Angewandte
Communications
Chemie
Organocatalysis
Brønsted Acid Catalyzed Addition of Enamides to ortho-Quinone
Methide Imines—An Efficient and Highly Enantioselective Synthesis
of Chiral Tetrahydroacridines
ˇ
Martin Kretzschmar, Tomꢀs Hodꢁk, and Christoph Schneider*
Abstract: The direct and highly enantioselective synthesis of
tetrahydroacridines was achieved through the phosphoric acid
catalyzed addition of enamides to in situ generated ortho-
quinone methide imines and subsequent elimination. This
novel one-step process constitutes a very efficient, elegant, and
selective synthetic approach to valuable N-heterocycles with
a 1,4-dihydroquinoline motif. By subsequent highly diastereo-
selective hydrogenation and N-deprotection the reaction prod-
ucts were easily converted into free hexahydroacridines with
a total of three new stereogenic centers.
A
n essential goal of modern synthetic organic chemistry is
Scheme 1. Concept behind this N-heterocycle synthesis.
the efficient and selective synthesis of complex, enantiomer-
ically pure compounds that exhibit significant biological
activity. In this respect catalytic, enantioselective processes
that ideally form several bonds in a single step are distin-
guished through high levels of efficiency and are becoming
increasingly important.[1]
Ortho-quinone methide imines are transient synthetic
intermediates which readily react with electron-rich 2p
components in hetero-Diels–Alder reactions and with nucle-
ophiles in conjugate 1,4-additions, both with reconstitution of
the aromatic p-system.[6] They can be generated by various
methods ranging from thermolysis and photolysis to acid- or
base-mediated eliminations.[7] However, currently only very
few catalytic, asymmetric examples exist that fully exploit the
synthetic potential of ortho-quinone methide imines.[8] Tunge
and Wang developed a palladium-catalyzed, formal [4+2]-
cycloaddition of alkylidene malononitriles leading to tetrahy-
droquinolines.[8a] Scheidt et al. revealed that azolium enolates
generated by N-heterocyclic carbene (NHC) catalysis react
with ortho-quinone methide imines in a highly enantioselec-
tive fashion to form dihydroquinolones.[8b] A Brønsted acid
catalyzed transfer hydrogenation of 1,2-dihydroquinolines
with Hantzsch esters was described by Li et al.[8c]
Due to their high biological activity 1,4-dihydroquinolines
are priviliged structural motifs in the field of medicine and
biology, exhibiting anticancerogenic, HIV integrase inhibit-
ing, and antimicrobial properties amongst others.[2] Hydro-
acridines also play an important role in treatment of
Alzheimerꢀs disease and have already been approved as
reversible inhibitors of acetylcholinesterase.[3] Despite this
huge potential only a few direct syntheses of this class of
substances are currently known, and even these have a limited
substrate scope.[4] A direct and broadly applicable synthetic
approach towards this important structural motif without
these limitations would be very desirable.
We herein report a conceptually novel, one-step synthetic
strategy comprising a highly enantioselective, phosphoric acid
catalyzed formal cycloaddition of enamides with in situ
generated ortho-quinone methide imines as the key step
(Scheme 1). Additionally, the tetrahydrobenzo[c]acridines
thus formed can be hydrogenated with full control of
diastereoselectivity to provide saturated hexahydroacridines
with two new stereogenic centers. The hexahydroacridines
structural motif, which closely resembles the tetrahydroqui-
nolines, is also well known for its versatile biological
activities.[5]
We[9] and other groups[10] recently reported phosphoric
acid catalyzed, highly enantioselective, conjugate additions of
different p-nucleophiles to the related ortho-quinone
methides which were obtained in situ from the corresponding
benzhydryl alcohols by dehydration. Pursuing this strategy we
were able to gain access to a broad range of benzoannulated
oxygen heterocycles with a high level of enantiocontrol.
Independently, Rueping and co-workers successfully trans-
ferred this concept to ortho-quinone methide imines in
conjugate addition reactions of alcohols and indoles
recently.[11]
On the basis of our previous work we envisioned the
synthesis of tetrahydroacridines starting from N-protected
amino benzhydryl alcohols and enamides.[12] The benzhydryl
alcohols were to be transformed in situ to hydrogen-bonded
ortho-quinone methide imines by a chiral phosphoric acid,[13]
which in a bifunctional catalysis mode would also form
a hydrogen bond to the enamide (Scheme 1). In an ensuing
[*] M. Sc. M. Kretzschmar, M. Sc. T. Hodꢀk, Prof. Dr. C. Schneider
Institut fꢁr Organische Chemie, Universitꢂt Leipzig
Johannisallee 29, 04103 Leipzig (Germany)
E-mail: schneider@chemie.uni-leipzig.de
Supporting information for this article can be found under:
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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