Chiral helical oligotriazoles: New class of anion-binding catalysts for the asymmetric dearomatization of electron-deficient N -heteroarenes

Article abstract of DOI:10.1021/ja507940k

Helical chirality and selective anion-binding processes are key strategies used in nature to promote highly enantioselective chemical reactions. Although enormous efforts have been made to develop simple helical chiral systems and thus open new possibilities in asymmetric catalysis and synthesis, the efficient use of synthetic oligo- and polymeric helical chiral catalysts is still very challenging and rather unusual. In this work, structural unique chiral oligotriazoles have been developed as C-H bond-based anion-binding catalysts for the asymmetric dearomatization of N-heteroarenes. These rotational flexible catalysts adopt a reinforced chiral helical conformation upon binding to a chloride anion, allowing high levels of chirality transfer via a close chiral anion-pair complex with a preformed ionic substrate. This methodology offers a straightforward and potent entry to the synthesis of chiral (bioactive)heterocycles with added synthetic value from simple and abundant heteroarenes.

Full text of DOI:10.1021/ja507940k

Communication
pubs.acs.org/JACS
Chiral Helical Oligotriazoles: New Class of Anion-Binding Catalysts
for the Asymmetric Dearomatization of Electron-Deficient
N‑Heteroarenes
Mercedes Zurro,†,‡ Soren Asmus,†,‡ Stephan Beckendorf,‡ Christian Muck-Lichtenfeld,‡
̈
̈
and Olga García Mancheno*,†,‡,§
̃
†Institute of Organic Chemistry, University of Munster, 48149 Munster, Germany
‡Institute for Organic Chemistry, University of Regensburg, 93053 Regensburg, Germany
§Straubing Center of Science, 94315 Straubing, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Helical chirality and selective anion-binding
processes are key strategies used in nature to promote
highly enantioselective chemical reactions. Although
enormous efforts have been made to develop simple
helical chiral systems and thus open new possibilities in
asymmetric catalysis and synthesis, the efficient use of
synthetic oligo- and polymeric helical chiral catalysts is still
very challenging and rather unusual. In this work,
structural unique chiral oligotriazoles have been developed
as C−H bond-based anion-binding catalysts for the
asymmetric dearomatization of N-heteroarenes. These
rotational flexible catalysts adopt a reinforced chiral helical
conformation upon binding to a chloride anion, allowing
high levels of chirality transfer via a close chiral anion-pair
complex with a preformed ionic substrate. This method-
ology offers a straightforward and potent entry to the
synthesis of chiral (bioactive)heterocycles with added
synthetic value from simple and abundant heteroarenes.
Figure 1. Anion-binding catalysis approach.
transformations, the development of original chiral catalyst-
motifs is highly desirable.
Encouraged by the great synthetic potential of enantioselective
anion-binding catalysis, we pursued the development of a
conceptually novel family of chiral helical organocatalysts
(Figure 2). The efficient transfer of chirality from oligo- and
polymeric helical catalysts is rather unusual;9 the design of simple
dynamic helical chiral systems that can easily be tuned and
controlled would offer new entries in asymmetric catalysis.10
Based on our first promising results using bistriazole-based
systems (BisTri) as selective chloride-anion-binding catalysts7
and inspired by known helicenes derived from prolonged
condensed aromatic systems that cannot adopt a planar
conformation,11 extended structures with four triazole units
(TetraTri) have been designed.12 Flexibility would still be
present in these systems since the (hetero)aromatic subunits
would be linked by σ-bonds. Having such highly flexible
structures, which in normal conditions will present in equilibrium
both linear and helical conformations, a reinforced defined
helical system can be envisioned upon complexation to a chloride
anion.13 Thus, a favored defined chiral helical triazole−chloride
anion complex might be formed. This special feature and concept
can be then employed for chasing challenging asymmetric
transformations using anion-binding catalysis.
nion-binding catalysis is becoming a powerful tool in
A
hydrogen-bond-donor catalysis and organic synthesis.1
Besides the more traditional H-bonding catalytic approaches
that imply the activation of neutral electrophiles2 or the use of
ion-pairing initiated by protonation with a Brønsted acid,3 anion-
binding catalysis is based on the activation of an ionic
electrophile by binding the catalyst to its counteranion (Figure
1). A close ion-pair between the substrate and the catalyst−anion
complex is formed, facilitating the attack of the nucleophile.
Moreover, when a chiral catalyst is used, the catalyst−anion
complex becomes chiral, and a chirality transfer to the final
product can be achieved.
In this regard, we became highly interested in the enantio-
selective dearomatization of simple and abundant heteroar-
omatic compounds,14 which constitutes an elegant and
straightforward approach to generate synthetically valuable N-
heterocycles possessing new stereocenters. N-Heterocycles are
widely occurring key structural units in a variety of natural and
synthetic bioactive molecules.15 Consequently, their synthetic
To date, (thio)ureas, based on strong polarized N−H bonds as
H-bond donors, have demonstrated a distinctive reactivity.1,4
However, in the past few years, catalyst structures such as
thiophosphoramides (based on N−H bonds),5 siladienols
(based on O−H bonds),6 or the bistriazoles recently introduced
by our research group7 (based on the cooperative action of “low-
polarized” C−H bonds as weak H-donors8) have also shown the
ability to promote reactions through anion-binding catalysis.
However, to further innovate in the area of anion-binding
catalysis and to attain previously inaccessible enantioselective
Received: August 3, 2014
Published: September 11, 2014
© 2014 American Chemical Society
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Table 1. Optimization of Catalyst, Acylating Agent, and
a
Nucleophile
Figure 2. Chiral helical reinforced conformation for asymmetric anion-
binding catalysis and designed triazole-based catalysts.
modification is of great importance in both academia and
industry. In recent years, several dearomatization reactions have
been developed; the most common strategy implies first the
activation of the heteroaromatic ring by N-acylation, followed by
nucleophilic attack.14 However, despite the high potential of
employing the dearomatization technique, catalytic asymmetric
processes are still very challenging and rare.14 Thus, only limited
methods implying organocatalysis for the efficient enantio-
selective nucleophilic dearomatization of electron-deficient N-
heteroarenes have been reported.6,16
Here we described a new kind of C−H bond-based helical
triazole anion-binding catalyst for the enantioselective dearoma-
tization of quinolines by C2-selective nucleophilic addition of
silyl ketene acetals as enolate equivalents.17
Initially, a small family of chiral triazole-based catalysts were
synthesized from appropriate bromo-substituted benzenes as
simple starting materials using iterative Sonogashira couplings,
terminal alkyne deprotection, and Cu-catalyzed azide−alkyne
1,3-cycloadditions (see Supporting Information (SI) for more
details). Chiral 1,2-diamines were used as backbone to
preorientate and later on guide the formation of one of the
two possible chiral helices upon binding to the chloride anion.
With these anion-binding catalysts TetraTri 1 and 2 in hand, we
explored the asymmetric dearomatization of quinolines (Table
1). N-Acyl Mannich addition with silyl ketene acetals was
selected as a suitable testing transformation for H-bond donor
activation, based on a prior related thiourea-based catalyzed
reaction with isoquinolines reported by Jacobsen et al.16a We
started our screening with simple and readily available quinoline
(3a) as a model substrate, 2,2,2-trichloroethyl chloroformate
(TrocCl, R1 = OCH2CCl3) as acylating agent, and isopropyl
TBS-ketene acetal 4a in the presence of 10 mol% of the TetraTri
catalyst. The reaction was carried out in methyl tert-butyl ether
(MTBE), initially at −78 °C, and allowed to slowly reach room
a
Conditions: (i) 3a (1.0 equiv) and R1COCl (1.0 equiv) in MTBE at
0 °C, 30 min; (ii) at the corresponding temperature, catalyst (2.5−10
mol%) and 4 (2 equiv) were added and stirred for 15 h. Isolated
yield. Values for er were determined by chiral HPLC.
b
c
temperature (rt) overnight. The first catalyst tested, (R,R)-1a,
already possessing an alkynyl substituent, provided a high
enantioselectivity (entry 1, 96:4 er). Use of the enantiomer (S,S)-
1a or the regioisomer (R,R)-2a with the same alkynyl
substitution pattern provided similar levels of enantioinduction
in forming the opposite enantiomer and product 5a, respectively
(entries 2,3). In contrast, the catalysts with no substituent 2b or
CF3 groups 2c showed low chirality transfer efficiencies (entries
4,5). Reaction in the presence of BisTri catalyst B1, which
cannot present helical chirality upon binding to the chloride
anion, was also carried out (entry 6). 5c was then obtained in
excellent yield but with a very poor enantioselectivity (41:59 er),
suggesting that the central chirality of the bis-diamine unit is not
sufficient for an efficient asymmetric induction. Subsequently, 1a
was further employed as the most efficient catalyst.
Despite the exceptional enantioselectivities obtained by the
experimentally simplified initial setup at −78 °C followed by a
gradual increase of the temperature, reactions under constant
temperatures and controlled gradients were then studied in order
gain a better understanding of the reaction requirements. When
the reaction was carried out at −78 °C for 15 h, comparable
enantioselectivity (95:5 er) and a lower yield (51%) were
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Communication
obtained (entry 7). As expected, higher reaction temperatures led
to a notable drop in the er (entries 8,9). These results show the
crucial influence of the initial reaction temperature on the
transfer of chirality from the catalyst to the product.
products 5 in higher er (5b, 5c), to attain as well high conversions
the study was completed with the iPr derivative as nucleophile.
Initial studies with methylquinolines already showed that
substitutions at nearly all positions at the quinoline core were
well tolerated, and 5d−f were obtained with high er (up to 98:2
er). However, substitution at the C3 position led to a significant
decrease on the er (5g, 72:28 er), and the presence of a
substituent at the C8 position (3h) inhibited completely the
reaction. These results could be explained in terms of steric
hindrance. Thus, a substituent in the C8 position will prevent the
bulky Troc group to rotate out from the active site, impeding the
attack of the nucleophile. On the other hand, substituents
attached to the C3 position might also hamper the approach of
the nucleophile to the C2 position, causing a deficient
differentiation of both faces of the quinoline derivative.
Furthermore, both the electron-poor and the electron-rich
substituted quinolines provided the dearomatized products 5i−q
in similar good yields and excellent enantioselectivities (typically
95:5 er). Interestingly, 4-methoxyquinoline provided the 2-
substituted chiral 4-quinolone 5p in a moderate 80:20 er.
The absolute configuration of the major enantiomer of 5b
(98:2 er) was determined as the (R) by comparison between the
measured and DFT-simulated CD spectra and by derivatization
of 5a (93:7 er) to the NH-free β-amino methyl ester19 (see SI).
Assuming the same behavior of the catalytic system, the
configuration of the other hydroquinoline products 5 was also
assigned as (R) by analogy.
It was next found that the reaction depended strongly on the
nature of the nucleophile and acylating agent employed (entries
10−14). Regarding the nucleophiles 4, a clear trend was
observed: the bulkier the silyl ketene acetal (tBu > iPr > Me)
was, the higher was the enantioselectivity. Thus, the tBu-
substituted reagent afforded the best enantioselectivity (98:2 er)
in a moderate yield (58%), while the iPr derivative provided both
a high enantioselectivity (96:4 er) and a good yield (76%).
Alternately, only chloroformates showed reactivity and selectiv-
ity. In particular, TrocCl led to the higher enantioselectivity,
while the other tested acylating agents induced poor chiral
inductions.18
Finally, the catalytic loading could also be reduced to 5 and 2.5
mol% without detriment on the enantioselectivity, but the
conversion decreased gradually (entries 15,16). As a compro-
mise, a catalytic loading of 5 mol% was chosen for the further
substrate scope studies (Table 2). Under the optimized
conditions, various commercially available quinolines with
different substitution patterns were explored. Though the
reaction with the tert-butyl ketene acetal provided generally the
a b c
, ,
Table 2. Scope of the Reaction
To get a better understanding on the activity and behavior of
the TetraTri catalysts, a 1H NMR titration of (R,R)-1a with the
preformed quinolinium chloride 6 as the active ionic substrate
was carried out. As it can be seen in Scheme 1, the proton signals
of the C−H bonds of the triazoles are clearly shifted downfield
after the addition of at least 1 equiv of the preformed ionic
substrate 6. For example, addition of 10 equiv of 6 translated to
the same chemical shift of ∼1.5 ppm for the H atoms of the both
BisTri subunits (blue and red). There are also slight changes in
the chemical shifts of other aromatic H atoms.20 All this suggests
Scheme 1. 1H NMR Titration of 1a with Quinolinium Salt 6
a
Conditions: (i) 3 (1.0 equiv) and TrocCl (1.0 equiv) in MTBE at 0
°C, 30 min; then −78 °C; (ii) catalyst 1a (5 mol%) and 4 (2 equiv)
were added, and the temperature was slowly allowed to reach rt (20−
b
c
24 h). Isolated yields. Values for er were determined by chiral
d
HPLC. 5 mmol scale reaction (2.5 mol% of 1a, 4 days).
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Journal of the American Chemical Society
Communication
2012, 4, 926. (c) Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013,
52, 534. (d) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518.
Seidel, D. Synlett 2014, 25, 783.
a cooperative H-bond to the chloride anion, which is
accommodated inside the helical cavity of the catalyst.
Circular dichroism (CD) titration of the catalyst (R,R)-1a
(0.133 mM solution in THF) with Bu4NCl was next carried out.
The characteristic chirality of the helical backbone allows
observing conformational changes in helically folding flexible
oligomers by CD spectroscopy. Binding of a guest, in our case a
chloride anion, might provoke the formation of an excess of one
of the helical forms. This type of conformational change will be
then associated with an induced CD effect. The titration curve
displayed in Figure 3 shows the envisioned reinforcement or
(2) (a) Pihko, P. M. Hydrogen Bonding in Organic Chemistry; Wiley-
VCH: Weinheim, 2009. (b) Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289. (c) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062. (d) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (e) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (f) Jacobsen, E. N.;
Knowles, R. R. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678.
(3) (a) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev. 2011,
40, 4539. (b) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem.
2012, 4, 603 and refs therein.
(4) Pioneering work: (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404.
(5) Borovika, A.; Tang, P.-I.; Klapman, S.; Nagorny, P. Angew. Chem.,
Int. Ed. 2013, 52, 13424.
(6) Schafer, A. G.; Wieting, J. M.; Fisher, T. J.; Mattson, A. E. Angew.
Chem., Int. Ed. 2013, 52, 11321.
(7) (a) Beckendorf, S.; Asmus, S.; Muck-Lichtenfeld, C.; García
̈
Mancheno, O. Chem.Eur. J. 2013, 19, 1581. (b) Asmus, S.;
̃
Beckendorf, S.; Zurro, M.; Muck-Lichtenfeld, C.; García Mancheno,
̈
̃
O. Chem. Asian. J. 2014, 9, 2178.
(8) Selected examples on triazole and triazolium salts C−H-based H-
donors: (a) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649.
(b) Meudtner, R. M.; Hecht, S. Angew. Chem., Int. Ed. 2008, 47, 4926.
(c) Juwarker, H.; Lenhardt, J. M.; Pham, D. M.; Craig, S. L. Angew.
Chem., Int. Ed. 2008, 47, 3740. (d) Ohmatsu, K.; Kiyokawa, M.; Ooi, T. J.
Am. Chem. Soc. 2011, 133, 1307.
(9) For example: (a) Yamamoto, T.; Suginome, M. Angew. Chem., Int.
Ed. 2009, 48, 539. (b) Reggelin, M.; Schultz, M.; Holbach, M. Angew.
Chem., Int. Ed. 2002, 41, 1614.
(10) Selected examples of helical chiral organocatalysts: (a) Takenaka,
N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Am.
Chem. Soc. 2010, 132, 4536. (b) Chen, J.; Captain, B.; Takenaka, N. Org.
Lett. 2011, 13, 1654. (c) Crittall, M. R.; Rzepa, H. S.; Carbery, D. R. Org.
Lett. 2011, 13, 1250. (d) Mortezaei, S.; Catarineu, N. R.; Canary, J. W. J.
Am. Chem. Soc. 2012, 134, 8054. (e) Chen, L.-A.; Xu, W.; Huang, B.; Ma,
J.; Wang, L.; Xi, J.; Harms, K.; Gong, L.; Meggers, E. J. Am. Chem. Soc.
2013, 135, 10598. (f) Wang, J.; Feringa, B. L. Science 2011, 331, 1429.
(11) Shen, Y.; Chen, C.-F. Chem. Rev. 2012, 112, 1463. Gingras, M.;
Figure 3. CD tritation of TetraTri 1a with Bu4NCl in THF.
amplification of the helical structure of the catalyst in solution by
binding to a chloride anion. Thus, addition of Cl−, translated into
a notable increase of the characteristic absorption bands at 250
and 265−280 nm in the positive and negative regions of the UV
spectrum, respectively.
In conclusion, novel helical chiral oligotriazoles have been
developed as anion-binding catalysts for the asymmetric
dearomatization of quinolines. These catalysts transfer the
chirality effectively to the dearomatized products via formation
of a close chiral anion-pair complex with a preformed N-
acylquinolinium ionic substrate. Cooperative binding of the
catalyst’s triazole and aromatic C−H bonds in its cavity to the
chloride anion, and the reinforced catalyst helical structure upon
this coordination, were confirmed by 1H NMR and CD titration
experiments, respectively. The unique features of the presented
triazole organocatalysts might also unveil further interesting
applications in asymmetric anion-binding catalysis.
́
Felix, G.; Peresuttiab, R. Chem. Soc. Rev. 2013, 42, 1007.
(12) Recent review on triazole chemistry: (a) Schulze, B.; Schubert, U.
S. Chem. Soc. Rev. 2014, 53, 2522. Application as catalysts:
(b) Beckendorf, S.; García Mancheno, O. Synthesis 2012, 44, 2162.
̃
(c) Neel, A. J.; Hehn, J. P.; Tripet, P. F.; Toste, F. D. J. Am. Chem. Soc.
2013, 135, 14044.
(13) Induction of helical chirality upon anion-binding: (a) Suk, J.;
Naidu, V. R.; Liu, X.; Lah, M. S.; Jeong, K.-S. J. Am. Chem. Soc. 2011, 133,
13938. (b) Suk, J.; Kim, D.; Jeong, K.-S. Org. Lett. 2012, 14, 5018. See
also refs 8a,b.
(14) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012,
51, 12662 and refs therein.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(15) Joule, J. A.; Mills, K. In Heterocyclic Chemistry, 5th ed.; Wiley: New
York, 2010.
AUTHOR INFORMATION
Corresponding Author
olga.garcia-mancheno@ur.de
Notes
■
(16) For example: (a) Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 6700. (b) Yamaoka, Y.; Miyabe, H.;
Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686. (c) Frisch, K.; Landa,
A.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 6058.
(17) Lead work: (a) Akiba, K.; Kobayashi, T.; Yamamoto, Y.
Heterocycles 1984, 22, 1519. Itoh, T.; Miyazaki, M.; Nagata, K.;
Ohsawa, A. Heterocycles 1997, 46, 83. First asymmetric example:
(b) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 6327.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Deutsche Forschungsgemeinschaft, the Fonds der Chem-
ischen Industrie, and the Deutscher Akademischer Austausch-
dienst are acknowledged for generous support.
(18) See SI for Br− and BF4− counteranion effects.
(19) Katayama, S.; Ae, N.; Nagata, R. Tetrahedron: Asymmetry 1998, 9,
4295.
(20) Zhang, Z.; Lippert, K. M.; Hausmann, H.; Kotke, M.; Schreiner, P.
R. J. Org. Chem. 2011, 76, 9764.
REFERENCES
■
(1) (a) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(b) Beckendorf, S.; Asmus, S.; García Mancheno, O. ChemCatChem
̃
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