TADDOL-Derived Cationic Phosphonites: Toward an Effective Enantioselective Synthesis of [6]Helicenes via Au-Catalyzed Alkyne Hydroarylation

Article abstract of DOI:10.1021/acscatal.8b01374

A series of cationic phosphonites, all sharing a TADDOL skeleton but decorated with different positively charged substituents at phosphorus, were synthesized and tested as chiral ancillary ligands on the Au-catalyzed intramolecular hydroarylation of appropriate diynes toward carbo[6]helicenes with different substitution patterns. Our studies showed that the Au complexes derived from phosphonites bearing 1,3-dimesityl-1,2,3-triazolium and 1,4-dimesityl-1,2,4-triazolium substituents are the best precatalysts for the desired cyclization in terms of regio- and enantioselectivity of the products obtained. In contrast, all of our attempts to prepare Au complexes from cationic phosphonites derived from CAACs failed, and only ligand decomposition products could be isolated.

Full text of DOI:10.1021/acscatal.8b01374

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2018, 8, 6079−6085
TADDOL-Derived Cationic Phosphonites: Toward an Effective
Enantioselective Synthesis of [6]Helicenes via Au-Catalyzed Alkyne
Hydroarylation
Leo D. M. Nicholls, Maximilian Marx, Thierry Hartung, Elisa Gonzalez-Fernandez, Christopher Golz,
́
́
and Manuel Alcarazo*
Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen, Tammannstraße 2, 37077 Gottingen,
̈
̈
̈
̈
Germany
S
* Supporting Information
ABSTRACT: A series of cationic phosphonites, all sharing a
TADDOL skeleton but decorated with different positively
charged substituents at phosphorus, were synthesized and
tested as chiral ancillary ligands on the Au-catalyzed
intramolecular hydroarylation of appropriate diynes toward
carbo[6]helicenes with different substitution patterns. Our
studies showed that the Au complexes derived from
phosphonites bearing 1,3-dimesityl-1,2,3-triazolium and 1,4-
dimesityl-1,2,4-triazolium substituents are the best precatalysts
for the desired cyclization in terms of regio- and
enantioselectivity of the products obtained. In contrast, all of
our attempts to prepare Au complexes from cationic
phosphonites derived from CAACs failed, and only ligand
decomposition products could be isolated.
KEYWORDS: asymmetric hydroarylation, Au catalysis, ligand design, helicenes, α-cationic ligands
Scheme 1. Au-Catalyzed Enantioselective Synthesis of
Helicenes
INTRODUCTION
■
The enantioselective synthesis of helicenes has received
considerable attention during the last few years due to their
continuously increasing number of applications, which range
from ligand design to molecular machines.1 Several diastereo-
and enantioselective methods to obtain helicene type molecules
have been reported;2 however, most of these protocols are only
valid to prepare heterohelicenes:3 that is, structures showing a
helical architecture but in which one or several carbon atoms
from the parent skeleton have been formally replaced by a
heteroatom. Highly enantioselective syntheses of purely carbon
based helicenes (carbohelicenes) are scarce and, when available,
their scope is still limited. To the best of our knowledge, the
first highly enantioselective synthesis of such ortho-annulated
3 were designed and subsequently used as ancillary ligands.6 In
3 the chiral information is provided by a well-precedented
TADDOL-derived moiety, whose modular synthesis allows an
easy modification of their structures upon convenience.7 In
addition, the positively charged imidazolium group directly
attached to phosphorus is responsible for the enhancement of
Lewis acidity at the metal center in comparison with traditional
catalysts; this was later translated into higher catalyst
efficiency.8
polybenzenoid systems was reported by Stary employing a Ni-
́
catalyzed [2 + 2 + 2] cycloaddition of appropriate triynes to
afford dibenzo[6]helicenes.4 Subsequent modifications of this
original method by either the Stary group or others have
́
allowed its extension to the preparation of structurally
differentiated [6]-, [7]-, or even higher order carbohelicenes.5
Very recently, our group reported a new route to
[6]carbohelicenes 1 via the sequential Au-catalyzed hydro-
arylation of suitably shaped diynes 2 (Scheme 1). In order to
promote the necessary reactivity at the metal center and
efficiently control the enantioselectivity of the cyclization
process, monodentate cationic phosphonites of general formula
In our preliminary screening, the optimization of the
TADDOL fragment of 3 was carried out, with ligands 3a,b,f
Received: April 11, 2018
Revised: May 21, 2018
© XXXX American Chemical Society
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being those identified as most adequate in terms of translating
enantioselectivity to the final helicene (Figure 1a). For
Figure 1. Structural design of cationic phosphonites: influence of the
cationic group.
synthetic convenience the cationic part, a 1,3-dimesitylimida-
zolium group, was kept fixed at that time. We anticipated,
however, that a more fine adjustment of the donor endowment
in cationic phosphonites could also be crucial to further control
the reactivity and/or the enantioselectivity of the final catalysts.
Changing the nature of the group bearing the positive charge
makes this tuning possible.9 That conviction let us embark on
the synthesis of a second generation of α-cationic phosphonites
bearing a broad series of cationic substituents and the study of
their influence in the model hydroarylation reaction. Specifi-
cally, imidazolium groups B and C and 1,2,4- and 1,2,3-
triazolium groups D−G were selected because from their
structures a minimal alteration of the original chiral pocket in
phosphonites 3 could be inferred. Hence, the influence of the
donor capacity of the ligands bound to gold on the
enantioselectivity of the process might be accurately assessed
without suffering from any significant disturbing effect derived
from steric factors. Substituents H−J were included in our
study in a deliberate attempt to further explore new structures
not previously considered (Figure 1b).
Figure 2. Cationic phosphonites prepared. Reagents and conditions:
(a) chlorophosphite (1.0 equiv), carbene (1.0 equiv) or carbodiphos-
phorane (1.0−1.8 equiv), Et2O or THF, and then NaSbF6 (3.0 equiv).
Yields: 5a, 57%; 5b, 51%; 5c, 66%; 5d, 44%; 5e, 31%; 5f, 32%; 5g,
34%; 5h, 30%; 5i, 12%; 5j, 68%; 5k−m, not isolated (directly
transformed to the corresponding Au complexes).
the exception of 1,4-dimesityl-3-methyl-1,2,4-triazol-5-ylidene,
whose preparation and X-ray structure are described in the
Supporting Information, all other carbenes used for the
condensation with chlorophosphites were prepared by
following previously described methods.10
The formation of the expected cationic phosphonites was
monitored by 31P NMR, where the distinct signal of
chlorophosphites slowly disappeared and a new signal at δ
138−180 ppm concomitantly arose. Coupling with the other
two phosphorus atoms makes this signal appear as a triplet in
5a,f with JP−P = 91.8 and 100.7 Hz, respectively. The solid-state
structures of ligands 5c,l,m were also determined by X-ray
diffraction analysis (Figure 3 and the Supporting Informa-
tion).11 As expected, the phosphorus atom is pyramidal in the
three ligands (sum of angles 291.8° for 5b, 292.8° for 5l, and
292.4° for 5m) and its electron pair points toward the inner
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Cationic Phos-
phonites. In our previous study, TADDOL units from ligand
3a with Ph substituents and an acetonide backbone, 3b sharing
the same backbone but with 4-(tert-butyl)phenyl groups, and 3f
bearing 4-(trifluoromethyl)phenyl substituents and a noncyclic
backbone were revealed to be the most suitable species to
induce high enantioselectivities in the benchmark helicene
synthesis. Hence, these motifs were chosen as starting points
for this survey. The necessary chlorophosphites 4 were
prepared on a gram scale following a modification of known
procedures.6,7 Subsequent reaction with the desired free
carbenes or carbodiphosphorane afforded phosphonites 5a−
m in moderate to good yields after anion exchange with
NaSbF6 (see Figure 2 and the Supporting Information). With
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ities are also shown in Scheme 2 (6h,k,m) and the Supporting
Information (6j).
It is of note that ligands 5c,g did not afford the desired Au
complexes; however, while many unidentified products are
formed by decomposition of 5c, the reaction between 5g and
(Me2S)AuCl is clean and the two new compounds that formed
could be isolated. Triaryl-substituted naphthalene 7 contains,
although modified, the carbon skeleton of the original
TADDOL unit, while dimeric Au complex 8, whose structure
could only be ascertained after X-ray analysis (Scheme 3), is
Scheme 3. Decomposition Products from 5g and Structures
a
of 7 and 8
Figure 3. X-ray structures of 5c,l. H atoms and SbF6 anions are
removed for clarity.11
part of the chiral cavity created by the TADDOL moiety. Of
note, most cationic phosphonites resist column chromato-
graphic purification on silica gel provided that this is done at
low temperature (−10 °C).
Mixing the corresponding cationic phosphonites 5a−m with
(Me2S)AuCl led to the formation of Au complexes 6a,b,d−f,h−
m, which were obtained as white or light yellow solids in good
to excellent yields (Scheme 2). Coordination of Au to the
Scheme 2. Synthesis of Au Complexes 6a−f,h−m and
Structures of 6h (Bottom Left), 6k (Top Right), and 6m
a
(Bottom Right)
a
Reagents and conditions: (a) (Me2S)AuCl (1.0 equiv), CH2Cl2. H
atoms and SbF6 anions are removed for clarity.11
composed of a CAAC-substituted phosphonous acid coordi-
nated to gold. The phosphorus atom in 5g is the most electron
poor atom along the series of ligands prepared due to the
strong electron-withdrawing effect of the iminium group.
Coordination of AuCl to this atom depletes even more
electron density and makes the cationic phosphonite unit of 5g
an excellent leaving group. This triggers the initial formation of
a carbocation, which starts a cascade consisting of Friedel−
Crafts cyclization, elimination of the phosphonous acid
derivative, acid-promoted elimination of methanol, and finally
[1,2]-sigmatropic migration of an aryl group to the newly
generated carbocation, leading to naphthalene 7 and Au
complex 8 as a side product (see the Supporting Information
for a detailed mechanistic proposal). TADDOL itself and some
of its derivatives bearing electron-rich substituents are sensitive
to Brønsted acids, and a similar naphthalene structure has been
previously reported as their decomposition product.12 Hence, it
is not surprising to observe a related transformation promoted
by coordination of the phosphonite ligand to a Lewis acid.
None of the other Au complexes prepared seem to be affected
by this undesired process.
a
Reagents and conditions: (a) (Me2S)AuCl (1.0 equiv), CH2Cl2.
Yields: 6a, 99%; 6b, 99%; 6d, 85%; 6e, 50%; 6f, 99%; 6h, 93%; 6i, 25%
(from 4i); 6j, 92%; 6k, 17% (from 4k); 6l, 22%, two steps; 6m, 20%,
two steps. In the crystal structures, H atoms and SbF6 anions are
removed for clarity.11
phosphorus center causes a pronounced upfield shift of the 31P
NMR signal in these compounds to a range of δ 110−114 ppm
for 6b,d,e,g−m and 129−131 ppm for 6a,f. Single crystals
suitable for X-ray structure determination of complexes
6h,j,k,m were obtained by slow diffusion of pentane or toluene
into saturated solutions of the title compounds in CH2Cl2; their
structural diagrams, which confirmed the expected connectiv-
Optimization of Diyne Precursor Synthesis. A previous
synthetic route for the preparation of diynes of general formula
2 has been reported by our group by starting from 2,7-
dimethylnaphthalene.6 That method, although reproducible
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a
and scalable, is quite time consuming, since it requires a
relatively long nine-step sequence to deliver the desired diynes.
For these reasons we envisioned a more efficient protocol,
which starts with the regioselective dibromination of
naphthalene-2,7-diol (9) using N-bromosuccinimide to obtain
10. Subsequent treatment of naphthalene 10 with Tf2O affords
bis-triflate 11. This tetrafunctionalized compound reacts with
aryl-substituted alkynes under typical Sonogashira conditions to
cleanly produce the 2,7-bis-alkynylated products 12a,b in good
to excellent isolated yields.13 Finally, at the last step of the
sequence alkynes 12a,b were transformed via Suzuki coupling
with appropriate boronic acids into the desired diynes 2.
Employing this improved pathway, we have been able to
shorten the original synthesis of the diyne precursors to only
four steps and substantially increase the overall yields of the
desired products (Scheme 4).
Table 1. Screening of Chiral Au-Phosphonite Complexes
b
c
Scheme 4. Synthesis of Diyne Precursors and X-ray Structure
of 2da
entry
ligand
substrate
temp (°C)
13:14:15:1
ee (%) 1ba
a
1
2
3
4
5
6
7
8
9
3f
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
2ba
−20
0
0:3:0:97
(+)-91
d
5a
5b
5h
5i
only 15ba
e
−20
−20
−20
−20
−20
−20
−20
45:5:0:50
(−)-60
(+)-84
(+)-87
(+)-82
(+)-84
(+)-85
(+)-82
0:4:0:96
0:2:0:98
0:13:0:87
0:4:0:96
0:2:0:98
0:2:0:98
5j
5k
5l
5m
a
Starting material was completely consumed after 96 h using 10 mol %
of catalyst and 10 mol % of AgSbF6 in C6H5F. Determined by H
NMR and/or HPLC. Determined by chiral HPLC. 5 mol % of
catalyst and 5 mol % of AgSbF6 were used as the catalyst mixture and
CH2Cl2 as solvent. Product 15ba was obtained in 43% isolated yield
b
1
c
d
e
after crystallization. Reaction time 72 h.
5i−m resulted in a reaction with a slightly lower enantiose-
lectivity. Note, however, that both 5i and 5l improve the
regioselectivity of the cyclization. This outcome is noteworthy
from a practical point of view, since separation of helicenes 1
from fulvenes 14 has proven to be a difficult task and usually
requires preparative HPLC.
Of note, ligand 5a bearing a very bulky phosphonium-
phosphorane group induces the selective formation of the
product of double 5-exo-dig cyclization 15ba, a bis-fulvene that
has been only detected under these conditions (for the X-ray
analysis of 15ba see the Supporting Information). We postulate
that the enormous steric demand of ligand 5a favors the
preferential coordination of Au to the external and less sterically
demanding carbon from the alkyne moieties in 2ba. This leads
to the formation of five- instead of six-membered rings after the
hydroarylation event.
The scope of the most promising catalysts, 5i,l, was further
evaluated using other diyne substrates which contain a
reasonably diverse pattern of substitution (Table 2). Gratify-
ingly, in comparison with 3f, triazolium-derived ligands
substantially improved the regioselectivity of the cyclization
toward the helicene products in all cases screened (compare,
for example, entries 3 and 4 or entries 19 and 20 in Table 2).
The enantioselectivity of the transformation also follows the
same trend for most of the substrates. Ligands 5i,l overtake the
performance of the imidazolium-based ligand 3f for products
1aa,bb,bc,be,ea,ga (ee values 85−94%); however, for 1da,dc,
ligand 3f is still able to afford the desired helicenes with slightly
a
Reagents and conditions: (a) NBS (2.0 equiv), CH3CN; (b) Tf2O,
(2.5 equiv); pyridine (3.0 equiv), 27%, two steps; (c) alkyne (7 equiv),
PdCl2(dppf) (5 mol %), CuI (10 mol %), 12a 81%, 12b 86%; (d)
boronic acid (4.0 equiv), Cs2CO3 (3.0 equiv), Pd2(dba)3 (4 mol %),
SPhos (8 mol %), 2bc 46%, 2bd 37%, 2be 24%, 2bf 22%, 2ca 43%. H
atoms are removed in the crystal structure for clarity.11
Catalysis. Once the substrate syntheses were optimized, we
initially examined the performance of the new catalysts on the
cycloisomerization of 2ba toward helicene 1ba (Table 1).
Special emphasis was placed on comparing the originally
optimized imidazolium-based ligand 3f against those which
have virtually identical sterical properties but contain either
substituted imidazolium or triazolium groups. Whereas 3f
affords helicene 1ab with 91% ee, its triazolium-derived cousins
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configuration.14 The photophysical properties of these five
helicenes (absorption and fluorescence spectra) are summar-
ized in the Supporting Information.
a
Table 2. Substrate Scope
CONCLUSIONS
■
A highly enantioselective synthesis of [6]helicenes of different
substitution pattern via the Au(I)-catalyzed intramolecular
hydroarylation of diynes is reported. In order to achieve the
necessary levels of reactivity and enantioselectivity, chiral
cationic phosphonite ligands containing imidazolium, 1,2,3-
triazolium, and 1,2,4-triazolium rests were designed and tested
as ancillary ligands. From the results obtained it can be
concluded that Au complexes derived from these ancillary
ligands are currently the most efficient catalysts for this kind of
enantioselective transformation. The modularity of the
synthetic route used to prepare ligands 3a−f and 5a−m,
combined with their surprisingly high stability, makes us
strongly believe they might find application in other
asymmetric Au-catalyzed processes. Studies to evaluate this
hypothesis are in progress in our laboratory.
c
d
entry ligand substrate product yield of 1 (%) 13:14:1 ee (%) 1
b
1
3f
5i
3f
5i
3f
5i
3f
5i
3f
5i
5l
3f
5i
3f
5e
5d
3f
5l
3f
5l
2bb
2bb
2bc
2bc
2be
2be
2bf
2bf
2da
2da
2da
2dc
2dc
2aa
2aa
2aa
2ea
2ea
2ga
2ga
1bb
1bb
1bc
1bc
1be
1be
1bf
1bf
1da
1da
1da
1dc
1dc
1aa
1aa
1aa
1ea
1ea
1ga
1ga
99
83
86
92
84
90
0:12:88
0:4:96
0:13:87
0:3:97
0:12:88
0:3:97
(+)-78
(+)-86
(+)-75
(+)-87
(+)-75
(+)-86
2
b
3
4
5
6
7
trace
b
8
76
7:7:86
16:3:81
9:2:89
0:1:99
0:13:87
0:5:95
0:1:99
0:0:100
0:0:100
3:14:83
0:1:99
0:13:87
0:1:99
(+)-92
(+)-97
(+)-92
(+)-88
(+)-95
(+)-85
(+)-63
(−)-66
(−)-70
(+)-87
(+)-94
(+)-86
(+)-89
b
9
99
10
11
12
13
14
15
16
17
18
19
20
33
48
b
ASSOCIATED CONTENT
* Supporting Information
92
■
S
93
82
94
95
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b01374.
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
b
76
98
b
94
95
a
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Starting material was completely consumed after 96 h at −20 °C,
except for entries 9 (30%), 10 (50%), and 11 (52%) using 10 mol % of
catalyst and 10 mol % of AgSbF6 in C6H5F. Calculated for inseparable
b
c
1
mixtures of 13, 14 and 1. Determined by H NMR and/or HPLC.
d
Determined by chiral HPLC.
Crystallographic data (CIF)
Crystallographic data (CIF)
superior ee values. Au catalysts derived from triazolium-
phosphonites are in general more active than their imidazolium
cousins. This is beautifully illustrated by the cyclization of the
deactivated substrate 2bf (Table 2, entries 7 and 8). While only
traces of the helicene are obtained employing precatalyst 3f, Au
complex 5i afforded the desired product 2bf with a remarkable
76% isolated yield (mixture of 3 isomers) and an ee value of
92%.
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Preparation of ligands, catalysts, and substrates, support-
ing crystallographic information, and chiral HPLC
analyses to determine the enantioselectivities of the
products (PDF)
The CD spectra of 1aa,bb,bc,bf,be have been recorded
(Figure 4). The shape and sign of these spectra correlate quite
well with that of P-[6]helicene, suggesting the same absolute
AUTHOR INFORMATION
Corresponding Author
*E-mail for M.A.: malcara@gwdg.de.
■
ORCID
Manuel Alcarazo: 0000-0002-5491-5682
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Deutsche Forschungsgemeinschaft
(Al 1348/4-2) and (INST 186/1237-1), and the Georg-August-
■
Universitat Gottingen is gratefully acknowledged. We thank Dr.
̈
̈
R. Goddard (Max-Planck-Institut fur Kohlenforschung, Mul-
̈
̈
heim an der Ruhr) for solving the structure of compounds 8
and 15ba and our NMR department for assistance.
Figure 4. ECD spectra of 1aa,bb,bc,bf,be.
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(4) (a) Janca
Vacek, J.; Pohl, R.; Bednar
̌
ri
̌
k, A.; Rybac
́
e
́
̌
k, J.; Cocq, K.; Chocholouso
̌
va,
́
J. V.;
I. G.;
ABBREVIATIONS
■
■
́
ova,
L.; Fiedler, P.; Císarova, I.; Stara,
̌
́
́
CAAC, cyclic alkyl amino carbene
Dipp, diisopropylphenyl
Stary, I. Rapid Access to Dibenzohelicenes and their Functionalized
́
Derivatives. Angew. Chem., Int. Ed. 2013, 52, 9970−9975. For a
nonbezenoid system, but still carbon-based, see: (b) Sawada, Y.;
Furumi, S.; Takai, A.; Takeuchi, M.; Noguchi, K.; Tanaka, K.
Rhodium-Catalyzed Enantioselective Synthesis, Crystal Structures,
and Photophysical Properties of Helically Chiral 1,1′-Bitriphenylenes.
J. Am. Chem. Soc. 2012, 134, 4080−4083. For former enantioselective
syntheses leading to moderate ee values, see: (c) Caeiro, J.; Pena, D.;
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