Enantioselective synthesis of [6]carbohelicenes

Article abstract of DOI:10.1021/jacs.6b12443

The use of α-cationic phosphonites derived from TADDOL as ancillary ligands has allowed a highly regio- and enantioselective synthesis of substituted [6]-carbohelicenes by sequential Au-catalyzed intramolecular hydroarylation of diynes. Key for these resu

Full text of DOI:10.1021/jacs.6b12443

Communication
pubs.acs.org/JACS
Enantioselective Synthesis of [6]Carbohelicenes
Elisa Gonzalez-Fernandez,† Leo D. M. Nicholls,† Lukas D. Schaaf,† Christophe Fares,‡
́
́
̀
Christian W. Lehmann,‡ and Manuel Alcarazo*,†
†Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstraße 2, 37077 Gottingen,
̈
̈
̈
̈
Germany
‡Max-Planck-Institut fur Kohlenforschung, Kaiser Wilhelm Platz 1, 45470 Muelheim an der Ruhr, Germany
̈
S
* Supporting Information
addition, the imidazolium unit introduces a positive charge which
eventually will be responsible for enhanced catalyst efficiency
(Figure 1).
ABSTRACT: The use of α-cationic phosphonites derived
from TADDOL as ancillary ligands has allowed a highly
regio- and enantioselective synthesis of substituted [6]-
carbohelicenes by sequential Au-catalyzed intramolecular
hydroarylation of diynes. Key for these results is the
modular structure of these new ligands, and the enhanced
reactivity that they impart to Au(I)-centers after
coordination.
Figure 1. Structural design of cationic phosphonites.
he asymmetric synthesis of ortho-annulated polycyclic
1
Tskeletons, helicenes, has received considerable attention
during the past decade as a result of their unique chiroptical
properties and their continually emerging applications in
different areas of chemistry such as asymmetric organo-2 or
transition metal catalysis,3 molecular machines,4 or liquid crystal
technology.5 Indeed, several diasteroselective approaches to
helicenes and helicene derivatives have been reported;6 yet,
syntheses built upon highly enantioselective catalytic processes
are still scarce.7
To bring our plan into practice, we first examined the synthesis
of cationic phosphonites 1a−g. Following known procedures,
diols 2a−g were prepared and subsequently condensed with
PCl3 to afford chorophosphites 3a−g.12 Pyridine revealed to be
the most suitable base for this step since it allows an efficient
separation of 3a−g from pyridinium hydrochloride by simple
filtration. This is crucial for the next and final step, which involves
the condensation of 3a−g with free N-heterocyclic carbenes to
afford 1a−g (Scheme 1).13
The formation of cationic phosphonites 1a−g was first
suggested by the rise of a characteristic 31P NMR signal (δ =
143−149 ppm), and subsequently confirmed by single crystal X-
ray diffraction of 1f. This first structure of a cationic phosphonite
is, in fact, quite suggestive. The geometry around the phosphorus
atom is pyramidal (sum of angles 298.1°) and the electron pair
located on this atom points toward the interior of the chiral cavity
created by the aromatic substituents of both the TADDOL and
imidazolium unit. Besides that, ligands 1a−g are stable enough to
resist chromatographic purification at low temperature, and can
be handled for short times in air without apparent decom-
position.
Mixing 1a−g with (Me2S)AuCl in dichloromethane led to the
formation of the corresponding Au(I) complexes 4a−g in good
to excellent isolated yields. Coordination of the phosphonite to
gold was evidenced by a pronounced upfield shift of their 31P
NMR signals (δ = 108−113 ppm), to a range that perfectly
overlaps with that of closely related Au(I)-phosphoramidite
complexes. Unambiguous confirmation of the expected con-
nectivity was once more obtained by X-ray diffraction of single
crystals of 4e, 4f and 4g (Scheme 2). The three structures depict
Our research group has investigated during the past few years
the synthesis and applications of α-cationic phosphines and their
applications in catalysis.8 The use of these strong π-acceptor
ligands has been proven to be highly beneficial in π-acid catalysis;
specifically, tremendous enhancement of catalyst activity has
been observed in the Au- and Pt-catalyzed intra- and
intermolecular hydroarylation of alkynes, which allowed these
transformations to be accomplished under comparatively mild
conditions.9 Encouraged by the realization that alkyne hydro-
arylation has the potential to assemble aromatic rings into
helicenes if applied on suitably designed substrates,10 we
embarked on the design of an enantioselective route toward
[6]carbohelicenes employing chiral cationic ancillary ligands.
Herein, we summarize our progress in this direction.
The starting point for our approach was the synthesis of a
library of chiral cationic phosphanes. Being aware of the
difficulties inherent to asymmetric gold catalysis,11 which stem
from its linear coordination geometry and the outer-sphere
nature of Au(I)-catalyzed processes, we reasoned that the new
ligand structure had to be highly modular in order to tackle this
challenge with any possibility of success. Cationic phosphonites
of general formula 1 fulfill this requirement. The chiral
information is provided by well-precedented TADDOL-derived
moieties, which are cheap, easy to tune, and have already
demonstrated their suitability in asymmetric gold catalysis.12 In
Received: December 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b12443
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
During our preliminary optimization of reaction conditions
with precatalyst 4a, we found that the desired helicene 7a was
formed with a very promising 86% ee employing 5 mol % of
catalyst at 0 °C in CH2Cl2. Note, however, that the
regioselectivity of the cyclization was not satisfactory and
considerable amounts of 8a, the product from the 5-exo-dig
cyclization of one of the alkynes, was also obtained (Table 1,
Scheme 1. Synthesis of Cationic Phosphonites and Structure
a
of 1h in the Solid State14
Table 1. Screening of Chiral Au-Phosphonite and Related
a
Complexes
a
Reagents and conditions: (a) PCl3, Pyridine, toluene, 0 → 60 °C; (b)
IMes, Et2O, −78 → 0 °C and then NaSbF6. Yields (3 steps): 1a, 69%;
1b, 29%; 1c, 48%; 1d, 72%; 1e, 64%; 1f, 79%; 1g, 65%. X-ray structure
of 1f; H atoms and anion removed for clarity.
the Au atom immersed into a deep chiral pocket that will likely be
key for the desired asymmetric transformation.
b
c
d
Entry Catalyst Temp. (°C) Yield (%)
Ratio 7a:8a
ee (%) 7a
1
4a
4b
4c
4d
4e
4f
0
0
98
97
70:30
69:31
88:12
89:11
98:2
(−)-86
(−)-63
(−)-36
(−)-57
(+)-14
(+)-77
(+)-63
(−)-88
(+)-82
(+)-82
(+)-91
(+)-40
(+)-24
Scheme 2. Synthesis of Au-Complexes 4a−h and Structures of
2
a
4e and 4g14
3
0
84
4
0
96
5
0
96
6
0
>98
84
80:20
93:7
7
4g
4a
4f
0
8
−20
−20
−20
−20
0
98
75:25
90:10
95:5
9
92
e
10
11
12
13
4g
4g
9
96
f
88
97:3
>98
>98
81:19
73:27
10
0
a
Reaction conditions: 5 mol % of catalyst and 5 mol % of AgSbF6 in
b
CH2Cl2, 72 h. Combined yields to 7a and 8a. Unless specified, the
amount of intermediate 6a in these mixtures was inferior to 2%.
c
d
Determined by 1H NMR and/or HPLC. Determined by chiral
e
f
HPLC. The reaction mixture still contained 21% of 6a. C6H5F used
as solvent, 10 mol% of 4g/AgSbF6, 96h.
a
Reagents and conditions: (a) (Me2S)AuCl, CH2Cl2, −20 °C → rt.
Yields: 4a, 99%; 4b, 98%; 4c, 91%; 4d, 91%; 4e, 77%; 4f, 94%; 4g,
99%. H atoms and SbF6 anion removed for clarity.
Entry 1). Neither changing the steric nor electronic nature of the
aryl substituents on the TADDOL moiety lead to any
improvement in terms of ee of 7a (Entries 2−5); yet, precatalyst
4d decorated with 4-(trifluoromethyl)phenyl group on the
TADDOL moiety substantially increased the regioselectivity of
the process toward formation of the helicene without eroding
irreversibly the enantioselectivity (7a:8a, 89:11; 57% ee; Entry
4). Hence, both the -Ph and p-CF3(C6H4)- rings were kept for
next optimization round consisting of the replacement of the
acetonide backbone by a more flexible dimethyl ether motif.
Once this first set of Au-precatalysts was made available, they
all were screened on the cyclization of diyne 5a into helicene 7a.
Substrates of general formula 5 were chosen as adequate starting
materials for the synthesis of [6]helicenes because they do not
contain any interfering element of chirality, and can be assembled
in gram scale through a robust and modular route (For the
synthesis of 5a−k, see the Supporting Information).
B
DOI: 10.1021/jacs.6b12443
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Journal of the American Chemical Society
Communication
The results obtained with precatalysts 4f and 4g were not
conclusive. The enantioselectivities obtained were lower than the
one provided by 4a; however, the regioselectivity toward 7a
could be further improved to a respectable 93:7 ratio with the aid
of complex 4g (Entry 7). The effect of lowering the temperature
to −20 °C was subsequently examined. Precatalyst 4a proved not
to be sensitive to this parameter (Entry 8); in contrast, under
these conditions complex 4g produced remarkable results in
terms of regio- and enantioselectivity (Entry 10). Finally, a
solvent screening identified fluorobenzene as the most
appropriate one for this transformation.15 Helicene 7a is thus
obtained with excellent regioselectivity and a remarkable 91% ee.
Note, however, that the catalyst loading had to be increased to
10% in order to obtain complete conversions. Under the same
conditions, the structurally related phosphoramidite Au-
complexes 9 and 10 do not display any catalytic activity, thus
demonstrating the activating effect of the imidazolium moiety.
Only at 0 °C some reactivity was observed, but the
regioselectivity and ee of the product obtained were inferior to
those induced by 4g (Entries 12 and 13). Au-complex 11, based
on a stronger σ-donor BINAP ligand does not show any activity
at 0 °C after activation with AgSbF6 (1 equiv).16
Figure 2. X-ray structure of rac-7b (left) and CD spectrum of 7e (right).
H atoms omitted for clarity. Ellipsoids shown at 50% probability. Only
one of the two independent molecules present in the unit cell is shown.
enantio-determining step of the whole process. With this idea in
mind, intermediate 6l bearing chiral (S)-1-phenylethoxy
substituents was prepared (See the Supporting Information).
The presence of additional elements of asymmetry in this
tetrahelicene renders isomers with different helicity dia-
steromers, making them observable by NMR spectroscopy. In
the measured temperature series, two coalescence phenomena
were observed. The first one with a coalescence temperature
(TC) of 313 K only involves exchange of o- and m-protons of the
internal phenyl substituent, indicating simple rotation of this
group (Scheme 3, blue arrows). The second, with a higher
With the optimal conditions in hand, the scope of the
cyclization was evaluated using diynes 5b−k which contain a
diverse substitution pattern (See the Supporting Information for
the X-ray structures of 5b and 5k). Gratifyingly, the high levels of
regio− and enantioinduction imparted by 4g were maintained
through the series reaching up to 99% ee (7e). Only the methyl
capped alkyne 5k afforded significantly lower ee for reasons that
are not completely understood at this moment (Chart 1).
Scheme 3. Dynamic Processes in Tetrahelicene Intermediates
a
Chart 1. Substrate Scope and Limitations
a
Reactions conditions: 5a−k (o.02 mmol) with catalyst 4g, 10 mol %,
AgSbF6 10 mol %, FC6H5 (o.o5M), −20 °C, 96 h. Yields are of the
isolated 7:8 mixtures; de values were determined by H NMR and
HPLC; ee values were determined by chiral HPLC. 5% of unreacted
1
coalescence temperature (TC = 338 K), interconverts all
diasteromeric pairs in 6l; therefore, it implies stereoinversion
of the helicene skeleton (Scheme 3, red arrows). NOESY/EXSY
experiments also corroborate this view.
Spectra were recorded at the indicated temperatures in d8-
toluene on a 500 MHz spectrometer. Only the −OMe region is
shown.
b
5b and 14% of intermediate 6b were still present in the reaction
c
mixture. 8% of unreacted 5c and 1% of intermediate 6c were still
d
present in the reaction mixture. Reaction carried out in dichloro-
e
methane. 3% of 6h was still present in the reaction mixture.
All our attempts to obtain single crystals from the
enantioenriched mixtures were unsuccessful, but racemates
readily crystallized. This was enough to confirm the helical
structure of the assembled products (Figure 2). To ascertain the
absolute configuration of the helicenes prepared, the CD spectra
of 7c, 7e, and 7g were recorded (See the Supporting Information
and Figure 2). The pattern and sign of these spectra correlate well
with the one reported for (P)-[6]helicene, suggesting the same
absolute configuration.17
At the coalescence temperature, the activation energy barriers
ΔG‡ were calculated to be 59.4 and 74.5 kJ/mol for the ring
rotation and skeleton inversion, respectively. As expected, these
values are slightly higher than those obtained for related
tetrahelicenes with no substituent in position 2.18 From the
Eyring plot of the exchange rates at different temperatures, the
thermodynamic parameters were estimated for the skeletal
inversion (See the Supporting Information, also for a similar
analysis of the ring rotation process). The enthalpy of activation
is relatively low, ΔH‡ = 33.5 kJ/mol, but there is a substantial
negative contribution of entropy of activation (ΔS‡ = −0.13 kJ/
Subsequently, a series of dynamic NMR studies was conducted
to determine whether the first or the second hydroarylation is the
C
DOI: 10.1021/jacs.6b12443
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
molK) to the ΔG‡, indicating that the entropy decreases to attain
the transition state. This hints to a highly ordered transition state
in which the phenyl substituent and the tetrahelicene unit are
probably perpendicular. Finally, the half-life of the diasteromers
of 6l was estimated to be approximately 5 s at −20 °C.
Comparing this fast equilibration with our experimental reaction
time (72−96 h), it can be concluded that a dynamic kinetic
resolution process takes place during the second cyclization
stemming from the preferred reaction of one enantiomer of 6
with the chiral catalyst.
In summary, a highly enantioselective synthesis of substituted
[6]helicenes has been achieved via sequential Au-catalyzed
hydroarylation of alkynes employing newly designed chiral
cationic phosphinites as ancillary ligands. Ongoing work in our
laboratory is focused on the further optimization of the
phosphonite ligands for the enantioselective synthesis of
heterohelicenes and higher order helicenes.
(5) Saito, N.; Kanie, K.; Matsubara, M.; Muramatsu, A.; Yamaguchi, M.
J. Am. Chem. Soc. 2015, 137, 6594−6601.
(6) For selected references, see: (a) Nakano, K.; Hidehira, Y.;
Takahashi, K.; Hiyama, T.; Nozaki, K. Angew. Chem., Int. Ed. 2005, 44,
7136−7138. (b) Grandbois, A.; Collins, S. K. Chem. - Eur. J. 2008, 14,
9323−9329. (c) Carreno, M. C.; Enríquez, A.; García-Cerrada, S.; Sanz-
̃
Cuesta, M. J.; Urbano, A.; Maseras, F.; Nonell-Canals, A. Chem. - Eur. J.
2008, 14, 603−620. (d) Sehnal, P.; Krausova,
́
Z.; Teply, F.; Stara,
́
I. G.;
I. J. Org. Chem. 2008, 73,
k, J.;
J. V.; Vacek, J.; Goryl, G.;
I.; Stary, I. Proc. Natl. Acad. Sci. U. S. A. 2009,
́
̌
Stary, I.; Rulíse
̌
k, L.; Saman, D.; Císaro
̌
va,
́
́
̌
2074−2082. (e) Sehnal, P.; Stara,
Cvacka, L.; Rulísek, L.; Chocholouso
Szymonski, M.; Císarova,
106, 13169−13174. (f) Janc
Chocholousova, J. V.; Vacek, J.; Pohl, R.; Bednar
Císarova, I.; Stara, I. G.; Stary, I. Angew. Chem., Int. Ed. 2013, 52, 9970−
9975. (g) Kimura, Y.; Fukawa, N.; Miyauchi, Y.; Noguchi, K.; Tanaka, K.
́
I. G.; Saman, D.; Tichy, M.; Míse
̌
́
̌
̌
̌ ́
va,
̌
́
́
̌
ari
̌
k, A.; Rybac
́
̌
ek, J.; Cocq, K.;
ova, L.; Fiedler, P.;
̌
́
́
́
̌
́
́
́
̌
Angew. Chem., Int. Ed. 2014, 53, 8480−8483. (h) Sam
S.; Rybac k, J.; Chocholousova, J. V.; Vacek, J.; Bednar
D.; Stara, I. G.; Stary, I. J. Am. Chem. Soc. 2015, 137, 8469−8474.
́
al, M.; Chercheja,
̌
́ ́
ova, L.; Saman,
́
e
̌
̌
́
́
́
(7) (a) Sawada, Y.; Furumi, S.; Takai, A.; Takeuchi, M.; Noguchi, K.;
Tanaka, K. J. Am. Chem. Soc. 2012, 134, 4080−4083. (b) Shibata, T.;
Uchiyama, T.; Yoshinami, Y.; Takayasu, S.; Tsuchikama, K.; Endo, K.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b12443.
■
S
Chem. Commun. 2012, 48, 1311−1313. (c) Janca
Cocq, K.; Chocholousova, J. V.; Vacek, J.; Pohl, R.; Bednar
Fiedler, P.; Císarova, I.; Stara, I. G.; Stary, I. Angew. Chem., Int. Ed. 2013,
̌
ri
̌
k, A.; Rybac
́
e
̌
k, J.;
̌
́
́
ova,
́
L.;
̌
́
́
́
Data for 1f (CIF)
Data for 4e (CIF)
Data for 4f (CIF)
Data for 4g (CIF)
Data for 5b (CIF)
Data for 5k (CIF)
Data for 7b (CIF)
Data for 7k (CIF)
52, 9970−9975. (d) Nakamura, K.; Furumi, S.; Takeuchi, M.; Shibuya,
T.; Tanaka, K. J. Am. Chem. Soc. 2014, 136, 5555−5558. (e) Kotzner, L.;
̈
Webber, M. J.; Martínez, A.; De Fusco, C.; List, B. Angew. Chem., Int. Ed.
2014, 53, 5202−5205. (f) Sako, M.; Takeuchi, Y.; Tsujihara, T.; Kodera,
J.; Kawano, T.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2016, 138,
11481−11484.
(8) (a) Alcarazo, M. Chem. - Eur. J. 2014, 20, 7868−7877. (b) Alcarazo,
M. Acc. Chem. Res. 2016, 49, 1797−1805.
̌
(9) (a) Petuskova, J.; Bruns, H.; Alcarazo, M. Angew. Chem., Int. Ed.
Experimental details and NMR spectra (PDF)
2011, 50, 3799−3802. (b) Carreras, J.; Patil, M.; Thiel, W.; Alcarazo, M.
J. Am. Chem. Soc. 2012, 134, 16753−16758. (c) Carreras, J.; Gopakumar,
G.; Gu, L.; Gimeno, A. M.; Linowski, P.; Petusk
Alcarazo, M. J. Am. Chem. Soc. 2013, 135, 18815−18823. (d) Kozma, A.;
̌
ova, J.; Thiel, W.;
AUTHOR INFORMATION
Corresponding Author
*malcara@gwdg.de
■
́
Deden, T.; Carreras, J.; Wille, C.; Petusk
̌
ova, J.; Rust, J.; Alcarazo, M.
Chem. - Eur. J. 2014, 20, 2208−2214. (e) Tinnermann, H.; Wille, C.;
́
Alcarazo, M. Angew. Chem., Int. Ed. 2014, 53, 8732−8736. (f) Haldon,
ORCID
́
E.; Kozma, A.; Tinnermann, H.; Gu, L.; Goddard, R.; Alcarazo, M.
Dalton Trans. 2016, 45, 1872−1876. (g) Dube, J.; Zheng, Y.; Thiel, W.;
Alcarazo, M. J. Am. Chem. Soc. 2016, 138, 6869−6877.
Manuel Alcarazo: 0000-0002-5491-5682
Author Contributions
E.G.F. and L.D.M.N. contributed equally.
Notes
(10) Mamane, V.; Hannen, P.; Furstner, A. Chem. - Eur. J. 2004, 10,
̈
4556−4575.
(11) (a) Widenhofer, R. Chem. - Eur. J. 2008, 14, 5382−5391.
(b) Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178−2181.
(c) Shapiro, N. D.; Toste, F. D. Synlett 2010, 675−691. (d) Pradal, A.;
Toullec, P. Y.; Michelet, V. Synthesis 2011, 1501−1514. (e) Zi, W.;
Toste, F. D. Chem. Soc. Rev. 2016, 45, 4567−4589.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Deutsche Forschungsgemeinschaft
(Al 1348/5-1) is gratefully acknowledged. We also thank A.
Deege and H. Hinrichs (MPI-Kohlenforschung) for the ee
determinations.
(12) For the use of TADDOL-derived phosphoramidites in
asymmetric catalysis, see: (a) Lam, H. W. Synthesis 2011, 2011−2043.
(b) Teller, H.; Flugge, S.; Goddard, R.; Furstner, A. Angew. Chem., Int.
̈
̈
Ed. 2010, 49, 1949−1953. (c) Teller, H.; Corbet, M.; Mantilli, L.;
Gopakumar, G.; Goddard, R.; Thiel, W.; Furstner, A. J. Am. Chem. Soc.
2012, 134, 15331−15432.
̈
REFERENCES
■
(1) (a) Shen, Y.; Chen, C. F. Chem. Rev. 2012, 112, 1463−1535.
(b) Gingras, M. Chem. Soc. Rev. 2013, 42, 968−1006. (c) Gingras, M.;
(13) Maaliki, C.; Lepetit, C.; Canac, Y.; Bijani, C.; Duhayon, C.;
Chauvin, R. Chem. - Eur. J. 2012, 18, 7705−7714.
(14) CCDC 1520358−1520365 contain the supplementary crystallo-
graphic data for this paper.
Fel
́
ix, G.;Peresutti, R. Chem. Soc. Rev. 2013, 42, 1007−1050. (d) Gingras,
M. Chem. Soc. Rev. 2013, 42, 1051−1095. (e) Urbano, A.; Carreno, M.
̃
C. Org. Biomol. Chem. 2013, 11, 699−708.
(15) Ilg, M. K.; Wolf, L. M.; Mantilli, L.; Fares
A. Chem. - Eur. J. 2015, 21, 12279−12284.
̀
, C.; Thiel, W.; Furstner,
̈
(2) (a) Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.;
Chandrakumar, A. J. Am. Chem. Soc. 2010, 132, 4536−4537. (b) Lu, T.;
Zhu, R.; An, Y.; Wheeler, S. E. J. Am. Chem. Soc. 2012, 134, 3095−3102.
(c) Gicquel, M.; Zhang, Y.; Aillard, P.; Retailleau, P.; Voituriez, A.;
Marinetti, A. Angew. Chem., Int. Ed. 2015, 54, 5470−5473.
(3) Saleh, N.; Shen, C.; Crassous, J. Chem. Sci. 2014, 5, 3680−3694.
(4) Chen, W. C.; Lee, Y. W.; Chen, C. T. Org. Lett. 2010, 12, 1472−
1475.
(16) Precatalyst 4g has also been preliminary tested in standard
cycloisomerization reactions. See the Supporting Information.
(17) Nakai, Y.; Mori, T.; Inoue, Y. J. Phys. Chem. A 2012, 116, 7372−
7385.
(18) Laarhoven, W. H.; Peters, W. H. M.; Tinnemans, A. H. A.
Tetrahedron 1978, 34, 769−777.
D
DOI: 10.1021/jacs.6b12443
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX