Experimental and computational studies into an ATPH-Promoted exo-selective IMDA reaction: A short total synthesis of Δ9-THC

Article abstract of DOI:10.1002/chem.201001176

(Figure Presented) Reversal of fortune: The inherent cis stereoselectivity of an intramolecular Diels-Alder reaction is reversed through promotion with aluminum tris(2,6-diphenylphenoxide) (ATPH), allowing a total synthesis of the natural product Δ^9<

Full text of DOI:10.1002/chem.201001176

DOI: 10.1002/chem.201001176
Experimental and Computational Studies into an ATPH-Promoted
exo-Selective IMDA Reaction: A Short Total Synthesis of D9-THC**
Emma L. Pearson,[a, c] Nicholas Kanizaj,[a, c] Anthony C. Willis,[a]
Michael N. Paddon-Row,*[b] and Michael S. Sherburn*[a, c]
Cannabinoids are tricyclic terpenoid compounds contain-
ing a benzopyran moiety. Of the 60 or so known plant-de-
rived cannabinoids, the most well known is (ꢀ)-D9-tetrahy-
drocannabinol (D9-THC; 1), a natural product isolated from
Cannabis sativa L. (Indian hemp) and the key psychoactive
constituent of marijuana.[1] It exhibits a range of activities
including antiemetic, analgesic, and antiglaucoma effects[2]
Scheme 1. Retrosynthetic analysis of D9-THC. P=protecting/stereodirect-
ing group.
and has been the focus of many synthetic studies.[3,4] In
recent times, synthetic interest in these structures has been
reinvigorated by the identification of the cannabinoid recep-
tors CB1 and CB2 and their selective binding of THC ana-
logues.[5] Existing synthetic approaches are dominated by
strategies involving the construction of ring B through the
union of suitably functionalized ring A and ring C building
blocks.[3,4] These previous studies have identified two main
issues associated with the synthesis of D9-THC: the stereose-
lective formation of the trans ring junction and the unwant-
ed, facile isomerization of its thermodynamically more
stable D8-isomer.[3a] Herein, we present a short diastereose-
lective synthesis of D9-THC (1) by a trans-selective intramo-
lecular Diels–Alder (IMDA)[6] reaction of an appropriately
functionalized, benzo-tethered, ester-linked 1,3,9-decatriene
3 as the key step (Scheme 1). The synthesis is noteworthy
for three reasons: 1) it differs from previous approaches in
that rings B and C are assembled in one step with concomi-
tant installation of the required D9-alkene (Scheme 2, 3!2),
2) it represents the first total synthesis application of Yama-
motoꢀs highly sterically hindered aluminum tris(2,6-diphe-
nylphenoxide) (ATPH) catalyst,[7] and 3) the synthetic work
is driven by an understanding of the stereoselectivity of the
key IMDA reaction, which in turn is provided through com-
putational analysis. Despite the presence of the cyclohexene
ring in many naturally occurring cannabinoids, there are
only three published synthetic approaches to cannabinoids
employing Diels–Alder reactions: 1) Korte, Dlugosch, and
Claussenꢀs approach to trans-cannabidiol through an inter-
molecular cycloaddition,[8] 2) Evansꢀ synthesis of D9-tetrahy-
drocannabinol through an enantioselective intermolecular
cycloaddition,[9] and 3) Inoueꢀs approach to the cis isomer of
D9-tetrahydrocannabinol through an IMDA reaction.[10]
The IMDA precursors 3a–3d, differing only in the nature
of the C12 phenol substituent, were synthesized from olive-
tol (4) through the short sequence depicted in Scheme 2.[11]
Protection of the two phenol groups in 4 as methoxyme-
thyl[3d] or ethoxyethyl ethers followed by C6-formylation of
the olivetol ring by directed ortho-lithiation and trapping
with DMF afforded aldehydes 5a (EE) and 5b (MOM),[12]
respectively. Selective deprotection[12] of one acetal group of
5a and 5b afforded monophenols 6a and 6b. Methyl ether
6c was obtained from 6b through alkylation of the free
[a] Dr. E. L. Pearson, Dr. N. Kanizaj, Dr. A. C. Willis,+
Prof. M. S. Sherburn
Research School of Chemistry, Australian National University
Canberra, ACT 0200 (Australia)
Fax : (+61)2-6125-8114
E-mail: sherburn@rsc.anu.edu.au
[b] Prof. M. N. Paddon-Row
School of Chemistry, The University of New South Wales
Sydney, NSW 2052 (Australia)
E-mail: m.paddonrow@unsw.edu.au
[c] Dr. E. L. Pearson, Dr. N. Kanizaj, Prof. M. S. Sherburn
ARC Centre of Excellence for Free Radical Chemistry
and Biotechnology (Australia)
[+] Correspondence author for crystallographic data (willis@rsc.anu.
edu.au)
[**] ATPH=aluminum tris(2,6-diphenylphenoxide), IMDA=intramolec-
ular Diels–Alder, THC=tetrahydrocannabinol.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001176
8280
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COMMUNICATION
Evidently, the influence of the size of the PO-substituent at
C12 has a negligible effect upon IMDA stereoselectivity.
The reaction of the phenol substrate 3d was complicated by
concomitant transesterification, a result that highlights the
need for phenol masking during the IMDA step.
Frustratingly, attempts to interconvert the cis cycloadduct
to the trans isomer through base-mediated epimerization
were also unsuccessful; the cis isomer is evidently the ther-
modynamic product in these reactions. It was clear, there-
fore, that the successful realization of this synthesis would
hinge upon a kinetically controlled trans-selective (i.e., exo)
IMDA reaction. A deeper understanding of the stereocon-
trolling features of this reaction was needed.
DFT calculations, at the B3LYP/6-31G(d) level of
theory,[14] were carried out on a simplified system, 8, in
which the methyl and pentyl spectator substituents are
absent, while retaining the 12-methoxy substituent because
this group was found to affect the IMDA cis/trans selectivi-
ty.[11] Transition structures (TS) were located for both the cis
and trans IMDA pathways of 8, uncatalyzed and catalyzed
by the Lewis acids AlCl3 and ATPH. Relative enthalpies
(H) and Gibbs free energies (G) between the cis- and trans-
TSs for each reaction (Xrel-TS =Xcis-TSꢀXtrans-TS; X=H, G) are
given in Table 2. Also given in Table 2 are the cis/trans prod-
uct ratios, calculated from the Grel-TS values at 298.15 K.
Scheme 2. Synthesis of IMDA precursors 3a–3d. Reagents and condi-
tions: a) For 5a: i) EVE (10 equiv), PPTS (0.2 equiv), CH2Cl2/DMF, 08C,
7 h; ii) nBuLi (1.5 equiv), DMF (2.0 equiv), THF, 08C, 3 h; for 5b:
i) MOMCl (2.4 equiv), NaH (2.6 equiv), DMF, 08C!RT, 3.5 h; ii) nBuLi
(1.5 equiv), DMF (2.0 equiv), THF, 08C, 2 h, 5b: 83% from 4; b) for 6a:
SiO2, CH2Cl2, 8.5 h, RT, 67% from 4; for 6b: 0.7m HCl, THF, RT, 3 h,
85%; c) i) MeI (2.0 equiv), Cs2CO3 (2.5 equiv), DMF, 358C, 2 h; ii) HCl
(aq) (1.0 equiv), THF, RT, 3 h, 6c: 82% from 6b; d) nBuLi (2.4 equiv),
BrPh3PCHC
A
75%; 7b: 99%; 7c: 85%; e) DBU (1.4 equiv), Cl(O)CCH=CH2
(1.1 equiv), CH2Cl2, ꢀ788C!RT, 1 h, 3a: 81%; 3b: 86%; 3c: 70%;
f) PPTS (0.2 equiv), MeOH, RT, 3.5 h, 3d: 81%. EVE=ethyl vinyl ether,
EE=ethoxyethyl, PPTS=pyridinium p-toluenesulfonate, MOM=me-
thoxymethyl.
[a]
Table 2. B3LYP/6-31G(d) cis/trans TS relative enthalpies (Hrel-TS
)
and
[a]
Gibbs free energies (Grel-TS
)
for Lewis acid catalyzed and uncatalyzed
IMDA reactions and cis/trans product ratios.
phenol and subsequent removal of the acetal protecting
group. Installation of the E-diene was achieved through
Wittig olefination of aldehydes 6a–6c and esterification of
the resulting phenols 7a–7c with acryloyl chloride afforded
the trienes 3a–3c. Removal of the protecting group in 3a
gave the triene phenol 3d.
[a]
[a]
The results of thermally promoted IMDA reactions of the
four trienes 3a–3d are summarized in Table 1. Mixtures rich
in the undesired cis-fused adduct cis-2 (ꢁ3:1 cis/trans) were
generated in all cases, regardless of the C12 substituent.[13]
Entry
Reactant
Hrel-TS
Grel-TS
cis/trans[b]
1
2
3
4
8a
0.6 (ꢀ0.6)[c]
ꢀ0.1 (ꢀ1.4)[c]
ꢀ1.5 (ꢀ2.4)[c]
8.3 (7.9)[c,e]
51:49 (63:37)[c]
65:35 (72:28)[c]
3:97 (4:96)[c,d]
1:99[e] (10:90)[c,e]
8a·AlCl3
8a·ATPH
8b
ꢀ1.3 (ꢀ3.0)[c]
7.0 (7.2)[c,e]
11.1[e] (5.8)[e]
10.5[e] (5.4)[e]
[a] Xrel-TS =Xcis-TSꢀXtrans-TS (X=H or G), both at 298.15 K and 1 bar pres-
sure. [b] Cis/trans ratios calculated using DG°
values at 298.15 K.
Table 1. Thermal cyclization of precursors 3a–3d.[a]
CT
[c] Toluene solvent using the polarizable continuum model (PCM) ap-
proximation. [d] PCM single-point vibrationless self-consistent field
(SCF) energies with gas phase thermal corrections. [e] Calculations at the
B3LYP/6-31++GACTHNUGRTNEUNG(d,p) level.
Recently, we explored the cis/trans selectivity in IMDA
reactions of a series of hexadienyl acrylates.[15,16] Interesting-
ly, we observed that, whereas the IMDA reaction of the
Entry
P
Yield[b] [%]
Product distribution
cis-2/trans-2[c]
1
2
3
4
EE
MOM
Me
96
86
71
75
76:24
77:23
cognate
system
possessing
the
ethylene
tether
ꢀ
ꢀ
( CH2CH2OC(=O) ) displays strong cis stereoselectivity,
the IMDA reactions of the benzo-tethered systems exhibit
moderate trans selectivity, for example, cis/trans=26:74
(Scheme 3).[15]
73:27
H
76:24[d]
[a] Reagents and conditions: butylated hydroxytoluene (BHT; 5 mol%),
PhMe, 1108C, 4–7 h. [b] Total yield of the isolated product. [c] Kinetic
product ratio from crude 1H NMR spectra. [d] The acrylate ester of cis-
2d makes up around 20% of the crude product mixture.
Our DFT calculations traced the origin of the preference
for the trans isomer to conjugation effects between the
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8281

M. S. Sherburn, M. N. Paddon-Row et al.
ꢀ
Figure 1. A possible stabilizing C3 H···O interaction leading to decreased
IMDA cis selectivity. Top: uncomplexed cis- and trans-IMDA TSs;
bottom: AlCl3-complexed cis- and trans-IMDA TSs.
Scheme 3. In IMDA reactions, unsubstituted benzo-tethered trienes give
If this explanation is correct, then the corresponding
phenoxide system, 8b, should display markedly strong trans-
IMDA selectivity, as a consequence of a stronger stabilizing
trans selectivity and C12-substituted systems give cis selectivity.
ꢀ
ꢀ
diene and the aromatic ring of the tether, as reflected in the
magnitude of the dihedral angle q between the diene and
the aromatic ring in the cis- and trans-IMDA TSs for 10.
Whereas the cis-TSs suffer nearly perpendicular diene–
arene dihedral angles of 103–1118, the trans-TSs benefit
from substantially increased conjugation between these two
groups, with dihedral angles in the 29–338 range (see
Scheme 3). These markedly different dihedral angles be-
tween the aromatic ring and the C3=C4 double bond in the
cis- and trans-IMDA TSs of 10 suggest that placement of a
large group at either C3 or C12 should disfavor the trans-TS
relative to the cis-TS. Both DFT calculations and experi-
mental findings confirmed this expectation: both Br and tri-
methylsilyl (TMS) substituents at C3 or C12 led to very high
cis-IMDA selectivities (>95% cis) (Scheme 3).[16]
On the basis of these findings, it was expected that the 3-
OMe substituent in 8a should likewise favor formation of
the cis-IMDA product. The predicted and observed selectiv-
ity, stereorandom (gas phase; calculations) or moderately cis
selectivity (toluene; calculation and experiment), is smaller
than might be expected (Table 1, Entry 3; Table 2, Entry 1).
Examination of the trans-transition-structure geometry,
trans-8a-TS, (Figure 1) reveals the possible existence of a
(C3) H···O interaction. Indeed, B3LYP/6-31++G
N
calculations on 8b confirm this prediction (Table 2): the
trans-TS is favored over the cis-TS by 99:1 (gas phase) and
90:10 (toluene). Carrying out the IMDA reaction on the
phenoxide anion derivative of 3d should, therefore, offer
easy access to high yields of trans product. Unfortunately,
we have been unable to obtain experimental verification of
this proposal. All attempts to generate the phenoxide of
triene 3d (Table 1) and effect its IMDA reaction have led to
complex mixtures of products.
Common Lewis acids are well known to enhance endo se-
lectivity in DA reactions[18] and we find this to be the case
for the AlCl3-catalyzed IMDA reaction of 8a (8a·AlCl3,
Table 2), the cis selectivity rising modestly with respect to
the uncatalyzed reaction. However, Yamamoto has shown
that ATPH can promote exo selectivity in certain DA reac-
tions, a result that was attributed to the difficulty in binding
the more sterically encumbered carbonyl oxygen in the endo
TS.[7] Nevertheless, we have witnessed endo stereoselectivity
in some ATPH-promoted IMDA reactions[15] and, to our
knowledge, no computational study has previously been car-
ried out on ATPH. Notwithstanding the large size of the
8a·ATPH system, we were able to calculate fully relaxed
IMDA cis- and trans-TSs for 8a·ATPH. As expected, the
calculations predict strong trans selectivity of about 96:4
(Table 2). The geometries of cis-8a·ATPH-TS and trans-
8a·ATPH-TS (Figure 2), regarding how the ATPH Lewis
acid wraps around the 8a donor TS, closely resembles that
ꢀ
ꢀ
stabilizing (C3) H···O (Me) H-bonding interaction. Thus,
ꢀ
the distance between the C3 H hydrogen and the methoxy
ꢀ
oxygen is only 2.36 ꢂ, which lies close to the (C) H···O dis-
tance determined from X-ray crystal structures of aldehyde–
Lewis acid complexes (2.41–2.59 ꢂ).[17]
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Chem. Eur. J. 2010, 16, 8280 – 8284

A Short Total Synthesis of D9-THC
COMMUNICATION
with the three trisphenyl ligand arms adopting identical hel-
icity. Inspection of the TS geometries (Figure 2) shows that,
whereas there appears to be no destabilizing steric interac-
tions between 8a and ATPH in trans-8a-TS, in cis-8a-TS the
ꢀ
C3 H hydrogen lies quite close (2.64 ꢂ) to one of the
ꢀ
ATPH phenyl groups (the C3 H hydrogen and the closest
aromatic carbon are colored green in Figure 2). The distance
Figure 2. Cis- and trans-IMDA transition structures of triene 8a com-
plexed by ATPH. Note the destabilizing steric interaction in the cis-TS
(green atoms).
Scheme 4. ATPH-catalyzed IMDA cyclization of 3b and 3c and the
formal total synthesis of D9-THC. Reagents and conditions: a) ATPH,
CH2Cl2, ꢀ18!08C, 8 h, 2b: 79%, 2c: 71%; b) MeMgCl (10 equiv),
Et2O, 35 8C, 30 min, 96%.
ꢀ
between the C3 H hydrogen and the centroid of this aro-
matic ring is 2.62 ꢂ, which is closer than the distance seen
National Facility in Canberra, Australia, which is supported by the Aus-
tralian Commonwealth Government.
in the methane···benzene complex (ꢁ2.7 ꢂ).[19]
Experimentally, ATPH promoted a dramatic reversal in
IMDA diastereoselectivity, favoring the trans isomer in two
of the four triene substrates, namely the MOM ether and
the methyl ether systems 3b and 3c (Scheme 4). With a suc-
cessful approach to the trans cycloadduct in hand, all that
remained was the elaboration into the natural product. The
formal total synthesis[20] of D9-THC (1) was completed by
the reaction of trans-2c with methyl magnesium chloride, to
afford hydroxy phenol 12. This compound has previously
been converted into 1 in two steps (Scheme 4).[3i,j]
Keywords: cannabinoids · density functional calculations ·
diastereoselectivity · Diels–Alder reactions · total synthesis
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In summary, a short synthetic route to D9-THC employing
a trans-selective IMDA reaction has been achieved. Thermal
reactions of trienes 2 gave cycloadduct mixtures 3 rich in
the cis diastereomer—but less so than was expected. Com-
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ridden through promotion with ATPH, in the first applica-
tion of this catalyst in total synthesis. Computational studies
indicate a destabilizing CH···arene interaction between the
substrate and catalyst in the TS leading to the cis isomer.
These insights promote the application of this remarkable
and under-utilized catalyst in synthesis.
Acknowledgements
Funding from the Australian Research Council (ARC) is gratefully ac-
knowledged. The computational research was undertaken on the NCI
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M. S. Sherburn, M. N. Paddon-Row et al.
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[13] The relative configuration of IMDA adduct 2 was elucidated by
single crystal X-ray analysis of cis-2c obtained from the deprotec-
tion of 2a. See the Supporting Information for details. CCDC-
Received: May 3, 2010
Published online: June 29, 2010
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