Enantioselective Total Synthesis of (-)-Δ9-Tetrahydrocannabinol via N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00198

Enantioselective syntheses of (-)-Δ⁸-tetrahydrocannabinol ((-)-Δ⁸-THC) and (-)-Δ⁹-THC have been achieved in eight and 10 steps, respectively, from a known cinnamic acid. The syntheses take advantage of an enantioselective

Full text of DOI:10.1021/acs.orglett.9b00198

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of (−)‑Δ9‑Tetrahydrocannabinol via
N‑Heterocyclic Carbene Catalysis
Adam Ametovski and David W. Lupton*
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
S
* Supporting Information
ABSTRACT: Enantioselective syntheses of (−)-Δ8-tetrahy-
drocannabinol ((−)-Δ8-THC) and (−)-Δ9-THC have been
achieved in eight and 10 steps, respectively, from a known
cinnamic acid. The syntheses take advantage of an
enantioselective N-heterocyclic carbene (NHC)-catalyzed (4
+ 2) annulation between donor−acceptor cyclobutanes and
cinnamoyl fluorides to construct the highly enantioenriched
cycloxyl β-lactone shown. Having constructed this A-ring
precursor, elaboration to (−)-Δ8-THC is achieved through β-
lactone alcoholysis followed by oxidation, dual decarbox-
ylation, trimethylation, and cationic cyclization. Finally, the
conversion to (−)-Δ9-THC is achieved with established chemistry.
hile over 200 phytocannabinoids are known,1 within
Wpopular culture their zeitgeist remains strongly linked to
(−)-Δ9-tetrahydrocannabinol ((−)-Δ9-THC, 1) and cannabi-
diol (2). The bioactivity of the former is elicited through
binding to the G protein-coupled receptors CB1 and CB2,2
with structural information regarding the mode of binding
emerging in 2017.2a While these compounds have captured
significant attention, other phytocannabinoids (i.e., 3−5) can
have distinct bioactivities and unusual molecular structures.3
enantiomer of THC in an efficient manner. In 2007 Trost and
Dogra reported the enantioselective synthesis of 16a through
ring-closing metathesis (RCM) to introduce the A ring.
Enabled by stereodivergent access to 1,7-diene 11, a related
RCM approach was used by Carreira in his elegant synthesis of
all stereoisomers of Δ9-THC.6b Finally, Leahy recently
developed a synthesis enabled by sigmatropic rearrangement
followed by RCM,6c while Zhou exploited high-pressure
enantioselective ketone reduction in his approach to 1 and
(−)-Δ8-THC (12).7
In 2016 we reported the enantioselective N-heterocyclic
carbene (NHC)-catalyzed synthesis of cyclohexyl β-lactones
(i.e., 13) from donor−acceptor cyclobutanes (i.e., 14) and
cinnamoyl fluorides (i.e., 15a).8a,9 The reaction displays broad
generality, and we envisioned that it could provide materials
(such as 13a or 13b) suited to the preparation of 1 (Scheme
1b). To realize this, decarboxylation and/or decarbonylation
would yield cyclohexene 16 or cyclohexanone 17, after which
exhaustive methylation and cationic cyclization would give 1.
This sequence should define a concise entry to 1 while being
amenable to the preparation of materials with a modified A
ring by the use of alternate cyclobutanes. Strikingly,
modification of the A ring has received limited attention in
studies of the bioactivity of (−)-Δ9-THC analogues.1 Herein
we report the enantioselective total syntheses of normethyl-
(−)-Δ9-THC (18), (−)-Δ8-THC (12), and (−)-Δ9-THC (1)
in six, eight, and 10 steps, respectively, from commercial
cinnamate 15b (X = OH),10 which itself can be derived from 6
in three steps.6c,10b
The chemical synthesis of Δ9-THC has been extensively
examined over the last 50 years,4−7 and a number of
enantiospecific approaches and syntheses of racemic Δ9-
THC have been developed. Many have been achieved through
terpenylation of olivetol (6), as typified by the enantioselective
synthesis from (−)-verbenol (7) reported by Mechoulam and
Gaoni (Scheme 1a).4a In contrast, enantioselective routes are
far more limited.5−7 In 1997 Evans reported the enantiose-
lective total synthesis of (+)-Δ9-THC via a bis(oxazoline)-
copper-catalyzed Diels−Alder reaction (8 + 9 → 10).5
Subsequent coupling to 6 and cyclization gave the unnatural
Received: January 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00198
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (a) Selected Previous Approaches to Δ9-THC; (b) Our Synthesis Plan
known donor−acceptor cyclobutane 14a (R = H)12 proceeded
without event to provide cyclohexyl β-lactone 13a in 45% yield
as a single diastereoisomer with excellent enantioselectivity
(98:2 er). While the yield was modest, this result is in keeping
with reactions of heavily substituted α,β-unsaturated acyl
azoliums.9j Krapcho decarboxylation13 of malonate 13a with
concomitant decarboxylation of the β-lactone provided a 2:1
mixture of cis- and trans-cyclohexenes 19 in 66% yield.
Conversion of the diastereomeric mixture to the desired trans-
19 was achieved in 85% yield using the conditions reported by
Trost and Dogra.6a Finally, two-step conversion of trans-19 to
normethyl-(−)-Δ9-THC (18) using conditions described by
Carreira6b closed the B ring and provided the desired product
in 62% isolated yield.
Scheme 2. Synthesis of Normethyl-(−)-Δ9-THC (18)
Having demonstrated the key reactions necessary for the
overall strategy, attention was directed toward the 9-methyl
group. Our preferred approach would exploit donor−acceptor
cyclobutane 14b (R = Me). However, all attempts to prepare
this material proved unsuccessful. An alternate approach
exploiting methyl ketone 20, a substrate used by Studer in a
related (4 + 2) annulation, was envisaged.8b Unfortunately,
union of ketone 20 with enal 15c under oxidative NHC
catalysis failed to give the desired cyclohexanone 13b (eq 1), as
only cinnamic acid derivatives were isolated.
Scheme 3. Optimization of the Opening of β-Lactone 13a
An alternate strategy to install the 9-methyl group involved
the preparation of ketone 17 by methanolysis of β-lactone 13a,
oxidation, and dual Krapcho decarboxylation (Scheme 1, 13a
→ 17). Global methylation followed by cationic cyclization
and elimination would then provide the cannabinoid targets.
This approach was initially met with difficulties due to the
facile formation of bicyclic lactone 21 upon cleavage of the β-
lactone (Scheme 3). Fortuitously, the reaction was sensitive to
the base, with KCN favoring the formation of the desired
Studies commenced by establishing the viability of the
general strategy through the preparation of 18 (Scheme 2). In
our methodological studies,8a 2,6-disubstituted cinnamoyl
fluorides (i.e., 15a) were not examined, and hence, their
viability in NHC catalysis needed to be determined. Following
conversion of commercially available and readily accessible
cinnamate 15b (X = OH)10 to acyl fluoride 15a (X = F),11 the
annulation of 15a was examined. Gratifyingly, reaction with the
B
DOI: 10.1021/acs.orglett.9b00198
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of (−)-Δ8 THC (12) and (−)-Δ9 THC (1)
E.; Taglialatela-Scafati, O.; Appendino, G. Nat. Prod. Rep. 2016, 33,
1357. (c) Reekie, T. A.; Scott, M. P.; Kassiou, M. Nat. Rev. Chem.
2017, 2, 0101.
alcohol 22. Using these conditions and immediately subjecting
alcohol 22 to oxidation with IBX gave β-keto ester 23 (Scheme
4). This material underwent dual Krapcho decarboxylation to
give cyclohexanone 17 in 32% isolated yield over the three
steps as a 2:1 mixture of diastereoisomers. Epimerization as
previously described then gave trans-17 in 83% isolated yield.
Finally, using modified conditions of Carreira, global
methylation followed by elimination and cyclization gave
(−)-Δ8-THC (12) in 40% isolated yield over the two steps.
Conversion of 12 to (−)-Δ9-THC (1) was achieved in two
steps using reported conditions.14
Methodological discoveries have the potential to enable new
approaches in multistep target-oriented synthesis. The studies
herein exploited an NHC-catalyzed (4 + 2) annulation to
provide cyclohexyl β-lactone 13a, which could be elaborated to
(−)-Δ8-THC (12) in six steps and (−)-Δ9-THC (1) in eight
steps. Overall, a concise approach to these cannabinoids has
been developed. In addition, by exploiting alternate cyclo-
butane starting materials, access to A-ring analogues of the
cannabinoids should be possible. The impact of modifications
in this region of 1 on CB1 and CB2 selectivity will be examined
in subsequent studies.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00198.
Experimental procedures, H and 13C NMR spectra of
new materials, and HPLC traces of chiral materials
(PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.lupton@monash.edu.
ORCID
David W. Lupton: 0000-0002-0958-4298
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.W.L. thanks the ARC for financial support through the
Discovery Program (DP170103567) and Dr. Tristan Reekie
(Australian National University) for useful conversations.
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DOI: 10.1021/acs.orglett.9b00198
Org. Lett. XXXX, XXX, XXX−XXX