Asymmetric Total Synthesis and Biological Evaluation of the Natural PDE4 Inhibitor Toddacoumalone

Article abstract of DOI:10.1021/acs.orglett.9b04355

We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a′ with the best PDE4 inhibitory activity (IC₅₀ = 0.18 μM).

Full text of DOI:10.1021/acs.orglett.9b04355

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Letter
Asymmetric Total Synthesis and Biological Evaluation of the Natural
PDE4 Inhibitor Toddacoumalone
Ke-Qiang Hou, Xue-Ping Chen, Yiyou Huang, Albert S. C. Chan, Hai-Bin Luo, and Xiao-Feng Xiong*
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ABSTRACT: We describe herein the first asymmetric total synthesis and biological evaluation of the natural PDE4 inhibitor
toddacoumalone and its stereoisomers. The key step of the total synthesis is a formal asymmetric [4 + 2] cycloaddition reaction
catalyzed by chiral secondary amine catalysts. A variety of pyranoquinolinones and 3-methylcrotonaldehyde are well tolerated under
the optimized reaction conditions, which paved the way for further SAR studies. Further biological evaluation showed 1a′ with the
best PDE4 inhibitory activity (IC50 = 0.18 μM).
he phosphodiesterases (PDEs) families, consisting of 11
Tmembers (PDE1-PDE11), are responsible for regulating
the cellular levels of the secondary signal messengers cyclic
adenosine monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP).1 Among all PDEs, phosphodiester-
ase-4 (PDE4) is the primary cAMP-specific hydrolase within
cells and has proven to be a therapeutic target of high interest
for pulmonary, dermatological, and severe neurological
diseases.2 Recently, PDE4 inhibitors roflumilast (for the
treatment of chronic obstructive pulmonary disease), apremi-
Figure 1. Representative PDE4 inhibitors and the natural isolated
toddacoumalone (1).
last (for the treatment of psoriatic arthritis), and crisaborole
(for the treatment of atopic dermatitis) have been approved by
the FDA, respectively (Figure 1).3−5 However, most of the
PDE4 inhibitors, including those applied in the clinic, have
severe dose-limiting gastric adverse effects, such as nausea,
emesis, and gastrointestinal reactions.6 Thus, the search for
novel PDE4 inhibitors continues unabated.
In 1991, Ishikawa and co-workers reported the isolation and
characterization of toddacoumalone (1) (Figure 1) with a
0.0077% yield in a racemic form from Toddalia asiatica (L.)
Lam. (Rutaceae).7 Later, toddacoumalone (1) was reported by
the Luo and Yin group to inhibit PDE4 with an IC50 of 0.14
μM, which was more potent than the commonly used positive
control rolipram (IC50 = 0.59 μM), by using tritium-labeled
adenosine 3′, 5′-cyclic monophosphate ([3H]-cAMP) as
substrate for identifying its inhibitory activity.8
Toddacoumalone is a highly potent PDE4 inhibitor with a
unique structure and potential clinical applications. However,
the scarce and extremely low abundance in nature limited its
comprehensive studies. The structure of toddacoumalone was
assigned by NMR analysis, which needs to be further verified.
In addition, the total synthesis of this molecule has not been
reported, which further prevented its development, including
Received: December 4, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04355
© XXXX American Chemical Society
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thorough biological evaluation, structure−activity relationship
(SAR) study, etc. More importantly, toddacoumalone exists as
a racemic form in nature. The two chiral centers within the
molecule have not yet been established, which is one of the
biggest obstacles for modern drug research, as all chiral centers
need to be identified. Our research interests include the
development of new synthetic strategies for bioactive
molecules, followed by SAR studies in searching for lead
structures with therapeutic purpose. Herein, we report a
concise asymmetric total synthesis of toddacoumalone through
the exploration of a formal catalytic asymmetric [4 + 2]
cycloaddition reaction catalyzed by secondary amine catalysts,
followed by investigating their inhibition potency on PDE4.
The retrosynthetic analysis of toddacoumalone (1a) is
depicted in Scheme 1. Structurally, toddacoumalone was
through a chiral secondary amine catalyzed reaction of 6a and
7a.
In the initial screening studies, 6a was treated with 7a in the
presence of the L-proline derived catalyst 8a in THF at room
temperature (Table 1, entry 1). To our delight, diaster-
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Retrosynthetic Analysis of Toddacoumalone (1a)
c
c
time
(d)
yield
b
dr (4a:4aa or
ee (4a:4aa or
entry
1
8
6
(%)
4b:4bb)
4b:4bb)
8a
8a
8a
8b
8c
8d
8e
8f
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
3
3
3
3
3
3
3
3
3
3
3
2
40
38
trace
35
42
40
41
42
39
46
45
70
55:45
52:48
−
44/44
44/43
−
d
2
3
e
4
5
6
7
8
9
51:49
55:45
51:49
51:49
52:48
53:47
52:48
52:48
52:48
1/0
68/82
73/81
91/91
−91/−91
88/90
93/93
−93/−93
93/93
8g
8e
8f
10
11
12
f
8e
characterized by a novel mixed dimer with a coumarin unit and
quinolinone unit connected by an alkene. The quinolinone
unit fused a chiral dihydropyran moiety which contains one
quaternary and one tertiary carbon chiral center. We proposed
that toddacoumalone (1a) could be obtained from coumarin
derivative 2 and quinolinone derivative alkene 3a through
Heck reaction as the final step.9 Coumarin derivative 2 could
be prepared in two steps from commercially available materials
according to the reported methods.10 The terminal olefin
group in the key intermediate 3a was envisioned to be
transformed from primary alcohol 4a via Grieco elimination.11
4a could be derived from the aldehyde 5a by a simple
reduction reaction. Thus, the preparation of quinolinone fused
dihydropyran aldehyde 5a was the key step in the total
synthesis of toddacoumalone. Inspired by the dienamine
catalyzed inverse-electron-demand Diels−Alder (IEDDA)
reactions, especially, the pioneering work by Jørgensen and
Chen,12 we proposed that the chiral dihydropyran moiety
could be constructed through a formal [4 + 2] cycloaddition
reaction by dienamine catalysis from quinolinone derived
diene 6a′ and commercially available 3-methylcrotonaldehyde
7a.13 We noticed that the nonisolable diene 6a′ exists in the
form of stable and isolable ring closing pyranoquinolinone 6a,
which could be in equilibrium with 6a′ through an oxa-6π
electrocyclic pathway.14 It is worth noting that 6a could be
easily prepared by one step from commercial starting
materials.15 Because the examples of using 6a in asymmetric
catalysis are rare, we first set out to explore the possibility of
accessing chiral quinolinone fused dihydropyran aldehyde 5a
a
Unless otherwise noted, reactions were performed with 6 (0.1
mmol), 7a (0.15 mmol), catalyst 8 (20 mol %), and BzOH (20 mol
%) in 1 mL of THF under room temperature. Combined isolated
yield of 4a and 4aa or 4b and 4bb. Determined by chiral HPLC
b
c
d
analysis of 4a and 4aa or 4b and 4bb. Adding 0.1 mL of H2O.
e
f
Adding 50 mg of 4 Å MS. With 6b (0.25 mmol), 7a (0.375 mmol),
8e (20 mol %), and BzOH (20 mol %) in 0.25 mL of THF.
eoisomers 5a and 5aa were isolated after 3 days, which were
reduced to the corresponding alcohols 4a and 4aa to facilitate
further characterizations. 4a and 4aa were obtained in
moderate yield with low enantioselectivity and poor diaster-
eoselectivity (Table 1, entry 1). Several frequently used
solvents were screened, and THF was witnessed to be the
suitable solvent (see Supporting Information, Table S1). The
addition of H2O or 4 Å MS did not improve the reaction
outcomes (Table 1, entries 2−3). Use of different acid
additives did not result in significant improvement (see
Supporting Information, Table S1). With the purpose of
improving the enantioselectivity and poor diastereoselectivity,
L-proline 8b and some of its known derivatives were tried, but
none of them gave remarkable better results compared with 8a
(see Supporting Information, Table S1). To further improve
the reaction results, catalysts 8c−8g were synthesized by a
similar reported synthetic process with the purpose of
increasing the steric hindrance, by fine-tuning the protecting
groups on the two hydroxyl groups.16 In general, 8c−8g with
bulky substituents displayed superior results to 8a (Table 1,
B
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a b c d
, , ,
entries 5−9). Luckily, catalyst 8e gave the best results and
delivered 4a and 4aa in moderate yield (41%) and high ee
value (91%), albeit with dissatisfactory diastereoselectivity
(Table 1, entry 7). Perhaps not surprisingly, catalyst 8f, which
is the enantiomer of 8e, gave 4a and 4aa in almost identical
yield and completely opposite enantioselectivity (Table 1,
entry 8). In addition, better results were obtained for alcohol
4b and 4bb by using 6b with a benzyl group on the nitrogen
atom (entries 10−11). Further optimization, including screen-
ing the reaction concentration, temperature, and reaction time
(see Supporting Information, Table S1), led to establishing the
optimal reaction conditions (Table 1, entry 12). Although poor
diastereoselectivities were observed for the reaction, this set of
conditions provided the opportunity to synthesize all possible
stereoisomers of the key intermediate 4, which could be
applied to prepare the isomers of toddacoumalone.
Scheme 2. Substrate Scope of the Reaction
With the optimized reaction conditions in hand, the scope of
the pyranoquinolinones 6a−6o to react with 7a was then
explored. As shown in Table 2, 6a−6c bearing different
a
Table 2. Substrate Scope of the Reaction
b
b
c
yield
dr
ee
entry
6
R1, R2, R3, R4
(%)
(4X:4XX)
(4X:4XX)
a
b
For reaction conditions, please see Table 1, entry 12. With catalyst
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me, H, H, H
Bn, H, H, H
Ph, H, H, H
Bn, F, H, H
Bn, Cl, H, H
Bn, Br, H, H
Bn, CF3, H, H
Bn, NO2, H, H
Bn, Me, H, H
Bn, iPr, H, H
Bn, tBu, H, H
Bn, Ph, H, H
60
70
55
60
61
73
73
45
64
56
51
58
68
63
54
51:49
52:48
51:49
52:48
55:45
51:49
54:46
55:45
50:50
52:48
55:45
56:44
53:47
53:47
55:45
91/91
93/93
94/94
84/85
85/85
87/87
89/87
73/68
90/90
93/87
91/85
92/85
90/83
91/91
81/79
c
8f. The dr was determined by the separated diastereomers of 4X and
4XX. The ee was determined by chiral HPLC analysis of the
separated 4X and 4XX.
d
gave slightly deterious results (Scheme 2A). As the nitrogen
atom exists in most of the pharmaceuticals and bioactive
molecules, we tried to incorporate additional nitrogen atom
into the pyranoquinolinone to explore the substrate diversity.
6r and 6s smoothly delivered the products, despite only
moderate enantioselectivities were observed (Scheme 2B). 6t−
6v, where a long alkyl chain or cycloalkane substitution was
readily tolerated, gave the corresponding products with good
ee and slightly reduced yield, which might be due to the
increased steric hindrance (Scheme 2C). Finally, the generality
of our catalytic system was also surveyed by using catalyst 8f,
as it can deliver the cycloadducts with different enantiomers
compared with catalyst 8e. 6w and 6x, which present new
types of pyranoquinolinones, were well tolerated, and high
enantioselectivities were detected (Scheme 2D). In addition,
4a′ and 4aa′, enantiomers of 4a and 4aa, could also be
obtained with high ee values by the catalysis of 8f, as they are
key intermediates for the synthesis of stereoisomers of
toddacoumalone (Scheme 2E).
After successfully preparing the key intermediates 4a, 4aa,
4a′, and 4aa′, we then set our attention toward completing the
total synthesis of toddacoumalone (Scheme 3A). According to
the Grieco protocol,11 the primary alcohol 4a first reacted with
o-nitrophenylselenocyanate and tributylphosphine to form a
selenide intermediate through the nucleophilic substitution on
the electron-deficient selenium, followed by treatment with
hydrogen peroxide to obtain the terminal alkene 3a in an 85%
overall yield with retained ee. As the final step, the two
fragments coumarin-derivative 2 and alkene 3a were coupled
through a Heck reaction in the presence of Pd(OAc)2,
9
10
11
12
13
14
15
6j
6k
6l
6m Bn, MeO, H, H
6n
6o
Bn, H, H, MeO
Bn, MeO, MeO, H
a
b
For reaction conditions, please see Table 1, entry 12. The dr was
c
determined by the separated diastereomers of 4X and 4XX. The ee
was determined by chiral HPLC analysis of the separated 4X and
4XX.
substituents on the nitrogen atom participated well in the
reaction and provided the desired products with high
enantioselectivities (Table 2, entries 1−3). A range of the
pyranoquinolinones bearing either electron-donating or
electron-withdrawing groups on the benzene ring, ranging
from the 6-position to 8-position, participated well in the
reaction to give the desired products in moderate to good yield
and high enantioselectivities (entries 4−7 and 9−14), although
the 6-NO2-pyranoquinolinone (6h) and 6,7-(MeO)2-pyrano-
quinolinone (6o) gave the products with slightly reduced
enantioselectivities (entries 8 and 15).
To further demonstrate the generality of this reaction, more
pyranoquinolinones (6p−6x, see Supporting Information
Figure S2) were examined, and the products were outlined
in Scheme 2. 6p gave the highest ee value up to 96%, while 6q
C
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Scheme 3. Total Synthesis and Structure Confirmation of
Toddacoumalone
Table 3. IC50 Values of the Active Compounds against
PDE4D2
compound
IC50 (μM)
compound
IC50 (μM)
1a
1a′
1.11 0.14
0.18 0.009
1aa
1aa′
>10
>20
Interestingly, 1aa and 1aa′, the stereoisomers of 1a and 1a′,
did not show remarkable inhibition activity, even when the
concentration was up to 10 μM or 20 μM, indicating that the
stereocenters within those molecules are critical for their
bioactivity on PDE4. Importantly, compound 1a′, which
showed at least 6-, 50-, and 100-fold potency over its
stereoisomers 1a, 1aa, and 1aa′, shed light on the primary
SAR information of how to further develop this compound.
The inhibitory curves of the two most active compounds (1a
and 1a′, IC50 = 1.11 and 0.18 μM) are represented in Figure 2.
tetrabutylammonium bromide (TBAB), and NaHCO3 to
accomplish the total synthesis of 1a in 60% yield. Gratifyingly,
high stereoselectivity was still obtained, even under such harsh
reaction conditions. By employing the same strategy, 1aa, 1a′,
and 1aa′, the other stereoisomers of 1a, could also be obtained
from intermediates 4aa, 4a′, and 4aa′, respectively. Thus, we
achieved the first asymmetric total synthesis of toddacoum-
alone and its stereoisomers with the overall yields ranging from
15% to 16% starting from 6a.
4a and 4aa are diastereoisomers. The absolute configuration
of 4a derived toddacoumlone 1a was unequivocally assigned by
single-crystal X-ray analysis (CCDC 1903774, Scheme 3A).
Thus, the absolute configuration of 4a and its enantiomer 4a′
were assigned. 4aa and 4aa′ are enantiomers. The absolute
configuration of 4aa′ was unambiguously assigned on the basis
of the single-crystal X-ray analysis of acid 9 (CCDC 1903773),
which was derived from 4aa′ by converting the corresponding
alcohol to aldehyde, followed by using the Pinnick oxidation to
obtain the carboxylic acid 9 (Scheme 3B).17 Thus, the absolute
configuration of 4a, 4aa, 4a′, and 4aa′ were all assigned.
Accordingly, the absolute configuration of 1a (from 4a), 1aa
(from 4aa), 1a′ (from 4a′), and 1aa′ (from 4aa′) were also all
assigned. After careful analysis of the NMR data of 1a, 1aa, 1a′,
and 1aa′, and comparison of the NMR data with NMR of the
natural isolated toddacoumalone (1),7,8 we confirmed that the
natural toddacoumalone (1) was composed of enantiomer 1a
and 1a′. As there were no crystal structure of toddacoumalone
reported, the single-crystal X-ray analysis of 1a not only
established the absolute configuration of the two chiral centers
but also confirmed the structure of toddacoumalone.
Figure 2. Inhibitory curves of compounds 1a, 1a′, and rolipram
(positive control) against PDE4D2.
The yields of this asymmetric [4 + 2] cycloaddition reaction
which were not satisfactory might be due to the slow
isomerization rate from oxa-6π electrocyclic ring closing
pyranoquinolinone 6a to ring opening 6a′. On the basis of
the stereochemistry of the obtained products, we also looked
into the poor diasteroselectivity of this reaction. As most of the
IEDDA reactions generally gave excellent diastereoselectiv-
ities,19 we speculated that this reaction did not occur as an
IEDDA reaction, but might be a step-wise formal [4 + 2]
cycloaddition reaction (a proposed transition state model was
provided; please see the Supporting Information, Figure S4).
Further mechanistic studies to fully explain the reaction
mechanism are currently underway.
In summary, we have achieved the first concise asymmetric
total synthesis of toddacoumalone and its stereoisomers by
developing diastereodivergent asymmetric [4 + 2] cyclo-
addition reactions catalyzed by secondary amine catalysts, with
the overall yield ranging from 15% to 16% starting from 6a. A
diverse range of pyranoquinolinones and 3-methylcrotonalde-
hyde were well tolerated under the optimized reaction
conditions. We also confirmed the structure of todacoumalone
and identified 1a′ to be most potent with an IC50 around 0.18
μM. Our study not only provided the primary SAR information
on these molecules but also clarified the stereochemistry is
critical for the bioactivities. Further investigations on the
reaction mechanism and medicinal chemistry studies of 1a′ to
develop the highly potent PDE4 inhibitor in search of lead
structures are currently underway in our laboratory.
Having the desired four stereoisomers of the synthesized
toddacoumalone in hand, we then investigated their inhibition
potency on PDE4 (Table 3). The inhibition potency on
PDE4D2 of the four compounds was determined using the
well-known PDE4 inhibitor rolipram as the reference
compound.18 The results of bioassay showed that compound
1a was potent with the IC50 values around 1 μM. 1a′ was the
most potent compound among its stereoisomers, with IC50
values around 0.18 μM, which was more potent than rolipram
and almost identical to the natural isolated toddacoumalone.8
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04355.
D
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Letter
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Corresponding Author
■
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Xiao-Feng Xiong − Sun Yat-sen University, Guangzhou,
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Other Authors
Ke-Qiang Hou − Sun Yat-sen University, Guangzhou,
China
Xue-Ping Chen − Sun Yat-sen University, Guangzhou,
China
Yiyou Huang − Sun Yat-sen University, Guangzhou,
China
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Albert S. C. Chan − Sun Yat-sen University, Guangzhou,
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Hai-Bin Luo − Sun Yat-sen University, Guangzhou,
China; orcid.org/0000-0002-2163-0509
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support by the National
Natural Science Foundation of China (No. 81602972),
Guangdong Natural Science Funds for Distinguished Young
Scholar (No. 2018B030306017), Guangdong Province Uni-
versities and Colleges Pearl River Scholar Funded Scheme
(2018), and Guangdong Provincial Key Laboratory of Chiral
Molecule and Drug Discovery (2019B030301005).
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