Synthesis of a tetracyclic lactam system of Nuevamine by four-component reaction and free radical cyclization

Article abstract of DOI:10.1016/j.tetlet.2010.07.047

A series of aza-analogs of nuevamine were prepared from readily available aldehyde, amine, and isonitrile compounds and maleic anhydride by combining a novel four-component reaction and free radical cyclization. The operational simplicity of this novel heterocycle synthesis process will be valuable for the synthesis of fused ring systems.

Full text of DOI:10.1016/j.tetlet.2010.07.047

Tetrahedron Letters 51 (2010) 4837–4839
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a tetracyclic lactam system of Nuevamine by four-component
reaction and free radical cyclization
*
Angel Zamudio-Medina, Ma. Carmen García-González, Juan Padilla, Eduardo González-Zamora
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, Iztapalapa, C. P. 09340, México, D.F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of aza-analogs of nuevamine were prepared from readily available aldehyde, amine, and isoni-
trile compounds and maleic anhydride by combining a novel four-component reaction and free radical
cyclization. The operational simplicity of this novel heterocycle synthesis process will be valuable for
the synthesis of fused ring systems.
Received 4 June 2010
Revised 2 July 2010
Accepted 8 July 2010
Available online 13 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Tetracyclic lactam alkaloids are of interest in drug research due
to their biological activities. One of the most important tetracyclic
systems that incorporates an isoindolo[2,1-a]isoquinoline skeleton
is nuevamine, 1, Figure 1. This alkaloid was the first reported
isoindoloquinoline natural product.1 The structure of 1 is interest-
ing from a pharmacological perspective due to the potential
biological activity of many of its derivatives: anti-inflammatory,
anti-microbial, anti-leukemic, and anti-tumoral properties. Many
synthetic approaches have been developed in an effort to obtain
nuevamine and its analogs.2–4
Microwave radiation is widely used as an easily-controlled heat
source for a number of applications, particularly the acceleration of
organic reactions.5 Microwave treatment shortens the reaction
times and gives high yields. Multicomponent reactions are very
important in synthetic organic chemistry.6 The Passerini three-
component reaction (P-3CR) and the Ugi three- and four-compo-
nent reactions (U-3R, and U-4CR) are of particular importance.
An isocyanide derivative is a common component in all three of
these coupling processes. Thus, these reactions have become
known as isocyanide-based multicomponent reactions (IMCR).6
IMCRs, which lead to an interesting heterocyclic scaffold, are
particularly useful for the construction of diverse chemical
libraries of drug-like compounds,6c however the combination of
this methodology with the appropriate postfunctionalization is
an extremely powerful synthetic tool for the preparation of struc-
turally diverse complex molecules.7
intramolecular free radical cyclization as a postfunctionalization
in a one-pot process.
Three-component condensation of 2-bromo benzaldehyde 2a,
allylamine 3, and the isonitrile 4 in methanol yielded, after 48 h
at room temperature, low yields of 5-amino-oxazole 5a, 27%. After
a brief systematic variation of the reaction parameters, it was
found that using microwaves as a heat source, Sc(OTf)3 as a
catalyst,8 and benzene as a solvent, promoted this transformation.
Stirring a solution containing aldehyde 2a, allylamine 3, and the
isonitrile 4 for 15 min in a sealed tube in a microwave reactor pro-
vided the 5-amino-oxazol 5a intermediate in an excess of 82%
yield, Scheme 1.
The Diels–Alder cycloaddition between the oxazol 5a, as an
aza-diene, and maleic anhydride 6, as a dienophile, in benzene at
60 °C for 15 min using microwave radiation provided the
pyrrolopyridinone 8a via the oxa-bridged intermediate 7a.9 This
intermediate spontaneously gave the compound 8a by a triple
domino sequence: lactamization, dehydration, and decarboxyl-
ation, and could not be isolated. The pyrrolopyridinone 8a was pro-
duced in 73% overall yield, Scheme 1.
This novel reaction was studied using the amine 3, isonitrile 4,
maleic anhydride 6, in benzene, and four aldehydes 2a, 2b,10 2c,11
and 2d,12,13 as starting materials. In all cases, the reaction was per-
formed with a catalytic quantity of Sc(OTf)3 and was completed
In connection with our ongoing project using IMCR and with
the goal of developing a new synthetic methodology for gaining
rapid access to new compound libraries, we describe the synthesis
of new molecules containing the aza-tetracyclic skeleton of
nuevamine by means of a novel four-component reaction and the
O
N
O
O
OMe
OMe
Nuevamine 1
* Corresponding author. Tel.: +52 55 58 04 4913; fax: +52 55 58 04 4666.
E-mail address: egz@xanum.uam.mx (E. González-Zamora).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.047

4838
A. Zamudio-Medina et al. / Tetrahedron Letters 51 (2010) 4837–4839
R2
R1
Br
O
O
R1
R2
CH3OH, R.T., 48 h
27 %
H
N
CN
H
N
H2N
O
Br
PhH, Sc(OTf)3 (0.03
equiv.), 60 ºC, 15 min,
MW, 82 %
N
O
2a
4
3
N
O
5a
R2
R1
Br
R2
R1
Br
N
N
N
O
O
O
O
O
R1
H
8b OH
8c OCH3
8d
R2
H
H
H
%
8a
73
30
80
N
N
O
5a
6
COOH
N
65 ºC, 15 min,
MW
OCH2O 84
O
O
7a
R2
N
N
R1
Bu3SnH
O
ACHN, MW,
90 min
N
9a 85 %
9b 40 %
9c 50 %
9d 85 %
O
Scheme 1.
within 40 min in only one step. The pyrrolopyridinones 8a–d were
produced in good yields, except for 8b, which was produced in 30%
yield (the reaction was not optimized). The low yield for 8b may
have been due to an interaction between Sc(OTf)3 and the hydroxy
group of the starting compound, 2b, Scheme 1.
Closure of the pyridine 8a, under the classical conditions of the
Heck reaction, did not give the expected compound 9a. However,
the use of a free radical reaction employing 1,10-azobis(cyclohex-
anecarbonitrile) (ACHN) as the initiator along with Bu3SnH yielded
the expected compound 9a in low yields.14 After optimizing condi-
tions using a microwave reactor, the yields for this transformation
were improved. The optimal conditions included Bu3SnH, ACHN,
and benzene as the solvent, with three sequential additions,
followed by irradiation at 138 °C, to yield four diastereomers of
the tetracycle 9a in 85% yield, Scheme 1.
Under these conditions, the desired aza-analogs of nuevamine 1
were prepared from moderate to good yields using the pyrrolopy-
ridinones 8b–d as starting materials. In all cases, the expected
compounds 9b–d were obtained in a mixture with a difficult
separation of the four diastereomers by silica gel column chroma-
tography. Only one diastereoisomer of the compounds 9a and 9d
was isolated by the use of preparative plates.
The scope of this novel multicomponent domino reaction was
evaluated by the inclusion of a free radical cyclization into the full
process. Thus, under the conditions established previously in the
multistep synthesis, the allylamine 3 and 2-bromo benzaldehyde
2a were sealed in a reaction tube and irradiated for 5 min at
50 °C. Subsequently, Sc(OTf)3 was introduced and the irradiation
was continued for an additional 5 min at the same temperature,
after which the isonitrile 4 was added and the mixture was
irradiated for 15 min at 80 °C. Next, the maleic anhydride 6 was
introduced and the irradiation was continued at 60 °C for an addi-
tional 15 min. Finally, three portions of Bu3SnH and ACHN in ben-
zene were added sequentially and the irradiation was continued at
138 °C for 30 min (each of them) in a single one-pot process, and
the isolated four diastereomers of 9a were obtained in over 72%
yield. The major diastereoisomer was isolated using preparative
plates.
This reaction is atom economical, seven chemical bonds and
three rings were created, and only water and CO2 were lost in this
multicomponent domino process via a combination of 4CR, Diels–
Alder cycloaddition, and two intramolecular ring closures (lactami-
zation, and 6-exo-trig free radical cyclization). Overall, the final
compound 9a was produced in good yield from the four readily
available starting materials, Scheme 1.
In summary, the synthesis of four aza-analogs of nuevamine was
achieved in a very short time via a multicomponent process that
included intramolecular free radical cyclization and microwave
assistance. The process involved reactions between aromatics
aldehydes, allylamine, a-isocyanoacetamide, and maleic anhydride
in the presence of catalytic quantities of Sc(OTf)3. The operational
simplicity involved in achieving these novel heterocycles is highly
attractive for a range of diversity-oriented synthetic approaches.
The development of this methodology as a one-pot synthesis using
readily available reagents is currently underway.
Acknowledgments
The authors thank CONACYT for the financial support (projects
51346-Q, 52292-Q) and for the scholarship awarded to J. A. Zamu-
dio-Medina and M.C. García-González. We thank A. Gutiérrez-
Carrillo for NMR spectra.

A. Zamudio-Medina et al. / Tetrahedron Letters 51 (2010) 4837–4839
4839
63.4, 55.4, 53.0, 43.0, 39.9; IR: 2842, 1694, 1441, 1112, 1015, 940, 701 cmꢀ1
HRMS: Calcd for C28H29N3O3Br [M+H]+: 534.1314. Found: 534.1395.
Typical procedure for the free radical cyclization: The corresponding
pyrrolopyridinone (0.091 mmol) was placed in 10 mL sealed CEM
Discover™ microwave reaction tube, solution containing Bu3SnH
(0.364 mmol) and ACHN (0.046 mmol) in 1 mL benzene was added in
sequence of three portions, in 30 min intervals, and the irradiation was
resumed at 138 °C (power 280 W). The solvent was removed under reduced
pressure. The crude product was purified by silica gel column chromatography
(hexane/AcOEt 1:1). The major diastereoisomer was isolated using preparative
plates.
;
References and notes
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8
a
a
a
10-Benzyl-5-methyl-9-morpholin-4-yl-5,11b-dihydro-6H-1,3-dio-xa-6a,11-diaza-
indeno[5,6-c]fluoren-7-one 9d. Selected spectral data for major diastereisomer 9d,
yield 85%, yellow powder, mp: 63 °C; 1H NMR (500 MHz, CDCl3, 298 K): d 7.85
(s, 1H), 7.66 (s, 1H), 7.37–7.39 (m, 2H), 7.19–7.23 (m, 3H), 6.61 (s, 1H), 5.96 (d,
J = 1.41 Hz, 1H), 5.90 (d, J = 1.41 Hz, 1H), 5.45 (s, 1H), 4.42 (d, J = 14.25 Hz, 1H),
4.35 (d, J = 14.25 Hz, 1H), 4.31 (dd, J = 13.28, 2.27 Hz, 1H), 3.83–3.87 (m, 4H),
3.54 (dd, J = 13.28, 4.31 Hz, 1H), 3.01–3.04 (m, 1H), 2.85–2.88 (m, 4H), 1.21 (d,
J = 7.05 Hz, 3H); 13C NMR (125 MHz, CDCl3, 298 K): d 161.2, 158.6, 147.7, 147.1,
146.4, 139.3, 132.7, 129.2, 128.4, 128.3, 126.3, 124.6, 124.2, 123.7, 108.1, 106.7,
101.0, 67.1, 59.3, 53.0, 43.5, 39.9, 35.0, 22.7; IR: 2854, 1693, 1482, 1114, 1035,
5. Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–9223.
6. (a) Dömling, A. Chem. Rev. 2006, 106, 17–89; (b) Zhu, J. Eur. J. Org. Chem. 2003,
1133–1144; (c) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH:
Verlag GmBH&Co. KGaA, 2005.
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Tye, H.; Whittaker, M. Tetrahedron Lett. 2003, 44, 4369–4371.
9. (a) González-Zamora, E.; Fayol, A.; Bois-Choussy, M.; Chiaroni, A.; Zhu, J. Chem.
Commun. 2001, 1684–1685; (b) Gámez-Montaño, R.; González-Zamora, E.;
Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351–6358.
10. Beja, A.; Paixão, J.; Silva, M.; Veiga, L.; Gonsalves, A.; Serra, A. Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun. 2000, 5, 354–355.
11. Moorthy, J.; Samanta, S. J. Org. Chem. 2007, 72, 9786–9789.
12. Capdevielle, P.; Lavigne, A.; Maumy, M. Tetrahedron 1990, 46, 2835–2844.
13. Chapsal, B.; Hua, Z.; Ojima, I. Tetrahedron Asymmetry 2006, 17, 642–657.
14. (a) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem. Commun.
2000, 1527–1528; (b) Abeywickrema, A.; Beckwith, A.; Gerba, S. J. Org. Chem.
1987, 52, 4072–4078.
;
932, 699 cmꢀ1 HRMS: Calcd for C28H28N3O4 [M+H]+: 470.2001. Found:
470.2012.
Typical procedure for obtaining the tetracycle 9 in one-pot process: allylamine
(0.350 mmol) and the corresponding benzaldehyde (0.315 mmol) were placed
in a 10 mL sealed CEM Discover™ microwave reaction tube to which 1 mL
benzene was added. The sealed tube was placed in the microwave reactor and
irradiated at 50 °C (power 4 W) for 5 min, then Sc(OTf)3 was introduced
(0.010 mmol) and irradiation was continued at 50 °C (power 4 W) for 5 min.
After this time, the isonitrile was added (0.420 mmol) and the solution was
irradiated at 80 °C (power 180 W) for 15 min. Maleic anhydride was added
(0.420 mmol) and irradiated at 60 °C (power 4 W) for 15 min. A solution
containing Bu3SnH (0.467 mmol) and ACHN (0.058 mmol) in 1 mL benzene
was added in a sequence of three portions, in 30 min intervals, and the
irradiation was resumed at 138 °C (power 280 W). The solvent was removed
under reduced pressure. The crude product, purified by silica gel column
chromatography (hexane/AcOEt 1:1) afforded four diastereomers of the
tetracycle 9. The major diastereoisomer was isolated by the use of prepara-
tive plates.
Typical procedure for obtaining the pyrrolopyridinone 8: allylamine (0.350 mmol)
and the corresponding benzaldehyde (0.315 mmol) were placed in a 10 mL
sealed CEM Discover™ microwave reaction tube to which 1 mL benzene was
added. The sealed tube was placed in the microwave reactor and irradiated at
50 °C (power 4 W) for 5 min, then Sc(OTf)3 was introduced (0.010 mmol) and
the irradiation was continued at 50 °C (power 4 W) for 5 min. After this time,
the isonitrile was added (0.420 mmol) and the solution was irradiated at 80 °C
(power 180 W) for 15 min. Maleic anhydride was added (0.420 mmol) and
irradiated at 60 °C (power 4 W) for 15 min. The crude product was purified by
silica gel column chromatography (hexane/AcOEt 1:1).
6-Allyl-2-benzyl-7-(2-bromo-5-methoxyphenyl)-6,7-dihydro-3-morpholinopyrrolo
[3,4-b]pyridin-5-one 8c. Selected spectral data for 8c, yield 80%, yellow powder,
mp: 95–97 °C; 1H NMR (500 MHz, CDCl3, 298 K): d 7.89 (s, 1H), 7.58 (d,
J = 8.8 Hz, 1H), 7.24–7.25 (m, 2H), 7.15–7.18 (m, 2H), 7.11–7.13 (m, 1H), 6.78
(dd, J = 8.8, 3.0 Hz, 1H), 6.23 (d, J = 3.0 Hz, 1H), 6.13 (s, 1H), 5.75–5.83 (m, 1H),
5.20 (dd, J = 10.1, 1.0 Hz, 1H), 5.12 (dd, J = 17.0, 1.0 Hz, 1H), 4.65 (dd, J = 15.4,
5.0, 1H), 4.32 (d, J = 13.6 Hz, 1H), 4.20 (d, J = 13.6 Hz, 1H), 3.81–3.83 (m, 4H),
3.65 (s, 3H), 3.48 (dd, J = 15.4, 7.2 Hz, 1H), 2.81–2.83 (m, 4H); 13C NMR
(125 MHz, CDCl3, 298 K): d 167.1, 162.2, 160.2, 159.3, 147.8, 139.2, 136.0,
134.0, 132.1, 128.9, 128.1, 126.1, 123.8, 123.7, 118.5, 116.0, 115.8, 113.3, 67.1,
10-Benzyl-5-methyl-9-morpholin-4-yl-5,11b-dihydro-6H-6a,11-di-aza-benzo[c]
fluoren-7-one 9a. Selected spectral data for major diastereisomer 9a, yield 72 %,
yellow powder, mp: 170–172 °C; 1H NMR (500 MHz, CDCl3, 298 K): d 8.11–
8.13 (m, 1H), 7.85 (s, 1H), 7.35–7.38 (m, 2H), 7.27–7.31 (m, 2H), 7.20–7.24 (m,
3H), 7.16–7.17 (m, 1H), 5.57 (s, 1H), 4.46 (d, J = 14.3 Hz, 1H), 4.36 (d,
J = 14.3 Hz, 1H), 4.35 (dd, J = 13.0, 2.3 Hz, 1H), 3.82–3.85 (m, 4H), 3.58 (dd,
J = 13.0, 4.5 Hz, 1H), 3.11–3.17 (m, 1H), 2.83–2.86 (m, 4H), 1.25 (d, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3, 298 K): d 166.8, 161.1, 158.5, 147.7, 139.4,
139.2, 131.7, 129.2, 128.5, 128.2, 127.5, 126.7, 126.4, 126.2, 124.4, 123.6, 67.1,
59.2, 52.9, 43.5, 39.9, 34.9, 22.6; IR: 1692, 1438, 1114, 1021, 952, 695 cmꢀ1
HRMS: Calcd for C27H28N3O2 [M+H]+: 426.2176. Found: 426.2178.
;