Letter

Cite This: Org. Lett. XXXX, XXX, XXX−XXX pubs.acs.org/OrgLett

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
‡
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
*
S Supporting Information
Downloaded via BOSTON UNIV on August 6, 2019 at 00:42:14 (UTC).

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.

T he phthalide (Z)-lugustilide (1) (Figure 1) is a

prominent constituent in a range of plants, perhaps
most notably Angelica sinensis (Danggui) which is exploited
(3), tokinolide A (4), riligustilide (5), and tokinolide C (6).3
Normally these dimers are isolated in racemic form and so
suggesting they are derived, in vivo, from monomer 1 by
extensively in traditional Chinese medicine (TCM).1 nonenzymatic processes. Natural products such as 1−5 are also
Compound 1 is often accompanied by one or more of a encountered in the traditional medicines based upon several
range of its possible [2 + 2]- and/or [4 + 2]-dimers2 including, genera of the plant family Apiaceae (Umbelliferae) and used in
for example, levistolide A (2, a.k.a. diligustilide), tokinolide B 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 Review this cites
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
Review these two new
recently
forms 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 to air as a solution in a range of solvents) to its fully aromatic,
such as 2−5 and their likely biogenesis, both the thermally and previously reported,14 and naturally-occurring counterpart 11.
photochemically-promoted dimerization reactions of (Z)- In commencing our studies of the photochemical behaviors
lugustilide (1) have been studied, albeit in a cursory fashion. of (Z)-lugustilide (1) (Table 1), we first exposed a ca. 0.13 M
So, for example, heating a solution of compound 1 in benzene toluene solution of this compound in a sealed quartz cuvette to
at 80 °C provided a mixture of the Diels−Alder dimers 2 and 3 Australian summertime sunlight for 10 h (entry 1, Table 1) but
in 2% and 3% yields, respectively.8 The former adduct can be only observed extensive decomposition.
obtained in 22% yield by heating the neat monomer 1 in a When a 0.13 M acetone solution of the substrate was
sealed tube at 160 °C.9 Furthermore, it was shown8 that on irradiated with a 500 W halogen lamp in a vessel open to the
heating adduct 3 at 200 °C this is converted into isomer 2, a air for 72 h (entry 2), a complex mixture of products was again
process that presumably involves a cycloreversion/readdition formed but now small amounts (<5%) of the monoepoxides
process operating under thermodynamic control. In attempts 12 and 13 (Figure 2) could be isolated from the product
to promote such Diels−Alder reactions, substrate 1 was treated mixture by flash chromatography. The former product, viz. 12,
with a range of Lewis acids but only linear dimers resulting has been obtained previously14,15 from natural extracts that
from intermolecular Michael addition reactions were ob- may also contain substrate 1 while the isomeric system 13 does
served.10 There has been just one study of the photolysis of not appear to have been reported before. In an effort to
compound 1 and this involved irradiating an acetone solution suppress decomposition pathways, a deoxygenated toluene
of it with a low-pressure mercury lamp under nitrogen at near solution of substrate 1 containing rose bengal was cooled to
ambient temperatures.11 Under such (presumably triplet −78 °C and then irradiated with the halogen lamp (entry 3),
sensitized) conditions a mixture of four products was obtained, but, once again, only complex mixtures of products were
one of which was shown to be riligustilide 5 (7%) and the observed.
other three being described as “novel” (but see below) and In contrast, under the same conditions but now without
symmetrical [2 + 2] photodimers that were obtained in 18.5%, sensitizer (entry 4), a mixture of eight photoproducts was
11%, and 7.5% yields. The structure of one of these was obtained and these could be isolated as discrete compounds
established by single-crystal X-ray analysis.11 using a combination of flash chromatographic and reversed-
The advent of new techniques for effecting photo- phase HPLC techniques. Five of these were identified, through
cycloaddition reactions of olefins12 prompted us to consider comparison with published spectroscopic data, as the natural
applying some of these to substrate 1 in an effort to establish products tokinolide B (3)8,16 (2%), tokinolide A (4)6d (2%),
how they might influence the distribution of product dimers riligustilide 5 (2%),6a,7,17 tokinolide C (6)6d (2%), and exo-
and higher order oligomers. In order to do so, we required Z,Z-3.3′,8.8′-diligustilide (14)11,18−20 (7%) (Figures 1 and 3).
access to compound 1 and obtained this from the parent The structures of compounds 5 and 14 were confirmed by
phthalide (7) using the route reported by Stermitz (Scheme single-crystal X-ray analysis (see Supporting Information (SI)
1).13 Thus, the enolate derived from compound 7 was trapped for details). Of the remaining three compounds, one proved to
be, as established by single-crystal X-ray analysis, the exo-
Scheme 1. Synthesis of (Z)-Lugustilide (1) from Phthalide isomer of riligustilide, namely compound 15 (2%). The other
(7) 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).
A significantly cleaner dimerization process was observed
when 5 mol % Ir(ppy)312d 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
with butanal and the mixture of aldol-type products 8 (98%) chromatographically less mobile one was also obtained in 15%
so-formed was subjected to a dissolving-metal reduction using yield. This must be (based on the nature of the olefinic proton
sodium in liquid ammonia/isopropanol and thereby affording resonances observed in the derived 1H NMR spectrum) a
the dihydro-aromatic 9 (60%). Mesylation of the hydroxyl dimer linked through the Δ3,8- and Δ6,7-bonds of two separate
group within this last compound was achieved under standard (Z)-lugustilide (1) subunits and a head-to-tail analogue of
conditions and heating the resulting ester 10 in refluxing compounds 5 and 15 and thus represented by either structure
pyridine afforded the target monomer 1 in 55% yield (from 9). 18 or 19 (Figure 4). Unfortunately, the unstable nature of this
All the spectral data recorded on the latter material matched crystalline product prevented the acquisition of spectroscopic
those reported previously for the natural product,11 a data that would allow a distinction to be made between these
compound that we found was readily oxidized (when exposed two possibilities.
B DOI: 10.1021/acs.orglett.9b02172
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters Letter

Table 1. Outcomes of the Photochemical Reactions of Compound 1 under a Range of Different Conditions
entry light source solvent,a catalyst temp,e time products (%)
1 sunlight toluene, none amb.,f 10 h decomposition
2 halogen acetone, none amb.,e 72 h 12 (<5%), 13 (<5%)
3 halogen toluene,b rose bengal −78 °C, 72 h complex mixture
4 halogen toluene,b none −78 °C, 72 h 3, 4, 5, and 6 (2% each), 14 (7%), 15 (2%), 16 and 17 (<1% each)
5 halogen toluene,b Ir(ppy)3 −78 °C, 48 h 3 and 5 (5% each), 14 (55%), 15 (5%)
6 halogen toluene,b F−Ir(ppy)3c −78 °C, 36 h 3 and 5 (9% each) 14 (58%), 15 (9%) 18 or 19 (15%)
7 halogen CH2Cl2,b aromatic ketoned 5 °C, 48 h 3 and 5 (6% each), 14 (63%), 15 (6%), 18 or 19 (11%)
8 330 nm LED MeCN,b Ir(ppy)3, i-PrNEt2, LiBF4 amb.,e 36 h 3 and 5 (8% each), 14 (70%), 15 (8%), 18 or 19 (5%)
9 390 nm (“blue”) LED MeCN,b Ru(bpy)Cl2, i-PrNEt2, LiBF4 amb.,e 4 h 3 (5%), 14 (46%), 21/22 (4%)
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
wall. bThis reaction was conducted under nitrogen. cF−Ir(ppy)3 = Ir[dF(F)ppy]2 (dtbbpy)PF6 where ppy = 2-phenylpyridinyl. dAcetophenone,
benzophenone or 2-acetylnaphthalene. etemp = temperature. famb. = ambient.

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.
Figure 2. Monoepoxides 12 and 13 obtained by photolysis of an In an effort to establish a capacity to change product
acetone solution of substrate 1 in the presence of air. distributions by manipulating the reaction conditions, an
acetonitrile solution of compound 1 was irradiated, in the
presence of Ru(bpy)Cl2, Hünig’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.

Figure 4. Structures of dimers 18 and 19. structure 20 has been assigned11 to a photodimer derived from
(Z)-lugustilide (1) while the isomeric one 22 has been
The same combination of products was obtained (entry 7) assigned to a natural product isolated from Angelica sinensis.19
in similar proportions on irradiating a dichloromethane However, comparisons of the 13C NMR spectral data sets
solution of compound 1 at 5 °C for 48 h in the presence of reported for these compounds reveal that they should both, in
acetophenone, benzophenone, or 2-acetylnaphthalene24 as fact, be represented by structure 14.20
sensitizer. However, the most effective protocol (entry 8) In attempts to prepare the recently isolated trimeric forms of
involved irradiating an acetonitrile solution of substrate 1, (Z)-lugustilide,7 1:1 mixtures of the last compound (viz. 1)
containing Ir(ppy)3, Hünig’s base, and lithium tetrafluorobo- and the naturally occurring dimer 4, 5, or 6 were each
rate maintained at ambient temperatures, with a 330 nm LED subjected to photolysis under a range of different conditions,
source (see Experimental Section in SI for details) for 36 h. but in no instance could any such adducts (trimers) be isolated
Under such conditions the same range of products was from these reaction mixtures. It is also interesting to note that
C DOI: 10.1021/acs.orglett.9b02172
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters Letter

photolysis of the (Z)-lugustilide precursor 9 under the various

conditions detailed above did not produce any reaction. We
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E DOI: 10.1021/acs.orglett.9b02172
Org. Lett. XXXX, XXX, XXX−XXX