Results and Discussion
Upon oxidative treatment, phenols can undergo the forma-
tion of polycycles instead of the anticipated ortho–ortho
coupling reaction. The most common structural motif is the
so called Pummererꢁs ketone, which is obtained as a result
of an ortho–para coupling and a subsequent 1,4-addition.[11]
In particular, 2,4-dimethylphenol is prone to the formation
of this architecture. When anodic protocols are applied, the
generation of larger dehydro-oligomers is observed.[6a] De-
rivative 2 seems to be the key intermediate for most of the
pentacyclic architectures found. When using an undivided
cell equipped with platinum electrodes and Ba(OH)2·8H2O
in methanol as electrolyte, 2 can be readily obtained by elec-
trolysis under constant current control. Compound 2 precipi-
tates during the electrolysis and can be isolated in almost
pure fashion by simple filtration (Scheme 1).[6b] This simple
protocol yields up to 24 g of 2 per run (52% yield), provid-
ing significant amounts for subsequent reactivity studies.
The complex central ring of 2 is formed in exclusive stereo-
selectivity. The proposed mechanism suggests the Pummer-
erꢂs ketone derivative as an intermediate in the formation of
2.[6] Since the derivative of Pummererꢂs ketone is obtained
as a mixture of enantiomers, dehydrotetramer 2 is provided
as a racemate. Diastereomer-mediated resolution with enan-
tiomerically enriched auxiliaries seemed to be the best way
to separate the generated diastereomers. In initial studies,
the hydroxyl group of the hemiketal was successfully modi-
fied by silylation or opened up by O-acylation of the phe-
nolic portion.[7] Several resolving agents including (ꢀ)-cam-
phanic acid chloride were found to be unsuitable for resolv-
ing racemic 2.
Therefore, the displacement of the 2,4-dimethylphenoxy
moiety by a removable auxiliary should be a viable route.
We decided to expand the amination reaction of 2 and to in-
troduce aliphatic amines with stereogenic information. To
the best of our knowledge, no similar transformation has
been previously reported. To explore the scope of this reac-
tion, compound 2 was initially treated with pyrrolidine and
CsF as fluoride source in acetonitrile heated to reflux,
whereby the expected tertiary amine 3a was obtained in
63% yield (Scheme 3). X-ray diffraction experiments of
suitable single crystals confirmed the anticipated structure.
Remarkably, in the solid state 3a is obtained in the ring-
opened cyclohexenone form. One reason for this observa-
tion is the formation of hydrogen bonding between the basic
pyrrolidine nitrogen (protonated moiety: pKa 10.46[12a]) and
the neighbouring hydroxyl hydrogen of the weak acid
Scheme 2. Formation of carbocation 2a and its reaction pathways, leading
to nucleophilic substitution (3) and semipinacol-type rearrangement
product 4.
equipped with four contiguous stereocentres. Treatment
with Lewis or Brønsted acids cleaves the 2,4-dimethylphe-
noxy moiety, generating the tertiary carbocation 2a. This in-
termediate opens up the possibility to introduce molecular
variation into the scaffold by simply switching the reaction
conditions (Scheme 2). In general, the central scaffold can
be conserved at low temperatures and the generated carbo-
cation 2a can be used for the selective conversion with nu-
cleophiles.[7,8] Raising the temperature changes the reactivi-
ty, and skeletal rearrangement (as typically expected for car-
bocations) becomes dominant. This pathway yields complex
architectures such as spirocycle 4 in a highly selective
manner.[7]
The molecular structure of 2 seems to be a promising plat-
form for the synthesis of natural product analogues.[7]
Hence, its modification might open an easy access to novel
pharmacologically active structures. For instance, spiropen-
tacycle 4 contains a central cyclopenta[b]benzofuran moiety,
which has been regarded as the biologically active compo-
nent in natural products of the rocaglamide family.[9] In pre-
vious studies, the stereospecific substitution of one phenoxy
fragment by an amino group was achieved. This amination
reaction was found upon treatment of 2 with NH4F in aceto-
nitrile at 808C.[7] An intramolecular hydrogen-bonding be-
tween the hydroxy group of the hemiketal (donor) and the
phenol ether moiety (acceptor) of 2 might decrease the
LUMO energy level of the latter,[10a] activating it towards
nucleophilic substitution (Figure 1). Their arrangement at
the same side of the central cyclohexene ring forms an ideal
docking site for incoming nucleophiles. On the other hand,
one methyl group at the cyclohexene points to the other
side of the molecule and leads to 1,3-diaxial repulsions.
Both effects are responsible for the high diastereoselectivity
in nucleophilic substitution reactions (Figure 1).[7,8] When no
good nucleophiles enter the reaction scene, several rear-
rangements of the backbone have been observed resulting
in complex molecular architectures.[7] Herein, we present
the nucleophilic substitution of the 2,4-dimethylphenoxy
moiety using optically pure a-chiral aliphatic or benzylic
amines and subsequent resolution of the diastereomeric spe-
cies.
Scheme 3. Formation of amino derivative 3a and its rearrangement to
spiropentacycle 4.
14786
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Chem. Eur. J. 2011, 17, 14785 – 14791