Synthesis and characterization of 2-substituted bornane pharmacophores for novel cannabinergic ligands

Article abstract of DOI:10.1016/j.tetlet.2008.07.029

Analogously to the fenchyl and adamantyl groups, the bornyl and epimeric isobornyl groups are compact lipophilic substituents that can be incorporated into drug design to improve pharmacological or physicochemical properties. Methods are reported for the

Full text of DOI:10.1016/j.tetlet.2008.07.029

Tetrahedron Letters 49 (2008) 5587–5589
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of 2-substituted bornane pharmacophores
for novel cannabinergic ligands
*
Richard I. Duclos Jr., Dai Lu, Jianxin Guo, Alexandros Makriyannis
Center for Drug Discovery, Northeastern University, 360 Huntington Avenue, 116 Mugar Life Sciences Building, Boston, MA 02115, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Analogously to the fenchyl and adamantyl groups, the bornyl and epimeric isobornyl groups are compact
lipophilic substituents that can be incorporated into drug design to improve pharmacological or physico-
chemical properties. Methods are reported for the synthesis and characterization of 2-substituted
norbornanes and bornanes that can serve as novel cannabinergic ligand intermediates.
Ó 2008 Published by Elsevier Ltd.
Received 8 May 2008
Revised 2 July 2008
Accepted 2 July 2008
Available online 6 July 2008
Keywords:
Norbornane
Bornyl
Isobornyl
Chiral HPLC
NMR
1. Introduction
2-substituted norbornanes and bornanes that were prepared and
characterized as intermediates in the synthesis of novel cannabi-
The pharmacological and physicochemical properties of certain
drug classes can be modified by incorporating compact lipophilic
moieties such as the fenchyl,1,2 adamantyl,3–7 and bornyl8 groups.
Examples include the CB2 inverse agonist SR1445289 as well as the
CB1 selective agonist AM411,10 a crystalline classical cannabinoid
analog with distinct pharmacological profiles.11–14 Analogously,
we have explored the incorporation of bornyl as well as the
epimeric isobornyl groups into our cannabinergic drug design to
further optimize ligand pharmacophoric properties. Here, we
report our methods for the synthesis and characterization of
noid analogs.
2. Results and discussion
The exo-2-aryl analog 3 of norbornane was conveniently pre-
pared (Scheme 1) by the same method that we described for the
preparation of 1-adamantyl analogs.10 Introduction of the norbor-
nyl group by Friedel–Crafts type alkylation of 2,6-dimethoxyphe-
nol (2) with ( )-exo-norborneol (1) in 70% methanesulfonic acid
gave the racemic exo-analog ( )-3 in three steps. However, the
7
OMe
OMe
1) 70% CH3SO3H, 80 °C
5
4
3
OH
+
OH
6
2) HP(O)(OEt)2, Et3N, CCl4,
0 °C to RT
1
2
OMe
OMe
H
H
3) Li/NH3, - 78 °C
( )-1
( )-exo-norborneol
2
( )-3
Scheme 1. Synthesis of 2-norbornane (exo) analog via Friedel–Crafts type alkylation.
Abbreviations: AM411, 3-(adamant-1-yl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol; COSY, correlation spectroscopy; NMR, nuclear magnetic
resonance; NOESY, nuclear Overhauser enhancement spectroscopy; SR144528, 5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-N-[(1S-endo)-1,3,3-trimethylbicy-
clo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide.
* Corresponding author. Tel.: +1 617 373 4200; fax: +1 617 373 7493.
E-mail address: a.makriyannis@neu.edu (A. Makriyannis).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.07.029

5588
R. I. Duclos Jr. et al. / Tetrahedron Letters 49 (2008) 5587–5589
Me
OMe
Me
OMe
1) Mg/THF, reflux, 8 h
Li/NH3, THF, -78 oC, 6 h
2) (1R)-(+)-camphor
Me
MeO
Cl
OMe
HO
4
5
(endo : exo = 2 : 1)
Me
7
Me
4
Me
5
7
Me
OMe
5
3
4
3
6
H
+
6
1
Me
2
Me 1
2
OMe
H
MeO
OMe
7
6
(exo-epimer)
(endo-epimer)
(endo : exo = 3 : 1)
Scheme 2. Synthesis of 2-bornyl (endo) and 2-isobornyl (exo) epimers via a Grignard addition.
Wagner–Meerwein rearrangement racemizes optically active nor-
bornanes and bornanes under acidic conditions and greatly limits
the usefulness of this method. Thus, we chose a different approach
for the synthesis of optically pure 1,7,7-trimethyl (bornane) deriv-
atives that could also provide us with both exo- and endo-epimers.
Bornanes were selected for the further exploration of the key
cannabinoid side chain pharmacophore as they represented a sub-
tle stereochemical variation of the adamantyl group, both are ten
carbon substituents. We now detail a useful method for preparing
endo- and exo-epimers of aryl as well as alkyl analogs of 2-bornane
with good stereocontrol. This route (Scheme 2) utilized a Grignard
reaction with (1R)-(+)-camphor to prepare both endo-(bornyl) and
exo-(isobornyl) 2-(3,5-dimethoxyphenyl)-1,7,7-trimethylbicyclo-
[2.2.1]heptane analogs, 6 and 7, respectively, that were synthetic
intermediates for a new series of classical cannabinoid analogs.15
The Grignard reagent prepared from 1-chloro-3,5-dimethoxyben-
zene (4) reacted with (1R)-(+)-camphor to give a 2:1 mixture of
3,5-dimethoxyphenyl adducts 5 that was inseparable by both flash
column chromatography and chiral HPLC, though we were able to
achieve separation after the subsequent step. The reported Grig-
nard reaction of a preformed complex of (1R)-(+)-camphor with
cerium(III) chloride16,17 that gives endo-adducts exclusively was
not used as both endo- and exo-adducts were desired. The major
product of Grignard addition was the endo-adduct as expected
from the corresponding reactions of Grignard reagents prepared
from bromobenzene,18,19 p-bromoanisole,20 and o-bromoanisole.21
The hydroxyl groups of the mixture of isoborneol and borneol ana-
logs 5 were removed according to the methods reported for the
corresponding anisole analog.21 Hydrogenolysis of the 2:1 mixture
with palladium on carbon produced some bornyl-skeletal rear-
rangement byproduct in addition to the desired reduction prod-
ucts. However, lithium/ammonia reduction cleanly afforded a 3:1
mixture of 5-bornyl-1,3-dimethoxybenzene (6) to 5-isobornyl-
1,3-dimethoxybenzene (7), the reduction converting some of the
exo-adduct of 5 to both reduction products 6 and 7. A small quan-
tity of the mixture was separated by HPLC on a Chiralpak AD
column to unambiguously identify the major product as the
endo-epimer 5-bornyl-1,3-dimethoxybenzene (6) that has an exo-
benzylic proton, and the minor product as the exo-epimer 5-iso-
bornyl-1,3-dimethoxybenzene (7) that has an endo-benzylic
proton. The chemical shift differences and coupling patterns of
the benzylic protons of 6 and 7 were in agreement with reported
values for bornyl and isobornyl analogs.22 The H-2exo proton of 6
was downfield relative to the H-2endo of 7. Also, we observed 4J-
coupling23 of the H-2exo benzylic proton of 5-bornyl-1,3-dime-
thoxybenzene (6) that was confirmed by COSY spectroscopy to
be coupling to the coplanar H-6exo. In contrast, the H-2endo benzylic
proton of exo-epimer 7 was a characteristic doublet of doublets.
The expected ‘W’ couplings of H-3exo to H-5exo for 6 and 7 were also
observed. Only couplings of adjacent exo-protons H-3exo and H-5exo
were observed to bridgehead H-4 of the bornane derivatives. Ob-
served scalar coupling constants (J) determined by first order anal-
ysis of individual proton signals for the endo- and exo-epimers are
given in Table 1. All assignments were ultimately confirmed by 2D
NOESY experiments (see Supplementary data). It was also found
that 2-alkyl substituted analogs, prepared in an analogous man-
ner,15 also have similar chemical shift effects, especially on H-
6
exo. Our NMR data should be useful in the assignment of spectra
from other bicyclo[2.2.1]heptane derivatives.24,25
Table 1
Observed coupling constants for endo-(bornyl) and exo-(isobornyl) epimers 6 and 7
endo-
exo-
Me
5
Me
5
7
7
Me
Epimer
(bornyl) 6
J (Hz)
Epimer
(isobornyl) 7
J (Hz)
Me
4
OMe
4
3
3
6
6
H
1
Me
Me 1
2
2
OMe
H
MeO
OMe
J2exo,3exo
11.5
5.4
2.5
13.2
4.5
3.5
J2endo,3exo
J2endo,3endo
4J2endo,6exo
J3exo,3endo
J3exo,4
8.0
9.2
0.0
12.5
4.4
2.6
4.4
12a
12a
2.7
4.4
9.4
12a
J2exo,3endo
4J2exo,6exo
J3exo,3endo
J3exo,4
4J3exo,5exo
4J3exo,5exo
J4,5exo
J4,5exo
4.5
J5exo,5endo
J5exo,6exo
J5exo,6endo
J5endo,6exo
J5endo,6endo
J6exo,6endo
12.5
12.0
4.1
4.6
9.4
J5exo,5endo
J5exo,6exo
J5exo,6endo
J5endo,6exo
J5endo,6endo
J6exo,6endo
13.1
a
Coupling constants determined within 0.5 Hz.

R. I. Duclos Jr. et al. / Tetrahedron Letters 49 (2008) 5587–5589
5589
6. Cincinelli, R.; Dallavalle, S.; Nannei, R.; Merlini, L.; Penco, S.; Giannini, G.;
Pisano, C.; Vesci, L.; Ferrara, F. F.; Zuco, V.; Zanchi, C.; Zunino, F. Bioorg. Med.
Chem. 2007, 15, 4863.
7. Brown, A. D.; Bunnage, M. E.; Glossop, P. A.; James, K.; Jones, R.; Lane, C. A. L.;
Lewthwaite, R. A.; Mantell, S.; Perros-Huguet, C.; Price, D. A.; Trevethick, M.;
Webster, R. Bioorg. Med. Chem. Lett. 2008, 18, 1280.
Acknowledgments
This work was supported by grants DA-7215, DA-3801, DA-152,
and DA-9158 from the National Institute on Drug Abuse.
8. Steinbrecher, T.; Hrenn, A.; Dormann, K. L.; Merfort, I.; Labahn, A. Bioorg. Med.
Chem. 2008, 16, 2385.
Supplementary data
9. Rinaldi-Carmona, M.; Barth, F.; Millan, J.; Derocq, J.-M.; Casellas, P.; Congy, C.;
Oustric, D.; Sarran, M.; Bouaboula, M.; Calandra, B.; Portier, M.; Shire, D.;
Brelière, J. C.; Le Fur, G. J. Pharmacol. Exp. Ther. 1998, 284, 644.
10. 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.; Järbe, T. U. C.; Lamb, R. J.;
Makriyannis, A. J. Med. Chem. 2005, 48, 4576.
11. Luk, T.; Jin, W.; Zvonok, A.; Lu, D.; Lin, X.-Z.; Chavkin, C.; Makriyannis, A.;
Mackie, K. Br. J. Pharmacol. 2004, 142, 495.
12. Järbe, T. U. C.; DiPatrizio, N. V.; Lu, D.; Makriyannis, A. Behav. Pharmacol. 2004,
15, 517.
Supplementary data (experimental procedures and character-
izations of all compounds. 700 MHz 1H NMR, COSY, and NOESY
spectra for endo-epimer 6 and exo-epimer 7 in CDCl3 solutions)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.07.029.
13. McLaughlin, P. J.; Brown, C. M.; Winston, K. M.; Thakur, G.; Lu, D.; Makriyannis,
A.; Salamone, J. D. Behav. Pharmacol. 2005, 16, 477.
14. McLaughlin, P. J.; Lu, D.; Winston, K. M.; Thakur, G.; Swezey, L. A.; Makriyannis,
A.; Salamone, J. D. Pharmacol. Biochem. Behav. 2005, 81, 78.
15. Lu, D.; Guo, J.; Duclos, R. I., Jr.; Bowman, A. L.; Makriyannis, A. J. Med. Chem.,
submitted.
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