A synthetic approach for (S)-(3-benzyl-3-methyl-2,3-dihydro-benzofuran-6- yl)-piperidin-1-yl-methanone, a selective CB2 receptor agonist

Article abstract of DOI:10.1016/j.tetlet.2012.04.076

(S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl- methanone, a selective CB2 receptor agonist, was obtained from 3-hydroxy-4-iodo benzoic acid in nine steps with 97.4% ee and 3.4% total yield, which involved palladium catalyzed tandem intramolecular Heck/Suzuki cross coupling reaction, chemical resolution with (+)-norephedrine and Wolf-Kishner reaction as the key steps. (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl- methanone will be evaluated in vivo studies and this approach will be applied in the optimization process of CB2 receptor agonist.

Full text of DOI:10.1016/j.tetlet.2012.04.076

Tetrahedron Letters 53 (2012) 3316–3318
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A synthetic approach for (S)-(3-benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-
piperidin-1-yl-methanone, a selective CB2 receptor agonist
⇑
Zhushou Luo, Mohamed Naguib
Anesthesiology Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
(S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone, a selective CB2 recep-
tor agonist, was obtained from 3-hydroxy-4-iodo benzoic acid in nine steps with 97.4% ee and 3.4% total
yield, which involved palladium catalyzed tandem intramolecular Heck/Suzuki cross coupling reaction,
chemical resolution with (+)-norephedrine and Wolf–Kishner reaction as the key steps. (S)-(3-Benzyl-
3-methyl-2,3-dihydro-benzofuran-6-yl)-piperidin-1-yl-methanone will be evaluated in vivo studies
and this approach will be applied in the optimization process of CB2 receptor agonist.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 19 March 2012
Revised 16 April 2012
Accepted 17 April 2012
Available online 24 April 2012
Keywords:
Intramolecular Heck/Suzuki cross coupling
Chemical resolution
Wolf–Kisher reaction
CB2 receptor agonist
The endogenous cannabinoid system is a complex system con-
sisting of two cannabinoid (CB) receptors (CB1—expressed primar-
ily in the brain and CB2—expressed primarily in the peripheral
immune system1 and in the central nervous system (CNS)2), seven
endogenous endocannabinoid ligands (arachidonic acid deriva-
tives) including anandamide (N-arachidonoylethanolamine) and
2-arachidonoylglycerol (2-AG),3 and several proteins responsible
for the regulation of endocannabinoid metabolic pathways, such
as monoacylglycerol lipase and fatty acid amide hydrolase.4 CB1
and CB2 are seven transmembrane, G protein-coupled receptors,
and they share 44% overall identity. Both receptors mediate the
inhibition of adenylyl cyclases and stimulation of mitogen-acti-
vated protein kinases (MAPK). However, CB1 receptor agonists
failed to show efficacy in patients with neuropathic pain compared
with placebo, and their use has resulted in a high incidence of psy-
chotropic adverse effects.5 In contrast, CB2 receptor agonists are
neuroprotective and are emerging as treatments for neuropathic
pain. Moreover, they lack the psychotropic adverse effects that
normally occur with CB1 agonists.6,7 Increasing interest has been
spurred in pharmaceutical companies and academia, and several
classes of selective CB2 agonists for the treatment of inflammatory
and neuropathic pain conditions have been reported.6,8
determined by X-ray crystal structure. In vitro hCB2 GTP
functional assay, compound 1 binds selectively to the CB2 receptor
(EC50: 108 nM on hCB2; >10 M on hCB1), which is better than its
c[
35S]
l
corresponding racemate (EC50: 128 nm on hCB2; >10
lM on
hCB1) and R enantiomer (EC50: 960 nm on hCB2, >10
lM on
hCB1). Racemate also showed (i) dose-dependent reversal of neuro-
pathic pain in spinal nerve ligation and paclitaxel-induced neurop-
athy rat models when administered intraperitoneally with ED50
value of 7.5 and 24 mg/kg, respectively, and (ii) prevention of
paclitaxel-induced neuropathy.6a However, compound 1 was only
obtained previously in very limited quantity using chiral HPLC
separation of the corresponding racemate.6b Thus, a scalable and
effective approach is needed for the synthesis and optimization of
compound 1.
Compound 1 has a quaternary carbon stereocenter at the ben-
zylic position in the ring system of 2,3-dihydro-1-benzofuran,
and presents an interesting synthetic challenge.9 The key reaction
for racemic synthesis of compound 1 and its analogs is shown in
Scheme 1. The synthesis utilized palladium catalyzed tandem
O
We initiated a research program aimed at identifying novel
selective CB2 agonists for the treatment of neuropathic pain, and
we identified (S)-(3-Benzyl-3-methyl-2,3-dihydro-benzofuran-
6-yl)-piperidin-1-yl-methanone 1 (Fig. 1) as a lead compound.6b
The absolute stereochemistry of compound 1 has also been
O
N
Ph
1
⇑
Corresponding author. Tel.: +1 216 444 6328; fax: +1 216 636 2043.
E-mail address: naguibm@ccf.org (M. Naguib).
Figure 1. Structure of (S)-(3-benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-
piperidin-1-yl-methanone.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.076

Z. Luo, M. Naguib / Tetrahedron Letters 53 (2012) 3316–3318
3317
O
O
O
O
R1
a
b
O
I
R1
O
HO
I
HO
I
N
N
OH
N
Pd(OAc)2, n-Bu4NCl
K2CO3, DMF, 80 oC
R2
R2
5
6
ArB(OH)2
Ar
O
O
O
Scheme 1. Synthesis of racemic 1 and its analogs.
H3CO
O
N
c
O
N
intramolecular Heck/Suzuki coupling reactions.6b,10 Although
asymmetric intramolecular Heck reaction has been widely used
in organic synthesis including the formation of quaternary chiral
carbon center,11 our attempt of enantioselective synthesis was
unsuccessful when we used different reaction conditions, chiral
ligands, palladium sources, and appropriate additives. We then uti-
lized chemical resolution approach using chiral resolving agent.12
As shown in Scheme 2, we expect to obtain chiral separable solid
salt 2 by the combination of appropriate chiral amine and racemic
acid 3, followed by further transformation to deliver compound 1.
Racemic acid 3 could be synthesized from tandem intramolecular
Heck/Suzuki coupling reactions of compound 4 and phenylboronic
acid.6b,10 Herein, we report our synthetic pathway of compound 1
based on this strategy.
CO2CH3
I
Ph
4
3
7
O
O
O
O
N
N
e
d
Ph
CO2H
CO2
OH
H3N
Ph
Ph
8
O
O
O
O
N
N
Coupling of 3-hydroxy-4-iodo benzoic acid 513 with piperidine
gave amide 6, which reacted with methyl 2-bromoacrylate to
afford 4 (Scheme 3). Compound 4 was subjected to Heck/Suzuki
coupling conditions leading to compound 7 in 53% yield. Basic
hydrolysis of 7 gave the racemic acid 3. Among the screened chiral
amine for chemical resolution, (+)-norephedrine gave desired
results. Acid 3 and (+)-norephedrine were dissolved in ethanol
under 75 °C, followed by slow addition of ethyl acetate to form a
little cloudy solution. Then the solution was filtered, the filtrate
cooled to room temperature, and stood at 4 °C overnight to give
white precipitate, which was filtered to give salt 8 in good yields
(24–33%) and high ee value (98.0%, see supplementary data). The
absolute stereochemistry was not determined at this stage. Salt 8
was then directly transformed into mixed anhydride followed by
NaBH4 reduction to afford alcohol 9 in 70% yield. Initially, 9 was
converted into its corresponding bromide followed by the treat-
ment with tributyltin hydride and AIBN in refluxing benzene to
afford only complex mixture. Finally Wolf–Kishner reaction14
was chosen to make this transformation. Swern oxidation of pri-
mary alcohol 9 gave aldehyde 10, which reacted with hydrazine
in diethylene glycol at 100 °C for 1 h followed by the addition of
potassium hydroxide and heating at 195 °C for additional 4 h to
g
f
O
CH2OH
Ph
Ph
10
9
O
O
OH
h
i
1
Ph
11
Scheme 3. Reagents and conditions: (a) piperidine, iPr2NEt, HATU, DMF, 23 °C,
16 h, 56%; (b) methyl 2-bromomethyl-acrylate, K2CO3, methyl ethyl ketone, reflux,
3 h, 86%; (c) phenylboronic acid, Pd(OAc)2, n-Bu4NCl, K2CO3, DMF, 80 °C, 16 h, 53%;
(d) NaOH, dioxane/H2O = 4/1, 23 °C, 48 h, 91%; (e) (+)-norephedrine, 24–33%; (f)
methyl chloroformate, THF, 0–23 °C; then NaBH4, ethanol, À78–0 °C, 70%; (g)
(COCl)2, DMSO, then Et3N, CH2Cl2, À78–23 °C, 93%; (h) NH2NH2, diethylene glycol,
100 °C, 1 h, then KOH, 195 °C, 4 h, 73%; (i) piperidine, iPr2NEt, HATU, DMF, 23 °C,
16 h, 92%.
afford acid 11. Acid 11 coupled with piperidine to give the
final product 1. Compound 1 was confirmed as the desired S
configuration product with 97.4% ee by the comparison of all spec-
troscopic data with authentic sample, which was previously
purified by chiral HPLC and assigned as S configuration by X-ray
crystallography.6b
O
O
O
O
N
N
In conclusion, we have developed an effective approach to
synthesize (S)-(3-benzyl-3-methyl-2,3-dihydro-benzofuran-6-yl)-
piperidin-1-yl-methanone 1, a selective CB2 receptor agonist with
3.4% total yield and high ee (97.4%). This approach involved tandem
intramolecular Heck/Suzuki coupling reaction of intermediate 4,
chemical resolution of intermediate acid 3 and Wolf–Kishner reac-
tion for the transformation of intermediate 9 into 1. Currently com-
pound 1 is evaluated in vivo studies and this approach is used in our
lab for the optimization of compound 1.
CO2
NH3R1R*2
Ph
Ph
1
2
O
OCH3
O
O
N
O
O
I
N
CO2H
Ph
Acknowledgments
3
4
Financial support for this work was provided by the Cleveland
Clinic Foundation. NMR and exact mass measurements were
Scheme 2. Synthetic strategy for compound 1.

3318
Z. Luo, M. Naguib / Tetrahedron Letters 53 (2012) 3316–3318
5. (a) Selvarajah, D.; Gandhi, R.; Emery, C. J. Diabetes Care 2010, 33, 128–130; (b)
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carried out at the supporting facilities at the chemistry department
of Case Western University. HPLC analysis was done at Mass Spec-
trometry II core lab at the Lerner Research Institute of Cleveland
Clinic Foundation. We thank Professor Gary Sulikowski for his
suggestions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
076.
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