Asymmetric organocatalytic synthesis of complex cyclopenta[ b ]quinoline derivatives

Article abstract of DOI:10.1021/ol201328s

An efficient one-pot procedure that provides a direct access to polycyclic hexahydrocyclopenta[b]quinoline derivatives having five stereogenic centers has been developed. The system displays great tolerance toward different aldehydes, anilines, and nitroa

Full text of DOI:10.1021/ol201328s

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3678–3681
Asymmetric Organocatalytic Synthesis of
Complex Cyclopenta[b]quinoline
Derivatives
Kim L. Jensen, Gustav Dickmeiss, Bjarke S. Donslund, Pernille H. Poulsen, and
Karl Anker Jørgensen*
Center for Catalysis, Aarhus University, 8000 Aarhus C, Denmark
kaj@chem.au.dk
Received May 17, 2011
ABSTRACT
An efficient one-pot procedure that provides a direct access to polycyclic hexahydrocyclopenta[b]quinoline derivatives having five stereogenic
centers has been developed. The system displays great tolerance toward different aldehydes, anilines, and nitroalkenes. The products are
obtained in high yields and excellent enantio- and diastereoselectivities.
Multicomponent reactions have the potential to provide
the high molecular diversity needed in the combinatorial
approaches for the preparation of bioactive compounds.1
In recent years, asymmetric organocatalytic domino
and cascade reactions have been utilized for the synth-
esis of complex enantiomerically enriched molecules
having multiple stereocenters.2 In comparison to
traditional stepwise approaches, the uninterrupted se-
quence of reactions in one flask reduces the number of
manual operations, thereby saving time, effort, and
production costs.
Nitrogen-containing heterocycles form an indispensible
class of compounds, which are important in the fields of
biochemistry, pharmaceutics, and material science.3 Among
these, the hexahydro-cyclopenta[b]quinoline core4 is a
virtually unexplored structure that is found in natural
products such as isoschizogaline and isoschizogamine5 as
well as steroid alkaloids (Figure 1).6
ꢀ
(1) (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.;
Eur. J. 2000, 6, 3321. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Tietze, L. F.; Brasche, G.;
Gerike, K. Domino Reactions in Organic Chemistry; Wiley-VCH:
Weinheim, 2006.
The cyclopenta[b]quinoline core structure may be ac-
cessed via an intramolecular aza-DielsꢀAlder reaction
(2) For selected reviews on organocatalysis, see: (a) Gaunt, M. J.;
Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today 2007,
€
12, 8. (b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int.
(3) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Oxford, U.K., 2000. For tetrahydroquinolines, see: (b) Katritzky, A. R.;
Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031 and references
herein.
(4) For racemic synthesis of hexahydrocyclopenta[b]quinoline deri-
vatives, see: (a) Magomedov, N. A. Org. Lett. 2003, 5, 2509. (b) Huang,
H.; Hu, W. Tetrahedron 2007, 63, 11850. (c) Bunce, R. A.; Nammalwar,
B.; Slaughter, L. M. J. Heterocycl. Chem. 2009, 46, 854.
(5) (a) Kariba, R. M.; Houghton, P. J.; Yenesew, A. J. Nat. Prod.
2002, 65, 566. For total synthesis studies, see:(b) Hubbs, J. L.; Heathcock,
C. H. Org. Lett. 1999, 1, 1315. (c) Padwa, A.; Flick, A. C.; Lee, H. I. Org.
Lett. 2005, 7, 2925. (d) Zhou, J.; Magomedov, N. A. J. Org. Chem. 2007,
72, 3808.
Ed. 2007, 46, 1570. (c) Chem. Rev. 2007, 107 (12), issue on organocata-
lysis. (d) MacMillan, D. W. C. Nature 2008, 455, 304. (e) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (f) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167. For recent examples, see:(g)
€
Enders, D.; Huttl, M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew.
Chem., Int. Ed. 2007, 46, 467. (h) Vo, N. T.; Pace, R. D. M.; O’Hara, F.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 404. (i) Simmons, B.; Walji,
A.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349. (j) Zhu,
D.; Lu, M.; Dai, L.; Zhong, G. Angew. Chem., Int. Ed. 2009, 48, 6089. (k)
Jiang, H.; Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2009, 48, 6844. (l) Wang, Y.; Han, R.-G.
Zhao, Y.-L.; Yang, S.; Xu, P.-F.; Dixon, D. J. Angew. Chem., Int. Ed.
2009, 48, 9834. (m) Lee, A.; Michrowska, A.; Sulzer-Mosse, S.; List, B.
Angew. Chem., Int. Ed. 2011, 50, 1707. (n) Dickmeiss, G.; Jensen, K. L.;
Worgull, D.; Franke, P. T.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 1580. (o) Ishikawa, H.; Honma, M.; Hayashi, Y. Angew.
Chem., Int. Ed. 2011, 50, 2824.
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(6) (a) Wofling, J.; Frank, E.; Schneider, G.; Bes, M. T.; Tietze, L. F.
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Synlett 1998, 1205. (b) Wofling, J.; Frank, E.; Schneider, G.; Tietze, L. F.
Eur. J. Org. Chem. 1999, 3013. (c) Mernyak, E.; Schneider, G.; Herbst-Irmer,
R.; Kubas, M.; Wolfing, J. Steroids 2006, 71, 558.
ꢀ
€
r
10.1021/ol201328s
Published on Web 06/10/2011
2011 American Chemical Society

Table 1. Aniline and Nitroalkene Scope for the Formation of 5a
entry
R2
R3
yield (%)b
ee (%)c
drd
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
5a - 82
5b - 72
5c - 75
5d - 83
5e - 70
5f - 79
5g - 79
5h - 85
5i - 66
5j - 75
5k - 73
5l - 78
5m - 73
99
99
99
99
99
99
99
99
99
99
99
99
99
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
19:1
2
Br
3
NO2
CO2Et
COMe
Me
OMe
H
Figure 1. Synthetic outline for the formation of cyclopenta-
[b]quinoline derivatives and possible sites of modification.
4
5
6
7
8
4-Br-C6H4
4-OMe-C6H4
3-NO2-C6H4
2-Cl-C6H4
2-furanyl
from a δ,ε-unsaturated aldehyde. Upon condensation
with an aniline derivative, the resulting intermediate will
undergo a cycloaddition/rearomatization (the Povarov
reaction)7 sequence, affording the tricycle.2n To the best
of our knowledge, no catalytic, asymmetric approaches
to these interesting and important N-heterocyclic struc-
tures have been described to date. Therefore, we ima-
gined a route (Figure 1), in which the introduction of a
stereocenter in the R-position of the aldehyde utilizing
aminocatalysis would provide a suitable intermediate
for the following condensation/cyclization cascade. Ide-
ally, the initially formed stereocenter would direct the
subsequent cycloaddition, thereby controlling the for-
mation of the optically active cyclopenta[b]quinoline
with high enantio- and diastereoselectivity.
We envisioned that employment of nitroalkenes in the
initial organocatalytic step would furnish structures that
allow for further expansion of molecular complexity and
diversity by selective functional group manipulations. For
example, reduction of the nitro group, and functionaliza-
tions at R1 and R3, depending on the chosensubstituents at
these positions, should be possible. Furthermore, selective
pairing of the R2 substituent and the aniline nitrogen could
furnish a tetracyclic alkaloid structure, whereas pairing
of the nitrogen with the ortho-hydrogen in another
hetero-DielsꢀAlder reaction could afford a differently
constructed polycyclic scaffold.
9
H
10
11
12
13e
H
H
H
CO2Me
H
19:1
a For reaction conditions, see Supporting Information. b Yield after
flash chromatography. c Determined by HPLC on a chiral stationary
phase. d Determined by 1H NMR spectroscopy of the crude reaction
mixture after workup. e 20 mol % of catalyst was employed.
10 mol % of (S)-2-(diphenyl(trimethylsilyloxy)methyl)-
pyrrolidine 38 in CH2Cl2 at ꢀ30 °C, and after 16 h full
and clean conversion to the Michael adduct was observed
(dr >20:1).2j The anticipated condensation/cycloaddition
reaction was then evaluated by treating the adduct with
aniline in the presence of TFA, which afforded the desired
product 5a with full conversion as an 87:13 mixture of
diastereoisomers.9 In order to achieve a higher selectivity
in the cyclization step a series of Brønsted acids were
investigated. (þ)-CSA and TsOH afforded the product in
excellent diastereoselectivity (dr >20:1); however, full
conversion was not achieved at ꢀ30 °C. By increasing
the temperature to 4 °C and employing TsOH the pro-
duct was isolated in 82% yield and with excellent stereo-
selectivities (99% ee and dr >20:1). With these conditions
in hand, the generality of the reaction was investigated
(Table 1).
The developed reaction concept displayed great toler-
ance toward a number of aniline derivatives. All the
reactions evaluated gave full conversion to the products
5aꢀg with high yields ranging from 83 to 70% and
excellent stereoselectivities (99% ee and >20:1 dr). The
electronic nature of the aniline had little effect on the
reaction outcome as both electron-poor (Table 1, entries
2ꢀ5) and electron-rich (Table 1, entries 6ꢀ7) anilines were
Herein, we present a simple and straightforward asym-
metric strategy to provide cyclopenta[b]quinoline deriva-
tives with high yields and excellent stereoselectivities. The
procedure applies simple starting materials under mild
reaction conditions, and significant possibilities for further
structural diversification are demonstrated by various
transformations.
We initiated our studies by performing the initial Mi-
chael reaction between (E)-6-phenylhex-5-enal (1a) and
nitroalkene 2a. The reaction was conducted employing
(8) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.;
Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
(9) The Michael adduct 12 epimerizes via iminium-ion-enamine
tautomerization prior to the aza-DielsꢀAlder reaction; see Supporting
Information.
(7) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656. (b) Kouznetsov,
V. V. Tetrahedron 2009, 65, 2721. For selected examples, see:(c) Laschat,
S.; Lauterwein, J. J. Org. Chem. 1993, 58, 2856.
Org. Lett., Vol. 13, No. 14, 2011
3679

successfully applied. Interestingly, no side products were
observed when 4-aminoacetophenone was employed
(entry 5), despite the presence of a ketone functionality.
When the reaction was attempted using 4-ethynylaniline,
hydration of the alkyne during workup afforded the
ketone product 5e.
Further examination of the reaction scope focused on
the nitroalkene part, and a series of cyclopenta[b]quinoline
derivatives were synthesized from neutral aniline 4a in
good yields (85ꢀ66%) and excellent enantioselectivities
(99% ee). In general, the position and electronic properties
of the aromatic ring had little or no effect on the outcome
(Table 1, entries 8ꢀ11). Nitroalkenes bearing furanyl and
ester moieties were alsoinvestigatedaffording the products
with slightly reduced diastereoselectivities (19:1) arising
from the initial organocatalyzed Michael reaction
(Table 1, entries 12ꢀ13).
obtained as a single diastereoisomer in 74% yield (99% ee)
when TFA was employed at ꢀ30 °C (Scheme 1). ortho-
Cyanoaniline and two disubstituted anilines were success-
fully applied affording the products 5wꢀy in good yields
(72ꢀ61%) and excellent stereoselectivities (g98% ee and
dr >20:1). Finally, 1-aminonaphthalene was studied and,
interestingly, TsOH gave the better result furnishing the
product in 67% yield with good selectivities (99% ee, dr
19:1).
To demonstrate the synthetic utility of this protocol a
number of transformations leading to more complex poly-
cyclic structures were performed (Scheme 2). Treating
5b,5f with formaldehyde in the presence of TFA resulted
in condensation between the aniline and formaldehyde
followed by a hetero-DielsꢀAlder/rearomatization se-
quence to yield two tetracyclic oxazine products 6 and 7
in 75% yield. When compound 5m, having a methyl ester
moiety as R2, was subjected to borane, a reductive cycliza-
tion occurred, forming pyrrolidine product 8 in 74% yield,
hereby creating a different tetracyclic alkaloid scaffold.
The vinyl substituent in compound 5t enables the intro-
duction of various new functionalities, exemplified by the
conversion into a primary alcohol 9 via a hydrobora-
tionꢀoxidation reaction in 64% yield. Furthermore, a
Suzuki coupling was performed introducing a phenyl
substituent on the cyclopenta[b]quinoline core structure
in 82% yield.
Next, a series of aldehydes were evaluated in combina-
tion with (E)-(2-nitrovinyl)benzene (2a) and different ani-
line derivatives (Table 2). Aldehydes with methyl- and
bromo-substituents in the para-position were successfully
applied affording good to high yields (55ꢀ79%) and
excellent stereoselectivities (99% ee and dr >20:1).
Furthermore, a vinyl substituted aldehyde could be im-
plemented, furnishing products 5sꢀu in good yields with
excellent enantio- and diastereoselectivities (Table 2,
entries 6ꢀ8). The vinyl group is a useful moiety for further
functionalization of the products.
Scheme 1. Examples of Ortho- and Di-Substituted Anilinesa
Table 2. Aldehyde and Aniline Scope for the Formation of 5a
entry
R1
R3
yield (%)b
ee (%)c
drd
1
2
3
4
5
6
7
8
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-Br-C6H4
vinyl
H
5n - 79
5o - 77
5p - 55
5q - 69
5r - 73
5s - 76
5t - 67
5u - 72
99
99
99
99
99
99
99
99
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
19:1
Br
NO2
H
CO2Et
H
vinyl
Br
vinyl
CO2Et
a For reaction conditions, see Supporting Information. b Yield after
flash chromatography. c Determined by HPLC on a chiral stationary
phase. d Determined by 1H NMR spectroscopy of the crude reaction
mixture after workup.
a 5z was synthesized employing TsOH.
To further evaluate the methodology, a number of
anilines with different substitution patterns were studied.
Disappointingly, when ortho-bromoaniline 4h was sub-
mitted to the developed reaction conditions using TsOH
as the Brønsted acid, compound 5v was obtained as a 4:1
mixture of diastereoisomers. This prompted us to study
different acids, and to our delight, the product 5v could be
Finally, reduction of the nitro group with Zn/AcOH was
achieved on 5k in quantitative yield (not shown; see
Supporting Information). These transformations clearly
show the diverse possibilities of scaffold and functional
group manipulations allowing access to structurally more
complex molecules.
3680
Org. Lett., Vol. 13, No. 14, 2011

Scheme 2. Functionalization of the Cyclopenta[b]quinoline
Derivatives
Scheme 3. Rationalization of Observed Stereochemistry
polycyclic hexahydrocyclopenta[b]quinoline deriva-
tives having five stereogenic centers. The system dis-
plays great tolerance toward different aldehydes,
anilines, and nitroalkenes. The synthetic usefulness
of the products was demonstrated through a number
of transformations introducing increased molecular
complexity. The strategy might also be implemented
for the construction of the corresponding cyclohexa-
[b]quinoline derivatives (octahydroacridines) by exten-
sion of the aldehyde carbon chain. Furthermore, the
compounds accessed by the described protocol could
eventually demonstrate their usefulness in medicinal
chemistry.
The absolute stereochemistry was unambiguously estab-
lished by X-ray crystallography of compound 5b.10
A
rationale for the observed stereochemistry is presented in
Scheme 3. The initial Michael addition product 12 is
formed with high syn-selectivity. The diastereoselectivity
of the following cyclization can be explained by an endo-
transition state. The intermediate adopts a conformation
in which the substituent of the R-stereocenter is placed in a
pseudo-equatorial position dictating the formation of the
trans-product.
Acknowledgment. This work was made possible by
grants from OChemSchool (K.A.J.) and the Carlsberg
Foundation (K.A.J.). Thanks are expressed to Dr. Jacob
Overgaard for performing X-ray analysis.
In conclusion, we have developed an efficient one-pot
procedure that provides a direct access to almost enantiopure
Supporting Information Available. Detailed experimen-
tal procedures and compound characterizations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) See Supporting Information for crystal structure. CCDC 822137
(5b) contains the supplementary data for this paper.
Org. Lett., Vol. 13, No. 14, 2011
3681