Total synthesis of Punicagranine

Article abstract of DOI:10.1016/j.tetlet.2019.150989

This communication details the first total synthesis of Punicagranine, a new pyrrolizine alkaloid isolated from the peels of the pomengranate, Punica granatum, the basis for traditional Chinese medicine, with anti-inflammatory activity. Two concise, 4–5 step routes were developed to rapidly prepare Punicagranine in 10.7–12.1% overall yields. One route features an intramolecular Heck reaction, while the other relies on a 1,3-dipolar cycloaddition. The latter route proceeds on scale to support future biological studies.

Full text of DOI:10.1016/j.tetlet.2019.150989

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Total synthesis of Punicagranine
Charles K. Perry, Craig W. Lindsley
PII:
S0040-4039(19)30744-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.150989
TETL 150989
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 July 2019
16 July 2019
26 July 2019
Please cite this article as: Perry, C.K., Lindsley, C.W., Total synthesis of Punicagranine, Tetrahedron Letters (2019),
doi: https://doi.org/10.1016/j.tetlet.2019.150989
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Charles K. Perry and Craig W. Lindsley
O
O
O
H
5 steps
4 steps
HO
O
N
O
N
NH
HO
10.7% overall
12.1% overall
O
1
, punicagranine

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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Total synthesis of Punicagranine
Charles K. Perryǂ and Craig W. Lindsley¥,ǂ*
¥Department of Chemistry, Department of Biochemistry,Vanderbilt University, Nashville, TN 37232-6600, U.S.A.
ǂDepartment of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232-6600, U.S.A.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
This communication details the first total synthesis of Punicagranine, a new pyrrolizine alkaloid
isolated from the peels of the pomengranate, Punica granatum, the basis for traditional Chinese
medicine, with anti-inflammatory activity. Two concise, 4-5 step routes were developed to
rapidly prepare Punicagranine in 10.7 to 12.1% overall yields. One route features an
intramolecular Heck reaction, while the other relies on a 1,3-dipolar cycloaddition. The latter
route proceeds on scale to support future biological studies.
Available online
Keywords:
2019 Elsevier Ltd. All rights reserved.
Punicagranine
total synthesis
1,3-dipolar cycloaddition
pyrrolizine
The peels of the pomegranate, Punica granatum, have been
used in traditional Chinese medicine as an anti-inflammatory
agent to treat a number of diseases, as well as possessing
significant anticancer activities.1-5 The report in 2019 by Du and
Sun describing the isolation and identification of a novel
pyrrolizine alkaloid, punicagranine (1) from the peels of Punica
granatum with anti-inflammatory activity attracted our attention,
as 1 represents an active component (Figure 1).6 Moreover, the
novel structure, drug-like features and potential for the generation
of active metabolites (due to the furanyl ketone moiety) in vivo
argued well for the synthesis of 1 and further biological
evaluation.
readily available/commercial materials 3 and 4. Route B, in
contrast disconnects the pyrrolidine ring juncture, 5, which could
be assembled via an intramolecular Heck reaction. An N-
alkylation and Friedel-Crafts reaction sequence leads to
commercial starting materials 6 and 7.
O
O
Friedel-Crafts
N
HO
O
Intramoelcular Heck
1
route B
O
route A
O
O
9
HO
HO
1,3-dipolar
cycloaddition
1
8
O
7
6
2
Friedel-Crafts
N
N
N
O
O
3'
5
4
Alkylation
I
3
6'
N
O
O
4'
5'
O
O 2'
O
O
2
5
1'
1
, punicagranine
O
O
O
O
O
O
N
O
Figure 1. Structure of punicagranine (1) and the numbering convention
(inset). This unique skeleton has never before been reported in nature. The
structure of 1 was determined by 1D- and 2D-NMR, and confirmed by single
X-ray crystal structure.
O
HN
OH
Cl
3
4
6
7
We envisioned two distinct retrosynthetic approaches to
access 1, employing fundamentally distinct strategies as depicted
in Figure 2, yet both requiring only four linear steps. Key bond
disconnections in route A lead to intermediate 2, which can be
assembled through a 1,3-dipolar cycloaddition reaction with
Figure 2. Retrosynthesis of 1. Route A, features a final Friedel-Crafts
acylation on the core 2, which can be derived N-formyl protected D,L-proline
3
and methyl propiolate 4. In Contrast, Route B features a final
intramolecular Heck reaction to assemble the pyrrolidine ring from 5, which
can be assembled via alkylation and an initial Friedel-Crafts acylation,
leading to 6 and 7.

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2
Tetrahedron
conditions gave punicagranine (1) in 87% yield. Overall, this
Route A was based on the work of Albonico,7 wherein a 5,6
route required only five steps from commercial materials and
10.7% overall yield; moreover, our synthetic 1 was in complete
agreement with that of the natural product.6,8
homologated congener of 2, a 5,6,7,8-tetrahydroindolizine 9, was
prepared in 82% yield via a cycloaddition of methyl propiolate 4
and N-formyl-2-piperidine carboxylic acid 8 through a 1,3-
dipolar intermediate (Figure 3). This approach had not been
applied to 5,5-systems, such as the requisite methyl 2,3-dihydro-
1H-pyrrolizine-7-carboxylate 2.
O
O
O
O
O
a
b
O
HN
NH
N
O
O
O
O
O
O
O
I
HO
O
N
O
N
4
6
12
5
O
Ac2O, 120 o
2h, 82%
C
O
O
O
8
9
O
c
d
Figure 3. Albonico’s 1.3-dipolar cycloaddition strategy to access a 5,6,7,8-
tetrahydroindolizine 8.
N
N
O
HO
O
O
11
1
Thus, we found this attractive and elected to evaluate if this
cycloaddition methodology would extend to a 5,5-system 2. In
the event, commercial D,L-proline 10 was converted to the N-
formyl derivative 3 in quantitative yield (Scheme 1).8 Following
the literature conditions,7 the reaction was sluggish, with little
conversion after two hours. Extending the reaction time to 16
hours delivered the desired methyl 2,3-dihydro-1H-pyrrolizine-7-
carboxylate 2 in a modest, unoptimized 39% yield. With 2 in
hand, a Friedel-Crafts reaction with furan-2-carbonyl chloride 7
provided 11. Finally, saponification of 11 under standard
conditions gave punicagranine (1) in 87% yield. Overall, this
route required only four steps and 12.1% overall yield; moreover,
our synthetic 1 was in complete agreement with that of the
natural product.6,8
Scheme 2. Route B Synthesis of 1. Reagents and conditions: (a) furan-2-
carbonyl chloride (7), AlCl3, ClCH2CH2Cl, rt, 2h, 63%; (b) i) 1,3-
dibromoethane, KOH, DMF, rt, 16h, 57%; ii) NaI, acetone, 60 oC, 1.5 h,
o
86%; (c) 10 mol % Pd(PPh3)4, K3PO4, tert-butylbenzene, 130 C, 16 h, 40%;
(d) 2 N NaOH, EtOH, 60 oC, 1h, 87%.
In conclusion, we have presented the first total synthesis of
punicagranine (1) utilizing two distinct routes that require only
four to five steps from commercial materials and proceed in 10.7-
12.1% overall yields. In addition, our modular synthetic approach
enables facile analog development, which will prove useful for
the future exploration of anti-inflammatory SAR around related
congeners, as well as target identification and metabolite
identification studies.
O
H
HO
O
N
HO
O
N
N
a
b
c
O
O
Acknowledgments
10
3
2
Financial support from the Warren Family and Foundation is
gratefully acknowledged and for establishing the William K.
Warren, Jr. Chair in Medicine.
O
O
O
O
d
N
N
O
HO
O
O
References and notes
11
1
[1] E. Shaygannia, M. Bahmani, B. Zamanzad, et al., J. Evid. Based
Complementary Altern. Med. 21 (2016) 221–227.
[2] National Pharmacopoeia Committee, Pharmacopoeia of
People’s Republic of China, Part 1, Chemical Industry Press,
Beijing, 2010, p. 87.
Scheme 1. Route A Synthesis of 1. Reagents and conditions: (a) CH2O2,
Ac2O, rt, 1 h, 99%; (b) methyl propiolate (4), Ac2O, 120 C, 16h, 39%; (c)
o
furan-2-carbonyl chloride (7), AlCl3, ClCH2CH2Cl, rt, 2h, 36%; (d) 2 N
NaOH, EtOH, 60 oC, 1h, 87%.
[3] S. Modaeinama, M. Abasi, M.M. Abbasi, et al., Asian Pac. J.
Cancer Prev. 16 (2015) 5697–5701.
[4] E.P. Lansky, R.A. Newman, J. Ethnopharmacol. 109 (2007)
177–206.
[5] G.W. Plumb, S. De Pascual-Teresa, C. Santos-Buelga, J.C.
Rivas-Gonzalo, G. Williamson, Redox Rep. 41 (2002) 41–46.
[6] H-y. Sun, N. Ma. T. Pan, et al., Tetrahedron Lett. 60 (2019)
1231-1233.
[7] M.T. Pizzorno, S.M. Albonico J. Org. Chem. 42 (1977) 909-910.
[8] See Supporting Information for full details.
[9] R.O. Alexander, P.T. Bohan, E.J. Alexanian J. Am. Chem. Soc.
137 (2015) 3731-3734.
In parallel, we also pursued alternative Route B (Scheme 2).
Here, methyl 1H-pyrrole-3-carboxylate 6 undergoes a Friedel-
Crafts reaction with 7 to provide the disubstituted pyrrole 12 in
63% yield. Alkylation of the pyrrole with 1,3-dibromopropane
proceeded smoothly, followed by
a Finkelstein reaction
generating the alkyl iodide 5 which set the stage for an
intramolecular Heck reaction. In this case, the intramolecular
Heck reaction required forcing conditions9 (i.e., refluxing tert-
butylbenzene for 16 hours), but proceeded in 40% yield to
deliver 11. As in Route A, saponification of 11 under standard

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Appendix A. Supplementary data
The following are the Supplementary data to this article:
AUTHOR INFORMATION
Corresponding Author
* E-mail: craig.lindsley@vanderbilt.edu
Phone: 615-322-8700, fax: 615-343-3088


First total synthesis of punicagranine
Two distinct routes, only 4-5 steps and >10%
overall yields

Sufficient material to support mechanism of
action studies