One-pot tandem route to fused indolizidines and quinolizidines: Application in the synthesis of alkaloids and bioactive compounds

Article abstract of DOI:10.1016/j.cclet.2021.01.018

Fused indolizidines and quinolizidines are important skeletons in a variety of natural products and pharmacologically important compounds. A one-pot tandem route from amide to fused indolizidines and quinolizidines is disclosed. This method is conducted in mild conditions and shows well tolerance of functional groups. It is also easy to be scaled up to gram scale and can be applied smoothly to the total synthesis of alkaloids such as (±)-crispine A, (±)-xylopinine, (±)-desbromoarborescidine A, (±)-harmicine and other bioactive substances.

Full text of DOI:10.1016/j.cclet.2021.01.018

Chinese Chemical Letters 32 (2021) 1713–1716
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
One-pot tandem route to fused indolizidines and quinolizidines:
Application in the synthesis of alkaloids and bioactive compounds
b,
Qiao Songa, Yan Liub, Linlin Caib, Xinyu Caob, Shan Qiana, , Zhouyu Wang
*
*
a
Department of Pharmaceutics Engineering, Xihua University, Chengdu 610039, China
b
Department of Chemistry, Xihua University, Chengdu 610039, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Fused indolizidines and quinolizidines are important skeletons in a variety of natural products and
pharmacologically important compounds. A one-pot tandem route from amide to fused indolizidines and
quinolizidines is disclosed. This method is conducted in mild conditions and shows well tolerance of
functional groups. It is also easy to be scaled up to gram scale and can be applied smoothly to the
total synthesis of alkaloids such as (ꢀ)-crispine A, (ꢀ)-xylopinine, (ꢀ)-desbromoarborescidine A,
(ꢀ)-harmicine and other bioactive substances.
Received 3 December 2020
Received in revised form 4 January 2021
Accepted 12 January 2021
Available online 15 January 2021
Keywords:
One-pot
Indolizidines
Quinolizidines
Scalable
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Alkaloids
Fused indolizidines and quinolizidines are found in a variety of
natural products as well as in pharmacologically important
compounds and possess a wide spectrum of biological activities
[1–5] (Fig. 1).
Movassaghi [20,21] and Huang [22] have conducted elegant works
in this field.
In 2008, Movassaghi’s group reported a method to synthesize
isoquinoline and β-carboline derivatives through a mild B–N
reaction by using trifluoromethanesulfonic anhydride (Tf2O) to
activate amide [20]. But unsubstituted indole derivatives were not
suitable for this method to synthesize corresponding β-carboline
derivatives, which limited its application scope to a certain
extent. And the synthesis of structurally more complicated
fused indolizidines and quinolizidines was also not involved
(Scheme 1b).
As part of our program to develop practical method for the
construction of pharmaceutical products [23,24], herein, a one-pot
tandem route [25–27] based on amide activation to fused
indolizidines and quinolizidines is disclosed (Scheme 1c).
5-Chloro-N-(4-methoxyphenethyl)pentanamide (6a) was se-
lected as the starting material for optimization of reaction
conditions. The intermediate dihydroisoquinoline other than the
desired tricyclic product (7a) was detected under the initial
reaction conditions (Table 1, entry 1). This finding suggested that
the activation of amide and B–N reaction went well, but reduction
following cyclization did not occur. This phenomenon might be
due to the poor solubility of the reductant NaBH4 in the aprotic
solvent CH2Cl2. The addition of methanol solved the problem
satisfactorily, giving the target product in 69% yield (Table 1, entry
2). We then screened potential bases (Table 1, entries 3–7), and
Inspired by the important value of these compounds in modern
pharmacology [6,7], scholars have devoted significant efforts to
their construction [8–15]. Among them, Bischler–Napieralski
reaction (B–N reaction) [16,17] offers a very important strategy
(Scheme 1a). However, harsh reaction conditions or highly
corrosive reagents such as POCl3 and P2O5 are involved in
traditional B–N reaction. Moreover, to obtain the target fused
ring, multiple steps of reactions are imperative, leading to reduced
yields and tedious operation due to the indispensable isolation and
purification of intermediates [8,9]. Although some other existing
methods are efficient, they also suffer from some inevitable
drawbacks, such as using hazardous reagents [10], expensive metal
catalysts [11,12] or commercially unavailable catalysts or sub-
strates [13,9–15].
In recent decades, amide activation has become an emerging
tool for chemoselective synthesis [18,19]. Researchers such as
* Corresponding authors.
E-mail addresses: qians33@163.com (S. Qian), zhouyuwang@mail.xhu.edu.cn
(Z. Wang).
https://doi.org/10.1016/j.cclet.2021.01.018
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Q. Song, Y. Liu, L. Cai et al.
Chinese Chemical Letters 32 (2021) 1713–1716
2-fluoropyridine (2-F-Py) was found to be the most efficient
(Table 1, entry 4). Nevertheless, increasing the amount of 2-F-Py
did not contribute to the improvement 9 and 10 of yield (Table 1,
entry 8). When base was absent, the reaction also occurred in spite
of reduced yield (Table 1, entry 3). The activation temperature was
subsequently investigated (Table 1, entries 9–10). With the
activation temperature decreased to ꢁ78 ꢂC, the product was
obtained in 93% yield (Table 1, entry 10). Other different reductants
including KBH4, NaBH3CN, and NaBH(OAc)3 were then tested, but
the outcomes were inferior to NaBH4.
We examined the substrate scope under the optimized
conditions. Substrates with electron-donating substitutions or
without any substitution in the aromatic nucleus all reacted
smoothly to generate corresponding fused indolizidines and
quinolizidines in good to excellent yields (Scheme 2, 7a–7k).
The reaction system was applied to substrates containing
somewhat electron-withdrawing groups. However, no desired
tricyclic products were detected. This was probably because the
reduced electron density on the aromatic ring led to difficulty in
the occurrence of the B–N reaction. Nevertheless, with the aid of
microwave, tricyclic compounds with somewhat electron-with-
drawing groups such as F-, Cl- and Br- were obtained in moderate
to good yields (Scheme 2, 7l–7q). The substitution position also
affected the reaction. The reaction with the substitute group in
para and meta positions proceeded smoothly under the regular
condition, whereas that with ortho substitution reacted only under
microwave (Scheme 2, 7r). We further investigated the impact of
ring size on the reaction. The results showed that seven-
membered fused ring was easily formed, while four-membered
fused ring was more difficult to obtain (Scheme 2, 7s–7t). In
addition, fused dihydrophenanthridine derivatives were obtained
in moderate yields using o-arylaniline-derived amides as sub-
strates through the Morgan–Walls reaction [28] (Scheme 2, 7u–
7v).
Fig. 1. Related natural products and drugs containing fused indolizidine or
quinolizidine structures.
Scheme 1. Comparison of previous works and this work.
Indole derivated fused indolizidines and quinolizidines were
also synthesized. Tryptamine-derived amides with indole nitro-
gen protected by methyl or benzyl were converted into
corresponding products in good yields (Scheme 2, 7w–7x). It
was worth noting that unsubstituted indole derivatives led to
rapid indolyl nitrogen sulfonylation by Tf2O, and these compounds
were unsuitable for Movassaghi’s method [20] to be activated and
underwent B–N reaction. Under our reaction condition, indole
derivatives without any substitution were converted into fused
tetrahydro-β-carbolines with sulfonylations on indolyl nitrogen.
The relatively low yields might be caused by insufficient Tf2O
which was consumed by indolyl nitrogen sulfonylation. When Tf2O
was adjusted to 2.2 equiv., the yields were improved obviously
(Scheme 2, 7y–7z).
Table 1
Optimization of reaction conditions.a
Entry
Base (equiv.)
Activation T (ꢂC) Reductant
Yield (%)b
1
2
3
4
5
6
7
2-Cl-Py (1.2)
2-Cl-Py (1.2)
–
ꢁ30
ꢁ30
ꢁ30
ꢁ30
ꢁ30
ꢁ30
ꢁ30
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NDc
69
12
75
61
Compounds 7o and 7y were converted into hydrochlorides, and
their structures were unequivocally confirmed by X-ray crystal
structure determination (Fig. 2).
2-F-Py (1.2)
2-I-Py (1.2)
Pyridine (1.2)
3,5-dimethylpyridine
(1.2)
2-F-Py (2.0)
2-F-Py (1.2)
2-F-Py (1.2)
2-F-Py (1.2)
2-F-Py (1.2)
2-F-Py (1.2)
Additionally, gram-scale syntheses of typical fused quinolizi-
dines were also realized through the protocol (Scheme 3).
Our method was further applied to synthesize natural
products or bioactive compounds. (ꢀ)-Crispine A (7aa, Scheme 4)
shows cytotoxic activity against HeLa human cancer cell lines [29].
It was synthesized smoothly by using our one-pot method in good
yield. A number of methods have been reported to synthesize
(ꢀ)-crispine A, which undergoes multiple reaction steps in
different ways [30–33], however, our protocol is one of the most
efficient. Compound 7ab (Scheme 4) is also a pharmacological
active substance that displays potent antagonist activity at α4β2
nicotinic acetylcholine receptors (nAChR), a ligand-gated ion
channel involved in a broad range of psychiatric and neurodegen-
erative disorders. In the reported method to synthesize compound
7ab, highly corrosive POCl3 and multi-step microwave-assisted
55
58
8
9
10
11
12
13
ꢁ30
0
ꢁ78
ꢁ78
ꢁ78
ꢁ78
NaBH4
NaBH4
NaBH4
KBH4
NaBH3CN
NaBH(OAc)3 76
73
66
93 (90)
86
80
a
Reaction conditions: 6a (0.5 mmol), Tf2O (1.1 equiv.), base, CH2Cl2 (5 mL), Ar,
activation temp., 30 min → 40 ꢂC, 2 h → reductant (2.0 equiv.), MeOH (5 mL), r.t., 2 h.
b
Yields were determined by 1H NMR with 1,1,2,2-tetrachloroethane as the
internal standard. Yield in parentheses is the isolated yield.
c
No reaction. Without MeOH on the reduction stage.
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Q. Song, Y. Liu, L. Cai et al.
Chinese Chemical Letters 32 (2021) 1713–1716
Scheme 3. Gram-scale synthesis.
Scheme 4. Application of this method to the synthesis of natural products and
bioactive compounds. Uniform reaction conditions unless otherwise noted:
Compound 6 (0.5 mmol), Tf2O (1.1 equiv.), 2-F-Py (1.2 equiv.), CH2Cl2 (5 mL), Ar,
ꢁ78 ꢂC, 30 min → 40 ꢂC, 2 h → MeOH (5 mL), NaBH4 (2.0 equiv.), r.t., 2 h. a Compound
7y or 7z (0.2 mmol), NaOH (4.0 mmol), H2O (4 mL), MeOH (16 mL), reflux, 2 h.
Scheme 2. Scope of this method. Uniform reaction conditions unless otherwise
noted: Compound 6 (0.5 mmol), Tf2O (1.1 equiv.), 2-F-Py (1.2 equiv.), CH2Cl2 (5 mL),
Ar, ꢁ78 ꢂC, 30 min → 40 ꢂC, 2 h → MeOH (5 mL), NaBH4 (2.0 equiv.), r.t., 2 h. a ꢁ78 ꢂC,
b
30 min → microwave, 120 ꢂC, 10 min → r.t., 2 h. Tf2O (2.2 equiv.).
diastereoisomer (7af, MCN-4612-E, Supporting information) [37]
was also isolated in the same reaction in 45% yield.
reaction with the temperature as high as 150 ꢂC were necessary
[34]. Herein, synthesis was conducted in milder condition and
more convenient method.
(ꢀ)-Harmicine (7ac, Scheme 4) exhibits strong antileishmania
activity [35] and (ꢀ)-desbromoarborescidine A (7ad, Scheme 4)
was an alkaloid discovered from the New Guinea tree Draconto-
melum mangiferum [12]. These compounds were easily obtained
from the detrifluoromethylsulfonylation of 7y and 7z in NaOH
solution (Scheme 4).
MCN-4612-Z (7ae, Scheme 4) is a potent uptake inhibitor for
norepinephrine (NE), dopamine (DA) and serotonin (5-HT),
which was developed as antidepressant drugs in 1980s [36].
It was synthesized using our protocol in 39% yield. And its
Furthermore, a new strategy was designed to synthesize
protoberberine (ꢀ)-xylopinine (7ag, Scheme 5). (ꢀ)-Xylopinine
is an alkaloid found in the stem of Xylopia laevigata (Annonaceae),
which exhibits strong in vitro cytotoxic activity toward various
tumor cell lines [38]. The amide substrate (6ad, Scheme 5) was
synthesized from 3,4-dimethoxyphenylethylamine (8, Scheme 5)
and 6,7-dimethoxyisochroman-3-one (9, Scheme 5), which was
then subjected to chlorination, B–N reaction, reduction of Schiff
base intermediate, and intramolecular cyclization in one-pot to
offer (ꢀ)-xylopinine as a racemate in 65% total yield. Among the
reported synthesis strategies for tetrahydroberberines [39–41],
our method is the one of the most efficient.
A plausible mechanism is illustrated in Scheme 6 taking
compound 7g as an example. Amide substrate (6g, Scheme 6)
was firstly activated by Tf2O to obtain a nitrilium ion [42,43]
(10, Scheme 6), which underwent Bischler–Napieralski reaction to
obtain cyclic iminium ion (11, Scheme 6). The iminium ion 11
was isolated and its structure was confirmed by 1H NMR, 13C NMR
and HRMS. 11 was subjected to reduction of the C N bond
¼
(12, Scheme 6) followed by intramolecular nucleophilic substitu-
tion to obtain polycyclic product 7g.
In summary, we propose
a facile tandem protocol to
construct fused indolizidines and quinolizidines. The protocol
is efficient because it integrates three step reactions in one-pot
and does not require isolation and purification of any
intermediate. The protocol can be easily scaled up to gram-
scale. Taking advantage of the mild reaction conditions and
functional group tolerance, the protocol was successfully
applied to synthesize natural products such as (ꢀ)-crispine A,
(ꢀ)-desbromoarborescidine A, (ꢀ)-harmicine, (ꢀ)-xylopinine
and other bioactive substances.
Fig. 2. X-ray crystal structure of 7o
ꢃ
HCl and 7y HCl.
ꢃ
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Q. Song, Y. Liu, L. Cai et al.
Chinese Chemical Letters 32 (2021) 1713–1716
Scheme 5. Total synthesis of protoberberine (ꢀ)-xylopinine.
References
[1] L. Wu, H. Ling, L. Li, L. Jiang, M. He, J. Pharm. Pharmacol. 59 (2007) 695–701.
[2] A. Padwa, M.D. Danca, Org. Lett. 4 (2002) 715–717.
[3] A.M. Peckham, J.A. Nicewonder, J. Pharm. Pract. 32 (2019) 450–457.
[4] S.(Bas)A.M.W. van den Broek, J.G.H. Lemmers, F.L. van Delft, F.P.J.T. Rutjes, Org.
Biomol. Chem. 10 (2012) 945–951.
[5] J. Wang, X. Lv, J. Xu, et al., J. Med. Chem. 188 (2020) 111976.
[6] H. Wang, Q. Dong, Q. Xie, P. Tang, Chin. Chem. Lett. 31 (2020) 685–688.
[7] Y. Zhang, K. Xie, A. Liu, et al., Chin. Chem. Lett. 30 (2019) 443–446.
[8] C. Weimar, S. Von Angerer, W. Wiegrebe, Arch. Pharm. (Weinheim) 18 (1991)
509–518.
[9] B. Hoefgen, M. Decker, P. Mohr, et al., J. Med. Chem. 49 (2006) 760–769.
[10] W.H. Pearson, W.K. Fang, J. Org. Chem. 65 (2000) 7158–7174.
[11] S. Zhou, R. Tong, Chem. Eur. J. 22 (2016) 7084–7089.
[12] E. Park, C.H. Cheon, Org. Biomol. Chem. 15 (2017) 10265–10275.
[13] K. Diker, K. El Biach, J. Lévy, J. Nat. Prod. 3 (1997) 791–793.
[14] N. Meyer, T. Opatz, European J. Org. Chem. 2006 (2006) 3997–4002.
[15] Y. Zhang, R.P. Hsung, X. Zhang, et al., Org. Lett. 7 (2005) 1047–1050.
[16] A. Bischler, B. Napieralski, Ber (1933) 1903–1908.
[17] Z. Wang, Z. Yu, Y. Yao, et al., Chin. Chem. Lett. 30 (2019) 1541–1544.
[18] D. Kaiser, N. Maulide, J. Org. Chem. 81 (2016) 4421–4428.
[19] D. Kaiser, A. Bauer, M. Lemmerer, N. Maulide, Chem. Soc. Rev. 47 (2018) 7899–
7925.
Scheme 6. The proposed mechanism.
[20] M. Movassaghi, M.D. Hill, Org. Lett. 10 (2008) 3485–3488.
[21] K.L. White, M. Movassaghi, J. Am. Chem. Soc. 138 (2016) 11383–11389.
[22] H.H. Huo, H.K. Zhang, X.E. Xia, P.Q. Huang, Org. Lett. 14 (2012) 4834–4837.
[23] X. Ran, Y. Long, S. Yang, et al., Org. Chem. Front. 7 (2020) 472–481.
[24] L. Yang, X. Ma, C. Yuan, et al., Eur. J. Med. Chem. 134 (2017) 230–241.
[25] Z. Cao, Q. Zhu, Y.W. Lin, W.M. He, Chin. Chem. Lett. 30 (2019) 2132–2138.
[26] Q.W. Gui, F. Teng, S.N. Ying, et al., Chin. Chem. Lett. 31 (2020) 3241–3244.
[27] W.B. He, L.Q. Gao, X.J. Chen, et al., Chin. Chem. Lett. 31 (2020) 1895–1898.
[28] G.T. Morgan, L.P. Walls, J. Chem. Soc. (1905) 2447–2456.
[29] K.R. Bailey, A.J. Ellis, R. Reiss, T.J. Snape, N.J. Turner, Chem. Commun. 44 (2007)
3640–3642.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
[30] G. Pandey, S.K. Tiwari, B. Singh, Tetrahedron Lett. 57 (2016) 4480–4483.
[31] S. Saha, Ch.V.R. Reddy, B. Patro, Tetrahedron Lett. 52 (2011) 4014–4016.
[32] H.J. Knölker, S. Agarwal, Tetrahedron Lett. 46 (2005) 1173–1175.
[33] S. Agarwal, O. Kataeva, U. Schmidt, H.J. Knölker, RSC Adv. 3 (2013) 1089–1096.
[34] F. Crestey, A.A. Jensen, C. Soerensen, et al., J. Med. Chem. 61 (2018) 1719–1729.
[35] T.S. Kam, K.M. Sim, Phytochemistry 47 (1998) 145–147.
[36] B.E. Maryanoff, D.F. McComsey, M.J. Costanzo, et al., J. Med. Chem. 27 (1984)
943–946.
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 81973189), Sichuan
Outstanding Young Scientific and Technological Talents Project
(No. 2020JDJQ0054), Sichuan Science and Technology Program
(No.19ZDYF0890), Scientific Research Foundation of the Education
Department of Sichuan Province (No. 18TD0023) and Xihua
University Talents Project (No. Z202030).
[37] S.J. Gharpure, D.S. Vishwakarma, R.K. Patel, Chem. Commun. 55 (2019) 6858–6861.
[38] L.R.A. Menezes, C.O. D’Sousa Costa, A.C.B.D.C. Rodrigues, et al., Molecules 21
(2016) 1–10.
[39] P.W. Jeffs, The protoberberine alkaloids, in: R.H.F. Manske (Ed.), The Alkaloids:
Chemistry and Physiology, Academic Press, 1967, pp. 41–115.
[40] S. Zhou, R. Tong, Org. Lett. 19 (2017) 1594–1597.
Appendix A. Supplementary data
[41] B. Horst, M.J. Wanner, S.I. Jørgensen, H. Hiemstra, J.H. van Maarseveen, J. Org.
Chem. 83 (2018) 15110–15117.
[42] A.B. Charette, M. Grenon, Can. J. Chem. 79 (2001) 1694–1703.
[43] J.L. Ye, Y.N. Zhu, H. Geng, P.Q. Huang, Sci. China Chem. 61 (2018) 687–694.
Supplementary material related to this article can be
found, in the online version, at doi:https://doi.org/10.1016/j.
cclet.2021.01.018.
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