Dynamic kinetic resolution in the asymmetric synthesis of atropisomeric biaryl[4] and [5]helicene quinones

Article abstract of DOI:10.1039/b907653k

Total control of axial and helical chirality elements of a (2-biphenyl)-substituted tetrahydro[5]helicene quinone and the configurationally stable dihydro[4]helicene analogue was achieved in a dynamic kinetic resolution process of an axially chiral racemi

Full text of DOI:10.1039/b907653k

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Dynamic kinetic resolution in the asymmetric synthesis of atropisomeric
biaryl[4] and [5]helicene quinonesw
Alfonso Latorre, Antonio Urbano* and M. Carmen Carreno*
˜
Received (in Cambridge, UK) 17th April 2009, Accepted 11th September 2009
First published as an Advance Article on the web 25th September 2009
DOI: 10.1039/b907653k
Total control of axial and helical chirality elements of a
(2-biphenyl)-substituted tetrahydro[5]helicene quinone and the
configurationally stable dihydro[4]helicene analogue was
achieved in a dynamic kinetic resolution process of an axially
chiral racemic diene promoted by an enantiopure sulfinyl
benzoquinone.
configurationally labile chiral axis leading to a unique helical
biaryl atropisomer.
In order to evaluate the influence of the ortho-substitution
around the chiral axis on the configurational stability of a
biaryl helicene quinone, as well as in the efficiency of this
asymmetric approach, the synthesis of (1-naphthyl)-substituted
vinyl tetrahydrophenanthrenes 1a and 1b (see ESIw), with a
OMe substituent in the ortho (R1 = OMe, R2 = H) or para
(R1 = H, R2 = OMe) positions with respect to the naphthyl
group, was initially planned (Scheme 1). Reaction of racemic
diene 1a, bearing an ortho OMe group at the biaryl moiety, with
2 equiv. of (SS)-5-methyl-2-(p-tolylsulfinyl)-1,4-benzoquinone
(2)12 gave, in 68% yield after chromatographic purification, a
50 : 50 mixture of two atropisomeric quinones (P,aS)-3a and
(P,aR)-4a, bearing axial and helical chirality elements. Both
[5]helicene structures resulted from the domino process13
including the asymmetric Diels–Alder reaction of both enantiomers
of the biaryl racemic diene 1a with sulfinyl quinone (SS)-2,
sulfoxide elimination and aromatization of the B ring on the
initially formed cycloadducts. The atropisomers (P,aS)-3a
(99% ee}14 and (P,aR)-4a (98% ee}14 were separated by
preparative HPLC (see ESIw). They showed the same (P)
configuration at the helix15 and the opposite configuration at
the chiral axis. This result indicated a similar reactivity of
both atropenantiomers of the diene 1a in the asymmetric
Diels–Alder reaction as well as a high configurational stability
of the chiral axis in both the starting diene and the final biaryl
helical structure.
Atropisomerism associated with the hindered rotation of a
single bond in ortho-substituted biaryls1 is a chiral feature
found in natural bioactive products2 and chiral ligands widely
used in asymmetric catalysis.3 Apart from aryl–aryl coupling,4
other atroposelective synthetic strategies reported involve
stepwise sequences starting with C–C aryl coupling reactions
followed by enantiodifferentiating transformations to install
the absolute configuration at the biaryl chiral axis.5 Other
chiral molecules lacking chiral centers are helicenes, non-
planar ortho-fused aromatic derivatives displaying helical
chirality.6 Their important properties both in the field of
new materials6b and medicinal chemistry6c have stimulated
the development of short and efficient syntheses, including
versatile asymmetric routes, during the last two decades.7 In
spite of the advances reached, the synthesis of enantiopure
molecules with both axial and helical chirality elements remains
an unsolved challenge. To the best of our knowledge, there are
no examples of helicenes bearing a biaryl substructure with
additional axial chirality.8
We recently succeeded in a short synthesis of enantiopure
helicenequinones9 based on the efficient transfer of chirality
from a homochiral sulfoxide10 to the helical structure. The
strategy stems from the domino Diels–Alder reaction–pyrolytic
sulfoxide elimination–aromatization process occurring when
adequately substituted vinyl dihydroaromatic derivatives react
with enantiopure sulfinyl quinones. This asymmetric approach
could be applied to the synthesis of atropisomeric systems by
introducing a biaryl moiety in the diene partner reacting with
the enantiopure sulfinyl quinones.
The reaction of (1-naphthyl)-substituted racemic diene 1b,
lacking the ortho methoxy group at the biaryl moiety, with
(SS)-2 gave rise, in 74% yield, to a non-separable 20 : 80
mixture of atropisomers (P,aR)-3b and (P,aS)-4b (93% ee)14,15
(Scheme 1). This result suggested that the absence of the OMe
group at the ortho position of the biaryl unit could allow the
interconversion between the atropisomers of 1b, thus facilitating
a partial DKR.11 A double asymmetric induction process had
occurred with efficient control of the helical chirality and the major
formation of the chiral axis with the aS absolute configuration.
The relative configurations of atropisomeric derivatives
(P,aS)-3a and (P,aR)-4a were demonstrated after an X-ray
diffraction study of (P,aR)-4a (Fig. 1),16 whereas those of
11-methoxy-substituted compounds (P,aR)-3b and (P,aS)-4b
Herein, we report a versatile enantioselective synthesis of
differently substituted atropisomeric biaryl[4] and [5]helicene
quinones, in which a dynamic kinetic resolution (DKR)11 of
the initial racemic biaryl-containing diene was achieved from a
1
´
´
´
Departamento de Quımica Organica (C-I), Universidad Autonoma de
Madrid, 28049-Madrid, Spain. E-mail: antonio.urbano@uam.es,
carmen.carrenno@uam.es; Fax: +34 91 4973966;
were assigned by comparison of their H-NMR spectra with
those of (P,aS)-3a and (P,aR)-4a. As can be seen in Fig. 1, the
naphthyl group situated at C-14 in (P,aR)-4a adopts a quasi
perfect parallel disposition with respect to the naphthoquinone
moiety of the helicene framework. This must be favoured by
the flexibility of the tetrahydroaromatic part which allows
intramolecular p-stacking17 between the aromatic rings.
Tel: +34 91 4973924
w Electronic supplementary information (ESI) available: Synthesis of
dienes (rac)-1a,b, (rac)-5 and (rac)-7, experimental procedures,
characterization and crystallographic data, and NMR spectra. CCDC
713295 and 713296. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b907653k
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Scheme 2 Efficient DKR process for the enantioselective synthesis of
(2-biphenyl)-substituted [5]helicene quinone (P,aS)-6.
Scheme 1 Diastereoselective synthesis of (1-naphthyl)-substituted
tetrahydro[5]helicene quinones 3a–4a and 3b–4b.
of the DKR as well as to evaluate the influence of the biaryl
substituent at C-12 on the configurational stability of such
[4]helicene quinones. In this case, the reaction of the
(2-biphenyl)-substituted racemic diene 7 (see ESIw) with 2 equiv.
of (SS)-2-(p-tolylsulfinyl)-1,4-benzoquinone (8)12a at À27 1C
gave rise, in a new efficient DKR process,11 to a sole
diastereoisomer (P,aS)-9a (85% ee)14,15 with 76% yield and
an efficient control of helical and axial chirality elements.
Compound 9a, whose relative configuration was assigned as
(P,aS) by similarity with derivative (P,aS)-6, was later easily
transformed into the OH free derivative (P,aS)-9b (TBAF,
THF, 0 1C, 1 h), in 75% yield (Scheme 3).
To evaluate the ability of a phenyl group situated at the
ortho position of the biaryl moiety in the initial diene to more
efficiently differentiate the reactivity of both atropenantiomers
in the DKR process, the (2-biphenyl)-substituted racemic
diene 5 was synthesized (see ESIw). When compound 5 was
submitted to reaction with 2 equiv. of sulfinyl quinone
(SS)-2 at À27 1C (Scheme 2), pentahelicenequinone (P,aS)-6
(95% ee)14,15 was obtained, as the unique diastereoisomer, in
75% yield. This result evidenced that an efficient DKR11 of the
stereolabile chiral axis of diene
5 had occurred. The
stereochemistry of the process could be a consequence of a
double asymmetric induction process where one of the diene
atropenantiomers cycloadds faster than the other. The high
yield observed suggested that, under the reaction conditions,
the interconversion between both diene atropenantiomers of 5
must be easily occurring before the cycloaddition takes place,
with a total control of the axial and helical chirality elements
of the final target. The relative configuration of (P,aS)-6 was
assigned after X-ray analysis (Scheme 2).16
It is noteworthy that both (2-biphenyl)-substituted
[4]helicene quinones (P,aS)-9a,b proved to be configurationally
stable at room temperature. It is well known that [4]helicene
quinones are only stable when having a bulky substituent such
as a tert-butyl group at the C-12 position.9a The origin of the
unexpected thermal stability of the helix of (P,aS)-9a,b could
be in the particular structure of such derivatives in which the
2-biphenyl substituent at C-12 adopts a double orthogonal
Encouraged by this result, we decided to extend the
usefulness of the DKR process to other analogues. The
synthesis of a (2-biphenyl)-substituted [4]helicene quinone
such as 9 (Scheme 3) would allow us to check the efficiency
Scheme 3 DKR for the enantioselective synthesis of configurationally
stable (2-biphenyl)-substituted [4]helicene quinone (P,aS)-9a.
Fig. 1 X-Ray ortep of (P,aR)-4a.
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disposition where the whole helicene framework seems to be
extended to a [8]helicene-like molecule (Scheme 3).
S. Menichetti, Chem.–Eur. J., 2008, 14, 5747–5750; (n) J. Ichikawa,
M. Yokota, T. Kudo and S. Umezaki, Angew. Chem., Int. Ed.,
2008, 47, 4870–4873.
In summary, we have evidenced the ability of a homochiral
sulfoxide situated on an enantiopure benzoquinone to transfer
its central chirality to a chiral axis and a helicene framework in
an efficient manner. The syntheses of biaryl[4] and [5]helicene
quinones was achieved in a very short, convergent and highly
enantioselective manner. The adequate substitution of the
biaryl diene partner sums up the resolution or dynamic kinetic
resolution of the initial chiral racemic biaryl axis.
8 There are several examples in the literature of helicenes bearing
phenyl groups with no substituents at the ortho positions:
(a) Y. Zhang, J. L. Petersen and K. K. Wang, Tetrahedron, 2008,
64, 1285–1293; (b) Y. Yang, W. Dai, Y. Zhang, J. L. Petersen and
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R. Annunziata, M. Benaglia, M. Cinquini, L. Raimondi,
K. K. Baldridge and J. S. Siegel, Org. Biomol. Chem., 2003, 1,
157–162; (d) H. Li, J. L. Petersen and K. K. Wang, J. Org. Chem.,
2001, 66, 7804–7810; (e) W. H. Laarhoven, W. H. M. Peters and A.
H. A. Tinnemans, Tetrahedron, 1978, 34, 769–777; (f) A. H.
A. Tinnemans and W. H. Laarhoven, J. Chem. Soc., Perkin Trans.
2, 1976, 1115–1120; (g) W. H. Laarhoven and P. G. F. Boumans,
Recl. Trav. Chim. Pays-Bas, 1975, 94, 114–118; (h) A. H.
A. Tinnemans and W. H. Laarhoven, J. Am. Chem. Soc., 1974,
96, 4617–4622; (i) A. H. A. Tinnemans and W. H. Laarhoven,
We thank MICINN (Grant CTQ2008-04691) for financial
support. A.L. wishes to thank MEC for a fellowship. We are
grateful to Dr Jordi Benet-Buchholz at ICIQ (Tarragona,
Spain) for determining the crystal structure of 4a.
Tetrahedron Lett., 1973, 14, 817–820.
´
9 (a) M. C. Carreno, A. Enrı
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.
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16 CCDC-713296 for (P,aR)-4a and CCDC-713295 for (P,aS)-6
contain the supplementary crystallographic data for this
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6654 | Chem. Commun., 2009, 6652–6654