Cyclooctatrienes from pyran-2-ones via a tandem [4 + 4]-photocycloaddition/ decarboxylation process

Article abstract of DOI:10.1039/b806871b

Irradiation of pyran-2-ones bearing pendent furans in aqueous MeOH followed by heating furnished fused bicyclic products containing a cyclooctatriene ring. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806871b

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Cyclooctatrienes from pyran-2-ones via a tandem
[4 + 4]-photocycloaddition/decarboxylation processw
Lei Li,a Charles E. Chaseb and F. G. West*a
Received (in College Park, MD, USA) 23rd April 2008, Accepted 2nd June 2008
First published as an Advance Article on the web 18th July 2008
DOI: 10.1039/b806871b
Irradiation of pyran-2-ones bearing pendent furans in aqueous
MeOH followed by heating furnished fused bicyclic products
containing a cyclooctatriene ring.
Appearance of the cyclooctane ring in natural products is
surprisingly frequent, given the challenges connected with its
direct formation from acyclic precursors in the flask.1 There has
been considerable activity focused on the development of
efficient and general methods for the construction of cyclo-
octanes, especially within a larger polycyclic skeleton.2,3 Among
these, strategies that form the ring through a cycloaddition
process are especially attractive, as they allow retrosynthetic
disconnection of two cyclooctane bonds and a corresponding
simplification to two smaller precursor fragments.4 In a fasci-
nating example of such a higher-order cycloaddition, 4,6-di-
methylpyran-2-one was shown by de Mayo et al. to undergo a
photochemical dimerization to furnish diastereomeric
cyclooctadienes with two lactone bridges (Scheme 1).5
Pyrolysis effected double decarboxylation by retrograde [4 + 2]-
cycloaddition to give tetramethylcyclooctatetraene.
More recently, we have shown that crossed intramolecular
[4 + 4]-photocycloadditions can be achieved using readily
accessible pyran-2-ones with pendent furan traps, providing
cyclooctadienes 2 or 3 with bridging ether and lactone.6 While
Scheme 1 Decarboxylation of pyran-2-one [4 + 4]-photocyclo-
adducts.
these reactions furnish cyclooctadienes in good yield, their
suitability for the construction of cyclooctanoid natural pro-
ducts depends upon the availability of convenient methods for
opening the lactone and ether bridges of the [4 + 4]-adducts.
Reductive opening of the lactone is possible, and this
approach is being applied in the synthesis of diterpenes of
the fusicoccin class.7 An alternative method for lactone re-
moval would utilize the decarboxylation process described by
de Mayo. Importantly, such a strategy potentially would
provide a single triene product 4 regardless of the ratio of
diastereomeric cycloadducts 2 and 3. Here we describe a
convenient, one-pot route to cyclooctatrienes via a tandem
photocycloaddition/decarboxylation process.
Decarboxylation in tandem with Diels–Alder cycloaddition
reactions of pyran-2-ones is often seen at the elevated
temperatures typically required for these processes,8 and de-
carboxylation of pyran-2-one/furan [4 + 4]-cycloadducts was
previously noted as a minor side reaction occuring in photo-
cycloadditions conducted without adequate cooling.6b With
this in mind, we examined the heat induced decarboxylation
of the previously described6b cyclooctadienes 2a and 3a
(Scheme 2). Initial pilot-scale experiments were carried out in
toluene. Exo cycloadduct 2a underwent slow decarboxylation
to give traces of 4a after extended heating at 80 1C, but
underwent quantitative conversion to 4a after 6 h at reflux.
To our surprise, endo cycloadduct 3a was inert to these
conditions, returning only starting material. Decarboxylation
of 2a in MeOH at 55 1C was complete after 3 h, while 3a
remained unconsumed after 24 h under these conditions.
Finally aqueous MeOH (40% v/v), the solvent system most
commonly employed for the photocycloaddition reactions, was
examined. Cycloadduct 2a was cleanly decarboxylated after 3 h
at 40 1C. While 3a was unreactive at this temperature, heating
a Department of Chemistry, University of Alberta, E3-43 Gunning-
Lemieux Chemistry Centre, Edmonton, AB, Canada T6G 2G2.
E-mail: frederick.west@ualberta.ca; Fax: +1 780-492-8231;
Tel: +1 780-492-8187
b Department of Chemistry, University of Utah, 315 S. 1400 East,
Rm. 2020, Salt Lake City, UT, 84112-0850, Current address: Eisai
Research Institute, 4 Corporate Drive, Andover, MA 01810, USA
w Electronic supplementary information (ESI) available: Representa-
tive experimental procedures and spectral data for photosubstrates
and cyclooctatrienes 4. CCDC 690017. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b806871b
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Table 1 Tandem photocycloaddition/decarboxylationa
Crude Yield
2:3
Sub-
4
Entry strate R1
R2
R3
R4
R5
ratiob (%)c
1
2
3
4
1a
1b
1c
1d
H
H
H
H
Me
Et
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
1.6 : 1 60d
2.7 : 1 62d
1.4 : 1 39d
Not
det.
13e
5
6
7
8
9
10
1e
1f
1g
1h
1i
Me
Me
Et
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
Me
H
3.1 : 1 60d
3.0 : 1 63d
1.4 : 1 63d
1.1 : 1 53d
1.48 : 1f 44g
Scheme 2 Thermal behavior of exo adduct 2a and endo adduct 3a.
–(CH2)3–
Me
H
H
H
at 55 1C for 5 h effected partial conversion to 4a. Complete
decarboxylation of 3a could be accomplished by microwave
heating at 120 1C (Biotage Initiator) for 1 h.
Me Me
Me
1j
H
H
Not
det.
48g
a
Since decarboxylation could be effected in aqueous MeOH,
we decided to examine the feasibility of a one-pot process
entailing initial irradiation of pyran-2-ones, followed immedi-
ately by thermal decarboxylation of the photolysate. Substrate
1a was irradiated under the standard conditions, then heated
at 55 1C for 14 h, to furnish 4a in 60% yield over two steps,
along with 6% recovered 3a (eqn (1)).
General procedure: Substrates were dissolved in ca. 40% (v/v) aq
MeOH (1 mg mLꢁ1) in a round bottom flask cooled in an ice-water
bath, and irradiated under Ar using a Hannovia 450 W medium-
pressure Hg vapor lamp. After 2 h, the reaction mixture was placed in
an oil bath and heated at 55 1C for 14 h. Aqueous work-up yielded
product as a crude oil, which was purified by flash chromatography.
b
Ratios were obtained by integration of alkene hydrogen resonances
in 1H NMR spectra of reaction mixture following irradiation at 0 1C.
Trace amounts of [2 + 2]-photoadducts were seen in the crude
mixtures from entries 1, 2, 5, 6 and 9, but were not present in
c
detectable quantities following thermolysis. Yields given are for
d
isolated product after chromatographic purification. Varying
amounts of unconsumed endo adduct 3 were isolated along with 4:
3a (6%), 3b (11%), 3c (12%), 3e (10%), 3f (8%), 3g (14%) and 3h
e
f
(8%). Thermolysis was carried out at 90 1C for 14 h. The major exo
isomer was formed in a 2 : 1 ratio of methyl epimers (2i and 2i0), while
ð1Þ
g
the endo isomer was obtained as a single diastereomer (3i). Decar-
To test the generality of this process, we then prepared
several additional pyran-2-one substratesz and subjected them
to the irradiation/thermolysis sequence used with 1a to furnish
cyclooctatrienes 4b–h (Table 1). Analysis of the crude reaction
mixture prior to thermolysis indicated preferential formation
of the exo cycloadduct in all but one case, in accord with
earlier observations. A general trend towards higher exo : endo
ratios was seen for examples with greater substitution on the
pyranone ring (entries 2, 5 and 6), while the presence of a C-5
methyl group on the furan ring had the opposite effect. For the
most part, the one-pot process occurred in good overall yield,
with the exception of the 6-phenyl substrate 1c and unsub-
stituted case 1d (entries 3 and 4), both of which underwent
photocycloaddition and thermolytic loss of CO2 only slug-
gishly. Notably, additional substitution on the pyran-2-one
ring (entries 5–7) did not affect the overall efficiency of this
two-step process, and additional substitution on the furan led
to only minor diminution in the overall yield (entry 8). In most
cases, significant quantities of unreacted endo cycloadduct
were isolated along with 4, a result of its slower decarboxy-
lation. However, extended heating to consume unreacted 3
was not desirable, due to slow decomposition of 4 under these
conditions. In several cases, microwave heating at 120–130 1C
for 1 h could effect complete consumption of 3; however,
boxylation product 4i was obtained as a 4.5 : 1 mixture of diaster-
eomers, and was accompanied by 20% of 3i. Decarboxylation product
4j was obtained as a 1 : 1 mixture of diastereomers, and was
accompanied by 12% of 3j.
because of the large solvent volumes required (typical con-
centration = 1 mg mLꢁ1) and the apparent sensitivity of 4 to
these conditions, simple heating at lower temperature was
found preferable.
Two examples with stereogenic centers in the tether were
examined (entries 9 and 10). The overall yield of the resulting
trienes 4i and 4j was somewhat decreased in these cases,
although both were accompanied by significant quantities of
unreacted 3 (20% of 3i and 12% of 3j). Notably, while the
presence of a methyl group adjacent to the furan had little
apparent effect on the stereochemical outcome (entry 10),
branching next to the pyranone ring led to a 4.5 : 1 ratio of
trienes 4i (entry 9). Moreover, endo isomer 3i was obtained as
a single diastereomer.y The origins of this promising diaster-
eoselectivity are under investigation.
These results establish the generality of the one-pot conver-
sion of pyran-2-ones to cyclooctatrienes, but the effect of
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methods using methyl-substituted allylic acetates. See ref. 6b and ESIw
for details.
y The single isomer of 3i that was isolated was a crystalline solid whose
X-ray diffraction analysis established its relative stereochemistry to be
syn (see below). Upon heating, 3i underwent decarboxylation to give
the major diastereomer of triene 4i. The 4.5 : 1 ratio of 4i diastereomers
is higher than expected based upon the initial mixture of [4 + 4]-
adducts following irradiation. This discrepancy may reflect selective
decomposition of the minor diastereomer of 4i during chromatographic
purification. (See ESIw for additional discussion of structural determi-
nation.)
Fig. 1 Minimized structures of exo adduct 2a and endo adduct 3a.
substitution, solvent and relative stereochemical configuration
on the efficiency of the decarboxylation step merit further
discussion. While additional substitution had little or no
negative effect on the overall yield of the two-step process,
the unsubstituted example 1d provided only minor amounts of
cyclooctatriene 4d, and required extended heating at higher
temperature. This, together with the increased rate of decar-
boxylation in polar solvents, suggests that the decarboxylation
transition state may possess significant polar character.
Importantly, enhanced rates of decarboxylation of pyran-2-
one/maleimide [4 + 2]-adducts in protic solvent vs. nonpolar
or polar aprotic solvents has been noted,9 and decarboxylation
of b-lactones often displays a marked dependence on solvent
polarity.10 The differing reactivity of endo and exo cycload-
ducts is more puzzling. In several cases that were examined in
detail, the endo cycloadduct was found to undergo loss of CO2
at a substantially lower rate than its exo isomer, and only endo
cycloadduct was isolated in those cases where unreacted
cycloadduct was recovered from the one-pot protocol. Mole-
cular modeling of 2a and 3a does not suggest a significant
difference in ground-state energy (Fig. 1);z however, it is
possible that the decarboxylation activation barrier for the
exo cycloadduct may be reduced through neighboring
group assistance by the adjacent ether bridge in a polar
decarboxylation.
z Molecular mechanics calculations used the MMFFaq force field
running in Spartan ’06. Energies of 2a and 3a were calculated to be
within 1 kcal molꢁ1 with or without correction for aqueous solvent.
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A concise and convenient method to access bicyclo[6.3.0]un-
decatrienes from simple heterocyclic precursors is described. A
tandem photocycloaddition/decarboxylation sequence can be
carried out in one pot using aqueous MeOH as solvent. The
triene products are expected to be amenable to a variety of
productive modification processes. Further studies, including
efforts to understand the stereospecific rates of thermal de-
carboxylation by endo and exo cycloadducts, are underway
and will be reported in due course.
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Notes and references
z Substrates 1b–h were prepared via palladium(0)-mediated allylation
of
Branched tether substrates 1i and 1j were prepared by analogous
4-hydroxypyran-2-ones
with
3-acetoxy-1-(2-furyl)propene.
Cossıo, J. Am. Chem. Soc., 1997, 119, 816.
´
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