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Angewandte
Communications
Asymmetric Synthesis
Asymmetric Brønsted Acid Catalyzed Synthesis of Triarylmethanes—
Construction of Communesin and Spiroindoline Scaffolds
Hsuan-Hung Liao, Adisak Chatupheeraphat, Chien-Chi Hsiao, Iuliana Atodiresei, and
Magnus Rueping*
Abstract: Aza-ortho-quinone methides allow the straightfor-
ward asymmetric synthesis of natural-product-inspired indole
scaffolds possessing a quaternary stereocenter. Our approach
provides access to diverse communesin and spiroindoline
derivatives with high enantioselectivity under mild reaction
conditions. Predictable substitution patterns are found to be the
key to our regiodivergent protocols.
T
he development of shorter synthetic routes for assembling
complex molecules with potential drug character is of great
interest from a synthetic as well as both ecological and
economical points of view. Therefore, the development of
efficient atom- and step-economical synthetic pathways is one
of the main goals in chemical synthesis.[1] The communesin[2]
and spiroindoline[3] skeletons are core structural elements in
a wide range of natural and synthetic products. Alkaloids
possessing these indole-derived heterocycle frameworks
exhibit a broad spectrum of biological activities and potential
for pharmacological drug discovery. However, progress in the
development of these important targets, especially in enan-
tioselective form, is relatively slow,[4,5] particularly due to the
complexity of the precursor structures and the difficulty in
finding a suitable chiral catalyst. Therefore we decided to
develop a catalytic asymmetric reaction protocol to build
triarylmethanes[6] which serve as precursors for the synthesis
of desired communesin and spiroindoline structures
(Scheme 1). Complete control in the synthesis of these
structurally different products can be achieved through the
installation of a suitable substituent at specific positions in the
indole starting material. Furthermore, the key to the success
of this asymmetric strategy relies on the judicious choice of
the aza-ortho-quinone methide (aza-o-QM)[7] intermediate
and the chiral catalyst.
Scheme 1. Aza-o-QMs as crucial intermediates in the enantioselective
synthesis of natural-product-inspired scaffolds.
molecules for drug design.[2d,e] Recent research has started to
focus on asymmetric catalytic variants as well, due to the
increasing number of chiral drugs identified in which enan-
tiomers proved to have significantly different effects in vivo.[8]
Considerable efforts have been devoted to the generation of
aza-o-QMs over the last decades,[9] including thermal extru-
sions, photolysis and acid- or base-mediated transformations.
Yet, aza-o-QMs have been less thoroughly studied in catalytic
asymmetric synthesis,[10,11] potentially due to the difficulties
associated with the stabilization of these highly reactive
species.
In this context the challenge consists in the rational choice
of a suitable chiral catalyst which can strike a right balance
between reactivity and stability. Here we report an efficient
regiodivergent Brønsted acid catalyzed protocol for the rapid
synthesis of diverse communesin and spiroindoline structures
with quaternary carbon stereocenters. The formation of
highly reactive aza-o-QM species is the key to success.
Brønsted acids, especially chiral phosphoric acids, have
proved to be highly efficient catalysts for a wide range of
asymmetric transformations under mild reaction condi-
tions.[12] The combination of Brønsted acid catalysis and
reactions of aza-o-QMs is promising for the development of
asymmetric transformations involving such reactive inter-
mediates. Classically, chiral phosphoric acids and derivatives
serve as bifunctional catalysts to lower the LUMO of
electrophiles by H-bonding and they activate the acidic
nucleophiles via the phosphoryl oxygen. Indeed, these
catalysts should also have the potential to strongly coordinate
to aza-o-QMs providing activation of the imine group by
hydrogen bonding or ion pairing,[13] and controlling the
selectivity of the addition with the attacking nucleophiles.
With these considerations in mind, we began our inves-
tigation on the functionalization of 2-substituted indoles.
Aza-o-QMs[7] are reactive intermediates in the biosyn-
thesis of natural products. Their high reactivity, which is due
to the driving force of rearomatization, can also be employed
in organic synthesis. Therefore, harnessing this unique
characteristic provided a new entry toward the synthesis of
complex natural product frameworks as well as unnatural
[*] M. Sc. H.-H. Liao, M. Sc. A. Chatupheeraphat, C.-C. Hsiao,
Dr. I. Atodiresei,[+] Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+49) 241-809-2665
E-mail: magnus.rueping@rwth-aachen.de
[+] X-ray structure determination.
Supporting information for this article is available on the WWW
15540
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 15540 –15544