Concise synthesis of the vasorelaxant alkaloids schwarzinicines A and B

Article abstract of DOI:10.1080/14786419.2021.1903005

A concise synthesis of the 1,4-diarylbutanoid–phenethylamine alkaloids, schwarzinicines A (1) and B (2), recently isolated from Ficus schwarzii, is reported. Key steps include a Claisen condensation to assemble the 1,4-diaryl-2-butanone intermediate, foll

Full text of DOI:10.1080/14786419.2021.1903005

Natural Product Research
Formerly Natural Product Letters
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Concise synthesis of the vasorelaxant alkaloids
schwarzinicines A and B
Fong-Kai Lee, Premanand Krishnan, Azira Muhamad, Yun-Yee Low, Toh-Seok
Kam, Kang-Nee Ting & Kuan-Hon Lim
To cite this article: Fong-Kai Lee, Premanand Krishnan, Azira Muhamad, Yun-Yee Low, Toh-Seok
Kam, Kang-Nee Ting & Kuan-Hon Lim (2021): Concise synthesis of the vasorelaxant alkaloids
schwarzinicines A and B, Natural Product Research, DOI: 10.1080/14786419.2021.1903005
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2021.1903005
Concise synthesis of the vasorelaxant alkaloids
schwarzinicines A and B
Fong-Kai Leea, Premanand Krishnana, Azira Muhamadb, Yun-Yee Lowc, Toh-Seok
Kamc, Kang-Nee Tinga and Kuan-Hon Lima
b
aSchool of Pharmacy, University of Nottingham Malaysia, Semenyih, Selangor, Malaysia; Malaysia
c
Genome Institute, Kajang, Selangor, Malaysia; Department of Chemistry, Faculty of Science,
University of Malaya, Kuala Lumpur, Malaysia
ABSTRACT
ARTICLE HISTORY
Received 5 January 2021
Accepted 8 March 2021
A concise synthesis of the 1,4-diarylbutanoid–phenethylamine
alkaloids, schwarzinicines A (1) and B (2), recently isolated from
Ficus schwarzii, is reported. Key steps include a Claisen condensa-
tion to assemble the 1,4-diaryl-2-butanone intermediate, followed
by a reductive amination to furnish the core skeleton of the tar-
get compounds. The overall synthetic yields of 1 and 2 were
9.1% and 3.5%, respectively. Synthetic (ꢀ)-1, (þ)-1 and ( )-1
exhibited comparable vasorelaxation as natural schwarzinicine A
on rat isolated aortic rings, suggesting that the observed vasore-
laxant effects were not influenced by the chirality at C-2.
KEYWORDS
Ficus schwarzii;
schwarzinicine; phenethyl-
amine; alkaloid; synthesis;
vasorelaxation
1. Introduction
Although Ficus (Moraceae) is one of the largest genera of flowering plants known to
date (Lansky et al. 2008), only several plants of this genus have been reported to pos-
sess ethnopharmacological uses. In our effort to explore Ficus species occurring in
Peninsular Malaysia for biologically active alkaloids (Yap et al. 2015, 2016; Al-
Khdhairawi et al. 2017), we recently reported the isolation of a series of new 1,4-diary-
lbutanoid–phenethylamine conjugates, viz., schwarzinicines A–G, from the leaves of F.
schwarzii. Since the basic skeleton of the schwarzinicines shows some resemblance to
that of dobutamine, which is a known phenylalkylamine vasorelaxant agent, we were
prompted to evaluate the relaxant effects of these alkaloids on isolated rat smooth
CONTACT Kuan-Hon Lim
KuanHon.Lim@nottingham.edu.my
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2021.1903005.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

2
F.-K. LEE ET AL.
Figure 1. Structures of compounds 1 and 2.
Scheme 1. Synthesis of schwarzinicines A (1) and B (2).
muscle tissues. Schwarzinicines A–D were found to exhibit selective and pronounced
relaxation on rat isolated aorta (Krishnan et al. 2020). However, the extremely low iso-
lation yields of these alkaloids (0.00002%–0.00180%, based on dry weight) precluded
further pharmacological investigations. Herein we report a concise first synthesis of
schwarzinicines A (1) and B (2) (Figure 1). The vasorelaxant effects of the synthetic
alkaloids on rat isolated aortic rings are also reported.
2. Results and discussion
The synthesis of schwarzinicines A (1) and B (2) commenced with the conversion of
the commercially available (3,4-dimethoxyphenyl)propionic acid (3) to its ethyl ester 4
via a Steglich esterification (Scheme 1). The carboxylic acid 3 was esterified with EtOH
in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)
and 4-dimethylaminopyridine (DMAP). Subsequent Claisen condensation of the orga-
nolithium reagent generated from the commercially available (3,4-dimethoxyphenyl)a-
cetonitrile (5) with ester
4 yielded the ketonitrile 6. Nitrile hydrolysis and
decarboxylation to ketone 7 were achieved by modification of a literature procedure
(Carroll and Spoerri 1938) involving a two-step, one-pot reaction sequence to give 7

NATURAL PRODUCT RESEARCH
3
Table 1. Vasorelaxant activity of synthetic alkaloids and dobutamine against phenylephrine-
induced contractiona.
b
b
Compound
n
EC50 (mM)
Emax (%)
(ꢀ)-1
5
5
6
6
5
2.98 0.44
2.43 0.50
2.34 0.52
1.19 0.23
2.50 1.11
119.0 5.6c
116.0 3.1c
119.0 4.4c
106.3 3.8c
92.0 5.0
(þ)-1
( )-1
( )-2
Dobutamine (positive control)
aVehicle control (n ¼ 7) with Emax 53.5 6.2%.
bEach value represents mean standard error of the mean (SEM) of n number of animals.
cUnpaired t-test: Significantly different from dobutamine (p < 0.05).
Figure 2. Vasorelaxant effects of (ꢀ)-1, (þ)-1, ( )-1, ( )-2 and dobutamine against phenylephrine-
induced contractions on rat isolated aortic rings. Data are expressed as the mean SEM (n ¼ 5
or 6).
in 61% yield as depicted in Scheme 1. It is worth noting that the ketone intermediate
7 was recently obtained as a natural product from Ficus nota and was given the trivial
name ficusnotin E (Latayada et al. 2017). Reductive amination of ketone 7 with
NaBH(OAc)3 in the presence of 3,4-dimethoxyphenethylamine (8) furnished schwarzini-
cine A (1) in 79% yield. Finally, N-methylation of 1 with MeI yielded schwarzinicine B
(2) in 38% yield.
The vasorelaxant effects of synthetic (ꢀ)-1, (þ)-1, ( )-1, and ( )-2 were evaluated
on phenylephrine-precontracted rat aortic rings. All the tested compounds exhib-
ited pronounced vasorelaxation (Emax 106–119%) in a concentration-dependent
manner, with EC50 values ranging between 1.19 and 2.98 mM (Table 1 and Figure
2). Synthetic (ꢀ)-1, (þ)-1, and ( )-1 were found to show comparable vasorelaxation
to natural schwarzinicine A, which was obtained as a scalemic mixture occurring in
an enantiomeric ratio of 4:1 (Krishnan et al. 2020). Additionally, synthetic ( )-2
showed comparable vasorelaxation to natural schwarzinicine B (2), which was
obtained as an enantiopure dextrorotatory isomer (Krishnan et al. 2020). These
observations suggested that the chirality at C-2 has no or little effect on vasorelax-
ant activities.

4
F.-K. LEE ET AL.
3. Experimental
3.1. General
All reactions were carried out under an inert atmosphere of N2. THF was purified and
dried based on the procedure reported by Simas et al. (2009). EtOH, CH2Cl2, and
ClCH2CH2Cl were dried using Sigma-Aldrich 3 Å MS (8–12 mesh) based on the proced-
ure reported by Williams and Lawton (2010). All chemicals were purchased from com-
mercial suppliers and used without further purification. Reactions were monitored by
TLC on Merck pre-coated silica gel 60 F254 plates. Preparative radial chromatography
was performed on a Harrison 7924 T Chromatotron using glass plates coated with
Merck silica gel 60 PF254 containing gypsum. Infrared spectra were recorded using a
PerkinElmer Spectrum 400 FT-IR/FT-FIR spectrometer. Optical rotations were deter-
1
mined on a JASCO P-1020 automatic digital polarimeter. H and 13C NMR spectra were
recorded in CDCl3 using tetramethylsilane as an internal standard on a Bruker 400,
600 or 700 MHz spectrometer. HRDARTMS were obtained on a JEOL AccuTOF-DART
mass spectrometer. Chiral-phase HPLC was performed on a Waters ACQUITY Arc
UHPLC System equipped with a Waters 2998 Photodiode Array (PDA) detector and a
Waters Fraction Collector III, using a Chiralpak IA column (4.6 ꢁ 150 mm, 5 mm, Daicel,
Japan) at ambient temperature.
3.2. Synthesis
3.2.1. Ethyl 3-(3,4-dimethoxyphenyl)propanoate (4)
To a stirred solution of (3,4-dimethoxyphenyl)propionic acid (3) (1.01 g, 4.80 mmol, 1
equiv) in CH2Cl2 (10 mL) was added EtOH (1.1 mL, 18.8 mmol, 3.9 equiv) and DMAP
(61.5 mg, 0.50 mmol, 0.1 equiv) at rt. The solution was ice-cooled prior to the addition
of EDC (918.4 mg, 4.79 mmol, 1 equiv). After stirring for 2.5 h at rt, the solution was
diluted with CH2Cl2 (10 mL) and washed with 0.5 M HCl solution (2 ꢁ 8 mL), followed
by saturated KHCO3 solution (2 ꢁ 8 mL). The organic layer was further washed with
brine (10 mL), dried (MgSO4), and subsequently concentrated in vacuo. The crude
product was purified by preparative radial chromatography, eluting with
EtOAc–hexane (1:1), to yield ester 4 as a light yellowish oil (937 mg, 3.93 mmol, 82%):
Rf ¼ 0.70 (EtOAc–hexane, 3:1); IR (neat) ꢀmax 2937, 2836, 1729, 1591, 1514, 1452, 1372,
1258, 1235, 1183, 1153, 1137, 1026 cmꢀ1 1H NMR (CDCl3, 700 MHz) d 6.79 (d,
;
J ¼ 8.1 Hz, 1H), 6.76–6.72 (m, 2H), 4.13 (q, J ¼ 7.1 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.90
(t, J ¼ 7.8 Hz, 2H), 2.60 (t, J ¼ 8.0 Hz, 2H), 1.24 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3,
175 MHz) d 173.0, 148.8, 147.5, 133.2, 120.1, 111.6, 111.3, 60.4, 55.9, 55.8, 36.2, 30.6,
14.2; HRDARTMS m/z 239.1277 [M þ H]þ (calcd for C13H19O4, 239.1283). The spectro-
scopic data were in good agreement with those reported in the literature (Lebel
et al. 2007).
3.2.2. 2,5-Bis-(3,4-dimethoxyphenyl)-3-oxo-valeronitrile (6)
To an ice-cooled solution of (3,4-dimethoxyphenyl)acetonitrile (5) (155.0 mg,
0.87 mmol, 2 equiv) in THF (10 mL) was slowly added n-BuLi (1.6 M, 0.55 mL, 0.88 mmol,
2 equiv). After stirring for 15 min, ester 4 (102.5 mg, 0.43 mmol, 1 equiv) in THF

NATURAL PRODUCT RESEARCH
5
(0.85 mL) was added into the solution. After stirring for 5 min, water (10 mL), and brine
(4 mL) were added into the reaction mixture. The mixture was extracted with CHCl3
(5 ꢁ 10 mL). The combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The crude product was purified by preparative radial chromatography, eluting
with Et2O–hexane (7:1), to yield ketonitrile 6 as a brown oil (37.8 mg, 0.1 mmol, 23%):
Rf ¼ 0.12 (Et2O–hexane, 8:1); IR (neat) ꢀmax 3005, 2921, 2848, 2249, 2205, 1726, 1593,
1
1513, 1462, 1419, 1259, 1237, 1141, 1023 cmꢀ1; H NMR (CDCl3, 700 MHz) d 6.87–6.82
(m, 2H), 6.74–6.70 (m, 2H), 6.60–6.56 (m, 2H), 4.55 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.84
(s, 3H), 3.82 (s, 3H), 2.94–2.78 (m, 4H); 13C NMR (CDCl3, 175 MHz) d 198.3, 149.8, 149.7,
148.8, 147.5, 132.3, 121.4, 120.6, 120.1, 116.3, 111.6 (ꢁ 2), 111.1, 110.4, 56.0 (ꢁ 2), 55.9,
55.8, 50.7, 41.2, 29.3; HRDARTMS m/z 387.1904 [M þ NH4]þ (calcd for
C21H27N2O5, 387.1920).
3.2.3. 1,4-Bis(3,4-dimethoxyphenyl)butan-2-one (7)
To a stirred solution of ketonitrile 6 (68.0 mg, 0.18 mmol, 1 equiv) in AcOH (6 mL) was
added concentrated HCl (6 mL) at rt. The mixture was then stirred for 2 h at 60 ꢂC.
After cooling to rt, water (22 mL) was added, and the solution was refluxed for 1 h.
The solution was subsequently extracted with CHCl3 (3 ꢁ 15 mL). The combined
organic layers were washed with saturated KHCO3 solution (3 ꢁ 10 mL), water
(2 ꢁ 10 mL), and subsequently brine (10 mL). The solution was then dried (Na2SO4) and
concentrated in vacuo. The crude product was purified by preparative radial chroma-
tography, eluting with CH2Cl2–hexane (2:1), to yield ketone 7 as a light yellowish oil
(36.8 mg, 0.11 mmol, 61%): Rf ¼ 0.61 (2% MeOH–CH2Cl2); IR (neat) ꢀmax 2999, 2935,
1
2835, 1709, 1591, 1511, 1455, 1256, 1234, 1141, 1023 cmꢀ1; H NMR (CDCl3, 400 MHz)
d 6.80 (d, J ¼ 8.1 Hz, 1H), 6.75 (d, J ¼ 8.7 Hz, 1H), 6.70 (dd, J ¼ 8.1, 2.0 Hz, 1H), 6.67 (d,
J ¼ 2.0 Hz, 1H), 6.65 (d, J ¼ 2.0 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 6H), 3.84 (s, 3H), 3.60 (s, 2H),
2.87–2.77 (m, 2H), 2.78–2.73 (m, 2H); 13C NMR (CDCl3, 100 MHz) d 208.0, 149.0, 148.8,
148.1, 147.3, 133.5, 126.5, 121.6, 120.1, 112.3, 111.7, 111.3, 111.2, 55.9 (ꢁ 2), 55.8 (ꢁ 2),
50.0, 43.5, 29.4; HRDARTMS m/z 345.1698 [M þ H]þ (calcd for C20H25O5, 345.1702). The
spectroscopic data were in good agreement with those reported in the literature
(Latayada et al. 2017).
3.2.4. Schwarzinicine A (1)
To a stirred solution of ketone 7 (138.7 mg, 0.40 mmol, 1 equiv) in ClCH2CH2Cl (5 mL)
was added 3,4-dimethoxyphenethylamine (8) (174.8 mg, 0.96 mmol, 2.4 equiv),
NaBH(OAc)3 (351.2 mg, 1.66 mmol, 4.2 equiv) and AcOH (0.05 mL, 0.87 mmol, 2.2 equiv).
The solution was stirred at rt for 28 h before addition of 1 M NaOH solution (4 mL).
The mixture was then extracted with EtOAc (3 ꢁ 10 mL). The combined organic layers
were washed with brine (4 mL), dried (Na2SO4), and concentrated in vacuo. The crude
product was purified by preparative radial chromatography, eluting with
EtOAc–hexane (2:1), to yield 1 as a light yellowish oil (162.9 mg, 0.32 mmol, 79%): Rf ¼
0.19 (EtOAc–hexane, 6:1); IR (neat) ꢀmax 2998, 2933, 2834, 1590, 1513, 1462, 1259,
1234, 1139, 1026 cmꢀ1
J ¼ 8.1 Hz, 1H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.67 (d, J ¼ 1.9 Hz, 1H), 6.66 (dd, J ¼ 6.7, 2.0 Hz,
2H), 6.63 (d, J ¼ 2.1 Hz, 1H), 6.62–6.61 (m, 1H), 6.61–6.59 (m, 1H), 3.86 (s, 3H), 3.85 (s,
;
1H NMR (CDCl3, 600 MHz) d 6.78 (d, J ¼ 8.6 Hz, 1H), 6.73 (d,

6
F.-K. LEE ET AL.
3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.92–2.86 (m, 1H), 2.79–2.69 (m,
3H), 2.70–2.64 (m, 2H), 2.64–2.57 (m, 3H), 1.81–1.74 (m, 1H), 1.74–1.66 (m, 1H); 13C
NMR (CDCl3, 150 MHz) d 148.9 (ꢁ 2), 148.8, 147.5 (ꢁ 2), 147.2, 134.9, 132.4, 131.7,
121.1, 120.5, 120.1, 112.3, 111.9, 111.7, 111.3, 111.2, 111.1, 58.7, 56.0, 55.9, 55.8 (ꢁ 4),
48.5, 40.3, 36.0, 35.6, 31.6; HRDARTMS m/z 510.2860 [M þ H]þ (calcd for
C30H40NO6, 510.2856).
3.2.5. Schwarzinicine B (2)
To a stirred solution of 1 (20.5 mg, 0.04 mmol, 1 equiv) in EtOH (2 mL) was added
K2CO3 (38.0 mg, 0.27 mmol, 6.8 equiv) and MeI (6 mL, 0.1 mmol, 2.5 equiv) in EtOH
(0.6 mL). The mixture was stirred at rt for 5.5 h before concentrated in vacuo. The
crude product was purified by preparative radial chromatography, eluting with Et2O,
to yield 2 as a light yellowish oil (8.0 mg, 0.02 mmol, 38%): Rf ¼ 0.17 (Et2O); IR (neat)
1
ꢀmax 2997, 2935, 2835, 1590, 1514, 1462, 1261, 1235, 1141, 1029 cmꢀ1; H NMR (CDCl3,
400 MHz) d 6.81–6.78 (m, 1H), 6.76 (d, J ¼ 6.8 Hz, 1H), 6.74 (d, J ¼ 7.9 Hz, 2H), 6.73 (d,
J ¼ 8.7 Hz, 1H), 6.65 (dd, J ¼ 8.1, 2.0 Hz, 1H), 6.62 (d, J ¼ 2.0 Hz, 1H), 6.57 (dd, J ¼ 6.2,
1.9 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.80 (s, 3H), 2.89 (dd,
J ¼ 13.0, 4.0 Hz, 1H), 2.84–2.59 (m, 6H), 2.62–2.53 (m, 1H), 2.39 (s, 3H), 2.44–2.29 (m,
1H), 1.75–1.63 (m, 1H), 1.63–1.52 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 148.8, 148.7,
148.6, 147.3, 147.1, 146.9, 135.3, 133.4 (ꢁ 2), 121.1, 120.6, 120.1, 112.3, 112.1, 111.7,
111.1 (ꢁ 2), 111.0, 64.5, 55.9 (ꢁ 3), 55.8 (ꢁ 3), 55.7, 36.9, 34.9, 34.6, 32.5 (ꢁ 2);
HRDARTMS m/z 524.3005 [M þ H]þ (calcd for C31H42NO6, 524.3012).
3.3. Chiral-phase HPLC separation of the enantiomers of schwarzinicine A (1)
( )-1 (12.5 mg) was dissolved in EtOH (1.8 mL) and resolved using a Chiralpak IA col-
umn eluting with hexane–EtOH–Et2NH (90:10:0.1), at a flow rate of 1.0 mL/min (600
injections, 3.0 mL each). Three combined fractions were eventually obtained, where the
25
first fraction corresponded to (ꢀ)-1 [tR 9.1 min; 3.4 mg; [a]D ꢀ11 (c 0.17, CHCl3)], the
second fraction to a mixture of (ꢀ)-1 and (þ)-1 in a ratio of 4:1 (3.0 mg), and the third
25
fraction to (þ)-1 [tR 10.1 min; 5.7 mg; [a]D þ11 (c 0.25, CHCl3)].
3.4. Evaluation of vasorelaxant effects on rat aortic rings
The assays were carried out following the method described previously (Krishnan
et al. 2020).
4. Conclusions
The first racemic synthesis of schwarzinicines A (1) and B (2) has been developed, thus
overcoming the problem of scarcity of material and enabling further pharmacological
investigations. The overall synthetic yields of schwarzinicines A (1) and B (2) were
9.1% and 3.5%, respectively. In addition to investigating the mechanism of action of
schwarzinicine A as a vasorelaxant, the preparation of multiple analogues of

NATURAL PRODUCT RESEARCH
7
schwarzinicine A for structure-activity relationship studies using the synthetic method-
ology described in this report is in progress, and the results will be reported in
due course.
Conflict of interest
The authors have declared that there is no conflict of interest.
Funding
This work was supported by MOHE Malaysia (FRGS/1/2017/STG01/UNIM/02/3 and FRGS/1/2017/
SKK10/UNIM/01/1) and Malaysia Toray Science Foundation (TML-CA/17.195(17/G62)).
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