Introduction
Aristolactams, e.g. the recently found Piperolactam E (1) [1], constitute a group of phenanthrene lactam alkaloids structurally and biogenetically related to aporphines, such as Bulbocapnine (2). The most important natural source of aristolactams are the leaves and roots of plants of the Aristolochia genus and extracts from these plants are still used in traditional folk medicine. In the same plants however, the corresponding nitrophenanthrene carboxylic acids, e.g. aristolochic acid IV (3), are found, which have been identified to cause nephropathy with a high risk for urothelial cancer in humans (aristolochic acid nephropathy, AAN)[2].
Aristolactams, on the other hand, are potent inhibitors of platelet aggregation and show significant cytotoxicity against different tumor cell lines, which renders them interesting synthetic targets.
Figure 1.
A straight-forward synthetic approach, including the lithiation of halogenated N-phosphorylbenzamides, cyclization of the aryne intermediate, Horner olefination of the phosphorylated aminocarbanion and Pd-catalyzed arene-arene coupling as key steps, has been developed by the Couture group [3-5].
We have recently published an alternative photochemical concept [6].
Since a direct oxidative phenanthrene-type ring closure (B → A) appears feasible even in the isoindolinone case, we envisaged the synthesis of arylalkylidene
isoindolinones B with the appropriate E-alkene
configuration (Scheme 1).
Scheme 1.
Consequently the benzylation of symmetric isoindoline-1,3-diones D
with arylacetic acids E and subsequent acid-catalyzed dehydration of
the 3-benzyl-3-hydroxyisoindolin-1-ones C appears as a short and simple approach to the
desired stilbene skeletons. Moreover, a straight-forward access to both B and
C is of general interest due to their biological potential [7].
Figure 2.
Results
In order to establish a combinatorial library of 3-benzyl-3-hydroxyisoindolin-1-ones
3 we examined the photochemistry of different
2-benzylisoindoline-1,3-diones 1 with various mono-
and polysubstituted phenylacetates 2, representative examples are summarized in Table 1.
Scheme 2.
Table 1.
| entry |
R1 |
R2 |
R3 |
R4 |
R5 |
R6 |
R7 |
| Typical yields are in the 90% range. |
| 3a |
H |
H |
H |
H |
H |
H |
H |
| 3b |
H |
H |
H |
H |
H |
OCH3 |
H |
| 3c |
H |
H |
H |
H |
OCH3 |
OCH3 |
H |
| 3d |
H |
H |
H |
H |
OCH3 |
OCH3 |
OCH3 |
| 3e |
H |
H |
OCH3 |
H |
H |
OCH3 |
H |
| 3f |
H |
H |
OCH3 |
H |
OCH3 |
OCH3 |
H |
| 3g |
H |
H |
H |
OCH3 |
H |
H |
H |
| 3h |
H |
H |
H |
H |
OCH3 |
H |
H |
| 3i |
OCH3 |
H |
H |
OCH3 |
H |
H |
H |
| 3j |
OCH3 |
H |
H |
H |
OCH3 |
H |
H |
| 3k |
OCH3 |
H |
H |
H |
OCH3 |
OCH3 |
H |
| 3l |
OCH3 |
H |
H |
H |
OCH3 |
OCH3 |
OCH3 |
| 3m |
H |
OCH3 |
H |
H |
OCH3 |
H |
H |
| 3n |
H |
OCH3 |
H |
OCH3 |
H |
H |
H |
| 3o |
F |
H |
H |
H |
OCH3 |
H |
H |
| 3p |
F |
H |
H |
H |
OCH3 |
OCH3 |
OCH3 |
| 3q |
H |
H |
F |
OCH3 |
H |
H |
H |
| 3r |
H |
H |
F |
H |
OCH3 |
H |
H |
| 3s |
H |
H |
F |
H |
OCH3 |
OCH3 |
H |
| 3t |
H |
H |
F |
H |
OCH3 |
OCH3 |
OCH3 |
General procedure:
A solution of 10 mMol of 2-benzylisoindoline-1,3-dione, 12.5 mMol of arylacetic acid and 6 mMol
of K2CO3 in 400 mL of a acetone/water (3:1) mixture is irradiated at
λ = 300 nm in a Rayonet photoreactor under a gentle stream of nitrogen at room temperature.
The reaction progress is monitored by TLC and pH-control, complete conversion of the phthalimide
is typically achieved after 4-6 h with a final pH of 9-10. Removal of the acetone from the reaction mixture on a
rotary evaporator yields the crude reaction product. Mostly, a white semi-crystalline material is obtained which
is simply filtered off and dried.
Large scale synthesis:
The photoreaction is easily upscaled to the 100 mMol range using the conditions of excimer
irradiation ([8]).
Thus, 20-30 g of crude product are obtained in 4-6 hours of irradiation in a
flow setup with a 308 nm XeCl excimer system (Figure 2) with 3.0 kW electrical power and an
approximate photon flux of 3.5 Einstein h-1.
Discussion
In all cases examined, the photoreactions could be driven to complete conversion of the phthalimide.
The necessary irradiation times however appeared were significantly shorter when using electron-rich
methoxy-substituted phenylacetates. Together with the triplet quenching constants obtained from time-resolved
UV-spectroscopy [9] we propose the following mechanistic scheme:
Electronic excitation of the isoindoline-1,3-diones 1 furnishes their triplet
states with high quantum yield. In the presence of the phenylacetates 2, these reactive
intermediates are efficiently quenched by photoinduced electron transfer (PET), i.e.
the excited 1 serve as strong oxidants (electron acceptors) and are reduced to their
corresponding radical anions (Scheme 3). The phenylacetates, on the other hand, act as electron donors,
i.e. they are oxidized to their corresponding radicals which eventually decarboxylate to
yield benzyl radicals (Scheme 4).
Scheme 3.
Depending on the electron donor capability of the phenylacetate 2, two different
pathways are operative: In the case of the parent phenylacetate (R4 - R7 = H), electron transfer
exclusively occurs from the carboxylate moiety (path I). Consequently, the reactivity resembles that of alkyl carboxylates
previously examined.
Scheme 4.
In (poly-)methoxy-substituted phenylacetates, the increased electron density now renders the oxidation
of the are part favourable. Quenching of the triplet state of 1
via path II, is about 103 faster
than via path I, resulting in reduced reaction times and increased yields.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG, Germany) and the Centre national de la recherche scientifique (CNRS, France) for the generous support of this work in the context of a French-German bilateral research project.
