Enantioselective Total Synthesis of Cannabinoids - A Route for Analogue Development

Article abstract of DOI:10.1021/acs.orglett.7b03668

A practical synthetic approach to Δ⁹-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.

Full text of DOI:10.1021/acs.orglett.7b03668

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of CannabinoidsA Route for
Analogue Development
Zachary P. Shultz,† Grant A. Lawrence,† Jeffrey M. Jacobson,† Emmanuel J. Cruz,†
and James W. Leahy*,†,‡,§
†Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE 205, Tampa, Florida 33620, United States
‡Center for Drug Discovery and Innovation, University of South Florida, 3720 Spectrum Boulevard, Suite 303, Tampa, Florida
33612, United States
§Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, MDC 7, 12901 Bruce B. Downs
Boulevard, Tampa, Florida 33612, United States
S
* Supporting Information
ABSTRACT: A practical synthetic approach to Δ9-tetrahy-
drocannabinol (1) and cannabidiol (2) that provides scalable
access to these natural products and should enable the
generation of novel synthetic analogues is reported.
then, attempts to establish a structure−activity relationship as
lants of the genus Cannabis have been of interest to
1
Phumans since at least the Neolithic era. While cloth made well as the pharmacokinetic and pharmacodynamic properties
of the cannabinoids have been well-studied.9 The subsequent
of hemp has been recovered that dates back to the Chou
dynasty,2 the earliest use of the plants for medicinal purposes
discovery and characterization of human cannabinoid receptors
such as CB1 and CB2 and the entire endocannabinoid system
has only increased the interest in pursuing small-molecule
therapeutics that modulate this system.10 Various formulations
of 1, under the generic name dronabinol, have been approved
by the U.S. Food and Drug Administration for the treatment of
nausea and vomiting as well as AIDS-related anorexia.11
Meanwhile, an orally available formulation of cannabidiol
(CBD, 2) is currently in phase 3 clinical trials in Canada.12
While many of the other cannabinoids also demonstrate
biological activity, they have not been well-studied, in part
because of their limited quantities. A synthetic source of them,
as well as of unnatural analogues, would allow for a greater
understanding of these subtle effects.
Our own interest in the cannabinoids was piqued by the
observation that they possess activity against the free-living
amoeba Naegleria fowleri,13 known colloquially as “the brain-
eating amoeba.” This free-living amoeba is ubiquitously found
in bodies of warm, fresh water and can infect humans by
entering through the nose and attacking the brain.14 More than
97% of these infections are fatal,15 which is why the discovery
that cannabinoids such as 1 and 2 inhibit the proliferation of
has been ascribed to Shennong as recorded in Shen Nong Ben
Cao Jing nearly 2000 years ago.3 In the intervening millennia, it
has reached at least six continents and gained a reputation for,
among other things, having been grown by the first president
of the United States4 and being used on Easter Island for
raising their moai statues.5
The biological effects from the consumption of Cannabis
plants are considerably complex, presumably because of the
large number of natural products produced by the plants.6
These cannabinoids, which vary greatly in number and
concentration among different strains, parts of the plant, and
even gender, exhibit their biological effects on mammalian and
microbial systems.7 The therapeutic potential for this class of
compounds has been under investigation since the discovery of
Δ9-tetrahydrocannabinol (THC, 1) (Figure 1) in 1964.8 Since
Received: November 26, 2017
Figure 1. Structures of THC and CBD.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03668
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Organic Letters
Letter
N. fowleri led us to search for a synthetic route that would
allow us to identify novel analogues that might be used to treat
such infections.
Scheme 1. Model Ireland−Claisen System Synthesis
There have been a number of successful approaches to the
total synthesis of 1.16 In fact, we were initially attracted to the
report by Dethe that the selective formation of the ring systems
of 1 or 2 could be achieved from 3 and the appropriate
resorcinol derivative simply by controlling the Lewis acid
cyclization conditions (Figure 2). In our hands (where R = n-
generation of the corresponding silyl ketene acetal under
kinetic conditions without HMPA prior to heating the reaction
to reflux.22 We were pleased to note that the corresponding
product was formed as a single diastereomer. We used an
amine base in an effort to avoid generation of any HCl during
the formation of the silyl ketene acetal, which we believed
would be crucial in the real system where a potential stabilized
carbocation could be formed using an electron-rich aryl ring.20
Following esterification of the acid, Grubbs olefin metathesis23
generated the anticipated cyclohexene 11, setting the stage for
us to try this approach for the cannabinoids.
Figure 2. Dethe cannabinoid synthesis.
pentyl), unfortunately, we repeatedly obtained complex
mixtures that required extensive HPLC purification to obtain
any pure products, though we were able to detect both THC
and CBD using both conditions. We therefore sought a
practical approach that would not only enable the exclusive
formation of 1 or 2 but also be amenable to the generation of
novel analogues. The formation of the common cyclohexene
via an olefin methathesis reaction, used elegantly by both Trost
and Dogra17 and Carreira and co-workers,18 was a particularly
attractive approach. We envisioned that the requisite diene
precursor could be prepared via an Ireland−Claisen rearrange-
ment,19 thus allowing all of the stereocenters to be derived
from a single stereocenter such as 6 (Figure 3). Upon seeing
Kim’s stereoselective total synthesis of perrottetinine,20 we
were confident that this strategy would prove viable.
Enone 13 could be readily prepared in short order from
olivetol (12) via a known formylation/aldol process (Scheme
2).17 A number of chiral catalysts and reagents are available for
Scheme 2. Installation of the Chiral Allylic Alcohol
We tested our Ireland−Claisen hypothesis by acylating
cinnamyl alcohol (7) with known acid 8 (Scheme 1).21 The
Ireland−Claisen rearrangement was then conducted by
the asymmetric reduction of ketones,24 and while we tried a
number of readily available methods, the best results we
obtained were via CBS oxazaborolidine 14,25 which proceeded
to give (−)-6 with 77% ee. While this was adequate to allow us
to prepare 1 and 2 with high enantiopurity because of the
presence of a crystalline intermediate (4; vide infra), we were
interested in developing a scalable and economically practical
approach to generate products with high enantiopurity. We
therefore sought to explore an enzymatic approach that would
use an inexpensive and readily available enzyme. Simple
reduction of 13 with sodium borohydride provided the
requisite racemic alcohol, and acylation with vinyl buyrate in
the presence of Savinase 12T provided the ester with >98% ee
in 38% overall yield for the three steps. While we were also
able to acylate ( )-6 using activated esters of 8 with high
enantiopurity under enzymatic conditions,26 the ready
availability of vinyl butyrate compared with the cost of
Figure 3. Retrosynthetic analysis of 1 and 2.
B
DOI: 10.1021/acs.orglett.7b03668
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generating the requisite activated esters made the former
approach more practical on a large scale.
With a viable source of (−)-6 in hand, acylation with 8
proceeded smoothly, and the Ireland−Claisen rearrangement
proceeded as expected (Scheme 3). While we explored a
generated with the inexpensive and readily available enzyme
Savinase 12T. Efforts to use these methods for the generation
of novel cannabinoid analogues will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 3. Ireland−Claisen Rearrangement
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03668.
Experimental details for the preparation and analysis of
all compounds (PDF)
Accession Codes
CCDC 1588045 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*Phone: (813) 974-4642. E-mail: jwleahy@usf.edu.
ORCID
variety of different conditions to effect this transformation, the
only discernible factor that resulted in a negative impact on the
reaction was the strict requirement for anhydrous conditions,
without which we observed a significant loss of diastereose-
lectivity. We were pleased to find that carboxylate 4 was a
crystalline product, which allowed us to obtain an X-ray
structure that confirmed the formation of the relative
stereocenters at both positions as expected. This also allowed
us to recrystallize all of our initial material into high
enantiopurity in an overall 48% yield of recrystallized 4 from
6 (ee = 77%). Furthermore, this product served as the
common intermediate for our synthesis of both 1 and 2.
Esterification of 4 and metathesis cyclization with Grubbs’
second-generation catalyst afforded cyclohexene 15, which
could be converted into 1 by exhaustive treatment with
methylmagnesium iodide followed by Lewis acid-mediated
cyclization (Scheme 4).27,28 Similarly, methylation of 4 led to
the formation of ketone 16, which could be cyclized and then
converted into 2 via Wittig methylenation and deprotection.
In summary, we have achieved an enantiospecific synthesis
of both THC and CBD from a common intermediate in which
the chirality can be derived from a single stereocenter
James W. Leahy: 0000-0003-3647-4489
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for support of this research by the University of
South Florida Office of Research and Innovation and the
Florida Center of Excellence for Drug Discovery and
Innovation. We gratefully acknowledge the efforts of the
University of South Florida X-ray Crystallography Core
Facility, and especially Dr. Lukasz Wojtas and Gaurav Verma
of the University of South Florida X-ray Crystallography Core
Facility, in obtaining the crystal structure of 16.
REFERENCES
■
(1) Abel, E. L. MarihuanaThe First Twelve Thousand Years;
Plenum Press: New York, 1980.
(2) Li, H.-L. Econ. Bot. 1974, 28, 437.
(3) Brand, E. J.; Zhao, Z. Front. Pharmacol. 2017, 8, 108.
(4) George Washington Grew Hemp. http://www.mountvernon.
org/george-washington/the-man-the-myth/george-washington-grew-
hemp (accessed July 23, 2017).
(5) Lipo, C. P.; Hunt, T. L.; Haoa, S. R. J. Archaeol. Sci. 2013, 40,
2859.
Scheme 4. Synthesis of THC and CBD
(6) Atakan, Z. Ther. Adv. Psychopharmacol. 2012, 2, 241.
(7) Appendino, G.; Gibbons, S.; Giana, A.; Pagani, A.; Grassi, G.;
Stavri, M.; Smith, E.; Rahman, M. M. J. Nat. Prod. 2008, 71, 1427.
(8) Gaoni, Y.; Mechoulam, R. J. Am. Chem. Soc. 1964, 86, 1646.
(9) Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, R. K.;
Melvin, L. S.; Johnson, M. R.; Martin, B. R. J. Pharmacol. Exp. Ther.
1993, 265, 218.
(10) Mallipeddi, S.; Janero, D. R.; Zvonok, N.; Makriyannis, A.
Biochem. Pharmacol. (Amsterdam, Neth.) 2017, 128, 1.
(11) U.S. Food and Drug Administration. Marinol. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2005/018651s021lbl.pdf
(accessed July 23, 2017).
(12) CTV News. Canadian Researchers To Study Cannabis Oil To
Treat Kids’ Epilepsy. http://www.ctvnews.ca/lifestyle/canadian-
C
DOI: 10.1021/acs.orglett.7b03668
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
researchers-to-study-cannabis-oil-to-treat-kids-epilepsy-1.3321008
(accessed July 23, 2017).
(13) Pringle, H. L.; Bradley, S. G.; Harris, L. S. Antimicrob. Agents
Chemother. 1979, 16, 674.
(14) Contis-Montes de Oca, A.; Carrasco-Yepez, M.; Campos-
Rodriguez, R.; Pacheco-Yepez, J.; Bonilla-Lemus, P.; Perez-Lopez, J.;
Rojas-Hernandez, S. Parasite Immunol. 2016, 38, 481.
(15) Capewell, L. G.; Harris, A. M.; Yoder, J. S.; Cope, J. R.; Eddy,
B. A.; Roy, S. L.; Visvesvara, G. S.; Beach, M. J.; Fox, L. M. J. Pediatric
Infect Dis Soc. 2015, 4, e68.
(16) See: Dethe, D. H.; Erande, R. D.; Mahapatra, S.; Das, S.; B., V.
K. Chem. Commun. 2015, 51, 2871 and references cited within.
A
practical synthesis of 2 and analogues has also been reported. See:
Kobayashi, Y.; Takeuchi, A.; Wang, Y. G. Org. Lett. 2006, 8, 2699.
(17) Trost, B. M.; Dogra, K. Org. Lett. 2007, 9, 861.
(18) Schafroth, M. A.; Zuccarello, G.; Krautwald, S.; Sarlah, D.;
Carreira, E. M. Angew. Chem., Int. Ed. 2014, 53, 13898.
(19) Martín Castro, A. M. Chem. Rev. 2004, 104, 2939.
(20) Song, Y.; Hwang, S.; Gong, P.; Kim, D.; Kim, S. Org. Lett. 2008,
10, 269.
(21) Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Osterhout, M. H.;
Price, A. T. J. Org. Chem. 1997, 62, 67.
(22) Conducting the reaction in the absence of HMPA allows for the
generation of the (E)-silylketene acetal, which results in the desired
stereochemical outcome. See: Ireland, R. E.; Wipf, P.; Armstrong, J.
D. J. Org. Chem. 1991, 56, 650. Kim’s use of HMPA allowed for their
generation of the (Z)-silylketene acetal, which corresponded to the
stereochemistry required for perrottetinine.20
(23) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.
(24) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(25) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K.
J. Am. Chem. Soc. 1987, 109, 7925.
(26) Details of this reaction are given in the Supporting Information.
(27) Salzer, W. Hoppe-Seyler's Z. Physiol. Chem. 1942, 274, 39.
(28) Stoss, P.; Merrath, P. Synlett 1991, 1991, 553.
D
DOI: 10.1021/acs.orglett.7b03668
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