Direct and Metal-Catalyzed Photochemical Dimerization of the Phthalide (Z)-Ligustilide Leading to Both [2 + 2] and [4 + 2] Cycloadducts: Application to Total Syntheses of Tokinolides A-C and Riligustilide

Article abstract of DOI:10.1021/acs.orglett.9b02172

Synthetically derived (Z)-ligustilide (1) has been subjected to photochemically-promoted dimerization processes under a range of conditions. By such means, varying distributions of the dimeric natural products tokinolides A-C (4, 3, and 6, respectively) and riligustilide (5) as well certain related (isomeric) compounds have been obtained. The structures of three of them have been confirmed by single-crystal X-ray analysis. The biosynthetic implications of the outcomes of this study are discussed.

Full text of DOI:10.1021/acs.orglett.9b02172

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct and Metal-Catalyzed Photochemical Dimerization of the
Phthalide (Z)-Ligustilide Leading to Both [2 + 2] and [4 + 2]
Cycloadducts: Application to Total Syntheses of Tokinolides A−C
and Riligustilide
Bingbing Sheng,† Yen Vo,‡ Ping Lan,† Michael G. Gardiner,‡ Martin G. Banwell,*,†,‡
and Pinghua Sun*,†
†Institute for Advanced and Applied Chemical Synthesis, Jinan University, Zhuhai, 519070, China
‡Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: Synthetically derived (Z)-ligustilide (1) has been subjected to photochemically-promoted dimerization processes
under a range of conditions. By such means, varying distributions of the dimeric natural products tokinolides A−C (4, 3, and 6,
respectively) and riligustilide (5) as well certain related (isomeric) compounds have been obtained. The structures of three of
them have been confirmed by single-crystal X-ray analysis. The biosynthetic implications of the outcomes of this study are
discussed.
(3), tokinolide A (4), riligustilide (5), and tokinolide C (6).3
he phthalide (Z)-lugustilide (1) (Figure 1) is a
Tprominent constituent in a range of plants, perhaps
Compound 1 is often accompanied by one or more of a
range of its possible [2 + 2]- and/or [4 + 2]-dimers2 including,
for example, levistolide A (2, a.k.a. diligustilide), tokinolide B
Normally these dimers are isolated in racemic form and so
most notably Angelica sinensis (Danggui) which is exploited
extensively in traditional Chinese medicine (TCM).1
suggesting they are derived, in vivo, from monomer 1 by
nonenzymatic processes. Natural products such as 1−5 are also
encountered in the traditional medicines based upon several
genera of the plant family Apiaceae (Umbelliferae) and used in
Native American cultures.3b,4 Many of the phthalide-based
components of such medicines have been subject to biological
evaluation and so revealing they can exert a plethora of
significant activities. So, for example, the parent compound 1
displays, inter alia, antioxidant, antispasmodic, antiasthmatic,
antiviral, analgesic, antimicrobial, insecticidal, phytotoxic, and
vasodilatory effects as well having neurologically beneficial
impacts.1,3−5
Dimers 2−5 and their various congeners exert a similarly
broad range of activities and have also been shown to act as
antioxidants and reduce blood viscosity. They also display
progestogenic and cytotoxic effects.1,3−6 Two naturally
occurring trimeric forms of 1 have also been reported7
recently and these, too, were obtained in racemic form.
Preliminary biological evaluation of them revealed that they
possess dose-dependent anti-inflammatory properties but do
not exert any notable cytotoxic or antimicrobial effects.7
Figure 1. Structure of (Z)-lugustilide (1) and its dimeric
cometabolites 2−6.
Received: June 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Given the significant therapeutic potential of compounds
such as 2−5 and their likely biogenesis, both the thermally and
photochemically-promoted dimerization reactions of (Z)-
lugustilide (1) have been studied, albeit in a cursory fashion.
So, for example, heating a solution of compound 1 in benzene
at 80 °C provided a mixture of the Diels−Alder dimers 2 and 3
in 2% and 3% yields, respectively.8 The former adduct can be
obtained in 22% yield by heating the neat monomer 1 in a
sealed tube at 160 °C.9 Furthermore, it was shown8 that on
heating adduct 3 at 200 °C this is converted into isomer 2, a
process that presumably involves a cycloreversion/readdition
process operating under thermodynamic control. In attempts
to promote such Diels−Alder reactions, substrate 1 was treated
with a range of Lewis acids but only linear dimers resulting
from intermolecular Michael addition reactions were ob-
served.10 There has been just one study of the photolysis of
compound 1 and this involved irradiating an acetone solution
of it with a low-pressure mercury lamp under nitrogen at near
ambient temperatures.11 Under such (presumably triplet
sensitized) conditions a mixture of four products was obtained,
one of which was shown to be riligustilide 5 (7%) and the
other three being described as “novel” (but see below) and
symmetrical [2 + 2] photodimers that were obtained in 18.5%,
11%, and 7.5% yields. The structure of one of these was
established by single-crystal X-ray analysis.11
to air as a solution in a range of solvents) to its fully aromatic,
previously reported,14 and naturally-occurring counterpart 11.
In commencing our studies of the photochemical behaviors
of (Z)-lugustilide (1) (Table 1), we first exposed a ca. 0.13 M
toluene solution of this compound in a sealed quartz cuvette to
Australian summertime sunlight for 10 h (entry 1, Table 1) but
only observed extensive decomposition.
When a 0.13 M acetone solution of the substrate was
irradiated with a 500 W halogen lamp in a vessel open to the
air for 72 h (entry 2), a complex mixture of products was again
formed but now small amounts (<5%) of the monoepoxides
12 and 13 (Figure 2) could be isolated from the product
mixture by flash chromatography. The former product, viz. 12,
has been obtained previously14,15 from natural extracts that
may also contain substrate 1 while the isomeric system 13 does
not appear to have been reported before. In an effort to
suppress decomposition pathways, a deoxygenated toluene
solution of substrate 1 containing rose bengal was cooled to
−78 °C and then irradiated with the halogen lamp (entry 3),
but, once again, only complex mixtures of products were
observed.
In contrast, under the same conditions but now without
sensitizer (entry 4), a mixture of eight photoproducts was
obtained and these could be isolated as discrete compounds
using a combination of flash chromatographic and reversed-
phase HPLC techniques. Five of these were identified, through
comparison with published spectroscopic data, as the natural
products tokinolide B (3)8,16 (2%), tokinolide A (4)6d (2%),
riligustilide 5 (2%),6a,7,17 tokinolide C (6)6d (2%), and exo-
Z,Z-3.3′,8.8′-diligustilide (14)11,18−20 (7%) (Figures 1 and 3).
The structures of compounds 5 and 14 were confirmed by
single-crystal X-ray analysis (see Supporting Information (SI)
for details). Of the remaining three compounds, one proved to
be, as established by single-crystal X-ray analysis, the exo-
isomer of riligustilide, namely compound 15 (2%). The other
two, which were the chromatographically most mobile ones,
must be (based on the nature of the olefinic proton resonances
observed in the derived 1H NMR spectra) dimers linked
through the Δ3,8- and Δ3a,7a-bonds of two separate (Z)-
lugustilide (1) subunits. Since the two possible head-to-head
forms of such dimers have been found to occur naturally (as
tokiaerialide21 and neodiligustilde22) and for which the 13C
NMR data do not match, we conclude these photoproducts are
the corresponding head-to-tail adducts 16 and 17 (each
obtained in <1% yield).
The advent of new techniques for effecting photo-
cycloaddition reactions of olefins12 prompted us to consider
applying some of these to substrate 1 in an effort to establish
how they might influence the distribution of product dimers
and higher order oligomers. In order to do so, we required
access to compound 1 and obtained this from the parent
phthalide (7) using the route reported by Stermitz (Scheme
1).13 Thus, the enolate derived from compound 7 was trapped
Scheme 1. Synthesis of (Z)-Lugustilide (1) from Phthalide
(7)
A significantly cleaner dimerization process was observed
12d
when 5 mol % Ir(ppy)3 was added to the reaction mixture
and irradiation was sustained for just 48 h (entry 5). Dimer 14
was now produced in 55% yield with the remaining three, viz.
3, 5, and 15, each being obtained in 5% yield. Using an iridium
catalyst incorporating fluorinated ligands, viz. Ir[dF(F)ppy]2-
(dtbbpy)PF6,23 led (entry 6) to slightly better outcomes in
terms of the yields of these same products, but now a new and
chromatographically less mobile one was also obtained in 15%
yield. This must be (based on the nature of the olefinic proton
with butanal and the mixture of aldol-type products 8 (98%)
so-formed was subjected to a dissolving-metal reduction using
sodium in liquid ammonia/isopropanol and thereby affording
the dihydro-aromatic 9 (60%). Mesylation of the hydroxyl
group within this last compound was achieved under standard
conditions and heating the resulting ester 10 in refluxing
pyridine afforded the target monomer 1 in 55% yield (from 9).
All the spectral data recorded on the latter material matched
1
resonances observed in the derived H NMR spectrum) a
dimer linked through the Δ3,8- and Δ6,7-bonds of two separate
(Z)-lugustilide (1) subunits and a head-to-tail analogue of
compounds 5 and 15 and thus represented by either structure
18 or 19 (Figure 4). Unfortunately, the unstable nature of this
crystalline product prevented the acquisition of spectroscopic
data that would allow a distinction to be made between these
two possibilities.
those reported previously for the natural product,11
a
compound that we found was readily oxidized (when exposed
B
DOI: 10.1021/acs.orglett.9b02172
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Organic Letters
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Table 1. Outcomes of the Photochemical Reactions of Compound 1 under a Range of Different Conditions
a
e
entry
light source
solvent, catalyst
temp, time
products (%)
f
1
2
3
4
5
6
7
8
9
sunlight
halogen
halogen
halogen
halogen
halogen
halogen
330 nm LED
toluene, none
acetone, none
amb., 10 h
decomposition
12 (<5%), 13 (<5%)
complex mixture
e
amb., 72 h
b
toluene, rose bengal
−78 °C, 72 h
b
toluene, none
−78 °C, 72 h 3, 4, 5, and 6 (2% each), 14 (7%), 15 (2%), 16 and 17 (<1% each)
b
toluene, Ir(ppy)3
−78 °C, 48 h
−78 °C, 36 h
5 °C, 48 h
3 and 5 (5% each), 14 (55%), 15 (5%)
3 and 5 (9% each) 14 (58%), 15 (9%) 18 or 19 (15%)
3 and 5 (6% each), 14 (63%), 15 (6%), 18 or 19 (11%)
3 and 5 (8% each), 14 (70%), 15 (8%), 18 or 19 (5%)
3 (5%), 14 (46%), 21/22 (4%)
b
c
toluene, F−Ir(ppy)3
b
d
CH2Cl2, aromatic ketone
b
e
MeCN, Ir(ppy)3, i-PrNEt2, LiBF4
amb., 36 h
b
e
390 nm (“blue”) LED MeCN, Ru(bpy)Cl2, i-PrNEt2, LiBF4
amb., 4 h
a
In every instance a 0.13 M solution of substrate 1 was used and this was normally contained in a Pyrex vessel with either a ca. 0.4 or 2 mm thick
b
c
d
wall. This reaction was conducted under nitrogen. F−Ir(ppy)3 = Ir[dF(F)ppy]2 (dtbbpy)PF6 where ppy = 2-phenylpyridinyl. Acetophenone,
benzophenone or 2-acetylnaphthalene. temp = temperature. amb. = ambient.
e
f
obtained but now in essentially quantitative combined yield.
When the same light source was employed at ambient
temperatures in the presence of copper(II) triflate,
(Ph3P)3AuCl, rhodium acetate dimer, or acetophenone, then
very slow reactions occurred and so only delivering small
amounts of a mixture of dimers 3, 5, 6, 14, and 15.
In an effort to establish a capacity to change product
distributions by manipulating the reaction conditions, an
acetonitrile solution of compound 1 was irradiated, in the
Figure 2. Monoepoxides 12 and 13 obtained by photolysis of an
acetone solution of substrate 1 in the presence of air.
presence of Ru(bpy)Cl2, Hunig’s base, and lithium tetra-
̈
fluoroborate,25 with a 390 nm (“blue”) LED at −78 °C for 4 h
(entry 9). This gave, in addition to the previously observed
products 3 (5%) and 14 (46%), a small amount (5%) of two
inseparable centro-symmetric dimers wherein, as judged by 1H
NMR spectroscopic analysis, the Δ3,8-bond of two separate
monomer units had been joined in the formation of these
cyclobutane-containing adducts. There are four possible
products of such a dimerization process, namely two head-
to-head and two head-to-tail adducts,2 and given that dimeric
pairs of the same type have very similar chromatographic
properties (see 5/15 and 16/17) and that the corresponding
head-to-head dimer 14 had a distinctly different mobility, we
tentatively propose that this inseparable and ca. 1:1 mixture is
comprised of compounds 20 and 21 (Figure 5). Interestingly,
Figure 3. Structures of the four cyclobutane-containing photo-
products 14−17.
Figure 5. Structures of the centro-symmetric dimers 20, 21, and 22.
structure 20 has been assigned11 to a photodimer derived from
(Z)-lugustilide (1) while the isomeric one 22 has been
assigned to a natural product isolated from Angelica sinensis.19
However, comparisons of the 13C NMR spectral data sets
reported for these compounds reveal that they should both, in
fact, be represented by structure 14.20
In attempts to prepare the recently isolated trimeric forms of
(Z)-lugustilide,7 1:1 mixtures of the last compound (viz. 1)
and the naturally occurring dimer 4, 5, or 6 were each
subjected to photolysis under a range of different conditions,
but in no instance could any such adducts (trimers) be isolated
from these reaction mixtures. It is also interesting to note that
Figure 4. Structures of dimers 18 and 19.
The same combination of products was obtained (entry 7)
in similar proportions on irradiating a dichloromethane
solution of compound 1 at 5 °C for 48 h in the presence of
acetophenone, benzophenone, or 2-acetylnaphthalene24 as
sensitizer. However, the most effective protocol (entry 8)
involved irradiating an acetonitrile solution of substrate 1,
containing Ir(ppy)3, Hunig’s base, and lithium tetrafluorobo-
̈
rate maintained at ambient temperatures, with a 330 nm LED
source (see Experimental Section in SI for details) for 36 h.
Under such conditions the same range of products was
C
DOI: 10.1021/acs.orglett.9b02172
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Letter
photolysis of the (Z)-lugustilide precursor 9 under the various
conditions detailed above did not produce any reaction. We
have not investigated Lewis acid catalyzed12e variants of such
processes or those that could afford the dimers themselves.
The foregoing results clearly demonstrate that a diverse
array of dimeric adducts of (Z)-lugustilide (1) can be obtained
under a range of photolytic conditions and that the precise
distribution of products is influenced, to a significant degree,
by the mode of irradiation. The biosynthetic implications of
our studies remain to be fully understood but raise questions,
for example, about whether or not naturally occurring
photosensitizers are involved in the production of cyclo-
butane-containing natural products 4−6. The persistent
formation, albeit at modest levels, of the thermodynamically
less-favored Diels−Alder adduct tokinolide B (3) in these
photochemically promoted reactions is also intriguing and
clearly indicates that mechanistic studies of all of these
processes are warranted. We are currently pursuing such
matters as well as investigating the dimerization of monomer 1
under various (other) open-shell conditions.26
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02172.
■
S
́
́
́
Plots and crystallographic data arising from the single
crystal X-ray analyses of compounds 5, 14, and 15;
experimental procedures for the formation of com-
pounds 3−6, 9, 11−17, 18 (or 19), and the mixture of
compounds 20 and 21 as well as H and 13C NMR
1
spectra of the same (PDF)
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CCDC 1918547−1918549 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: Martin.Banwell@anu.edu.au.
*E-mail: tsunph@jnu.edu.cn.
ORCID
Ping Lan: 0000-0002-9285-3259
Martin G. Banwell: 0000-0002-0582-475X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council, the ANU Institute
of Advanced Studies, the National Natural Science Fund
(Grant 81872759) of China, and the Pearl River Scholar
Program of Guangdong Province for financial support. The
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