Concise total syntheses of Marinoquinolines A-C

Article abstract of DOI:10.1016/j.tetlet.2011.12.124

The first concise total syntheses of pyrroloquinoline natural products, Marinoquinolines A-C, have been achieved in six linear steps from commercially available starting materials. The key steps were a reaction between (p-tolylsulfonyl)methylisocyanide (TosMIC) and α, β-unsaturated ester under basic condition to prepare the pyrrole moiety and Morgen-Walls reaction to construct quinoline ring.

Full text of DOI:10.1016/j.tetlet.2011.12.124

Tetrahedron Letters 53 (2012) 1271–1274
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise total syntheses of Marinoquinolines A–C
Lijun Ni a,b, Ziyuan Li a,b, Fan Wu b, Jinyi Xu b, Xiaoming Wu a,b, Lingyi Kong a,c, Hequan Yao a,b,
⇑
a State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
b Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
c Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first concise total syntheses of pyrroloquinoline natural products, Marinoquinolines A–C, have been
achieved in six linear steps from commercially available starting materials. The key steps were a reaction
Received 15 November 2011
Revised 23 December 2011
Accepted 30 December 2011
Available online 5 January 2012
between (p-tolylsulfonyl)methylisocyanide (TosMIC) and
prepare the pyrrole moiety and Morgen-Walls reaction to construct quinoline ring.
Ó 2012 Elsevier Ltd. All rights reserved.
a, b-unsaturated ester under basic condition to
Keywords:
Total synthesis
Natural product
Marinoquinoline
Pyrroloquinoline
Antitumor
4
The efficient syntheses of bioactive heterocyclic natural
products or libraries are of major importance to academia and
pharmaceutical industry due to the potential bioactivities of
heterocylic molecules. Recently, Muller and co-workers isolated
several pyrroloquinoline natural products, such as Marinoquino-
lines A–F (1–6, Fig. 1), from Ohtaekwangia kribbensis.1 Among
them, marinoquinoline A (1) has been isolated by the same group
from the marine bacterium Rapidithrix thailandica and its struc-
ture was well characterized by X-ray crystallography.2,3 The
structural details of 2–6 were also elucidated by extensive 1D
and 2D NMR experiments.1 Preliminary biological screening of
these compounds indicated that all of them showed multiple
activities, such as antibacterial and antifungal activities, as well
as moderate cytotoxicity against several cancer cell lines with
5
NH
3
NH
2
N
N
CH3
1
Marinoquinolines A (1)
Marinoquinolines B (2)
NH
NH
OH
N
N
Marinoquinolines D (4)
Marinoquinolines C (3)
IC50 values ranging from 0.3 to 8.0 l
g/mL.1 The unique structural
features and interesting bioactive properties of these natural
products promote us to initiate the total syntheses of them for
further pharmacological study.
NH
NH
O
N
Typical synthetic route to pyrroloquinoline moiety reported in
the literature relies on palladium-catalyzed annulation of haloge-
nated aminoquinoline in one step.4a,b Limitations to this approach
include the use of expensive transition metal catalysts and phos-
phine ligands, relatively harsh reaction conditions and difficulty
to install functional group at 2-position of pyrroloquinoline. There-
fore, developing a flexible route to 2-substituted pyrroloquinoline
is still desirable.
N
NH
HN
Marinoquinolines E (5)
Marinoquinolines F (6)
Figure 1. Structures of Marinoquinolines A–F (1–6).
We envisioned that the pyrroloquinolinone scaffold of the
target compounds could be synthesized stepwise via a sequence
of reactions: (i) constructing substituted pyrrole unit, (ii) building
⇑
Corresponding author. Tel.: +86 25 83271042; fax: +86 25 83301606.
E-mail address: hyao@cpu.edu.cn (H. Yao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.124

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L. Ni et al. / Tetrahedron Letters 53 (2012) 1271–1274
quinoline ring through condensation. In the past few decades, lots
of efforts have been made developing practical methods for the
synthesis of pyrrole unit bearing appropriate functionality. Among
them, van Leusen pyrrole synthesis through a reaction of TosMIC
CHO
NO2
a
NH
d
NO2
TosMIC
NO2
11
7
8
with a Michael acceptor, such as a, b-unsaturated ester, represents
one of the most convenient methods to access to 3, 4-disubstituted
pyrroles.5a This procedure has been extensively applied to the syn-
thesis of various pyrroles, in which the substituent at 3-position
comes from the Michael acceptor.5a–e In 2002, Smith et al. demon-
strated a modified route to 3-aryl and 3, 4-diarylsubstituted
pyrroles in one step from TosMIC and readily accessible arylsubsti-
tuted alkenes in moderate to good yields.6 Considering the feasibil-
ity of constructing pyrrole unit using the above methods, we herein
wish to describe the first and concise total syntheses of 1–3 using
TosMIC methodology.
b, c
NH
NHAc
NH2
12
9
TosMIC
Poor yield
NH
Our retrosynthetic analysis of 1–3 is outlined in Scheme 1. 1–3
could be prepared via a decarboxylation of A. We envisioned that
the quinoline scaffold of 1–3 could be constructed by Morgen-
Walls reaction from amide B. The pyrrole moiety of B would be
acquired by Leusen’s methodology between a, b-unsaturated ester
C and commercially available reagent TosMIC. Finally, C could be
readily derived from commercially available aldehyde 7.
NHAc
10
As the carboxyl group of A must be removed at late stage to
accomplish the total syntheses of the desired products, we first
tried Smith’s single-step method to prepare the key intermediate
of 1 as shown in Scheme 2. Thus, Wittig coupling of aldehyde 7
with CH3PPh3I and DBU in THF, reduction by Fe powder in mixed
solvents at 85 °C and acetylation with CH3COCl smoothly gave
the phenylethylene 9. When we tested the pyrrole synthesis under
several conditions, however, we found that 9 could not efficiently
convert into pyrrole 10 under smith’s condition (no reaction or in
very poor yield). This result could be explained by the fact that
electron-rich arylethylene exhibits poor reactivity, while elec-
tron-deficient arylethylene generally afforded pyrrole product in
high yield.6 Indeed, we found the condensation between 2-nitro-
phenylethylene 8 and TosMIC in anhydrous DMSO using t-BuOK
as a base could furnish pyrrole 11 in about 80% yield. However,
the subsequent reduction of nitro group of 11 under various stan-
Scheme 2. Initial synthesis of pyrrole moiety of 1. Reagents and conditions: (a)
CH3PPh3I, DBU, reflux, 2 h, (45%); (b) Fe/NH4Cl, EtOH/THF/H2O = 6/2/1, 85 °C, 1 h;
(c) CH3COCl, Et3N, CH2Cl2, rt 4 h (65%, two steps); (d) TosMIC, t-BuOK, anhydrous
DMSO, rt, 1 h (80%).
CHO
NO2
a
COOEt
NO2
7
13
14a CH3COCl
14b (CH3)2CHCH2COCl
b, c
EtOOC
14c
BnCOCl
COOEt
NH
d
.
dard conditions, such as Fe/NH4Cl, Fe/HOAc, H2/Pd-C, and SnCl2
H2O, failed to give the desired product 12.
We then applied Leusen’s methodology to the syntheses of our
targets. Leusen has demonstrated that the reaction between Tos-
NHCOR
NHCOR
16a R = CH3
16b R = CH2CH(CH3)2
16c
TosMIC
15a R = CH3
15b R = CH2CH(CH3)2
15c
R = Bn
R = Bn
MIC and
high yields with very good functional group tolerance. As depicted
in Scheme 3, Knoevenagel condensation of aldehyde 7 furnished
a, b-unsaturated ester could provide various pyrroles in
Scheme 3. Total synthesis of 1–3. Reagents and conditions: (a) (i) CH2(COOH)2,
piperidine, pyridine, 85 °C, 12 h; (ii) EtBr, K2CO3/DMF, rt, overnight (86% over two
steps) or EtOH conc. H2SO4, reflux, overnight (68% over two steps); (b) Fe/NH4Cl,
EtOH/THF/H2O = 6/2/1, 85 °C, 1 h; (c) 14a–14c, Et3N, CH2Cl2, rt, 4 h (82% for 15a,
73% for 15b, 75% for 15c, two steps); (d) TosMIC, t-BuOK, anhydrous DMSO, rt, 1 h
(76% for 16a, 68% for 16b, 45% for 16c).
a,
EtOOC
EtOOC
Decarboxylation
Mogen-Walls
reaction
NH
NH
R
1-3
b-unsaturated acid, which was then converted into ester 13 under
EtBr/K2CO3 or EtOH/H2SO4 in good yields. Very interestingly,
reduction of 13 by Fe powder in mixed solvents, could generated
free amine, which was followed by acetylation with RCOCl
NH
N
O
R
B
A
(14a–14c) to furnish the desired
a, b-unsaturated esters 15a–
15c. As expected, condensation of 15a–15c with TosMIC proceeded
smoothly to afford pyrroles 16a–16c under Leusen’s condition in
48–76% yields.
Leusen's Pyrrole
synthesis
After we achieved the key intermediates 16a–16c, we next ap-
plied Morgen-Walls reaction7 to constructing the quinoline unit.
As shown in Table 1, treatment of 16a with SOCl2 or P2O5 gave
the desired product 17a in very low yield (Table 1, entries 1, 2),
while the use of PPA or Tf2O failed to produce 17a (entries 3, 4).
Very gratifyingly, treatment of 16a-16c with TFAA or refresh
distilled POCl3 in anhydrous toluene or CH3CN smoothly afforded
O
O
S
COOEt
CHO
NO2
N
+
NHR
C
Me
TosMIC
7
Scheme 1. Retrosynthetic analysis of Marinoquinolines A–C (1–3).

L. Ni et al. / Tetrahedron Letters 53 (2012) 1271–1274
1273
Table 1
using readily available starting materials. The synthetic route is
highlighted by the construction of the pyrrole moiety via a reaction
a
The screening of Morgen-Walls reaction
EtOOC
EtOOC
between TosMIC and a, b-unsaturated ester under basic condition
and the efficient construction of quinoline ring through Morgen-
Walls reaction. In particular, our synthetic route could enable the
installation of various functional groups at 2-position of pyrrolo-
quinoline, which facilitates the syntheses of other related natural
products and structural modification for further pharmacological
study.
NH
Conditions
NH
R
Morgen-Walls
reaction
NHCOR
N
16a R = CH3
16b R = CH2CH(CH3)2
16c
17a R = CH3
17b R = CH2CH(CH3)2
17c
R = Bn
R = Bn
b
Acknowledgments
Entry
Substrate
Condition
Yield
1
2
3
4
5
6
7
8
9
16a
16a
16a
16a
16a
16a
16a
16b
16c
SOCl2,CH3CN, reflux, 12 h
P2O5, CH3CN, reflux, 12 h
17a, 5%
Financial support from NCET 2008 and Fok Ying Tong Education
Foundation (121040) by the Ministry of Education of China,
2009ZX09103-128 and Fundamental Research Funds for the Cen-
tral Universities (JKZ2009002 and JKGZ201110 for HY) are highly
appreciated.
17a, 34%
17a, N.R
17a, N.R
17a, 84%
17a, 80%
17a, 92%
17b, 85%
17c, 90%
Tf2O, DMAP, CH2Cl2, rt12 h
PPA, CH3CN, reflux, 12 h
TFAA, CH3CN, reflux, 12 h
POCl3, Toluene, reflux, 12 h
POCl3, CH3CN, reflux, 12 h
POCl3, CH3CN, reflux, 12 h
POCl3, CH3CN, reflux, 12 h
Supplementary data
a
All reactions were performed in 0.5 mmol scale in anhydrous solvents.
Isolated yield after flash column chromatography.
b
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.124.
pyrroloquinolines 17a in excellent yields (entries 5–7). Similarly,
treatment of 16b and 16c with POCl3 in anhydrous CH3CN could af-
ford the corresponding products 17b and 17c in 85% and 90%
yields, respectively (entries 8, 9).8–10
References and notes
1. Okanya, P. W.; Mohr, K. I.; Gerth, K.; Jansen, R.; Muller, R. J. Nat. Prod. 2011, 74,
603.
Finally, we examined the decarboxylation of 17a–17c to synthe-
size 1–3 and the results are summarized in Table 2. We first used
17a as a substrate to probe an optimal reaction condition. We
found that treatment of 17a under several typical conditions such
2. Srisukchayakul, P.; Suwanachart, C.; Sangnoi, Y.; Kanjana-Opas, A.; Hosoya, S.;
Yokota, A.; Arunpairojana, V. Int. J. Syst. Evol. Microbiol. 2007, 57, 2275.
3. Kanjana-Opas, A.; Panphon, S.; Fun, H.; Chantrapromma, S. Acta Crystallogr.
2006, E62, 2728.
4. (a) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826; (b) Nazaré, M.; Schneider, C.;
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526.
5. (a) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron
Lett. 1972, 52, 5337; (b) van Leusen, D.; van Leusen, A. M. Org. React. 2003, 57,
419; (c) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587; (d)
Dijkstra, H. P.; ten Have, R.; van Leusen, A. M. J. Org. Chem. 1998, 63, 5332; (e)
Pavri, N. P.; Trudell, M. L. J. Org. Chem. 1997, 62, 2649; (f) Zhu, R.; Xing, L.; Liu, Y.;
Deng, F.; Wang, X. Y.; Hu, Y. J. Organomet. Chem. 2008, 693, 3897.
6. Smith, N. D.; Huang, D.; Cosford, N. D. P. Org. Lett. 2002, 4, 3537.
7. (a) Morgen, C. T.; Walls, P. L. J. Chem. Soc. 1931, 2447; (b) Morgen, C. T.; Walls, P.
L. J. Chem. Soc. 1932, 2225.
as Ag2CO3/HOAc,11 NaOH/EtOH, or NaOH/(CH2OH)2 at high tem-
12
perature only gives 1 in very poor yields (table 2, entries 1–3). The
decarboxylation of 17a could proceed smoothly to afford 1 in about
65% yield with concentrated HCl for 12 h (entry 4).13 The carboxyl-
ate groups of 17b and 17c could also be removed under the same
condition to afford 2–3 (entries 5, 6). The structures of 1–3 were
confirmed by 1H NMR, 13C NMR, IR, and HRMS (ESI).14–16 The spec-
troscopic data of 1–3 were identical to those of authentic samples
reported in the literature.1
8. Compound 17a: White solid; mp. 196–198 °C; IR (KBr) 3474, 2922, 1716, 1443,
1369, 1292, 1195, 1150, 1103, 758 cmÀ1 1H NMR (300 MHz, CDCl3) d 9.63–
;
In summary, the first concise total syntheses of Marinoquino-
lines A–C (1–3) in short linear steps were successfully achieved
9.66 (m, 1H), 8.16 (s, 1H), 8.09–8.13 (m, 1H), 7.60–7.63 (m, 2H), 4.44 (q,
J = 7.1 Hz, 2H), 1.44 (d, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 164.67,
145.78, 143.54, 133.53, 129.80, 127.85, 127.13, 127.08, 126.50, 125.79, 123.11,
111.90, 60.42, 20.50, 14.49; HRMS (ESI) m/z calcd for C15H15N2O2: 254.1055;
Found: 254.1068.
9. Compound 17b: White solid; mp. 180–182 °C; IR (KBr) 3504, 3085, 2929, 1712,
1686, 1587, 1357, 1154, 1135 cmÀ1 1H NMR (300 MHz, CDCl3) d 10.15 (br, 1H),
;
Table 2
Optimization of decarboxylation of 17a–17ca
9.64–9.67 (m, 1H), 8.05–8.14 (m, 1H), 7.57–7.65 (m, 2H), 4.42 (q, J = 7.1 Hz,
2H), 2.99 (d, J = 6.9 Hz, 2H), 2.10–2.19 (m, 1H), 1.44 (d, J = 7.1 Hz, 3H), 0.67 (d,
J = 6.5 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 164.88, 149.53, 143.33, 134.15,
130.00, 127.67, 127.19, 127.14, 125.80, 123.16, 111.71, 60.44, 43.13, 22.23,
14.52; HRMS (ESI) m/z calcd for C15H15N2O2: 297.1525; Found: 297.1538.
10. Compound 17c: White solid; mp 175–176 °C; IR (KBr) 3448, 2920, 1707, 1589,
EtOOC
Conditions
NH
NH
1480, 1175, 1105, 760 cmÀ1 1H NMR (300 MHz, CDCl3) d 9.61–9.64 (m, 1H),
;
N
R
N
R
8.16–8.19 (m, 1H), 7.29 (s, 1H), 7.62–7.67 (m, 2H), 7.15–7.19 (m, 2H), 6.79–
6.82 (m, 2H), 4.52 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 1.40 (d, J = 7.1 Hz,
3H); 13C NMR (75 MHz, d6-DMSO) d 165.55, 150.04, 144.86, 140.112, 135.86,
130.63, 130.36, 130.14, 129.89, 127.83, 127.69, 127.58, 127.01, 126.52, 123.90,
111.37, 61.18, 40.81, 15.77; HRMS (ESI) m/z calcd for C21H19N2O2: 330.1368;
Found: 330.1385.
17a R = CH3
1 R = CH3
2 R = CH2CH(CH3)2
17b R = CH2CH(CH3)2
17c
R = Bn
3
R = Bn
b
Entry
Substrate
Condition
Yield
11. Lu, P.; Sanchez, C.; Cornella, J.; Larrosa, I. Org. Lett. 2009, 11, 5710.
12. Kim, H. J.; Lindsey, J. S. J. Org. Chem. 2005, 70, 5475.
13. Mundle, S. O. C.; Lacrampe-Couloume, G.; Lollar, B. S.; Kluger, R. J. Am. Chem.
Soc. 2010, 132, 2430.
1
17a
NaOH, EtOH, then 10% Ag2CO3, 5% HOAc,
DMSO, 120 °C
1, NR
2
3
17a
17a
17a
17b
17c
NaOH, EtOH, reflux, 12 h
NaOH, (CH2OH)2, 120–160 °C
Conc. HCl, reflux, 12 h
Conc. HCl, reflux, 12 h
Conc. HCl, reflux, 12 h
1, Trace
1, 10%
1, 65%
2, 72%
3, 57%
14. Marinoquinoline A (1): White solid; mp. 238–240 °C; IR (KBr) 3457, 3081, 2922,
1587, 1533, 1480, 1198, 1137, 751 cmÀ1 1H NMR (300 MHz, CD3COCD3) d
;
4
11.12 (br s, 1H), 8.19–8.24 (m, 1H), 7.98–8.02 (m, 1H), 7.57 (d, J = 2.8 Hz, 1H),
7.29 (s, 1H), 7.46–7.56 (m, 2H), 7.15–7.19 (m, 2H), 7.11 (d, J = 2.8 Hz, 1H), 2.83
(s, 3H); 13C NMR (75 MHz, CD3COCD3) d 146.97, 143.88, 129.94, 128.46, 127.17,
126.14, 125.72, 124.28, 123.79, 102.05, 21.32; HRMS (ESI) m/z calcd for
5c
6c
a
b
c
The reactions were performed in 0.43 mmol scale.
Isolated yield after flash column chromatography.
The reactions were performed in 0.25 mmol scale.
C
12H11N2: 182.0844; Found: 182.0849.
15. Marinoquinoline B (2): White solid; mp 196–198 °C; IR (KBr) 3463, 2956, 2926,
1588, 1482, 1362, 752 cmÀ1 1H NMR (300 MHz, CD3COCD3) d 11.16 (br s, 1H),
;

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L. Ni et al. / Tetrahedron Letters 53 (2012) 1271–1274
8.23–8.26 (m, 1H), 8.03–8.06 (m, 1H), 7.48–7.58 (m, 3H), 7.14–7.15 (m, 1H),
s, 1H), 8.23–8.26 (m, 1H), 8.05–8.08 (m, 1H), 7.49–7.57 (m, 3H), 7.43 (d,
J = 7.5 Hz, 2H), 7.25 (t, J = 7.1 Hz, 2H), 7.13–7.18 (m, 2H), 4.57 (s, 3H); 13C NMR
(75 MHz, CD3COCD3) d 148.95, 143.82, 139.96, 130.25, 129.76, 129.36, 129.18,
127.48, 127.09, 126.26, 125.99, 124.29, 123.77, 41.62; HRMS (ESI) m/z calcd for
3.08 (d, J = 7.2 Hz, 1H), 2.83 (s, 3H), 2.42–2.52 (m, 1H),1.04 (d, J = 7.2 Hz, 6H);
13C NMR (75 MHz, CD3COCD3) d 150.01, 143.70, 130.00, 129.83, 128.60, 126.96,
125.97, 125.57, 124.04, 123.63, 101.86, 44.00, 28.93, 22.96; HRMS (ESI) m/z
calcd for C15H17N2: 224.1324; Found: 224.1313.
C
18H15N2: 258.1157; Found: 258.1170.
16. Marinoquinoline C (3): White solid; mp 187–188 °C; IR (KBr) 3445, 3086, 2914,
1588, 1480, 1363, 1125, 724 cmÀ1 1H NMR (300 MHz, CD3COCD3) d 11.04 (br
;