Synthesis of (-)-Δ9-trans-tetrahydrocannabinol: Stereocontrol via mo-catalyzed asymmetric allylic alkylation reaction

Article abstract of DOI:10.1021/ol063022k

(Chemical Equation Presented) Δ⁹-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetric alkylation reaction of the extremely sterically congested bis-ortho-substitut

Full text of DOI:10.1021/ol063022k

ORGANIC
LETTERS
2007
Vol. 9, No. 5
861-863
Synthesis of
(-)-
9-trans-Tetrahydrocannabinol:
Stereocontrol via Mo-Catalyzed
∆
Asymmetric Allylic Alkylation Reaction
Barry M. Trost* and Kalindi Dogra
Department of Chemistry, Stanford UniVersity, Stanford, California 94305
bmtrost@stanford.edu
Received December 14, 2006
ABSTRACT
∆
9-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetric
alkylation reaction of the extremely sterically congested bis-ortho-substituted cinnamyl carbonate in high regio- and enantioselectivity.
(-)-∆9-trans-Tetrahydrocannabinol (∆9-THC, 1) isolated1
from female Cannabis satiVa L. in 1964 has been identified
as the primary psychomimetic component of marijuana. It
is also known to show antiemetic, antiglaucoma, and
analgesic properties. Currently it is administered as an
antinauseant to patients undergoing chemotherapy. Discovery
of the cannabinoid receptors CB1 and CB2 and ∆9-THC
analogues2 that bind selectively to them has led to a need
for the development of a flexible synthetic route that would
yield target compounds easily in high yields and in stereo-
chemically pure form.
product enantioselectively from achiral starting materials. The
problems associated with the synthesis of THC involve the
control of cis-trans stereochemistry at the cyclohexene ring
and the position of the double bond, i.e., ∆9 vs ∆8, the latter
being thermodynamically more stable.
Our reterosynthetic analysis of the molecule envisioned
all of the stereochemistry resulting from a single Mo-
catalyzed asymmetric allylic alkylation (AAA) reaction (see
the abstract). Alkylation of malonate adduct 4 with 3 should
(3) Selected examples: (a) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc.
1965, 87, 3273. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1967, 89, 4552. Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am. Chem. Soc.
1972, 94, 6159. (b) Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W. J. Am.
Chem. Soc. 1966, 88, 2079. Fahrenholtz, K. E.; Lurk, M.; Kierstead, R. W.
J. Am. Chem. Soc. 1967, 89, 5934. (c) Chan, T. H.; Chaly, T. Tetrahedron
Lett. 1982, 23, 2935. (d) Rickards, R. W.; Ronneberg, H. J. Org. Chem.
1984, 49, 572. (e) Childers, W. E., Jr.; Pinnick, H. W. J. Org. Chem. 1984,
49, 5276. (f) Malkov, A. V.; Koovsky, P. Collect. Czech. Chem. Commun.
2001, 66 (8), 1257. (g) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002,
67, 8771. William, A. D.; Kobayashi, Y. Org. Lett. 2001, 3, 2017.
(4) (a) Evans, D. A.; Shaughnessy, E. A.; Barnes, D. M. Tetrahedron
Lett. 1997, 38, 3193. (b) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka,
T.; Matt, P. V.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy,
E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582.
THC itself has been prepared numerous times, though most
routes are either racemic or derive their chirality from chiral
building blocks.3 Only Evan’s4 route targets the natural
(1) Mechoulam, R.; Gaoni, Y. J. Am. Chem. Soc. 1964, 86, 1646.
(2) (a) Mahadevan, A.; Siegel, C.; Martin, B. R.; Abood, M. E.;
Belestskaya, I.; Razdan, R. K. J. Med. Chem. 2000, 43, 3778. (b) Drake,
D. J.; Jensen, R. S.; Busch-Petersen, J.; Kawakami, J. K.; Fernandez-Garcia,
M. C.; Fan, P.; Makriyannis, A.; Tius, M. A. J. Med. Chem. 1998, 41,
3596. (c) Harrington, P. E.; Stergiades, I. A.; Erickson, J.; Makriyannis,
A.; Tius, M. A. J. Org. Chem. 2000, 65, 6576. (d) Tius, M. A.; Makriyannis,
A.; Zou, X. L.; Abadji, V. Tetrahedron 1994, 50, 2671.
10.1021/ol063022k CCC: $37.00
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Published on Web 02/01/2007

furnish the substrate for ring-closing metathesis (RCM). The
RCM in itself results in a fixed geometry of double bond
thus solving the problem of co-formation of ∆8-THC seen
in many syntheses. Decarboxylation of the malonate after
RCM was planned to result in the required trans stereo-
chemistry of 2. Grignard addition to ester 2 followed by
demethylation to the free phenol and cyclization yields 1.
Varying the aromatic group in 5, the alkylating partner 3, or
the Grignard reagents one can potentially prepare different
analogues of THC without fundamentally changing the
chemistry involved.
the lithium alkoxide of 10 with dry CO2 gas gives the
corresponding carbonate, which rearranges in the presence
of PdCl2(CH3CN)2 to yield the more stable linear carbonate
that decomposes to the alcohol 9 on workup (Figure 1). A
Allyl alcohol 9 was easily prepared in high yield from
commercially available olivetol, 6, in 4 steps (Scheme 1).
Figure 1. Isomerization of branched 10 to linear alcohol 9.
74% yield of 9 was observed with 6% recovered 10. To the
best of our knowledge this reaction has not been previously
reported. This alternate strategy using this novel isomeriza-
tion should prove to be a more efficient, atom economical
approach to cinnamyl alcohols then the more traditional
protocol based upon olefination.
Scheme 1
With the carbonate in hand we began examining the allylic
alkylation reaction. Although molybdenum is known for
giving the product resulting from attack at the more sub-
stituted carbon, we were concerned that the two o-methoxy
groups on the aryl ring would make this reaction sterically
unfavorable. Nevertheless, the reaction of carbonate 5 with
sodium dimethyl malonate under standard conditions of 10
mol % [Mo(CO)3C7H8] and 15 mol % chiral ligand S,S-11
proceeded sluggishly but gratifyingly gave only the branched
product 4 in 95% yield and 95% enantiomeric excess. The
reaction was optimized to reduce catalyst loading and the
optimized conditions are shown in eq 1.
Lithiated dimethyl olvitol was quenched with dry DMF to
yield the aldehyde 8 in 83% yield. Wadsworth-Horner-
Emmons reaction of 8 with sodium triethylphosphonoacetate
resulted in the corresponding R,â-unsaturated ethyl ester,
which was subjected without further purification to DIBAL-H
reduction to yield 97% of 9. Preparation of carbonate 5
proved to be a little tricky because the compound is sensitive
to both acid and base, including silica chromatography condi-
tions. A preparation of 5 clean enough to take into the Mo-
alkylation reaction was achieved by titrating alcohol 9 with
BuLi at -78 °C in ether and quenching the resulting alkoxide
with methyl chloroformate also at -78 °C. Washing the
organic layer with ice-cold water followed by solvent re-
moval gave carbonate 5 as a waxy solid, which is stable to
storage.
The branched allyl alcohol 10 is prepared by condensation
of acrolein with lithiated 7 in one step in 91% yield (Scheme
2). We planned to use the carbonate prepared from 10 in
Attempts to alkylate the malonate adduct 4 with 3 under
numerous conditions met with no success (Scheme 3). The
electrophile 3 slowly disappeared under the reaction condi-
tions due to 1,2-elimination, giving rise to isoprene. To
examine whether this or the steric demands of making a
quaternary center at the congested malonate carbon was the
cause for failure, we tried the addition of MeI, but observed
only trace amounts of the desired adduct. This led us to
believe steric congestion was the cause of failure, and hence
we prepared the monoester 12 under Krapcho decarboxyla-
tion6 conditions in 83% yield, which reduced steric demands.
Since the enolates of methyl esters are generally stable only
below -35 °C we attempted to carry out the alkylation at
Scheme 2
the Mo-AAA reaction to reduce the number of steps and
increase the efficiency of the synthesis. Unfortunately it
proved impossible to prepare either the carbonate or the
acetate of 10, due to their facile decomposition aided by the
highly electron rich aromatic ring.
(5) (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. (b) Overman,
L. E. Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(6) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, G. E.;
Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138.
We did, however, take advantage of this to isomerize the
branched alcohol 10 into the linear alcohol 9.5 Treatment of
862
Org. Lett., Vol. 9, No. 5, 2007

chromatography, converted to their respective methyl esters,
and subjected to ring closing metathesis using the second
generation Grubb’s ruthenium carbene catalyst,7 providing
the anti and syn cyclohexene compounds 2 and 16. The syn
compound 16 was easily recycled by equilibrating to anti 2
by treatment with NaOMe in MeOH for 3 days. Addition of
MeLi to the cyclized ester 2 at -78 °C resulted in formation
of the tertiary alcohol 17 in 92% yield (Scheme 4).
Scheme 3
With the end in sight, compound 17 was treated with BBr3
to yield the free phenol by demethylation of both ethers
(Scheme 5). We hoped that the free bis-phenol would
subsequently cyclize under the acidic reaction conditions to
give 1. Unfortunately we got a complex mixture of products.
The use of other acidic reagents for demethylation resulted
in similar fates. Finally we decided to carry out the reaction
in a stepwise manner using NaSEt in DMF, which is known
to stop at monodeprotection of aryl diethers.8 The reaction
-40 °C. Our best result was only a 50% yield of the adduct
13 using triflate 3c (Scheme 3). The competing elimination
reaction was still a problem due to the slower rate of
alkylation at the reduced temperature.
Therefore a nucleophile whose enolate would be stable at
room temperature or higher was required. We believed that
the dianion of the acid 14 would meet our needs (Scheme
4). This acid is prepared from 4 using classical conditions
proceeded as expected to yield 97% of 18, [R]23 -52 (c
D
0.79, CHCl3) (lit.9 [R]26 -44 (c 0.20, CHCl3)). Formation
D
of the cyclized ether was achieved by treating 18 with ZnBr2
in the presence of MgSO4. The resulting compound was
subjected to NaSEt in DMF without further purification to
yield the desired ∆9-THC 1 in 61% yield [R]25 -152 (c
D
0.46, CHCl3) (lit.6 [R]28 -150 (c 1.0, CHCl3).
D
In summary, the use of the molybdenum-catalyzed asym-
metric alkylation reaction developed in this group provided
the stereochemical framework to synthesize ∆9-THC in
enantiomericaly pure form and 30% overall yield from
olivetol dimethyl ether. The regio- and enantioselectivity of
the Mo AAA is undiminished even in this sterically
congested example. Furthermore, a simple and efficient two-
step protocol for the synthesis of cinnamyl alcohols has also
been developed.
Scheme 4
Acknowledgment. We thank the General Medical Sci-
ences Institute and the National Institutes of Health (GM
13598) and Merck for their generous support of our
programs. We are also indebted to Johnson Matthey for a
generous gift of palladium salts. Mass spectra were provided
by the Mass Spectrometry Regional Center of the University
of California, San Francisco supported by the NIH Division
of Research Resources.
in 97% yield, as shown in Scheme 5. The dianion of acid
14 cleanly underwent alkylation with iodide 3b to yield 84%
of 15 as a 2.4:1 mixture of anti and syn isomers at the newly
formed center. The two isomers were separated using column
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Scheme 5
OL063022K
(7) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(8) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327.
(9) William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771.
Org. Lett., Vol. 9, No. 5, 2007
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