Stereoselective intramolecular hydrogen abstraction by a chiral benzophenone derivative

Article abstract of DOI:10.1039/b108858k

An unprecedented stereoselective photoreduction of a chiral BZP is observed in steady state as well as in time-resolved studies.

Full text of DOI:10.1039/b108858k

Stereoselective intramolecular hydrogen abstraction by a chiral
benzophenone derivative
Miguel A. Miranda,* Luis A. Martínez, Abdelouahid Samadi, Francisco Boscá and Isabel M. Morera
Departamento de Química—Instituto de Tecnología Química UPV—CSIC, Universidad Politécnica de
Valencia, Camino de Vera s/n 46071. Valencia, Spain. E-mail: mmiranda@qim.upv.es; Fax: +34 96
3877349; Tel: +34 96 3877344
Received (in Cambridge, UK) 1st October 2001, Accepted 19th December 2001
First published as an Advance Article on the web 16th January 2002
An unprecedented stereoselective photoreduction of a chiral
BZP is observed in steady state as well as in time-resolved
studies.
pling products 3a,b and 4a,b is inherited from that of the pure
enantiomeric reactants (KP and DCHDM). Thus, the generation
Hydrogen abstraction by benzophenone (BZP) from suitable
donors has attracted considerable attention in the last two
decades and is one of the most general and best-known
photochemical reactions. The transient species detected upon
laser flash photolysis of BZP include its triplet, the ketyl radical
(BZPH·) and the radical anion (BZP·2). Reaction of BZP n–p*
triplets with allylic hydrogens gives BZPH·, which may form
benzhydrol BZPH2, dimerize to pinacol (BZPH)2 or yield cross-
coupled dimers.1
A photochemical reaction may be stereoselective when a
chiral sensitizer is involved in the process.2 Previously, it has
been shown that bichromophoric compounds containing cova-
lently linked sensitizer and substrate-derived substructures can
be useful for modeling photochemical enantioselective events.
Thus, in the electron transfer between excited p–p* ketones and
amino acids a high degree of enantioselective discrimination
has been achieved; this has been related to the possible
enantioselectivity of the photobiological properties of drugs.3
Ketoprofen (KP, 2-(3-benzoylphenyl)propionic acid), a cur-
rently used nonsteroidal anti-inflammatory drug containing the
BZP chromophore,4 behaves as a photosensitizing agent in
humans.5 Hydrogen abstraction from and formation of adducts
to target biomolecules appear to be the main processes
responsible for KP-induced phototoxicity and photoallergy. The
former process is known to play a key role in the photodynamic
lipid peroxidation leading to cell membrane lysis, where
polyunsaturated fatty acids serve as hydrogen source.6
In connection with the potential enantioselectivity of drug-
photosensitized lipid peroxidation, we have prepared two
diastereomeric bichromophores starting from (S)-KP and a
chiral cyclohexa-1,4-diene moiety containing the double allylic
system present in linoleic acid and other polyunsaturated fatty
acids.
Scheme 1
1,2-Dimethylcyclohexa-2,5-dienecarboxylic acid was syn-
thesized through Birch reduction and subsequent methylation of
o-toluic acid.7 Esterification (via the acid chloride) with (R)-
pantolactone produced a diastereomeric mixture (Scheme 1),
which was resolved into its individual components by a
combination of fractioned recrystallization and column chroma-
tography. The structure of a crystalline sample corresponding to
the RS isomer was established by X-ray diffraction. Reduction
of the separated isomers by LiAlH4 followed by semi-
preparative HPLC, using acetonitrile+water+acetic acid as
eluent, yielded the pure enantiomers of 1,2-dimethylcyclohexa-
2,5-diene-1-methanol (DCHDM). They were reacted with the
acid chloride of (S)-KP to give the corresponding esters 1 and
2.
Independent photolysis of 1 and 2 in argon-bubbled acetoni-
trile solution yielded 3 or 4, respectively. In each case, a pair of
diastereomers was obtained (3a,b or 4a,b, Scheme 2), whose
separation was achieved by sequential column chromatography
and HPLC. In both cases, the a+b ratio was ca. 1. Their
characterization was based on NMR (1H and 13C) as well as MS
spectral data. The stereochemistry of the intramolecular cou-
Scheme 2
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Fig. 2 Photophysical studies on bichromophores 1 and 2. A: Transient
absorption spectrum for the SR isomer upon 355 nm laser excitation. A
similar spectrum was obtained for the SS isomer. B: Decay traces observed
for both isomers at 330 nm.
Fig. 1 Photocyclization of bichromophores 1 and 2. A: monitoring of BZP
absorption band disappearance for the SR isomer. Similar spectra were
obtained for the SS isomer, although reaction times were higher. B:
comparison of the results obtained for both diastereomers.
initiation step of photodynamic lipid peroxidation, and thus cell
membrane disruption, might be more easily promoted by one of
the drug enantiomers. Hence, although the results here obtained
with the intramolecular process in model systems should not be
overemphasized, it appears that photooxidation of polyunsatu-
rated fatty acid may be a stereoselective process.
Financial support by the Spanish DGICYT (Project PB
97/0339 and postdoctoral grant to L. A. M.) is gratefully
acknowledged.
of a new asymmetric center upon cyclization (i.e. the reduced
carbonyl carbon) is responsible for the formation of a pair of
diastereomers starting either from 1 or from 2.
Remarkably, the rate of photocyclization upon steady state
photolysis was clearly higher in the case of 1 (SR diastereomer).
The reaction was followed by monitoring the disappearance of
the typical BZP absorption band centered at ca. 254 nm. This is
shown in Fig. 1A. Fig. 1B compares the results obtained for the
SR and SS bichromophores. Thus, after 5 min of irradiation in
acetonitrile solution, more than 60% of starting 1 was consumed
while under similar conditions only 20% of SS isomer 2 had
reacted. As the coupling products are generated upon intra-
molecular cyclization of an intermediate biradical, these results
suggest that the key hydrogen abstraction process is ster-
eoselective.
In order to gain some mechanistic insight, photophysical
studies were also carried out on both bichromophores. Upon
laser excitation (Nd:YAG, 355 nm) of 1023 M acetonitrile
solutions of both esters, the recorded transient spectra showed
two bands with maxima at ca. 330 and 540 nm (Fig. 2A). The
decay traces at 330 nm (see Fig. 2B) allowed to determine the
lifetimes (t = 1.8 and 1.6 ms for 1 and 2, respectively). The
transients were assigned as the biradicals formed upon intra-
molecular hydrogen abstraction. In connection with the ster-
eoselectivity of the photoreduction process, it was very
interesting to realize that biradical formation was ca. 30% more
efficient for the SR isomer. This explains the results obtained in
the steady-state experiments.
The observed stereoselectivity may be due to the fact that,
according to 3D models, the methyl group at C-2 of (S)-
DCHDM hinders both hydrogen abstraction and cyclization of
the resulting biradical as compared to (R)-DCHDM. The
destabilizing interaction between this methyl group and the a-
carbonyl methyl can also be clearly observed in the models of
the final products 3 and 4.
Summarizing, this work reports an unprecedented ster-
eoselective photoreduction of a chiral BZP upon intramolecular
hydrogen abstraction. This stereoselectivity is observed in the
steady state as well as in time-resolved studies. Since KP is a
chiral photosensitizing drug, our results suggest that the
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