Division of Organic Chemistry (Synthesis)
National Chemical Laboratory
Pune - 411 008, India
Fax: +91-212-335153
Abstract
Members of the plant family Berberidaceae are known to contain a new
class of isoindolobenzazocine alkaloid magallanesine, isolated from Berberis
darwinii. The unique framework of isoindolobenzazocine (I) contains the medium
ring nitrogen heterocycle which is generally most difficult to prepare by
conventional cyclization methods. As an extension of our research program in
the synthetic utilization of photinduced electron transfer (PET) generated
arene radical cation (II), to assess the feasibility of preparing carbocyclic
and spiro-cyclic compounds, we report herein a straightforward method for the construction of benzazocine skeleton.
Considering the importance of carbocyclization reaction in the synthesis of
biologically active natural products, our attention was drawn towards the
possible utilization of intramolecular nucleophilic substitution of aromatic
rings with efficient nucleophiles.
Many nucleophilic photosubstitution reactions involve the intermediacy
of a radical cation particularly with easily oxidized substrates such as alkoxy
aromatic or aryl ethers, the solvent or some additive acting as electron
acceptor. The aromatic radical ions are relatively stable under favourable
conditions but they are short lived when created by photochemical electron
transfer since back electron transfer to the closely lying radical ion of
opposite sign is highly effective. Hence a low quantum yield is usually
measured for these reactions.The stabilization of aromatic radical or ion is
assured by resonance with the aromatic ring and is sufficiently stabilized,
this process is competitive with back electron transfer and other chemical
processes.
Investigations from our group have provided novel applications of the
sensitised PET generated arene radical cations from methoxy substituted
aromatic compounds for preparing variety of oxygen, nitrogen and carbocyclic
aromatic compounds by intramolecular nucleophilic cyclisation reactions. For
illustration, coumarins are synthesised (70-90%) directly from the PET
cyclisations of corresponding cinnamic acids. The ground state of DCN is used as an
electron acceptor in these transformations. The occurence of this photoreaction
is complete in a sensitised manner. Several observations, such as diffusion
controlled fluorescence quenching of cinnamic acids with DCN and exergonic
values for the free energy change (dGet) suggests the ET pathways for this
reaction. The regiospecificity of the cyclisation mode is in accord with the
calculated electron densities (Huckel or MNDO) at different carbons of the HOMO
of the arene radical cation. Precocenes-I, a potent antijuvenile hormone
compound and their various analogues, 2-alkylated dihydrobenzofurans, believed
to possess antifungal and phytoalexin properties, are also prepared using this
methodology.
The success of the strategy is further exemplified by the synthesis of
carbo- and spiro-annulated aromatic compounds by the intramolecular cyclisation
of silyl enol ethers to PET generated arene radical cations. Two different
types of carbocyclic compounds, varying in ring sizes, may be synthesised
starting from the same ketone, as two different types of silyl enol ethers can be produced using either thermodynamic or kinetic enolisation
procedures.
The spirocyclic compound structurally related to antitumour antibiotic
fredericamycin - A, islated from Streptomyces griseus, bearing a unique
spiro[4.4]nonane centre, is also prepared using this strategy as key step.
The synthetic utility of these cyclisations is further utilized in the
construction of benzazocine skeleton. A variety of benzazocines exhibit
analgesic and anti-inflammatory activities. These benzazocine ring system are
generally very difficult to prepare by the use of conventional cyclization
methods. Our work demonstrate a short route to this framework using PET induced
photocyclization reaction as the key step.
Experimental section
A typical photochemical reaction procedure consists of the irradiation of a
mixture of silyl enol ehters (2 mmol) and DCN 0.06 g (0.34 mmol) in 500 ml of
CH3CN:H2O (4:1) for 4-5 h through Pyrex
filtered light (> 280 nm, all light
absorbed by enol ether only) using 450 W Hanovia lamp without removing the
dissolved oxygen. Excess irradiation time should be avoided to control side
reactions leading to secondary products. The progress of the reaction is
monitored by TLC and GC. The irradiation is discontinued immediately after the
complete consumption of starting silyl enol ether. Removal of solvent and
chromatographic purification of the photolysis mixture gave desired cyclized
product in 52% yield, characterized by IR, 1H, 13C NMR and mass spectral data.
DCN was recovered quantitatively (98%) at the end of the reaction. During the
irradiation of silyl enol ethers, small amount (~ 10%) of precursor
starting aldehyde also formed which has been shown to be formed by the thermal
reversion of the silyl enol ethers by adequate control experiments.
The starting silyl enol ether was prepared as depicted in the following scheme,
using known procedures under standard conditions.
References
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Pandey G, Supramol. Photochem., 1996, in press
ed. V. Ramamurthy.
Acknowledgement
M.K. thanks the CSIR, New Delhi for the award of a Senior Research
Fellowship, and Director NCL, Dr Krishnan SMIS (NCL) for
constant help and encouragement.
