High-pressure diels-alder cycloadditions between benzylideneacetones and 1,3-Butadienes: Application to the synthesis of (R,R)-(-)- and (S,S)-(+)-Δ8-tetrahydrocannabinol

Article abstract of DOI:10.1021/jo100785w

High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the mild Lewis acid HfCl ₄2THF allows these reactions to efficiently and regioselectively produce a series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton. Application to the synthesis of Δ⁸-trans-THC in both enantiomeric pure forms is based on the successful resolution of selected cycloadduct by the SAMP-hydrazone method.

Full text of DOI:10.1021/jo100785w

pubs.acs.org/joc
High-Pressure Diels-Alder Cycloadditions between Benzylideneacetones
and 1,3-Butadienes: Application to the Synthesis of (R,R)-(-)- and
(S,S)-(þ)-Δ8-Tetrahydrocannabinol
Eleonora Ballerini, Lucio Minuti,* and Oriana Piermatti
ꢀ
Dipartimento di Chimica, Universita degli Studi di Perugia, via Elce di Sotto 8, 06123 Perugia, Italy
lucio@unipg.it
Received April 21, 2010
High-pressure Diels-Alder reactions of various alkoxy/alkyl-substituted benzylideneacetones with
methyl-1,3-butadienes are reported. Activation by high pressure (8-11 kbar) in combination with the
mild Lewis acid HfCl4 2THF allows these reactions to efficiently and regioselectively produce a
3
series of ortho-substituted cyclohexenyl-benzene cycloadducts, that are useful precursors for the
expeditious construction of the privileged 6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton.
Application to the synthesis of Δ8-trans-THC in both enantiomeric pure forms is based on the
successful resolution of selected cycloadduct by the SAMP-hydrazone method.
Introduction
The 6,6-dimethyltetrahydro-6H-benzo[c]chromene sys-
tem occurs in a wide variety of natural products with diverse
biological activities; it has been selected as a privileged struc-
ture due to its capacity to interact with a variety of cellular
targets.1 Representative examples of natural products pos-
sessing this privileged structural motif include the Cannabi-
noids (i.e., Δ9-THC 1 and Δ8-THC 2) (Figure 1), a well-
known group of structurally related natural products, that
have been isolated from Cannabis sativa var. indica.2 Their
FIGURE 1. Tetrahydrocannabinol (THC) family.
potent bioactivities have stimulated the development of
many synthesis and pharmacological investigations.3 Exten-
sive Structure Activity Relationship (SAR) studies have
highlighted the need to develop a flexible synthetic route
that will allow target compounds to be produced easily, in
high yields, and in stereochemically pure form.
*To whom correspondence should be addressed. Phone: þ39.075.5855545.
Fax: þ39.075.5855560.
(1) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.;
Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939–9953.
(2) (a) Razdan, R. K. Pharmacol. Rev. 1986, 38, 75–149. (b) Crombie, L.
Pure Appl. Chem. 1986, 58, 693–700. (c) Crombie, L. W.; Crombie, M. L.;
Firth, D. F. J. Chem. Soc., Perkin Trans. 1 1988, 1263–1270. (d) Feigenbaum,
J. J.; Richmond, S. A.; Weissman, Y.; Mechoulam, R. Eur. J. Pharmacol.
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Young, A. C.; Bonner, T. I. Nature 1990, 346, 561–564. (f) Devane, W. A.;
Hanus, L.; Breuer, A.; Pertwee, R. G.; Stevenson, L. A.; Griffin, G.; Gibson,
D.; Mandelbaum, A.; Etinger, A.; Mechoulam, R. Science 1992, 258, 1946–
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DOI: 10.1021/jo100785w
r
Published on Web 05/17/2010
J. Org. Chem. 2010, 75, 4251–4260 4251
2010 American Chemical Society

Ballerini et al.
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SCHEME 1. Proposed Synthesis of the Δ8-trans-THC Family
SCHEME 2. Synthesis of Benzylideneacetones
Previous reports from this laboratory described a new and
environmentally safe method for building the tetrahydro-
6H-benzo[c]chromene structural unit by Diels-Alder reac-
tions of low reactive 3-substituted coumarins with methyl-
1,3-butadienes.4 These studies have demonstrated the
benefits of using high pressure as the activating method in the
Diels-Alder strategy to obtain polysubstituted benzo[c]-
chromene templates, under milder conditions without the use
of a metallic catalyst, thus highlighting the high-pressure
technology as a valuable tool in eco-friendly processes.5 Using
hydroxy-substituted 3-cyanocoumarins as dienophiles, we
have developed a Diels-Alder strategy for synthesizing a range
of hydroxy-substituted cis-6a-cyanobenzo[c]chromenones and
have applied it to the synthesis of Δ6-3,4-cis-cannabidiol and
Δ8-cis-tetrahydrocannabinol (3), in order to open a route to
the non-natural Δ8-cis-tetrahydrocannabinol family.4b
Most natural tetrahydrocannabinol products, such as (-)-
Δ9-THC (1) and (-)-Δ8-THC (2), have a trans stereochem-
istry at the cyclohexene ring, instead of the cis-fused ring
system that was obtained with our reported strategy.
serious drawbacks such as harsh reaction conditions, low
yields, and little flexibility and therefore great difficulty in
constructing libraries of cannabinoid analogues and other
new natural product-like compounds.3,6 We envisioned a
new eco-friendly method for constructing the 6,6-dimethyl-
tetrahydro-6H-benzo[c]chromene skeleton, including the
Δ8-trans-THC (2). The strategy is based on a Diels-Alder
reaction of alkoxy/alkyl-substituted benzylideneacetones 4
with 1,3-butadienes (5) followed by Grignard addition,
demethylation, and cyclization (Scheme 1).
It was obvious that the success of the plan would primarily
hinge on whether the deactivated di- and trisubstituted (R=
CH2OCH3, CH3; R1=H, OCH2OCH3, OCH3, C5H11) ben-
zylideneacetones 4 could be made to react with methyl-1,3-
butadienes (5).
Thus, in continuation to our research directed toward the
synthesis of compounds that incorporate the benzo[c]-
chromene subunit, we here report (i) the study of the Diels-
Alder reaction of benzylideneacetones 4 with 1,3-butadienes
5 (Scheme 1) and (ii) the conversion of selected cycloadducts
6 into their corresponding racemic Δ8-trans-THC (2) along
with their non-natural analogues 7. We also report an
efficient protocol for obtaining Δ8-trans-THC 2 in both
enantiomeric pure forms (Scheme 1).
Various syntheses of compounds belonging to the natural
trans-THC family have been reported, but almost all of the
strategies are based on the condensation of a proper aro-
matic ring system, with chiral building blocks available from
chiral pool-based monoterpenes. Most strategies suffer from
Results and Discussion
(4) (a) Girotti, R.; Marrocchi, A.; Minuti, L.; Piermatti, O.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2006, 71, 70–74. (b) Ballerini, E.; Minuti, L.;
Piermatti, O.; Pizzo, F. J. Org. Chem. 2009, 74, 4311–4317.
Benzylideneacetone Synthesis. The necessary benzylide-
neacetones 4 can be readily synthesized in high yields
€
(5) (a) Klarner, F.-G.; Diedrich, M. K.; Wigger, A. E. In Chemistry Under
Estreme or Non-Classical Conditions; van Eldik, R., Hubbard, C. D., Eds.;
Wiley: New York, 1997; Chapter 3. (b) Jurczak, J.; Gryko, D. T. In Chemistry
Under Estreme or Non-Classical Conditions; van Eldik, R., Hubbard, C. D.,
Eds.; Wiley: New York, 1997; Chapter 4. (c) Isaacs, N. S. In High-Pressure
Techniques in Chemistry and Physics; Harwood, L. M., Moody, C. J., Eds.;
Oxford: New York, 1997; Chapter 7. (d) Ibata, T. In Organic Synthesis at High
Pressures; Matsumoto, K., Achenson, R. M., Eds.; Wiley: Toronto, Canada, 1991;
Chapter 9. (e) Minuti, L.; Taticchi, A.; Costantini, L. Recent Res. Dev. Org.
Chem. 1999, 3, 105–116. (f) Minuti, L. In Eco-Friendly Processes and Proce-
dures for the Synthesis of Fine Chemicals; RSC Green Chemistry series; The
Royal Society of Chemistry : Cambridge, UK, 2009; Chapter 7.
(6) (a) Taylor, E. C.; Lenard, K.; Shvo, Y. J. Am. Chem. Soc. 1966, 88,
367–369. (b) Fahrenholtz, K. E.; Lurie, M.; Kierstead, R. W. J. Am. Chem.
Soc. 1967, 89, 5934–5941. (c) Mechoulam, R.; Braun, P.; Gaoni, Y. J. Am.
Chem. Soc. 1967, 89, 4552–4554. (d) Razdan, R. K.; Dalzell, H. C.; Handrick,
R. G. J. Am. Chem. Soc. 1974, 96, 5860–5865. (e) Rickards, R. W.;
Ronneberg, H. J. Org. Chem. 1984, 49, 572–573. (f) Childers, W. E., Jr.;
Pinnick, H. W. J. Org. Chem. 1984, 49, 5276–5277. (g) Evans, D. A.; Barnes,
D. M.; Johnson, J. S.; Lecta, T.; Von Matt, P.; Miller, S. J.; Murry, J. A.;
Norcross, R. D.; Shaughnessy, E. A.; campos, K. R. J. Am. Chem. Soc. 1999,
121, 7582–7594.
4252 J. Org. Chem. Vol. 75, No. 12, 2010

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TABLE 1. Diels-Alder Reactions of 20-Methoxybenzylideneacetone (4a) with 2,3-Dimethyl-1,3-butadiene (5x) and Isoprene (5y) under Atmospheric and
High-Pressure Conditions
entry
dienea
mediumb
time (h)
pressure (kbar)
temp (°C)
catalystc
product
yieldd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
5x
5x
5x
5xf
5x
5x
5x
5x
5x
5x
5x
5x
5y
5y
5yf
5y
5y
5y
5y
CH2Cl2
PhMe
H2O
115
115
52
48
48
70
16
16
16
16
16
16
115
72
52
55
70
16
16
atm
atm
atm
atm
atm
10
8
8
8
8
8
50
110
150
110
50
50
22
22
22
22
22
22
110
150
110
50
50
22
6ax
6ax
6ax
6ax
6ax
6ax
6ax
6ax
6ax
6ax
43e
45e
49
41
92
80
85
55
SolFC
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
HfCl4 2THF
3
HfCl4 2THF
3
HfCl4 2THFg
AlCl3 2THF
3
3
Sc(OTf)3
EtAlCl2
AlCl3
8
atm
atm
atm
atm
10
8
H2O
6ay
6ay
6ay
6ay
6ay
6ay
32e
35e
45
SolFC
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
HfCl4 2THF
3
28e
85
HfCl4 2THF
3
8
22
HfCl4 2THFg
74
3
a3 equiv of 1,3-diene was used. bConcentration of 1a = 0.1 M. 10 mol % of catalyst was used. dYields of isolated cycloadducts. Conversion
c
e
determined by 1H NMR of crude reaction mixture. f10 equiv of 1,3-diene was used. g25 mol % of catalyst was used.
(80-93%) and with total selectivity by aldol condensation of
benzaldehydes 9 and acetone7 (Scheme 2). While 9a-c are
commercially available aldehydes, the others were prepared
by formylation reaction of the corresponding benzene deri-
vatives 8d-f.3h,4b The (E)-configuration of the carbon-carbon
double bond for all benzylideneacetones 4 was confirmed from
deneacetone 4e and isoprene 5y that reportedly occurs in the
autoclave at high temperature (185 °C) to give an unspecified
mixture of two compounds.10
Thus, the reactions of 20-methoxybenzylideneacetone 4a
with dienes 5x,y were chosen as the initial model for our
system and investigated under atmospheric and high-
pressure conditions. The results of the optimization study
are summarized in Table 1.
the 16.4-16.6 Hz coupling constant values measured for 3J3,4
.
Diels-Alder Reaction of Benzylideneacetones 4 with 1,3-
Butadienes 5. The Diels-Alder cycloadditions of benzylide-
neacetones are still scarcely explored, owing to the low
reactivity of the benzylideneacetone double bond. For ex-
ample, thermal reaction of unsubstituted benzylideneace-
tone with cyclopentadiene or 2-(diphenylphosphinyl)-1,3-
butadiene under atmospheric pressure gives only low to
moderate yields of mixtures of the corresponding adducts
(35-64% and 30-38%, respectively),8 while with cyclohex-
adiene a satisfactory yield was obtained when the reaction
was performed under 13 kbar of pressure and in the presence
of Yb(OTf)3 catalyst.9 Our synthetic plan requires the use of
alkoxy/alkyl-substituted benzylideneacetones which are de-
activated as dienophiles in the Diels-Alder reaction by the
electron-donating alkoxy/alkyl groups in the 20-, 40-, and
60-positions. However, to the best of our knowledge, no
examples of Diels-Alder reaction between 1,3-butadienes
and alkoxy/alkyl-substituted benzylideneacetones have been
reported except the cycloaddition reaction between benzyli-
Under atmospheric pressure, the reaction of 20-methoxy-
benzylideneacetone (4a) with both dienes 5 did not occur
when performed for a long time (115 h) at 50 °C in methylene
chloride or at 110 °C in toluene (Table 1, entries 1, 2, and 13).
A low conversion of 4a to 6ax or 6ay (32-49%) was obtained
under aqueous or solvent-free conditions at 150 and 110 °C,
respectively (Table 1, entries 3, 4, 14, and 15), or by heating
4a and dienes 5 in methylene chloride at 50 °C in the presence
of HfCl4 2THF (Table 1, entries 5 and 16).
3
The unsatisfactory results (low conversions and/or high
temperature and long reaction time) obtained under normal
pressure conditions make the procedure unsuitable on sensi-
tive substrates and in the total synthesis of natural and non-
natural products. Considering the powerful pressure-
induced acceleration of the Diels-Alder reactions,4,5 we
studied the cycloadditions of 20-methoxybenzylideneacetone
(4a) with dienes 5 under high pressure in an effort to find
more efficient and eco-friendly conditions for these trans-
formations.
€
(7) Knolker, H.-J.; Ahrens, B.; Gonser, P.; Heininger, M.; Jones, P. G.
Tetrahedron 2000, 56, 2259–2271.
(8) (a) Dinwiddie, J. G., Jr.; McManus, S. P. J. Org. Chem. 1963, 28,
2416–2419. (b) Minami, T.; Chikugo, T.; Hanamoto, T. J. Org. Chem. 1986,
51, 2210–2214.
(10) Korte, F.; Dlugosch, E.; Claussen, U. Liebigs Ann. Chem. 1965, 685,
2210–2214. When we repeated the reaction between 4e and 5y under the
reaction conditions described in this paper a 1.5:1 mixture of the regioisomers
6ey/10ey was obtained with a 36% yield, lower than that reported by the
authors (72%).
(9) Kisman, A. C.; Kerr, M. A. Org. Lett. 2000, 22, 3517–3520.
J. Org. Chem. Vol. 75, No. 12, 2010 4253

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JOCArticle
TABLE 2. Diels-Alder Reactions of Benzylideneacetones 4b-f with 2,3-Dimethyl-1,3-butadiene (5x) and Isoprene (5y)
entry
dienophilea
dieneb
t (h)
P (kbar)
T (°C)
catalystc
products
yieldd (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4b
4b
4b
4b
4b
4b
4b
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
4d
4e
4e
4e
4e
4f
5x
5x
5x
5x
5y
5y
5y
5x
5y
5y
5y
5x
5x
5y
5y
5y
5y
5y
5x
5y
5y
5y
5x
5y
5y
130
16
16
24
130
20
20
22
72
22
24
130
24
130
72
16
22
16
20
24
24
24
18
24
20
atm
11
11
11
atm
11
10
11
11
11
11
atm
11
atm
11
11
11
11
11
11
11
11
11
50
22
22
22
50
22
22
22
50
22
22
50
22
50
50
22
22
22
22
22
22
22
22
22
22
HfCl4 2THF
3
6bx
6bx
6bx
6bx
6by
6by
6by
6cx
<5 e
81
HfCl4 2THF
3
AlCl3 2THF
3
75
Sc(OTf)3
HfCl4 2THF
55e
<5 e
81
f
3
3
3
3
HfCl4 2THF
AlCl3 2THF
68
70
28
80
HfCl4 2THF
6cy/10cy (1.5:1)g
6cy/10cy (16:1)g
6cy/10cy (22/1)g
6dx
HfCl4 2THF
3
AlCl3 2THF
HfCl4 2THF
70
3
<5 e
71
3
HfCl4 2THF
HfCl4 2THF
6dx
6dy
3
<5 e
25
3
6dy/10dy (1:1)g
6dy/10dy (7:1)g
6dy/10dy (24/1)g
6dy/10dy (9:1)g
6ex
HfCl4 2THF
3
84
75
60
AlCl3 2THF
3
Yb(OTf)3
HfCl4 2THF
75
3
3
3
HfCl4 2THF
AlCl3 2THF
6ey/10ey (12:1)g
6ey/10ey (24/1)g
6ey/10ey (15/1)g
6fx
8010
72
Yb(OTf)3
HfCl4 2THF
60
72
73
62
3
3
3
4f
4f
11
11
HfCl4 2THF
AlCl3 2THF
6fy/10fy (11:1)g
6fy/10fy (18/1)g
aConcentration of dienophile = 0.1 M. b3 equiv of 1,3-diene was used. c10 mol % of catalyst was used. dYields of isolated cycloadducts. eConversion
determined by 1H NMR of crude reaction mixture. f25 mol % of catalyst was used. gRegioisomeric ratio was determined by GC and 1H NMR analyses.
When a mixture of 4a and 2,3-dimethyl-1,3-butadiene (5x)
in methylene chloride was compressed to 10 kbar for 70 h at
50 °C, a 41% isolated yield of 6ax was obtained (Table 1,
entry 6). Similarly, under identical conditions isoprene (5y)
gave 6ay in low yield (28%) (Table 1, entry 17). Activation by
high pressure in combination with Lewis acid catalysis
allowed the same reactions to proceed satisfactorily under
much milder conditions. Indeed, using hyperbaric conditions
In view of these results, the study was extended to the
Diels-Alder reactions of dialkoxy-substituted benzylide-
neacetones 4b-f to determine the scope of the reaction
(Table 2 and Figure 2). The alkoxy group in the 20-position
of benzylideneacetones is essential for the pyran ring forma-
tion of the THC family (see Scheme 1), whereas those in 40- or
60-positions are useful to have access to desoxy-cannabinoids
and to the characteristic 1-hydroxy group of cannabinoids,
respectively (Figure 1).
(8 kbar) and the mild Lewis acid HfCl4 2THF (10 mol %)
3
the cycloadditions of 4a with 5x at room temperature (22 °C)
occurred in a shorter reaction time (16 h) with good yields
(92%) (Table 1, entry 7). Under identical conditions, iso-
prene (5y) gave 6ay regioselectively and in high yield (85%)
(Table 1, entry 18). In the case of the 8 kbar pressure
Under atmospheric conditions, the HfCl4 THF-catalyzed
3
cycloadditions of 4b or 4d with both dienes 5 at 50 °C for a
long time (130 h) gave a negligible (<5%) conversion
(Table 2, entries 1, 5, 12, and 14). This was the result of the
deactivation of the dienophilic components 4b and 4d with
respect to 4a by the two alkoxy groups and illustrates the
cycloaddition of 4a with 5x, the use of AlCl3 2THF gave a
3
slightly reduced yield (85%) (Table 1, entry 9), whereas
Sc(OTf)3 gave a low yield (55%) (Table 1, entry 10). The
use of conventional Lewis acids, such as EtAlCl2 and AlCl3,
resulted in an extensive polymerization (Table 1, entries 11
and 12). Thus, it was found that the hafnium(IV) or alumi-
num catalyst, when used as THF-complex salts, is essential
for the current reactions at high pressure. To the best of our
need for the hyperbaric conditions. Thus, when the HfCl4
3
THF-catalyzed cycloadditions of 4b-f with 5x were com-
pressed to 11 kbar for 16-24 h at 22 °C, the corresponding
cycloadducts were given in satisfactory yields (70-81%)
(Table 2, entries 2, 8, 13, 19, and 23). With isoprene (5y),
the cycloaddition of 4b regioselectively produced the adduct
6by in 81% yield (Table 2, entry 6), whereas the cycloaddi-
tions of 4c-f gave good yields (73-84%), but were less
regioselective producing mixtures of para/meta adducts 6cy/
10cy, 6dy/10dy, 6ey/10ey, and 6fy/10fy (Figure 2) in ratios
16/1, 7/1, 12/1, and 11/1, respectively (Table 2, entries 10, 16,
20, and 24). To obtain more information about the para-
meters that control the regioselectivity, the cycloaddition
knowledge the catalytic efficiency of HfCl4 2THF and
3
AlCl3 2THF in high-pressure Diels-Alder reactions has
3
never been reported5 and may be ascribed to their great
ability to coordinate the carbonyl oxygen of 4a together with
the air-stability and ease-of-use of these THF-complex salts,
which limit the polymerization of diene.
4254 J. Org. Chem. Vol. 75, No. 12, 2010

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JOCArticle
TABLE 3. Attempted Deprotection/Cyclization on 11 and 12
entry
reagent
conditions
result
1
2
3
4
5
6
7
8
9
10
11a
11a
11a
11b
11b
11b
11b
12
THF, 2-Propanol, HClconc, rt, 24 h
MeOH, p-TsOH, 30 °C, 21 h
NaSEt, DMF, 140 °C, 7 h
mixture
mixture
NRa
mixture
mixture
NRa
mixture
mixture
mixture
mixture
NaHSO4 SiO2, CH2Cl2, rt, 2 h
3
BF3 Et2O, CH2Cl2, rt, 5 h
3
MeOH, p-TsOH, 30 °C, 3 h
catecholborane, CH2Cl2, 0 °C, 1 h
THF, 2-propanol, HClconc, rt, 10 h
NaHSO4 SiO2, CH2Cl2, rt, 5 h
12
12
3
BF3 Et2O, CH2Cl2, rt, 5 h
3
aNR: no reaction.
it was expected that under the acidic reaction conditions, the
tertiary alcohols 11a,b, obtained by methylation of adducts
6dy and 6fy, would undergo deprotection of both MOM
groups and simultaneous cyclization to give the pyran ring in
one step (Scheme 3). Thus, the addition of MeMgBr to the
cycloadducts 6dy and 6fy at 60 °C resulted in the formation
of the corresponding tertiary alcohols 11a and 11b in good
yields (98% and 97%, respectively) (Scheme 3).
However, every attempt to achieve a one-step deprotec-
tion of both protecting groups or deprotection/cyclization
on 11a,b was unsuccessful. Alcohols 11a,b were treated with
various acidic reagents (Table 3, entries 1-7), and 11a was
converted to the cannabidiene 12 and then treated with acidic
reagents (Table 3, entries 8-10), but no reagents provided
the desidered products 2 and 7a,.
FIGURE 2. Diels-Alder cycloadducts.
reactions with isoprene (5y) were also investigated by using
high-pressure activation alone or high pressure in combina-
tion with the mild Lewis acids AlCl3 2THF or Yb(OTf)3. At
50 °C, the uncatalyzed 11 kbar pressure reactions of 5y with
4c and 4d both gave poor yields (<30%) and poor regios-
electivities (Table 2, entries 9 and 15). However, compared to
3
the HfCl4 THF-catalyzed reactions, the use of AlCl3 2THF
3
3
in the 11 kbar pressure cycloadditions of isoprene (5y) with
4c-f led to a significant increase in regioselectivity, but
slightly lower yields of the corresponding cycloadducts 6
and 10 (Table 2, entries 11, 17, 21, and 25). Under 11 kbar of
pressure, the use of Yb(OTf)3 in the reactions of 5y with 4d
and 4e led to lower yields and less regioselectivity compared
We then decided to carry out the deprotection/cyclization
on tertiary alcohols 13a,b, obtained by adding MeMgBr to
the O-methylated cycloadducts 6cy and 6ey (Scheme 4).
When the dimethylethers 13a,b were treated with NaSMe
in DMF according to Feutrill,11 monodemethylation occur-
red to furnish the corresponding diols 14a,b12 (Scheme 4).
The formation of cyclized ethers 15a,b was then achieved in
high yields (80% and 78%, respectively) by treating 14a,b
with ZnBr2 in the presence of MgSO4 according to the
literature data.6g,3e,h The remaining methoxy group on
15a,b was then removed with NaSMe (10 equiv) in DMF
at 140 °C to afford the desidered Δ8-trans-THC (2) and the
6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-benzo[c]chromen-
1-ol (7a) in 66% and 68% yields, respectively. The Δ8-THC
to AlCl3 2THF (Table 2, entries 18 and 22).
3
Application to the Synthesis of the Δ8-THC Family. With
the alkoxy-substituted cyclohexenylbenzenes 6 in hand, we
then turned our attention to the synthesis of Δ8-THC (2) and
its anologues 7. The next step toward the synthesis of the Δ8-
THC family was the Grignard addition to the carbonyl
carbon of cycloadducts 6, followed by the removal of the
protective groups on the aromatic ring and subsequent
construction of the pyran ring (see abstract). Among the
cycloadducts 6, compounds 6dy and 6fy with the MOM
protection on the aromatic part were initially chosen because
1
(2) synthesized in our laboratory was characterized by H
and 13C NMR, IR, and MS spectra. The 1H NMR (400 MHz)
SCHEME 3. Attempts to Synthesize Δ8-THCs 2 and 7a
J. Org. Chem. Vol. 75, No. 12, 2010 4255

Ballerini et al.
JOCArticle
SCHEME 4. Racemic Synthesis of Δ8-THCs 2 and 7a
SCHEME 5. Resolution of Racemic 6ey via SAMP Derivati-
zation and Synthesis of (R,R)-(-)- and (S,S)-(þ)-Δ8-THCs 2a
spectrum was identical with that (60 MHz) previously re-
ported for the natural Δ8-THC (2).6a-d
Synthesis of (R,R)-(-)- and (S,S)-(þ)-Δ8-THCs (2). Hav-
ing synthesized racemic Δ8-THC (2), we then developed an
efficient protocol to obtain enantiomerically enriched Δ8-
THCs. The procedure is based on the resolution of the cyclo-
adduct 6ey by applying the SAMP-hydrazone method.13
The acetyl derivative 6ey was treated with commercially avail-
able (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)
(16) to obtain a mixture of the two diastereoisomeric SAMP-
hydrazones 17. The mixture was chromatographed over
silica gel, eluting with 9:1 petroleum ether/Et2O to give dia-
stereomerically pure (S,R,R)-(þ)-17 ([R]D þ73 (c 1.99,
CHCl3)) and (S,S,S)-(þ)-17 ([R]D þ115 (c 1.28, CHCl3)) in
40% and 37% yield, respectively. Enantiomerically pure (R,
R)-(-)-6ey ([R]D -23 (c 1.34, CHCl3)) and (S,S)-(þ)-6ey
([R]D þ22 (c 0.6, CHCl3)) were obtained in 75% and 65%
yield, respectively, upon hydrolysis of the corresponding
SAMP-hydrazones 17 with oxalic acid. It should be noted
that the SAMP (16) was recovered in 70% yield. Confirma-
tion that no racemization had occurred under the reaction
conditions was achieved by reamination of (R,R)-(-)-6ey
with (S)-(-)-SAMP 16 to provide (S,R,R)-(þ)-17 as a single
diastereomer (85%).
aReagents and conditions: (a) p-TsOH, heptane, 100°C, 47 h; (b)
column chromatography; (c) Et2O, aqueous oxalic acid, rt, 4 d; (d)
MeMgBr, toluene, 60°C, 1,5 h; (e) 3 equiv of NaSMe, DMF, 140°C, 3 h;
(f) ZnBr2, MgSO4, CH2Cl2, rt, 15 h; (g) 10 equiv of NaSMe, DMF,
140°C, 10 h.
With the same sequence established for the synthesis of
racemic Δ8-THC 2, the (R,R)-(-)-Δ8-THC 2 ([R]D -245 (c
0.78, CHCl3)) and (S,S)-(þ)-Δ8-THC 2 ([R]D þ240 (c 0.94,
CHCl3)) were prepared from (R,R)-(-)-6ey and (S,S)-(þ)-
6ey, respectively, through the key intermediates (R,R)-(-)-
13b ([R]D -13 (c 1.28, CHCl3)) and (S,S)-(þ)-13b ([R]D þ15 (c
0.78, CHCl3)), and (R,R)-(-)-15b ([R]D -178 (c 0.65, CHCl3))
and (S,S)-(þ)-15b ([R]D þ178 (c 0.545, CHCl3)) (Scheme 5).
Structural Analysis. All compounds were purified by
column chromatography or by recrystallization with the
exception of 10cy-fy. All attempts to isolate these com-
pounds in pure form were unsuccessful; their structures were
assigned by using enriched mixtures. The complete 1H NMR
assignments, as well as the trans-stereochemical assignment,
were based on the relevant 1H NMR coupling constant value
and on 2D-COSY, NOESY, HMQC, and HMBC14 experi-
ments. The (E)-configuration of all benzylideneacetones 4
was confirmed from 16.4 to 16.6 Hz coupling constant values
(11) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 1327–1328.
(12) Compounds 14a,b were revealed by GC-MS, and after a short
purification were subjected to the next step.
(13) Minuti, L.; Taticchi, A.; Marrocchi, A. Tetrahedron: Asymmetry,
2000, 10, 4221-4225 and references cited therein.
(14) The signals of C-20 and C-60 carbons, for the adducts 6cx,ex,fx and
6cy,dy,fy and 10dy,ey and 12 in the 13C NMR spectra are absent.
We observed the C-20 and C-60 signals in the HMBC experiment for the
adduct 6ey.
4256 J. Org. Chem. Vol. 75, No. 12, 2010

Ballerini et al.
JOCArticle
from selected Diels-Alder cycloadducts 6ey and 6cy, respec-
tively, by Grignard addition, demethylation, and pyran ring
formation. An easy and efficient resolution of cycloadduct
6ey by the SAMP-hydrazone method provided a rapid
synthesis of Δ8-THC 2 in both enantiomeric pure forms.
Our proposed strategy to 6,6-dimethyltetrahydro-6H-
benzo[c]chromene-based privileged structures 7 is a new
synthetic route that may be applied to the synthesis of a
variety of naturally occurring products (i.e Δ8-THC family)
for use in bioassays and SAR studies. Future applications of
this methodology to the synthesis of other natural products
will be reported.
Experimental Section
General Procedure for the Diels-Alder Reaction of Benzyl-
ideneacetones 4a-f with Dienes 5x,y. The catalyzed cycloaddi-
tion reactions of benzylideneacetones 4 with dienes 5 were
accomplished (A) at normal pressure and (B) under 8-11 kbar
pressure conditions. Details are listed in Tables 1 and 2.
Condition A. The catalyst (10-25 mol %) was added to a
stirred solution of benzylideneacetone 4 (1.5 mmol) in 15 mL of
dry toluene or CH2Cl2 and the mixture was left at room
temperature for 30 min. Diene 5 (3 mol equiv) and a few crystals
of hydroquinone were then added and the mixture was poured
into an oil bath under magnetic stirring at the indicated reaction
temperature and time. The cooled mixture was poured into a
saturated NaHCO3 solution (15 mL) and extracted twice with
CH2Cl2.
The combined extracts were washed with saturated brine,
dried (Na2SO4), and evaporated under vacuo. The crude mix-
ture was purified by column chromatography on silica gel by
using a 9:1 mixture of petroleum ether/diethyl ether as eluent to
give cycloadducts 6.
Condition B. A solution of benzylideneacetone 4 (1.5 mmol) in
10 mL of CH2Cl2 was placed in a 15 mL Teflon vial; the catalyst
(10-25 mol %) was added and the mixture was left at room
temperature for 30 min. Diene 5 (2-4 molar equiv) and a few
crystals of hydroquinone were then added and the vial was filled
with the solvent. The vial was closed and kept at 8-11 kbar at
the indicated temperature for the appropriate time. After dep-
ressurizing, the mixture was worked up and purified as above
giving pure cycloadducts 6.
6ax: white solid, mp 75-76 °C (n-hexane); IR (CHCl3) 1702
(CdO) cm-1; 1H NMR (400 MHz; CDCl3) δ 1.64 (s, 3H, CH3),
1.68 (s, 3H, CH3), 1.91 (s, 3H, CH3CdO), 2.09 (dd broad, 1H,
J = 16.7, 4.4 Hz, H-5β), 2.17 (d broad, 2H, J = 7.0 Hz, H-2R,
H-2β), 2.28 (dd broad, 1H, J=16.7, 11.3 Hz, H-5R), 3.16 (ddd,
1H, J=10.8, 10.8, 5.3 Hz, H-1), 3.48 (ddd, 1H, J=10.8, 8.5, 7.5
Hz, H-6), 3.84 (s, 3H, OCH3), 6.85 (d, 1H, J=8.2 Hz, H-30), 6.89
(t, 1H, J=7.5 Hz, H-50), 7.11 (d, 1H, J=7.5 Hz, H-60), 7.16 (dd,
1H, J=8.2, 7.5 Hz, H-40); 13C NMR (400 MHz, CDCl3) δ 18.7
(2C), 28.1, 34.7, 36.6, 38.6, 52.7, 55.3, 110.7, 120.8, 123.6, 125.6,
127.3, 127.8, 132.2, 156.9, 212.2; MS (m/e) (rel intensity) 43 (45),
77 (18), 91 (66), 95 (27), 107 (36), 115 (18), 121 (98), 122 (35), 135
(32), 136 (17), 137 (95), 145 (100), 150 (43), 161 (46), 173 (17), 213
(22), 214 (23), 215 (66), 216 (21), 258 (Mþ, 68). Anal. Calcd for
C17H22O2: C, 79.03; H, 8.58. Found: C, 79.17; H, 8.45.
6ay: oil; IR (CHCl3) 1702 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 1.69 (s, 3H, 4-CH3), 1.92 (s, 3H, CH3CdO), 2.13-2.33
(m, 4H, H-2R, H-2β, H-5R, H-5β), 3.11 (ddd, 1H, J=10.5, 10.5,
5.6 Hz, H-1), 3.53 (ddd, 1H, J=10.5, 9.5, 6.5 Hz, H-6,), 3.84 (s,
3H, OCH3), 5.46 (s broad, 1H, H-3), 6.86 (d, 1H, J = 8.2 Hz,
H-30), 6.90 (t, 1H, J = 7.5 Hz, H-50), 7.12 (d, 1H, J = 7.5 Hz,
H-60), 7.17 (dd, 1H, J=8.2, 7.5 Hz, H-40); 13C NMR (400 MHz,
CDCl3) δ 23.1, 28.2, 28.5, 36.2, 36.8, 51.6, 55.3, 110.7, 118.8,
120.9, 127.4, 127.9, 132.2, 134.0, 156.8, 212.3; MS (m/e) (rel
FIGURE 3. Structure assigned to (a) cycloadducts 6y and (b) cyclo-
adducts 10y. The arrows indicate the observed 2D-NOESY correla-
tion for cycloadducts: (a) 6ey (R = Me, R0 = C5H11) and (b) 10dy
(R = MOM, R0 = C5H11).
measured for 3J3,4. The trans-configuration of H-1 and H-6
protons for all adducts 6 and 10 was based on the relevant
interproton coupling constant values (3J1,6=10.5-11.6 Hz),
typical for a trans-pseudoaxial orientation. This configura-
tion was further supported by 2D-NOESY experiments. The
NOESY correlation peaks observed between H-1 and H-2R
and H-5R, and between H-6 and H-2β and H-5β, together
with the absence of a correlation peak between H-1 and H-6
confirmed the trans-relationship of H-1 and H-6 (Figure 3).
The regiochemical assignment of the methyl group at C-4 in
adducts 6y (Figure 3a) and at C-3 in adducts 10y is supported
by the 2D-NOESY experiments performed on 6ey and 10dy,
respectively (Figure 3). The presence of NOESY correlation
peak was observed between H-3 and H-2R and H-2β, and
between the 4-Me protons and H-5R and H-5β for adduct
6ey (Figure 3a), while the NOESY correlation peak was
observed between H-4 and H-5R, and H-5β, and between the
3-Me protons and H-2R and H-2β for adduct 10dy
(Figure 3b), thus indicating the assigned regiochemistry of
the methyl group at C-4 and at C-3 for 6ey and 10dy,
respectively. Finally, support for the structure depicted in
Figure 3 for the adducts 6ay-dy, 6fy, and 10ey was given by
the great similarity of the proton and carbon shifts of
comparable sites of the cyclohexene ring of these adducts
with 6ey and 10dy, respectively.
The trans configurations of Δ8-THCs 2 and 7a were con-
firmed by comparing the NMR data with those of previously
reported natural Δ8-THC (2)6a-d and with those of our pre-
vious work.4b
Conclusions
In summary, a high-yielding method for constructing the
6,6-dimethyltetrahydro-6H-benzo[c]chromene skeleton 7 via
Diels-Alder reactions of low reactive alkoxybenzylidenea-
cetone derivatives 4 with methyl-1,3-butadienes 5 was
developed. The cycloaddition reactions were activated by
a combination of high pressure (8-11 kbar) and the mild
Lewis acid HfCl4 2THF or AlCl3 2THF that are useful
3
3
THF-complex salts which prevent the polymerization of the
dienes 5 and allow these reactions to occur in high yield
under mild reaction temperatures. Application to the synthesis
of Δ8-THC 2 and its analogue 7a has been accomplished
J. Org. Chem. Vol. 75, No. 12, 2010 4257

Ballerini et al.
JOCArticle
intensity) 43 (35), 77 (18), 91 (53), 93 (24), 108 (25), 115 (17), 121
(100), 122 (15), 145 (67), 146 (11), 159 (21), 161 (35), 186 (14), 201
(66), 202 (11), 244 (Mþ, 62). Anal. Calcd for C16H20O2: C, 78.65;
H, 8.25. Found: C, 78.78; H, 8.31.
δ 18.7 (2C), 27.9, 34.0, 35.6, 36.2, 51.3 (2C), 56.1, 94.6 (2C),
108.3 (2C), 120.6, 123.7, 126.0, 127.7, 156.7 (2C), 212.5; MS m/e
(rel intensity) 43 (27), 45 (100), 107 (15), 123 (46), 147 (16), 149
(14), 150 (22), 198 (17), 215 (19), 227 (14), 229 (42), 241 (35), 253
(14), 271 (21), 286 (14), 303 (34), 348 (Mþ, 3). Anal. Calcd for
C20H28O5: C, 68.94; H, 8.10. Found: C, 68.81; H, 8.06.
6bx: White solid, mp 64-65 °C (n-hexane); IR (CHCl3) 1702
(CdO) cm-1; 1H NMR (400 MHz; CDCl3) δ 1.62 (s, 3H, CH3),
1.66 (s, 3H, CH3), 1.90 (s, 3H, CH3CdO), 2.07 (dd broad, 1H,
J = 16.7, 4.6 Hz, H-5β), 2.14 (d broad, 2H, J = 7.5 Hz, H-2R,
H-2β), 2.27 (dd broad, 1H, J=16.7, 10.6 Hz, H-5R), 3.11 (ddd,
1H, J=10.9, 10.9, 5.3 Hz, H-1), 3.36 (ddd, 1H, J=11.1, 8.1, 8.1
Hz, H-6), 3.77 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.42 (d, 1H,
J = 7.2 Hz, H-50), 6.43 (s, 1H, H-30), 6.99 (d, 1H, J = 7.2 Hz,
H-60); 13C NMR (400 MHz, CDCl3) δ 18.6 (2C), 27.9, 34.7, 36.3,
38.8, 52.9, 55.2, 55.3, 98.7, 104.3, 123.5, 124.5, 125.7, 128.3,
157.8, 159.1, 212.3; MS (m/e) (rel intensity) 43 (14), 91 (13), 106
(11), 107 (28), 121 (17), 135 (12), 150 (40), 151 (86), 152 (12), 175
(100), 176 (18), 191 (56), 206 (17), 246 (12), 288 (Mþ, 25). Anal.
Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C, 74.86; H, 8.34.
6by: oil; IR (CHCl3) 1702 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 1.68 (s, 3H, 4-CH3), 1.91 (s, 3H, CH3CdO), 2.10-2.33
(m, 4H, H-2R, H-2β, H-5R, H-5β), 3.06 (ddd, 1H, J=10.4, 10.4,
5.5 Hz, H-1), 3.41 (ddd, 1H, J=10.8, 7.5, 7.5 Hz, H-6), 3.78 (s,
3H, OCH3), 3.81 (s, 3H, OCH3), 5.44 (s broad, 1H, H-3), 6.43 (d,
1H, J=6.9 Hz, H-50), 6.44 (s, 1H, H-30), 7.01 (d, 1H, J=6.9 Hz,
H-60); 13C NMR (400 MHz, CDCl3) δ 23.1, 28.1, 28.6, 36.0,
37.1, 51.9, 55.2, 55.3, 98.8, 104.4, 118.8, 124.6, 128.5, 134.1,
157.9, 159.2, 212.6; MS m/e (rel intensity) 91 (30), 138 (100), 139
(28), 151 (53), 175 (71), 274 (Mþ, 10). Anal. Calcd for C17H22O3:
C, 74.42; H, 8.08. Found: C, 74.59; H, 8.05.
6cx: white solid; mp 79-80 °C (n-hexane); IR (CHCl3) 1701
(CdO) cm-1; 1H NMR (400 MHz; CDCl3) δ 1.46 (s, 3H, CH3),
1.51 (s, 3H, CH3), 1.71 (s, 3H, CH3CdO), 1.76 (d broad, 1H, J=
16.4 Hz, H-5β), 1.87 (d broad, 1H, J=16.3 Hz, H-2β), 2.09 (dd
broad, 1H, J = 16.3, 10.8 Hz, H-2R), 2.37 (dd broad, 1H, J =
16.4, 11.5 Hz, H-5R), 3.45 (ddd, 1H, J=11.6, 11.6, 4.8 Hz, H-1),
3.54 (ddd, 1H, J=11.5, 11.5, 5.1 Hz, H-6), 3.63 (s, 6H, 20-OCH3,
60-OCH3), 6.35 (d, 2H, J=8.3 Hz, H-30, H-50), 6.94 (t, 1H, J=
8.3 Hz, H-40); 13C NMR (400 MHz, CDCl3) δ 18.7 (2C), 27.9,
33.7, 35.5, 36.1, 51.1, 55.6, 55.8, 104.3 (2C), 119.2, 123.6, 126.1,
127.5, 213.0; MS m/e (rel intensity) 43 (60), 91 (44), 107 (32), 138
(52), 150 (52), 151 (83), 152 (25), 175 (100), 176 (17), 191 (14), 288
(Mþ, 2). Anal. Calcd for C18H24O3: C, 74.97; H, 8.39. Found: C,
74.82; H, 8.35.
6dy: oil; IR (CHCl3) 1702 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 1.69 (s, 3H, 4-CH3), 1.90 (s, 3H, CH3CdO), 1.97 (dd
broad, 1H, J =17.3, 5.3 Hz, H-5β), 2.22 (m, 2H, H-2R, H-2β),
2.55 (dd broad, 1H, J = 17.3, 11.4 Hz, H-5R), 3.51 (s, 6H,
-OCH3, -OCH3), 3.57 (ddd, 1H, J=10.8, 10.8, 6.1 Hz, H-1),
3.79 (ddd, 1H, J = 11.6, 11.6, 5.3 Hz, H-6), 5.19 (s, 4H, 20-
OCH2-, 60-OCH2-), 5.47 (s broad, 1H, H-3), 6.77 (d, 2H, J=
8.3 Hz, H-30, H-50), 7.07 (t, 1H, J=8.3 Hz, H-40); 13C NMR (400
MHz, CDCl3) δ 23.2, 28.0, 29.5, 33.7, 34.7, 50.4, 56.1 (2C), 94.7
(2C), 108.3 (2C), 118.9, 120.6, 127.8, 134.5, 212.8; MS m/e (rel
intensity) 43 (24), 45 (100), 123 (30), 135 (17), 147 (17), 198 (20),
201 (13), 215 (45), 227 (30), 239 (13), 257 (23), 289 (20), 334 (Mþ,
4). Anal. Calcd for C19H26O5: C, 68.24; H, 7.84. Found: C,
68.08; H, 7.88.
10dy: oil; 1H NMR (400 MHz; C6D6) δ 1.71 (s, 3H, 3-CH3),
1.88 (s, 3H, CH3CdO), 2.00 (dd, 1H, J = 17.1, 4.1 Hz, H-2R),
2.24-2.40 (m, 1H, H-5β, H-2β), 2.90 (m, 1H, H-5R), 3.31 (s, 6H,
-OCH3, -OCH3), 3.90 (ddd, 1H, J=11.6, 11.6, 4.9 Hz, H-1),
4.13 (ddd, 1H, J = 11.6, 11.6, 5.1 Hz, H-6), 4.98 (s, 4H, 20-
OCH2-, 60-OCH2-), 5.59 (s broad, 1H, H-4), 6.90-7.05 (m,
3H, H-30, H-40, H-50); 13C NMR (400 MHz, CDCl3) δ 23.4, 28.1,
29.9, 33.3, 33.9, 50.7, 56.1, 94.7, 108.3, 120.5, 121.4, 127.8, 132.1,
212.5; MS m/e (rel intensity) 43 (15), 45 (100), 123 (9), 147 (10),
198 (16), 215 (12), 227 (12), 334 (1).
6ex: light yellow oil; IR (CHCl3) 1703 (CdO) cm-1; 1H NMR
(400 MHz; CDCl3) δ 0.9 (t, 3H, J=6.6 Hz, CH3-), 1.33 (m, 4H,
-CH2CH2-), 1.59 (m, 2H, -CH2-), 1.62 (s, 3H, CH3), 1.66 (s,
3H, CH3), 1.87(s, 3H, CH3CdO), 1.90 (d broad, 1H, J=16.4 Hz,
H-5β), 2.0 (d broad, 1H, J=16.2 Hz, H-2β), 2.25 (dd broad, 1H,
J=16.2, 11.2 Hz, H-2R), 2.52 (t, 2H, J=7.8 Hz, -CH2-), 2.53
(m, 1H, H-5R), 3.61 (m, 2H, H-1, H-6), 3.78 (s, 6H, 20-OCH3, 60-
OCH3), 6.33 (s, 2H, H-30, H-50); 13C NMR (400 MHz, CDCl3) δ
14.0, 18.7 (2C), 22.5, 27.9, 31.0, 31.6, 33.6, 35.5, 36.3, 36.4, 51.2,
55.5, 55.7, 104.5 (2C), 116.3, 123.6, 126.2, 142.7, 213.3; MS m/e
(rel intensity) 43 (35), 91 (15), 107 (31), 150 (38), 152 (54), 208
(78), 209 (22), 221 (100), 245 (100), 358 (Mþ, 17). Anal. Calcd for
C23H34O3: C, 77.05; H, 9.56. Found: C, 77.24; H, 9.48.
6ey: white solid; mp 39-41 °C (n-hexane); IR (CHCl3) 1700
(CdO) cm-1; 1H NMR (400 MHz; CDCl3) δ 0.90 (t, 3H, J=6.9
Hz, -CH3), 1.28-140 (m, 4H, -CH2-CH2-), 1.60 (m, 2H,
-CH2-), 1.68 (s, 3H, 4-CH3), 1.86 (s, 3H, CH3CdO), 1.91 (dd
broad, 1H, J = 17.8, 5.1 Hz, H-5β), 2.10-2.30 (m, 2H, H-2R,
H-2β), 2.52 (m, 1H, H-5R), 2.53 (t, 2H, J = 7.8 Hz, -CH2-),
3.55 (ddd, 1H, J =11.2, 11.2, 5.3 Hz, H-1), 3.67 (ddd, 1H, J =
11.5, 11.5, 6.2 Hz, H-6), 3.80 (s, 6H, 20-OCH3, 60-OCH3), 5.43 (s
broad, 1H, H-3), 6.34 (s, 2H, H-30, H-50); 13C NMR (400 MHz,
CHCl3) δ 14.0 (C-500), 22.5 (C-400), 23.2 (4-CH3), 28.0
(CH3CdO), 29.4 (C-2), 31.0 (C-200), 31.6 (C-300), 33.2 (C-6),
34.8 (C-5), 36.4 (C-100), 50.4 (C-1), 55.9 (20-OCH3, 60-OCH3),
104.5 (C-30, C-50), 116.3 (C-10), 118.8 (C-3), 134.7 (C-4), 142.7
(C-40), 158.5 (C-20, C-60), 213.5 (CdO); MS m/e (rel intensity)15
43 (12), 152 (32), 208 (42), 221 (30), 245 (100), 246 (18), 301 (8),
344 (Mþ, 16). Anal. Calcd for C22H32O3: C, 76.70; H, 9.36.
Found: C, 76.81; H, 9.32.
6cy: white solid, mp 33-34 °C (n-hexane); IR (CHCl3) 1700
(CdO) cm-1 1H NMR (400 MHz; CDCl3) δ 1.53 (s, 3H,
;
4-CH3), 1.72 (s, 3H, CH3CdO), 1.78 (dd broad, 1H, J = 17.2,
5.1 Hz, H-5β), 1.97-2.15 (m, 2H, H-2R, H-2β), 2.37(dd broad,
1H, J=17.2, 11.6 Hz, H-5R), 3.41 (ddd, 1H, J=11.3, 11.3, 5.5
Hz, H-1), 3.66 (ddd, 1H, J=11.5, 11.5, 5.3 Hz, H-6), 3.65 (s, 6H,
20-OCH3, 60-OCH3), 5.29 (s broad, 1H, H-3), 6.37 (d, 2H, J=8.3
Hz, H-30, H-50), 6.96 (t, 1H, J = 8.3 Hz, H-40); 13C NMR (400
MHz, CDCl3) δ 23.2, 28.0, 29.4, 33.3, 34.5, 50.3, 55.9 (2C), 104.3
(2C), 118.8, 119.1, 127.6, 134.6, 213.2; MS m/e (rel intensity) 43
(20), 77 (13), 91 (28), 93 (16), 121 (13), 138 (100), 139 (17), 151
(61), 175 (86), 176 (15), 191 (15), 274 (Mþ, 12). Anal. Calcd for
C17H22O3: C, 74.42; H, 8.08. Found: C, 74.56; H, 8.12.
10cy: MS m/e (rel intensity) 43 (12), 91 (18), 91 (28), 136 (19),
121 (13), 138 (56), 151 (46), 175 (100), 176 (16), 191 (13), 274
(Mþ, 2).
6dx: oil; IR (CHCl3) 1701 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 1.64 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.91 (s, 3H,
CH3CdO), 1.97 (dd broad, 1H, J=17.2, 4.7 Hz, H-5β), 2.07 (dd
broad, 1H, J=16.7, 4.5 Hz, H-2β), 2.27 (dd broad, 1H, J=16.7,
11.3 Hz, H-2R), 2.58 (dd broad, 1H, J = 17.2, 11.2 Hz, H-5R),
3.50 (s, 6H, -OCH3, -OCH3), 3.63 (ddd, 1H, J=11.5, 11.5, 4.9
Hz, H-1), 3.75 (ddd, 1H, J=11.5, 11.5, 5.3 Hz, H-6), 5.18 (s, 4H,
20-OCH2-, 60-OCH2-), 6.77 (d, 2H, J = 8.3 Hz, H-30, H-50),
7.06 (t, 1H, J = 8.3 Hz, H-40); 13C NMR (400 MHz, CHCl3)
10ey: oil; 1H NMR (400 MHz; C6D6) δ 0.97 (t, 3H, J=7.1 Hz,
CH3-), 1.37 (m, 4H, -CH2-CH2-), 1.63-1.77 (m, 2H,
-CH2-), 1.70 (s, 3H, 3-CH3), 1.89 (s, 3H, CH3CdO), 2.02
(dd, 1H, J=17.1, 4.1 Hz, H-2R), 2.13-2.55 (m, 3H, H-5β, H-2β,
H-2R), 2.59 (t, 2H, J = 7.7 Hz, -CH2-), 2.92 (m, 1H, H-5R),
(15) Claussen, U.; Fehlhaber, H. W.; Korte, F. Tetrahedron 1966, 22,
3535–3543.
4258 J. Org. Chem. Vol. 75, No. 12, 2010

Ballerini et al.
JOCArticle
3.50 (s, 6H, 20-OCH3, 60-OCH3), 3.92 (ddd, 1H, J = 11.5, 11.5,
4.9 Hz, H-1), 4.13 (ddd, 1H, J=11.5, 11.5, 5.1 Hz, H-6), 5.56 (s
broad, 1H, H-4), 6.40 (s, 2H, H-30 e H-50); 13C NMR (400 MHz,
CDCl3) δ 16.0, 20.7, 23.6, 28.1, 30.0, 30.8, 31.5, 32.9, 33.8, 35.5,
50.7, 55.7 (2C), 103.9 (2C), 108.4, 121.6, 132.0, 142.7; MS m/e
(rel intensity) 43 (9), 152 (16), 208 (33), 221 (22), 245 (100), 246
(18), 261 (6), 344 (Mþ, 6).
1.57 (m, 2H, -CH2-), 1.65 (s, 3H, 4-CH3), 1.83 (dd broad, 1H,
J=17.5, 4.3 Hz, H-5β), 1.89 (m, 1H, H-2β), 2.21 (d broad, 1H,
J=17.1 Hz, H-2R), 2.51 (t, 2H, J=7.7 Hz, -CH2-), 2.56 (ddd,
1H, J = 11.2, 11.2, 5.2 Hz, H-6), 2.69 (dd broad, 1H, J =17.5,
10.4 Hz, H-5R), 3.44 (ddd, 1H, J=11.3, 11.3, 5.9 Hz, H-6), 3.47
(s, 3H, -OCH3), 3.51 (s, 3H, -OCH3), 5.18 (AB system, 2H,
-OCH2-), 5.19 (AB system, 2H, -OCH2-), 5.41 (s broad, 1H,
H-3), 6.62 (s, 1H, H-30or H-50), 6.63 (s, 2H, H-30 or H-50); 13C
NMR (400 MHz, CDCl3) δ 14.1, 22.5, 22.9, 24.9, 28.9, 29.3,
31.0, 31.6, 32.8, 36.2, 36.4, 45.1, 56.2, 56.3, 74.2, 94.5, 95.1,
108.6, 108.7, 119.8, 120.1, 134.0, 143.4, 154.7, 157.2. Anal. Calcd
for C25H40O5: C, 71.39; H, 9.59. Found: C, 71.47; H, 9.52.
13a: oil; MS (m/e) (rel intensity) 43 (17), 134 (128), 193 (24),
231 (30), 257 (37), 271 (21), 275 (52), 281 (100), 283 (33), 289 (87),
290 (Mþ, 19).
6fx: oil; IR (CHCl3) 1701 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 0.89 (t, 3H, J = 6.9 Hz, -CH3), 1.32 (m, 4H,
-CH2CH2-), 1.57 (m, 2H, -CH2-), 1.63 (s, 3H, CH3), 1.68
(s, 3H, CH3), 1.90 (s, 3H, CH3CdO), 1.95 (dd broad, 1H, J =
17.2, 4.5 Hz, H-5β), 2.05 (dd broad, 1H, J=16.7, 4.7 Hz, H-2β),
2.27 (dd broad, 1H, J=16.7, 11.4 Hz, H-2R), 2.50 (t, 2H, J=7.9
Hz, -CH2), 2.57 (dd broad, 1H, J=17.2, 11.2 Hz, H-5R), 3.50
(s, 6H, 20-OCH3, 60-OCH3), 3.60 (ddd, 1H, J = 11.4, 11.4, 4.9
Hz, H-1), 3.67 (ddd, 1H, J=11.4, 11.4, 6.2 Hz, H-6), 5.17 (s, 4H,
20-OCH2, 60-OCH2), 6.60 (s, 2H, H-30, H-50); 13C NMR
(400 MHz, CDCl3) δ 14.0, 18.7 (2C), 22.5, 27.9, 30.9, 31.6,
34.0, 35.6, 36.2, 36.4, 51.4, 56.1 (2C), 94.8 (2C), 108.5 (2C),
117.7, 123.7, 126.1, 143.1, 213.0; MS m/e (rel intensity) 43 (26),
45 (100), 107 (17), 119 (13), 123 (27), 149 (12), 150 (19), 193 (40),
217 (13), 268 (53), 269 (13), 275 (40), 281 (22), 285 (12), 299 (35),
356 (13), 373 (45), 418 (Mþ, 3). Anal. Calcd for C25H38O5: C,
71.74; H, 9.15. Found: C, 71.62; H, 9.12.
13b: oil; IR (CHCl3) 3690.1 (OH) cm-1; 1H NMR (400 MHz;
CDCl3) δ 0.75 (t, 3H, J =7.1 Hz, -CH3), 0.87 (s, 3H, CH3C-
OH), 0.88 (s, 3H, CH3C-OH), 1.18 (m, 4H, -CH2CH2-),
1.40-1.55 (m, 2H, -CH2-), 1.48 (s, 3H, 4-CH3), 1.62 (dd
broad, 1H, J = 17.3, 4.4 Hz, H-5β), 1.72 (m, 1H, H-2β), 2.03
(d broad, 1H, J=17.3 Hz, H-2R), 2.37 (ddd, 1H, J=11.3, 11.3,
5.3 Hz, H-1), 2.39 (t, 2H, J=7.5 Hz, -CH2-), 2.51 (dd broad,
1H, J=17.3, 11.4 Hz, H-5R), 3.27 (ddd, 1H, J=11.4, 11.4, 5.2
Hz, H-6), 3.64 (s, 6H, 20-OCH3, 60-OCH3), 5.24 (s broad, 1H,
H-3), 6.20 (s, 1H, H-30), 6.23 (s, 1H, H-50); 13C NMR (400 MHz,
CDCl3) δ 14.0, 22.5, 22.8, 24.8, 28.8, 29.3, 31.0, 31.6, 32.3,
36.2, 36.4, 45.1, 55.2, 55.7, 74.1, 104.5, 104.9, 118.5, 120.0,
134.0, 142.9, 156.7, 159.2; MS m/e (rel intensity) 43 (9), 91 (7),
152 (8), 178 (9), 221 (100), 222 (16), 234 (19), 235 (10), 274 (13),
277 (44), 287 (11), 292 (11), 299 (20), 342 (22), 360 (Mþ, 7).
Anal. Calcd for C23H36O3: C, 76.62; H, 10.06. Found: C, 76.79;
H, 9.98.
6fy: oil; IR (CHCl3) 1701 (CdO) cm-1; 1H NMR (400 MHz;
CDCl3) δ 0.89 (t, 3H, J=6.9 Hz, CH3-), 1.31 (m, 4H, -CH2-
CH2-), 1.57 (m, 2H, -CH2-), 1.69 (s, 3H, 4-CH3), 1.90 (s, 3H,
CH3CdO), 1.96 (dd, 1H, J=17.1, 5.0 Hz, H-5β), 2.13-2.30 (m,
2H, H-2R, H-2β), 2.50 (t, 2H, J = 7.8 Hz, -CH2-), 2.55 (dd
broad, 1H, J = 17.1, 11.2 Hz, H-5R), 3.51 (s, 6H, 20-OCH3, 60-
OCH3), 3.54 (ddd, 1H, J = 11.0, 11.0, 5.6 Hz, H-1), 3.73 (ddd,
1H, J = 11.6, 11.6, 5.3 Hz, H-6), 5.18 (s, 4H, 20-OCH2-, 60-
OCH2-), 5.46 (s broad, 1H, H-3), 6.60 (s, 2H, H-30, H-50); 13C
NMR (400 MHz, CDCl3) δ 14.0, 22.5, 23.3, 28.0, 29.5, 30.9,
31.6, 33.9, 34.9, 36.2, 50.5, 56.1 (2C), 94.4 (2C), 108.5 (2C),
117.7, 118.9, 134.6, 143.2, 213.1; MS m/e (rel intensity) 43 (26),
45 (100), 109 (19), 193 (43), 217 (13), 225 (14), 231 (11), 268 (39),
269 (13), 275 (37), 285 (42), 295(10), 297 (31), 309 (10), 327 (30),
342 (12), 359 (17), 404 (Mþ, 10). Anal. Calcd for C24H36O5: C,
71.26; H, 8.97. Found: C, 71.34; H, 9.03.
12:16 SOCl2 (6 drops) was added to an ice-cold solution of
alcohol 11a (78.4 mg, 0.224 mmol) in 2.09 mL of dry pyridine.
After 15 min, the solution was allowed to warm to rt, then
diluted with brine and extracted twice with ether and twice with
ethyl acetate. The extract was washed twice with HCl 0.1 M and
several times with water until neutral, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
chromatography, eluting with petroleum ether/diethyl ether
(7:3) to give 12 (75% yield) as an oil. 1H NMR (400 MHz;
CDCl3) δ 1.53 (s, 3H, CH3), 1.69 (s, 3H, 30-CH3), 1.95 (dd broad,
1H, J = 17.2, 4.6 Hz, H-20β), 2.05 (d broad, 1H, J = 17.1 Hz,
H-50β), 2.18 (m, 1H, H-50R), 2.60 (dd broad, 1H, J=17.2, 10.8
Hz, H-20R), 3.19 (ddd, 1H, J=11.4, 11.4, 5.1 Hz, H-60), 3.49 (s,
6H, 1-OCH3, 3-OCH3), 3.62 (ddd, 1H, J = 11.5, 11.5, 5.2 Hz,
H-10), 4.48 (s broad, 1H, H-100), 4.61 (s broad, 1H, H-100), 5.17
(m, 4H, 1-OCH2-, 3-OCH2-), 5.48 (s broad, 1H, H-40), 6.77
(m, 2H, H-4, H-6), 7.05 (t, 1H, J=8.3 Hz, H-5); 13C NMR (400
MHz, CDCl3) δ 18.4, 23.3, 32.5, 34.9, 35.5, 44.5, 56.0 (2C), 94.7,
95.0, 108.0, 108.2, 110.3, 120.7, 122.0, 127.1, 134.3, 148.9; MS
m/e (rel intensity) 45 (100), 123 (11), 147 (12), 161 (17), 173 (10),
175 (12), 187 (25), 205 (24), 211 (16), 213 (23), 219 (37), 255 (22),
287 (42), 332 (Mþ, 5). Anal. Calcd for C20H28O4: C, 72.26; H,
8.49. Found: C, 72.39; H, 8.42.
10fy: MS m/e (rel intensity) 43 (21), 45 (80), 193 (30), 217 (24),
268 (100), 269 (23), 275 (88), 281 (22), 285 (39), 297 (34), 327 (24),
404 (Mþ, 16).
General Procedure for Preparing Alcohols 11a,b and 13a,b.3i
To a solution of cycloadduct 6 (0.274 mmol) in toluene
(18.5 mL) was slowly added a 3.0 M solution of CH3MgBr in
ether (0.91 mL, 2.74 mmol) at room temperature. The mixture
was heated at 60 °C for 1.5 h and then cooled to room
temperature. The reaction was quenched with saturated NH4Cl
solution, poured into brine, and extracted with ether. The
combined organic layers were dried over Na2SO4 and concen-
trated to give the desired alcohols 11 and 13 (98% yield).
11a: oil; IR (CHCl3) 3690 (OH) cm-1; H NMR (400 MHz;
CDCl3) δ 1.06 (s, 3H, CH3C-OH), 1.07 (s, 3H, CH3C-OH),
1.66 (s, 3H, 4-CH3), 1.85 (dd broad, 1H, J=18.2, 4.9 Hz, H-5β),
1.91 (dd broad, 1H, J=17.2, 11.1 Hz, H-2β), 2.23 (d broad, 1H,
J=17.2 Hz, H-2R), 2.59 (ddd, 1H, J=11.2, 11.2, 5.2 Hz, H-6),
2.70 (dd broad, 1H, J = 18.2, 10.2 Hz, H-5R), 3.48 (s, 3H,
-OCH3), 3.51 (ddd, 1H, J = 11.2, 11.2, 4.5 Hz, H-6), 3.52 (s,
3H, -OCH3), 5.20 (AB system, 2H, -OCH2-), 5.21 (AB system,
2H, -OCH2-), 5.43 (s broad, 1H, H-3), 6.81 (m, 2H, H-30, H-50),
7.10 (t, 1H, J = 8.3 Hz, H-40); 13C NMR (400 MHz, CDCl3) δ
22.9, 25.0, 28.8, 29.2, 33.0, 36.2, 45.1, 56.2, 56.3, 74.1, 94.5, 95.0,
108.4, 108.6, 120.1, 123.0, 127.8, 133.9, 154.9, 157.5. Anal. Calcd
for C20H30O5: C, 68.54; H, 8.36. Found: C, 68.28; H, 8.32.
11b: oil; IR (CHCl3) 3690 (OH) cm-1; 1H NMR (400 MHz;
CDCl3) δ 0.89 (t, 3H, J = 7.0 Hz, -CH3), 1.05 (s, 3H,
CH3C-OH), 1.07 (s, 3H, CH3C-OH), 1.31 (m, 4H, -CH2CH2-),
Procedure for Preparing Δ8-trans-THCs 2 and 7a. According
to the procedure described by Trost et al.5b for synthesis of Δ9-
THC, starting from alcohol 13a,b (0.2 mmol) and NaSMe (0.6
equiv) dissolved in DMF (2 mL), after stirring at 140 °C for 3 h
diols 14a and 14b were obtained in 94% and 90% yields, respec-
tively. Then, formation of the cyclized ethers 15a and 15b (80% and
78% yields, respectively) was achieved by treating a solution of
14a,b (0.18 mmol) in CH2Cl2 (7 mL) with ZnBr2 (0.35 mmol) and
MgSO4 (150 mg) at rt for 12 h. Finally, a solution of ethers 15a,b
(0.13 mmol) and NaSMe (1.3 mmol) in DMF (10 mL) was stirred
(16) Handrick, G. R.; Razdan, R. K.; Uliss, D. B.; Dalzell, H. C.; Boger,
E. J. Org. Chem. 1977, 42 (15), 2563–2568.
J. Org. Chem. Vol. 75, No. 12, 2010 4259

Ballerini et al.
JOCArticle
at 140 °C for 10 h to afford the desidered racemic Δ8-THC (2) and
the analogue 7a in 66% and 68% yields, respectively.
(t, 3H, J = 6.9 Hz, -CH3), 1.10-1.24 (m, 4H, -CH2CH2-),
1.33-1.60 (m, 5H, -CH2-, H-400, H-300), 1.46 (s, 3H,
CH3-CdN), 1.50 (s, 3H, 4-CH3), 1.66-1.76 (m, 2H, H-5β,
H-300), 1.87 (d broad, 1H, J = 16.8 Hz, H-2R), 1.99-2.14 (m,
2H, H-2β, H-500), 2.34 (t, 2H, J=7.8 Hz, -CH2-), 2.49 (m, 1H,
H-5R), 2.56 (dd, 1H, J=9.5, 6.9 Hz, -OCH2-), 2.73-2.78 (m,
2H, H-200, H-500), 2.84 (dd, 1H, J=9.5, 3.5 Hz, -OCH2-), 3.00
(s, 3H, -OCH3), 3.20 (ddd, 1H, J=11.5, 11.5, 5.1 Hz, H-1), 3.47
(ddd, 1H, J=11.5, 11.5, 5.2 Hz, H-6), 3.59 (s, 3H, 20-OCH3), 3.64
(s, 3H, 60-OCH3), 5.25 (s broad, 1H, H-3), 6.14 (s, 1H, H-30), 6.16
(s, 1H, H-50); 13C NMR (400 MHz, CDCl3) δ 13.7, 14.0, 21.9,
22.5, 23.4, 26.3, 30.7, 31.1, 31.7, 33.6, 34.6, 36.5, 45.2, 53.4, 55.1,
55.8, 58.9, 66.1, 74.5, 103.8, 104.6, 116.8, 119.4, 134.5, 142.2,
157.4, 159.4, 170.6; MSm/e (rel intensity) 43 (6), 73 (9), 91 (6), 105
(6), 137 (27), 173 (6), 207 (13), 221 (43), 300 (20), 301 (16), 411
(100), 412 (30), 456 (Mþ, 31). Anal. Calcd for C28H44N2O3: C,
73.64; H, 9.71; N, 6.13. Found: C, 73.51; H, 9.65; N, 6.06.
(S,S,S)-(þ)-17: pale-yellow oil; [R]D þ115 (c 1.28, CHCl3); IR
(CHCl3) 1607 (CdN) cm-1; 1H NMR (400 MHz; CDCl3) δ 0.79
(t, 3H, J =7.1 Hz, -CH3-), 1.14-1.29 (m, 4H, -CH2CH2-),
1.38-1.55 (m, 6H, -CH2-, H-400, H-300, H-500), 1.49 (s, 3H,
CH3-CdN), 1.57 (s, 3H, 4-CH3), 1.74-1.85 (m, 2H, H-5β,
H-300), 1.99 (d broad, 1H, J = 16.6 Hz, H-2R), 2.09 (dd broad,
1H, J=16.6, 11.4 Hz, H-2β), 2.41 (t, 2H, J=7.7 Hz, -CH2-),
2.44 (m, 1H, H-500), 2.52 (m, 1H, H-5R), 2.90-2.98 (m, 2H,
H-200, -OCH2-), 3.17 (s, 3H, -OCH3), 3.14-3.21 (m, 1H,
-OCH2-), 3.27 (ddd, 1H, J = 11.4, 11.4, 5.0 Hz, H-1), 3.50
(ddd, 1H, J=11.5, 11.5, 5.1 Hz, H-6), 3.67 (s, 6H, 20-OCH3, 60-
OCH3), 5.33 (s, 1H, H-3), 6.19 (s, 2H, H-30, H-50); 13C NMR
(400 MHz, CDCl3) δ 14.0 (2C), 22.0, 22.5, 23.3, 26.7, 30.3, 31.3,
31.5, 33.7, 34.8, 36.4, 44.9, 53.6, 55.3, 55.8, 59.0, 66.1, 75.4,
103.8, 104.6, 116.9, 119.5, 134.5,142.2, 157.5, 159.5, 168.8; MS
m/e (rel intensity) 43 (4), 70 (7), 105 (10), 144 (34), 221 (91), 222
(15), 301 (10), 310 (10), 342 (33), 343 (11), 411 (100), 412 (41), 456
(Mþ, 22). Anal. Calcd for C28H44N2O3: C, 73.64; H, 9.71; N,
6.13. Found: C, 73.48; H, 9.62; N, 6.08.
14a: oil; MS m/e (rel intensity) 43 (10), 59 (11), 77 (13), 91 (11),
107 (18), 124 (11), 135 (15), 137 (46), 150 (14), 175 (100), 176 (13),
187 (10), 190 (19), 215 (83), 216 (13), 243 (11), 258 (63), 259 (12),
276 (Mþ, 17).
14b: pale-yellow oil; IR (CHCl3) 3689.9 (OH) cm-1; MS m/e
(rel intensity) 207 (38), 245 (100), 246 (21), 260 (14), 272 (15), 273
(12), 285 (37), 286 (10), 328 (32), 346 (Mþ, 17).
15a: pale-yellow oil; MS m/e (rel intensity) 91 (10), 137 (18), 160
(12), 175 (100), 176 (13), 190 (19), 215 (60), 216 (11), 258 (Mþ, 67).
15b: purified by silica gel chromatography, eluting with 97:3
petroleum ether/diethyl ether; colorless oil; 1H NMR (400 MHz;
CDCl3) δ 0.73 (t, 3H, J=6.9 Hz,-CH3), 0.92 (s, 3H, 6-CH3), 1.16
(m, 4H, -CH2-CH2-), 1.21 (s, 3H, 6-CH3), 1.42 (m, 2H,
-CH2-), 1.53 (s, 3H, 9-CH3), 1.58-1.73 (m, 3H, H-7R, H-7β,
H-10R), 1.93-2.02 (m, 1H, H-10β), 2.34 (t, 2H, J = 8. 2 Hz,
-CH2-), 2.49 (ddd, 1H, J=11.2, 11.0, 4.7 Hz, H-6a), 2.99 (dd
broad, 1H, J=16.8, 3.7 Hz, H-10a), 3.64 (s, 3H, OCH3), 5.25 (s,
1H, H-8), 6.09 (s, 1H, H-2), 6.15 (s, 1H, H-4); 13C NMR
(400 MHz, CDCl3) δ 14.0, 18.4, 22.6, 23.5, 27.6, 28.0, 30.8,
31.6, 31.8, 36.0, 36.2, 45.1, 55.1, 76.4, 103.0, 110.2, 111.9, 119.2,
135.0, 142.5, 154.3, 158.9; MS m/e (rel intensity) 43 (7), 91 (7),
174 (7), 188 (10), 207 (30), 215 (12), 245 (100), 272 (46), 273 (21),
285 (42), 286 (15), 328 (Mþ, 97). Anal. Calcd for C22H32O2: C,
80.44; H, 9.82. Found: C, 80.57; H, 9.76.
Δ8-trans-THC (2): purified by silica gel chromatography, elut-
ing with 95:5 petroleum ether/diethyl ether; colorless oil; IR
(CHCl3) 3597.6 (OH) cm-1; 1H NMR (400 MHz; CDCl3) δ 0.73
(t, 3H, J=7.1 Hz, -CH3), 0.95 (s, 3H, 6-CH3), 1.10-1.20 (m, 4H,
-CH2-CH2-), 1.22 (s, 3H, 6-CH3), 1.38 (m, 2H, -CH2-), 1.54
(s, 3H, 9-CH3), 1.60-1.75 (m, 3H, H-10R, H-7β, H-7R), 1.99 (m,
1H, H-10β), 2.28 (m, 2H, -CH2-), 2.54 (ddd, 1H, J=10.8, 10.8,
4.7 Hz, H-6a), 3.04 (dd, 1H, J=16.2, 4.6 Hz, H-10a), 4.68 (s, 1H,
OH), 5.27 (s, 1H, H-8), 5.94 (s, 1H, H-2), 6.12 (s, 1H, H-4); 13C
NMR (400 MHz, CDCl3) δ 14.0, 18.5, 22.5, 23.5, 27.5, 27.9, 30.6,
31.3, 31.5, 35.4, 36.0, 44.9, 76.7, 107.6, 110.1, 110.5, 119.3, 134.7,
142.7, 154.7, 154.8; MS m/e(rel intensity) 119 (6), 174 (13), 193 (20),
201 (12), 231 (100), 232 (19), 246 (16), 258 (41), 259 (15), 271 (36),
272 (14), 314 (Mþ, 72). Anal. Calcd for C21H30O2: C, 80.21; H, 9.62.
Found: C, 80.33; H, 9.54.
Hydrolysis of the SAMP-Hydrazones (S,R,R)-(þ)-17 and (S,
S,S)-(þ)-1713 and Synthesis of (R,R)-(-)- and (S,S)-(þ)-Δ8-
THCs (2). An aqueous saturated solution of oxalic acid (0.6
mL) was added to a solution of (S,R,R)-(þ)-17 (0.124 g, 0.27
mmol) in diethyl ether (3.96 mL). The resulting mixture was
vigorously stirred for 4 days at room temperature. Then, the
reaction mixture was diluted with Et2O, washed with saturated
aq NaHCO3, and dried (Na2SO4). Evaporation of the solvent
under vacuum gave a residue that was purified by column
chromatography over silica gel. Elution with 9:1 petroleum
ether/diethyl ether afforded 93 mg (75%) of pure (R,R)-(-)-
6ey; [R]D -23 (c 1.34, CHCl3).
7a: purified by silica gel chromatography, eluting with 95:5
petroleum ether/diethyl ether; colorless oil; 1H NMR (400 MHz;
CDCl3) δ 0.95 (s, 3H, 6-CH3), 1.23 (s, 3H, 6-CH3), 1.55 (s, 3H,
9-CH3), 1.60-1.75 (m, 3H, H-10R, H-7β, H-7R), 1.99 (m,1H,
H-10β), 2.57 (ddd, 1H, J = 11.1, 11.1, 4.7 Hz, H-6a), 3.06 (dd,
1H, J=16.4, 4.3 Hz, H-10a), 4.63 (s, 1H, OH), 5.28 (s, 1H, H-8),
6.10 (d, 1H, J=8.0 Hz, H-2), 6.27 (d, 1H, J=8.0 Hz, H-4), 6.78
(t, 1H, J = 8.0 Hz, H-3); 13C NMR (400 MHz, CDCl3) δ 18.4,
23.5, 27.5, 27.9, 31.7, 35.9, 44.9, 76.7, 107.2, 110.4, 113.3, 119.3,
127.3, 134.7, 155.0, 152.2; MS m/e (rel intensity) 77 (13), 91 (13),
107 (12), 115 (12), 123 (23), 147 (12), 161 (100), 162 (20), 165 (10),
173 (12), 175 (15), 176 (35), 187 (12), 201 (100), 202 (19), 229 (21),
244 (Mþ, 100). Anal. Calcd for C16H20O2: C, 78.65; H, 8.25.
Found: C, 78.81; H, 8.32.
By using the procedure described above, hydrolysis of (S,S,
S)-(þ)-17 (0.102 g, 0.22 mmol) gave pure ketone (S,S)-(þ)-6ey in
65% yield; [R]D þ22 (c 0.6, CHCl3).
The procedure described for the synthesis ofracemic Δ8-THC2
(vide supra) was repeated with enantiomerical pure cyloadducts
(R,R)-(-)-6ey and (S,S)-(þ)-6ey to afford the (R,R)-(-)-Δ8-
THC 2 ([R]D -245 (c 0.78, CHCl3)) and (S,S)-(þ)-Δ8-THC 2
([R]D þ240 (c 0.94, CHCl3)), respectively, through the intermedi-
ates (R,R)-(-)-13b ([R]D -13 (c 1.28, CHCl3)) and (S,S)-(þ)-13b
([R]D þ15(c 0.78, CHCl3)), and(R,R)-(-)-15b ([R]D -178 (c 0.65,
CHCl3)) and (S,S)-(þ)-15b ([R]D þ178 (c 0.545, CHCl3)).
SAMP-Hydrazones (S,R,R)-(þ)-17 and (S,S,S)-(þ)-17.13
A
few crystals of p-TsOH were added to a solution of rac-6ey
(0.145 g, 0.42 mmol) and SAMP [S-(-)-16] (0.12 mL, 0.86 mmol)
in 0.9 mL of heptane and then heated at 100 °C for 47 h. After
cooling at room temperature, the reaction was diluted with
Et2O, washed with saturated aq NaHCO3, and dried (Na2SO4).
Evaporation of the solvent under vacuum gave a 1:1 mixture of
two diastereoisomeric hydrazones 17, which was chromato-
graphed on silica gel (9:1 petroleum ether/diethyl ether) to give
diastereomerically pure (S,S,S)-(þ)-17 and (S,R,R)-(þ)-17 in
40% and 37% yields, respectively.
Acknowledgment. The authors thank the Fondazione
Cassa Risparmio Perugia and the Ministero dell’Istruzione
ꢀ
dell’Universita e della Ricerca (MIUR) for financial support.
Supporting Information Available: General experimental
procedures and analytical data for all new compounds, as well as
1H and 13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(S,R,R)-(þ)-17: pale-yellow oil; [R]D þ73 (c 1.99, CHCl3); IR
(CHCl3) 1608 (CdN) cm-1; 1H NMR (400 MHz; CDCl3) δ 0.73
4260 J. Org. Chem. Vol. 75, No. 12, 2010