained in 95% overall yield via Suzuki−
Miyaura cross-coupling of 1-bromo-3,5-dimethoxybenzene and
benzofuran-2-boronic acid followed by double methyl ether
cleavage (Scheme 2). Disappointingly, we initially observed very
poor yields for 2, likely caused by the low solubility of resorcinol
1 in CH2Cl2 at −78 °C. This problem was solved by utilizing a
solvent mixture (CH2Cl2/acetone = 20:1), and the tetrahydro-
dibenzopyran 2 was formed in 85% yield (determined by GC-
FID with mesitylene as an internal standard). To avoid loss of
product during purification, as observed upon isolation of
(−)-Δ8-THC (see above), the crude product was directly used
for the next step without any further purification.
The diastereoselective hydroboration of the double bond in 2
with subsequent oxidation to the corresponding alcohol was
studied next. In 1995, J. W. Huffman et al. showed that
hydroboration and oxidation of the methyl ether protected Δ8-
THC using BH3·THF provided a 1:1 mixture of the two
diastereoisomeric alcohols in 77% yield.15 Applying Huffman’s
conditions on the free phenol 2, we obtained after NaOOH
oxidation a 1:1 mixture of both isomers (as measured by GC-
FID) in 58% yield over three steps (cyclization/hydroboration/
oxidation), demonstrating that the cascade is feasible without
protection of the phenolic HO-group. In order to increase
selectivity, we switched to bulkier boranes and found that with
Sia2BH, which performed well on the O-methyl protected
substrate,14 a high selectivity for, but disappointingly low yield of,
(−)-machaeriol D was obtained (12% over three steps).
Variation of the steric demand of the hydroboration reagent
revealed that thexylborane is best suited in terms of yield and
selectivity. Hence, hydroboration of 2 with thexylborane in THF
for 1.5 h at 80 °C and oxidation of the corresponding crude
alkylborane 3 provided (−)-machaeriol D with an excellent 97:3
selectivity (measured by GC-FID) in 45% overall yield for this
three-step sequence (cyclization/hydroboration/oxidation).
Importantly, the crude hydroboration product 3 also serves as
an intermediate for the synthesis of (−)-machaeriol B by simple
hydrodeborylation. To this end, intermediate 3 was successfully
reduced by applying a protocol developed by Renaud et al. for the
transformation of alkylboranes to the corresponding alkanes
under an air atmosphere by addition of 4-tert-butylcatechol16 to
give (−)-machaeriol B in 44% isolated yield over three steps
(cyclization/hydroboration/protodeborylation) with 19:1 dia-
stereoselectivity (see SI).
On the basis of the crystal structure of an agonist bound to the
human CB1 receptor, structure activity studies of side chain
modified THC derivatives have received much attention
recently.17 For example, Trauner and Carreira described a six-
step synthesis of Br-substituted (−)-Δ9-THC as an intermediate
for late-stage diversification through transition-metal catalyzed
cross-coupling.18 Motivated by these reports, we tested 1-bromo-
3,5-dihydroxybenzene (1.2 equiv) as a resorcinol coupling
partner in the reaction with (S)-cis-verbenol under our standard
protocol (HBF4·OEt2 (2.0 equiv), CH2Cl2, −78 °C for 2 h then
rt for 1 h) to afford 4.19 As for the synthesis of (−)-Δ8-THC, the
tetrahydrodibenzopyran 4 was not further purified and directly
used as a crude product in a Pd-catalyzed Suzuki−Miyaura
coupling with three different trifluoroborates to give the THC-
derivatives 5a, 5b, and 5c in yields ranging from 25−32% over the
two steps (Scheme 3). These THC congeners bear different
pharmacologically interesting side chains, such as the trans-2-
B
DOI: 10.1021/acs.orglett.8b01005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. One-Step Synthesis of (−)-Δ8-Br-THC and
Subsequent Suzuki−Miyaura Cross-Coupling Provides
(−)-Δ8-THC Derivatives with Different Side Chains
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ASSOCIATED CONTENT
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S
* Supporting Information
(17) Hua, T.; Vemuri, K.; Nikas, S. P.; Laprairie, R. B.; Wu, Y.; Qu, L.;
Pu, M.; Korde, A.; Jiang, A.; HO, J.-H.; Han, G. W.; Ding, K.; Li, X.; Liu,
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(19) We found by GC-MS that small amounts of the double alkylation
product of 1-bromo-3,5-dihydroxybenzene were formed in the crude
product (ratio single/double alkylation = 4:1; as determined by GC-
FID).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01005.
1
Experimental procedures, characterization data, and H
and 13C spectra (PDF)
AUTHOR INFORMATION
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Corresponding Author
*E-mail: studer@uni-muenster.de.
ORCID
Armido Studer: 0000-0002-1706-513X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Dr. Felix Klotter (University of Munster) for
conducting some experiments on the optimization study and
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Maren Wissing (University of Munster) for helpful discussions.
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This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG).
C
DOI: 10.1021/acs.orglett.8b01005
Org. Lett. XXXX, XXX, XXX−XXX