A Short, Efficient, and Stereoselective Synthesis of Piperine and its Analogues

Article abstract of DOI:10.1055/s-0037-1611652

A quantitative synthesis of piperine from commercially available starting material is presented. The synthesis relies on a stereoselective nucleophilic attack of an in situ generated cuprate onto a cyclobutene lactone. The so-formed aryl-substituted cyclobutene spontaneously undergoes a conrotatory 4π-electrocyclic ring opening to form the 4-aryl pentadienoic acid as a single diastereoisomer. The high-yielding synthesis can be easily modulated on the aryl and on the amide moiety for the synthesis of a wide range of piperine analogues.

Full text of DOI:10.1055/s-0037-1611652

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
Synlett
A. Bauer et al.
Letter
A Short, Efficient, and Stereoselective Synthesis of Piperine and
its Analogues
Adriano Bauer ◊
Jun-Hyun Nam ◊
O
O
O
O
OH
4π
conrot.
amide
formation
N
Cu
Nuno Maulide*
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3-0
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O
Institute of Organic Chemistry, University of Vienna, Währinger
Straße 38, 1090 Vienna, Austria
MgBr
piperine
nuno.maulide@univie.ac.at
◊
These authors contributed equally to this work
Piperine synthesized in quantitative yield
Full stereocontrol
Modulation of the aryl and the amide moiety
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
Received: 26.11.2018
Accepted after revision: 16.12.2018
Published online: 14.01.2019
and chronic breast pain.2c Studies have shown that piperine
is a potent desensitizer of human TRPV1, rendering its
structure a potent scaffold for the design of improved
TRPV1 agonists.2
DOI: 10.1055/s-0037-1611652; Art ID: st-2018-b0768-l
c,d
License terms:
Moreover, piperine has been recently identified as an al-
losteric modulator of the -amino butyric acid type A
Abstract A quantitative synthesis of piperine from commercially avail-
able starting material is presented. The synthesis relies on a stereose-
lective nucleophilic attack of an in situ generated cuprate onto a cy-
clobutene lactone. The so-formed aryl-substituted cyclobutene
spontaneously undergoes a conrotatory 4-electrocyclic ring opening
to form the 4-aryl pentadienoic acid as a single diastereoisomer. The
high-yielding synthesis can be easily modulated on the aryl and on the
amide moiety for the synthesis of a wide range of piperine analogues.
3a
(GABA ) receptor. The mode of action of piperine is thus
A
analogous to commonly used drugs such as benzodiaze-
pines, widely used as sleep-inducing agents. 3 In addition,
it has been shown that piperine derivatives are efficient in-
b,c
4
hibitors of vascular smooth muscle cell proliferation. Anti-
depressant5b and antitumor activities along with insecti-
cidal properties5 are also attributed to this intriguing mol-
ecule which can be technically found in almost every
modern kitchen in the world.
5c
d
Key words total synthesis, piperine, alkaloid, cyclobutene, pericyclic
reaction, stereoselective, organometallic chemistry
Despite the numerous demonstrated beneficial thera-
peutic properties of piperine, biological applications are
limited by its poor solubility in aqueous media. This im-
In 1820, the Danish physicist and chemist Hans Chris-
tian Ørstedt, pursuing an interest in the isolation of ‘new al-
kalis’, reported a new alkaloid from pepper (piper nigrum),
6
plies that new synthetic routes towards piperine analogues
are highly desirable.
1
which he called piperine. Piperine would ultimately gain
5
the attention of the chemistry and physiology communi-
Piperine can be easily extracted and its basic hydroly-
2
ties mostly due to its wide range of biological activities.
sis, yielding piperic acid, opens up the preparation of many
7
This was foreshadowed by the original communication
itself, where Ørstedt noted that an ethanolic solution of
amide analogues for biological evaluation. This approach is
unfortunately limited by nonexchangeability of the aryl
moiety. Most approaches for the synthesis of 1-carbonyl-4-
aryl-substituted dienes typically make use of a (2 + 2), (3 +
1), or a (1 + 2 + 1) carbon disconnection. In this regard Wit-
tig olefination,8 olefin metathesis,9 palladium-catalyzed
1
piperine has an ‘exceptionally pungent taste’. The pungen-
cy of piperine can be attributed to its agonistic nature to-
wards the heat- and acidity-sensing TRPV ion channels,
which are associated with temperature and pain regulation
2a,b
10
in the human body.
A range of human disorders are
cross-coupling, or ruthenium-catalyzed vinyl–alkyne cou-
linked to the overexpression of TRPV1, including inflamma-
tory bowel disease (ulcerative colitis and Crohn’s disease)
pling11 have been employed as dominant strategies.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
Synlett
A. Bauer et al.
Letter
a) Mihovilovic et al. (ref. 12)
O
amide
formation
O
O
Pd catalyst
ArBr
R
R
OH
N
Ar
N
R
R
b) Chandrasekhar et al. (ref. 13)
N
NHTs
O
O
ArMgBr
R
Ar
H
Ar
N
O
R
c) This work
O
Cu
O
amide
formation
O
OH
N
O
MgBr
Scheme 1 Previous work and this work
A rather unconventional approach is the direct coupling
of the aryl moiety with the diene or a diene precursor. Mi-
hovilovic and coworkers reported an efficient Heck reaction
approach in which an aryl bromide is coupled to a pentadi-
via acyl chloride substitution with piperidine afforded pip-
erine in more than 95% isolated yield.18 Through the route
presented herein, this alkaloid was thus available in only
three quantitative steps from pyrone 1 and with full stereo-
selectivity (Scheme 2).
4,12
enoic amide (Scheme 1, a).
Another intriguing, earlier
approach, relies on the addition of a Grignard reagent to a
furfural hydrazone, which rearranges to the corresponding
pentadienal under the reaction conditions (Scheme 1, b).13
Herein we would like to present a different strategy to-
wards the synthesis of piperine analogues. The bicyclo
MgBr
O
O
3a
O
hν, Et2O
15 °C
95%
LiCl, CuCN
–78 °C to –40 °C
O
–
O
O
[
2.2.0] lactone 2 and its derivatives have been deployed in
OH
>
O
>95%
previous work by our group and others as a versatile elec-
O
O
14
trophile. In particular, we have shown that copper-medi-
ated nucleophilic addition is a very robust method for a
1
2
4a (piperic acid)
single isomer
14f
trans-selective allylic substitution of 2.
O
N
SOCl2, DCM
piperidine
>95%
The installation of an electron-rich moiety (such as –OR
O
O
or –N ) in this position has been earlier shown to facilitate a
3
subsequent, spontaneous 4-electrocyclic opening. This is
likely due to a push–pull relationship between the carbox-
ylic acid and the electron-donating substituent.1
5
5aa (piperine)
We hypothesized that an aryl moiety might be suffi-
ciently electron donating in order to induce a similar push–
pull effect and enable facile electrocyclic ring opening, ei-
ther spontaneously at room temperature or upon mild
heating. Importantly, the transient trans-configured cy-
clobutene should undergo opening according to a thermally
allowed, conrotatory movement torquoselective for the E,E-
diene product.
Scheme 2 A simple three-step synthesis of piperine
Encouraged by these results, we investigated the syn-
thesis of three different piperic acid analogues by using dif-
ferent Grignard reagents for the ring opening of bicyclolac-
tone 2. The 5-phenylpentadienoic acid (4b) was prepared in
quantitative yield, while the para-methoxyphenyl- and the
2-thiophenyl- analogues were formed in slightly lower
yields. Nevertheless, geometric selectivity was excellent in
Lactone 2 was prepared in quantitative yield photo-
14f
19
chemically, as previously reported. In the event, we found
that addition of the in situ formed cuprate (from its corre-
sponding Grignard reagent 3a) directly led to piperic acid
all cases (Scheme 3). Finally, the corresponding amides
were formed as before via standard acyl chloride substitu-
tion (Scheme 4).18 It should be noted that amides 5bb and
(
4a) as the sole product in a single, quantitative step.16 As
5cb have been previously reported to enhance GABA -in-
A
expected, 4a was formed exclusively as the E,E-diene iso-
mer in a clean reaction. Straightforward amide formation
duced chloride currents more strongly than natural piper-
ine (789% ± 72% and 883% ± 70%, respectively).
17
12
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
Synlett
A. Bauer et al.
Letter
Supporting Information
MgBr
LiCl, CuCN
O
O
O
OH
4π
conrot.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611652.
–
78 °C to –40 °C
OH
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
O
2
4'
4
References and Notes
O
O
(1) Ørstedt, H. C. Journal für Chemie und Physik 1820, 29, 80.
(
2) (a) Bley, K. R. Exper. Opin. Invest. Drugs 2004, 13, 1445.
b) Gavva, N. R.; Bannon, A. W.; Surapaneni, S.; Hovland, D. N. Jr;
OH
OH
(
O
S
4b >95%
4d 84%
Lehto, S. G.; Gore, A.; Juan, T.; Deng, H.; Han, B.; Klionsky, L.;
Kuang, R.; Le, A.; Tamir, R.; Wang, J.; Youngblood, B.; Zhu, D.;
Norman, M. H.; Magal, E.; Treanor, J. J. S.; Louis, J.-C. J. Neurosci.
OH
MeO
4c 75%
2
007, 27, 3366. (c) Szallasi, A. Trends in Pharm. Sci. 2005, 26,
437. (d) Gunthorpe, M. J.; Szallasi, A. Curr. Pharm. Design 2008,
4, 32.
Scheme 3 Synthesis of piperic acid analogues 4
1
(
3) (a) Zaugg, J.; Baburin, I.; Strommer, B.; Kim, H.-J.; Hering, S.;
Hamburger, M. J. Nat. Prod. 2010, 73, 185. (b) Whiting, P. J. Curr.
Opin. Pharmacol. 2006, 6, 24. (c) Riss, J.; Cloyd, J.; Gates, J.;
Collins, S. Acta Neurol. Scand. 2008, 118, 781.
HN
O
O
SOCl2, DCM
OH
N
(4) Mair, E. M.; Liu, R.; Atanasov, A. G.; Wimmer, L.; Nemetz-
Fiedler, D.; Sider, N.; Heiss, E. H.; Mihovilovic, M. D.; Dirsch, V.
M.; Rollinger, J. M. Planta Med. 2015, 81, 1065.
4
5
(
5) (a) Vasavirma, K.; Upender, M. Int. J. Pharm. Pharm. Sci. 2014, 6,
34. (b) Li, S.; Wang, C.; Koike, K.; Nikaido, R.; Wang, M. W.
J. Asian Nat. Prod. Res. 2007, 9, 421. (c) Sunila, E. S.; Kuttan, G.
J. Ethnopharmacol. 2004, 90, 339. (d) Tavares, W. S.; Cruz, I.;
Petacci, F.; Freitas, S. S.; Serrao, J. E.; Zanuncio, J. C. J. Med. Plants
Res. 2011, 5, 5301.
O
O
N
N
S
5ba 87%
5da 90%
O
(6) Gorgani, L.; Mohammadi, M.; Najafpour, G. D.; Nikzad, M.
Compr. Rev. Food Sci. Food Saf. 2017, 16, 124.
N
(
7) Umadevi, P.; Deepti, K.; Venugopal, V. R. Med. Chem. Res. 2013,
MeO
O
5
ca 75%
2
2, 5466.
(8) (a) Olsen, R. A.; Spessard, G. O. J. Agric. Food Chem. 1981, 29,
42. (b) Schobert, R.; Siegfried, S.; Gordon, G. J. J. Chem. Soc.,
O
N
9
N
Perk. Trans. 1 2001, 2393. (c) O’Brien, C. J.; Lavigne, F.; Coyle, E.
E.; Holohan, A. J.; Doonan, B. J. Chem. Eur. J. 2013, 19, 5854.
9) Lipshutz, B. H.; Ghorai, S.; Boskovic, Z. V. Tetrahedron 2008, 64,
MeO
5
cb 78%
5
bb 95%
(
6
949.
10) (a) Abarbri, M.; Parrain, J.-L.; Duchene, A. Synth. Commun. 1998,
8, 239. (b) Naskar, D.; Roy, S. Tetrahedron 2000, 1369.
11) Schabel, T.; Plietker, B. Chem. Eur. J. 2013, 19, 6938.
(12) Wimmer, L.; Schönbauer, D.; Pakfeifer, P.; Schöffmann, A.;
Khom, S.; Hering, S.; Mihovilovic, M. D. Org. Biomol. Chem. 2015,
13, 990.
Scheme 4 Synthesis of piperine analogues 5
(
2
In conclusion, we herein presented a conceptually new
approach to the synthesis of 4-aryl-substituted pentadieno-
ic acids and their amides in excellent yield and geometrical
(
20–26
stereoselectivity.
This enabled a preparation of the nat-
(13) Chandrasekhar, S.; Venkat Reddy, M.; Srinivasa Reddy, K.;
Ramarao, C. Tetrahedron Lett. 2000, 41, 2667.
ural product piperine in quantitative yield over three steps
from commercially available 2-pyrone 1. Analogues can be
readily synthesized through this modular and operationally
simple procedure.
(
14) (a) Frébault, F.; Luparia, M.; Oliveira, M. T.; Goddard, R.;
Maulide, N. Angew. Chem. Int. Ed. 2010, 49, 5672. (b) Luparia,
M.; Audisio, D.; Maulide, N. Synlett 2011, 735. (c) Luparia, M.;
Oliveira, M. T.; Audisio, D.; Frébault, F.; Goddard, R.; Maulide, N.
Angew. Chem. Int. Ed. 2011, 50, 12631. (d) Audisio, D.; Luparia,
M.; Oliveira, M. T.; Kluett, D.; Maulide, N. Angew. Chem. Int. Ed.
Funding Information
2
012, 51, 7314. (e) Souris, C.; Frébault, F.; Audisio, D.; Farès, C.;
Funding by the Austrian Research Fund (FWF Project P27194) is
Maulide, N. Synlett 2013, 24, 1286. (f) Souris, C.; Misale, A.;
Chen, Y.; Luparia, M.; Maulide, N. Org. Lett. 2015, 17, 4486.
gratefully acknowledged.
A
ustir
a
n
R
esearc
h
F
u
n
d
(P
2
7
1
9
4)
(g) Gutekunst, W. R.; Baran, P. S. J. Am. Chem. Soc. 2011, 133,
1
9076. (h) Nistanaki, S.; Boralsky, L. A.; Pan, R. D.; Nelson, H.
Acknowledgment
ChemRxiv. 2018, DOI: 10.26434/chemrxiv.7245167.v2.
15) For spontaneous ring opening of cyclobutenes, see: (a) Binns, F.;
Hayes, R.; Ingham, S.; Saengchantara, S. T.; Turner, R. W.;
Wallace, T. W. Tetrahedron 1992, 48, 515. (b) Binns, F.; Hayes, R.;
(
We are grateful to the University of Vienna for continued generous
support of our research programs.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
Synlett
A. Bauer et al.
Letter
Hodgetts, K. J.; Saengchantara, S. T.; Wallace, T. W.; Wallis, C. J.
Tetrahedron 1996, 52, 3631. (c) Sheldrake, H. M.; Wallace, T. W.;
Wilson, C. P. Org. Lett. 2005, 7, 4233. (d) Ingham, S.; Turner, R.
W.; Wallace, T. J. Chem. Soc,. Chem. Commun. 1985, 1664.
conversion. Thereafter, volatiles were removed under reduced
pressure, and the flask was flushed with argon again (an argon-
filled balloon was attached to the rotary evaporator). To the
resulting residue anhydrous DCM was added (1 mL), and the
amine was added dropwise (0.40 mmol, 2.0 equiv.). Afterwards,
the solution was stirred for 1 h at room temperature. Finally, the
reaction mixture was quenched and washed with saturated
(
16) Magnesium turnings (1.60 mmol, 3.0 equiv.) were suspended in
a flamed-dried Schlenk tube containing anhydrous THF (3 mL)
which was previously flushed with argon. A solution of an aryl-
bromide in dry THF (1.60 mmol, 1.0 equiv. in 2 mL) was added
dropwise under stirring. The mixture was stirred at room tem-
perature until the magnesium was fully solubilized. LiCl (3.20
mmol, 6 equiv.) was flame-dried in another Schlenk tube under
vacuum. After flushing with argon and cooling to room tem-
perature CuCN (1.60 mmol, 3 equiv.) was added to the solid,
suspended in anhydrous THF (5 mL), and stirred for 20 min at
room temperature. The green solution was cooled down to –40 °C,
followed by an addition of the Grignard (1.60 mmol, 3 equiv.)
and further stirred for 40 min. Afterwards, the reaction mixture
was cooled down to –78 °C. After stirring for 15 min, an ethereal
solution of lactone 2 (0.53 mmol, 1 equiv.) was added, and the
reaction mixture was allowed to warm up slowly to –30 °C. The
reaction was quenched by the dropwise addition of aqueous
HCl (1 M, 5 mL), and the obtained solution was warmed up
quickly to room temperature (the dry ice bath was removed).
Upon dilution with EtOAc (10 mL), the reaction mixture was
extracted and washed with aqueous HCl (1 M) whereby the
aqueous layer was neutralized with sufficient NaOH (5 M) in
order to deprotonate the formed hydrocyanic acid. The organic
layer was dried over Na SO , filtered, and the solvent was
aqueous NaHCO solution, and the aqueous layer was extracted
3
3 times with DCM. The combined organic layer was dried over
Na SO , filtered, and volatiles were removed under reduced
2
4
pressure to yield the pure amide. Further purification via flash
chromatography gave the desired amide. (Gradient: EtOAc/hep-
tane 10:90 to EtOAc/heptane 60:40).
(19) The crude NMR of 4b, 4c, and 4d suggested that traces (<5%
NMR yield) of another geometrical isomer was present which
was easily separated by column chromatography. We were not
able to find this side product after purification.
(20) Kotretsou, S. I.; Georgiadis, M. P. Org. Prep. Proced. Int. 2000, 32,
161.
(21) Wani, N. A.; Singh, S.; Farooq, S.; Shankar, S.; Koul, S.; Khan, I. A.;
Rai, R. Bioorg. Med. Chem. Lett. 2016, 26, 4174.
(22) Wang, Z.; He, Z.; Zhang, L.; Huang, Y. J. Am. Chem. Soc. 2018, 140,
735.
(23) Yasir, A.; Ishtiaq, S.; Jahangir, M.; Ajaib, M.; Salar, U.; Khan, K. M.
Med. Chem. 2018, 14, 269.
(24) Shen, Y.; Zhou, Y. J. Chem. Soc., Perkin Trans. 1 1992, 22, 3081.
(25) Spectroscopic data of 1, 2, 4a, 4b, 4c, 4d, 5aa, 5ba,24
2
0
14f
21
22
10b
10b
23
4
12
12
5ca, 5bb, and 5cb matches previously reported spectra.
2
4
removed under reduced pressure. Purification of the crude acid
was performed via column chromatography (EtOAc/hep-
tane/acetic acid 10%:89%:1%) to yield the 4-aryl-substituted
pentadienoic acid as a solid.
(26) Characterization of 5da
1
H NMR (400 MHz, CDCl ):  = 7.37 (ddd, J = 14.6, 11.1, 0.6 Hz, 1
3
H), 7.23 (d, J = 5.0 Hz, 1 H), 7.07 (d, J = 3.5 Hz, 1 H), 7.01–6.93 (m,
2 H), 6.70 (dd, J = 15.3, 11.2 Hz, 1 H), 6.45 (d, J = 14.7 Hz, 1 H),
(
17) Copper(I) iodide lead only to messy reactions with traces of
desired product.
3.60 (d, J = 24.6 Hz, 2 H), 3.52 (s, 2 H), 1.71–1.55 (m, 7 H). 13
C
NMR (151 MHz, CDCl ):  = 165.40, 142.03, 131.18, 127.97,
3
(
18) In a flame-dried Schlenk tube the carboxylic acid 4 (0,20 mmol,
127.90, 126.80, 125.99, 120.62, 47.04, 43.38, 26.86, 25.74,
24.78. HRMS (ESI): m/z calcd for [M + Na] : 270.0923; found:
+
1.0 equiv.) was dissolved in anhydrous DCM (1 mL), followed by
the addition of thionyl chloride (0.40 mmol, 2.0 equiv.). The
reaction was stirred at room temperature until the solid dis-
solved completely. Heating to reflux can be applied for a faster
270.0926. ATR-FTIR: 3001, 2935, 2854, 2237, 1631, 1588, 1513,
1435, 1358, 1295, 1254, 1222, 1190, 1133, 1118, 1043, 1018,
990, 953, 907, 872, 853, 833, 805, 726, 644, 575, 543, 532 cm–1
.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D