Communications
DOI: 10.1002/anie.201006608
Asymmetric Synthesis
An Asymmetric Organocatalytic One-Pot Strategy to
Octahydroacridines**
Gustav Dickmeiss, Kim L. Jensen, Dennis Worgull, Patrick T. Franke, and
Karl Anker Jørgensen*
A major focus of organocatalysis[1] has been the development
of domino, cascade, and one-pot reactions.[2] These classes of
reactions enable the construction of molecules with great
structural complexity with a minimum of manual operations,
thereby saving time, effort, and production cost. Moreover,
given the current focus on the development of more environ-
mental-friendly procedures, these reactions, with their fewer
purification steps, are useful alternatives to the classical
stepwise approaches.
Recently, the aza-Diels–Alder reaction between an N-aryl
imine and an olefin moiety (the Povarov reaction)[3] has
attracted considerable attention,[4,5] as this reaction provides a
simple route to a variety of nitrogen-containing polycyclic
structures. In general, N heterocycles are of broad interest
due to their vast abundance in natural and pharmaceutical
compounds, and for instance tetrahydroquinolines have
shown biological activity in numerous examples.[6] However,
though they possess a tetrahydroquinoline core structure,
suggesting potentially interesting biological properties, the
class of octahydroacridines remains virtually unexplored due
to their limited availability. This type of compounds may be
accessed through an intramolecular Povarov reaction, in
which an e,z-unsaturated aldehyde upon condensation with
an aryl amine, subsequently undergoes a formal cycloaddition
and re-aromatization, affording the final product. However,
access to optically active octahydroacridines has so far
exclusively been based on a chiral pool approach and,
furthermore, limited diastereomeric control is often
observed.[7] To the best of our knowledge, no catalytic
asymmetric approaches to these interesting N-heterocyclic
structures have been described to date.
Scheme 1. Synthetic outline for the formation of octahydroacridines.
TMS=trimethylsilyl.
subsequent cycloaddition, hereby controlling the formation of
the optically active octahydroacridines with high diastereo-
selectivity.
Herein, we describe a protocol for the preparation of a
series of octahydroacridines having four stereocenters with
excellent enantio- and diastereomeric control. A rationale for
the stereochemical outcome of the reaction is proposed, and
further derivatizations of the products are demonstrated, such
as the selective hydrolysis of one of the nitrile functionalities,
leading to octahydroacridines with five stereocenters.
In order to reach an efficient one-pot protocol, the initial
organocatalytic addition step was first investigated. At the
outset, slightly modified conditions to those previously
reported[2e] were applied. Accordingly, with malononitrile
2a, 2 equiv of hex-2-enal (1a), and 10 mol% of (S)-2-[bis(3,5-
bistrifluoromethylphenyl)trimethylsilyloxymethyl]pyrroli-
dine (3) as the catalyst in CH2Cl2, full and clean conversion to
the desired Michael addition intermediate was observed.
Consequently, the anticipated condensation/Povarov cascade
was attempted, and, gratifyingly, the addition of 1.5 equiv of
4-nitroaniline (4a) and 2 equiv of trifluoroacetic acid (TFA)
to the diluted reaction mixture at À308C gave clean
conversion to the proposed product with excellent diastereo-
meric control. With these conditions in hand, the scope of the
reaction was examined by varying the a,b-unsaturated
aldehyde 1, malononitrile 2, and aniline 4 (Table 1).
We imagined a route (Scheme 1), in which the addition of
malononitrile derivatives to an a,b-unsaturated aldehyde
employing aminocatalysis would furnish a suitable intermedi-
ate, which could be trapped in a following condensation/
cyclization cascade by an aniline derivative. Optimally, the
stereocenter of the initial addition step would direct the
[*] G. Dickmeiss, K. L. Jensen, Dr. D. Worgull, Dr. P. T. Franke,
Prof. Dr. K. A. Jørgensen
The developed reaction concept showed great tolerance
towards a variety of aliphatic a,b-unsaturated aldehydes 1.
Saturated and unsaturated side chains of different length were
successfully applied (Table 1, entries 1–5, 18) and, further-
more, benzyl ether and homobenzyl functionalities were
tolerated (entries 6 and 7). Generally, high yields (59 to 93%),
taking into account the multiple reaction steps being
involved, were observed with excellent stereocontrol (89 to
99% ee and > 20:1 d.r. in all examples). Interestingly, no
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax: (+45)8919-6199
E-mail: kaj@chem.au.dk
[**] This work was supported by OChemSchool, the Carlsberg Founda-
tion, and the Deutsche Forschungsgemeinschaft (D.W.). We thank
Dr. Jacob Overgaard for performing X-ray analysis.
Supporting information for this article is available on the WWW
1580
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1580 –1583