Synthesis of cyclobutane lignans via an organic single electron oxidant-electron relay system

Article abstract of DOI:10.1039/c3sc50643f

A direct method to synthesize lignan cyclobutanes and analogs via photoinduced electron transfer is presented. A variety of oxygenated alkenes are employed to furnish terminal or substituted cyclobutane adducts with complete regiocontrol, yielding cycload

Full text of DOI:10.1039/c3sc50643f

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Synthesis of cyclobutane lignans via an organic single
electron oxidant–electron relay system†
Cite this: DOI: 10.1039/c3sc50643f
*
Michelle Riener and David A. Nicewicz
A direct method to synthesize lignan cyclobutanes and analogs via photoinduced electron transfer is
presented. A variety of oxygenated alkenes are employed to furnish terminal or substituted cyclobutane
adducts with complete regiocontrol, yielding cycloadducts with trans stereochemistry. Key to minimizing
competing cycloreversion is the inclusion of an aromatic electron relay (ER). This method has been
adapted to the synthesis of the natural products magnosalin and pellucidin A.
Received 7th March 2013
Accepted 11th April 2013
DOI: 10.1039/c3sc50643f
www.rsc.org/chemicalscience
as lead compounds for the development of antifungal, antiviral,
and anticancer drugs.3 Several cyclobutane lignan natural
Introduction
Cyclobutane rings are prominent structural features in a
number of natural products including terpenes, steroids, fatty
acids, as well as the more modest lignan and neolignan
compounds (Scheme 1).1 The chemically and architecturally
diverse lignan family features over two-dozen cyclobutane-con-
taining members, which are comprised of two fused phenyl-
propanoid subunits.2 Many of these cyclobutane lignans and
neolignans have signicant bioactivity and are oen considered
products have notable inhibitory activity toward nitric oxide
synthase (NOS) enzymes,4 as well as potent binding to the
glucocorticoid receptor (GR).5 Despite the biological importance
of this class of compounds, there have been few efforts devoted
to the stereoselective synthesis of cyclobutane lignans and
potentially valuable analogs. Herein, we report a method for the
stereoselective synthesis of C2-symmetric cyclobutane alkene
dimers (eqn (1)) that has been applied to the total syntheses of
the lignans magnosalin,6 endiandrin A,3,7 and the lignan-like
cyclobutane, pellucidin A,8 of which we propose a revised
structure.
Cyclobutane lignan biosynthesis has been proposed to occur
via the homodimerization of the requisite styrene.9 The inter-
molecular head-to-head dimerization of such styrenes has been
attempted via direct photolytic sensitization using ultraviolet
light, however, this method typically results in the exclusive
formation of meso isomers.10 Olen isomerization can also
compete with cycloaddition and the subsequent alkene isomers
can go on to form multiple stereoisomeric products that can
oen make isolation of single isomers challenging.11 We
hypothesized that a single electron transfer (SET) approach12
could provide a biomimetic route to the all trans-cyclobutane
core found in many bioactive lignan natural products.
Seminal work by Ledwith,13 Bauld14 and others15 has
demonstrated that catalytic quantities of single electron
oxidants promote [2 + 2] alkene cycloaddition manifolds.
Lewis11 and others16 have also seen success by implementing
photooxidants activated by ultraviolet light. However, the
Scheme 1 Several examples of bioactive cyclobutane lignan natural products
and derivatives.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC
27599-3290, USA. E-mail: nicewicz@unc.edu; Web: http://www.chem.unc.edu/people/
faculty/nicewicz/
† Electronic supplementary information (ESI) available. CCDC 932605. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3sc50643f
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photooxidants were employed in stoichiometric amounts,11 and
reactions were hampered by three competing pathways: olen
isomerization, back electron transfer, and cycloreversion.17
Furthermore, notable amounts of decomposition and byprod-
ucts were observed when the photooxidant was excited with
ultraviolet light. During the preparation of this manuscript,
Yoon and coworkers reported an alkene heterodimerization
strategy using a ruthenium photooxidant that largely prevents
this competing cycloreversion process.18 By judicious selection
of a photooxidant with an excited state reduction potential that
is higher than the alkene substrate, but is lower than the
subsequent cycloadduct, Yoon was able to successfully realize a
number of alkene [2 + 2] heterodimerizations with starting
alkenes close to the redox potential of anethole. Chiba and co-
workers have also successfully realized the heterodimerization
between unactivated alkenes and 3,4-dihydro-2H-pyran by
electrochemical methods.19 Although a very unique and effec-
tive redox tag mechanism is proposed, reactions required the
unactivated alkene to be present in high excess.
Table 1 Effect of electron relays as an additive in the [2 + 2] dimerization of
anetholea
Entry
Electron relayb
Equivalents
Yield
1
2
3
None
None
0.25
0.25
0.5
0.5
0.25
0.5
0%
13%
16%
18%
54%
0%
Anthracene (+1.21 V)
Naphthalene (+1.61 V)
Naphthalene
Naphthalene
NPh3 (+0.91 V)
Naphthalene
4
5c
6
7d
8e
0%
0%
Naphthalene
0.5
a
Reactions were carried out for 24 h, unless otherwise noted. 1H NMR
b
yields are reported. Peak potentials of electron relay in parenthesis.
c
d
e
Reaction time was 5 days. Reaction in the dark. Reaction in the
absence of p-OMeTPT.
Results and discussion
To access the more variably oxygenated cyclobutane lignans and
derivatives, we sought to develop a method whereby tuning the naphthalene (60 kcal molꢀ1) we propose the polyarenes behave
photooxidation catalyst was not necessary. We proposed that a as an electron-relay, similar to methyl viologen.23 Unfortunately,
single photooxidation catalyst could be used in conjunction long reaction times (5 days) were required for higher levels of
with an arene or polyarene acting as an additive would expand conversion (54% yield, entry 4). If the oxidation potential of the
the cycloaddition substrate scope to include lignan cyclo- additive was vastly lower than the starting material, no cyclo-
butanes. Although the addition of similar reagents have been butane adduct was attained (entry 6). Control experiments
observed as co-sensitizers in the past, we anticipated that conrmed that cyclodimerization was not possible in the
oxidation of the electron relay (ER) by the organic photooxidant absence of light or the p-OMeTPT catalyst.
in its triplet excited state would instead result in the formation
To test the viability of this method, we next turned our
of a cation radical capable of oxidizing the alkene starting attention to additional styrene derivatives. First, we investigated
material. The relay would be required to have a marginally the oxidative dimerization of 2,4-dimethoxy-b-methylstyrene
higher oxidation potential than the alkene substrate of interest (entry 2, Table 2). An additive with a lower oxidation potential
to minimize the unproductive cycloreversion process by inhib- was implemented since the oxidation potential of this styrene is
iting the oxidation of the cycloadduct.20
signicantly lower than anethole. By including anthracene as
In the selection of a single electron photooxidant, we focused the additive, the dimer of 2,4-dimethoxy b-methyl styrene was
our attention on triaryloxopyrylium salts as potential candidates obtained in 46%. Derivatives of anethole bearing an alkene
due to their excitation in the visible region (hy > 400 nm).21,22 The (entry 3) and a protected amine (entry 4) furnished synthetically
use of triaryloxopyrylium salts is also potentially advantageous useful amounts of the cycloadducts (51% and 42% yields,
due to minimization of Coulombic attraction between catalyst respectively).
and substrate aer single electron transfer that ultimately is
Homodimerization of 6-methoxyindene gave the highest
believed to hinder unproductive back-electron transfer. Of the yields in the presence of propylene oxide as the additive (entry
triaryloxopyrylium salts considered, we elected to employ 2,4,6- 5). At this time, we do not have denitive mechanistic data to
tris(4-methoxyphenyl)pyrylium tetrauoroborate ( p-OMeTPT) as determine the role of the propylene oxide, however it is possible
it has an excited state reduction potential signicantly higher that the epoxide forms a Lewis base complex with the cation
than all of the styrenes we planned to investigate that could be radical to prevent polymerization, which is the predominant
attenuated with an appropriate ER.
reactivity observed in its absence.
We rst examined the homodimerization of anethole as a
Curiously, our system did not seem amenable to styrenes
test case for this proposal. Subjecting anethole in acetonitrile to with electron-rich substitution at the meta position, despite the
3 mol% of p-OMeTPT in the presence of 450 nm LEDs afforded presence of another electron rich substituent in the para posi-
only starting material (Table 1, entry 1). However, in the pres- tion (entry 7). It is conceivable that due to the presence of the
ence of electron relays such as anthracene or naphthalene, meta donating substituent, the charge density of the cation
appreciable quantities of the cyclobutane adduct were observed radical is mainly located on the arene ring rather than the
(entries 2–4). Since the triplet energy of the excited photo- alkene, preventing productive reactivity.24 To support this
catalyst (51 kcal molꢀ1
)
is below the triplet energy of notion, a derivative in which the meta substituent possessed an
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electron withdrawing group furnished modest amounts of the
desired cyclodimer (31% yield, entry 8). As the oxidation
potential of this substrate is closest to the photooxidant, it is
plausible that the oxidation potential of the cyclodimer is
higher than the photooxidant. This method was also tolerant of
cyclic enamines such as the Cbz protected 3,4-dihydropyridine,
giving the cycloadduct in good yield (78%, entry 9). It should be
noted that (1) signicantly higher yields of the cyclobutane
adducts were obtained in all cases where electron relays were
employed and (2) the nature of the ER remains unchanged upon
completion of the reaction, and is easily removed during
purication.
Table 2 [2 + 2] Dimerization of aromatic alkenes via photoinduced electron
transfera
Entry Substrate
Electron relay Product
Yieldb,c
0.5 equiv.
naphthalene
54%
(0%)
To extend this method, we next considered the head-to-head
dimerization of terminal styrenes (Table 3). Not surprisingly,
unsubstituted styrenes were extremely susceptible to polymer-
ization when subjected to the previously developed conditions
for b-substituted substrates. In an attempt to inhibit the poly-
merization pathway, we carried out the reactions at cryogenic
temperatures in the presence of an electron relay. Using
anthracene as the electron relay, we were able to obtain the
[2 + 2] cycloadducts of 4-methoxystyrene and 2,4-dimethoxy-
styrene in good yield (83% and 73%, entries 1 and 2). In order to
1
0.25 equiv.
anthracene
46%
(3%)
2
0.5 equiv.
naphthalene
51%
(30%)
3
4
use the more electron-rich 2,4,5-trimethoxystyrene as
a
substrate, diethylaniline (Ep/2 ¼ +0.66 V vs. Ag/AgCl) was
employed to prevent cycloreversion and subsequent polymeri-
zation (entry 3). This furnished a cyclobutane adduct that
matched the spectral data of the natural product pellucidin
0.5 equiv.
naphthalene
42%
(27%)
Table 3 [2 + 2] dimerization of monosubstituted alkenes via photoinduced
electron transfera
3 equiv.
propylene
oxide
72%
(0%)
5d
6e
None
(62%)
Electron
relay
Entry Substrate
1
Product
Yieldb,c
0.25 equiv.
anthracene
0%
(0%)
7
8
0.75 equiv.
anthracene
83% (0%)
0.5 equiv.
anthracene
2
3
73% (0%)
34% (0%)
None
(31%)
15 mol%
diethylaniline
0.25 equiv.
naphthalene
78%
(14%)
9f
a
Reactions carried out in 0.4 M degassed acetonitrile. b Average of two
4d
None
(99%)
c
isolated yields on a 100 mg scale. Parenthetical product yield in
d
absence of electron relay. Reaction carried out at 0 ꢁC in sparged
e
dichloromethane. Reaction carried out at ꢀ10 ꢁC in sparged
dichloromethane. f Reaction carried out at ꢀ10 ꢁC in acetonitrile.
a
b
Reactions carried out in 0.4 M of sparged acetone. Average of two
c
isolated yields of 100 mg scale. Parenthetical product yield in
d
absence of electron relay. Reaction was carried out at 0 ꢁC.
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A. According to Bamya and coworkers, the structure of the head-
to-head dimer was proposed to be the meso isomer.8 To verify
the stereochemistry, X-ray quality crystals were obtained, which
unambiguously revealed the trans geometry of the cyclobutane
substituents. Lastly, the dimerization of N-vinyl carbazole,
which had been previously reported by Bauld, furnished the
desired cycloadduct in a quantitative yield (entry 4).
Most importantly, we were able to utilize this method to
synthesize two lignan cyclobutane natural products. Treatment
of E-asarone to the oxidative reaction conditions in the presence
of 0.5 equiv. of anthracene furnished magnosalin in 50% yield.
This result is in contrast to the direct irradiation (hy > 300 nm)
of E-asarone, where Yamamura observed the formation of the
meso isomer, heterotropan, as the sole adduct in 15% yield.10
Attempts at synthesizing endiandrin A via a [2 + 2] cycloaddition
of meta-oxygenated anethole derivatives were not successful,
presumably for the aforementioned reasons. However, we were
able to further elaborate the anethole cyclobutane dimer 1
(Table 1, entry 1) by a bromination, demethylation and
methoxylation25 sequence to furnish endiandrin A in 59% yield
over 3 steps. This represents the rst synthesis of the bioactive
cyclobutane lignan.
Fig. 1 Cycloreversion was prominent when an additive was excluded (eqn(4))
and circumvented when the additive was employed (eqn(5)).
Fig. 2 Working mechanism for the alkene cyclodimerization reaction.
most likely reduces cyclobutane cation radical 4. In the absence
of the ER, the cycloaddition is reversible, most likely due to
single electron oxidation of the cyclobutane by p-MeOTPT.
Presently, we propose that the ER suppresses cycloreversion by
shielding the cyclobutane products from oxidative degradation
by the oxopyrylium salt.
To probe the role of the ER additive and its effect on cyclo-
reversion, we resubmitted the cyclodimer 2 in entry 2, Table 2 to
the standard conditions. In the absence of the electron relay,
the cyclodimer was recovered in 65% yield and signicant
quantities (11%) of the alkene monomer were observed. The
remainder of the mass balance was attributed to unidentiable
decomposition products. Conversely, when 2 was resubmitted
to the reaction conditions containing 0.5 equiv. of anthracene,
83% of 2 was recovered and only trace amounts of the styrene
monomer were observed. These results suggest that the pres-
ence of anthracene is critical to impeding the cycloreversion
process (Fig. 1).26
Conclusions
We have devised a simple and direct method for the synthesis of
C2-symmetric cyclobutanes including magnosalin, various
lignan analogs, and 1,1 unsubstituted cyclobutane compounds.
By including an electron relay additive, we have offered a
protocol for preventing cycloreversion and polymerization of b-
substituted styrenes and terminal styrenes, respectively. This
method sheds light on a possible biosynthesis of lignans via a
single electron oxidation pathway.
Based on these results, we propose the following mecha-
nistic hypothesis (Fig. 2). Following excitation of the p-OMeTPT,
Acknowledgements
oxidation of the electron relay (ER) provides the active oxidant The project described was supported by The University of North
.
(ER +), which oxidizes the alkene substrate. Aer cycloaddition Carolina at Chapel Hill, generous funding from NIGMS (R01
with another molecule of alkene starting material, the ER or 3 GM098340) and an Eli Lilly New Faculty Award.
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