Total Synthesis of the Marine Alkaloid Discoipyrrole C via the MoOPH-Mediated Oxidation of a 2,3,5-Trisubstituted Pyrrole

Article abstract of DOI:10.1021/acs.jnatprod.7b00872

A total synthesis of the marine alkaloid discoipyrrole C (3) is described. In the pivotal step, the 2,3,5-trisubstituted pyrrole 19 was treated with MoOPH in the presence of MeOH, and the resulting methoxylated 1,2-dihydro-3H-pyrrol-3-one 20 subjected to reaction with potassium carbonate in MeOH then trifluoroacetic acid and H₂O. This gave a mixture of target 3 and its dehydration product, and the structure of the former compound was confirmed by single-crystal X-ray analysis.

Full text of DOI:10.1021/acs.jnatprod.7b00872

Article
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Cite This: J. Nat. Prod. XXXX, XXX, XXX−XXX
Total Synthesis of the Marine Alkaloid Discoipyrrole C via the
MoOPH-Mediated Oxidation of a 2,3,5-Trisubstituted Pyrrole
Qiao Yan, Xiang Ma, Martin G. Banwell,* and Jas S. Ward
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: A total synthesis of the marine alkaloid discoipyrrole C (3) is described. In the pivotal step, the 2,3,5-trisubstituted
pyrrole 19 was treated with MoOPH in the presence of MeOH, and the resulting methoxylated 1,2-dihydro-3H-pyrrol-3-one 20
subjected to reaction with potassium carbonate in MeOH then trifluoroacetic acid and H2O. This gave a mixture of target 3 and
its dehydration product, and the structure of the former compound was confirmed by single-crystal X-ray analysis.
he production of discoipyrroles A−D by the marine
Tbacterium Bacilluus hunanensis was reported by the
MacMillan group in 2013 and, on the basis of a range of
spectroscopic studies, these alkaloids were assigned structures
1−4, respectively.1 In addition to congeners 1, 2, and 4
embodying the previously unobserved 3H-benzo[d]pyrrole-
[1,3]oxazine-3,5-dione heterocyclic framework, all four com-
pounds showed intriguing biological properties. Specifically,
each of them inhibited the discoidin domain receptor 2 or
DDR2-dependent migration of BR5 fibroblasts. They also
showed selective cytotoxicity toward DDR2 mutant lung cancer
cell lines with IC50 values in the 120 to 400 nM range.1
The racemic nature of the first three of these alkaloids and
the isolation of the fourth as a ca. 1:1 mixture of
diastereoisomers led to the proposal that the core structures
of the discoipyrroles are produced in vivo by nonenzymatic
pathways.1,2 Support for this proposition followed from the in
vitro assembly, under close to physiological conditions, of
congener 1 from co-occurring and structurally simpler
metabolites.1,2 This biomimetic approach to the alkaloids has
also been used to prepare a range of analogues including the
bis-O-methyl ether of compound 4.3
We have recently described4,5 modular total syntheses of
2, and 4. While discoipyrrole C (3) is the structurally simplest
member of this small family of natural products, it is distinct
because it lacks the benzannulated 1,3-oxazinan-6-one ring
system associated with congeners 1, 2, and 4. Rather it
embodies a 2-alkyl-2-hydroxy-1,2-dihydro-3H-pyrrol-3-one core
and thus bears some structural resemblance to the biologically
discoipyrroles A, B, and D that involve, as key intermediates,
tetrasubstituted pyrroles wherein a benzoic acid moiety is
attached to the ring-nitrogen through the ortho-position. On
treatment of such systems with oxodiperoxymolybdenum-
(pyridine)(hexamethylphosphoric triamide) (MoOPH),6,7
they undergo oxidative cyclization with the carboxylic acid
residue acting as an internal nucleophile, thus producing the
central hetereocyclic ring system characteristic of compounds 1,
Received: October 18, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
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DOI: 10.1021/acs.jnatprod.7b00872
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Scheme 1. Synthesis of the 2,3,5-Trisubstituted Pyrrole 10 and its Reaction with the Ley−Griffith Reagent
active natural products myceliothermophins A and B,
oteromycin, pyrrocidine A, and PI-090 (each of which
embodies a 5-alkyl-5-hydroxy-1,5-dihydro-2H-pyrrol-2-one
moiety).8,9 The labile nature of the core of discoipyrrole C,
its intriguing biological properties, and the lack of any
published work on its synthesis prompted us to begin exploring
methods for doing so. Herein we report the outcomes of our
studies on this topic that have culminated in the total synthesis
of compound 3 and its characterization by single-crystal X-ray
analysis.
establishing whether or not a 2,3,5-trisubstituted pyrrole (and,
therefore, lacking a substituent on the ring nitrogen) could be
oxidized in the presence of a nucleophilic solvent such as
MeOH (and in an analogous way to that observed for certain
indoles7) so as to generate a 2-alkyl-2-methoxy-1,2-dihydro-3H-
pyrrol-3-one that it was expected could be hydrolyzed to form
the heterocyclic core of discoipyrrole C. So, following our
earlier work, the readily available pyrrole-2-carboxaldehyde (5)
was brominated using N-bromosuccinimide (NBS) at low
temperature, thereby generating the known4a dibromo-
derivative 6 (83%). Compound 6 was readily engaged in a 2-
fold Suzuki−Miyaura cross-coupling reaction with an excess of
the commercially available arylboronic acid 7 under standard
conditions, thus affording the previously reported4a diarylated
pyrrole 8 (85%), and this was itself treated with isopropylmag-
RESULTS AND DISCUSSION
■
Converting the 2,3,5-Trisubstituted Pyrrole 10 into
the Corresponding 2-Alkyl-2-hydroxy-1,2-dihydro-3H-
pyrrol-3-one. Our initial studies (Scheme 1) focused on
B
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Scheme 2. Outcome of the Oxidation of Pyrrole 10 with MoOPH in the Presence of MeOH
Scheme 3. Outcomes of Treating Compound 12 with Aqueous Acid
nesium bromide to afford the secondary alcohol 94a in 95%
yield. Treatment of compound 9 with lithium aluminum
hydride resulted in its reductive deoxygenation to afford the
required 2,3,5-trisubstituted pyrrole 104a in 75% yield. In an
initial attempt to effect the desired oxidation of compound 10 it
was treated with the Ley−Griffith reagent.10,11 A very slow and
clean reaction ensued, but this involved an oxidative
dimerization process that afforded the bis-pyrrole 11 (98%
brsm), the structure of which was determined by single-crystal
X-ray analysis. No evidence for the formation of the desired 2-
alkyl-2-methoxy-1,2-dihydro-3H-pyrrol-3-one was obtained.
In contrast to the foregoing, when a 1:1 v/v CH2Cl2/MeOH
solution of substrate 10 was treated with MoOPH6 at ambient
temperatures, a quite distinct oxidation process (Scheme 2)
took place, thus affording a mixture of compounds 12 (24%),
13 and 14 (15% combined yield), and the known12 diketone 15
(51%). Subjection of this mixture to flash column chromatog-
raphy allowed for the isolation of the first and last of these
products in pure form, while amides 13 and 14 were obtained
as a ca. 1:1 mixture. The spectroscopic data recorded on the 2-
alkyl-2-methoxy-1,2-dihydro-3H-pyrrol-3-one 12 were in com-
plete accord with the assigned structure, but final confirmation
of this followed from a single-crystal X-ray analysis. On the
other hand, the spectroscopic data recorded on 4,4′-
dimethoxybenzil (15) matched those reported in the
literature.12 The mixture of compounds 13 and 14 was
obtained as a crystalline conglomerate, and an individual
crystal of each was subjected to X-ray analysis, thereby
establishing the illustrated structures for them. Clearly
compounds 13, 14, and 15 result from oxidative cleavage of
the pyrrole ring11 associated with the starting material 10, but
the details of the pathway(s) involved have yet to be fully
investigated.
Despite the dominance of the oxidative cleavage processes
described immediately above, sufficient quantities of compound
12 could be obtained so as to test whether or not it could be
successfully hydrolyzed to give the corresponding 2-hydroxy-
1,2-dihydro-3H-pyrrol-3-one. Disappointingly, on treating this
C
DOI: 10.1021/acs.jnatprod.7b00872
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Scheme 4. Completion of a Total Synthesis of Discoipyrrole C (3)
substrate with trifluoroacetic acid (TFA) in a mixture of
CH2Cl2 and H2O under conditions similar to those employed
by Uchiro and co-workers (Scheme 3),8,9 only traces of the
target compound 16 were observed, the major one formed
being the elimination product 17 (87%) embodying an
exocyclic olefin. The illustrated Z-configuration about this
double bond is assigned by analogy with the work of Uchiro
and co-workers.8 Fortunately, when the same substrate was
treated with TFA in the same solvent mixture but now at lower
temperatures and for shorter periods of time, compound 16
assigned structure. The strong resemblance of these data to
those reported1 for natural product 3 was notable.
Various attempts were made to convert, through 2-fold
demethylation, bis-ether 16 into discoipyrrole C including by
treating the former compound with boron tribromide.
Unsurprisingly, though, only decomposition of the substrate
was observed under such conditions.3,5 Accordingly, a pathway
to compound 3 was pursued wherein such a demethylation
reaction was effected prior to the pyrrole oxidation step. The
successful outcome of this approach is detailed immediately
below.
was produced in 93% yield. All of the spectroscopic data
acquired on product 16, which represents the bis-O-methyl
ether of discoipyrrole C, were completely in accord with the
Completing a Total Synthesis of Discoipyrrole C. A
synthesis of discoipyrrole C (3) that exploited the results of the
D
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resonances employed for spectra recorded in (CD3)2CO were 2.05
and 29.8/206.3 ppm. Low-resolution ESI mass spectra were recorded
on a single quadrupole liquid chromatograph−mass spectrometer,
while high-resolution measurements were conducted on a time-of-
flight instrument. Low- and high-resolution EI mass spectra were
recorded on a magnetic-sector machine. Analytical thin-layer
chromatography (TLC) was performed on aluminum-backed 0.2
mm thick silica gel 60 F254 plates as supplied by Merck. Eluted plates
were visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolyb-
dic acid/ceric sulfate/sulfuric acid (conc)/H2O (37.5 g:7.5 g:37.5
g:720 mL) or potassium permanganate/potassium carbonate/5%
sodium hydroxide aqueous solution/H2O (3 g:20 g:5 mL; 300 mL).
Flash chromatographic separations were carried out following
protocols defined by Still et al.14 with silica gel 60 (40−63 μm) as
the stationary phase and using the AR- or HPLC-grade solvents
indicated. The melting points of solids purified by such means were
recorded directly (i.e., after they had crystallized from the concentrated
chromatographic fractions). Starting materials and reagents were
generally available from Sigma−Aldrich, Merck, TCI, Strem, or
Lancaster Chemical Companies and were used as supplied. Drying
agents and other inorganic salts were purchased from the AJAX, BDH,
or Unilab Chemical Companies. Tetrahydrofuran (THF), MeOH, and
CH2Cl2 were dried using a Glass Contour solvent purification system
that is based upon a technology originally described by Grubbs et al.15
Where necessary, reactions were performed under a nitrogen
atmosphere.
Synthesis of 4,5-Dibromo-1H-pyrrole-2-carbaldehyde (6). In
a modification of a published procedure,4a a magnetically stirred
solution of commercially available 1H-pyrrole-2-carbaldehyde (5)
(5.00 g, 52.6 mmol) in anhydrous THF (200 mL) and protected from
light using aluminum foil was cooled to −78 °C, then treated with
NBS (20.60 g, 115.7 mmol). The cooling bath was then removed, and
the reaction mixture allowed to warm to 22 °C, stirred at this
temperature for 20 h, then recooled to 0 °C and treated with Na2SO3
(14.00 g, 111.08 mmol). The resulting mixture was stirred at 0 °C for
0.5 h, then filtered through a pad of diatomaceous earth. The filtrate
was concentrated under reduced pressure to give a brown oil, and
subjecting this material to flash chromatography (silica, 1:19 → 1:9 v/
v EtOAc/40−60 petroleum ether gradient elution) afforded, after
concentration of the appropriate fractions (Rf = 0.4 in 1:4 v/v EtOAc/
40−60 petroleum ether elution), 4,5-dibromo-1H-pyrrole-2-carbalde-
hyde (6)4a (11.0 g, 83%): pink, crystalline solid; the 1H and 13C NMR
spectroscopic data acquired on this material matched those reported4a
previously.
above-mentioned studies is outlined in Scheme 4. This started
with the 2-fold demethylation of the diarylated pyrrole 10 using
boron tribromide. The resulting bis-phenol 18 (87%) was
acetylated under conventional conditions, and the bis-ester 19
(96%) so-formed was treated with MoOPH in CH2Cl2/MeOH,
thus affording a mixture of compounds 20 and 21 in ca. 80%
combined yield. Traces of the isomeric α-aryl-β-amidocinna-
mates 22 and 23 were also evident in the 1H NMR spectrum of
the crude reaction mixture obtained from the oxidation of
pyrrole 19, but these could not be obtained in quantities
sufficient for rigorous characterization. In contrast, each of
oxidation products 20 and 2113 could be purified by flash
column chromatography and fully characterized. When
compound 20 was treated with potassium carbonate in
MeOH, the bis-phenol 24 was obtained in 97% yield. Exposure
of compound 24 to TFA in a CH2Cl2/H2O mixture at 0 °C for
less than an hour followed by workup in the cold then gave
discoipyrrole C (3) in 89% yield. Traces of the dehydration
product 25 were also produced under these conditions, and
more of this (61%) was formed when extended reaction times
and higher temperatures were employed in the hydrolysis step
(see Experimental Section). Once again, the illustrated Z-
configuration about this double bond is assigned by analogy
with the work of Uchiro and co-workers.8
All of the spectroscopic data acquired on the synthetically
derived compounds 3 and 25 were in full accord with the
illustrated structures, and those derived from the former
product proved an excellent match with those reported1 for
discoipyrrole C by the MacMillan group (see the Supporting
Information for a tabulated comparison of the relevant 13C
NMR data sets). A single-crystal X-ray analysis was undertaken
on compound 3, and this served to confirm its structure and,
therefore, that of the natural product.
It is interesting to note that the heterocyclic core associated
with the dehydration product 25 is similar to that seen in the
natural product myceliothermophin E.8 Furthermore, there
were indications that, on standing, compound 25 began to
rearrange to its E-isomer. A related isomerization was observed
during the synthesis of myceliothermophin E.8
CONCLUSIONS
■
Synthesis of 4,5-Bis(4-methoxyphenyl)-1H-pyrrole-2-carbal-
dehyde (8). In a modification of a published procedure,4a
a
The MoOPH-mediated oxidation of N-unsubstituted pyrroles
provides a hitherto unrecognized capacity to generate function-
alized 1,2-dihydro-3H-pyrrol-3-ones such as discoipyrrole C.
The opportunities to extend the types of processes reported
here to related systems seem significant, although there is an
attendant need to understand the mechanistic detail of these
reactions and thereby optimize them. Work directed to such
ends are now underway in our laboratories, and the outcomes
of relevant studies will be reported in due course.
magnetically stirred mixture of 4,5-dibromo-1H-pyrrole-2-carbalde-
hyde (6) (4.90 g, 19.38 mmol), (4-methoxyphenyl)boronic acid (7)
(8.83 g, 58.13 mmol), Pd(PPh3)4 (820 mg, 0.71 mmol), and Na2CO3
(12.32 g, 116.24 mmol) in deoxygenated 1,2-dimethoxyethane/H2O
(198 mL of a 6:1 v/v mixture) was heated at 85 °C under a nitrogen
atmosphere for 20 h, then cooled to 22 °C before being poured into
H2O (200 mL) and extracted with EtOAc (3 × 150 mL). The
combined organic phases were then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 3:17 v/v EtOAc/
40−60 petroleum ether elution). Concentration of the appropriate
fractions (Rf = 0.6 3:7 v/v EtOAc/40−60 petroleum ether elution)
gave 4,5-bis(4-methoxyphenyl)-1H-pyrrole-2-carbaldehyde (8) (5.00
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
measured on an Optimelt automated melting point system and are
uncorrected. Infrared spectra (νmax) were recorded on a Perkin−Elmer
1800 Series FTIR spectrometer. Samples were analyzed as thin films
on KBr plates. Proton (1H) and carbon (13C) NMR spectra were
recorded at room temperature in base-filtered CDCl3, CD3OD, or
(CD3)2CO on a Varian spectrometer operating at 400 MHz for proton
and 100 MHz for carbon nuclei. The signal due to residual CHCl3
appearing at δH 7.26 and the central resonance of the CDCl3 triplet
appearing at δC 77.2 were used to reference 1H and 13C NMR spectra,
respectively. For spectra recorded in CD3OD these were referenced to
the signals at δH 3.31 and δC 49.0, respectively, while the equivalent
1
g, 85%): yellow, crystalline solid; the H and 13C NMR spectroscopic
data acquired on this material matched those reported4a previously.
Synthesis of 1-(4,5-Bis(4-methoxyphenyl)-1H-pyrrol-2-yl)-2-
methylpropan-1-ol (9). In a modification of a published
procedure,4a a magnetically stirred solution of 4,5-bis(4-methox-
yphenyl)-1H-pyrrole-2-carbaldehyde (8) (922 mg, 3.00 mmol) in
anhydrous THF (60 mL) maintained at 0 °C under an atmosphere of
nitrogen was treated, dropwise over 0.08 h, with isopropylmagnesium
bromide solution (3.75 mL of a 2.4 M solution in 2-methyltetrahy-
drofuran, 9.00 mmol). The ensuing mixture was stirred at 0 °C for 1 h,
E
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then quenched by the slow addition of ice (CAUTION!
EXOTHERMIC REACTION). The ensuing mixture was poured into
H2O (100 mL) and extracted with EtOAc (3 × 100 mL). The
combined organic phases were then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 1:9 v/v EtOAc/40−
60 petroleum ether elution) to give, after concentration of the
appropriate fractions (Rf = 0.7, 2-fold elution in 3:7 v/v EtOAc/40−60
2.98 mmol) in CH2Cl2/MeOH (80 mL of a 1:1 v/v mixture)
maintained at 22 °C and protected from light using aluminum foil was
treated with MoOPH6 (5.18 g, 11.9 mmol). The reaction mixture was
stirred at 22 °C for 16 h, then quenched with H2O (30 mL) before
being diluted with EtOAc (50 mL). The ensuing mixture was filtered
through a pad of diatomaceous earth, and the separated aqueous phase
associated with the filtrate was extracted with EtOAc (3 × 100 mL).
The combined organic phases were then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 1:9 → 3:7 v/v
EtOAc/40−60 petroleum ether gradient elution) to give three
fractions, A−C.
1
petroleum ether), alcohol 9 (999 mg, 95%): clear, colorless oil; H
NMR (400 MHz, CD3OD) δ 7.23 (m, 2H), 7.17 (m, 2H), 6.83−6.74
(complex m, 4H), 6.10 (s, 1H), 4.31 (d, J = 7.5 Hz, 1H), 3.76−3.74
(complex m, 6H), 2.05 (m, 1H), 1.06 (d, J = 6.6 Hz, 3H), 0.90 (d, J =
6.5 Hz, 3H) (signals due to OH and NH groups protons not
observed); 13C NMR (100 MHz, CD3OD) δ 159.6, 158.9, 135.1,
131.6, 130.3, 129.9, 128.1, 128.0, 121.6, 114.8, 114.6, 108.3, 75.0, 55.6,
35.5, 19.6, 19.3 (one signal obscured or overlapping); IR νmax 3404,
2958, 2835, 1519, 1245, 1178, 1033, 833 cm−1; MS (EI, 70 eV) m/z
351 (M+•, 100), 349 (90); HRMS m/z 351.1836 M+• (calcd for
C22H25NO3, 351.1834).
Synthesis of 5-Isobutyl-2,3-bis(4-methoxyphenyl)-1H-pyr-
role (10). LiAlH4 (650 mg, 17.13 mmol) was added to a magnetically
stirred solution of alcohol 9 (2.15 g, 6.12 mmol) in THF (108 mL)
maintained at 22 °C under an atmosphere of nitrogen. The resulting
mixture was stirred magnetically while being heated under reflux for 16
h. After this time the reaction mixture was cooled to 0 °C, then
quenched by the slow addition of ice (CAUTION! EXOTHERMIC
REACTION AND POSSIBILITY OF HYDROGEN EVOLUTION).
The ensuing mixture was poured into H2O (200 mL) and extracted
with EtOAc (3 × 150 mL), and the combined organic phases were
then dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to flash column
chromatography (silica, 1:9 v/v EtOAc/40−60 petroleum ether
elution) to give, after concentration of the appropriate fractions (Rf
= 0.5 in 3:7 v/v EtOAc/40−60 petroleum ether elution), 5-isobutyl-
2,3-bis(4-methoxyphenyl)-1H-pyrrole (10)4a (1.95 g, 95%): pink,
crystalline solid; the 1H and 13C NMR spectroscopic data acquired on
this material matched those reported4a previously.
Synthesis of 2,2′-Diisobutyl-4,4′,5,5′-tetrakis(4-methoxy-
phenyl)-1H,1′H-3,3′-bipyrrole (11). A magnetically stirred solution
of 5-isobutyl-2,3-bis(4-methoxyphenyl)-1H-pyrrole (10) (120 mg,
0.36 mmol) in CH2Cl2 (40 mL) was treated with 4-methylmorpholine
N-oxide (46 mg, 0.39 mmol) and molecular sieves (80 mg of
powdered and activated 4 Å material), then tetra-n-propylammonium
perruthenate (TPAP) (25 mg, 0.07 mmol). The resulting mixture was
stirred at 22 °C for 96 h and then filtered through a pad of
diatomaceous earth. The filtrate was concentrated under reduced
pressure to give a black oil. Subjection of this material to flash
chromatography (silica, 1:19 → 1:9 v/v EtOAc/30−40 petroleum
ether gradient elution) afforded two fractions, A and B.
Concentration of fraction A (Rf = 0.1 in 3:7 v/v EtOAc/40−60
petroleum ether) gave compound 12 (268 mg, 24%): yellow,
1
crystalline solid, mp 125−127 °C; H NMR [400 MHz, (CD3)2CO]
δ 7.54 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0
Hz, 2H), 6.92 (s, 1H), 6.81 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.77 (s,
3H), 3.16 (s, 3H), 1.89−1.76 (complex m, 3H), 0.92 (d, J = 6.5 Hz,
6H); 13C NMR [100 MHz, (CD3)2CO] δ 199.0, 171.7, 163.0, 158.9,
131.1, 131.0, 125.7, 124.6, 114.8, 114.2, 111.3, 92.3, 55.8, 55.4, 50.7,
46.2, 24.8, 24.6, 24.3; IR νmax 3257, 2957, 1605, 1498, 1463, 1251,
1175, 1029, 836 cm−1; MS (ESI, + ve) m/z 404 [(M + Na)+, 100%],
382 [(M + H)+, 15]; HRMS m/z 382.2016 [M + H]+ (calcd for
C23H28NO4, 382.2013).
Concentration of fraction B (Rf = 0.2 in 3:7 v/v EtOAc/40−60
petroleum ether) gave a ca. 1:1 mixture of compounds 13 and 14 (160
1
mg, 15%): yellow, crystalline solid, mp 130−132 °C; H NMR (400
MHz, CDCl3) δ 11.81 (s, 1H), 9.62 (s, 1H), 9.47 (s, 1H), 7.39 (d, J =
9.0 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.11 (s, 1H), 7.03−6.95
(complex m, 6H), 6.89 (d, J = 9.0 Hz, 2H), 6.74−6.68 (complex m,
4H), 3.86 (s, 3H), 3.85 (s, 3H), 3.75(0) (s, 3H), 3.74(7) (s, 3H), 2.30
(d, J = 7.1 Hz, 2H), 2.18 (m, 1H), 1.98 (m, 3H), 1.00 (d, J = 6.6 Hz,
6H), 0.88 (d, J = 6.5 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 194.6,
192.3, 171.8, 170.9, 161.5, 160.1, 159.7, 158.5, 153.8, 151.7, 131.9,
131.8(0), 131.7(7), 130.7, 128.3, 127.3, 126.6, 125.3, 125.2, 120.1,
114.7, 113.9(9), 113.9(8), 113.4, 55.5(1), 55.4(8), 55.3, 55.2, 47.6,
46.7, 26.0, 25.9, 22.6, 22.5; IR νmax 3273, 2959, 1665, 1604, 1510,
1464, 1248, 1176, 1030, 833 cm−1; MS (ESI, + ve) m/z 757 [(2M +
Na)+, 25%], 390 [(M + Na)+, 50], 368 [(M + H)+, 25], 284 (100);
HRMS m/z 368.1860 [M + H]+ (calcd for C22H26NO4, 368.1856).
Concentration of fraction C (Rf = 0.3 in 3:7 v/v EtOAc/40−60
petroleum ether) gave benzil 1512 (410 mg, 51%): yellow solid, mp =
130−132 °C (lit.12 mp 132−133 °C); 1H NMR (400 MHz, CDCl3) δ
7.95 (d, J = 9.0 Hz, 4H), 6.97 (d, J = 9.0 Hz, 4H), 3.88 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 193.6, 165.0, 132.5, 126.5, 114.4, 55.8; IR
νmax 1657, 1598, 1573, 1510, 1263, 1162, 1018, 880, 832 cm−1; MS
(EI, 70 eV) m/z 270 (M+•, 15%), 136 (85), 135 (100), 107 (35), 92
(70), 77 (75), 64 (30); HRMS m/z 270.0894 M+• (calcd for
C16H14O4, 270.0892).
Synthesis of 2-Hydroxy-2-isobutyl-4,5-bis(4-methoxyphen-
yl)-1,2-dihydro-3H-pyrrol-3-one (16). A magnetically stirred
solution of 2-isobutyl-2-methoxy-4,5-bis(4-methoxyphenyl)-1,2-dihy-
dro-3H-pyrrol-3-one (12) (20 mg, 0.05 mmol) in CH2Cl2/H2O (480
μL of a 4:1 v/v mixture) maintained at 0 °C under a nitrogen
atmosphere was treated, dropwise over 0.08 h, with trifluoroacetic acid
(200 uL, 2.61 mmol). The ensuing mixture was stirred at 0 °C for 25
min, and then H2O (10 mL) followed by EtOAc (10 mL) were added
at the same temperature. The separated organic phase was washed, at 0
°C, with H2O (1 × 10 mL) and then NaHCO3 (2 × 10 mL of a
saturated aqueous solution) until the pH of the aqueous washings was
between 5 and 7. The organic phase was dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 1:1 v/v EtOAc/40−
60 petroleum ether elution) to give, after concentration of the
appropriate fractions (Rf = 0.2 in 1:1 v/v EtOAc/40−60 petroleum
Concentration of fraction A (Rf = 0.5 in 3:7 v/v EtOAc/40−60
petroleum ether) gave compound 10 (80 mg, 67% recovery): pink
solid; identical, in all respects, with an authentic sample.
Concentration of fraction B (Rf = 0.4 in 3:7 v/v EtOAc/40−60
petroleum ether) gave compound 11 (38 mg, 32% or 98% brsm):
white, crystalline solid, mp 160−162 °C; 1H NMR [400 MHz,
(CD3)2CO] δ 9.55 (s, 2H), 7.20 (d, J = 9.0 Hz, 4H), 6.98 (d, J = 9.0
Hz, 4H), 6.76 (d, J = 9.0 Hz, 4H), 6.66 (d, J = 9.0 Hz, 4H), 3.75 (s,
6H), 3.71 (s, 6H), 2.23−2.08 (complex m, 4H), 1.85 (m, 2H), 0.78 (d,
J = 6.6 Hz, 6H), 0.73 (d, J = 6.5 Hz, 6H); 13C NMR [100 MHz,
(CD3)2CO] δ 158.5, 158.3, 132.0, 131.3, 130.9, 128.8, 128.0, 126.5,
122.5, 116.4, 114.3, 113.8, 55.4, 55.3, 36.7, 28.6, 23.1, 23.0; IR νmax
3383, 2954, 2834, 1514, 1286, 1242, 1176, 1033, 832 cm−1; MS (EI,
70 eV) m/z 669 (50%), 668 (M+•, 100), 625 (20), 624 (45); HRMS
m/z 668.3626 M+• (calcd for C44H48N2O4, 668.3614).
Synthesis of 2-Isobutyl-2-methoxy-4,5-bis(4-methoxyphen-
yl)-1,2-dihydro-3H-pyrrol-3-one (12), (Z)-N-(1,2-Bis(4-methox-
yphenyl)-3-oxoprop-1-en-1-yl)-3-methylbutanamide (13), (E)-
N-(1,2-Bis(4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-3-methyl-
butanamide (14), and 1,2-Bis(4-methoxyphenyl)ethane-1,2-
dione (15). A magnetically stirred solution of compound 10 (1.00 g,
1
ether), compound 16 (18 mg, 93%): light yellow oil; H NMR (400
MHz, CD3OD) δ 7.46 (d, J = 9.0 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H),
6.93 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.77
(s, 3H), 1.88 (d, J = 6.1 Hz, 2H), 1.71 (m, 1H), 0.97 (d, J = 6.5 Hz,
3H), 0.95 (d, J = 6.6 Hz, 3H) (signals due to OH and NH groups
F
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Journal of Natural Products
Article
protons not observed); 13C NMR (100 MHz, CD3OD) δ 202.3, 174.1,
163.9, 159.6, 131.8, 131.6, 126.0, 124.4, 115.0, 114.7, 108.8, 88.9, 56.0,
55.6, 46.7, 25.1, 24.7, 24.6; IR νmax 3286, 2956, 1651, 1606, 1524,
1497, 1251, 1176, 1030, 837 cm−1; MS (ESI, + ve) m/z 757 [(2M +
Na)+, 100%], 390 [(M + Na)+, 45], 368 [(M + H)+, 15]; HRMS m/z
368.1861 [M + H]+ (calcd for C22H26NO4, 368.1856).
2.24(2) (s, 3H), 1.97 (m, 1H), 0.97 (d, J = 6.5 Hz, 6H); 13C NMR
[100 MHz, (CD3)2CO] δ 169.6(9), 169.6(7), 150.2, 149.8, 136.0,
133.6, 132.4, 129.7, 129.0, 126.6, 122.6, 122.4, 121.8, 109.4, 37.6, 22.8,
21.0(0), 20.9(8) (one signal obscured or overlapping); IR νmax 3377,
2956, 1747, 1514, 1369, 1217, 1196, 1015, 912, 848 cm−1; MS (EI, 70
eV) m/z 391 (M+•, 50%), 348 (35), 306 (100), 264 (70), 234 (30);
HRMS m/z 391.1791 M+• (calcd for C24H25NO4, 391.1784).
Synthesis of (5-Isobutyl-5-methoxy-4-oxo-4,5-dihydro-1H-
pyrrole-2,3-diyl)bis(4,1-phenylene) Diacetate (20) and
Oxalylbis(4,1-phenylene) Diacetate (21). A magnetically stirred
solution of compound 19 (1.00 g, 2.98 mmol) in CH2Cl2/MeOH (80
mL of a 1:1 v/v mixture) maintained at 22 °C and protected from light
with aluminum foil was treated with MoOPH6 (5.18 g, 11.9 mmol).
The ensuing mixture was stirred at 22 °C for 16 h, then quenched with
H2O (30 mL) before being diluted with EtOAc (1 × 50 mL), then
filtered through a pad of diatomaceous earth. The separated aqueous
phase associated with the filtrate was extracted with EtOAc (3 × 100
mL), and the combined organic phases were then dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue thus
obtained was subjected to flash column chromatography (silica, 1:9 →
3:7 v/v EtOAc/40−60 petroleum ether gradient elution) to give two
fractions, A and B.
Concentration of fraction A (Rf = 0.2, eluted twice with 3:7 v/v
EtOAc/40−60 petroleum ether) gave compound 20 (324 mg, 29%):
yellow, crystalline solid, mp 79−81 °C; 1H NMR (400 MHz, CD3OD)
δ 7.59 (d, J = 8.7 Hz, 2H), 7.19 (m, 4H), 7.00 (d, J = 8.7 Hz, 2H), 3.23
(s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.87 (m, 2H), 1.77 (m, 1H), 0.96
(m, 6H) (signal due to NH group proton not observed); 13C NMR
(100 MHz, CD3OD) δ 201.0, 175.2, 171.2, 170.6, 154.9, 150.6, 131.2,
131.1, 130.5, 129.5, 123.5, 122.6, 111.3, 93.8, 51.3, 46.4, 24.8(4),
24.7(5), 24.7, 20.9(1), 20.8(8); IR νmax 3270, 2958, 1754, 1663, 1518,
1370, 1198, 1167, 1016, 912 cm−1; MS (EI, 70 eV) m/z 437 (M+•,
55%), 407 (50), 364 (45), 322 (45), 252 (65), 210 (100); HRMS m/z
437.1837 M+• (calcd for C25H27NO6, 437.1838).
Synthesis of (Z)-4,5-Bis(4-methoxyphenyl)-2-(2-methylpro-
pylidene)-1,2-dihydro-3H-pyrrol-3-one (17). A magnetically
stirred solution of 2-isobutyl-2-methoxy-4,5-bis(4-methoxyphenyl)-
1,2-dihydro-3H-pyrrol-3-one (12) (30 mg, 0.08 mmol) in CH2Cl2/
H2O (710 μL of a 4:1 v/v mixture) maintained at 0 °C under a
nitrogen atmosphere was treated, dropwise over 5 min, with
trifluoroacetic acid (300 μL, 3.91 mmol). The ensuing mixture was
stirred at 0 °C for 1 h, then warmed to 22 °C, and stirred at this
temperature for a further 2.5 h. The mixture thus obtained was then
quenched with H2O (1 × 10 mL), before being extracted with EtOAc
(2 × 15 mL). The combined organic phases were washed with H2O (1
× 20 mL) and NaHCO3 (2 × 10 mL of a saturated aqueous solution)
before being dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to flash column
chromatography (silica, 1:9 → 3:17 v/v EtOAc/40−60 petroleum
ether gradient elution) to give, after concentration of the appropriate
fractions (Rf = 0.5 in 1:1 v/v EtOAc/40−60 petroleum ether),
1
compound 17 (24 mg, 87%): light orange oil; H NMR (600 MHz,
CD3OD) δ 7.47 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 6.93 (d,
J = 9.0 Hz, 2H), 6.84 (d, J = 9.0 Hz, 2H), 6.08 (d, J = 10.5 Hz, 1H),
3.83 (s, 3H), 3.78 (s, 3H), 2.98 (m, 1H), 1.18 (d, J = 6.5 Hz, 6H)
(signal due to NH group proton not observed); 13C NMR (150 MHz,
CD3OD) δ 186.5, 165.8, 163.6, 159.8, 137.6, 132.0, 131.6, 129.3,
125.9, 124.1, 115.0, 114.8, 113.6, 55.9, 55.7, 28.1, 22.8; IR νmax 2961,
1602, 1578, 1496, 1433, 1252, 1175, 1032, 832 cm−1; MS (ESI, + ve)
m/z 721 [(2M + Na)+, 100%], 350 [(M + H)+, 65]; HRMS m/z
350.1751 [M + H]+ (calcd for C22H24NO3, 350.1751).
Synthesis of 4,4′-(5-Isobutyl-1H-pyrrole-2,3-diyl)diphenol
(18). A magnetically stirred solution of compound 10 (1.00 g, 2.98
mmol) in anhydrous CH2Cl2 (200 mL) maintained at −78 °C under
an atmosphere of nitrogen was treated, dropwise over 0.17 h, with
boron tribromide (2.2 mL, 23.62 mmol). The ensuing mixture was left
to warm to 22 °C over 20 h and then quenched by the slow addition of
ice (CAUTION! EXOTHERMIC REACTION). The ensuing mixture
was poured into H2O (200 mL) and extracted with CH2Cl2 (3 × 100
mL). The combined organic phases were then dried (Na2SO4),
filtered, and concentrated under reduced pressure. The residue thus
obtained was subjected to flash column chromatography (silica, 1:4 v/
v EtOAc/40−60 petroleum ether elution) to give, after concentration
of the appropriate fractions (Rf = 0.5 in 1:1 v/v EtOAc/40−60
Concentration of fraction B (Rf = 0.5, eluted twice with 3:7 v/v
EtOAc/40−60 petroleum ether) gave compound 2113 (391 mg, 47%):
1
pale yellow, crystalline solid, mp 88−90 °C; H NMR [400 MHz,
(CD3)2CO] δ 8.06 (d, J = 8.7 Hz, 4H), 7.39 (d, J = 8.7 Hz, 4H), 2.31
(s, 6H); 13C NMR [100 MHz, (CD3)2CO] δ 194.1, 169.2, 157.1,
132.3, 131.2, 123.7, 21.0; IR νmax 1760, 1671, 1596, 1369, 1187, 1155,
1013, 911, 665 cm−1; MS (ESI, + ve) m/z 349 [(M + Na)+, 100%];
HRMS m/z 349.0686 (M + Na)+ (calcd for C18H14O6Na, 349.0683).
Synthesis of 4,5-Bis(4-hydroxyphenyl)-2-isobutyl-2-me-
thoxy-1,2-dihydro-3H-pyrrol-3-one (24). A magnetically stirred
solution of compound 20 (98 mg, 0.22 mmol) in MeOH (10 mL)
maintained at 0 °C was treated, in one portion, with potassium
carbonate (34 mg, 0.25 mmol). The ensuing mixture was maintained
at 0 °C for 1 h, then treated with H2O (20 mL) before being
concentrated under reduced pressure. The residue thus obtained was
extracted with EtOAc (3 × 50 mL), and the combined organic phases
were then dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a yellow solid. This material was subjected to flash
column chromatography (silica, 1:1 v/v EtOAc/40−60 petroleum
ether elution) and gave, after concentration of the appropriate
fractions (Rf = 0.1 in 1:1 v/v EtOAc/40−60 petroleum ether),
compound 24 (77 mg, 97%): yellow, crystalline solid, mp 124−126
°C; 1H NMR (600 MHz, CD3OD) δ 7.42 (d, J = 9.0 Hz, 2H), 6.96 (d,
J = 9.0 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H),
3.20 (s, 3H), 1.84 (m, 2H), 1.73 (m, 1H), 0.95 (d, J = 6.5 Hz, 3H),
0.94 (d, J = 6.6 Hz, 3H) (signals due to OH and NH groups protons
not observed); 13C NMR (150 MHz, CD3OD) δ 200.7, 175.6, 162.5,
157.1, 131.9, 131.8, 124.5, 122.7, 116.4, 116.2, 111.7, 93.5, 51.1, 46.4,
24.8, 24.7(2), 24.7(0); IR νmax 3250, 2957, 2930, 1647, 1605, 1587,
1526, 1492, 1428, 1236, 1172, 834 cm−1; MS (ESI, + ve) m/z 376 [(M
+ Na)+, 100%], 354 [(M + H)+, 10]; HRMS m/z 354.1705 (M + H)+
(calcd for C21H24NO4, 354.1700).
1
petroleum ether), compound 18 (800 mg, 87%): light yellow oil; H
NMR (400 MHz, CD3OD) δ 7.14 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 9.0
Hz, 2H), 6.67 (m, 4H), 5.86 (s, 1H), 2.45 (d, J = 7.1 Hz, 2H), 1.91
(m, 1H), 0.97 (d, J = 6.5 Hz, 6H), (signals due to OH and NH groups
protons not observed); 13C NMR (100 MHz, CD3OD) δ 156.6, 155.9,
132.5, 130.9, 130.3, 129.8, 127.4, 127.3, 121.5, 116.0, 115.9, 108.6,
38.1, 30.4, 22.9; IR νmax 3363, 2955, 2868, 1699, 1519, 1433, 1365,
1227, 1171, 834 cm−1; MS (EI, 70 eV) m/z 307 (M+•, 20%), 264
(100); HRMS m/z 307.1573 M+• (calcd for C20H21NO2, 307.1572).
Synthesis of (5-Isobutyl-1H-pyrrole-2,3-diyl)bis(4,1-phenyl-
ene) Diacetate (19). A magnetically stirred solution of compound 18
(690 g, 2.24 mmol) in dry CH2Cl2 (42 mL) maintained at 0 °C under
an atmosphere of nitrogen was treated with triethylamine (940 μL,
6.74 mmol) and acetyl chloride (800 μL, 11.25 mmol). After being
maintained at 0 °C for a further 0.5 h the reaction mixture was
quenched with H2O (100 mL) and extracted with CH2Cl2 (3 × 100
mL). The combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 3:17 v/v EtOAc/
40−60 petroleum ether elution) to give, after concentration of the
appropriate fractions (Rf = 0.3 in 3:7 v/v EtOAc/40−60 petroleum
Synthesis of Discoipyrrole C (3). A magnetically stirred solution
of 4,5-bis(4-hydroxyphenyl)-2-isobutyl-2-methoxy-1,2-dihydro-3H-
pyrrol-3-one (24) (61 mg, 0.17 mmol) in CH2Cl2/H2O (6.65 mL
of a 4:1 v/v mixture) maintained at 0 °C under a nitrogen atmosphere
1
ether), compound 19 (843 mg, 96%): clear, colorless oil; H NMR
[400 MHz, (CD3)CO] δ 10.01 (s, 1H), 7.34 (m, 4H), 7.02 (m, 4H),
6.05 (d, J = 2.7 Hz, 1H), 2.52 (d, J = 7.1 Hz, 2H), 2.24(3) (s, 3H),
G
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was treated, dropwise over 5 min, with trifluoroacetic acid (670 μL,
8.75 mmol). The ensuing mixture was stirred at 0 °C for 25 min, and
then H2O (10 mL) followed by EtOAc (10 mL) were added at the
same temperature. The separated organic phase was washed, at 0 °C,
with H2O (1 × 10 mL), then NaHCO3 (2 × 10 mL of a saturated
aqueous solution), until the pH of the aqueous washings was between
5 and 7. The separated organic layer was dried (Na2SO4), filtrated, and
concentrated under reduced pressure, and the residue thus obtained
was subjected to flash column chromatography (silica, 1:1 v/v EtOAc/
40−60 petroleum ether elution). Concentration of the appropriate
fractions (Rf = 0.1, eluted twice in 1:1 v/v EtOAc/40−60 petroleum
ether) then gave discoipyrrole C (3) (52 mg, 89%): light yellow solid,
no melting point (decomposition above 141 °C); 1H NMR (400
MHz, CD3OD) δ 7.38 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H),
6.76 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 9.0 Hz, 2H), 1.87 (d, J = 6.1 Hz,
2H), 1.69 (m, 1H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H)
(signals due to OH and NH groups protons not observed); 13C NMR
(100 MHz, CD3OD) δ 202.2, 174.4, 162.2, 156.9, 131.9, 131.8, 125.0,
123.1, 116.3, 116.1, 108.9, 88.8, 46.7, 25.1, 24.7, 24.6; IR νmax 3278,
2958, 1606, 1527, 1492, 1429, 1234, 837 cm−1; MS (ESI, + ve) m/z
701 [(2M + Na)+, 65%], 362 [(M + Na)+, 100], 340 [(M + H)+, 15];
HRMS m/z 340.1548 (M + H)+ (calcd for C20H22NO4, 340.1543).
Synthesis of (Z)-4,5-Bis(4-methoxyphenyl)-2-(2-methylpro-
pylidene)-1,2-dihydro-3H-pyrrol-3-one (25). A magnetically
stirred solution of compound 24 (27 mg, 0.08 mmol) in CH2Cl2/
H2O (710 μL of a 4:1 v/v mixture) maintained at 0 °C under a
nitrogen atmosphere was treated, dropwise over 5 min, with
trifluoroacetic acid (280 uL, 3.66 mmol). The ensuing mixture was
stirred at 0 °C for 1 h, then warmed to 22 °C and stirred at this
temperature for another 2.5 h before being quenched with H2O (1 ×
10 mL), then extracted with EtOAc (2 × 15 mL). The combined
organic phases were washed with H2O (1 × 20 mL) and then
NaHCO3 (2 × 10 mL of a saturated aqueous solution) before being
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue thus obtained was subjected to flash column
chromatography (silica, 1:1 v/v EtOAc/40−60 petroleum ether
elution) to give two fractions, A and B.
(2θmax = 147.6°), R = 0.036 [for 3920 reflections with I > 2.0σ(I)]; Rw
= 0.099 (all data), S = 1.03.
Compound 13: crystals obtained as colorless masses from acetone
C22H25NO4, M = 367.43, T = 150 K, monoclinic, space group P21/c, Z
= 8, a = 12.4371(1) Å, b = 14.4844(1) Å, c = 22.3921(2) Å; β =
98.146(1)°; V = 3993.10(6) Å3, Dx = 1.222 g cm−3, 8040 unique data
(2θmax = 147.6°), R = 0.039 [for 7086 reflections with I > 2.0σ(I)]; Rw
= 0.105 (all data), S = 1.03.
Compound 14: crystals obtained as colorless masses from acetone
C22H25NO4, M = 367.43, T = 150 K, monoclinic, space group P21/c, Z
= 8, a = 9.2101(3) Å, b = 20.2873(7) Å, c = 21.2870(11) Å; β =
96.731(4)°; V = 3950.0(3) Å3, Dx = 1.236 g cm−3, 8073 unique data
(2θmax = 52.8°), R = 0.048 [for 5212 reflections with I > 2.0σ(I)]; Rw
= 0.119 (all data), S = 1.02.
Structure Determination. The image for compound 14 was
measured on a diffractometer (Mo Kα, graphite monochromator, λ
= 0.710 73 Å) fitted with an area detector, and the data were extracted
using the DENZO/Scalepack package.16 Images for compounds 3, 11,
12, and 13 were measured on a diffractometer (Cu Kα, mirror
monochromator, λ = 1.541 84 Å) fitted with an area detector, and the
data were extracted using the CrysAlis package.17 The structure
solutions for all five compounds were solved with ShelXT18 and
refined using ShelXL19 in the OLEX2 package.20
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00872.
Data derived from the single-crystal X-ray analyses of
1
compounds 3, 11, 12, 13, and 14; H NMR spectra of
1
compounds 6, 8, and 10; H and 13C NMR spectra of
compounds 3, 9, 11−21, 24, and 25 (PDF)
Crystallographic data (CIF)
Concentration of fraction A (Rf = 0.1, eluted twice with 1:1 v/v
EtOAc/40−60 petroleum ether) afforded discoipyrrole C (3) (9 mg,
35%): yellow solid that was identical, in all respects, with the material
obtained earlier.
AUTHOR INFORMATION
Corresponding Author
*Tel: +61-2-6125-8202. Fax: +61-2-6125-8114. E-mail: Martin.
Banwell@anu.edu.au.
■
Concentration of fraction B (Rf = 0.1 in 1:1 v/v EtOAc/40−60
petroleum ether) afforded compound 25 (15 mg, 61%): light orange
oil; 1H NMR [600 MHz, (CD3)2CO] δ 8.23 (s, 1H), 7.43 (d, J = 9.0
Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 6.73 (d, J
= 9.0 Hz, 2H), 5.81 (d, J = 10.3 Hz, 1H), 2.98 (m, 1H), 1.13 (d, J =
6.5 Hz, 6H) (signals due to OH groups protons not observed); 13C
NMR [150 MHz, (CD3)2CO] δ 185.6, 162.4, 160.6, 156.4, 136.8,
131.3, 131.1, 125.1, 123.7, 123.5, 116.2, 115.7, 113.1, 27.3, 22.8; IR
νmax 3200, 2962, 2869, 1691, 1526, 1491, 1456, 1348, 1236, 1172,
1067, 928, 835 cm−1; MS (EI, 70 eV) m/z 321 (M+•, 100%), 319 (30),
280 (30), 210 (35); HRMS m/z 321.1365 M+• (calcd for C20H19NO3,
321.1365).
Crystallographic Data. Compound 3: crystals obtained as
colorless masses from EtOAc/acetone/petroleum ether (40−60),
C20H21NO4, M = 339.38, T = 150 K, monoclinic, space group P21/n, Z
= 4, a = 9.8726(1) Å, b = 12.6801(1) Å, c = 18.1414(2) Å; β =
92.315(1)°; V = 2269.19(4) Å3, Dx = 0.993 g cm−3, 4554 unique data
(2θmax = 147.6°), R = 0.034 [for 4193 reflections with I > 2.0σ(I)]; Rw
= 0.092 (all data), S = 1.05.
Compound 11: crystals obtained as colorless masses from acetone/
hexane, C44H48N2O4·2(C3H6O), M = 785.00, T = 150 K, monoclinic,
space group P21/n, Z = 4, a = 19.2834(19) Å, b = 10.8405(9) Å, c =
24.0533(13) Å; β = 90.220(7)°; V = 5028.1(7) Å3, Dx = 1.037 g cm−3,
9690 unique data (2θmax = 144.4°), R = 0.114 [for 4982 reflections
with I > 2.0σ(I)]; Rw = 0.380 (all data), S = 1.13.
Compound 12: crystals obtained as colorless masses from EtOAc,
C23H27NO4, M = 381.45, T = 150 K, monoclinic, space group C2/c, Z
= 8, a = 21.8292(3) Å, b = 15.8674(2) Å, c = 12.3179(2) Å; β =
91.099(1)°; V = 4265.80(11) Å3, Dx = 1.188 g cm−3, 4309 unique data
ORCID
Martin G. Banwell: 0000-0002-0582-475X
Notes
The authors declare no competing financial interest.
Atomic coordinates, bond lengths and angles, and displacement
parameters have been deposited at the Cambridge Crystallo-
graphic Data Centre (CCDC nos. 1573703, 1573704, 1573705,
1573706, and 1573707). These data can be obtained free-of-
charge via www.ccdc.cam.ac.uk/data_request/cif, by emailing
data_request@ccdc.cam.ac.uk, or by contacting the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: + 44 1223 336033.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council, the Institute of
Advanced Studies, and ANU Connect for financial support.
Q.Y. is the grateful recipient of a CSC grant provided by the
People’s Republic of China, while X.M. acknowledges the
generous support of the Guangzhou Elite Program.
REFERENCES
■
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Legako, A. G.; Yousufuddin, M.; White, M. A.; MacMillan, J. B. J. Am.
Chem. Soc. 2013, 135, 13387−13392.
H
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DOI: 10.1021/acs.jnatprod.7b00872
J. Nat. Prod. XXXX, XXX, XXX−XXX