First asymmetric synthesis of planar chiral [2.2]metacyclophanes

Article abstract of DOI:10.1039/c3cc42275e

A general three step asymmetric synthesis of planar chiral [2.2]metacyclophanes utilizing selective benzylic and aryl metalations is described. The final enantioselective step is achieved using a (-)-sparteine mediated aryl metalation, following which ele

Full text of DOI:10.1039/c3cc42275e

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First asymmetric synthesis of planar chiral [2.2]metacyclophanes
We have illustrated a general three step asymmetric synthesis
of planar chiral [2.2]metacyclophanes starting from inexpensive
xylenes. The theme of our short synthetic strategy is the
combination of selective benzylic and aryl metalations. The
exploration of [2.2]metacyclophanes as potential planar chiral
catalysts and ligands is now an exciting possibility.
See Donal F. O’Shea
Chem. Commun., 2013, 49, 6125.
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First asymmetric synthesis of planar chiral
[2.2]metacyclophanes†
Cite this: Chem. Commun., 2013,
49, 6125
Marco Blangetti, Helge Muller-Bunz and Donal F. O’Shea*
¨
Received 28th March 2013,
Accepted 14th April 2013
DOI: 10.1039/c3cc42275e
www.rsc.org/chemcomm
A general three step asymmetric synthesis of planar chiral [2.2]meta-
cyclophanes utilizing selective benzylic and aryl metalations is described.
The final enantioselective step is achieved using a (À)-sparteine mediated
aryl metalation, following which electrophile reaction gives planar chiral
cyclophanes with enantiomeric ratios (er) above 90 : 10.
Despite their first racemic synthesis in 1972, [2.2]metacyclophanes
have failed to receive the same level of interest given to their isomeric
relatives [2.2]paracyclophanes.1 Planar chiral [2.2]paracyclophanes
have recently found application as promising chiral ligands and have
proven a valuable contribution to the growing family of planar chiral
scaffolds.2 As part of our ongoing interest in selective metalation
strategies,3 we recently developed a two step racemic synthesis of
planar chiral [2.2]metacyclophanes from inexpensive m-xylenes.4
Both transformative steps utilize LiNK metalation conditions (BuLi,
KOtBu, TMP(H)) for m-xylene benzylic deprotonation with subsequent
in situ oxidative C–C coupling. For example, the synthesis of substrate
1 can be achieved by a hetero-oxidative coupling of m-xylene and
1-substituted-2,4-dimethylbenzenes.4 Using LiNK conditions, a regio-
selective dimetalation at the thermodynamically favored benzylic
positions provided 2 with in situ oxidative ring closure producing
the racemic planar chiral cyclophane 3 (Scheme 1).
Scheme 1 Racemic synthesis of planar chiral [2.2]metacyclophanes.
A consequence of the ortho substituent pattern of one of the aryl
rings of 1 is that the R substituent is positioned at C-4 position of the
cyclophane, rendering it planar chiral. This two-step strategy provides
the very desirable feature of a short synthetic route to these chiral
scaffolds but the additional challenge of an asymmetric synthesis
remains unmet. Rather than attempt the development of asymmetric
ring closure of substrates 2, the success of which may vary with
different R substituents, an alternative more general approach outlined
in Scheme 2 was envisaged. This strategy would rely on the use of both
thermodynamic and kinetic metalations to provide an asymmetric
synthesis in three steps from m-xylenes. The first stage would exploit
Scheme 2 Proposed asymmetric synthesis of planar chiral cyclophanes.
School of Chemistry & Chemical Biology, University College Dublin, Belfield,
Dublin 4, Ireland. E-mail: donal.f.oshea@ucd.ie; Tel: +353-1-7162425
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectral data, HPLC, NMR spectra for all new compounds racemisation
data for 11a–c. CCDC 920658 and 920659. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c3cc42275e
LiNK metalation/oxidative coupling of m-xylene and a 1-substituted-3,5-
dimethylbenzene to provide 4 which has a meta-substitution pattern for
the R substituent and methyl group (Scheme 2). Repeating the reaction
sequence on 4 would produce the achiral cyclophane 5 with a
c
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Table 2 Optimisation of enantioselective metalation conditions
substituent (R) in C-5 position. If the R substituent is capable of
directing a kinetic ortho metalation,5 this would facilitate substitution
at the C-4 position thereby rendering the cyclophane 6 chiral. If a
metalation/electrophile trapping could be achieved in an asymmetric
manner to produce 7, then a diverse set of functional groups could be
introduced via electrophile reaction. Enantioselective lithiations have
been previously reported for the synthesis of planar chiral ferrocenes,6
chromium–arenes7 and 1,11-dioxa[n]paracyclophanes.8
In this report we outline our success with this strategy to deliver the
first asymmetric synthesis of planar chiral [2.2]metacyclophanes. For
this first preliminary account, two different directing groups OMe and
CON(iPr)2 were selected. The required 1,2-diarylethanes 8a and 8b were
synthesized by cross-coupling of m-xylene with 1-methoxy-3,5-dimethyl-
benzene and N,N-diisopropyl-3,5-dimethylbenzamide respectively
(Table 1, entries 1 and 2). To probe the effect of having both cyclophane
aryl rings substituted, the bibenzyl 8c was generated from a homo-
coupling of 1-methoxy-3,5-dimethylbenzene (entry 3). Cyclophane ring
closure was achieved by dimetalation/oxidative ring closure to produce
achiral C-5 substituted cyclophanes 9a and 9b and the C-5/13
dimethoxy substituted derivative 9c in yields from 31–42% (Table 1).
To confirm the directed ortho metalation (DoM) strategy, 9a was
metalated under the kinetic conditions of BuLi/KOtBu at À78 1C and
treated with CD3OD. 2H NMR analysis showed 75% deuterium
incorporated into the ortho-position of 9a-D1, with no deuterium
observed in the other aryl ring or the bridging methylenes (Table 1).
The natural product alkaloid (À)-sparteine, which can be isolated in
significant quantities from papilionaceous plants, remains one of the
Entry
9
RLi
T (1C) Solvent
Product Yield (%) e.r.a
1
2
3
4
5
6
7
8
a
a
a
a
a
a
a
a
b
b
b
b
c
BuLi
BuLi
sBuLi rt
À78
Ether
Ether
Ether
Ether
Ether
Ether
Ether
—
—
15
51
18
43
65
58
—
—
—
73
76
—
46
—
rt
11a
11a
11a
11a
11a
11a
72 : 18
81 : 19
82 : 18
89 : 11
91 : 9
85 : 15
—
sBuLi À78
sBuLi À60
sBuLi À40
sBuLi À20
sBuLi
BuLi
0
À40
0
Heptane 11a
9
Ether
Heptane
Ether
Ether
Ether
Ether
—
—
—
—
10
11
12
sBuLi
sBuLi À40
11b
11b
—
74 : 26
85 : 15
—
sBuLi À78
most successful ligands for enantioselective organolithium chemistry.9 13
BuLi
À78
14
c
sBuLi À40
11c
91 : 9
Accordingly, an optimisation study of the (À)-sparteine mediated
a
metalation of 9a with varying alkyllithiums, solvents and temperatures
Compared to racemic samples generated using (i) sBuLi/PMDTA (ii)
ClCO2Et.
was carried out with ethyl chloroformate used as electrophile (Table 2).
Gratifyingly, optimal metalation conditions to produce 10a were identi-
fied as sBuLi/(À)-sparteine in diethyl ether at À40 1C, which following whereas at higher temperatures poorer enantio-discrimination was
treatment with chloroformate at À78 1C, gave the ester substituted observed (entries 4, 5, and 7). Alternative conditions using BuLi as
cyclophane 11a in 65% yield and an er of 91 : 9 (Table 2, entry 6). Using base or using sBuLi in a hydrocarbon solvent gave very poor metala-
these conditions at lower temperatures (À78 1C) did not improve the er, tions (entries 1, 2, and 8). For amido-substituted cyclophane 9b, it was
found that metalation at the lower temperature of À78 1C gave a better
er of 85 : 15 when compared to À40 1C (entries 11 and 12). This is
Table 1 Synthesis of achiral [2.2]metacyclophanes 9a–c
consistent with the fact that the CON(iPr)2 group is a stronger ortho-
directing group than OMe. Encouragingly, the dimethoxy-substituted
cyclophane 9c also gave an excellent er of 91 : 9 when reacted under
identical conditions to that of 9a (entry 14).
Assignment of the absolute configuration of the predominant
enantiomer of 11a was carried out using X-ray crystallography. The
major isomer was purified by chiral HPLC and crystallized by the
slow evaporation of a diethyl ether solution. Single crystal diffraction
analysis showed it crystallized in the P21 space group with absolute
configuration assigned as Rp (Fig. 1).10a
While 11a had the expected structural features of a [2.2]metacyclo-
phane ring,11 it was interesting to observe that the C4/5 di-substitution
pattern caused the ester group to rotate by 86.11 to the plane of the
aromatic cyclophane ring. This contrasts to the mono C-4 carboxy
substituted cyclophane in which the torsion angle is only 16.614b
and can be rationalised by electronic repulsion between the
oxygen atoms of the ester and ether groups. Ester saponification
of a rac-11a was readily achieved with KOH in 2-propanol12 to
give the C4/C5 CO2H/OMe substituted cyclophane 11d which
Entry
R
R1
8
Yield (%)
9
Yield (%)
1
2
3
MeO
CON(iPr)2
MeO
H
H
MeO
a
b
c
40
30
92
a
b
c
42
31
35
c
6126 Chem. Commun., 2013, 49, 6125--6127
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The generality of this synthetic strategy was illustrated by
reaction of the enantioselectively metalated cyclophanes 10a–c with
the series of electrophiles, DMF, I2, diethyl chlorophosphate and
chlorodiphenylphosphine (Table 3). In each case the reaction was
successful with ers the same or slightly better than that obtained
for ethyl chloroformate. This is indicative of the metalation reaction
being the enantio-discriminating step with the er of the product not
being overly electrophile dependent.
Finally, the racemisation barriers (DG*) of 11a–c were deter-
mined as 141.6, 134.5 and 135.4 kJ molÀ1 respectively, on the
basis of the absolute rate equation, by experimentally following
their racemisation in NMP at 453 K. These values are suffi-
ciently high to encourage future investigation of [2.2]meta-
cyclophanes as potential planar chiral catalysts and ligands.
In summary, the first general enantioselective synthesis of
planar chiral [2.2]metacyclophanes has been accomplished.
The structural features of the C4/C5 substituted derivatives
identified by X-ray analysis may assist in predictive design of
catalysts and ligands. The facile three step synthesis and
relatively high inversion barrier to racemisation indicates their
potential as planar chiral catalysts and ligands, which to date
has not been explored. We thank the European Research
Association ERA-Chemistry and the Irish Research Council
(IRC) for financial support.
Fig. 1 Single molecule structure of Rp-11a. Thermal ellipsoids drawn at the 50%
probability level.
Fig. 2 X-Ray structure of rac-11d (P21/c space group). Thermal ellipsoids drawn
at the 50% probability level (CO2H group disorder neglected).
Notes and references
¨
1 (a) K. Schlogl, Top. Curr. Chem., 1984, 125, 27; (b) B. Kainradl,
was analysed by X-ray crystallography.10b As in the ester deri-
vative above, the carboxylate group has a large torsion angle
with respect to the aryl ring of 70.01. Unusually, in the extended
structure, the carboxylates of 11d are hydrogen bonded to a
neighbouring molecule by a single hydrogen bonding motif
with an OÁ Á ÁO distance of 2.63 Å as shown in Fig 2. This gives
rise to a catemeric one-dimensional hydrogen bonded network
in which neighbouring molecules of 11d associate with each
other via a two-point hydrogen bonding contact in a head-to-
head staggered manner.13 This contrasts with the mono-C4
carboxy substituted cyclophane which crystallized as the more
common centrosymmetric carboxylate dimer.4b
E. Langer, H. Lehner and K. Schlogl, Liebigs Ann. Chem., 1972,
¨
766, 16.
2 (a) T. M. Konrad, J. T. Durrani, C. J. Cobley and M. L. Clarke, Chem.
Commun., 2013, 49, 3306; (b) J. F. Schneider, R. Frohlich and
¨
J. Paradies, Isr. J. Chem., 2012, 52, 76; (c) J. Paradies, Synthesis,
2011, 3749; (d) B. Dominguez, A. Zanotti-Gerosa and W. Hems, Org.
Lett., 2004, 6, 1927; (e) S. E. Gibson and J. D. Knight, Org. Biomol.
Chem., 2003, 1, 1256; ( f ) S. Brase, S. Dahmen, S. Hofener,
F. Lauterwasser, M. Kreis and R. E. Ziegert, Synlett, 2004, 2647;
(g) R. Gleiter and H. Hopf, Modern Cyclophane Chemistry, Wiley-
VCH, Weinheim, 2004; (h) P. J. Pye, K. Rossen, R. A. Reamer,
N. N. Tsou, R. P. Volante and P. J. Reider, J. Am. Chem. Soc., 1997,
119, 6207.
¨
¨
3 (a) P. Fleming and D. F. O’Shea, J. Am. Chem. Soc., 2011, 133, 1698;
(b) M. Blangetti, P. Fleming and D. F. O’Shea, J. Org. Chem., 2012,
77, 2870.
4 (a) M. Blangetti, P. Fleming and D. F. O’Shea, Beilstein J. Org. Chem.,
2011, 7, 1249; (b) M. Blangetti, H. M. Bunz and D. F. O’Shea,
Tetrahedron, 2013, 69, 4285.
Table 3 Electrophile reaction with 10a–c
5 M. C. Whisler, S. MacNeil, V. Snieckus and P. Beak, Angew. Chem.,
Int. Ed., 2004, 43, 2206.
6 W.-P. Deng, V. Snieckus and C. Metallinos, Chiral Ferrocenes in
Asymmetric Catalysis, Wiley-VCH, Weinheim, 2010.
7 S. E. Gibson and H. Ibrahim, Chem. Commun., 2002, 2465.
8 K. Kanda, K. Endo and T. Shibata, Org. Lett., 2010, 12, 1980.
9 (a) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and S. Thayumanavan,
Acc. Chem. Res., 1996, 29, 2283; (b) D. Hoppe and T. Hense, Angew.
Chem., Int. Ed. Engl., 1997, 36, 2282.
10 (a) CCDC 920659 (Rp-11a); (b) CCDC 920658 (rac-11d).
11 For example, step-wise anti-confirmation of aryl rings which have
significant distortion from planarity (8.31 and 7.21) and inter-
annular distance of 2.64 Å.
12 Saponification of Rp-11a was also achievable under these conditions
without racemisation.
13 For other catemer examples see: (a) P. Sanphui, G. Bolla, U. Das,
A. K. Mukherjee and A. Nangia, CrystEngComm, 2013, 15, 34;
(b) D. Das and G. R. Desiraju, Chem.–Asian. J., 2006, 1–2, 231;
(c) K. Kobayashi, T. Shirasaka, E. Horn and N. Furukawa, Tetrahedron
Lett., 1999, 40, 8883.
Entry
10
E"
11
E
Yield (%)
e.r.
1
2
3
4
5
6
7
a
a
a
a
b
c
c
DMF
I2
ClP(O)(OEt)2
ClP(Ph)2
DMF
ClP(O)(OEt)2
DMF
e
f
g
h
i
j
k
CHO
I
P(O)(OEt)2
P(O)Ph2
CHO
P(O)(OEt)2
CHO
68
59
58
69
59
40
58
91 : 9
93 : 7
95 : 5
95 : 5a
84 : 16
90 : 10
91 : 9
a
Oxidation occurred on work up.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 6125--6127 6127