Synthesis of nuevamine aza-analogues by a sequence: I-MCR-aza-Diels-Alder- Pictet-Spengler

Article abstract of DOI:10.1055/s-0032-1317622

A series of nuevamine aza-analogues were prepared in moderate to good yields in two reaction steps. The synthetic strategy involves an isonitrile-based multicomponent reaction, including an aza-Diels-Alder cycloaddition and Pictet-Spengler reaction as postcondensation. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317622

LETTER
▌2951
lSetyternthesis of Nuevamine Aza-Analogues by a Sequence: I-MCR–Aza-Diels–
Alder–Pictet–Spengler
Synthesis of Nuevamine Aza-Analogues
Alejandro Islas-Jácome,a,b Luis E. Cárdenas-Galindo,b Alberto V. Jerezano,c Joaquín Tamariz,c Eduardo González-Za-
mora,*a Rocío Gámez-Montaño*b
a
Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco
186, Col. Vicentina Iztapalapa, C. P. 09340, México D. F., México
Fax +52(55)58044666; E-mail: egz@xanum.uam.mx
b
Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, C. P.
36050, Guanajuato, Guanajuato, México
Fax +52(473)73200068168; E-mail: rociogm@ugto.mx
c
Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala
S/N, Col. Casco de Santo Tomás, C. P. 11340, México D. F., México
Received: 03.09.2012; Accepted after revision: 24.10.2012
ther through a Parham cyclization or a Pomeranz–Fritsch–
Abstract: A series of nuevamine aza-analogues were prepared in
Bobbitt, Pictet–Spengler, or Bischler–Napieralski reac-
moderate to good yields in two reaction steps. The synthetic strate-
tion. Other sophisticated methods have also been em-
gy involves an isonitrile-based multicomponent reaction, including
an aza-Diels–Alder cycloaddition and Pictet–Spengler reaction as
postcondensation.
ployed, these involving either harsh conditions, sensitive
reagents, or multiple steps.4
Key words: nuevamine aza-analogue, I-MCR, aza-Diels–Alder,
S-oxidation, Pictet–Spengler cyclization
The formation of ring B has been performed by an intra-
molecular Heck cyclization of aromatic enamides 3,5
(Scheme 1, path B). There are few reports in the literature
about the preparation of nuevamine aza-analogues.6
Heterocyclic compounds of type tetrahydroisoindolo-
[1,2-a]isoquinoline amides are an important class of tetra-
cyclic lactams with a relatively high occurrence in
nature.1 (±)-Nuevamine (1)2 is an alkaloid isolated from
Berberis Darwinii Hook, which occupies a special place
in natural product chemistry, since it was the first recog-
nized tetrahydroisoindolo[1,2-a]isoquinoline amide re-
ported from natural sources (Scheme 1).
During the annulation process to prepare the lennoxamine
aza-analogues 5 by a Pummerer cyclization of S-oxides 4,
the tetrahydroazaisoindolo[1,2-a]isoquinoline amides 6
were unexpectedly isolated in moderate to good yields
(Scheme 2).
The use of a combination of isocyanide-based multicom-
ponent reactions (I-MCR)7 with other postcondensation
processes is a powerful tool to prepare numerous highly
functionalized heterocyclic molecules and compounds
with high molecular complexity, in a minimum of steps,
from either commercially available or readily isolable
starting materials.
Two main general approaches for the synthesis of tetrahy-
droisoindolo[1,2-a]isoquinoline amides have been report-
ed.3 They differ in the type of annulation process and in
the hetero-ring unit embedded in the alkaloid skeleton
formed in the last step. Thus, ring A (Scheme 1, path A)
of the tetrahydroisoquinoline unit, in molecules fused
with the isoindolinone moiety, has generally been built ei-
As a part of our own efforts to develop short and versatile
routes for the preparation of novel nitrogen heterocyclic
O
N
B
O
O
A
OMe
N
OMe
N
I
path A
path B
X
O
O
2
3
(±)-nuevamine (1)
Scheme 1 General approaches for the synthesis of tetrahydroisoindolo[1,2-a]isoquinoline amides
SYNLETT 2012, 23, 2951–2956
Advanced online publication: 23.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317622; Art ID: ST-2012-S0737-L
© Georg Thieme Verlag Stuttgart · New York

2952
A. Islas-Jácome et al.
LETTER
O
O
O
O
O
O
N
N
N
N
N
N
R
N
N
N
Me
O
S
S
R
R
lennoxamine aza-analogues 5
S-oxides 4
nuevamine aza-analogues 6
Scheme 2 Unexpected nuevamine aza-analogue formation
structures,8 we herein describe the synthesis of an aza- involves a consecutive process Ugi-3CR/aza-Diels–
analogue series of tetrahydroisoindolo[1,2-a]isoquinoline Alder, followed by aromatization (Scheme 3).
amides. Our strategy (Scheme 3) involved six processes in
two steps: (1) I-MCR; (2) aza-Diels–Alder; (3) aromatiza-
It is likely that the mechanism of formation pyrrolo[3,4-
b]pyridin-5-ones 11 starts from 5-aminooxazoles 12 (Ugi-
tion; (4) S-oxidation; (5) acyloxysulfonium β-elimination;
3CR adducts), which reacts with maleic anhydride (10) by
and (6) Pictet–Splenger cyclization. This strategy is based
an aza-Diels–Alder cycloaddition to obtain cycloadduct
on the preparation of pyrrolo[3,4-b]pyridin-5-ones 11 and
13a (Scheme 4). Then, an intramolecular N-acylation oc-
their use as key intermediates in the Pictet–Spengler
curs to give intermediate 14 (path a). However, an alterna-
reaction.
tive cyclization mechanism may be considered,11 which
In the first step, the pyrrolo[3,4-b]pyridin-5-one series take place from 5-aminooxazoles 12 involving first inter-
11a–d was prepared in moderate to good yields applying molecular transamidation to lead amide 13b (path b), fol-
the protocol recently reported by our group,6d,9,10 which lowed by the intramolecular Diels–Alder reaction to give
16'
15'
O
NH2
S
O
4
O
3
N
9
8
R
16
6N
17
5
21
20
19
15
25
26 R
22
2
10
11
7
N
7
8
18
1
Sc(OTf)3
27
28
+
24
23
12
13
S
12'
13'
PhMe
MW, 80 °C
60 min
O
29'
30'
O
29
30
CN
14
O
N
31
O
O
11a, R = 3,4-MeO (68%)
11b, R = 2,3-MeO (62%)
11c, R = 3,4-HO (42%)
11d, R = 2,5-MeO (58%)
10
9
1) MCPBA
CH2Cl2
0 °C
2) TFAA
CH2Cl2
30 min
19'
18'
O
O
9
15
N
10
19
7N
8
18
6
6a, R1 = R4 = H, R2 = R3 = OMe
6b, R1 = R2 = OMe, R3 = R4 = H
6c, R1 = R4 = H, R2 = R3 = OH
6d, R1 = R4 = OMe, R2 = R3 = H
11
12
20
21
14
5
N
13Me
17
4
R4
16
22'
22
23
R1
1
2
23'
3
R3
25R2
24
26
Scheme 3 Synthesis of nuevamine aza-analogues 6a–d
Synlett 2012, 23, 2951–2956
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Nuevamine Aza-Analogues
2953
R
Ph
O
S
R
aza-Diels–Alder
N-acylation
NH
R
path a
Ph
S
O
N
O
Bn
N
O
N
O
O
Ph
S
O
O
N
NH
O
13a
O
+
O
O
Bn
N
R
10
N
O
H
N
O
Bn
14
aza-Diels–Alder
COOH
N-acylation
O
Ph
12
S
O
N
O
path b
N
decarboxylation
N
Bn
O
13b
O
O
O
O
H
R
R
N
N
dehydration
N
N
N
Bn
N
Bn
OH
S
S
Ph
11
Ph
15
Scheme 4 Mechanism for the formation of pyrrolo[3,4-b]pyridine-5-ones 11
intermediate 14. Aromatization process from 14 to 11 can compound 6d under the same conditions (Table 1, entry
be explained by decarboxylation of the β-keto acid func- 6), only the starting material was observed. Compound 6d
tion of 14, followed by an intermolecular base-assisted was first isolated at 20% of yield under heating at reflux
dehydration process of compound 15 favored by the tem- (Table 1, entry 7). We tried to improve the result by using
perature that was used.12
microwaves as a heat source, with a slight increase in the
yield (Table 1, entry 8). Finally, with the idea of increas-
ing the temperature, we changed the solvent from dichlo-
romethane to ethanol raising the yield to 38% (Table 1,
entry 9). The lowest yield obtained for derivative 6d is
probably due to the hindrance effect of the methoxy group
as R4 during the final cyclization. One important feature
of this process is that the starting materials (corresponding
to S-oxides 4) were ever recovered, and for this reason ad-
ditional trials were carried out to increase the yield of 6d,
even using higher temperatures. However, decomposition
of both the final product and starting material was ob-
served.
In the second step, compounds 11a–d were S-oxidized to
obtain the corresponding S-oxide series 4a–d employing
the typical oxidation conditions (MCPBA, CH2Cl2,
0 °C).13 As part of our interest in obtaining compounds
containing the lennoxamine skeleton from the sulfoxides
4a–d via a Pummerer-type cyclization,14 we used the con-
ditions reported by Ishibashi et al.,15 which employs triflu-
oroacetic anhydride (TFAA) as the S-oxide activator to
promote the final cyclization process. To our surprise, the
unexpected nuevamine aza-analogue 6a was isolated in
moderate yield.16
After the characterization of novel compound 6a, we as-
sumed that the reaction was carried out by a Pictet–Spen-
gler cyclization.17 Table 1 (entry 2) shows that compound
6a was isolated at a yield of 89% when the reaction was
The structure of these novel compounds 6a–d was estab-
lished by spectroscopic analysis (1H, 13C, DEPT, COSY,
HSQC, HMBC, IR, and HRMS).
carried out at 0 °C, and of 92% at room temperature (Ta- A reasonable reaction mechanism that can account for the
ble 1, entry 3). The latter conditions were employed for conversion of the S-oxides 4 into the corresponding nue-
the preparation of nuevamine aza-analogues 6b,c (Table vamine aza-analogues 6 is depicted in Scheme 5. Conden-
1, entries 4 and 5). When the attempt was made to obtain sation of 4 with TFAA gives the acyloxysulfonium salts
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2951–2956

2954
A. Islas-Jácome et al.
LETTER
One possible rationalization for the observed behavior of
the S-oxide group is the acidity of proton H-7 and the sta-
bility of the resulting enamide moiety in 17. Both effects
promote the elimination of the leaving group in interme-
diate 16.18
Table 1 Results for Nuevamine Aza-Analogues 3a–d
Entry
Conditions
Time (h) Yield (%) Product
1
2
3
4
5
6
7
8
9
CH2Cl2, –45 °C
CH2Cl2, 0 °C
16
8
60
89
92
87
60
n.r.
20
24
38
6a
6a
6a
6b
6c
6d
6d
6d
6d
The generation of the N-acyliminium ions from enamides
is facilitated by the acidic reagent, the solvent, and the
substrate structure.19 Although the role of S-oxides as pre-
cursors of N-acyliminium ions in a Pummerer–Mannich
cascade process has been reported by Padwa et al.,20 the
Pictet–Spengler reaction observed in this work appears to
be a new contribution in these closely related transforma-
tions.
CH2Cl2, 25 °C
CH2Cl2, 25 °C
CH2Cl2, 25 °C
CH2Cl2, 25 °C
CH2Cl2, reflux
CH2Cl2, MW, 52 °C
EtOH, MW, 75 °C
3
3
3
24
36
3
In summary, this methodology represents a powerful tool
for the preparation of nuevamine aza-analogues and
shows the potential of the Pictet–Spengler cyclization as
an Ugi postcondensation.21 In contrast to the conventional
methodologies for the preparation of tetrahydroisoindolo-
isoquinoline amides, which require strong conditions; the
present methodology uses mild conditions. This synthetic
strategy is an example of a sustainable annulation process
in which only one step is required for the preparation of
the key precursor. The asymmetric version of this meth-
odology is currently in process, and it will be reported in
due course.
1.5
16, which by a subsequent trifluoroacetate ion assisted
β-elimination process provides the enamide intermediate
17. Tautomerization of the latter gives the reactive N-acyl-
iminium ion intermediates 18. Then, a TFA-promoted
Pictet–Spengler cyclization furnishes 6. The highly fa-
vored 6-endo-trig cyclization gave the novel nitrogen
polyheterocycles 6 under mild protic conditions.
O
O
N
O
O
N
N
N
R
R
N
Bn
N
Bn
H
O
O
S
O
S
OOCCF3
F3C
O
CF3
OOCCF3
4
16
base-assisted
β-elimination
O
N
O
O
O
N
enamine–
N-acyliminium
Bn
N
N
N
tautomerization
R
Me
R
N
Bn
18
17
6-endo-trig
TFA
Pictet–Spengler
cyclization
O
O
N
N
N
Me
R
6
Scheme 5 Plausible reaction mechanism for the transformation of 4 to 6
Synlett 2012, 23, 2951–2956
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Nuevamine Aza-Analogues
2955
Montaño, R.; Ibarra-Rivera, T.; El Kaim, L.; Miranda, L. D.
Synthesis 2010, 1285.
(9) Islas-Jácome, A.; González-Zamora, E.; Gámez-Montaño,
R. Tetrahedron Lett. 2011, 52, 5245.
(10) Procedure for the Synthesis of Pyrrolo[3,4-b]pyridin-5-
ones 11a–d: Selected Compound 6-(3,4-
Acknowledgment
Financial support from Consejo Nacional de Ciencia y Tecnología
(CONACyT) is gratefully acknowledged (grants 290662_UG,
51346-Q, 83446, 166747, 156801 and 52292-Q), as is the scholar-
ship awarded to A.V. Jerezano (202139). J.T. also acknowledges
SIP-IPN for grants received (20100236 and 20110172). We thank
A. Gutierrez-Carrillo for NMR spectra, L.D. Miranda-Gutiérrez for
fruitful comments and M. en C. Carlos J. Cortés-García for techni-
cal support. J.T. is a fellow of the EDI-IPN and COFAA-IPN pro-
grams.
Dimethoxyphenethyl)-2-benzyl-6,7-dihydro-3-
morpholino-7-[(phenylthio)methyl]pyrrolo[3,4-
b]pyridin-5-one (11a)
3,4-Dimethoxyphenethylamine (0.671 mmol, 1.0 equiv) and
2-thiophenylacetaldehyde (0.603 mmol, 0.9 equiv) were
placed in a 10 mL sealed CEM DiscoverTM microwave
reaction tube and diluted in 1.0 mL of dry toluene. Then, the
mixture was irradiated (MW, 80 °C, 25 W) for 10 min and
Sc(OTf)3 (0.0211 mmol, 0.03 equiv) was added. The
mixture was irradiated (MW, 80 °C, 25 W) for 10 min, and
2-isocyano-1-morpholino-3-phenylpropan-1-one (0.805
mmol, 1.2 equiv) was added. The mixture was again
irradiated (MW, 80 °C, 25 W), this time for 15 min, and
maleic anhydride (0.805 mmol, 1.2 equiv) was added.
Finally, this reaction mixture was irradiated (MW, 80 °C, 25
W) for 15 min, and the solvent was removed under reduced
pressure. The crude was dissolved in CH2Cl2 (5.0 mL) and
washed with a concentrated aq solution of NaHCO3 (3 × 25
mL) and with brine (3 × 25 mL). The organic layer was dried
with Na2SO4, and the solvent was removed under vacuum.
The residue was immediately purified using a silica gel
chromatoflash (hexane–EtOAc = 2:1) to afford compound
11a (68%) as a pale yellow powder; mp 58–59 °C; Rf = 0.25
(hexane–EtOAc = 1:1).
References and Notes
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Spectral Data for Compound 11a
1H NMR (500 MHz, CDCl3): δ = 7.79 (s, 1 H, H-4), 7.25–
7.13 (m, 10 H, HAr), 6.76–6.69 (m, 3 H, HAr), 4.51 (m, 1 H,
H-7), 4.27 (d, J = 14.2 Hz, 1 H, H-10), 4.19 (d, J = 14.2 Hz,
1 H, H-10), 4.21–4.13 (m, 1 H, H-17), 3.83 (s, 3 H, H-25),
3.83–3.79 (m, 4 H, H-16), 3.78 (s, 3 H, H-26), 3.56 (dd, J =
14.1, 3.8 Hz, 2 H, H-27), 3.25–3.19 (m, 1 H, H-17), 2.96–
2.89 (m, 1 H, H-18), 2.88–2.82 (m, 1 H, H-18), 2.82–2.80
(m, 4 H, H-15). 13C NMR (125 MHz, CDCl3): δ = 167.0 (C-
5), 161.1 (C-2), 158.3 (C-8), 148.9 (C-23), 147.8 (C-3),
147.6 (C-22), 139.2 (C-11), 135.2 (C-28), 131.0 (C-19),
130.7 (C-12), 128.8 (C-13), 128.8 (C-29), 128.3 (C-30),
126.7 (C-14), 126.2 (C-31), 125.1 (C-9), 123.2 (C-4), 120.5
(C-20), 111.8 (C-21), 111.2 (C-19), 67.1 (C-16), 60.1 (C-7),
55.9 (C-25, C-26), 52.9 (C-15), 41.7 (C-17), 39.8 (C-10),
35.6 (C-27), 34.0 (C-18). FT-IR (film in CH2Cl2): 1691
(C=O) cm–1. HRMS: m/z calcd for C33H31N3O4S: 595.2505;
found: 595.2507.
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To a stirred solution of S-oxide 4a (0.034 mmol, 1.0 equiv)
in CH2Cl2 (1.0 mL) at 0 °C, drops of TFAA (0.172 mmol, 5.0
equiv) were added. After stirring at r.t. for 3 h, the solvent
was removed under reduced pressure, and the crude was
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2951–2956

2956
A. Islas-Jácome et al.
LETTER
dissolved in CH2Cl2 (1.0 mL), and washed with an aq
solution of NaHCO3 (3 × 10 mL) and with brine (3 × 10
mL). The organic layer was dried with Na2SO4, and the
solvent was removed under vacuum. The residue was
immediately purified using a silica gel chromatoflash
(hexane–EtOAc = 1:1) to afford compound 6a (92%) as a
pale pink powder; mp 72–74 °C; Rf = 0.15 (hexane–EtOAc
= 1:1).
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Spectral Data for Compound 6a
1H NMR (500 MHz, CDCl3): δ = 7.84 (s, 1 H, H-9), 7.67 (s,
1 H, H-4), 7.27–7.16 (m, 5 H, HAr), 6.55 (s, 1 H, H-1), 4.67–
4.63 (m, 1 H, H-6), 4.50 (d, J = 14.5 Hz, 1 H, H-20), 4.32 (d,
J = 14.5 Hz, 1 H, H-20), 3.83–3.79 (m, 7 H, H-19, H-25),
3.67 (s, 3 H, H-26), 3.42–3.26 (m, 1 H, H-6), 3.06–2.99 (m,
1 H, H-5), 2.84–2.82 (m, 4 H, H-18), 2.76–2.72 (m, 1 H, H-
5), 1.81 (s, 3 H, H-13). 13C NMR (125 MHz, CDCl3): δ =
167.7 (C-8), 163.5 (C-16), 161.0 (C-11), 148.0 (C-3), 147.7
(C-10), 147.5 (C-2), 139.6 (C-21), 129.6 (C-16), 128.9 (C-
22), 128.3 (C-23), 126.2 (C-24), 124.6 (C-17), 123.7 (C-9),
123.1 (C-15), 111.2 (C-1), 109.9 (C-4), 67.2 (C-19), 63.1 (C-
12), 55.9 (C-25), 55.8 (C-26), 53.0 (C-18), 40.0 (C-20), 34.7
(C-6), 29.0 (C-5), 27.9 (C-13). FT-IR (film in CH2Cl2): 1693
(C=O) cm–1. HRMS: m/z calcd for C33H29N3O4S: 485.2315;
found: 485.2314.
(17) (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104,
2311. (b) Chrzanowska, M.; Rozwadowska, M. D. Chem.
Synlett 2012, 23, 2951–2956
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