Synthesis and evaluation of opioid receptor-binding affinity of elaeocarpenine and its analogs

Article abstract of DOI:10.1016/j.bmcl.2010.01.062

Both enantiomers of elaeocarpenine (1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic aldehydes 8-10 via a flexible route previously established for total synthesis of grandisines, and their binding affinities for μ-, κ- and δ-opioid receptor subtypes were evaluated. We found that (9R)-1 exhibited higher affinity than (9S)-1 for all the subtypes, but the enantiomers showed little subtype selectivity. Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indolizidine unit of (9S)-1 showed μ-selective and μ-, κ-selective binding, respectively.

Full text of DOI:10.1016/j.bmcl.2010.01.062

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1601–1603
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of opioid receptor-binding affinity
of elaeocarpenine and its analogs
Haruaki Kurasaki a, Iwao Okamoto b, Nobuyoshi Morita b, Osamu Tamura b,
*
a Exploratory Research Laboratories, Kyorin Pharmaceutical Co., Ltd 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
b Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Both enantiomers of elaeocarpenine (1) and its analogs, 21, 22, 25, and 27, were synthesized from bicyclic
aldehydes 8–10 via a flexible route previously established for total synthesis of grandisines, and their
binding affinities for l-, j- and d-opioid receptor subtypes were evaluated. We found that (9R)-1 exhib-
ited higher affinity than (9S)-1 for all the subtypes, but the enantiomers showed little subtype selectivity.
Analogs 21 having a pyrrolizidine skeleton and 27 having a stemona-type skeleton in place of the indo-
Received 28 November 2009
Revised 15 December 2009
Accepted 13 January 2010
Available online 22 January 2010
lizidine unit of (9S)-1 showed
l
-selective and
l
-,
j
-selective binding, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Elaeocarpenine
Opioid receptors
Agonists of all three opioid receptor subtypes have antinocicep-
tive activity together with unwanted side effects, including respi-
ratory depression, modulation of gastrointestinal motility, and
physical dependence.1 Because endogenous opioid peptides are
neither stable nor selective for specific opioid receptor subtypes,
highly selective nonpeptide opioid ligands have been developed
as research tools and candidate therapeutic agents.2 Extensive
studies over the past decade have shown that d-opioid receptor
agonists produce antinociception in animal models of pain without
adverse effects.3 Therefore, d-opioid receptor is an attractive target
for development of new analgesics.4
Elaeocarpenine (1), possessing an indolizidine skeleton linked
to a methyl phenol unit, was isolated as a racemate from the Papua
New Guinean plant, Elaeocarpus fuscoides, by Carroll and co-work-
ers, and displays affinity for d-opioid receptor (Fig. 1).5,6 Other
structurally and pharmacologically related natural products in-
clude the indolizidine alkaloids isoelaeocarpicine (2), isoelaeocar-
pine (3), elaeocarpine (4),7 and grandisines 5–7.8 Because of the
structural diversity and pharmacological activity, these com-
pounds may become attractive as lead compounds for the develop-
ment of new analgesics.
route that would also be applicable to various elaeocarpenine ana-
logs as candidates for selective d-opioid receptor agonists.
We recently reported the total synthesis of grandisines B (6), D
(5), and F (7) from the common key intermediate 9.9 Now, we de-
scribe the first enantioselective total synthesis of elaeocarpenine
(1) and its analogs from 8–10 via concise and flexible routes similar
to those used for the synthesis of grandisines. The affinities of these
compounds for the three opioid receptor subtypes were evaluated.
Compounds (9S)-1, (9R)-1, 21, 22, 25, and 27 were prepared from
aldehydes 8–10 and ent-9, which were synthesized from
L
- or D
-malic acid using a previously reported method (Scheme 1).9a
Hydroxyacetals 11–13 were obtained by reaction of 8-1010 with eth-
ane-1,2-diol with azeotropic removal of water, followed by deacety-
lation in the presence of a catalytic amount of NaOEt in EtOH or
O
O
O
O
H
H
N
N
9
N
H
H
OH
OH
R1
OH
isoelaeocarpine (3) (R1 = α-H)
elaeocarpenine (1) isoelaeocarpicine (2)
Although elaeocarpenine (1) has a simple structure and potent
d-opioid receptor affinity among these indolizidine alkaloids, no
total synthesis has been reported, and its affinity for other opioid
elaeocarpine (4) (R1 = β-H)
O
H
O
N
H
O
H
H
receptor subtypes (l and j) has not been evaluated. Hence, we
N
H
N
N
were interested in synthesizing elaeocarpenine (1) via a flexible
H2N
O
O
H
grandisine F (7)
grandisine D (5)
grandisine B (6)
* Corresponding author. Tel.: +81 42 721 1578; fax: +81 42 721 1579.
E-mail address: tamura@ac.shoyaku.ac.jp (O. Tamura).
Figure 1. Structures of elaeocarpus alkaloids.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.062

1602
H. Kurasaki et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1601–1603
AcO
H
HO
H
O
O
H
c, d
a, b
OHC
O
O
O
O
L-malic acid
N
N
O
N
n
n
n
8: n = 1
9: n = 2
10: n = 3
11: n = 1
12: n = 2
13: n = 3
14: n = 1
15: n = 2
16: n = 3
20: n = 1, R1 = MOM, R2 = CH3
21: n = 1, R1 = H, R2 = CH3
22: n = 2, R1 = CH3, R2 = CH3
23: n = 2, R1 = MOM, R2 = CH3
(9S)-1: n = 2, R1 = H, R2 = CH3
24: n = 2, R1 = MOM, R2 = H
25: n = 2, R1 = H, R2 = H
i
R2
O
H
H
e, f
g, h
OHC
N
N
i
i
n
n
OR1
17: n = 1
18: n = 2
19: n = 3
26: n = 3, R1 = MOM, R2 = CH3
27: n = 3, R1 = H, R2 = CH3
i
AcO
H
O
H
9
OHC
N
O
D-malic acid
N
OH
(9R)-1
ent-9
Scheme 1. Reagents and conditions: (a) HOCH2CH2OH, TsOH (cat), C6H6, reflux, 2–13 h, 75–79%; (b) NaOEt, EtOH, rt, 2 h or K2CO3 aq, MeOH, rt, 1 h, 70–93%; (c) ClCSOPh,
DMAP, ClCH2CH2Cl, 60 °C, 3–24 h; (d) nBu3SnH, AIBN (cat), C6H6, reflux, 30 min, 67–94% (two steps); (e) LiAlH4, THF, reflux, 1 h, 80–93%; (f) TsOH, acetone–H2O, reflux, 30 min
or HClO4 aq, acetone–CH2Cl2, rt, 3 h; (g) Ar-I12,13, nBuLi, THF, ꢀ78 °C to rt, 1 h; (h) Dess–Martin periodinane, CH2Cl2, rt, 3 h, 15–52% (two steps); (i) TFA, CH2Cl2, rt, 1 h, 49–77%.
excessK2CO3 inH2O–MeOH. Removalofthehydroxyl groupof11–13
was conducted by using the Barton–McCombie deoxygenation pro-
tocol.11 Thus, alcohols 11–13 were converted to the corresponding
thionocarbonated, whichwere treatedwith nBu3SnH andAIBN, lead-
ingtoacetals14–16in67–94%overallyields. Theamides 14–16were
reduced with LiAlH4 to give the amines, in which the acetals were
deprotected by acid hydrolysis using TsOH, affording aldehydes 18
and 19. However, in the case of 17, the yield of deacetalization under
similar conditions was low due to the instability of 17. Thus, 17 was
obtained by treatment with HClO4 at room temperature and was
used immediately for the next step without chromatographic purifi-
cation. Aldehydes17–19wereexposedtolithiumreagentsgenerated
from aryl iodides12,13 by lithium–halogen exchange followed by
treatment with Dess–Martin periodinane to give ketones 20, 22,
23, 24, and 26. Finally, syntheses of 1, 21, 25, and 27 were accom-
plished by removal of the MOM group with TFA. The 1H and 13C
NMR data of our synthetic (9S)-1 and (9R)-114 were in complete
agreement with those previously reported.5
increase in
substantial
loid skeleton, showed selectivity for both
In summary, we have completed the first enantioselective total
synthesis of elaeocarpenine (1) and several analogs in a concise
and flexible manner and evaluated their binding affinities for opi-
oid receptor subtypes. Our findings demonstrate that the absolute
l
l
-affinity with reduced d- and
-selectivity, whereas 27, possessing a stemona alka-
- and -receptors.
j-affinity, resulting in
l
j
configuration at C-9 in 1 is important for binding to
l-, d- and
j-opioid receptors; (9R)-1 has markedly higher affinity than (9S)-
1. Moreover, changes in the size of the piperidine ring of 1 may
provide a means to modulate the binding affinity and selectivity
for receptor subtypes. Our synthetic approach should also provide
access to other related analogs to broaden the SAR. Studies are
ongoing in our laboratories.
Table 1
Binding affinity of (9S)-1, 22, 25, (9R)-1, 21, and 27 for opioid receptor subtypesa
R2
O
Opioid receptor-binding affinities of the new compounds for the
H
human
were determined by radioligand competition analysis using
[3H]DAMGO ( ), [3H]DADLE (d), and [3H]U69593 ( ).15 The results
l- and d-opioid receptors and the rat j- opioid receptor
S
N
n
OR1
l
j
are shown in Table 1. In general, the new compounds had weak
binding affinities in the micromolar range and showed weaker
affinity for d-opioid receptor than for l- and j- receptors. Masking
Compd
n
R1
R2
Affinity (Ki, lM)
lb
dc
jd
of the phenolic-OH group and removal of the methyl group of (9S)-
1 (22 and 25) led to unchanged or decreased affinity for all three
opioid receptors compared with (9S)-1. Our data suggest that the
absence of a hydrogen-bond donor group on the aromatic group
(9S)-1
22
25
(9R)-1
21
27
2
2
2
2
1
3
H
Me
H
H
H
Me
Me
H
Me
Me
Me
45
>200
49
18
3.2
13
94
24
20
83
12
35
4.0
>200
>200
14
>200
>200
(22) increases j-selectivity by decreasing in vitro l- and d-receptor
H
affinity. Interestingly, (9R)-1 is about 2–7-fold more active than
(9S)-1, but shows essentially no opioid receptor subtype selectiv-
ity. This result suggested that the absolute configuration of C-9
in 1 is important for activity. Replacement of the indolizidine skel-
eton of 1 with a pyrrolizidine skeleton (21) resulted in a 14-fold
a
Radioligand-based binding assays were performed with human
l
).
-, d- and rat j-
opioid receptor in transfected HEK-293 cells (
l) or CHO cells (d,
j
b
[3H]DAMGO was used.
c
[3H]DADLE was used.
d
[3H]U69593 was used.

H. Kurasaki et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1601–1603
1603
similar indolizidine skeleton were isolated as optically active compounds. It is
unclear whether natural 1 is racemic or enantiomeric at this stage.
7. (a) Johns, S. R.; Lamberton, J. A.; Sioumis, A. A.; Wunderlich, J. A. Chem.
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Guymer, G.; Carroll, A. R. J. Nat. Prod. 2006, 69, 1295.
Acknowledgments
We are grateful to Dr. T. Ishizaki of Kyorin Pharmaceutical Co.,
Ltd for extensive support of this project and Dr. Y. Fukuda of Kyorin
Pharmaceutical Co., Ltd for his encouragement and suggestions.
9. (a) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Org. Lett. 2009, 11, 1179;
(b) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Chem. Eur. J. 2009, 15,
12754.
References and notes
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were easily separated by column chromatography after acetalization of 8–10.9a
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MOMCl and K2CO3 in DMF.
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14. (9S)-1 trifluoroacetic acid salt: colorless oil; ½a D26
ꢁ
+7.3 (c 0.18, MeOH); IR (ATR)
3030, 1663, 1464, 1177, 1131 cmꢀ1 1H NMR (600 MHz, DMSO-d6) d 10.35 (br
;
s, 1H), 9.73 (br s, 1H), 7.13 (dd, J = 8.4, 7.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.69
(d, J = 7.8 Hz, 1H), 6.60 (t, J = 3.6 Hz, 1H), 4.55–4.49 (m, 1H), 3.61–3.54 (m, 1H),
3.37–3.31 (m, 2H), 3.18–3.11 (m, 1H), 2.57–2.48 (m, 3H), 2.11–2.04 (m, 2H),
2.02 (s, 3H), 1.86–1.78 (m, 1H); 13C NMR (150 MHz, DMSO-d6) d 196.7, 154.1,
140.5, 136.4, 135.5, 129.9, 125.9, 120.6, 113.0, 58.2, 52.8, 43.3, 28.1, 22.6, 20.5,
18.4; MS (ESI+): m/z: 258 [M+H]+; HRMS (ESI+): m/z: calcd for C16H20NO2:
258.1494, found 258.1494 [M+H]+.
(9R)-1 trifluoroacetic acid salt: colorless oil; ½a D26
ꢀ7.5 (c 0.22, MeOH); The
ꢁ
spectral data were identical with those of (9S)-1.
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6. It is reported that elaeocarpenine (1) was isolated as a racemate, on the basis of
a measured optical rotation of 0°, whereas grandisine alkaloids possessing a