Enantioselective Synthesis of 1-Aryl Benzo[5]helicenes Using BINOL-Derived Cationic Phosphonites as Ancillary Ligands

Article abstract of DOI:10.1002/anie.202010021

The synthesis of unprecedented BINOL-derived cationic phosphonites is described. Through the use of these phosphanes as ancillary ligands in Au^I catalysis, a highly regio- and enantioselective assembly of appropriately designed alkynes into 1-(

Full text of DOI:10.1002/anie.202010021

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Accepted Article
Title: Enantioselective Synthesis of 1-Aryl Benzo[5]helicenes Using
BINOL-Derived Cationic Phosphonites as Ancillary Ligands
Authors: Manuel Alcarazo, Pablo Redero, Thierry Hartung, Jianwei
Zhang, Leo D.M. Nicholls, Guo Zichen, Martin Simon, and
Christopher Golz
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10.1002/anie.202010021
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Enantioselective Synthesis of 1-Aryl Benzo[5]helicenes Using
BINOL-Derived Cationic Phosphonites as Ancillary Ligands
Pablo Redero,‡ Thierry Hartung,‡ Jianwei Zhang, Leo D. M. Nicholls, Guo Zichen, Martin Simon,
Christopher Golz, and Manuel Alcarazo.*
[*]
P. Redero, T. Hartung, Dr. J. Zhang, Dr. L. D. M. Nicholls, G. Zichen, M. Simon, Dr. C. Golz, Prof. Dr. M. Alcarazo
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstr. 2, 37077-Göttingen, Germany
E-mail: malcara@gwdg.de
[‡]
Equal contribution from both authors
Supporting information for this article is given via a link at the end of the document.
Abstract The synthesis of unprecedented BINOL-derived cationic
phosphonites is described. Through the use of these phosphanes as
ancillary ligands in Au(I) catalysis, a highly regio- and enantioselective
of enantioinduction; hence, alternative chiral platforms were
evaluated giving preference to those scaffolds that have already
demonstrated their suitability in asymmetric Au catalysis.[14] As a
result from that initial screening Au complexes 3, containing a
cationic phosphonite derived from BINOL, were identified as the
most promising catalysts to promote the formation of 1 in terms of
isolated yield and levels of regio- and enantioinduction (Figure 1).
Herein, the synthesis and structure these new Au-catalysts,
together with their catalytic performance, are reported.
assembly
of
appropriately
designed
alkynes
into
1-
(aryl)benzo[5]carbohelicenes is achieved. The modular synthesis of
these ligands and the enhanced reactivity that they impart to Au(I)-
centers after coordination have been found to be the key features that
allow an optimization of the reaction conditions until the desired
benzo[5]helicenes are obtained with high yield and enantioselectivity.
The unique physical and chiroptical properties of helicenes,
which ultimately derive from their π-expanded ortho-fused
architecture, and the continuously emerging number of their
applications in areas as diverse as molecular machines[1] or liquid
crystal technology,[2] has led to the flourishing of this chemistry.[3]
A
number of synthetic approaches are available for the
Figure 1. Au-catalysed enantioselective synthesis of benzo[5]helicenes and
structure of the newly designed family of BINOL-derived catalysts.
preparation of carbo-,[4] hetero-,[5] extended,[6] expanded,[7] and
even multi-helicene structures;[8] however, very often the desired
helicoidally-shaped architectures are obtained as racemic
mixtures, which need to be separated by high performance liquid
chromatography (HPLC). The development of effective
enantioselective strategies towards helicenes and helicene-like
molecules is therefore desirable and challenging in equal
amounts. Consider, as an illustrative example, the assembly of
the [5]helicene skeleton. Many racemic and several
diasteroselective syntheses have been reported in recent years,[9]
but despite being a prototype scaffold in helicene chemistry, the
number of highly enantioselective approaches available is still
low.[10]
BINOL-derived α-cationic phosphonites 4a-f were prepared
via a two-step process starting from known diols 5a-f.[15] First,
reaction of 5a-f with PCl3 in the presence of pyridine delivered the
corresponding chlorophosphites 6a-f, which were subsequently
submitted, without further purification, to reaction with 3,4-
dimethyl IMes (7) affording phosphonites 4a−f in moderate to
good yields. The methyl groups at the backbone of the
imidazolium moiety are essential to block these positions and
avoid the formation of side-adducts derived from the
corresponding mesoionic carbenes. Column chromatography on
silica gel of the crude reaction mixtures delivered analytically pure
samples of 4a-f in moderate yields (Scheme 1). Formation of the
expected cationic phosphonites was initially suggested by 31P
NMR, where a distinct signal for the cationic phosphonites arises
at δ = 135−155 ppm. Subsequently, monocrystals of 4a were
grown and its solid-state structure was determined by X-ray
diffraction analysis (See Scheme 1 and the Supplementary
Information). In this compound the phosphorus atom adopts the
expected pyramidal geometry (sum of angles around P = 302.9°);
therefore, retaining an electron pair available for coordination.
Being aware of the potential offered by Au-catalysed
intramolecular hydroarylation reactions for the assembly of
conveniently designed alkynes into condensed polyarenes;[11] we
conceived the enantioselective synthesis of benzo[5]helicenes of
general formula 1 from readily available [4]helicene substrates
containing a pendant alkyne moiety 2. An aryl rest was installed
at the alkyne terminus to obtain configurationally stable products;
otherwise, the enantiomers of unsubstituted [5]helicenes slowly
interconvert at ambient temperature.[ 12 ] Building upon the
experience of our laboratory in the enantioselective synthesis of
other helicenes using Au-catalysts bearing TADDOL-derived
cationic phosphonites as ancillary ligands, we initially screened
the available set of these catalysts for the cyclisation of 2 in 1.[13]
Soon however, it was clear that the chiral environment provided
by the TADDOL moiety was not able to promote acceptable levels
Reaction of 4a-f with (Me2S)AuCl in CH2Cl2 led to the
formation of the corresponding Au(I) complexes 3a−f, which were
obtained as white or light yellow solids in good to excellent
isolated yields. Upon coordination of Au to the phosphonites a
pronounced upfield shift of their 31P-NMR signals (δ = 105−115
ppm) is observed. Previously reported cationic phosphonite-Au
1
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10.1002/anie.202010021
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complexes resonate at identical range.[13a,b] Finally, unambiguous
confirmation of the expected connectivity was again obtained, in
this case by X-ray diffraction of monocrystals of 4b (See Scheme
2 and the Supplementary Information).
temperature of -10°C. All reactions were allowed to proceed until
total consumption of the starting material or stopped after 48h. As
mentioned previously, TADDOL-derived catalysts are not
appropriate for this cyclisation. The best result was obtained with
complex 8, which furnished 2a with only 33% ee (Table 1, Entry
1). Classical BINOL-phosphoramidite Au complexes 9a-b
afforded low conversions at -10°C, as expected for neutral
ancillary ligands; also poor enantioselectivities were observed
regardless of any possible matched/mismatched effect between
the chiral diol or amine fragments (Entries 2-3).[18] Gratifyingly,
already the less sterically demanding catalyst of the new series,
3a, was able to promote the desired cyclisation towards 1a with
high conversion, regio- (1a:10a; 98:2), and enantioselectivites
(93 % ee) (Entry 4). Replacement of the phenyl rests at positions
3 and 3’ of the BINOL moiety by mesityl groups was detrimental
in terms of yield and ee (Entry 5), while introducing 2-naphthyl
fragments at the same positions improved the ee up to 97% at the
expense of a slightly lower regioselectivity (1a:10a; 95:5) (Entry
6). Installing 9-anthranyl rests at the BINOL basically cancels any
catalytic activity in 3d (Entry 7); while catalyst 3e, decorated with
biphenyl rests, afforded complete regioselectivity towards 1a
maintaining high enantioselectivity (Table 1, Entry 8). Finally, the
best compromise was obtained rigidifying the catalyst periphery
with 2-pyrenyl substituents; this slightly improves the
enantioselectivity if compared to 3e, without eroding the
conversion or regioselectivity (Entry 9).
Table 1. Screening of Chiral Au-Phosphonite and related Complexes.
Scheme 1. Synthesis and structure of α-cationic phosphonites 4a-f.aReagents
and conditions: a) PCl3 (1.1 equiv.), pyridine (3 equiv.), toluene, 1h, 60°C; b)
MeIMes (1 equiv.), NaSbF6 (3 equiv.), Et2O, -78°C→rt; yields over two steps: 4a,
73%; 4b, 16%; 4c, 47%; 4d, 37%; 4e, 34%, 4f, 18%. X-ray structure of 4a; H
atoms, solvent molecules and SbF6 anion removed for clarity.[16]
Entry
Catalyst
8
Conv (%)a
86
Ratio 1a:10ª
87:13
>99:1
85:15
98:2
ee (%) 1b
(+)-33
(-)-61
(-)-40
(-)-93
(-)-86
(-)-97
(-)-8
1
2
3
4
5
6
7
8
9
9a
11
9b
35
3a
>98
3b
55
97:3
3c
>98
95:5
3d
<5
n.d.
3e
>98
>98(88)c
>99:1
>99:1
(+)-94
(+)-95
3f
Scheme 2. Synthesis and Structure of Au-complexes 3a-f. aReagents and
conditions: a) (Me2S)AuCl (1 equiv.), CH2Cl2, 1h, -20°C→rt; yields: 3a, 98%;
3b, 67%; 3c, 78%; 3d, 67%; 3e, 95%, 3f, 97%. X-ray structure of 3b; H atoms,
solvent molecules and SbF6 anion removed for clarity.[16]
Once this initial set of Au-precatalysts was prepared, their
performance on the cyclization of model alkyne 2a into
benzo[5]helicene 1a was evaluated. This substrate, as all of
general formula 2 were readily obtained in only two steps via
oxidative photocyclization of conveniently substituted stilbenes,
followed by Suzuki-coupling to install the pending diphenylethyne
unit.[17] For details see the Supplementary Information.
Reactions were carried out at 0.1 mmol scale in CH2Cl2 (0.05 M). aConversions
and 1a:10a ratios were determined by 1H NMR of the crude reaction mixtures.
bDetermined by chiral HPLC. cIsolated yields in parenthesis.
With the most adequate catalyst already identified, the scope
of the cyclization was evaluated. Hence, a series of alkyne
substrates 2a-p, which contain diverse substitution pattern at
different positions of their structure were prepared and submitted
to the optimized cyclisation conditions. We were pleased to see
that the high levels of regio- and enantioinduction imparted by 3f
Our initial explorative conditions were set up as follows:
catalyst loading of 5 mol %, CH2Cl2 as solvent and a working
2
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were maintained for most of the substrates studied; moreover,
some structure-reactivity relationships could be clearly
established (Figure 2).
applied. m-Substituents at the same ring are also tolerated (1f-g),
but in that case the ee’s substantially decay. Me- and MeO-
substituents can be incorporated at the external rim of the
helicene structure keeping remarkable levels of regio- and
enantioselectivity 1h-j and 1l-n. Remarkably, the extension of the
π-system by additional benzannulation is also possible with good
enantioselectivity even if an undecorated phenyl ring substitutes
the alkyne terminus (1p). Better yields and regioselectivities are
expected by introducing electron donating groups at the p-
position of that ring. Finally, alkyl-substituted substrates undergo
the desired cyclisation as well, albeit with moderate regio- and
enantioselectivity (1o).
Colourless blocks of 1a suitable for X-ray diffraction analysis
were obtained via vapor diffusion of hexane into
a
dichloromethane solution of this compound. The thus obtained
molecular structure reveals that the absolute configuration of 1a
to be P (Figure 3a). Both, the Flack and Hooft parameters (0.05(5)
and 0.05(3), respectively) unambiguously support this
assignment. Additionally, the circular dichroism spectrum (EDC)
of 1a was also recorded (Figure 3c); comparison of its spectrum
with those reported for other 1-substituted [5]helicenes further
confirms the assignment of the helicity.[12b] Finally, a pure sample
of 10h was obtained after HPLC separation and crystallized from
hexane. Through this analysis the connectivity of the minor
regioisomers obtained in this cyclisation could be determined;
they depict a dibenzo[a,m]tetraphene structure (Figure 3b). The
absorption and fluorescence spectra of 1a are also shown in
Figure 3d.
Figure 3. a) X-ray structure of 1a; b) X-ray structure of 10h, solvent molecules
were removed for clarity;[16] c) EDC spectrum of 1a and d) UV-Vis absorption
and fluorescence spectrum of the same molecule.
In summary, we report herein the synthesis of a new family of
α-cationic phosphonites derived from BINOL, and their application
as ancillary ligands. Specifically, a highly enantioselective route
for the synthesis of 1-aryl substituted benzo[5]carbohelicenes has
been achieved via the Au-catalysed intramolecular hydroarylation
of appropriate alkynes. While the chiral pocket around the Au
atom should not be very different to that created by
phosphoramidites of similar structure, the unique donor properties
of the cationic ligands prepared render the corresponding Au-
catalysts more active than those, allowing the transformation to
occur under cryogenic conditions. While the substrate structure
Figure 2. Substrate scope and limitations. Reaction conditions: 3f, 5 mol%,
AgSbF6, 5 mol%, CH2Cl2, (0.05M), -10°C, 24-48h. Yields are of isolated
products; in parenthesis 1:10 ratios determined by 1H-NMR; ee values by were
determined by chiral HPLC.
Electron donating groups are necessary in p-position of the
terminal aryl rest of 2 to secure high conversions, regio-, and
enantioselectivities 1a-e. Electron withdrawing substituents in that
position, or even an unsubstituted terminal phenyl rest, make the
reaction extremely slow and low yielding under the conditions
3
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still plays a fundamental role, this seems to be very useful to gain
control over the regio- and enantioselectivity of the whole process.
Single crystal X-ray analysis unambiguously determined the
connectivity of the new benzo[5]helicenes obtained and
established their absolute configuration. Ongoing research in our
laboratory is focused on the further optimization of the catalytic
system herein presented towards the enantioselective synthesis
of other carbo- and heterohelicenes of higher order and multi-
helicoidal architectures.
Financial support from the Deutsche Forschungsgemeinschaft (Al
11348/4-3, INST 186/1237-1 and INST 186/1298-1) is gratefully
acknowledged. We also thank Dr. R. Goddard (MPI
Kohlenforschung, Mülheim/Ruhr) for the X-ray analysis of 3b.
Conflict of Interest
The authors declare no competing financial interests.
Keywords: [5]helicenes • asymmetric catalysis • Au catalysis •
ligand design • cationic phosphonites
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4
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Entry for the Table of Contents
A new family of α-cationic phosphonites derived from BINOL has been synthesized. Their use as ancillary ligands in Au(I) catalysis
allows the enantioselective assembly of 1-aryl [5]helicenes with excellent yields and in up to 98% ee.
5
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