Angewandte
Chemie
the initially formed cyclopentenones 2k and 2n are the most
thermodynamically stable products (trisubstituted double
bond), and, are therefore, those that were always isolated
(no rearrangement 2!3 occurs). Another interesting obser-
vation is that the major diastereoisomer for products 2a, 2b,
and 2d was the cis-isomer, whereas in all the other cases (2c,
2e–g, and 2n) the trans-isomer was favored. Probably, the
trans-isomer is the preferred product of the intramolecular
aldol reaction; but, in the case where the products are easily
enolizable (R2 = CO2R), it rapidly epimerizes to afford the
more stable cis-analogue. As proof of the efficiency of the
new method, it was applied to the high yielding (72%) one-
step synthesis of the natural product, untenone A (2b),[13]
from furan-containing natural product, plakorsin A (1b, itself
made in just four steps).
Singlet oxygen is an ideal reagent for many reasons; one
of the most important is because it fits very well into the
modern paradigm which targets greater sustainability in
chemistry.[8a,c] Not only is this profile due to its intrinsic
characteristics (atom economy, selectivity etc.), but it arises
from the conditions under which it can be employed (for
example, green solvents, natural sensitizers). We, therefore,
next sought to improve the environmental credentials of the
method by testing whether parts of this transformation could
be undertaken in water. Initially, the same protocol was
applied, except the reductant (Me2S) and the appropriate
base (Et3N or NaOH) were added in water instead of MeOH
affording the desired 4-hydroxy-2-cyclopentenones (3c, 3h,
3j, and 3o–q, Scheme 4).[9] Using mild basic conditions
(Et3N), cyclopentenones 3c and 3p were afforded as the
sole products of the reaction because activation (benzyl or
dimethylallyl group at the 2-position of the starting furan)
promoted the intramolecular aldol reaction. The desired
product 3j was also isolated without the formation of any
other product. This behavior is similar to that observed in the
case of 5j and is attributable to activation by the enol form of
the pendant methyl ketone. In the cases of substrates 1h and
1o, using lower NaOH concentrations (0.1m), led to a mixture
of thermodynamic (3) and kinetic products arising from the
regioisomeric aldol condensation of the intermediate ene-
dione followed by rearrangement (6, never produced as the
1
sole product, Scheme 4), as determined by H NMR spec-
troscopy. An increase in the final concentration of NaOH to
0.2m results to the exclusive formation of 3h and 3o. In terms
of applications for this method, it should be noted that
allethrolone (3o),[4g,14] a useful pyrethrin insecticide,[15] has
now been synthesized in one step starting from the very
simple furan 1o.
Looking to further simplify the protocol, we next sought
to study the consequences of removing the reducing agent.
Scheme 5, with its summary of the conversions of substrate 4a
(produced by photooxidation of 1a) under different con-
ditions, reinforces the flexibility of the method and its
Scheme 5. Conversions of intermediate 4a.
potentially diverse applications. Although scaffold 7 is
common in natural products,[16] the result that attracted our
attention was the formation of cyclopentenone 2a in water
and in the absence of a reducing agent. Intriguingly, the same
reaction done in water, but with Me2S, had furnished
the isomerized analogue of cis-enedione
C
(Scheme 2), trans-enedione 8. To understand the
transformation of 4a into 2a mechanistically, the
reaction was monitored by 1H NMR spectroscopy.
This experiment revealed the unexpected formation
of a never previously observed intermediate, endo-
peroxy-bis-hemiketal[17]
9
(Scheme 6), which,
although not very stable, could, with care, be isolated.
This led us to propose the mechanism shown in
Scheme 6 wherein the hydroperoxy intermediate 4 is
hydrolyzed by p-toluenesulfonic acid (PTSA), in
water, to hemiketal D, which then ring expands to
afford endoperoxy-bis-hemiketal 9 via the interme-
diacy of E. Intermediate 9 could then collapse
(induced by heat, or base) to furnish enedione A
(via E), which, in turn, would yield the desired
cyclopentenone 2 or 3 after cyclization. On the basis
of this result, a variety of substituted furans were
successfully subjected to this simplified protocol and
the results are shown in Scheme 7 (conditions A).
Thus, cyclopentenones 2a and 2d were produced by
treating their respective intermediates of type 4 with
catalytic PTSA in H2O followed by addition of small
Scheme 4. Synthesis of 4-hydroxy-2-cyclopentenones in water. The final concen-
tration of the base is reported. Lower yield for 3q due to its high solubility in
water.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!
Kalaitzakis, Dimitris
