Synthesis of a Highly Potent and
Selective m-Opioid Ligand
Peter W. DeMatteoa, Yong Sok Leeb, Arthur E. Jacobsona, and Kenner C. Ricea
a Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of
Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415
b Center for Molecular Modeling, Division of Computational Bioscience, CIT, National Institutes of Health, DHHS, Bethesda, MD 20892
Opioids and their derivatives are among the most potent analgesics available, as well as some of the most abused.1
A better understanding of their mode of action enables development of more potent and hopefully less abusable
derivatives. This will also enable the synthesis of better tools (opioid-inspired synthetic compounds) to aid in the
understanding of the physiological, biochemical, and neurological roots of addiction.2 Inspired by the picomolar
binding activity of compound 1,3 we sought to further enhance the selectivity by substituting a related
pharmacophore4 (2) for cyclazocine. Assembly of compound 3 will also give us insight as to what amino acid
residue in the opioid receptor the biphenylphenolic moiety is interacting with, which could then be exploited in the
design of future m-opioid agonists.
1,4 dimethoxybezene was lithiated in the presence of TMEDA and added to N-benzyl-4-piperidone to give
carbinol 4. The crude carbinol was dehydrated with stoichiometric methanesulfonic acid to give
tetrahydropyridine 5. Alkylation of tetrahydropyridine 5 gave eneamine 6, which can either be isolated via
chromatography or reacted crude through a bromination/reduction sequence to give diastereomeric bromides 7
and 8 in approximately a 2:1 ratio. A novel microwave etherification was discovered to deliver compound 9 as a
major diastereomer, regardless of which diastereomeric bromide precursor was used. Deprotection and triflation
of the crude phenol gave compound 10 with ~15% unreacted methyl ether 9 as an inseparable, benign impurity.
A microwave-assisted Suzuki coupling was used to complete the biphenyl moiety giving compound 12, which
was used to proof the reaction sequence as there only existed 0.2 mmol of enantiopure triflated compound 2 to
react convergently with 4’-MeO-biphenylethylamine through the problematic carbamoylation step.
Debenzylation, demethylation, and phenethylation of compound 12 will give racemic 3 to accompany
enantiopure 3 for in vitro testing.
References:
1. Nutt, David et al. 24 The Lancet 2007, 369, 1047-1053. DOI: 10.1016/S0140-6736(07)60464-4)
2. NIDA homepage. www.drugabuse.gov (accessed July 6, 2012).
3. Wentland, et al. Bioorganic & Medicinal Chemistry, 2012, 22, 7340-7344. DOI: 10.1016/j.bmcl.2012.10.081
4. Kim, J. H. et al. Bioorganic & Medicinal Chemistry, 2011, 19, 3434-3443. DOI: 10.1016/j.bmc.2011.04.028.
Acknowledgements
The work of the Drug Design and Synthesis Section, CBRB, NIDA, and NIAAA was supported by the NIH Intramural Research Programs of the National Institute on Drug
Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). The X-ray crystallography was supported by NIDA through an Interagency Agreement #Y1-
DA1101 with the Naval Research Laboratory (NRL). We thank Dr. Klaus Gawrisch and Dr. Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA) for
NMR access. The authors also express their gratitude to Noel Whittaker and the Mass Spectrometry Facility at the NIDDK for the mass spectral data.
OMe
MeO NBnO
OMe
MeO
NBn
HO
OMe
MeO
NBn
1. sBuLi/TMEDA
0°C --> RT, 1h
2.
MsOH/PhMe
reflux, 4h
~90% (GC)
50 g scale
chromatographed product
solidifies on standing
54% yield
HCl salt crop 1 - 15% recovery
M.L. NMR good - 76% yield
91% overall
1. sBuLi/THF, -50°C, 1h
2. EtBr --> RT
OMe
MeO
NBn
5.5g
3.46 g 57%
1. NBA/THF, -78°C, 1h
2. HCl/NaBH3CN/MeOH
RT
OMe
MeO
NBn
Br
20%
+
OMe
MeO
NBn
Br
13%
4 5
6 7 8
5
DCE, 150°C
MW 15 min
Bn
N
O
MeO
69% yield
9:1 d.r.
chiral resolution can be done
on debenzylated piperidine
with mandelic acid.
7
0.5 mmol
9
1. BBr3/DCM, 0°C, 1h
2. Tf2O/TEA/CHCl3
Bn
N
O
TfO
quant. (15% OMe)
(dppf)PdCl2•DCM 10 mol%
TEA/CO/DMSO 85°C o/n
NH2
Br 2 eq.
Bn
N
O
HN
O
30% (50% BRSM)
10
Br
11
11
Pd(P(Ph)3)4 5 mol%
2N KOH, THF
85°C, 15 min, MW
MeO
B(OH)2
O
H
N
O
O
NBn
40% yield
12
N
O
TfO
2-OTf
O
H
N
O
O
N
3'
(dppf)PdCl2•DCM 10 mol%
TEA/CO/DMSO 76°C 16h
O
NH2
2 eq.
41% yield
HO
H
N
O
O
NN
H
N
O
HO
N
HO
cyclazocine
1
HO
O
N
4aS ,9aR
2-phenethyl-4a-ethyl-1,2,3,4,4a,
9a-hexahydrobenzofuro[2,3-c]pyridin-6-ol
2
3
Ki
[3H]DAMGO (m) [3H]Naltrindole (d) [3H]U69,593 (k)
cyclazocine
1
0.16 ± 0.01 2.0 ± 0.22 0.07 ± 0.01
0.0056 ± 0.00073 0.81 ± 0.12 0.49 ± 0.011
m:d:k
1:13:0.4
1:145:88
0.70 ± 0.062 75 ± 8.8 88 ± 8 1:11:13
O
HO
N
HO
natural morphine
A
B
C
D
E
R1
R2
HO
N R3
H
N
R4
O
R5phenazocine
E. L. May, 1955 hexahydrobenzofurano
[2,3-c]pyridin-6-ol
A. J. Hutchinson, 1989
HO
A
B
D
A
E
D'