Design, Synthesis, and Monoamine Oxidase Inhibitory Activity of (+)-Cinchonaminone and Its Simplified Derivatives

Article abstract of DOI:10.1021/acsmedchemlett.1c00310

The absolute structure of an indole alkaloid (+)-cinchonaminone by total synthesis of both (+)-cinchonaminone and its enantiomer was determined. The main focus of the study was the enantioselective synthesis of both enantiomers of a chiral cis-3,4-disubstituted piperidine. We also evaluated monoamine oxidase (MAO) inhibitory activities of these enantiomers. Furthermore, its structurally simplified derivatives were synthesized that did not have any chiral center. Two of these derivatives showed stronger MAO inhibitory activities than that of (+)-cinchonaminone.

Full text of DOI:10.1021/acsmedchemlett.1c00310

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Letter
Design, Synthesis, and Monoamine Oxidase Inhibitory Activity of
(+)-Cinchonaminone and Its Simplified Derivatives
Yuta Sato, Naoko Oyobe, Takao Ogawa, Sayo Suzuki, Hiroshi Aoyama, Tomonori Nakamura,
Hiromichi Fujioka, Satoshi Shuto, and Mitsuhiro Arisawa*
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ABSTRACT: The absolute structure of an indole alkaloid (+)-cin-
chonaminone by total synthesis of both (+)-cinchonaminone and its
enantiomer was determined. The main focus of the study was the
enantioselective synthesis of both enantiomers of a chiral cis-3,4-
disubstituted piperidine. We also evaluated monoamine oxidase
(MAO) inhibitory activities of these enantiomers. Furthermore, its
structurally simplified derivatives were synthesized that did not have
any chiral center. Two of these derivatives showed stronger MAO
inhibitory activities than that of (+)-cinchonaminone.
KEYWORDS: Total synthesis, indole alkaloid, absolute structure determination, monoamine oxidase (MAO) inhibitory activity,
structurally simplified derivatives
onoamine oxidase (MAO)1 is an oxidase present in the
outer mitochondrial membrane and plays a role in
biosynthetic pathway of cinchona alkaloids and the structure of
other cinchona alkaloids.3 However, as for the reported cases
of total synthesis, there is only one case of racemic synthesis,4
and there is no report of total asymmetric synthesis; the
absolute configuration of the compound itself has not been
clarified. Here in the background research, we describe the
determination of the absolute configuration of (+)-cinchona-
minone ((+)-1) and design, synthesis, and MAO inhibition
activities of structurally simplified derivatives of (+)-cinchona-
minone ((+)-1).
Based on the previously reported racemic synthetic method,
we decided to synthesize the chiral piperidine units (+)-2 and
(−)-2 and the indole unit 3, which will be subjected to a cross-
coupling reaction to give (+)-1 and (−)-1 (Scheme 2).
Therefore, we first worked on synthesizing optically pure
piperidine units (+)-2 and (−)-2. Our retrosynthetic analysis
for (+)-2 and (−)-2 is shown in Scheme 3.
M
inactivating neurotransmitters in vivo, metabolizing mono-
amines ingested as drugs and those included in food. Two
subtypes of MAO, MAO-A and MAO-B, inhibitors have been
applied to the drug therapy of central nervous system diseases
because they inactivate neurotransmitters in the central
nervous system. MAO-A inhibitors are mainly used in the
treatment of depression. On the other hand, MAO-B inhibitors
are used to treat Parkinson’s disease and attention deficit
hyperactivity disorder (ADHD). In this way, MAO is an
attractive target for drug discovery.
(+)-Cinchonaminone (1, Scheme 1) is an indole alkaloid
isolated from Cinchonae Cortex in 1989 and has been reported
Scheme 1. Proposed Absolute Structure of
(+)-Cinchonaminone (1)
The 3-position vinyl group of piperidine unit 2 could be
constructed by the dehydration reaction of the primary alcohol
14. The alcohol 14 could be obtained by diastereoselective
reduction of the unsaturated ester 13, which could be
synthesized by oxidation of the secondary alcohol 12 and a
subsequent Horner−Wadsworth−Emmons (HWE) reaction.
It was also considered that the iodomethylene group at the 4-
to have inhibitory activity against bovine plasma-derived MAO
(IC50 = 31.7 μM);2 the structural feature of (+)-cinchonami-
none ((+)-1) is that it has an indole ring and a cis-3,4-
disubstituted piperidine ring at the indole 2-position. The
piperidine rings C3 and C4 are asymmetric carbons, and the
configuration of (+)-cinchonaminone ((+)-1) in the piperidine
ring was estimated (3R, 4S) by Noro et al. (1989) based on the
Received: June 1, 2021
Accepted: August 13, 2021
https://doi.org/10.1021/acsmedchemlett.1c00310
© XXXX American Chemical Society
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Scheme 2. Our Retrosynthesis Analysis for (+)-1 and (−)-1
Table 1. Asymmetric Hydroboration of 11 and Subsequent
Protection of the Primary Alcohol with the TBDPS Group
yield of 17
(%) second
step
temp time
yield of 12
ee
(%)
run
borane
Cy2BH
(°C)
(h) (%) first step
1
2
3
4
5
6
7
8
60
−40
60
rt
0
0
3
24
3
24
24
48
48
48
92
6
92
89
87
85
90
89
88
89
a
(+)-IpcBH2
(+)-IpcBH2
(+)-IpcBH2
(+)-IpcBH2
(+)-IpcBH2
(+)-IpcBH2
21
47
52
62
61
64
65
a
90
81
55
79
34
77
a
a
Scheme 3. Retrosynthesis of Optically Pure cis-3,4-
Disubstituted Piperidine Unit 2
a
a
−25
0
b
(−)-IpcBH2
a
b
(3S,4S)-17. (3R,4R)-17.
have decreased significantly under the conditions of −40 °C.
Therefore, we examined the reaction temperature (runs 3−7)
and found that the higher the reaction temperature, the higher
the yield of 12, and the longer the reaction time, the better the
yield of 12 (runs 5 and 6). Although the best optical purity of
17 was 62% ee, we increased it to 91% ee by recrystallizing 17
(Scheme S2). From the above results, considering the reaction
time and the yield of the reaction from 11 to 17, including
recrystallization, the condition of entry 6 at 0 °C and 48 h was
judged the most suitable.
Compound 12 was also converted to known compound 196
to determine its absolute configuration (Scheme 4). The actual
Scheme 4. Synthesis of 19 from 12
position of compound 2 could be constructed by the Appel
reaction of a primary alcohol. It was also considered that the
asymmetric carbon center at the 4-position could be
constructed by the hydroboration reaction of the allyl alcohol
compound 11. It was thought that 11 could be synthesized
from commercially available compound 10 in three steps.
We first investigated the stereoselective synthesis of the
piperizine unit 2 by using racemic substrates. Preparation of 11
is summarized in Scheme S1 in the Supporting Information.
Next, the key reaction, the asymmetric hydroboration
reaction, was examined (Table 1). The optical purity was
determined using compound 17, in which the primary hydroxy
group of diol 12 was protected with a TBDPS group.5 When a
THF solution of optically pure borane (+)-IpcBH2, which has
been widely used in asymmetric hydroboration reactions, and
compound 11 was stirred at −40 °C, the expected compound
12 was obtained in low yield (6%; run 2). Since the reaction
temperature of the optimum conditions for synthesizing rac-12
was 60 °C (run 1), we considered that the reaction rate might
experimental results were shown in Scheme S3. As a result of
comparing the optical rotation value of the synthesized N-Bn
protected 19 with the literature value,6a we found that (3R,
4R)-12 and (3S,4S)-12 were obtained when (+)-IpcBH2 and
(−)-IpcBH2 were used, respectively.
The conversion of compound 17 to unsaturated ester 13 was
explained in the Supporting Information.
First, the Z-form unsaturated ester rac-(Z)-13 was used for
examination. No selectivity was found in the production ratio
of the cis-form and trans-form with the Pd catalyst, but the cis-
form tended to be selectively obtained when the Pt catalyst was
used.7 The structures of the obtained compounds rac-cis-14
and rac-trans-14 were determined by the difference in the
B
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coupling constant between the protons at the 2-axial position
and the 3-position of the piperidine ring.
Scheme 5. Synthesis of Piperidine Unit rac-2
The diastereoselective catalytic reduction of the obtained
key intermediate 13 was examined (Tables 2 and 3). The
Table 2. Diastereoselective Catalytic Reduction of Z-13
rac-cis-14
rac-trans-14
rac-(Z)-13
the desired piperidine unit rac-2 was obtained by the Appel
reaction. As described, we successfully established a synthetic
route for the piperizine unit using the racemic substrates.
Finally, both of the optically pure piperidine units (3R,4R)-
and (3S,4S)-2 were synthesized using the established pathway
from commercially available compound 10 in 12 steps
(Scheme S5).
run
catalyst
(%)
(%)
(%)
1
2
3
4
5
Pd/C (10 wt %)
Pd/C (5 wt %)
Pd(OH)2/C (10 wt %)
Pt/C (10 wt %)
41
39
98
97
75
85
9
PtO2 (10 mol %)
(+)- and (−)-Cinchonaminone were synthesized using the
synthesized optically pure piperidine unit (3R,4R)-2 or
(3S,4S)-2 and indole unit 38 (Scheme 6). After Zn was
inserted into the carbon−iodine bond of the optically pure
piperidine unit 2, CuCN and 2 equiv of LiCl were added to
obtain the corresponding organic copper art reagent.
Compound 27 was obtained using a cross-coupling reaction
between this reagent and the indole unit 3. Subsequently, after
converting the secondary alcohol to a ketone by Dess-Martin
oxidation, the Boc group and the MOM group were removed
with hydrochloric acid-methanol to yield (3R,4S)-cinchona-
minone and (3S,4R)-cinchonaminone in 22 steps.
Table 3. Diastereoselective Catalytic Reduction of E-13
rac-cis-14
(%)
rac-trans-14
rac-(E)-13
run
catalyst
(%)
(%)
1
2
Pd/C (10 wt %)
PtO2 (10 mol %)
24
63
65)
27
The optical rotations of the two isomers of synthesized
cinchonaminone were measured (Scheme 7). The optical
rotations of (3R,4S)-cinchonaminone and (3S,4R)-cinchona-
double bond and ester group of the synthesized unsaturated
ester 13 were successively reduced using a heterogeneous
catalyst and lithium aluminum hydride, respectively, to obtain
the corresponding alcohol 14.
In addition, the reduction of the E-form rac-(E)-13 was also
examined in the same manner, and the same tendency as in the
case of the Z-form was found for the cis/trans-selectivity of the
products due to the difference in the metal catalyst. However,
the cis-selectivity of the products was lower than that used in
the Z-form as the substrate.
In other words, from the results obtained by the present
study and the discussions reported in the literature,8 it became
clear that catalytic reduction of the Z-form unsaturated ester
13 using platinum oxide selectively produced the cis-form.
Next, we moved to the synthesis of piperidine unit 2 from
cis-alcohol 14 (Schemes 3 and 5). Alcohol rac-14 was
converted to a terminal alkene rac-21 via the corresponding
selenoxide to construct a vinyl group at the 3-position.
Subsequently, the TBDPS group at the 4-position was
removed using HF/pyridine to synthesize rac-21, and then
24
24
minone were [α]
respectively. Since the optical rotation of the natural
(+)-cinchonaminone is [α]
= +10.3° and [α]
= −9.7°,
D
D
= +10.0°,2 it turned out that
22
D
the absolute configuration of the piperidine rings C3 and C4 of
the (+)-cinchonaminone is (3R,4S).
The hMAO-A and hMAO-B inhibitory activity of the
synthesized (+)- and (−)-1 was evaluated (Table 4). Both (+)-
and (−)-1 had similar inhibitory activities for hMAO-B,
although they had almost no inhibitory activity for hMAO-A.
Considering the above biological activities results and
docking study of (+)- and (−)-1 with hMAO-A (PDB:
2Z5X,9 Figure 1a) and hMAO-B (PDB: 2V5Z,10 Figure 1b),11
we hypothesized that the vinyl moiety at the C3-position of
piperidine was not necessary for hMAO inhibition. Hence, we
designed structurally simplified derivatives of 29 without the
asymmetric two carbons in the piperizine moiety (Scheme 8).
We also noticed that the hydroxyethyl moiety at the C3-
position of the indole is surrounded by the hydrophilic region
C
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Scheme 6. Synthesis of (3R,4S)-1 and (3S,4R)-1
Figure 1. Docking of (+)- and (−)-1 in a) hMAO-A (PDB: 2Z5X)
and b) hMAO-B (PDB: 2V5Z). Blue compound: (+)-1. Green
compound: (−)-1. The hydrophilic region of the protein is colored
red. It is considered that ethyl alcohol does not form hydrogen bonds
and has a high affinity because it is located in the highly hydrophilic
part of the pocket. In hMAO-A, it was suggested that the nitrogen in
the indole moiety and the carbonyl oxygen of Ile325 were hydrogen-
bonded via water and that the hydrogen bonded to the nitrogen in the
piperidine moiety and the carbonyl oxygen of Ala111 were hydrogen-
bonded. In hMAO-B, it was suggested that Phe343 and Tyr326 form
a π−π interaction with the indole moiety.
Scheme 7. Optical Rotation of (3R,4S)-1 and (3S,4R)-1
Scheme 8. Designed Structurally Simplified Derivatives of 1
and 29−31 and Their Retrosynthesis Analysis
Table 4. hMAO-A and hMAO-B Inhibitory Activities of the
a
Synthesized (+)- and (−)-1
IC50 (μM)
(+)-1
>1000
412 108
(−)-1
>1000
488 137
hMAO-A
hMAO-B
a
Mean SD (n = 3).
essential for the hMAO-A or -B binding to restrict the relative
special positioning of the indole and the piperizine moieties
due to its rather significant steric repulsion for the eclipsed 2-
side chain and therefore designed compound 31 having a
methyl substituent at the 3-position.
of the hMAO-B, and we designed compound 30 without the
hydroxyethyl substituent at the indole 3-position. We further
considered the substituent at the indole 3-position may be
D
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Using the same coupling for the synthesis of 1, 29−31 were
successfully prepared from indole units 3, 32,12 and 3313 and
piperidine unit 34 (Scheme S6).14 Then, hMAO-A and
hMAO-B inhibitory activities of the synthesized analogs 29−
31 were evaluated (Table 5). Although compound 29 did not
Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0808, Japan; orcid.org/0000-0002-7937-
670X; Email: arisaw@phs.osaka-u.ac.jp
Authors
Yuta Sato − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
Naoko Oyobe − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
Takao Ogawa − Faculty of Pharmaceutical Sciences, Hokkaido
University, Sapporo 060-0808, Japan
Table 5. hMAO-A and hMAO-B Inhibitory Activity of 29−
a
31
IC50 (μM)
29
30
31
Sayo Suzuki − Graduate School of Pharmaceutical Sciences,
Keio University, Tokyo 105-8512, Japan
hMAO-A
hMAO-B
>1000
>1000
720 87
66.6 18.9
82.5 14.7
121 38.2
Hiroshi Aoyama − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Tomonori Nakamura − Graduate School of Pharmaceutical
Sciences, Keio University, Tokyo 105-8512, Japan
Hiromichi Fujioka − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan;
orcid.org/0000-0002-9970-4248
Satoshi Shuto − Faculty of Pharmaceutical Sciences, Hokkaido
University, Sapporo 060-0808, Japan; orcid.org/0000-
0001-7850-8064
a
Mean SD (n = 3).
show any inhibitory activities for hMAO-A and hMAO-B,
compounds 30 and 31 were moderately potent. It was
interesting that compound 30, which has a methyl substituent
at the 3-position of indole, had some selectivity for hMAO-A
probably due to the expected steric repulsion, although
compound 31, which has no substituent at the 3-position of
indole had some selectivity for hMAO-B. Among compounds
29−31, compound 30 showed both the highest selectivity as
selectivity index (SI) 11 (IC50 value of hMAO-A/IC50 value of
hMAO-B) and the highest hMAO-B inhibitory activity,
suggesting some alkyl-substituent effect at the C3-position of
the indole in hMAO-B inhibitory activity and selectivity. We
have calculated the selectivity index (SI) according to the
previous report.15 On the other hand, the hMAO-A inhibitory
activity was changed by modifying the substituent at the C3-
position of the indole, but no obvious association between
them, such as hMAO-B, was observed. We observed that the
subtype selectivity of 30 and 31 was changed just by the
methyl substituent at the C3-position of the indole, probably
due to preferable conformational difference. We believe these
are useful results to further the development of hMAO
inhibitors.
In conclusion, we synthesized (+)-cinchonaminone and its
enantiomer, (+)- and (−)-1, based on the enantioselective
synthesis of both enantiomers of a chiral cis-3,4-disubstituted
piperidine derivative and determined the absolute structure of
(+)-cinchonaminone. Furthermore, we designed and synthe-
sized a simplified (+)-cinchonaminone derivative to obtain
compound 30, which showed both the highest selectivity with
selectivity index 11 (IC50 value of hMAO-A/IC50 value of
hMAO-B) and the highest hMAO-B inhibitory activity. We
think that the compounds we have synthesized this time are
worth assessing whether or not they have the biological activity
confirmed by other cinchona alkaloids.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00310
Author Contributions
Y.S. and N.O. contributed equally.
Notes
The authors declare no competing financial interest.
Crystallographic data for CCDC 2074803 can be accessed free
of charge at www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENTS
■
This study was partially supported by a Grant-in-Aid from
JSPS KAKENHI (Grant No. JP 15KT0063), by the Platform
Project for Supporting Drug Discovery and Life Science
Research (Basis for Supporting Innovative Drug Discovery and
Life Science Research (BINDS)) from AMED under Grant
Number JP20am0101084, and by the Cooperative Research
Program of “Network Joint Research Center for Materials and
Devices” from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00310.
Experimental details, characterization data, and copies of
1H and 13C NMR spectra (PDF)
CIF file (CIF)
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AUTHOR INFORMATION
■
Corresponding Author
Mitsuhiro Arisawa − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan;
E
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