Stereodivergent total synthesis of Δ9-tetrahydrocannabinols

Article abstract of DOI:10.1002/anie.201408380

All four stereoisomers of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same

Full text of DOI:10.1002/anie.201408380

Angewandte
Chemie
DOI: 10.1002/anie.201408380
Natural Product Synthesis
Hot Paper
Stereodivergent Total Synthesis of D9-Tetrahydrocannabinols**
Michael A. Schafroth, Giuseppe Zuccarello, Simon Krautwald, David Sarlah, and
Erick M. Carreira*
Abstract: All four stereoisomers of D9-tetrahydrocannabinol
(D9-THC) were synthesized in concise fashion using stereo-
divergent dual catalysis. Thus, following identical synthetic
sequences and applying identical reaction conditions to the
same set of starting materials, selective access to the four
stereoisomers of THC was achieved in five steps.
An ongoing challenge in chemical synthesis is the develop-
ment of efficient transformations that provide rapid and
selective access to the full stereochemical array of molecules
with multiple stereogenic centers.[1] Such stereodivergent
processes have particular potential in natural product syn-
theses as they can provide both simplified and more direct
synthetic pathways to any given stereoisomer of a natural
product. Stereodivergent synthesis can also have beneficial
impact beyond the realm of synthetic chemistry. The biolog-
ical properties of an organic compound directly depend on its
stereochemical configuration. As such, the ability to access all
stereoisomeric permutations of a target molecule allows
complete evaluation of stereochemical structure–activity
relationships. The preparation of different diastereoisomers
of a given natural product or lead candidate traditionally
relies on a combination of substrate- and/or catalyst-con-
trolled reactions. Consequently, this results in deviation from
the primary synthetic sequence and thus different synthetic
routes to the diastereomeric targets.[2] A largely unmet
challenge, however, is the discovery and development of
uniform synthetic strategies that provide controlled access to
any given stereoisomer of a target. Herein, we report the
implementation of such a strategy in the context of the total
synthesis of the D9-tetrahydrocannabinols (1, all stereoiso-
mers) that relies on an early stereodivergent step followed by
a short uniform sequence (Figure 1). The two diastereoiso-
mers of D9-tetrahydrocannabinol [D9-THC, (6aR,10aR)-1 and
(6aS,10aR)-1, Figure 1a] were isolated from flowering tops of
female plants of several Cannabis sativa L. varieties.[3] The
more abundant (À)-D9-trans-THC [(6aR,10aR)-1] is currently
used for the treatment of anorexia,[4] as an anti-nauseant for
Figure 1. a) Naturally occurring trans/cis diastereoisomers of D9-tetra-
hydrocannabinol and b) synthetic roadmaps comparing stereodiver-
gent (in black) with traditional approaches (in gray).
patients undergoing chemotherapy,[5] and for the manage-
ment of neuropathic pain and spasticity,[6] with side effects
including motor impairment and psychosis. Most of the
pharmacological effects of this natural product are due to
activation of two types of G-protein-coupled receptors,
namely the central cannabinoid receptor CB1, which is
distributed mainly in the brain, and the peripheral cannabi-
noid receptor CB2, which is found almost exclusively in the
immune system.[7] However, recent studies indicate that some
of the effects of THC and other cannabinoids result from
a CB1- and CB2-independent mechanism, suggesting that
other receptors are involved in the biological response.[8] Such
polypharmacology, that is, the activity of a compound at
multiple targets, is not uncommon and some antipsychotics
are indeed known to bind to more than 20 targets.[9] Our
interests in developing a general method for the identification
of ligand–receptor interactions and the broad medicinal
importance of cannabinoid receptors have led us to develop
a uniform synthetic route to the four stereoisomers of D9-
THC.[10] Rapid access to any of the four stereoisomers
demonstrates the utility of stereodivergent dual catalysis in
stereoselective synthesis, and allows investigation of the
(poly)pharmacology of all stereoisomers.
[*] M. A. Schafroth, G. Zuccarello, S. Krautwald, Dr. D. Sarlah,
Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie
Eidgençssische Technische Hochschule Zꢀrich
HCI H335, Vladimir-Prelog-Weg 3, Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
Homepage: http://www.carreira.ethz.ch
[**] We are grateful to the ETH Zꢀrich, the Swiss National Science
Foundation (200020_152898), and the Swiss Commission for
Technology and Innovation (CTI, 15175.1 PFLS-LS) for financial
support.
Although D9-trans-THC has been prepared several times,
only three enantioselective syntheses of the optically pure
natural product have been reported to date.[3,11,12] None of
these synthetic routes were able to provide access to the
diastereoisomeric D9-cis-THC as the enantioselectivity-induc-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408380.
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ing step inherently set the configuration of both stereocenters
in a single step. As part of our ongoing program on the study
of iridium-catalyzed enantioselective transformations,[13] we
became interested in their application to the synthesis of
complex molecules.[14] We have recently disclosed the concept
of stereodivergent dual catalysis[15] as a rational approach to
selectively access any given stereoisomer of a molecule
bearing two stereocenters.[16] It involves simultaneously
using two chiral catalysts, each of which exerts full and
independent control over the configuration of one of the
centers. To date, the concept has been implemented in the
a-allylation of aldehydes catalyzed by a chiral Ir/(P,olefin)
complex and a chiral amine. We envisioned expanding this
method to provide a general entry into the chiral tetrahydro-
6H-benzo[c]chromene motifs found in many biologically
active compounds,[17] including the THCs. Significantly, this
process would selectively set the requisite cis or trans
relationship at the cyclohexene ring, a formidable problem
associated with the synthesis of these compounds.
The synthesis of all stereoisomers of D9-tetrahydrocanna-
binol commenced with stereodivergent dual catalytic
a-allylation of 5-methylhex-5-enal (3) with allylic alcohol
2
[11c] (Scheme 1). Accordingly, a set of two chiral catalysts, an
Ir/(P,olefin) complex and a secondary amine, were employed
for concurrent activation of allylic alcohol 2 and aldehyde 3.
In the presence of 3 mol% of [{Ir(cod)Cl)}2], 12 mol% of
(R)-L or (S)-L, and 15 mol% of Jørgensen amine (R)-A or
(S)-A, all possible stereoisomers of g,d-unsaturated aldehyde
product 4 were obtained in good yields (55–62%) and
excellent selectivities (d.r. ꢀ 15:1, e.r. > 99:1). A notable
difference to our previously disclosed conditions for the
a-allylation of linear aldehydes[15b] is the use of Zn(OTf)2 as
the promoter. This additive proved to be superior to Brønsted
acids as the highly electron-rich allylic alcohol 2 underwent
rapid ionization and decomposition in the presence of protic
promoters. Importantly, we also noted that epimerization at
Scheme 1. Stereodivergent preparation of all stereoisomers of 4. d.r.
determined by analysis of the 1H NMR spectrum of the unpurified
reaction mixture. e.r. of the corresponding primary alcohols deter-
mined by supercritical fluid chromatography (SFC) on a chiral sta-
tionary phase. Ar=3,5-(CF3)2-C6H3, cod=1,5-cyclooctadiene,
DCE=1,2-dichloroethane, Tf=trifluoromethanesulfonyl.
at 08C to 1608C at reduced pressure (150 mm Hg) delivered
the tertiary alcohol with concomitant removal of the phenolic
methyl groups.[19] After aqueous workup and extraction, the
organic phase (CH2Cl2) was treated with ZnBr2, which
induced aryl ether formation[20] and furnished D9-THC (1,
all stereoisomers) in 41–65% yield over the final sequence.
In conclusion, we have developed a fully stereodivergent
total synthesis of D9-tetrahydrocannabinols that provides
rapid and controlled access to any isomer of the natural
product, including the two naturally occurring stereoisomers
(À)-D9-cis-THC and (À)-D9-trans-THC [(6aS,10aR)-1 and
(6aR,10aR)-1, respectively]. The synthesis relies on a key
stereodivergent dual catalytic step that secures any given
stereoisomer of g,d-unsaturated aldehyde 4 in excellent
selectivity from the same set of starting materials under
identical conditions. A uniform sequence of four additional
steps then completes the synthesis of all stereoisomers of 1.
Additional efforts to gain insight into the biological activity of
the unnatural stereoisomers of 1 and to further expand the
strategy to other natural products are currently underway in
our laboratories and will be reported in due course.
À
the C-a center following C C bond formation was substan-
tially reduced in the presence of Zn(OTf)2, a notable
challenge associated with this specific class of products.
Finally, this reaction was also conducted on gram scale,
affording the stereoisomeric products with comparable yields
and selectivities.
With all four stereoisomers of 4 in hand, the synthetic plan
called for development of a uniform synthetic sequence that
would convert all product isomers into the respective D9-
tetrahydrocannabinols. Thus, as depicted in Scheme 2, ring-
closing metathesis using Grubbsꢀ second-generation cata-
lyst[18] first secured cyclohexenecarbaldehydes 5 in 85–92%
yield. Pinnick oxidation of the aldehydes to the corresponding
carboxylic acids, followed by treatment with trimethylsilyl-
diazomethane gave the corresponding methyl esters 6 (60–
66% yield over two steps). This order of chemical events
proved to be crucial to obtain 6 in high yields and without
noticeable erosion of diastereomeric purity.
To complete the synthesis of the THCs, we designed
a one-pot sequence that streamlined conversion of ester 6 into
1 through formation of a tertiary alcohol and double methyl
ether deprotection, followed by subsequent intramolecular
etherification. Thus, treatment of ester 6 with excess MeMgI
Received: August 20, 2014
Published online: && &&, &&&&
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Chemie
1349; b) A. Andries, J. Frystyk, A. Flyvbjerg, R. K. Støving, Int.
J. Eat. Disord. 2014, 47, 18.
[5] M. A. Ware, P. Daeninck, V. Maida, Ther. Clin. Risk Manage.
2008, 4, 99.
[6] a) R. G. Pertwee, Mol. Neurobiol. 2007, 36, 45; b) F. A. Camp-
bell, M. R. Tramꢂr, D. Carroll, D. J. M. Reynolds, R. A. Moore,
H. J. McQuay, Br. Med. J. 2001, 323, 13.
[7] a) K. Mackie, Annu. Rev. Pharmacol. Toxicol. 2006, 46, 101; b) J.
Romero, L. Lastres-Becker, R. de Miguel, F. Berrendero, J. A.
Ramos, J. Fernandez-Ruiz, Pharmacol. Ther. 2002, 95, 137.
[8] a) W. Xiong, K. Cheng, T. Cui, G. Godlewski, K. C. Rice, Y. Xu,
L. Zhang, Nat. Chem. Biol. 2011, 7, 296; b) A. Zimmer, A. M.
Zimmer, A. G. Hohmann, M. Herkenham, T. I. Bonner, Proc.
Natl. Acad. Sci. USA 1999, 96, 5780; c) M. Oz, Pharmacol. Ther.
2006, 111, 114; d) L. Zhang, W. Xiong, Vitam. Horm. 2009, 81,
315; e) S. P. Welch, J. W. Huffman, J. Lowe, J. Pharmacol. Exp.
Ther. 1998, 286, 1301.
[9] J.-U. Peters, J. Med. Chem. 2013, 56, 8955.
[10] A. P. Frei, O.-Y. Jeon, S. Kilcher, H. Moest, L. M. Henning, C.
Jost, A. Plꢁckthun, J. Mercer, R. Aebersold, E. M. Carreira, B.
Wollscheid, Nat. Biotechnol. 2012, 30, 997.
[11] For enantioselective syntheses, see: a) D. A. Evans, E. A.
Shaughnessy, D. M. Barnes, Tetrahedron Lett. 1997, 38, 3193;
b) D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P. V. Matt,
S. J. Miller, J. A. Murry, R. D. Norcross, E. A. Shaughnessy,
K. R. Campos, J. Am. Chem. Soc. 1999, 121, 7582; c) B. M. Trost,
K. Dogra, Org. Lett. 2007, 9, 861; d) L.-J. Cheng, J.-H. Xie, Y.
Chen, L.-X. Wang, Q.-L. Zhou, Org. Lett. 2013, 15, 764.
[12] For representative syntheses of racemic D9-tetrahydrocannabi-
nol, see: a) R. Mechoulam, Y. Gaoni, J. Am. Chem. Soc. 1965, 87,
3273; b) R. Mechoulam, P. Braun, Y. Gaoni, J. Am. Chem. Soc.
1967, 89, 4552; c) R. Mechoulam, P. Braun, Y. Gaoni, J. Am.
Chem. Soc. 1972, 94, 6159; d) K. E. Fahrenholtz, M. Lurie, R. W.
Kierstead, J. Am. Chem. Soc. 1966, 88, 2079; e) K. E. Fahren-
holtz, M. Lurie, R. W. Kierstead, J. Am. Chem. Soc. 1967, 89,
5934; f) T. H. Chan, T. Chaly, Tetrahedron Lett. 1982, 23, 2935;
g) R. W. Rickards, H. Rçnneberg, J. Org. Chem. 1984, 49, 572;
h) W. E. Childers, H. W. Pinnick, J. Org. Chem. 1984, 49, 5276;
i) A. V. Malkov, P. Kocovsky, Collect. Czech. Chem. Commun.
2001, 66, 1257; j) A. D. William, Y. Kobayashi, Org. Lett. 2001, 3,
2017; k) A. D. William, Y. Kobayashi, J. Org. Chem. 2002, 67,
8771; l) E. L. Pearson, N. Kanizaj, A. C. Willis, M. N. Paddon-
Row, M. S. Sherburn, Chem. Eur. J. 2010, 16, 8280.
Scheme 2. Stereodivergent preparation of all stereoisomers of D9-THC
(1). Reagents and conditions: a) Grubbs II cat. (3 mol%), CH2Cl2,
258C, 92% for (S,S)-5, 87% for (R,S)-5, 90% for (S,R)-5, 85% for
(R,R)-5; b) NaClO2 (2.3 equiv), NaH2PO4 (2.0 equiv), 2-methyl-2-
butene (30 equiv), tBuOH/H2O, 258C; c) Me3SiCHN2 (1.1 equiv),
C6H6/MeOH (1:1), 08C, 66% for (S,S)-6, 60% for (R,S)-6, 61% for
(S,R)-6, 65% for (R,R)-6; d) MeMgI (10 equiv), Et2O, 08C to 1608C,
ambient pressure to 150 mm Hg; then addition of ZnBr2 upon workup
in CH2Cl2, 258C, 57% for (S,S)-6, 41% for (R,S)-6, 45% for (S,R)-6,
65% for (R,R)-6. R=C5H11. Atom numbering in the nomenclature of
1 (shown in Figure 1a) has been dropped for clarity; thus, (S,S)-1 is
(6aS,10aS)-1, and so on.
Keywords: dual catalysis · stereodivergent synthesis ·
tetrahydrocannabinol · total synthesis
[13] For selected recent examples, see: a) M. A. Schafroth, D. Sarlah,
S. Krautwald, E. M. Carreira, J. Am. Chem. Soc. 2012, 134,
20276; b) J. Y. Hamilton, D. Sarlah, E. M. Carreira, Angew.
Chem. Int. Ed. 2013, 52, 7532; Angew. Chem. 2013, 125, 7680;
c) J. Y. Hamilton, D. Sarlah, E. M. Carreira, J. Am. Chem. Soc.
2014, 136, 3006.
.
[1] For recent perspectives, see: a) C. S. Schindler, E. N. Jacobsen,
Science 2013, 340, 1052; b) M. T. Oliveira, M. Luparia, D.
Audisio, N. Maulide, Angew. Chem. Int. Ed. 2013, 52, 13149;
Angew. Chem. 2013, 125, 13387.
[14] O. F. Jeker, A. G. Kravina, E. M. Carreira, Angew. Chem. Int.
Ed. 2013, 52, 12166; Angew. Chem. 2013, 125, 12388.
[15] a) S. Krautwald, D. Sarlah, M. A. Schafroth, E. M. Carreira,
Science 2013, 340, 1065; b) S. Krautwald, M. A. Schafroth, D.
Sarlah, E. M. Carreira, J. Am. Chem. Soc. 2014, 136, 3020.
[16] For selected examples of methods that give access to the full set
of product stereoisomers from the same set of starting materials,
see: a) X. Tian, C. Cassani, Y. Liu, A. Moran, A. Urakawa, P.
Galzerano, E. Arceo, P. Melchiorre, J. Am. Chem. Soc. 2011, 133,
17934; b) B. Wang, F. Wu, Y. Wang, X. Liu, L. Deng, J. Am.
Chem. Soc. 2007, 129, 768; c) J. Gao, S. Bai, Q. Gao, Y. Liu, Q.
Yang, Chem. Commun. 2011, 47, 6716; d) X.-X. Yan, Q. Peng, Q.
Li, K. Zhang, J. Yao, X.-L. Hou, Y.-D. Wu, J. Am. Chem. Soc.
2008, 130, 14362; e) M. Luparia, M. T. Oliveira, D. Audisio, R.
Goddard, N. Maulide, Angew. Chem. Int. Ed. 2011, 50, 12631;
Angew. Chem. 2011, 123, 12840; f) A. Nojiri, N. Kumagai, M.
Shibasaki, J. Am. Chem. Soc. 2009, 131, 3779; g) Y. Huang, A. M.
Walji, C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc.
[2] For examples of the synthesis of all four stereoisomers of
mefloquine, see: a) J. Ding, D. G. Hall, Angew. Chem. Int. Ed.
2013, 52, 8069; Angew. Chem. 2013, 125, 8227; b) N. Schꢁtzen-
meister, M. Mꢁller, U. M. Reinscheid, C. Griesinger, A. Leonov,
Chem. Eur. J. 2013, 19, 17584; for other selected recent examples,
see: c) Y. Sridhar, P. Srihari, Eur. J. Org. Chem. 2013, 578; d) M.
Valli, P. Bruno, D. Sbarbada, A. Porta, G. Vidari, G. Zanoni, J.
Org. Chem. 2013, 78, 5556; e) M. Morgen, S. Bretzke, P. Li, D.
Menche, Org. Lett. 2010, 12, 4494.
[3] a) R. Mechoulam, Y. Gaoni, J. Am. Chem. Soc. 1964, 86, 1646;
b) E. C. Taylor, K. Lenard, Y. Shvo, J. Am. Chem. Soc. 1966, 88,
367; c) R. M. Smith, K. D. Kempfert, Phytochemistry 1977, 16,
1088; d) C. E. Turner, M. A. Elsohly, E. G. Boeren, J. Nat. Prod.
1980, 43, 169.
[4] a) A. N. Verty, M. J. Evetts, G. J. Crouch, I. S. McGregor, A.
Stefanidis, B. J. Oldfield, Neuropsychopharmacology 2011, 36,
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
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Communications
2005, 127, 15051; h) B. Simmons, A. M. Walji, D. W. C. MacMil-
lan, Angew. Chem. Int. Ed. 2009, 48, 4349; Angew. Chem. 2019,
131, 4413; i) Y. Chi, S. T. Scroggins, J. M. J. Frꢃchet, J. Am. Chem.
Soc. 2008, 130, 6322.
[18] a) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953; b) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010,
110, 1746.
[19] a) H. Simonis, P. Remmert, Ber. Dtsch. Chem. Ges. 1914, 47, 269;
b) E. Spꢄth, Ber. Dtsch. Chem. Ges. 1914, 47, 766; c) E. Spꢄth,
Monatsh. Chem. 1915, 36, 1; d) B. J. F. Hudson, E. Walton, J.
Chem. Soc. 1946, 85 – 87; e) W. S. Johnson, C. A. Erickson, J.
Ackerman, J. Am. Chem. Soc. 1952, 74, 2251; f) Y. Yang, T. J. L.
Mustard, H.-Y. Cheong, S. L. Buchwald, Angew. Chem. Int. Ed.
2013, 52, 14098; Angew. Chem. 2013, 125, 14348.
[17] For selected examples, see: a) T.-S. Wu, M.-L. Wang, P.-L. Wu,
Tetrahedron Lett. 1995, 36, 5385; b) K. Minagawa, S. Kouzuki, K.
Nomura, T. Yamaguchi, Y. Kawamura, K. Matsushima, H. Tani,
K. Ishii, T. Tanimoto, T. Kamigauchi, J. Antibiot. 2001, 54, 890;
c) O. Shirota, K. Takizawa, S. Sekita, M. Satake, J. Nat. Prod.
1997, 60, 997.
[20] P. Stoss, P. Merrath, Synlett 1991, 553.
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Angewandte
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Communications
Natural Product Synthesis
M. A. Schafroth, G. Zuccarello,
S. Krautwald, D. Sarlah,
E. M. Carreira*
&&&& — &&&&
Stereodivergent Total Synthesis of D9-
Tetrahydrocannabinols
No stereoisomer left behind: A concise
synthesis of tetrahydrocannabinol (THC)
is described that provides rapid and
controlled access to any stereoisomer of
the product, including the naturally
occurring stereoisomers D9-trans-THC
and D9-cis-THC. By application of stereo-
divergent dual catalysis to the same set of
starting materials, all four isomers of
THC were obtained in five steps using
a uniform synthetic sequence and identi-
cal reaction conditions.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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