Light-driven enantioselective organocatalysis

Full text of DOI:10.1002/anie.200901603

Communications
DOI: 10.1002/anie.200901603
Photochemistry
Light-Driven Enantioselective Organocatalysis**
Christiane Mꢀller, Andreas Bauer, and Thorsten Bach*
In recent years, organocatalysis has emerged as an important
area of modern catalysis that complements metal catalysis
and enzyme catalysis.[1] Many chiral compounds that could
not be prepared previously in enantiomerically pure form by
other transformations, or which were only obtained in tedious
reaction sequences, were made accessible by organocatalytic
reactions.[2] Nonetheless, there are still many product classes
that are not available by conventional enantioselective
organocatalysis. Any reaction pathway requiring photochem-
ical but not thermal activation is inherently impossible to be
catalyzed by a classical organocatalyst unless the process of
photochemical activation and catalysis are separated.[3] Pro-
cesses in which light energy serves as direct driving force for
enantioselective bond formation require the design of chiral
organocatalysts to harvest light and allow sensitization of the
substrate by energy or electron transfer.[4,5] After initial
success in this area employing a catalytic photoinduced
electron transfer (up to 70% ee with 30 mol% catalyst),[6]
herein we present a chiral organocatalyst that combines a
significant rate acceleration by triplet energy transfer[7] with
high enantioselectivities. In the studied test reaction
(Scheme 1), a yield of 90% and an enantioselectivity of
92% ee were achieved with only 10 mol% of this catalyst.
The intramolecular [2+2] photocycloaddition of quino-
lone 1, first described by Kaneko et al., leads to two
regioisomeric products: the predominant straight product 2,
and the crossed product 3.[8] This particular transformation
was selected as test reaction, because it delivers a cyclo-
addition product by a rapid five-membered ring closure,[9] and
because it had already been shown by Krische et al.[10] that a
sensitization of this reaction is possible by a chiral benzophe-
none (19% ee with 25 mol% catalyst). The latter result
provided hope that a catalytic reaction course might be
feasible with the benzophenone 4 described earlier.[6] The
solvent, trifluorotoluene,[11] and the irradiation conditions
(l = 366 nm) were adapted to achieve maximum stability and
selective excitation of the sensitizer. Indeed, compound 1
shows only a weak UV absorption at wavelengths of more
than 350 nm. Consequently, the irradiation with a light source
that emits at 366 nm (see Supporting Information), resulted
only in a low conversion after one hour at ambient temper-
ature (Table 1, entry 1).
Benzophenone 4 was then used as catalyst, but unfortu-
nately, it performed less successfully than expected in the
attempted enantioselective catalysis experiments. A rate
acceleration of the reaction was observed, but the enantio-
selectivities remained low. The best result was achieved in
trifluorotoluene at À258C (Table 1, entry 2). At lower
temperatures (using toluene as the solvent), no conversion
took place. As the relatively low triplet energy and the
comparably short wavelength absorption of benzophenone 4
were probably responsible for the disappointing results, the
synthesis of xanthone 5 as a potentially more active catalyst
was attempted. The synthesis required careful optimization,
and commenced with the commercially available fluorophe-
nol 6 (Scheme 2). After protection of the hydroxy group,
nucleophilic substitution with the sodium salt 7 of methyl
salicylate produced biarylether 8. Upon saponification of the
ester group, the xanthone ring was formed by an intra-
molecular Friedel–Crafts acylation.[12] Product 9 was obtained
as the free phenol after cleavage of the isopropyl protecting
group. Esterification with the mixed anhydride rac-10 (see the
Supporting Information)[13,14] produced intermediate product
rac-11. Subsequent reduction of the nitro group was accom-
panied by an ester aminolysis,[15] and the resulting ortho-
hydroxyanilide could be cyclized smoothly to the required
Scheme 1. Intramolecular [2+2] photocycloaddition of prochiral 4-(3’-
butenyloxy)quinolone 1 to the products 2/ent-2 and 3/ent-3.
[*] C. Mꢀller, Dr. A. Bauer, Prof. Dr. T. Bach
Lehrstuhl fꢀr Organische Chemie I
Technische Universitꢁt Mꢀnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
Fax: (+49)89-2891-3315
E-mail: thorsten.bach@ch.tum.de
[**] This project was supported by the Deutsche Forschungsgemein-
schaft as part of the Schwerpunktprogramm Organokatalyse (Ba
1372-10).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901603.
6640
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Angewandte
Chemie
Table 1: Intramolecular [2+2] photocycloaddition of substrate 1 to form products 2 and 3 (Scheme 1):
Influence of catalysts on conversion and enantioselectivity.
69% yield (89% based on recov-
ered starting material). Comparison
of the catalysis results (Table 1,
entries 3–7) with the background
reaction (Table 1, entry 1) reveals
that the success of the catalyst is
largely due to its ability to signifi-
cantly reduce any unsensitized pho-
tocycloaddition—an effect of its
Entry
Catalyst
Mol%[a] t [h] Conv. [%][b] Yield [%][b]
r.r.[c]
ee (2) [%][d] ee (3) [%][d]
1
2
3
4
5
6
7
8
–
4
5
5
5
5
5
–
10
10
10
10
5
1
1
1
2
4
1
1
1
14
57
64
78
90
50
73
39
–
86/14
75/25
78/22
77/23
>99/1
78/22
79/21
79/21
–
–
17
90
91
–
90
90
89
55
95
78
77
39
92
91
91
90
94
–
n.d.[e]
94
–
20
10
UV
absorption
properties
xanthone
(Figure 1).
[a] Reactions were carried out under argon in deaerated trifluorotoluene as solvent at À258C (irradiation
at 366 nm) and with a substrate concentration of 5 mm (see Supporting Information). [b] The
conversion and yield were determined gravimetrically after separation of substrate (1) and products
(2,3). Conversion and yield are calculated based on recovered starting material. [c] The 2/3 regiomeric
ratio (r.r.) was determined by HPLC. [d] The enantiomeric excess (ee) was determined by HPLC. [e] The
ee value could not be determined in this case.
As a consequence, the enantio-
selectivity depends only marginally
on the catalyst concentration
(Table 1, entries 6, 7). It decreased
slightly with 5 mol% catalyst
(Table 1, entry 6), and increased to
Scheme 2. Synthesis of the xanthone sensitizer 5 starting with com-
mercially available fluorophenol 6 (see also Supporting Information).
DMAP=4-dimethylaminopyridine, py=pyridine, TFA=trifluoroacetic
acid, TFAA=trifluoroacetic anhydride.
Figure 1. Mode of action of catalyst 5 illustrated by the normalized
absorption spectra of substrate 1 (c) and xanthone 5 (c), and by
the normalized emission spectrum of the irradiation source (c).
benzoxazole. A separation of enantiomers from the racemic
mixture rac-5 was possible by semipreparative chiral HPLC,
so that the desired xanthone 5 and its enantiomer ent-5 were
available for catalysis experiments.
Xanthone catalyst 5 shows a relatively high absorption
coefficient at wavelengths l ꢀ 350 nm (e350 = 9200 in PhCF3;
Figure 1). The chirality turnover achieved with 10 mol% 5
was extraordinarily high, with enantioselectivities reaching or
exceeding 90% ee for both products 2 and 3 after one hour of
irradiation at À258C (Table 1, entry 3). Conversion increased
with increasing reaction time (Table 1, entries 4, 5) but
isolation became troublesome owing to decomposition of
the sensitizer.
94% ee with 20 mol% of catalyst (Table 1, entry 7). The
regioisomeric product 3 turned out to be unstable under the
irradiation conditions, and thus isolable quantities were not
detected after four hours of irradiation (Table 1, entry 5). The
comparison of 5 with the parent compound xanthone
(Table 1, entry 8) underscores the point that intramolecular
sensitization by triplet energy transfer[7] within the substrate–
catalyst complex 1·5 is more efficient than intermolecular
sensitization. As depicted in Figure 1, the catalyst 5 achieves a
selective excitation of substrate 1 and therefore fulfills
perfectly the requirements of a chiral triplet sensitizer for
enantioselective photoreactions:
1. The activation process works only selectively if there is
little or no spectral overlap between substrate and catalyst
in a wavelength region in which an excitation of the
catalyst is possible with a given light source. For catalyst 5,
The best compromise from a preparative perspective was
to stop the reaction with 10 mol% catalyst after 2 h and 78%
conversion. Under these conditions, products were isolated in
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Communications
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this optical window appears ideally positioned (Figure 1)
to avoid direct excitation of substrate 1.
2. The triplet energy of the sensitizer must be significantly
higher than the triplet energy of the substrate to allow
rapid energy transfer even at low temperature. Based on
the estimated[16] triplet energies for quinolone 1 (ET
ꢁ 280 kJmolÀ1) and xanthone 5 (ET ꢁ 310 kJmolÀ1), this
criterion is fulfilled for both components of complex 1·5.
3. The substrate–catalyst complex must form effectively to
ensure that the sensitization in this complex is faster than
intermolecular sensitization. In the example presented
herein, complex formation was achieved by hydrogen
bonding, employing a motif previously established in a
stoichiometrically applied template.[13,17]
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Although many solutions are conceivable to meet the
requirements listed above, we believe that the catalyst we
have constructed can serve as a prototype for further
developments in the field. Its application to synthetically
relevant transformations of quinolones is currently under
investigation.
Received: March 24, 2009
[14] T. Bach, H. Bergmann, K. Harms, J. Am. Chem. Soc. 1999, 121,
10650 – 10651.
Published online: May 26, 2009
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Schering Foundation Symposium Proceedings “Organocatalysis”
(Eds.: M. T. Reetz, B. List, S. Jaroch, H. Weinmann), Springer,
Berlin, 2008, pp. 255 – 280.
Keywords: cycloadditions · enantioselectivity · organocatalysis ·
photochemistry · sensitizers
.
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