Asymmetric catalysis on the nanoscale: The organocatalytic approach to helicenes

Article abstract of DOI:10.1002/anie.201400474

The first asymmetric organocatalytic synthesis of helicenes is reported. A novel SPINOL-derived phosphoric acid, bearing extended π-substituents, catalyzes the asymmetric synthesis of helicenes through an enantioselective Fischer indole reaction. A variety of azahelicenes and diazahelicenes could be obtained with good to excellent yields and enantioselectivities. Twisting indoles: A novel chiral Bronsted acid, specifically designed for long-range control on a nanoscale, catalyzes the asymmetric synthesis of azahelicenes through a Fischer indolization. The method has the advantage of starting from simple achiral starting materials, which can be modified by changing the protecting group (R²) or the terminal substituents (R¹, R³). The products can be further oxidized to polyaromatic systems.

Full text of DOI:10.1002/anie.201400474

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Angewandte
Communications
DOI: 10.1002/anie.201400474
Helicenes
Asymmetric Catalysis on the Nanoscale: The Organocatalytic
Approach to Helicenes**
Lisa Kçtzner, Matthew J. Webber, Alberto Martꢀnez, Claudia De Fusco, and Benjamin List*
Abstract: The first asymmetric organocatalytic synthesis of
helicenes is reported. A novel SPINOL-derived phosphoric
acid, bearing extended p-substituents, catalyzes the asymmetric
synthesis of helicenes through an enantioselective Fischer
indole reaction. A variety of azahelicenes and diazahelicenes
could be obtained with good to excellent yields and enantio-
selectivities.
asymmetric [3,3] sigmatropic rearrangement to furnish enan-
tioenriched azahelicenes of type 3 [Eq. (1)]. This approach
would have the strategic advantage of starting from relatively
simple, achiral starting materials. Furthermore, its modular
nature would enable variation of the apical substituent (R1)
on the helicene by changing the N-substituent on the starting
hydrazine, and of the terminal substituents (R2 and R3) by the
selection of suitable hydrazines and ketones, respectively.
M
olecules exhibiting helical chirality have attracted sig-
nificant attention in fields as diverse as catalysis, materials
science, molecular self-assembly, and biology.[1] As a conse-
quence, a number of approaches to their synthesis, especially
in an enantioselective fashion, have been investigated.[1,2] In
this regard, catalytic asymmetric methods are particularly
attractive, but have proven to be highly challenging: unlike in
common asymmetric catalysis, which builds stereogenic
carbon centers, helical chirality is a phenomenon of the
nanoscale, thus creating particular length-scale requirements
for catalysts. Examples have previously been reported and
have, in almost all cases relied on transition-metal-catalyzed
[2+2+2] cycloadditions.[3] However, an expansion of the
accessible structural diversity of chiral (hetero)helicenes for
further investigations appeared to be desirable. Inspired by
our recent development of a catalytic asymmetric Fischer
indole synthesis,[4] we became interested in developing an
enantioselective organocatalytic approach to helicenes. We
now report a chiral Brønsted acid catalyzed asymmetric
synthesis of helicenes applying the Fischer indolization.
As a planar heterocycle, indole has been part of a number
of helical molecules.[5] In fact, the very first documented
examples of both a pentahelicene[5a] and a hexahelicene[5b]
synthesis were achieved with indole formation as the final
step.
In light of the specific length-scale challenges associated
with helical molecules, we speculated that common phospho-
ric acids with phenyl-derived substituents in the 3,3’-position
are too short-ranged to control the enantioselectivity of such
reactions. For high levels of stereocontrol, the catalyst would
need extended p-substituents in the 3,3’-position that could
engage in a potential p-p stacking interaction with the
polyaromatic system present in the formed enehydrazine,
holding the intermediate in a chiral nanometer sized pocket
(Figure 1). In this way, the catalyst could induce the screw
sense of the helicene.
We thus hoped that, in accordance with the established
mechanism of the Fischer indolization,[6] upon condensation
of a phenyl hydrazine (1) with an appropriate polyaromatic
ketone (2), an enantiopure Brønsted acid might promote an
[*] L. Kçtzner, Dr. M. J. Webber, Dr. A. Martꢀnez, Dr. C. De Fusco,
Prof. Dr. B. List
Figure 1. Concept for the asymmetric synthesis of azahelicenes using
p-p stacking interactions on a nanoscale, and the 3D model of catalyst
(S)-5e with the enehydrazine intermediate derived from 3a.
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[**] We gratefully acknowledge generous support from the Max Planck
Society, the European Research Council (Advanced Grant “High
Performance Lewis Acid Organocatalysis, HIPOCAT”), and the
Ministero dell’Istruzione, dell’Universitꢂ e della Ricerca (MIUR)
(fellowship for C.D.F.). We also thank the members of our HPLC,
NMR, MS, and crystallography departments for their support.
Based on this concept, we synthesized various catalysts
bearing extended p-substituents, such as phenanthryl, anthra-
cenyl, and pyrenyl. These catalysts contain the features which
were important for our proposal and should enable long-
range control to induce enantioselectivity on the nanoscale.[7]
We began our investigations using hydrazine 1a and
polycyclic ketone 2a as model substrates (Table 1). Different
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400474.
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Table 1: Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent
T [8C]
e.r.[b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
5a
5c
5c
5e
5e
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
25
25
25
25
À7
57:43
68.5:31.5
52.5:47.5
53.5:46.5
68.5:32.5
82.5:17.5
85.2:14.8
91:9
9[c]
95.5:4.5
[a] Reactions were carried out on a 0.01 mmol scale with 5 mg
Amberlite CG50 for 24 h (100% conversion). [b] Determined by HPLC
analysis on a chiral stationary phase. [c] 3 days were required for 100%
conversion.
protecting groups were screened, and the best results were
obtained using a p-iodobenzyl group (PIB; see the Supporting
Information).[4a] Various chiral phosphoric acids with differ-
ent backbones were investigated.[8] Complete conversion was
achieved in 24 h when reactions were carried out in toluene at
room temperature. In general, SPINOL-derived catalysts[9]
gave better enantioselectivities than the corresponding
BINOL derivatives. Different solvents were tested, with
catalyst 5c (R = 9-anthracenyl) affording the best enantio-
selectivity when CH2Cl2 was used (Table 1, entry 7). As
expected, a notable increase in the enantioselectivity of the
process was observed when the p-surface of the 3,3’-substitu-
ents of the catalyst was enhanced. The use of novel catalyst 5e
bearing 1-pyrenyl substituents resulted in a promising enan-
tiomeric ratio of 91:9 at room temperature (Table 1, entry 8),
which could be improved to 95.5:4.5 by lowering the temper-
ature to À78C (Table 1, entry 9).
Scheme 1. Substrate scope of the azahelicene synthesis. a) Oxidation
of (P)-3a (derived from (R)-5e): chloranil (5 equiv), DPP (1 equiv),
CHCl3, 508C, 5 h, 76%.
tivities. The structure of 3a, including its absolute config-
uration, was assigned unambiguously by X-ray crystallogra-
phy (see the Supporting Information). This compound shows
M helicity when the S enantiomer of catalyst 5e is used and
can be isolated with a high enantiomeric ratio of 95.5:4.5.
Oxidation of (P)-3a, with an excess of tetrachloro-1,4-
benzoquinone (chloranil) and diphenylphosphate (DPP)
readily provides polyaromatic compound (P)-6a in 76%
yield. The use of a thiophene-derived ketone is also possible
and gives an enantioselectivity of 96:4 for 3b, the absolute
configuration of which was also assigned by X-ray crystallog-
raphy (see the Supporting Information). Even a SiMe3-
substituted helicene (3i) could be generated with a similar
enantioselectivity as that observed with unsubstituted heli-
cene 3e.
As shown in our previous study, the weakly acidic resin
Amberlite CG50, which bears carboxylic acid groups, has the
remarkable ability to facilitate catalyst turnover without
diminishing the level of enantioselectivity.[4] The addition of
500 mgmmolÀ1 of resin proved ideal, with higher loadings
leading to decreased enantioselectivity. It is noteworthy that
the reaction proceeds slowly in the absence of resin, but still
with catalyst turnover (see the Supporting Information).
With the optimized conditions in hand we studied the
scope of this transformation for different hydrazines and
ketones (Scheme 1). Hydrazine 1a reacted smoothly with
different polycyclic ketones to give the corresponding [6]aza-
helicenes 3a–c in good to excellent yields and enantioselec-
We further became interested in extending our approach
to the synthesis of diazahelicenes through a double Fischer
indolization. Indeed, treating hydrazine 7 with commercially
available ketone 8 led to a diazahelicene, which interestingly
now bears only one benzyl group (Scheme 2).
This compound was highly sensitive to oxidation, which
rendered the purification and full characterization more
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change in the enantiomeric ratio over different time periods
at 2408C in tetraglyme. The resulting data allowed us to
calculate the racemization barrier (DG°) to be 172.2 Æ
0.4 kJmolÀ1 (Figure 2b). This value is very similar to the
reported barrier of [7]helicene (175.1 kJmolÀ1).[13a]
In conclusion, we have developed a mild and powerful
organocatalytic enantioselective synthesis of helicenes
through catalytic asymmetric Fischer indole reactions. This
approach gives access to enantioenriched azahelicenes start-
ing from simple achiral starting materials, which allow broad
substrate diversity. A new SPINOL-derived chiral phosphoric
acid has been designed specifically for long-range control on
a nanoscale.
Scheme 2. Synthesis of diazahelicenes 6j–l by a double Fischer indoli-
zation, followed by oxidation and protection.
challenging than for the previous azahelicenes (Scheme 1).
Thus, we decided to directly oxidize product 3j to the
polyaromatic diazahelicene 6j. As expected, 6j was isolated
as the monobenzylated product with a good enantiomeric
ratio of 6:94.[10] Following the reaction by mass spectrometry
(MS) we were able to detect benzylamine, which was released
during the reaction. We assume, that after the [3,3] sigma-
tropic rearrangement, the free enamine attacks the formed
benzylimine. This imine could be stabilized by the hydrazine,
the formed hydrazone, or by the indole, depending on when
the benzylamine released (see the Supporting Informa-
tion).[11] The selective loss of one benzyl group in the presence
of catalyst 5e allowed modifications of product 6j, such as
a benzylation to obtain the symmetrical compound 6k or the
addition of a PIB group in this position to give product 6l.
This interesting result potentially broadens the substrate
scope, as other substituents could readily be introduced by
this route.
We recorded the CD spectra of (M)-3a, (P)-3a, and (P)-
6a to assign the helicity of our products. We found a significant
agreement between the CD characteristics of our azaheli-
cenes and those of (+)-(P)-[6]helicene, whose absolute
configuration is known (Figure 2a).[12] In this way we could
ascribe independently the P (dextrorotatory) and M (levor-
otatory) helicity of our products by both CD spectroscopy and
X-ray crystallography.
Received: January 16, 2014
Published online: April 15, 2014
Keywords: Brønsted acid catalysis · Fischer indole synthesis ·
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helicenes · organocatalysis
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[10] The corresponding doubly benzylated compound was only
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