Oxaza adamantyl cannabinoids. A new class of cannabinoid receptor probes

Article abstract of DOI:10.1021/jo061352c

(Chemical Equation Presented) The preparation of C3 oxaza adamantyl cannabinoids has been described starting from phloroglucinol. Straightforward manipulations of the aromatic ring lead to a bromononaflate that is a benzyne precursor and that serves as a common intermediate for the synthesis of diverse C3-substituted tricyclic cannabinoids. Generation of the benzyne in the presence of an oxaza adamantyl amide anion results in efficient and regiospecific addition to C3 of the aromatic ring. This represents an attractive strategy for the synthesis of classical tricyclic cannabinoids that bear a modified aromatic appendage. The oxaza adamantyl cannabinoids that have been prepared represent a new class of ligands for the CB1 and CB2 receptors.

Full text of DOI:10.1021/jo061352c

Oxaza Adamantyl Cannabinoids. A New Class of Cannabinoid
Receptor Probes
David Le Goanvic and Marcus A. Tius*
UniVersity of Hawaii, Chemistry Department, Honolulu, Hawaii 96822, and The Cancer Research Center
of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813
tius@gold.chem.hawaii.edu
ReceiVed June 29, 2006
The preparation of C3 oxaza adamantyl cannabinoids has been described starting from phloroglucinol.
Straightforward manipulations of the aromatic ring lead to a bromononaflate that is a benzyne precursor
and that serves as a common intermediate for the synthesis of diverse C3-substituted tricyclic cannabinoids.
Generation of the benzyne in the presence of an oxaza adamantyl amide anion results in efficient and
regiospecific addition to C3 of the aromatic ring. This represents an attractive strategy for the synthesis
of classical tricyclic cannabinoids that bear a modified aromatic appendage. The oxaza adamantyl
cannabinoids that have been prepared represent a new class of ligands for the CB1 and CB2 receptors.
Introduction
It has long been known that the aliphatic side chain is
important for determining the cannabinergic potency of classical
tricyclic cannabinoids and also that the presence of a tert-alkyl
The discovery of the two cannabinoid receptors, CB11,2 and
CB2,3 ushered in a new era in research into the chemistry and
the pharmacology of this class of compounds. Both receptors
are membrane-bound and belong to the family of G-protein-
coupled receptors (GPCRs). The structural analysis of CB1 and
CB2 as well as the study of their interactions with their ligands
are hampered by the lack of a crystal structure. Consequently,
there is little direct evidence for the mode(s) of interaction
between the ligand and receptor.4 The recognition of CB1 as
an important therapeutic target for, inter alia, glaucoma,5 pain,6
and appetite modulation7 indicates a need for a better under-
standing of the specific interactions between the cannabinoid
pharmacophore and the key amino acids associated with the
CB1 binding site.
(4) For leading references, see: (a) Huffman, J. W.; Miller, J. R. A.;
Liddle, J.; Yu, S.; Thomas, B. F.; Wiley, J. L.; Martin, B. R. Bioorg. Med.
Chem. 2003, 11, 1397-1410. (b) Papahatjis, D. P.; Nikas, S. P.; Kourouli,
T.; Chari, R.; Xu, W.; Pertwee, R. G.; Makriyannis, A. J. Med. Chem. 2003,
46, 3221-3229. (c) Papahatjis, D. P.; Nikas, S. P.; Andreou, T.; Makriy-
annis, A. Bioorg. Med. Chem. Lett. 2002, 12, 3583-3586. (d) Khanolkar,
A. D.; Lu, D.; Fan, P.; Tian, X.; Makriyannis, A. Bioorg. Med. Chem. Lett.
1999, 9, 2119-2124. (e) Huffman, J. W.; Liddle, J.; Duncan, S. G., Jr.;
Yu, S.; Martin, B. R.; Wiley, J. L. Bioorg. Med. Chem. 1998, 6, 2383-
2396. (f) Papahatjis, D. P.; Kourouli, T.; Abadji, V.; Goutopoulos, A.;
Makriyannis, A. J. Med. Chem. 1998, 41, 1195-1200. (g) Busch-Petersen,
J.; Hill, W. A.; Fan, P.; Khanolkar, A.; Xie, X.-Q.; Tius, M. A.; Makriyannis,
A. J. Med. Chem. 1996, 39, 3790-3796.
(5) (a) Roesch, S.; Ramer, R.; Brune, K.; Hinz, B. J. Pharm. Exp. Ther.
2006, 316, 1219-1228. (b) Jarvinen, T.; Pate, D. W.; Laine, K. Pharmacol.
Ther. 2002, 95, 203-220.
(1) Devane, W. A.; Dysarz, F. A., III.; Johnson, M. R.; Melvin, L. S.;
Howlett, A. C. Mol. Pharmacol. 1988, 34, 605-613.
(2) Matsuda, L. A.; Lolait, S. J.; Brownstein, M. J.; Young, A. C.; Bonner,
T. I. Nature (London) 1990, 346, 561-564.
(3) Munro, S.; Thomas, K. L.; Abu-Shaar, M. Nature (London) 1993,
365, 61-65.
(6) (a) Huang, S. M.; Walker, J. M. In Cannabinoids as Therapeutics;
Mechoulam, R., Ed.; Birkha¨user Verlag: Basel, 2005; p 149. (b) Smith, P.
F. Curr. Opin. InVest. Drugs 2002, 3, 859-864.
(7) (a) Barth, F.; Rinaldi-Carmona, M. In Cannabinoids as Therapeutics;
Mechoulam, R., Ed.; Birkha¨user Verlag: Basel, 2005; p 219. (b) Koch, J.
E. Pharmacol., Biochem. BehaV. 2001, 68, 539-543.
10.1021/jo061352c CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/29/2006
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J. Org. Chem. 2006, 71, 7800-7804

Oxaza Adamantyl Cannabinoids
of the condensation product.14 Although we wanted to retain
the advantages of this route, an ancillary goal was the synthesis
of an advanced tricyclic intermediate that could be used to
prepare a variety of C3-substituted cannabinoids. With this in
mind, we condensed diacetates 4 and 5 with phloroglucinol 6.
Whereas condensation of 4 and 5 with resorcinol 7 proceeds in
70% yield, the corresponding process with 6 was more chal-
lenging, in large part because of the insolubility of 6 in
dichloromethane or chloroform, the preferred solvents for this
reaction. After considerable experimentation, we found that
exposure of a mixture of 4, 5, and 6 in dichloromethane/acetone
(4/1, v/v) in the presence of a small excess of p-toluenesulfonic
acid at room temperature for 20 min led to the desired
condensation product 8 in 40% yield. The conversion of 8 to
tricyclic cannabinoid 9 was straightforward and took place in
84% yield upon exposure of 8 to SnCl4 in nitromethane.
FIGURE 1. Adamantyl and heteroadamantyl cannabinoids.
appendage at C1′ potentiates receptor binding affinity.8 Nev-
ertheless, it was surprising that cannabinoids bearing a pendant
adamantyl group at C3 in place of the n-pentyl group that is
found in the naturally occurring materials, such as 1 (AM744),
were tolerated in both the CB1 and CB2 binding sites.9
Furthermore, considerable receptor subtype selectivity was
observed, depending on the relative orientation of the adamantyl
group with respect to the tricyclic nucleus.9 The ability of the
receptor to accommodate the steric bulk of the 1-adamantyl
group revealed an unanticipated flexibility and furthermore
suggested that introducing heteroatomic functionality on the
adamantane structure could be used to interrogate the receptor.
Changes in binding affinities of cannabinoids bearing substituted
adamantyl residues might indicate the close proximity of polar
amino acid residues within the binding pocket. The synthesis
of oxaza adamantane 17 has been reported;10,11 therefore, oxaza
adamantyl cannabinoids 2 and 3 (Figure 1) were designed and
prepared as the first ligands with which to test this concept.
Because the northern aliphatic hydroxyl group is known to be
an important pharmacophore, the C9 hydroxyl was incorporated
into the structures of 2 and 3.
We assumed that the two phenolic hydroxyl groups at C1
and C3 in 9 could be easily distinguished and that selective
functionalization of the more accessible hydroxyl group at C3
would be possible. Our strategy was to first actiVate the C3
hydroxyl toward nucleophilic displacement by nitrogen and then
protect the C1 hydroxyl. We chose to convert the C3 phenol to
the corresponding nonaflate (Nf ) SO2C4F9). The aryl nonaflates
are attractive alternatives to the triflate. They are readily prepared
and are more stable toward chromatography or hydrolytic
cleavage than the corresponding triflates.15 The best conditions
for the conversion of 9 to nonaflate 11 have been described by
Zhu.16 Treatment of 9 with 4-nitrophenylnonaflate 10 in DMF
with CsF at room temperature led to monononaflate 11 in 57%
yield. The regiochemical outcome of this reaction was deter-
mined by converting 11 to the phenolic acetate and observing
an nOe correlation between the axial C10 proton and the acetate
methyl group.
Results and Discussion
One of the most attractive approaches to the synthesis of the
tricyclic cannabinoid structure is according to the Lilly synthesis
of nabilone, whereby a resorcinol is combined with a mixture
of diacetates 4 and 5 (see Scheme 1) under acid catalysis.12
The diacetates are easily derived in two steps from nopinone,
the product of ozonolytic cleavage of â-pinene.13 Minor
modifications to this strategy have led to improved overall yields
Our initial plan had been to use a palladium-catalyzed
amination process to form the aryl-nitrogen bond.17 Although
we were successful in coupling the O-benzyl ether derivative
of 11 with morpholine, our best efforts produced only 15% of
the adduct with oxaza adamantane 17. Fortunately we were able
to apply an alternative strategy that promises to be general for
the introduction of nitrogen as well as carbon nucleophiles.
The elegant work of Suzuki and co-workers has demonstrated
a general approach to the synthesis of substituted benzynes that
is summarized in eq 1.18 Lithium-halogen exchange in 21 leads
to elimination of triflate with formation of methoxybenzyne 22.
When this process was carried out in the presence of ketene
acetal 23, [2+2] cycloaddition took place to produce benzocy-
clobutane 24 in excellent yield. It is noteworthy that this reaction
is general and that it produces a single regioisomer of the
product. The regioselectivity has been rationalized in terms of
(8) (a) Adams, R. HarVey Lect. 1942, 37, 168-197. (b) Adams, R.;
Harfenist, M.; Loewe, S. J. Am. Chem. Soc. 1949, 71, 1624-1628.
(9) Lu, D.; Meng, Z.; Thakur, G. A.; Fan, P.; Steed, J.; Tartal, C. L.;
Hurst, D. P.; Reggio, P. H.; Deschamps, J. R.; Parrish, D. A.; George, C.;
Ja¨rbe, T. U. C.; Lamb, R. J.; Makriyannis, A. J. Med. Chem. 2005, 48,
4576-4585. See also: (a) McLaughlin, P. J.; Lu, D.; Winston, K. M.;
Thakur, G.; Swezey, A.; Makriyannis, A.; Salamone, J. D. Pharmacol.,
Biochem. BehaV. 2005, 81, 78-88. (b) Ja¨rbe, T. U. C.; DiPatrizio, N. V.;
Lu, D.; Makriyannis, A. BehaV. Pharmacol. 2004, 15, 517-521.
(10) (a) Stetter, H.; Heckel, K. Tetrahedron Lett. 1972, 9, 801-804. (b)
Stetter, H.; Heckel, K. Chem. Ber. 1973, 106, 339-348.
(11) (a) Portmann, R. E.; Ganter, C. HelV. Chem. Acta 1973, 56, 1962-
1985. (b) Ganter, C.; Portmann, R. E. HelV. Chem. Acta 1971, 54, 2069-
2077.
(12) Archer, R. A.; Blanchard, W. B.; Day, W. A.; Johnson, D. W.;
Lavagnino, E. R.; Ryan, C. W.; Baldwin, J. E. J. Org. Chem. 1977, 42,
2277-2284.
(13) See: Boger, D. L.; Mullican, M. D.; Hellberg, M. R.; Patel, M. J.
Org. Chem. 1985, 50, 1904-1911. Caution! As is the case for all
ozonolyses, one must be fastidious in destroying all traces of ozonide before
concentrating the product. The ozonolysis of â-pinene has resulted in at
least one serious accident that was reported in the August 6, 1990, issue of
Chemical & Engineering News. It is often the case that the reductive
decomposition of ozonides is a relatively slow process when Me2S is used
as the reducing agent, as was the case in the laboratory that reported the
accident in 1990. We routinely use thiourea for ozonide decomposition and
have experienced no problems with this reaction. The use of thiourea for
ozonolysis workups has been described: Gupta, D.; Soman, R.; Dev, S.
Tetrahedron 1982, 38, 3013-3018.
(14) Drake, D. J.; Jensen, R. S.; Busch-Petersen, J.; Kawakami, J. K.;
Conception Fernandez-Garcia, M.; Fan, P.; Makriyannis, A.; Tius, M. A.
J. Med. Chem. 1998, 41, 3596-3608.
(15) Zhang, X.; Sui, Z. Tetrahedron Lett. 2003, 44, 3071-3073.
(16) Neuville, L.; Bigot, A.; Tran Huu Dau, M. E.; Zhu, J. J. Org. Chem.
1999, 64, 7638-7642.
(17) Buchwald has reported palladium-catalyzed aminations of aryl
nonaflates: Anderson, K. W.; Mendez-Perez, M.; Priego, J.; Buchwald, S.
J. Org. Chem. 2003, 68, 9563-9573.
J. Org. Chem, Vol. 71, No. 20, 2006 7801

Goanvic and Tius
SCHEME 1a
a (a) p-TsOH, CH2Cl2/acetone (4/1), rt, 20 min; 40%. (b) SnCl4, MeNO2, rt, 20 h; 84%. (c) CsF, 10, DMF, rt, 12 h; 57%. (d) 2,4,4,6-
Tetrabromocyclohexadienone, CHCl3/p-dioxane 0 °C to room temperature, overnight; 58%. (e) NaBH4, THF/i-PrOH, rt, 40 min; 77% 13 + trace 14. (f)
K-Selectride, THF, -78 °C to room temperature, 3 h; 63%. (g) MeOCH2Cl, (i-Pr)2NEt, CH2Cl2, 0 °C to room temperature, 5 h; 15, 74%; 16, 82%. (h) 17,
n-BuLi, THF, -78 °C, 20 min; 19, 72%; 20, 72%. (i) TMSBr, CH2Cl2, -40 °C, 3 h; 2, 66%; 3, 64%.
the polarization of the triple bond and suggests that for
electronic, as well as steric, reasons the addition of 17 (as its
conjugate base) to benzyne 18 (Scheme 1) will lead to the
desired C3-substituted cannabinoid.19
â (equatorial) alcohol 13 in 77% yield, accompanied by a trace
of the C9 R (axial) diastereomer 14. Alcohol 14 was the
exclusive product when 12 was reduced with K-Selectride at
-78 °C. The two diastereomers were readily distinguishable
on the basis of the C9 carbinol proton NMR chemical shift and
multiplicity. In 13, the C9 proton appears as a multiplet at 3.79-
3.88 ppm (CDCl3, 300 MHz), which is consistent with an axial
proton. In 14, the proton at C9 appears as a broad singlet at
4.28 ppm, as is consistent for an equatorial proton.
Both hydroxyl groups in 13 and 14 were protected simulta-
neously as the methoxymethyl ether derivatives, leading to 15
(74% yield) and 16 (82% yield), respectively. The key reaction,
benzyne generation, followed by addition of the conjugate base
of 17, was carried out by treating a solution of 15 and 2.4 equiv
of 17 in THF with 4.8 equiv of n-BuLi at -78 °C. The reaction
was rapid and clean and led to 19 in 72% yield. The process
was repeated with 16, leading to 20 in 72% yield as well. It is
noteworthy that if any addition of n-BuLi to the benzyne takes
place it represents a minor side reaction. The deprotonation of
17 to produce the amide must be faster than lithium-bromine
exchange because no quenching of benzyne by proton transfer
was observed. An excess of 17 was used in these reactions;
however, the unreacted amine was recovered and reused. The
benzynes that are generated from 15 and 16 represent versatile
reactive intermediates that should be suitable for the synthesis
of diverse tricyclic cannabinoids.
Tricyclic nonaflate 11 (Scheme 1) was brominated according
to the conditions described by Trost and Toste to produce
bromide 12 in 58% yield.20 The conditions for this reaction must
be chosen carefully so as to avoid introducing multiple bromine
atoms into the highly activated aromatic. Because it was our
goal to produce both diastereomers of the C9 alcohol, the
carbonyl group in 12 was first reduced with NaBH4 to give C9
(18) (a) Hamura, T.; Hosoya, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe,
M.; Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. HelV. Chim. Acta
2002, 85, 3589-3604. (b) Hamura, T.; Ibusuki, Y.; Uekusa, H.; Matsumoto,
T.; Suzuki, K. J. Am. Chem. Soc. 2006, 128, 3534-3535. (c) Hosoya, T.;
Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki, K. Synlett 1995, 2,
177-179. For related work, see: Liu, Z.; Larock, R. C. J. Org. Chem.
2006, 71, 3198-3209.
(19) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Suzuki, K. Tetrahedron
Lett. 1995, 36, 3377-3380.
(20) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090-
3100.
7802 J. Org. Chem., Vol. 71, No. 20, 2006

Oxaza Adamantyl Cannabinoids
SCHEME 2a
a (a) Pd/C, HOAc, H2, rt, 3 days; HCl, H2O. (b) TsCl, Na2CO3, H2O/CH2Cl2 (1/1), rt, 12 h; 79% from 25. (c) LiAlH4, Et2O, rt, 4 h; 93%. (d) PhI(OAc)2,
I2, hυ, C6H12, 50 °C, 1 h; 50% + ca. 20% of 26. (e) Na, naphthalene, DME, -50 °C, 10 min; 48%.
The last step of the synthesis, removal of the two methoxy-
methyl protecting groups from 19 and 20, proved to be
unexpectedly difficult. For example, exposure of either 19 or
20 to conventional deprotection protocols (HCl, PPTS) led to
aminodiol products in less than 50% yield in slow reactions.
The reason for this is not obvious but may be related to the
buffering effect of the nitrogen atom. Protecting group removal
was accomplished successfully according to Hanessian’s pro-
cedure,21 by treating 19 and 20 with TMSBr in dichloromethane
at -40 °C for 3 h. The yields of 2 and 3 were 66% and 64%,
respectively.
The synthesis of oxaza adamantane 17 deserves some
comment. A synthesis of 17 has been described by Stetter10
and co-workers in six steps from 1,5-cyclooctadiene, in which
the oxa bridge was installed through a bis bromoetherification
process. A similar synthesis of 17 has been described by
Portmann, in which the oxa bridge was introduced through a
bis oxymercuration process.11 Because both syntheses com-
mence with 1,5-cyclooctadiene and lead to mixtures of bicyclo
[3.3.1] and bicyclo [4.2.1] isomers, we were motivated to
develop the synthesis of 17 that is summarized in Scheme 2.
Aminoketone 25 has been prepared by Momose and co-
workers in a single step in 78% yield from benzylamine
hydrochloride, acetone dicarboxylic acid, and glutaraldehyde.22
Hydrogenolytic cleavage of the benzyl protecting group, fol-
lowed by N-tosylation, led to tosylate 26 in 79% yield. Ketone
reduction gave alcohol 27 in 93% yield. Oxidative closure of
the pyran ring was accomplished photochemically in the
presence of PhI(OAc)2 and iodine according to Marchand and
co-workers’ procedure in 50% yield.23 The N-benzyl protecting
group was not compatible with the conditions for the oxidative
cyclization, hence the need for the N-tosylate. Reductive
cleavage of the tosylate led to 17.24
that regiospecificity is likely to be observed regardless of the
steric requirement of the substituent because of the electronic
bias for C3 attack on the benzyne referred to above. In this
context, it is worth noting that steric steering by the tert-alkyl
substituent in resorcinol 7 determines the regiospecificity during
acid-catalyzed condensation with acetates 4 and 5. Absent the
tert-alkyl group on the aromatic fragment, this approach cannot
be applied because mixtures of regioisomeric condensation
products are invariably formed. In the approach that has been
described above, the symmetry of the phloroglucinol renders
the issue moot during the condensation with 4 and 5. This allows
us to retain the attractive features of the Lilly synthesis of
nabilone without the requirement for a sterically bulky sub-
stituent on the aromatic ring. This method is currently being
applied to the synthesis of a series of heteroadamantyl cannab-
inoids related to 2 and 3. The syntheses of these materials and
their binding affinities to CB1 and CB2 for the series will be
reported in future publications.
Experimental Section
(1R,4R,5R)-6,6-Dimethyl-4-(2,4,6-trihydroxyphenyl)bicyclo-
[3.1.1]heptan-2-one 8. To a solution of phloroglucinol (500 mg,
3.97 mmol) and diacetates 4 and 5 (1.15 g, 4.76 mmol) in CH2-
Cl2/acetone (4/1) at 0 °C was added TsOH (820 mg, 4.76 mmol).
The resulting mixture was stirred at room temperature for 20 min
and then quenched with aqueous NaHCO3 solution. The organic
phase was extracted with EtOAc. The combined organic extracts
were washed with brine, dried (Na2SO4), and evaporated to dryness.
Purification of the crude reaction mixture by flash column chro-
matography on silica gel (eluent: EtOAc/Hexane 3/7) afforded
product 8 (416 mg, 40% yield) as a white powder: mp 110-120
°C; Rf ) 0.29 (60% EtOAc in hexanes); [R]25 +54.3 (c 3.55,
D
1
MeOH); H NMR (300 MHz, CD3OD) δ 0.94 (s, 3H), 1.35 (s,
3H), 2.14 (t, J ) 6.0 Hz, 1H), 2.35-2.48 (m, 3H), 2.57-2.62 (m,
1H), 3.67 (dd, J ) 7.5, 18.6 Hz, 1H), 3.95 (t, J ) 8.1 Hz, 1H),
5.85 (s, 2H); 13C NMR (75 MHz, CD3OD) δ 22.4, 24.9, 26.6, 30.0,
38.8, 43.2, 48.8, 59.3, 95.9, 108.9, 157.3, 158.5, 220.2; IR (neat)
2929, 1655, 1612, 1467, 1373, 1265, 1156, 1014 cm-1; mass
spectrum (EI) m/z 262 (56), 219 (32), 179 (57), 177 (37), 165 (85),
152 (100), 139 (79), 126 (88), 93 (40), 83 (100), 77 (36), 69 (63);
exact mass calculated for C15H18O4 262.1200, found 262.1231.
(6aR,10aR)-1,3-Dihydroxy-6,6-dimethyl-7,8,10,10a-tetrahydro-
6H-benzo[c]chromen-9(6aH)-one 9. To a solution of 8 (100 mg,
0.38 mmol) in nitromethane (10 mL) was added SnCl4 (375 µL,
3.2 mmol). The resulting mixture was stirred at room temperature
for 20 h and then poured onto ice and extracted with Et2O. The
organic extracts were combined, washed with 1 M HCl solution,
water, and aqueous NaHCO3 solution, dried (Na2SO4), and evapo-
rated to dryness. Purification of the crude reaction mixture by flash
column chromatography on silica gel (eluent: EtOAc/Hexane 3/7)
afforded product 9 (84 mg, 84% yield) as a white powder: mp
140-150 °C; Rf ) 0.32 (50% EtOAc in hexanes); [R]25D -64.6 (c
Conclusions
In conclusion, synthesis of the first heteroadamantyl cannab-
inoids has been described. The key step is the condensation of
the oxaza adamantane with a benzyne that is derived from the
tricyclic cannabinoid nucleus. This represents a new strategy
for the regiospecific introduction of substituents at C3 that will
be generally useful for cannabinoid synthesis.25,26 It is significant
(21) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984,
25, 2515-2518. For an example of the application of this method to a
polyfunctional molecule, see: Judd, T. C.; Williams, R. M. Angew. Chem.,
Int. Ed. 2002, 41, 4683-4685.
(22) Momose, T.; Toshima, M.; Toyooka, N.; Hirai, Y.; Eugster, C. H.
J. Chem. Soc., Perkin Trans. 1 1997, 9, 1307-1313.
(23) Marchand, A. P.; Kumar, V. S.; Hariprakasha, H. K. J. Org. Chem.
2001, 66, 2072-2077.
(24) In recent work, we have determined that the yield of the reductive
cleavage step can be improved greatly by limiting the amount of water that
is used during workup, thereby minimizing losses of product.
(25) For a review of cannabinoid synthesis, see: Tius, M. A. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1997; Vol. 19, p 185.
1
0.85, MeOH); H NMR (300 MHz, CD3OD) δ 1.08 (s, 3H), 1.42
(26) For an alternative approach to the synthesis of C3 amino cannab-
inoids, see: Petrzilka, T.; Lusuardi, W. G. HelV. Chim. Acta 1973, 56, 510-
518.
J. Org. Chem, Vol. 71, No. 20, 2006 7803

Goanvic and Tius
(s, 3H), 1.45-1.57 (m, 1H), 1.92 (td, J ) 2.4, 12.3 Hz, 1H), 2.02-
2.18 (m, 2H), 2.47-2.25 (m, 2H), 2.69-2.78 (m, 1H), 3.78-3.84
(m, 1H), 5.76 (d, J ) 2.4 Hz, 1H), 5.85 (d, J ) 2.4 Hz, 1H); 13C
NMR (125 MHz, CD3OD) δ 19.0, 27.9, 28.1, 36.0, 41.5, 46.8, 77.8,
96.6, 96.7, 104.3, 111.2, 156.6, 158.3, 214.6; IR (neat) 2973, 1690,
1620, 1462, 1366, 1134, 1015 cm-1; mass spectrum (EI) m/z 262
(100), 247 (29), 205 (21), 179 (57), 152 (85), 139 (26), 126 (12),
93 (40), 77 (11), 69 (39); exact mass calculated for C15H18O4
262.1200, found 262.1185.
Benzyne Generation and Trapping. Preparation of 19. To a
solution of bromononaflate 15 (190 mg, 0.27 mmol) and oxaza
adamantane 17 (90 mg, 0.65 mmol) in 1 mL of THF at -78 °C
was added dropwise n-BuLi (550 µL, 1.3 mmol, solution in hexane).
The mixture was stirred for 20 min, quenched with H2O, and
extracted with Et2O (3×). The combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated to dryness.
Purification of the crude reaction mixture by flash column chro-
matography on silica gel (eluent: EtOAc/hexane 3/7) afforded
473 (M+, 100), 412 (M+ - OCH2CH3, 17), 367 (24), 298 (5); exact
mass calculated for C27H39NO6 473.2800, found 473.2752.
Tricyclic Cannabinoid 2. To a solution of compound 19 (71
mg, 0.15 mmol) in 1 mL of CH2Cl2 at -40 °C was added dropwise
TMSBr (2.25 mL, 0.9 mmol) in solution in CH2Cl2 in 6 aliquots
over 3 h. The mixture was stirred for 1 h at -40 °C, quenched
with H2O, and extracted with CH2Cl2 (3×). The combined organic
extracts were dried (Na2SO4) and evaporated to dryness. Purification
of the crude reaction mixture by flash column chromatography on
silica gel (eluent: EtOAc/hexane 8/2) afforded product 2 (38 mg,
66% yield) as an oil: Rf ) 0.14 (30% EtOAc in hexanes); [R]25
D
1
-84.2 (c 0.90, MeOH); H NMR (300 MHz, CD3OD) δ 0.93 (q,
J ) 11.7 Hz, 1H), 1.04 (s, 3H), 1.14-1.44 (m, 6H), 1.85-2.12
(m, 10H), 2.38 (td, J ) 2.7, 11.1 Hz, 1H), 3.44-3.50 (m, 1H),
3.68-3.77 (m, 1H), 4.02 (s br, 2H), 4.14 (s br, 2H), 5.87 (d, J )
2.4 Hz, 1H), 5.97 (d, J ) 2.4 Hz, 1H); 13C NMR (125 MHz, CD3-
OD) δ 19.2, 27.2, 28.3, 34.2, 34.7, 36.7, 40.4, 49.1, 50.4, 68.8,
71.4, 77.8, 96.5, 96.8, 104.3, 150.4, 157.1, 158.6; IR (neat) 2935,
1621, 1569, 1515, 1440, 1333, 1189, 1139, 1053 cm-1; mass
spectrum (EI) m/z 385 (M+, 100), 367 (M+ - H2O, 42), 348 (152),
326 (17), 298 (23), 260 (6); exact mass calculated for C23H31NO4
385.2300, found 385.2225.
product 19 (89 mg, 72% yield) as an oil: Rf ) 0.23 (30% EtOAc
1
in hexanes); [R]25 -23.7 (c 0.56, CHCl3); H NMR (300 MHz,
D
CD3OD) δ 0.94 (s, 3H), 1.05-1.20 (m, 2H), 1.25 (s, 3H), 1.28-
1.38 (m, 1H), 1.80-1.85 (dm, 4H), 1.90-1.95 (dm, 4H), 2.06 (dm,
1H), 2.28-2.36 (td, J ) 2.7, 11.4 Hz, 1H), 3.27 (s, 3H), 3.29-
3.35 (m, 1H), 3.38 (s, 3H), 3.57 (m, 1H), 3.96 (s br, 2H), 4.05 (s
br, 2H), 4.62 (s, 2H), 5.02 (d, J ) 6.6 Hz, 1H), 5.07 (d, J ) 6.9
Hz, 1H), 5.92 (d, J ) 2.4 Hz, 1H), 6.18 (d, J ) 2.7 Hz, 1H); 13C
NMR (125 MHz, CD3OD) δ 19.1, 27.2, 28.2, 34.2, 34.3, 34.4, 34.9,
38.5, 50.4, 55.5, 56.6, 68.8, 77.4, 77.8, 95.9, 96.0, 96.3, 98.9, 106.1,
150.7, 156.8, 159.0; IR (neat) 2939, 1615, 1564, 1496, 1151, 1107,
1054, 1026 cm-1; mass spectrum (EI) m/z 473 (M+, 100), 412 (M+
- OCH2CH3, 9), 205 (6), 152 (28); exact mass calculated for
C27H39NO6 473.2800, found 473.2776.
Tricyclic Cannabinoid 3. To a solution of compound 20 (32.6
mg, 0.07 mmol) in 1 mL of CH2Cl2 at -40 °C was added dropwise
TMSBr (1.05 mL, 0.42 mmol) in solution in CH2Cl2 in 6 aliquots
over 3 h. The mixture was stirred for 1 h at -40 °C, quenched
with H2O, and extracted with CH2Cl2 (3×). The combined organic
extracts were dried (Na2SO4) and evaporated to dryness. Purification
of the crude reaction mixture by flash column chromatography on
silica gel (eluent: EtOAc/hexane 8/2) afforded product 3 (17 mg,
64% yield) as an oil: Rf ) 0.20 (30% EtOAc in hexanes); [R]25
D
1
-42.3 (c 0.93, MeOH); H NMR (300 MHz, CD3OD) δ 1.08 (s,
Benzyne Generation and Trapping. Preparation of 20. To a
solution of bromononaflate 15 (126 mg, 0.18 mmol) and oxaza
adamantane 17 (61 mg, 0.44 mmol) in 1 mL of THF at -78 °C
was added dropwise n-BuLi (370 µL, 0.9 mmol, solution in hexane).
The mixture was stirred for 20 min, quenched with H2O, and
extracted with Et2O (3×). The combined organic extracts were
washed with brine, dried (Na2SO4), and evaporated to dryness.
Purification of the crude reaction mixture by flash column chro-
matography on silica gel (eluent: EtOAc/hexane 3/7) afforded
product 20 (60 mg, 72% yield) as a solid: mp 104-106 °C; Rf )
0.26 (30% EtOAc in hexanes); [R]25D -65.4 (c 1, CHCl3); 1H NMR
(300 MHz, CD3OD) δ 1.06 (s, 3H), 1.09-1.18 (m, 1H), 1.34 (s,
3H), 1.40-1.70 (m, 5H), 1.90-2.04 (m, 8H), 2.78-2.84 (m, 1H),
3.29-3.35 (m, 1H), 3.42 (s, 3H), 3.47 (s, 3H), 3.98 (m, 1H), 4.05
(s br, 2H), 4.15 (s br, 2H), 4.70 (d, J ) 6.9 Hz, 1H), 4.81 (d, J )
6.9 Hz, 1H), 5.11-5.17 (m, 2H), 6.01 (d, J ) 2.4 Hz, 1H), 6.27
(d, J ) 2.4 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 19.3, 24.3,
28.0, 30.6, 32.5, 34.2, 34.3, 35.9, 50.8, 55.6, 56.5, 68.8, 72.7, 77.8,
95.4, 95.9, 96.3, 98.9, 106.7, 150.5, 157.0, 159.0; IR (neat) 2939,
1616, 1563, 1497, 1148, 1109, 1039 cm-1; mass spectrum (EI) m/z
3H), 1.13-1.22 (m, 1H), 1.29-1.66 (m, 9H), 1.90-2.03 (m, 8H),
2.87 (td, J ) 2.7, 11.4 Hz, 1H), 3.30-3.37 (m, 1H), 4.02 (s br,
2H), 4.14 (s br, 2H), 5.87 (m, 1H), 5.96 (m, 1H); 13C NMR (125
MHz, CD3OD) δ 19.4, 23.6, 28.1, 30.9, 34.2, 38.0, 51.0, 67.6, 68.8,
77.7, 96.6, 96.9, 104.9, 150.2, 157.2, 158.6; IR (neat) 2938, 1621,
1568, 1514, 1440, 1334, 1189, 1138, 1064 cm-1; mass spectrum
(EI) m/z 385 (M+, 100), 367 (M+ - H2O, 72), 348 (22), 298 (38),
247 (6), 205 (19); exact mass calculated for C23H31NO4 385.2300,
found 385.2248.
Acknowledgment. This work was supported by a grant from
the National Institute on Drug Abuse (DA07215). We thank
Professor Alexandros Makriyannis for useful discussions and
for providing guidance in the cannabinoid ligand design.
Supporting Information Available: Spectroscopic data (1H and
13C NMR) for 2, 3, 8, 9, 11-16, 19, 20, 27, and 28. Experimental
conditions for the synthesis of 11-17 and 26-28. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO061352C
7804 J. Org. Chem., Vol. 71, No. 20, 2006