Total synthesis, structural revision and biological evaluation of γ-elemene-type sesquiterpenes

Article abstract of DOI:10.1039/c8ob02005a

Total synthesis and absolute configuration confirmation of γ-elemene-type sesquiterpenes, which possess vast potential for biological activities, was investigated based on a convergent synthetic strategy. A key intermediate with all functional groups of this family of natural products was accessed by an intermolecular aldol reaction and then an acetylation of a known ketone (12) derived from commercially available verbenone. The versatile intermediate can be easily transformed into structurally different γ-elemene-type sesquiterpenes based on control of base-promoted cyclization manipulation in different solvents. The utility of this robust approach is illustrated by the first syntheses of elema-1,3,7(11),8-tetraen-8,12-lactam (4′) and 8β-methoxy-isogermafurenolide (6a), as well as the syntheses of elem-1,3,7,8-tetraen-8,12-olide (3) and hydroxyisogermafurenolide (5) in only 6 or 7 steps. In addition, the structure of the reported 5βH-elem-1,3,7,8-tetraen-8,12-olide (1) was revised as elem-1,3,7,8-tetraen-8,12-olide (3) by comparison of their identified datum, and the absolute configuration of elema-1,3,7(11),8-tetraen-8,12-lactam was confirmed as 4′. Furthermore, the inhibitory effect of all synthesized natural compounds and their natural analogues on cancer cell proliferation was evaluated. Among them compounds 3, 4 and 4′ were found to possess potent inhibitory activity against Kasumi-1 and Pfeiffer. Meanwhile, preliminary structure-activity relationships for these compounds are discussed.

Full text of DOI:10.1039/c8ob02005a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Total synthesis, structural revision and biological
evaluation of γ-elemene-type sesquiterpenes†
Cite this: Org. Biomol. Chem., 2018,
16, 7843
Changchun Yuan, *a Shangyong Zhong,a Xingyi Li,a Yanhong Wang,a
Miao-Miao Xun, a Yunli Baia and Kongkai Zhu*b
Total synthesis and absolute configuration confirmation of γ-elemene-type sesquiterpenes, which
possess vast potential for biological activities, was investigated based on a convergent synthetic strategy.
A key intermediate with all functional groups of this family of natural products was accessed by an inter-
molecular aldol reaction and then an acetylation of a known ketone (12) derived from commercially avail-
able verbenone. The versatile intermediate can be easily transformed into structurally different
γ-elemene-type sesquiterpenes based on control of base-promoted cyclization manipulation in different
solvents. The utility of this robust approach is illustrated by the first syntheses of elema-1,3,7(11),8-
tetraen-8,12-lactam (4’) and 8β-methoxy-isogermafurenolide (6a), as well as the syntheses of elem-
1,3,7,8-tetraen-8,12-olide (3) and hydroxyisogermafurenolide (5) in only 6 or 7 steps. In addition, the
structure of the reported 5βH-elem-1,3,7,8-tetraen-8,12-olide (1) was revised as elem-1,3,7,8-tetraen-
8,12-olide (3) by comparison of their identified datum, and the absolute configuration of elema-1,3,7
(11),8-tetraen-8,12-lactam was confirmed as 4’. Furthermore, the inhibitory effect of all synthesized
natural compounds and their natural analogues on cancer cell proliferation was evaluated. Among them
compounds 3, 4 and 4’ were found to possess potent inhibitory activity against Kasumi-1 and Pfeiffer.
Meanwhile, preliminary structure–activity relationships for these compounds are discussed.
Received 16th August 2018,
Accepted 2nd October 2018
DOI: 10.1039/c8ob02005a
rsc.li/obc
counterpart of structure I (Scheme 1A), which was generally
regarded as a biogenetic process,5a and 5-hydroxy-1H-pyrrol-2
Introduction
Heterocycles are a significantly important class of compounds, (5H)-ones could be obtained by ammonolysis of
which are extensively present in various biologically active γ-hydroxybutenolides or γ-ylidenebutenolides in some trans-
molecules.1 Specifically, not only are the heterocyclic motifs of formations (Scheme 1B).5 Owing to their biological properties
γ-hydroxybutenolides, γ-ylidenebutenolides, 5-hydroxy-1H- and unique structures, there are numerous synthetic
pyrrol-2(5H)-ones and 5-ylidenepyrrol-2(5H)-ones widely found approaches for the synthesis of these important scaffolds.5,6
as an essential unit in a vast variety of bioactive natural pro- And natural products containing these structural units have
ducts and other substances of biomedical significance,1c,2,3 also attracted growing interest in the chemical and biological
but they are also important synthons in organic synthesis4 as communities.5c,6g,7
well. Structurally (Scheme 1A), the structure I, sometimes with
Elemenes are a group of natural products of closely related
different substituent groups in R1, R2 and R3, could be structure found in a variety of plants and possess various
assigned to the fundamental skeleton of γ-hydroxybutenolides
and 5-hydroxy-1H-pyrrol-2(5H)-ones, and the structure II
for γ-ylidenebutenolides and 5-ylidenepyrrol-2(5H)-ones.
Chemically, structure II can be regarded as a dehydrated
aNational Demonstration Center for Experimental Chemical Engineering
Comprehensive Education, School of Chemical Engineering and Technology,
North University of China, Taiyuan 030000, P.R. China.
E-mail: ycc543700483@nuc.edu.cn
bSchool of Biological Science and Technology, University of Jinan, Jinan 250022,
P.R. China. E-mail: bio_zhukk@ujn.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02005a
Scheme 1 The structure of γ-hydroxybutenolides, γ-ylidenebutenolides,
5-hydroxy-1H-pyrrol-2(5H)-ones and 5-ylidenepyrrol-2(5H)-ones, and their
chemical relations.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7843–7850 | 7843

View Article Online
Paper
Organic & Biomolecular Chemistry
activities. Among them, there are some γ-elemene-type sesqui- γ-elemene-type sesquiterpene similar to compound 8 in struc-
terpenes bearing the abovementioned scaffolds (Fig. 1). In ture, along with 8β-methoxy-isogermafurenolide (6a) were iso-
2015, three elemene-type sesquiterpenes (1, 5 and 9) were iso- lated from the rhizomes of Curcuma phaeocaulis by Qiu et al.
lated from the essential oil of Curcuma wenyujin by Chen et al.8 in 2015,13 all showing a weak inhibitory effect against LPS-
Biological investigation for inhibitory activity against lipopoly- induced nitric oxide production.
saccharide (LPS)-induced nitric oxide (NO) shows that they
As early as 1988, Bohlmann had paid attention to the syn-
exhibited weak inhibitory activities against NO production (IC50 thesis of various cytotoxic elemanolides found in the plant
73.18 3.81, 59.97 3.96 and 30.62 2.63 μM, respectively).8a family of Compositae.14 The divinylcyclohexanone prepared
Originally, compound
1
was named 5βH-elem-1,3,7,8- from Hagemann’s ester had been utilized as a key intermedi-
tetraen-8,12-olide and a structure was proposed for it as ate for a synthetic approach, which leads to the synthesis of
(5R,6S)-3,6-dimethyl-5-(prop-1-en-2-yl)-6-vinyl-5,6-dihydrobenzo- compounds 5, 8 and 9 in racemic form.14 Beyond that, there is
furan-2(4H)-one (1, Fig. 1) by Chen and co-workers,8a but the some work focusing on the study of chemical transformation
spectral data of compound 3 synthesized by us were found to between this group natural products.11a,15 On the other hand,
be in good accordance with those of the isolated compound. So although some synthetic studies and several bioevaluations on
we revised the structure of this compound as 3. Interestingly the inhibition of LPS-induced nitric oxide production or cyto-
and logically, the stereochemistry of γ-elemene lactone (2) iso- toxic activity of this group of natural products have been
lated from Commiphora molmol resin by Ayyad et al. in 2015, studied, the asymmetric total synthesis and bioevaluations on
which displayed remarkable cytotoxic activity against NIH3T3 the anti-tumor effect of this group of natural products have
cells (IC50 10 0.02 μM), should be structure 1 deduced by us.9 not been reported yet. Moreover, a synthetic strategy suitable
Compound 5 was also isolated from Curcuma xanthorrhiza by for these natural compounds from a common synthetic inter-
Fan et al.10a in 2015 as well as from Curcuma wenyujin DREG by mediate has not been reported yet. Herein, we describe the
Yin et al. in 2016,10b and showed moderate antibacterial activity total synthesis and absolute configuration confirmation of 4
in pathogenic bacteria.10b Compound 9 was found in other and its natural analogs (3, 5 and 6a), as well as the in vitro
plants as well, such as Lindera strychnifolia or Neolitsea hiiranen- anti-tumor evaluations of all synthesized natural products on
sis.11 Specifically, elema-1,3,7(11),8-tetraen-8,12-lactam (4), the the inhibitory effect towards the proliferation of leukemia and
absolute configuration of which was ultimately confirmed as 4′ lymphoma cells.
by us, together with hydroxyisogermafurenolide (5) and isoger-
mafurenolide (8) were isolated from the rhizomes of Curcuma
wenyujin in 2013, and compounds 4 and 5 showed stronger
activities than compound 8 for the inhibition of LPS-induced
Results and discussion
nitric oxide production (IC50 9.4 1.6, 17.5 2.4, >100 μM,
Our proposal for the synthesis of these γ-elemene-type sesqui-
terpenes is shown in Scheme 2. Retrosynthetically, compound
respectively).12 8βH-Elema-1,3,7(11)-trien-8,12-lactam (7),
a
Fig. 1 Examples of γ-elemene-type sesquiterpenes.
Scheme 2 Retrosynthetic analysis.
7844 | Org. Biomol. Chem., 2018, 16, 7843–7850
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
4 as a dehydrated counterpart of compound 10 could be cyclized methodology to furnish γ-alkylidenebutenolide pro-
obtained by dehydration of 5-hydroxy-1H-pyrrol-2(5H)-one 10. moted by DBU reveals a very powerful application in the total
Compound 10 is accessible from γ-ylidenebutenolides 3 or synthesis of lindenane sesquiterpenoids,7e,g,16 converting 11 to
γ-hydroxybutenolide 5 through an aminolysis reaction by 3 in 94% yield. Interestingly, comparing the spectral data (1H
ammonium hydroxide. The different γ-butenolide frameworks NMR and 13C NMR) of synthetic 3 with isolated natural pro-
in compounds 3, 5 and 6a are constructed via a DBU-promoted ducts 1 and 2, we found that it was in good accordance with
cyclization developed by Liu’s group from a common inter- natural product 1 reported by Chen et al. So the structural revi-
mediate 11 (strategy B, Scheme 2),16 which could be made by sion of this natural product was confirmed as 3 (see the ESI†
routine derivatization of
a commercially available chiral for details), and the stereochemistry of γ-elemene lactone (2)
compound 13 including a Michael addition reaction, a ring- should be structure 1, whose relative configuration wasn’t pro-
opening of the cyclobutane and an aldol reaction. In addition, vided by Ayyad et al. originally.9 To achieve elema-1,3,7(11),8-
inspired by this methodology NH3-promoted cyclization/ tetraen-8,12-lactam (4), 3 was first converted into 10 through
aminolysis cascades were envisioned, allowing the single-step an aminolysis reaction by ammonium hydroxide in a sealed
assembly of 5-hydroxy-1H-pyrrol-2(5H)-one 10 from intermedi- tube. Subsequently, 10 was treated with pTsOH·H2O in THF,
ate 11 (strategy A, Scheme 2).
affording the natural product elema-1,3,7(11),8-tetraen-8,12-
As outlined in Scheme 3, the synthesis of ketone 12 com- lactam (4) in 83% yield in 2 steps. The spectral data (1H NMR,
menced from (+)-verbenone (13). According to the known pro- 13C NMR and HRMS) of synthetic 4 are in good agreement
cedure,16 13 was converted into enol acetate 14 in two steps, with those of the natural product, but the inconsistency of
which was subsequently deprotected by K2CO3 in MeOH, optical rotation exists between our synthesized sample and the
giving the known derivative 12.17 Ketone 12 was subjected to natural product. The optical rotation for the natural product is
an aldol reaction with methyl pyruvate affording 15, in which positive, [α]2D0 +39.0 (c 0.01, MeOH), whereas the optical
the tertiary alcohol was then acetylated to produce 11.
rotation for synthetic 4 is negative, [α]2D6 −72.7 (c 1.28, MeOH),
With the key intermediate 11 in hand, we firstly aimed which is similar to that of its synthetic analog 3, [α]2D6 −65.2 (c
towards the syntheses of 3 (Scheme 4) which can lead to the 2.46, CHCl3). It is worth noting that the optical rotation of 12
total synthesis of natural product 4 (strategy B, Scheme 2). The is in good agreement with that of the literature (see the ESI†
Scheme 3 Construction of the key intermediate 11.
Scheme 4 Syntheses of natural products 3, 4’, 5 and 6a from 11.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7843–7850 | 7845

View Article Online
Paper
Organic & Biomolecular Chemistry
for details).17 These facts implied that the absolute configur- cascade, developed by us, can complement the established
ation of the natural product 4 should be that of its enantiomer. methodology of 5-hydroxy-1H-pyrrol-2(5H)-one construction. In
In general, we completed the syntheses of 3 and 4 in 6 and 8 consideration of the completely opposite optical rotation data
longest linear steps, respectively, from the commercially avail- between synthetic compound 4 and the natural one, we were
able (+)-verbenone (13).
on a journey toward the absolute configuration confirmation
Having successfully prepared 3 and 4, our attention turned of this natural product. Our confirmed synthetic tour
towards the synthesis of the natural analogs 5 and 6a based on (Scheme 4, shown in blue) started with commercially available
a diversity-oriented approach (Scheme 4). Compound 11 was (−)-verbenone to afford compound 4′ in 7 steps by the use of
subjected to DBU/H2O affording a single isomer 5 in 74% exactly the same procedure as 4, and pleasingly, the optical
yield, whose characterization data were in good accord with rotation of 4′ {[α]2D2 +54.3 (c 0.64, MeOH)} is similar to that of
those reported except for the optical rotation (see the the natural product reported by Dong, [α]2D0 +39.0 (c 0.01,
Experimental section for details). Meanwhile, the formal syn- MeOH).12 Meanwhile, other characterized data of 4′ were in
thesis of isogermafurenolide (9) can be accomplished via one- full agreement with those reported, securing the absolute con-
step manipulation according to known chemistry.11a figuration of the natural product as 4′.
8β-Methoxy-isogermafurenolides 6a and 6b were acquired as
Successfully achieving these four natural products (3, 4′, 5
an inseparable diastereomeric mixture in a ratio of 1.79 : 1 and 6a) and their natural analogs (4 and 6b), we turned our
with 61% yield utilizing MeOH as a solvent, along with com- attention to evaluate their bioactivity assay. To detect whether
pound 3 in 31% yield. This inseparable diastereomixture can these compounds were sufficient to inhibit cancer cell prolifer-
be further purified by preparative HPLC to give separable 6a ation, we screened one leukemia (Kasumi-1) and two lym-
and 6b (see the Experimental section for details), and their phoma (Pfeiffer and Karpas-422) cell lines using the CellTiter-
structures were confirmed by the NMR spectra of 1H, 13C, Glo assay and EED226 was selected as a positive control.18 The
NOESY, DEPT, HSQC and HMBC (see the ESI† for details). IC50 values (Fig. 2 and Table 1) demonstrate that compounds
Pleasingly, the identified characterization data of 6a were in 3, 4 and 4′ were potent in inhibiting cell proliferation in a
full agreement with those reported as a racemate.13 Inspired
and encouraged by this base-promoted cyclization method-
ology, we are impelled to try to synthesise 5-hydroxy-1H-pyrrol-
2(5H)-one 10 with ammonium hydroxide as a promoter from
intermediate 11. Satisfactorily, 11 was subjected to the mixed
Table 1 Anti-proliferative effect of compounds in Kasumi-1, Pfeiffer
and Karpas-422 cells. The unit of IC50 is μM
solution of ammonium hydroxide (25% in H2O) in THF with a
Compounds
Kasumi-1 (IC50
)
Pfeiffer
Karpas-422
volume ratio of 1 : 3 at 120 °C in a sealed tube, immediately
affording compound 3. Prolonging the reaction by 28 hours,
the reaction afforded compound 10. Dehydration of 10 gave
compound 4 in 81% yield in two steps. Finally, elema-1,3,7
(11),8-tetraen-8,12-lactam (4) can be prepared in only 7 steps
from the commercially available (+)-verbenone (13).
Meanwhile, the NH3-promoted cyclization/aminolysis reaction
3
4
4′
5
41.35
21.10
26.41
>100
45.18
56.70
74.89
—
41.99
24.87
25.18
>100
67.13
67.27
97.10
0.1186
64.49
69.18
>100
>100
>100
>100
>100
0.1155
6
6a
6b
EED226
Fig. 2 Dose response curves for the synthesized compounds against three cancer cell lines with EED226 as a positive control.
7846 | Org. Biomol. Chem., 2018, 16, 7843–7850
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
dose-dependent manner and notably showed high potency internal reference (CDCl3: 1H NMR = 7.26, 13C NMR = 77.16;
1
toward Kasumi-1 and Pfeiffer (Table 1), whereas 4 and its CD3OD: H NMR = 3.31 and 4.87, 13C NMR = 49.00). The fol-
enantiomer 4′ showed no significant difference. Compounds 4 lowing abbreviations were used to explain the multiplicities:
and 4′ showed stronger inhibitory activity regarding cancer cell s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet
proliferation than compounds 3, 5, 6a and 6b, suggesting that and br = broad. Coupling constants (J) are reported in hertz
the inhibitory activities of 4 and 4′ might benefit from the (Hz). Optical rotations were measured in the sodium D line
nitrogen atom. It is worth noting that the double bond of with a 100 mm path length cell, and are reported as follows:
C8vC9 might also be a vital factor for activity against cancer [α]TD, concentration (g per 100 mL), and solvent. High-resolu-
cell proliferation according to the significant difference of tion mass spectra (HRMS) were recorded on a FTMS-7 spectro-
effects between compounds 3, 5, 6a and 6b.
meter and are reported as m/z (relative intensity). Accurate
masses are reported for the molecular ion [M + Na]+, [M + H]+,
or [M − H]−. Infrared (IR) spectra were recorded on a NEXUS
670 FT-IR Fourier transform infrared spectrophotometer and
are reported in wavenumbers (cm−1).
Conclusion
In summary, we have completed the total synthesis and absol-
ute configuration confirmation of four γ-elemene-type sesqui-
terpenes in 6 or 7 steps from commercially available com-
Synthesis
Compound 12. To a methanol (80.0 mL) solution of com-
pounds (+)-verbenone or (−)-verbenone. The good match of pound 14 (3.80 g, 17.2 mmol), which can be prepared accord-
the characterization data between synthetic 3 and the reported ing to the known procedure in 2 steps,16 was added K2CO3
natural product 1 prompted us to revise its molecular structure (720 mg, 5.21 mmol) at 0 °C. Then the reaction was allowed to
as 3, which also confirmed the relative configuration of warm to rt and stirred overnight, before it was quenched with
natural product 2 as 1. The mismatch of the optical rotation HCl (6 M in H2O, 1.70 mL) at 0 °C. Then the mixture was con-
data between synthetic 4 and the natural product prompted us centrated to remove MeOH and diluted by H2O (30.0 mL). The
to revise its absolute configuration as 4′ and accomplish the aqueous layer was extracted with EtOAc (3 × 100 mL). The com-
total synthesis of 4′ in 7 steps, which confirmed the absolute bined organic layers were dried over Na2SO4, filtered and con-
configuration of this natural product. This convergent syn- centrated under reduced pressure. The residue was purified
thesis outlines the preparation of the key intermediate 11, with using flash column chromatography on silica gel (50 : 1 pet-
further efficient and rapid cyclization to yield the natural pro- roleum ether–EtOAc) to provide compound 12 (a known com-
ducts. It is anticipated that the described general synthesis pound,17,19 2.52 g, 82%,) as a yellow oil. [α]D26 −25.0 (c 6.88,
strategy can be useful to prepare related classes of compounds. CHCl3), {Lit.17a [α]D20 −26.2 (c 1.05, CHCl3)}; {Lit.17b [α]D20 −29.2
Inhibitory activity on cancer cell proliferation of these syn- (c 1.44, CHCl3)}; IR (thin film): 2961, 2948, 1717, 1638, 1383,
thetic natural products and their natural analogues was also 1339, 912, 905, 469, 459 cm−1 1H NMR (600 MHz, CDCl3) δ
;
evaluated, and among them compounds 3, 4 and 4′ were 5.84 (dd, J = 17.4, 10.2 Hz, 1H), 4.97 (d, J = 10.8 Hz, 1H), 4.92
found to possess potent inhibitory activity against Kasumi-1 (s, 1H), 4.91 (d, J = 17.4 Hz, 1H), 4.69 (s, 1H), 2.48 (d, J = 13.2
and Pfeiffer.
Hz, 1H), 2.43–2.35 (m, 3H), 2.10 (dd, J = 13.8, 1.8 Hz, 1H),
2.05–1.98 (m, 1H), 1.95–1.90 (m, 1H), 1.77 (s, 3H), 0.99 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 210.8, 147.1, 145.8, 113.5,
111.20, 53.8, 51.8, 44.2, 41.3, 28.1, 25.1, 17.9; HRMS (ESI): m/z
calcd for C12H19O [M + H]+ 179.1430; found, 179.1430. The
enantiomer of compound 12 can be synthesized from commer-
Experimental details
Materials and methods
All reactions were performed in flame-dried round-bottom cially available (−)-verbenone in the same operation, and the
flasks fitted with rubber septa under a positive pressure of optical rotation for this enantiomer is [α]2D2 +19.4 (c 0.55,
nitrogen, unless otherwise noted. Air- and moisture-sensitive CHCl3).
liquids and solutions were transferred via a syringe or
Compound 15. To a solution of LDA, prepared from DIPA
cannula. Diisopropylamine (DIPA) was distilled from calcium (2.86 g, 3.96 mL, 28.3 mmol) and nBuLi (2.5 M in hexane,
hydride under argon; tetrahydrofuran (THF) was distilled from 11.3 mL, 28.3 mmol) in THF (60.0 mL) was added 12 (2.52 g,
sodium-benzophenone under argon; and all other reagents 14.1 mmol) in THF (20.0 mL) at 0 °C and the resulting mixture
were used directly from the supplier without further purifi- was stirred for 30 min at the same temperature. A mixture of
cation unless otherwise noted. Flash chromatography was per- methyl pyruvate (2.89 g, 2.56 mL, 28.3 mmol) and ZnCl2
formed using silica gel (200–300 mesh). Reactions were moni- (3.86 g, 28.3 mmol) in THF (40.0 mL) was added to the above
tored using thin-layer chromatography (TLC). Visualization solution at 0 °C. After stirring for another 2 h, saturated NH4Cl
was achieved under a UV lamp (254 nm and 365 nm) and by solution (30.0 mL) was added to this reaction. The resulting
developing the plates with p-anisaldehyde. 1H and 13C NMR mixture was concentrated to remove THF and saturated
spectra were recorded on a Bruker Advance III-HD 600 MHz Rochelle salt (30.0 mL) was added. Then the aqueous layer was
NMR spectrometer with TMS as the internal standard and extracted with EtOAc (3 × 100 mL). The combined organic
were calibrated using residual undeuterated solvent as an layers were dried over Na2SO4, filtered and concentrated under
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7843–7850 | 7847

View Article Online
Paper
Organic & Biomolecular Chemistry
reduced pressure. The residue was purified using flash column 5.00 mL) in THF (15.0 mL) was heated to 120 °C in a sealed-
chromatography on silica gel (10 : 1 petroleum ether–EtOAc) to tube for 28 h. After concentration under reduced pressure,
recycle compound 12 (0.93 g, 37%) and furnish compound 15 crude product 10 was obtained and directly used for the next
(2.39 g, 60%; 95% brsm) as an inseparable diastereomixture step. To a solution of the above crude product 10 in THF
and a yellow oil.
(20.0 mL) was added pTsOH·H2O (63.7 mg, 0.335 mmol) at
Compound 11. pTsOH·H2O (2.42 g, 12.7 mmol) was added 0 °C. The resulting mixture was allowed to warm to rt and
to a solution of 15 (2.39 g, 8.52 mmol) in Ac2O (21.7 g, stirred overnight. The mixture was quenched with saturated
20.0 mL, 0.213 mol) at 0 °C. Then the reaction was allowed to aqueous NaHCO3 solution (30.0 mL). The layers were separ-
warm to rt and stirred overnight, before it was added to a solu- ated and the aqueous layer was extracted with EtOAc (3 ×
tion of NaHCO3 (35.8 g, 0.426 mol) in H2O (200 mL) at 0 °C 100 mL). The combined organic layers were dried over Na2SO4,
and stirred until bubbling ceased. The mixture was extracted filtered, and concentrated under reduced pressure. The
with EtOAc (3 × 100 mL). The combined organic layers were residue was purified using flash column chromatography on
dried over Na2SO4, filtered and concentrated under reduced silica gel (petroleum ether/EtOAc 4 : 1) to provide compound 4
pressure. The residue was purified using flash column chrom- (0.124 g, 81% for 2 steps) as a white solid. [α]2D6 −72.7 (c 1.28,
atography on silica gel (10 : 1 petroleum ether–EtOAc) to MeOH), {Lit.12 [α]D20 +39.0 (c 0.01, MeOH)}; IR (thin film): 3373,
furnish 11 (2.75 g, 84%) as an inseparable diastereomixture 3172, 1746, 1695, 1412, 1261, 1021, 912, 800, 737 cm−1
;
1H
1
and a colorless oil. Compound 11 was not identified using H NMR (600 MHz, CDCl3) δ 7.68 (s, 1H), 5.84 (dd, J = 17.4, 10.2
and 13C NMR and was directly used for the following reaction.
Hz, 1H), 5.29 (s, 1H), 5.04 (dd, J = 10.2, 0.8 Hz, 1H), 4.99 (dd,
Compound 3. Product 11 (0.344 g, 1.07 mmol) was dissolved J = 17.4, 0.8 Hz, 1H), 4.89 (s, 1H), 4.76 (s, 1H), 2.69 (ddd, J =
in THF (15.0 mL) and DBU (0.812 g, 0.800 mL, 5.33 mmol) was 16.8, 4.8, 1.0 Hz, 1H), 2.58 (ddd, J = 17.4, 10.2, 1.2 Hz, 1H),
slowly added at 0 °C. The resulting mixture was allowed to 2.46 (dd, J = 8.4, 5.4 Hz, 1H), 1.86 (s, 3H), 1.69 (s, 3H), 1.12 (s,
warm to rt and stirred overnight, before it was concentrated 3H); 13C NMR (150 MHz, CDCl3) δ 173.2, 146.7, 146.1, 141.3,
under reduced pressure to remove THF. Then the residue was 136.6, 125.0, 115.9, 114.3, 113.0, 51.4, 42.0, 25.3, 24.0, 22.0,
directly purified using flash column chromatography on silica 8.3; HRMS (ESI): m/z calcd for C15H19NaNO [M + Na]+ 252.1359
gel (10 : 1 petroleum ether–EtOAc) to provide compound 3 found 252.1361. Compound 4′ can be synthesized from com-
(0.232 g, 94%)8a as a white solid. [α]D26 −65.2. (c 2.46, CHCl3) or mercially available (−)-verbenone in the same experimental
[α]D22 −55.5 (c 2.46, MeOH) {Lit.8a [α]2D0 −12.7 (c 0.021, MeOH)}; procedure as compound 4, and the optical rotation for this
IR (thin film): 3082, 2967, 2925, 1771, 1670, 1651, 1378, 1318, enantiomer is [α]2D2 +54.3 (c 0.64, MeOH).
1293, 1221, 1062, 918, 870, 758, 580, 553 cm−1
;
1H NMR
Compound 5. Product 11 (0.126 g, 0.391 mmol) was dis-
(600 MHz, CDCl3) δ 5.84 (dd, J = 17.4, 10.8 Hz, 1H), 5.47 (s, solved in H2O (10.0 mL) and DBU (0.297 g, 0.292 mL,
1H), 5.07 (d, J = 10.8 Hz, 1H), 5.01 (d, J = 17.4 Hz, 1H), 1.95 mmol) was slowly added at 0 °C. The resulting mixture
4.92–4.92 (m, 1H), 4.78 (s, 1H), 2.74 (ddd, J = 16.8, 4.8, 1.2 Hz, was allowed to warm to rt and stirred overnight, before it was
1H), 2.63 (ddd, J = 17.3, 8.4, 1.2 Hz, 1H), 2.47 (dd, J = 8.4, diluted by further H2O (20.0 mL). Then the aqueous layer was
4.8 Hz, 1H), 1.89 (s, 3H), 1.70 (s, 3H), 1.15 (s, 3H); 13C NMR extracted with EtOAc (3 × 50 mL). The combined organic layers
(150 MHz, CDCl3) δ 171.4, 149.0, 148.0, 146.0, 145.3, 120.5, were dried over Na2SO4, filtered, and concentrated under
114.9, 114.5, 113.6, 50.9, 42.0, 25.6, 23.9, 22.2, 8.6; HRMS reduced pressure. The residue was purified using flash column
(ESI): m/z calcd for C15H18NaO2 [M + Na]+ 253.1199; found, chromatography on silica gel (petroleum ether/EtOAc 5 : 1) to
253.1195.
provide compound 5 (71.8 mg, 74%) as a white solid in a
Method A for compound 4. A solution of compound 3 single product. The spectra of H NMR and 13C NMR of com-
(229.1 mg, 0.99 mmol) and ammonium hydroxide (25% in pound 5 are well in accord with the natural product hydroxy-
H2O, 5.00 mL) in THF (15.0 mL) was heated to 120 °C in a isogermafurenolide.11a,14 [α]D26 +125.6 (c 1.00, CDCl3) or [α]2D2
sealed-tube for 24 h. After concentration under reduced +58.3 (c 2.67, dioxane) {Lit.11a [α]D22 +4.7 (c 0.996, dioxane)}; IR
pressure, crude product 10 was obtained and directly used for (thin film): 3342, 1748, 1689, 1643, 1435, 1380, 1325, 1239,
1
the next step. To a solution of the above crude product 10 in 1143, 1128, 1084, 1008, 899, 913, 765, 726 cm−1 1H NMR
;
THF (20.0 mL) was added pTsOH·H2O (94.2 mg, 0.495 mmol) (600 MHz, CDCl3) δ 5.70 (dd, J = 17.4, 10.8 Hz, 1H), 5.00 (d, J =
at 0 °C. The resulting mixture was allowed to warm to rt and 10.8 Hz, 1H) 4.99 (s, 1H), 4.97 (d, J = 16.8 Hz, 1H), 4.74 (s, 1H),
stirred overnight. The mixture was quenched with saturated 2.86 (br s, 1H, –OH), 2.72 (t, J = 13.8 Hz, 1H), 2.56 (dd, J = 13.8,
aqueous NaHCO3 solution (30.0 mL). The layers were separ- 3.6 Hz, 1H), 2.14 (d, J = 14.4 Hz, 1H), 2.05 (dd, J = 13.2, 3.0 Hz,
ated and the aqueous layer was extracted with EtOAc (3 × 1H), 1.83 (s, 3H), 1.77 (s, 3H), 1.76 (d, J = 12.6 Hz, 1H), 1.27 (s,
100 mL). The combined organic layers were dried over Na2SO4, 3H); 13C NMR (150 MHz, CDCl3) δ 172.0, 160.2, 147.6, 144.9,
filtered, and concentrated under reduced pressure. The 122.2, 114.3, 112.1, 102.9, 54.4, 49.5, 40.8, 27.2, 24.5, 17.9, 8.4;
residue was purified using flash column chromatography on HRMS (ESI): m/z calcd for C15H19O3 [M − H]− 247.1340; found,
silica gel (petroleum ether/EtOAc 4 : 1) to provide compound 4 247.1336.
(0.188 g, 83% for 2 steps) as a white solid.
Compounds 6a and 6b. Product 11 (0.328 g, 1.02 mmol) was
Method B for compound 4. A solution of compound 11 dissolved in MeOH (15.0 mL) and DBU (0.776 g, 0.762 mL,
(0.216 g, 0.67 mmol) and ammonium hydroxide (25% in H2O, 5.10 mmol) was slowly added at 0 °C. The resulting mixture
7848 | Org. Biomol. Chem., 2018, 16, 7843–7850
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
was allowed to warm to rt and stirred overnight, before it was
concentrated under reduced pressure to remove MeOH. Then
Conflicts of interest
the residue was directly purified using flash column chromato- There are no conflicts to declare.
graphy on silica gel (14 : 1 petroleum ether–EtOAc) to provide
compound 3 (68.1 mg, 31%) as a white solid and compound 6
(0.163 mg, 61%) as a white solid. Compound 6 contains 6a
Acknowledgements
and 6b as an inseparable diastereomixture in a ratio of 1.79 : 1
1
determined using H NMR. An aliquot of this diastereomeric We acknowledge financial support from the National Natural
mixture 6 was further separated using preparative HPLC Science Foundation of China (21702192).
(YMC-Triart C18, hexane/i-PrOH = 80/20, flow rate = 3.0 mL
min−1, column temperature = 20 °C, λ = 254 nm) to give 6a
and 6b (retention time: tr1 = 14.5 min for 6b, tr2 = 16.1 min
References
for 6a). The 1H NMR and 13C NMR spectra of 6a are
identical to those of natural 8β-methoxy-isogermafurenolide,13
and the structures of 6a and 6b were also confirmed by
NMR spectra of NOESY, DEPT, HSQC and HMBC (see the ESI†
for details).
1 For selected reviews, see: (a) J. D. Faulkner, Nat. Prod. Rep.,
1999, 16, 155–198; (b) K. C. Nicolaou, D. Vourloumis,
N. Winssinger and P. S. Baran, Angew. Chem., Int. Ed., 2000,
39, 44–122; (c) B. M. Fraga, Nat. Prod. Rep., 2003, 20, 392–
413; (d) S. Dadiboyena and A. Nefzi, Eur. J. Med. Chem.,
2011, 46, 5258–5275; (e) K. Chanda, R. A. Hiremathad,
M. Singh, M. A. Santos and R. S. Keri, Pharmacol. Rep.,
2017, 69, 281–295.
6a (8β-methoxy-isogermafurenolide): [α]2D6 +96.3 (c 1.22,
CDCl3) (natural 6a was reported as a racemate); 1H NMR
(600 MHz, CD3OD) δ 5.76 (dd, J = 17.4, 10.8 Hz, 1H), 4.98 (s,
1H), 4.96 (dd, J = 11.4, 0.6 Hz, 1H), 4.95 (dd, J = 17.6, 1.2 Hz,
1H), 4.77 (s, 1H), 3.15 (s, 3H), 2.63 (dd, J = 4.2, 13.8 Hz, 1H),
2.59 (dt, J = 12.6, 1.2 Hz, 1H), 2.14 (dd, J = 12.6, 3.6 Hz, 1H),
2.10 (d, J = 13.8 Hz, 1H), 1.85 (d, J = 1.2 Hz, 3H), 1.77 (s, 3H),
1.67 (d, J = 13.8 Hz, 1H), 1.21 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 173.6, 160.7, 149.3, 146.4, 125.2, 114.5, 112.2, 107.5,
55.2, 50.6, 49.6, 41.8, 28.3, 24.9, 18.0, 8.1; HRMS (ESI): m/z
calcd for C16H23O3 [M + H]+ 263.1642; found, 263.1641.
6b (8α-methoxy-isogermafurenolide): [α]2D6 −149.4 (c 0.46,
2 Selected
reviews
for
γ-hydroxybutenolides
and
γ-ylidenebutenolides, see: (a) G. Lian and B. Yu, Chem.
Biodiversity, 2010, 7, 2660–2691; (b) Z.-J. Zhan, Y.-M. Ying,
L.-F. Ma and W.-G. S, Nat. Prod. Rep., 2011, 28, 594–629;
(c) B. M. Fraga, Nat. Prod. Rep., 2012, 29, 1334–1366;
(d) Y.-J. Xu, Chem. Biodiversity, 2013, 10, 1754–1773;
(e) B. Zhou, Y. Wu, S. Dalal, E. F. Merino, Q.-F. Liu,
C.-H. Xu, T. Yuan, J. Ding, D. G. I. Kingston, M. B. Cassera
and J.-M. Yue, J. Nat. Prod., 2017, 80, 96–107.
1
CDCl3); H NMR (600 MHz, CD3OD) δ 6.22 (dd, J = 17.4, 10.8
Hz, 1H), 5.08 (d, J = 17.4 Hz, 1H), 4.97 (d, J = 11.4 Hz, 1H), 4.86
(s, 1H), 4.68 (s, 1H), 3.07 (s, 3H), 2.77 (t, J = 4.8 Hz, 1H),
2.69–2.68 (m, 2H), 2.26 (d, J = 14.4 Hz, 1H), 1.89 (d, J = 14.4
Hz, 1H), 1.83 (s, 3H), 1.75 (t, J = 0.6 Hz, 3H), 1.00 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 173.4, 159.4, 148.7, 148.3, 127.0,
113.9, 110.2, 107.7, 50.4, 49.9, 46.6, 40.8, 28.0, 26.3, 25.5, 8.4;
HRMS (ESI): m/z calcd for C16H23O3 [M + H]+ 263.1642; found,
263.1640.
Inhibitory effect on the proliferation of leukemia (Kasumi-1)
and lymphoma cells (Pfeiffer and Karpas-422). These three
human cancer cells were cultured in RPMI1640 medium sup-
plemented with 10% FBS and 1% penicillin/streptomycin
under 5% CO2 at 37 °C. After confirmation that cells were in
linear log-phase growth, these cells were plated in 24-well
plates in a volume of 100 μL and treated with compounds in
corresponding concentration (DMSO as control) for 4 days.
Cell viability tests were carried out using a Cell Titer-Glo
luminescence assay. Briefly, 100 μL of reconstituted Cell Titer-
Glo reagent was added to each well. Then the plates were
shaken for 2 minutes for cell lysis and incubated at room
temperature for 10 minutes. Then 100 μL of the mixture
was transferred to a white 96-well luminometer plate and
luminescence was measured via an Envision luminometer
(PerkinElmer). All treatments were determined in triplicate,
and data were normalized for control cells. GraphPad Prism
6.0 to was used fit the IC50 values.
3 Selected reviews and examples for 5-hydroxy-1H-pyrrol-2
(5H)-ones and 5-ylidenepyrrol-2(5H)-ones: (a) B. Nay,
N. Riache and L. Evanno, Nat. Prod. Rep., 2009, 26, 1044–
1062; (b) J. Caruano, G. G. Muccioli and R. Robiette, Org.
Biomol. Chem., 2016, 14, 10134–10156; (c) L. S. Hoang,
M. H. Tran, J.-S. Lee, Q. M. T. Ngo, M. H. Woo and
B. S. Min, Chem. Pharm. Bull., 2016, 64, 507–511.
4 Selected examples for γ-butenolides, see: (a) D. Noutsias
and G. Vassilikogiannakis, Org. Lett., 2012, 14, 3565–3567;
(b) A. Munoz and R. P. Murelli, Tetrahedron Lett., 2012, 53,
6779–6781; (c) M. Klopfleisch, R. A. Seidel, H. Görls,
H. Richter, R. Beckert, W. Imhof, M. Reiher, G. Pohnert
and M. Westerhausen, Org. Lett., 2013, 15, 4608–4611;
(d) W. H. Miles, Curr. Org. Synth., 2014, 11, 244–267;
(e) V. Kotzabasaki, G. Vassilikogiannakis and M. Stratakis,
Org. Lett., 2016, 18, 4982–4985; (f) W. H. Miles,
D. M. Thamattoor, R. E. Cerbone, D. J. Beidemana,
S. M. Zeiders, N. E. Jasiewicz, S. M. Petersen, B. J. Naimoli,
J. V. Leo, I. B. G. Suarsana, J. S. George and N. J. Albano,
Synthesis, 2016, 924–934. Selected examples for γ-lactams,
see: (g) M. G. Kalshetti and N. P. Argade, J. Org. Chem.,
2017, 82, 11126–11133; (h) D. Mori, Y. Kimura, S. Kitamura,
Y. Sakagami, Y. Yoshioka, T. Shintani, T. Okamoto and
M. Ojika, J. Org. Chem., 2007, 72, 7190–7198.
5 Selected examples: (a) Y. Liu, J. Ma, Y. Wang, P. O. Donkor,
Q. Li, S. Gao, Y. Hou, Y. Xu, J. Cui, L. Ding, F. Zhao,
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 7843–7850 | 7849

View Article Online
Paper
Organic & Biomolecular Chemistry
N. Kang, L. Chen and F. Qiu, Eur. J. Org. Chem., 2014,
Int. Ed., 2014, 53, 10970–10974; (m) D. Kalaitzakis,
D. Noutsias and G. Vassilikogiannakis, Org. Lett., 2015, 17,
3596–3599; (n) E. Anselmi, K. Cherry, C. Maaliki, S. Inack
Ngi, A. Duchêne, J. Thibonnet and M. Abarbri, Synthesis,
2016, 48, 1407–1413, A-G. For the biological study, see:
(o) D. Cornut, H. Lemoine, O. Kanishchev, E. Okada,
F. Albrieux, A. H. Beavogui, A.-L. Bienvenu, S. Picot,
J.-P. Bouillon and M. Médebielle, J. Med. Chem., 2013,
56, 73–83; (p) W.-K. Goh, C. R. Gardner, K. V.
G. Chandra Sekhar, N. N. Biswas, S. Nizalapur, S. A. Rice,
M. Willcox, D. S. Black and N. Kumar, Bioorg. Med. Chem.,
2015, 23, 7366–7377.
8 (a) G. Xia, L. Zhou, J. Ma, Y. Wang, L. Ding, F. Zhao,
L. Chen and F. Qiu, Fitoterapia, 2015, 103, 143–148;
(b) Y. Lou, F. Zhao, H. He, K.-F. Peng, L.-X. Chen and
F. Qiu, Chem. Biodiversity, 2010, 7, 1245–1253.
9 S.-E. N. Ayyad, T. R. Hoye, W. M. Alarif, S. M. A. Ahmadi,
S. A. Basaif, M. A. Ghandourah and F. A. Badria,
Z. Naturforsch., 2015, 70, 87–92.
5540–5548; (b) F. Fellug, F. Ghelfi, U. M. Pagnoni,
A. F. Parsons, M. Pattarozzi, F. Roncaglia and E. Valentin,
Synthesis, 2007, 1882–1886; (c) D. Mori, Y. Kimura,
S. Kitamura, Y. Sakagami, Y. Yoshioka, T. Shintani,
T. Okamoto and M. Ojika, J. Org. Chem., 2007, 72, 7190–
7198; (d) N. N. Biswas, S. K. Kutty, G. M. Iskander,
M. Mielczarek, M. M. Bhadbhade, C. R. Gardner,
D. S. Black and N. Kumar, Tetrahedron, 2016, 72, 539–546;
(e) S. Seo and M. C. Willis, Org. Lett., 2017, 19, 4556–4559.
6 Selected examples for γ-butenolides, see: (a) M. Aquino,
I. Bruno, R. Riccio and L. Gomez-Paloma, Org. Lett., 2006,
8, 4831–4834; (b) V. Kotzabasaki, G. Vassilikogiannakis and
M. Stratakis, J. Org. Chem., 2016, 81, 4406–4411; (c) B. Mao,
M. Fañanás-Mastral and B. L. Feringa, Chem. Rev., 2017,
117, 10502–10566; (d) J. Hou, A. Ee, W. Feng, J.-H. Xu,
Y. Zhao and J. Wu, J. Am. Chem. Soc., 2018, 140, 5257–5263.
Selected examples for γ-lactams, see: (e) G. B. Gill,
G. D. James, K. V. Oates and G. Pattenden, J. Chem. Soc.,
Perkin Trans. 1, 1993, 2567–2579; (f) L. Yang, C.-H. Lei, 10 (a) C. Zhang, J. Ji, M. Ji and P. Fan, Phytochem. Lett., 2015,
D.-X. Wang, Z.-T. Huang and M.-X. Wang, Org. Lett., 2010,
12, 3918–3921; (g) H. Uchiro, N. Shionozaki,
Y. Kobayakawa, H. Nakagawa and K. Makino, Bioorg. Med.
12, 215–219; (b) H.-F. Huang, C.-J. Zheng, Z.-R. Mo,
W.-Q. Yin, G.-Y. Chen, C.-R. Han and X. Huang, Chem. Nat.
Compd., 2016, 52, 527–530.
Chem. Lett., 2012, 22, 4765–4768; (h) W. Hou, B. Zhou, 11 (a) K. Takeda, I. Horibe and H. Minato, J. Chem. Soc. C,
Y. Yang, H. Feng and Y. Li, Org. Lett., 2013, 15, 1814–1817;
(i) D. Kalaitzakis, A. Kouridaki, D. Noutsias, T. Montagnon
1968, 569–572; (b) S.-L. Wu and W.-S. Li, J. Chin. Chem.
Soc., 1995, 42, 555–560.
and G. Vassilikogiannakis, Angew. Chem., Int. Ed., 2015, 54, 12 G. Qiu, P. Yan, W. Shao, J. Zhou, W. Lin, L. Fang, X. Zhao
6283–6287; ( j) M. I. D. Mardjan, J.-L. Parrain and and J. Dong, Chem. Pharm. Bull., 2013, 61, 983–986.
L. Commeiras, Adv. Synth. Catal., 2016, 358, 543–548; 13 J.-H. Ma, F. Zhao, Y. Wang, Y. Liu, S.-Y. Gao, L.-Q. Ding,
(k) N. Chopin, S. Iikawa, J. Bosson, A. Lavoignat, G. Bonnot,
A.-L. Bienvenu, S. Picot, J.-P. Bouillon and M. Médebielle,
Bioorg. Med. Chem. Lett., 2016, 26, 5308–5311.
L.-X. Chen and F. Qiu, Org. Biomol. Chem., 2015, 13, 8349–
8358.
14 D. Friedrich and F. Bohlmann, Tetrahedron, 1988, 44, 1369–
7 Selected total synthetic studies for γ-hydroxybutenolides
1392.
and γ-ylidenebutenolides, see: (a) A. K. Cheung and 15 (a) H. Hikino, K. Agatsuma and T. Takemoto, Tetrahedron
M. L. Snapper, J. Am. Chem. Soc., 2002, 124, 11584–11585;
Lett., 1968, 24, 2855–2858; (b) H. Hikino, K. Agatsuma and
(b) N. Furuichi, H. Hara, T. Osaki, M. Nakano, H. Mori and
T. Takemoto, Chem. Pharm. Bull., 1970, 18, 752–755.
S. Katsumura, J. Org. Chem., 2004, 69, 7949–7959; 16 (a) C. Yuan, B. Du, L. Yang and B. Liu, J. Am. Chem. Soc.,
(c) A. K. Cheung, R. Murelli and M. L. Snapper, J. Org.
Chem., 2004, 69, 5712–5719; (d) S. N. Patil and F. Liu, Org.
Lett., 2007, 9, 195–198; (e) G. Yue, L. Yang, C. Yuan,
X. Jiang and B. Liu, Org. Lett., 2011, 13, 5406–5408;
2013, 135, 9291–9294; (b) B. Du, C. Yuan, T. Yu, L. Yang,
Y. Yang, B. Liu and S. Qin, Chem. – Eur. J., 2014, 20, 2613–
2622; (c) C. Yuan, B. Du, H. Deng, Y. Man and B. Liu,
Angew. Chem., Int. Ed., 2017, 56, 637–640.
(f) D. T. Hog, R. Webster and D. Trauner, Nat. Prod. Rep., 17 (a) T. Sato, Y. Gotoh, M. Watanabe and T. Fujisawa, Chem.
2012, 29, 752–779; (g) G. Yue, L. Yang, C. Yuan, B. Du and
B. Liu, Tetrahedron, 2012, 68, 9624–9637; (h) L. Otero,
B. Vaz, R. Àlvarez and À. R. de Lera, Chem. Commun., 2013,
Lett., 1983, 1533–1536; (b) M. Kato, M. Watanabe, B. Vogler,
B. Z. Awen, Y. Masuda, Y. Tooyama and A. Yoshikoshi,
J. Org. Chem., 1991, 56, 7071–7076.
49, 5043–5045; (i) L. Wang, H. Wang, Y. Li and P. Tang, 18 W. Qi, K. Zhao, J. Gu, Y. Huang, Y. Wang, H. Zhang,
Angew. Chem., Int. Ed., 2015, 54, 5732–5735. Selected total
synthetic studies for 5-hydroxy-1H-pyrrol-2(5H)-ones and
M. Zhang, J. Zhang, Z. Yu, L. Li, L. Teng, S. Chuai,
C. Zhang, M. Zhao, H.-M. Chan, Z. Chen, D. Fang, Q. Fei,
L. Feng, L. Feng, Y. Gao, H. Ge, X. Ge, G. Li, A. Lingel,
Y. Lin, Y. Liu, F. Luo, M. Shi, L. Wang, Z. Wang, Y. Yu,
J. Zeng, C. Zeng, L. Zhang, Q. Zhang, S. Zhou, C. Oyang,
P. Atadja and E. Li, Nat. Chem. Biol., 2017, 13, 381–388.
5-ylidenepyrrol-2(5H)-ones,
Y. Shimotsu, S. Mizumoto, N. Mase, H. Yoda and
K. Takabe, Heterocycles, 2004, 63, 1013–1016;
(k) N. Shionozaki, T. Yamaguchi, H. Kitano, M. Tomizawa,
see:
( j)
J.-I.
Bessho,
K. Makino and H. Uchiro, Tetrahedron Lett., 2012, 53, 5167– 19 (a) M. Kato, B. Vogler, Y. Tooyama and A. Yoshikoshi,
5170; (l) K. C. Nicolaou, L. Shi, M. Lu, M. R. Pattanayak,
A. A. Shah, H. A. Ioannidou and M. Lamani, Angew. Chem.,
Chem. Lett., 1990, 151–154; (b) G. Majetich, P. A. Grieco
and M. Nishizawa, J. Org. Chem., 1977, 42, 2327–2329.
7850 | Org. Biomol. Chem., 2018, 16, 7843–7850
This journal is © The Royal Society of Chemistry 2018