Enantioselective Synthesis of 1,12-Disubstituted [4]Helicenes

Article abstract of DOI:10.1002/anie.201915870

A highly enantioselective synthesis of 1,12-disubstituted [4]carbohelicenes is reported. The key step for the developed synthetic route is a Au-catalyzed intramolecular alkyne hydroarylation, which is achieved with good to excellent regio- and enantioselectivity by employing TADDOL-derived (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol) α-cationic phosphonites as ancillary ligands. Moreover, an appropriate design of the substrate makes the assembly of [4]helicenes of different substitution patterns possible, thus demonstrating the synthetic utility of the method. The absolute stereochemistry of the newly prepared structures was determined by X-ray crystallography and characterization of their photophysical properties is also reported.

Full text of DOI:10.1002/anie.201915870

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Accepted Article
Title: Enantioselective Synthesis of 1,12-Disubstituted [4]Helicenes
Authors: Manuel Alcarazo, Thierry Hartung, Rafael Machleid, Martin
Simon, and Christopher Golz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915870
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10.1002/anie.201915870
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of 1,12-Disubstituted [4]Helicenes
Thierry Hartung, Rafael Machleid, Martin Simon, Christopher Golz and Manuel Alcarazo *[a]
Inversion barriers for [n]helicenes and derivatives
Abstract: A highly enantioselective synthesis of 1,12-disubstituted
[4]carbohelicenes is reported. Key for the synthetic route developed
is a Au-catalysed intramolecular alkyne hydroarylation step, which is
achieved with good to excellent regio- and enantioselectivity levels
Me
Me
‡ = 41.4 kcal/mola
Me
employing TADDOL-derived α-cationic phosphonites as ancillary
ligands. Moreover, an appropriate design of the substrate makes
possible the assembly of [4]helicenes of different substitution
patterns, thus demonstrating the synthetic utility of the method. The
absolute stereochemistry of the newly prepared structures was
determined by X-ray crystallography; their photophysical
characterization is reported as well.
‡ = 21.2 kcal/mola
‡ = 4.1 kcal/mola
∆
∆
∆
G
G
G
Me
‡ = 24.1 kcal/molb
‡ = 39.1 kcal/molb
‡ = 36.2 kcal/molb
∆
∆
∆
G
G
G
Figure 1. Inversion barriers for [4]-, [5]- and [6]helicenes and their Me-
Carbohelicenes are screw-shaped molecules formally de-
rived from the ortho-condensation of benzene rings.[ 1 ] Even
though no stereogenic centers are present in their structures,
the twisted geometry imposed by their connectivity makes them
chiral, being the energetic barrier for the interconversion
between the two enantiomeric forms strongly dependent on the
number of ortho-fused benzene units. The first member of the
carbohelicene family showing an helicoidally structure is
[4]helicene, which is configurationally unstable under ambient
conditions.[ 2 ] [5]helicene can be resolved, but its still low
activation energy of racemization (ΔG‡ = 24.1 kcal/mol) does not
hamper the slow interconversion of the enantiomers. Hence, the
racemization of these structures is typically complete after a
couple of days at room temperature.[3] The first configurationally
stable member of the helicene family is [6]helicene. Its
racemization only occurs after intensive heating (ΔG‡ = 36.2
kcal/mol; t1/2(rac) = 48 min. at 205 °C), making this scaffold the
first one among carbohelicenes intrinsically useful to design
thermally stable chiral architectures. [4]
a
substituted derivatives; Calculated values at the B3LYP/6-31G(d) level of
theory; b Experimental values.
In spite of the impressive development already achieved in
the synthesis of helicenes,[1] and the number of applications that
configurationally stable low order helicenes have found in
8
]
diverse areas such as asymmetric catalysis,[
chiral
recognition,[ 9] or the design of molecular machines,[ 10] highly
enantioselective syntheses of [5]carbohelicene derivatives are
11
,
12 ]
scarce;[
and to the best of our knowledge, no
enantioselective route is available for the preparation of 1,12-
disubstituted[4]helicenes.[13]
Being aware of the potential offered by Au-catalysed hy-
droarylation reactions for the assembly of conveniently designed
alkynes into polyarenes;[ 14 ] we conceived the enantiomeric
synthesis of 1,12-disubstituted [4]helicenes from substrates of
general formulae A or B (Figure 2).
R'
Notwithstanding, the absolute configuration of low order [4]
and [5]helicenes can be fixed either by installation of appropriate
substituents at one or both termini of their fjord region, or by
embedment of the helicene moiety into a more extended π-
conjugated scaffold.[5] As illustrative example, on incorporating
just a methyl substituent in position 1- of [5]helicene, the
enantiomerization barrier increases up to ΔG‡ = 39.1 kcal/mol,
making 1-(methyl)[5]helicene even more reluctant to racemize
than [6]helicene.[6] The situation is analogue for [4]helicenes, but
these structures require positions 1- and 12- to be
simultaneously substituted in order to freeze the racemization
process (Figure 1). [7]
This work
R'
R1/2
R1
O
O
OR
OR
A
P
Au
1
R1
SbF6
Cl
2
R1/2
R'
[Au]
12
R'
R1/2
Mes
Mes
N
=
R1
N
N
N
or
B
1
N
Mes
Mes
Mes
Figure 2. Synthetic approaches to the enantioselective synthesis of 1,12-
disubstituted [4]helicenes.
TADDOL-derived monodentate α-cationic phosphonites recently
developed in our laboratory were chosen as ancillary ligands for
the preparation of the necessary Au-precatalysts 2 due to their
high modularity, which allows the easy tuning of the chiral
pocket around the Au atom; and their cationic character,
ultimately responsible for the enhanced activity of the actual
[a]
T. Hartung, R. Machleid, 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
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201915870
Angewandte Chemie International Edition
COMMUNICATION
catalytic species if compared with other Au-catalysts of similar
structure but derived from neutral ligands.[15]
(CF3)Ph substituents, was able to promote the desired double
cyclisation towards [4]helicene 1a with excellent enantio- (97 %
ee) and regioselectivites (1a:9a; 98:2) (Table 1, Entry 5). The
catalytic system suffers however from low reactivity, and
reaction times of up to four days were necessary.
a)
OTf
R
B(OH)2
R
a)
Table 1. Screening of chiral Au-phosphonite complexes in the hydroarylation
of mono- and diynes towards [4]helicenesa
R
,
3a R = Ph; 3b
, R = p-(OMe)Ph; , R = p-(CF
, R = p-(Me)Ph
OTf
Br
4
5a-d
3c
3d
3)Ph
b)
R
R
R2
R1
R1
a), b)
c), a)
3a-d
or
OH
conditions
8a-b
9a-e
R2
1a-e
OH
6
8a
8b
; R = OMe, R' = H
; R = H, R' = OMe
7a
7b
; R = OMe
; R = H
Entry
1
Au cat
2a
Subst.
3a
Yield (%)
50
1:9
1 (ee %)
R'
75:25
50:50
94:6
68:32
98:2
99:1
98:2
96:4
97:3
93:7
>99:1
98:2
94:6
1a (-36)
1a (-30)
1a (-8)
1a (28)
1a (97)
1a (98)
1a (99)
1a (98)
1b (97)
1c (89)
1d (95)
1e (88)
1e (97)
c)
R
Mes
R
F3C
Mes
R
R
CF3
2
2b
2c
3a
13
Mes
3
3a
91
N
N
N
N
O
O
O
O
O
OMe
OMe
N
R
Me
N
OMe
OMe
O
O
4
2d
2e
3a
52
N
P
P
O
P
Au
Cl
SbF6
Mes
Me
Au
Cl
Mes
Au
Cl
Mes
5
3a
94
R
R
CF3
SbF6
6
7b
2f
3a
97
SbF6
R
R
CF3
; R = H
; R = tBu
; R = Ph
2a
2b
2c
; R = H
; R = CF
2d
2e
; R = iPr
2f
2g
2g
2g
2g
2g
2g
2g
3a
98
; R = Mes
2g
3
8b,c
9b
10b,d
11b,c
12b,d
13b,d
3a
95
3b
3c
94
84
3d
8a
4
57
8b
65
aReaction conditions: 3a-d (0.02 mmol), catalysts 2a-g, 10 mol%, AgSbF6 10
mol%, FC6H5 (0.05 M), -20 °C, 96 h. Yields are of the isolated 1:9 mixtures;
regioisomer ratios were determined by 1H NMR and ee values by chiral HPLC.
bCH2Cl2 was used as solvent (0.05 M), 48h.. cReaction carried out at 0 °C.
dCatalyst loading of 5 mol%.
Scheme 1. Synthesis of [4]helicene precursors and structures of the catalysts
tested. Reagents and conditions: (a) Pd2(dba)3 (5 mol%), SPhos (10 mol%),
Cs2CO3 (4 equiv.), THF/H2O (10:1), 80°C, 24h, 3a, 62%; 3b, 67%; 3c, 65%;
3d, 89%;(b) 19 (9 mol%), AgSbF6 (9 mol%), DCM, 7a, 87%; 7b, 42%, both
from 6 (two steps); (c) Tf2O (1.5 equiv.), pyridine, and then 5a or 5c, Pd2(dba)3
(5 mol%), SPhos (10 mol%), Cs2CO3 (2 equiv.), THF/H2O (10:1), 80°C, 24h,
8a, 60%; 8b, 25% (two steps). X-ray structure of 2g, H atoms, co-crystalized
solvents and SbF6 anions are removed for clarity. Arene moieties are drawn as
reduced sticks, ellipsoids drawn at 50% probability level.[16]
In an attempt to solve this issue, the imidazolium moiety in
ligand 2e was exchanged by more electron withdrawing 1,2,3-
triazolium units, but keeping the already optimal chiral
environment around the Au atom. Both resulting catalysts, 2f
and 2g, were able to match or even slightly overtake the already
outstanding regio- and enantioselectivities of 2e (Table 1,
Entries 6 and 7), but importantly employing 2g reaction times
were shortened to only two days. No product derived from the 5-
exo-dig cyclization of the substrate was observed in any of these
experiments. A final solvent screening indicated that 2g does not
require the employment of fluorobenzene to maintain excellent
levels of enantioinduction; highly competitive results were also
obtained working in dichloromethane (Table 1, Entry 8).[15a]
Finally, crystals of precatalyst 2g were obtained, and its
molecular connectivity was confirmed by X-ray diffraction (See
Scheme 1c and the Supporting Information).
We began our investigation by synthesizing dialkyne 3a,
which was obtained by Suzuki coupling between known
bistriflate 4 and boronic acid 5a (Scheme 1a).[17] Subsequently,
a complete array of Au precatalysts 2a-g were screened on the
successive double hydroarylation required to transform that
model substrate into [4]helicene 1a. Our initial explorative
conditions were set up as follows: catalyst load of 10 mol %,
fluorobenzene as solvent and a working temperature of -20°C.
All reactions were allowed to proceed for 96 hours or until total
consumption of the starting material.
The performance of catalysts 2a-c, all containing an
acetonide backbone, was modest in terms of regio- and
enantioselectivity (Table 1, Entries 1-3). Interestingly,
replacement of the acetonide motif by methoxy groups, such as
in Au complexes 2d-e, improved the catalysts’ performance.[18]
Specifically, catalyst 2e, which additionally contain four p-
Using the conditions already optimized, the respective cy-
clizations of diynes 3b-c into 1b-c took similarly place with high
levels of regio- and enantioselectivity (Table 1, Entries 9 and 10).
Interestingly, the more reactive nature of 3c, decorated with
terminal p-anisyl substituents allowed a reduction of the catalyst
load to only 5 mol% without significant erosion of the yield. On
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10.1002/anie.201915870
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COMMUNICATION
the other hand, the cyclization of diyne 3d, bearing strong
electron withdrawing CF3-substituents proved to be difficult and
only traces of the desired [4]helicene 1d was obtained under
standard reaction conditions, although with outstanding ee (4%
isolated yield, 95% ee). The mono-cycled intermediate is the
main species present in the mixture (Table 1, Entry11).
Key for the success of this synthetic plan was the effective
preparation of phenanthrene intermediates 15a-d by
intramolecular hydroarylation of the corresponding alkynes.
While for substrates 13a-b, containing a terminal alkyne, the
cycloisomerization proceeded successfully in the presence of
catalytic amounts of PtCl2,[19] neither PtCl2 or Ph3PAuCl/AgSbF6
were able to satisfactorily promote the hydroarylation step for
internal alkynes 14c-d. Only the employment of Au precatalyst
19, containing a strongly π-acceptor N-arylpyridinio phosphine
as ancillary ligand, induced the formation of 15c-d in
synthetically practical yields. [20]
For substrates 18a-c (R2 = Me), the performance of 2g (5
mol%) is mediocre in terms of regio- and enantioselectivity
(Table 2, Entries 1-3), and significant amounts of undesired ben-
zo[m]tetraphenes 21a-c were obtained as side products.
Interestingly, complete control over the enantioselectivity (97-
99% ee) is achieved by formal exchange of the Me- groups at
position R2 by Ph- ones (substrates 18d-f); however, the
regioselectivity of the cyclisation for these substrates is still far
from ideal (Table 2, Entries 4-6). Note that 8a,b only differ from
18d-f in a remote benzannulation, but this seems to be crucial to
effectively direct the hydroarylation to the inner position of the
phenanthrene (Table 1, Entries 11-12).
The hydroarylation of substrates 8a and 8b towards non
C2-symmetrically substituted 1e proceeded in both cases with
acceptable yields. The same major enantiomer was obtained
from both reactions, albeit the enantioselectivity of the
cyclisation is slightly eroded when using 8a as substrate (Table
1, Entries 12 and 13). Considering that only one hydroarylation
event is required to obtain 1e from these substrates, it is not
surprising that only 5 mol% of precatalyst 2g is required for the
reactions to conclude in 48h. The X-ray structure of substrate 8a
and precursor 7a are depicted in the Supporting Information.
Encouraged by these results, and seeking to further
explore the viability of our cycloisomerization protocol towards
other [4]helicene structures, additional alkyne precursors were
evaluated. Thus, phenanthrene derivatives 18a-j were prepared
following a multistep route, which is described in detail in
Scheme 2.
O
Br
R2
O
R2
a)
H
R2
b)
OR3
B(OH)2
H
Table 2. Scope of the Au-catalized hydroarylation of 18a-j towards
[4]helicenesa
= Ph
= Me
3 = OMe
3 = OBn
,
10a R2
11a
11b
, R
OR3
OR3
,
10b R2
, R
13a-c
12a-c
2 = OMe
10c
, R
2 = R3 = Me;
2 = Ph; R3 = Me
2 = OMe; R3 = Bn
a
R4
212
R2
and , R
11
12
10
9
13
b
c
, R
2
5
a)
3
4
1
R
18a-j
, R
c)
R1
d)
R1
8
6
7
R4
20a-j
21a-j
R1
R1
R1
R2
R1
R2
R2
R2
h)
Entry
Subst.
18a
18b
18c
18d
18e
18f
Yield (%)
93
20:21
20 (ee %)
20a (60)
20b (75)
20c (70)
20d (97)
20e (99)
20f (98)
20g (67)
20h (79)
20i (92)
20j (90)
f) or g)
e)
1
2
63:37
42:58
44:56
69:31
54:46
38:62
90:10
98:2
OR3
OR3
OTf
OH
43
17a-d
14c-d
14-17
15a-d
= Me; R3 = Me;
= Me; R3 = Me;
16a-d
= Ph; R3 = Me
3
85
1 = H; R2
1 = Ph; R2
1 = H; R2
a
c
b
, R
, R
, R
= OMe; R3 = Bn
1 = Ph; R2
d
, R
4
93
i)
= Me; R4 = H
= Me; R4 = Me
= Me; R4 = OMe
= Ph; R4 = H
= Ph; R4 = Me
= Ph; R4 = OMe
= Me; R4 = H
= Me; R4 = Me
= OMe; R4 = H
= OMe; R4 = Me
5
93
1 = H; R2
1 = H; R2
1 = H; R2
1 = H; R2
1 = H; R2
18a
; R
18b
; R
18c
; R
18d
; R
18e
; R
R1
6
75
+
Cy
Cy
Au
Cl
N
P
7
18g
18h
18i
87
Me
Me
8
93
R2
1 = H; R2
18g 1 =Ph; R2
18h 1 =Ph; R2
18i 1 =Ph; R2
18f
; R
9
93
99:1
R4
SbF6
; R
Me
; R
18j
10
94
95:5
18a-j
19
; R
18j 1 =Ph; R2
; R
aReaction conditions: 18a-j (0.02 mmol), catalyst 2g, 5 mol%, AgSbF6 10
mol%, CH2Cl2 (0.05 M), -20 °C, 48 h. Yields are of the isolated 20:21 mixtures;
regioisomer ratios were determined by 1H NMR and ee values by chiral HPLC.
Scheme 2. Synthesis of non-symmetric [4]helicene precursors. Reagents and
conditions: a) Pd(AcO)2 (3 mol%), SPhos, (3 mol%), K3PO4 (2.0 equiv.),
toluene:dioxane (10:1), 12a, 92%, 12b, 91%, 12c, 87%; b) Ohira-Bestmann
reagent (3.0 equiv.), K2CO3 (3.0 equiv.), MeOH, 13a, 95%, 13b, 99%, 13c,
87%; c) PhI (1.0 equiv.), CuI (3 mol%), PdCl2(PPh3)2 (2 mol%), Et3N (5 mL),
14c, 89%, 14d, 71%; d) PtCl2 (10 mol %), toluene, 85°C, 15a, 60%; 15b, 89%;
e) 19 (10 mol%), AgSbF6 (10 mol%), DCM, 15c, 73%; 15d, not isolated; f)
BBr3, DCM, 16a, 99%; 16b, 85%; 16c, 73%; g) BCl3 (2 equiv.), C6HMe5 (3
equiv.),16d, 67% (two steps); h) Tf2O (1.2 equiv.), Et3N, 17a, 79%; 17b, 75%;
17c, 98%, 17d, 95%; i) 5a-c, Pd2(dba)3 (5 mol%), SPhos (10 mol%), Cs2CO3
(2 equiv.), THF/H2O (10:1), 80°C, 24h, 18a, 89%; 18b, 92%; 18c, 68%; 18d,
51%; 18e, 43%; 18f, 38%; 18g, 67%; 18h, 75%; 18i, 62%; 18j, 81%.
Similarly, alkynes 18g-h only differentiate from 18a-b in a
phenyl substituent from the outer rim of the phenanthrene;
however, for these structures the cyclisation is again selectively
directed to the desired position affording 20g-h with high
regioselectivity (Table 2, Entries 7-8). The best results of the
series were obtained for substrates 18i-j (R1 = Ph, R2 = OMe),
which were transformed into 20i-j with excellent regio- and
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10.1002/anie.201915870
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COMMUNICATION
The absorption and fluorescence spectra of the [4]helicenes
synthesized can be found in the Supplementary Information.
Interestingly, compounds 1a-e display blue fluorescence, with
the emission maximum being located at 438-440 nm. The
emission bands for 20a-j, architectures characterized by only
one benzannulation of the parent [4]helicene, are slightly blue-
shifted and appear at 426-433 nm.
enantioselectivities. Further scrutiny is ongoing to fully
understand effect of remote substitutions on the hydroarylation
site, but it seems to be a constant that catalyst 2g promotes
higher enantioselectivites for π-extended structures.[15]
The connectivity of parent [4]helicene 1a was
unambiguously confirmed by X-ray crystallography employing a
racemic single crystal (Figure 3). In this compound the vertical
distance between the overlapping C1 and C7 carbon atoms is
3.243(1) Å, which is basically identical to the value in [6]helicene
(3.215Å). On the other hand, the torsion angles along the inner
rim in 1a (from C1 to C7, φ = 20.3, 27.6, 27.6, 20.3°) vary
significantly if compared to those in [6]helicene (φ = 11.2, 30.1,
31.0, 15.2°), in particular for rings A and D. This is likely to be
caused by the higher tolerance to geometrical distortion of the
one point connected phenyl groups.[ 21] To examine the chiral
stability of the [4]helicenes prepared, enantioenriched 1a (98%
ee) was heated at 180 °C in 1,2-dichlorobenzene for 24h and
later monitored by chiral HPLC. No erosion of the ee was
observed, highlighting the configurational stability of 1,12-
disubstituted [4]helicenes.
Figure 4. Circular dichroism spectra of 1a-c and 1e in dichloromethane.
Figure 3: X-ray structure of rac-1a (left) and 20j (right). H atoms are removed
In summary, we report herein the first highly enantioselective
synthesis of 1,12-disubstituted [4]carbohelicenes, which is
achieved through the Au-catalyzed intramolecular hydroarylation
of appropriate alkynes, employing a TADDOL-derived α-cationic
phosphinite as ancillary ligand. Single crystal X-ray analysis
unambiguously determined the connectivity of the new
structures obtained and established their absolute configuration.
Ongoing work in our laboratory is focused on the further
optimization of the catalytic system developed towards the
enantioselective synthesis of higher order carbohelicenes and
other polyhelical scaffolds.
for clarity and ellipsoids drawn at 50% probability level.[16]
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft
(AL 1348/8-1, INST 186/1237-1 and INST 186/1324-1) is
gratefully acknowledged.
The absolute configuration of the newly prepared helicenes was
determined to be P- from the X-ray analyses of single crystals of
20i and 20j (See Figure
3
and the Supplementary
Information).[22] For 20i, both the Flack and Hooft parameters
(0.01(4) and 0.04(3), respectively) unambiguously support this
assignment. For 20j identical conclusion can be reached
(0.01(12) and 0.09(5) for the Flack and Hooft parameters
respectively). The higher estimated standard deviation for the
last case is attributed to lower data redundancy for this
measurement. Importantly, both independent results point to the
same absolute configuration. Additionally, the circular dichroism
spectra for [4]helicenes 1a-e are shown in Figure 4. Comparison
of these EDC spectra with that reported by Yamaguchi for a
1,12-dimethyl substituted [4]helicene further confirms the
assignment of the helicity made by crystallographic
techniques.[23]
Keywords: [4]helicenes • Enantioselective synthesis•
Asymmetric catalysis • Au catalysis • Ligand design
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COMMUNICATION
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10.1002/anie.201915870
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Minimalistic helicenes. The use of
chiral Au-catalyst bearing an α-
cationic TADDOL-derived phosphonite
as ancillary ligand allows the
enantioselective assembling of one of
the smallest helical polyarene
T. Hartung, R. Machleid, M. Simon, C.
Golz, M. Alcarazo*
R'
O
R'
R1
Page No. – Page No.
R1
OR
OR
R1/2
O
R1/2
P
Enantioselective Synthesis of 1,12-
Disubstituted [4]Helicenes
Au
SbF6
Cl
R'
architectures that can be conceived:
1,12-disubstituted [4]helicenes.
R'
Up to 99% ee
This article is protected by copyright. All rights reserved.