Expedited Synthesis of Matrine Analogues through an Oxidative Cascade Addition/Double-Cyclization Radical Process

Article abstract of DOI:10.1002/ejoc.201700208

The addition of a nicotinate–xanthate derivative to N-allylindoles and N-allylpyrroles resulted in polycyclic heterocycle-fused pyridonaphthyridines through a tandem radical intermolecular/intramolecular oxidative addition reaction sequence that created three new C–C bonds and two new rings in a single event. Such polyheterocycles showcase the matrine alkaloid framework and are similar to indole–monoterpenoid natural products.

Full text of DOI:10.1002/ejoc.201700208

A Journal of
Accepted Article
Title: Expedited synthesis of matrine analogues based on an oxidative
cascade addition/double-cyclization radical process.
Authors: Luis D. Miranda, Simón Olguín-Uribe, Marco Vinicio Mijangos,
Yoarhy Alejandro Amador-Sánchez, and Miguel Angel
Sanchez-Carmona
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700208
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700208
Supported by

10.1002/ejoc.201700208
European Journal of Organic Chemistry
COMMUNICATION
Expedited synthesis of matrine analogues based on an oxidative
cascade addition/double-cyclization radical process.
Simón Olguín-Uribe,[a][b] Marco V. Mijangos,[a] Yoarhy A. Amador-Sánchez,[a] Miguel A. Sánchez-
Carmona[a] and Luis D. Miranda*[a]
1
44 and are a resourceful strategy for cascade termination for the
45 rapid synthesis of polycyclic motifs.[8][9]
2
3
4
5
6
7
8
Abstract: The addition of a nicotinate-xanthate derivative to N-
O
O
allylindoles and N-allylpyrroles resulted in polycyclic heterocycle-
H
H
H
N
H
fused
pyrido-naphthyridines
via
a
tandem
radical
N
H
intermolecular/intramolecular oxidative addition reaction sequence
that creates three new C-C bonds and two new rings in a single
event. Such polyheterocycles showcase the matrine alkaloid
H
H
H
N
N
O
2
1
Matrine
Oxymatrine
framework and are similar to indole-monoterpenoid natural products.
46
47
Figure 1. Matrine and oxymatrine structures
9 Introduction
10 Natural products have an important place in medicinal chemistry
11 as they are an ever-increasing source of bioactive molecules
12 useful for drug development.[1] Given that natural product
13 scaffolds and motifs are considered privileged starting points for
14 drug discovery programs, there is a great demand for the
15 development of strategies and methodologies for the rapid
16 access to derivatives and analogues of these structures.[2] As an
17 extension of our research program in diversity oriented
18 synthesis,[3] we have focused our attention on the alkaloids
19 matrine (1) and oxymatrine (2), which are the main alkaloids in
20 the root of Sophora flavescens Aint (Figure 1).[4] These alkaloids
21 feature a dipyrido-naphthyridine tetracyclic system and display a
22 wide variety of biological activities such as anti-tumor activity,[5a]
23 antiinflamoatory activity,[5b] as well as activity against the
24 hepatitis B virus,[5c] among others.[5d] Interestingly although
25 several derivatives of 1 have been prepared in different
26 medicinal programs, most of them have been synthetized from
27 the natural product itself and,5d to the best of our knowledge,
a) Zard's work
MeO2C CO2Me
O
MeO2C
O
MeO2C
O
CO2Me
CO2Me
SC(S)OEt
CO2t-Bu
N
3
lauroyl
peroxide
N
N
+
H
H
CO2t-Bu
S
CO2t-Bu
N
N
O
EtO
S
N
O
5
4
6, 44% (3:1)
O
b) This work
S
lauroyl
peroxide
CO2Me
N
H
R
+
EtO
S
R
H
N
CO2Me
N
N
O
7
8
O
9, 31-45% (2:1)
oxidative cascade addition/double-cyclization radical process
48
28 only five total synthesis can be found in the literature for this kind
29 of alkaloid.[6] Among those synthesis, Zard and co-workers have
49 Scheme 1.
A
xanthate-based radical cascade process to assemble the
50 tetracyclic matrine system.
30 described an elegant synthetic approach using an impressive
31 tandem xanthate-based radical process to assemble the
32
tetracyclic system in a single step from simple starting materia5ls1 Results and Discussion
33 (Scheme 1a).[6e] In the process, three new C-C bonds and two
34 new rings were created. Following this line of reasoning, we
52 The synthesis of the key xanthate 7 was carried out using the
35 developed the idea that a small library of indole/pyrrole-matrine
36 analogs (9) might be readily available through a similar cascade
37 process starting from the corresponding N-allyl heterocycles
38 (e.g., 8, Scheme 1b). In this case, the cascade radical
39 termination would be an oxidative rearomatizing step,[7][8] rather
40 than a xanthate transfer as occurs in the original process. As we
53 three-step protocol described below. First, catalytic
54 hydrogenation of methyl nicotinate (10) followed by N-
55 bromoacetylation yielded the bromoacetamide 11, which was
56 used crude and subjected to the nucleophilic substitution
57 reaction to afford, after just one chromatographic purification, the
radic5al8 pure xanthate 7 in 78% overall yield in gram scale (Scheme 2).
41 have demonstrated, the xanthate-based oxidative
42 substitutions on aromatic and heteroaromatic systems are
43 efficient processes in both inter-[7] and intramolecular fashion,
O
O
O
1) Pd/C;
Et3N/MeOH
MeO
KSC(S)OEt
MeCN
MeO
OMe
N
O
N
2)
N
O
S
S
Br
Br
[a]
[b]
Instituto de Química
O
10
Cl
O
7
Universidad Nacional Autónoma de México
Circuito Exterior, Ciudad Universitaria, Coyoacán, México City
04510, México. E-mail: lmiranda@unam.mx
Universidad Autónoma Metropolitana-Iztapalapa, México, Cd. Mx.,
09340 México.
Et3N/DCM
11
78% overall
59
60 Scheme 2. Synthesis of xanthate 7.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700208
European Journal of Organic Chemistry
COMMUNICATION
1
1
On the other hand, N-allyl heterocyclic derivatives were als4o6 9a-c.[11] All diastereomeric ratios were determined by H NMR.
easily synthetized by the alkylation of different substituted indol4e7 Structures of 9b-syn and 9d-anti were further corroborated by
and pyrrole derivatives with allyl bromide using NaOH as a bas4e8 single-crystal X-ray analysis (Table 3).[12]
2
3
4
5
6
in DMSO, at room temperature in an open flask (Table 1).
49
50 Table 2. Optimization of tandem radical process
H
Table 1. Synthesis of N-allyl heterocycles.
O
N
51
conditions
N
N
N
8a
(1.5 eq.)
7
+
+
H
(1.0 eq.)
MeO2C
O
MeO2C
H
H
R
R
NaOH (2 equiv.)
DMSO
+
Br
9a-syn
9a-anti
N
N
H
entry
reagent
DLP
conditions[b]
time[c]
Yield (%)
syn:anti
2:1
2 equiv.
O
1 equiv.
Indole or pyrrole
8
N-allyl-heterocycle
1
2
3
DCE/Reflux
DCM/O2/r.t.
DCE/M.W.
6
6
34
trace
43
O
N
H
OMe
CN
Et3B
n.d.
N
N
N
DLP
1.5
2:1
8a
8b
8d
8c
90 %
65 %
95 %
88 %
52 a) All reactions were carried out in dry solvents. b) Determined by 1H NMR. r.t.
53 = room temperature; M.W. = microwaves.
O
N
O
N
N
O
H
8f
63%
54 Table 3. Scope of the tandem oxidative radical addition
8g
70 %
8e
63 %
7
8
Indolo-matrines 9a-d:
Pyrrolo-matrines 9e-g:
9
We then proceeded to test our proposal using N-allylindole 8a
H
H
O
N
O
N
10 as the model substrate. When performing the reaction with 1.5
11 equiv. of heterocycle 8a and 1 equiv. of xanthate 7 in the
12 presence of dilauroyl peroxide (DLP, 1.2 eq. added portionwise)
13 in refluxing 1,2-dichloroethane (DCE), we were pleased to
14 observe the expected pentacyclic indolo-matrine analog 9a as
15 the major product, and isolated it in 34% yield as a 2:1 mixture
16 of syn:anti diastereomers as indicated by NMR analysis (Entry 1,
17 Table 2). The coupling constant for ring-fused methine
18 hydrogens was of particular importance for the stereochemical
19 assignment, resulting in 3J = 3.8 Hz for the 9a-syn diastereomer,
20 and 3J = 10.9 Hz for the 9a-anti diastereomer.
21 In an effort to perform the reaction at room temperature, this
22 radical cascade process was also studied using Et3B/O2 as both
23 initiator and oxidant. Under these conditions, only decomposition
24 of starting xanthate
25 chromatography (Entry 2, Table 2).
N
N
N
N
N
N
H
H
O
O
MeO2C
MeO2C
MeO2C
MeO2C
H
H
H
H
syn : anti a = 2 : 1
9e-anti
syn : anti a = 3 : 1
9a-anti
9a-syn
9e-syn
43 % yield b
33 % yield b
O
O
H
H
N
O
N
O
N
N
N
O
N
N
N
H
H
O
O
O
MeO2C
MeO2C
MeO2C
MeO2C
H
H
H
H
syn : anti a = 2 : 1 9f-anti
syn : anti a = 2 : 1
9f-syn
9b-syn
9b-anti
37 % yield b
32 % yield b
MeO
MeO
H
O
O
H
O
N
O
N
N
N
N
N
N
N
MeO2C
O
H MeO2C
H
MeO2C
O
H
MeO2C
MeO2C
MeO2C
H
H
H
syn : anti a = 2 : 1
syn : anti a = 2 : 1
7
was observed by thin layer
9c-anti
9g-syn
9c-syn
9g-anti
40 % yield b
31 % yield b
26 Finally, when the reaction was carried out under microwave
27 assistance, the yield of the diastereomeric mixture 9a-syn/anti
28 was increased to 43%, retaining the same diastereomeric ratio
29 (i.e., syn:anti = 2:1) and the reaction time was greatly reduced
30 from 6 to 1.5 hours (Entry 3, Table 2). We decided to establish
31 the latter conditions as optimal.
CN
CN
H
O
N
N
N
N
O
H
MeO2C
MeO2C
H
H
9d-anti
X-ray structure c
syn : anti a = 3 : 1 9d-anti
9b-syn
9d-syn
X-ray structure c
45 % yield b
55
32 With the optimal conditions set, the scope of this tandem
33 intermolecular/intramolecular oxidative radical addition was
34 examined using supplementary 8b-g N-allyl heterocycles. Thus,
35 indolo-matrine analogs bearing a C-3-substitued indole ring (9b-
36 d) were obtained in comparable yields (31-45%), with moderate
56 a) All diastereomeric ratios were determined by 1H NMR. b) Yields refer for
57 the isolated mixture of syn/anti diastereomers. c) For clarity, hydrogens (green
58 atoms) are only shown in the fused rings.
59
selectivity toward the syn-diastereomer in all cases (Table 36).0 Bearing in mind the cascade nature of this process, where three
37
61 new C-C bonds are created together with two new rings by
62 means of four tandem steps, i.e., an intermolecular radical
63 addition followed by two consecutive intramolecular radical
38 Similarly, when the N-allylpyrroles 8e-g were coupled with
39 xanthate 7, the corresponding tetracyclic pyrrolo-matrine
40 analogs were obtained in moderate yields (33-41%) for both
41 unsubstituted and C-2-substituted pyrrole derivatives. In the
42 same manner, as with the indole derivatives, the syn-
43 diastereomer was slightly favored (Table 3). It is important to
64 additions and
a
final oxidation-rearomatization step, we
65 considered the yields (31-45%) as good. For instance, for the 3-
66 cyanoindole-derivative 9d with the highest yield (45%), we
mention that physical separation of both diastereomers v6ia7 estimated an 82 % yield per step in the cascade. In the same
44
45 preparative TLC was successful only with the indolo-matrines
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700208
European Journal of Organic Chemistry
COMMUNICATION
1
2
3
4
5
6
7
8
9
way, for 3-carboxymethylindole-derivative 9c with the lowest
global yield (31%), the estimated yield per step was 75%.
The moderate selectivity for the syn-diastereomer in all cases
43 Keywords: free radical • cascade process • matrine • indole •
44 xanthate
can be rationalized by analysis of the plausible transition states
45 [1]
For selected recent reviews see: a) T. Rodrigues, D. Reker, P. Schneider, G.
Schneider, Nature Chem., 2016, 8, 531–541. b) H. Yuan, Q. Ma, L. Ye and G. Piao,
Molecules, 2016, 21, 559–18. c). M. E. Maier, Org. Biomol. Chem., 2015, 13,
5302–5343. d) A. L. Harvey, R. A. Edrada-Ebel, R. J. Quinn, Nat. Rev. Drug
Discov., 2015, 14, 111–129. e) M. S. Butler, A. A. B. Robertson, M. A. Cooper, Nat
Prod Rep, 2014, 31, 1612–1661.
13 and 14 (Scheme 3). The proposed transition state 13 with the
46
47
pendant heterocycle side chain in the pseudo-equatorial position
48
is more sterically congested than its counterpart transition state
14 with the heterocyclic side chain in a pseudo-axial disposition,
49
50
which would ultimately lead to the 9-syn as the mayor
51 [2]
For recent examples see: a) L. Zheng, Y. Bin, Y. Wang, R. Hua, J. Org. Chem.
2016, 81, 8911−8919; b) E. M. Woerly, J. Roy, M. D. Burke, Nature Chem. 2014, 6,
484-491; c) S. Santra, P. R. Andreana, Angew. Chem. Int. Ed. 2011, 50, 9418–
9422; d) D. Robbins, A. F. Newton, C. Gignoux, J.-C. Legeay, A. Sinclair, M. Rejzek,
C. A. Laxon, S. K. Yalamanchili, W. Lewis, M. A. O'Connell, R. A. Stockman, Chem.
Sci., 2011, 2, 2232–2235; e) D. Morton, S. Leach, C. Cordier, S. Warriner, A.
Nelson, Angew. Chem. Int. Ed. 2009, 48, 104–109. For reviews see: f) J. P. Nandy,
M. Prakesch, S. Khadem, P. T. Reddy, U. Sharma, P. Arya, Chem. Rev. 2009, 109,
1999–2060; g) K. Kumar, H. Waldmann, Angew. Chem. Int. Ed. 2009, 48, 3224 –
3242.
10 diastereomer. These results are in complete accordance with
52
11 Zard’s observation.6e
53
54
55
56
57
58
59
60
61 [3]
62
a) L. D. Miranda, E. Hernández-Vázquez, J. Org. Chem. 2015 80, 10611−10623; b)
Ma-C. García–González, E. Hernández-Vázquez, R. E. Gordillo-Cruz, L. D.
Miranda, Chem. Commun., 2015, 51, 11669-11672.
63
64 [4]
65
a). Q. Fu, Q. Fang, B. Feng, S. Sun, W. Du, E. Amut, A. Xiao, C. Chang, J.
Chromatogr. B 2011, 879, 894–900.ꢀb) Z. J. Wu, D. M. Sun, D. M. Fang, J. Z. Chen,
P. Cheng and G. L. Zhang, Int. J. Mass Spectrom., 2013, 341–342, 28–33.
a) Y. Liu, Y. Xu, W. Ji, X. Li, B. Sun, Q. Gao, C. Su, Tumor Biology, 2014, 35,
12
66
67 [5]
68
13 Scheme 3. Stereochemical rationalization.
5111–5119. b) 1
B. Zhang, Z.-Y. Liu, Y.-Y. Li, Y. Luo, M.-L. Liu, H.-Y. Dong,
69
Y.-X. Wang, Y. Liu, P.-T. Zhao, F.-G. Jin, Z.-C. Li, Eur. J. Pharm. Sci., 2011, 44,
573–579. c) L.-M. Gao, Y.-X. Han, Y.-P. Wang, Y.-H. Li, Y.-Q. Shan, X. Li, Z.-G.
Peng, C.-W. Bi, T. Zhang, N.-N. Du, J.-D. Jiang, D. Q. Song, J. Med. Chem., 2011,
54, 869–876. For a review see: d) J. Huang and H. Xu, Curr. Top. Med. Chem.,
2016, 16, 3365-3378.
14 Conclusions
70
71
We have disclosed a strategy for the rapid synthesis of ne7w2
15
73
16 polycyclic indole/pyrrole-matrine analogs 9-syn/anti via an
74 [6]
17 oxidative radical cascade coupling between simple N-allyl-
a) J. Chen, L. J. Browne, N. C. Gonnela, L. Chugaev, J. Chem. Soc. Chem.
Commun. 1986, 905-907; b) S. Okuda, M. Yoshimoto, K. Tsuda, Chem. Pharm.
Bull. 1966, 14, 275; c) L. Mandell, K. P. Singh, J. T. Gresham, W. J. Freeman, J.
Am. Chem. Soc. 1965, 87, 5234-5236. d) S. V. Watkin, N. P. Camp, R. C. D. Brown,
Org. Lett. 2013, 15, 4596-4599. e) L. Boiteau, J. Boivin, A. Liard, B. Quiclet-Sire, S.
Z. Zard, Angew. Chem. Int. Ed. 1998, 37, 1128-1131.
75
18 heterocycles 8 and readily available xanthate 7 in good
76
19 preparative yields and moderate diastereoselectivity. In the
77
20 process three new C-C bonds (including an all-carbon
78
quaternary center) and two new rings are created in a sing78le90 [7]
a) Y. M. Osornio, R. Cruz-Almanza, V. Jiménez-Montaño, L. D. Miranda, Chem.
Commun., 2003, 2316-2317; b) P. E. Reyes-Gutiérrez, R. O. Torres-Ochoa, R.
Martínez, L. D. Miranda, Org. Biomol. Chem. 2009, 7, 1388-1396; c) E. Flórez-
López, L. B. Gómez-Pérez, L: D. Miranda, Tetrahedron Lett., 2010, 51, 6000-6002.
a) For xanthate-based radical oxidative cascade processes see: a) A. Biechy, S. Z.
Zard, Org. Lett., 2009, 11, 2800–2803; b) F. Lebraux, B. Quiclet-Sire, S. Z. Zard,
Org. Lett., 2009, 11, 2844–2847; c) M. El Qacemi, L. Ricard, S. Z. Zard, Chem.
Commun., 2006, 4422–4424; d) E. Bacqué, M. El Qacemi, S. Z. Zard, Org. Lett.,
2004, 6, 3671–3674; e) F. Gagosz, S. Z. Zard, Org. Lett., 2002, 4, 4345–4348; f) Y.
M. Osornio; L. D. Miranda, Rev. Soc. Quím. Méx., 2004, 48, 288–292; g) E. W.
Tate, S. Z. Zard, Tetrahedron Lett., 2002, 43, 4683–4686.
21
22 synthetic step. Furthermore, the oxidative rearomatizing
81
23 termination step of this cascade allowed the straightforward
82
24 incorporation of the indole and pyrrole aromatic nucleus into the
83
25 matrine framework and avoid the xanthate transfer in the
84 [8]
26 product. We anticipate that these conjugated polyheterocycles
85
27 could be of interest for medicinal chemistry, as they share the
86
28 biologically active matrine-framework and resemble indole
87
29 monoterpenoid alkaloids, which are also biologically relevant.[180]8
89
30 Given the modular nature of this cascade reaction, new
90
31 polyheterocycles might be readily available by switching the
91 [9]
For reviews on xanthate-based radical chemistry, see: a) B. Quiclet-Sire, S. Z. Zard
Isr. J. Chem. 2016 doi:10.1002/ijch.201600094. b) B. Quiclet-Sire, S. Z. Zard,
Synlett, 2016, 27, 680–701. c) B. Quiclet-Sire, S. Z. Zard, Beilstein J. Org. Chem.
2013, 9, 557– 576; d) S. Z. Zard, “Xanthates and Related Derivatives as Radical
Precursors”, in Encyclopedia of Radicals in Chemistry, Biology and Materials, John
Wiley & Sons, Ltd, Chichester, UK, 2012; e) B. Quiclet-Sire, S. Z. Zard, Chem. Eur.
J. 2006, 12, 6002–6016.
32 radical acceptor partner with other suitable N-allylic heterocycles
92
33 to expeditiously populate and explore further the chemical space.
93
34
These studies are currently underway in our laboratory and w9ill4
35 be published in due course.
95
96
97
36 Acknowledgements
98 [10]
a) Q. Pan, N. R. Mustafa, K. Tang, Y. H. Choi, R. Verpoorte, Phytochemistry Rev.
2016, 15, 221-250; b) M. Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod.
Rep. 2013 30, 694-752; c) S. E. O’Connor, J. J. Maresh, Nat Prod Rep, 2006, 23,
532–547; d) T.-S. Kam, K.-H. Lim in The Alkaloids: Chemistry and Biology, vol. 66
(Ed.: G. A. Cordell), Academic Press, Amsterdam, 2008, pp. 1–111.
37 Financial support from DGAPA-UNAM (project PAPIIT9-9
100
38 IN210516) is gratefully acknowledged. We also thank R. Patiño,
101
39 A. Peña, E. Huerta, I. Chavez, R. Gabiño, L. Ma. C. García-
102
40 González, Velasco and J. Pérez for technical support. The
103 [11]
41 authors show gratitude to Simón Hernandez-Ortega and Alfredo
In the cases of compounds 9c, 9f and 9g, complete purification could not be
accomplished by flash cromatography, and where obtained along with a minor
amount (< 4% by 1H NMR) of an unknown impurity.
104
105
42 Toscano for X-ray crystallography.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700208
European Journal of Organic Chemistry
COMMUNICATION
1
2
3
[12]
The crystal structures were deposited in the Cambridge Crystallographic Data
Centre (CCDC): 1531989 (9b-syn) 1532012 (9d-anti).
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700208
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Cascade process *
matrine analogs
O
- Oxidative Radical Cascade
O
- 3 new C-C bonds
- 2 new rings
H
MeO
Simón Olguín-Uribe, Marco V. Mijangos,
Yoarhy A. Amador-Sánchez Miguel
Sánchez-Carmona and Luis D. Miranda*
N
DLP (1.2 eq)
N
N
N
+
N
+
N
H
Cl
Cl
O
MeO2C
S
OEt
MeO2C
H
H
O
M.W. 89 °C
d.r. up to 3 : 1
7 examples, up to 45 % yield
O
Page No. – Page No.
The addition of a nicotinate-xanthate derivative to N-allylindoles and N-allylpyrroles
resulted in polycyclic matrine analogs, via an oxidative cascade addition/double-
cyclization radical process.
Expedited synthesis of matrine
analogues based on an oxidative
cascade addition/double-cyclization
radical process.
This article is protected by copyright. All rights reserved.