Biomimetic synthesis of thiaplidiaquinones A and B

Article abstract of DOI:10.1021/np300790g

A biomimetic synthesis of the biologically active ascidian metabolites thiaplidiaquinones A and B is described. Reaction of geranylbenzoquinone with Et₃N in CH₂Cl₂ yielded two isomeric quinones, comprising the benzo[c]chro

Full text of DOI:10.1021/np300790g

Note
pubs.acs.org/jnp
Biomimetic Synthesis of Thiaplidiaquinones A and B
Iman M. Khalil, David Barker, and Brent R. Copp*
School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
S
* Supporting Information
ABSTRACT: A biomimetic synthesis of the biologically active ascidian metabolites thiaplidiaquinones A and B is described.
Reaction of geranylbenzoquinone with Et3N in CH2Cl2 yielded two isomeric quinones, comprising the benzo[c]chromene-7,10-
dione core of the natural products. Subsequent reaction with hypotaurine yielded the title compounds and their dioxothiazino
regioisomers.
hile the majority of metabolites biosynthesized by
ascidians are alkaloids or peptide related,1 ascidians of
lead compound.7 As part of our interest in exploring the
structure−activity relationships of benzo[c]chromene-7,10-
dione natural products,8 herein we report a biomimetic
synthesis of both thiaplidiaquinones A (4) and B (5) and
their anticipated natural product dioxothiazine regioisomers.
While this paper was in preparation, Carbone et al. reported a
synthesis of thiaplidiaquinone A.9
W
the genus Aplidium are known as a rich source of prenylated
quinone and hydroquinone natural products.2 Derived from
geranylated or farnesylated hydro- or benzoquinone (e.g., 1),3
these typically bioactive metabolites can embody intramolecular
(e.g., conicol, 24) or intermolecular ring closures (e.g.,
longithorone A, 35), yielding complex architectural scaffolds.
We speculated that the biosynthetic origin of the
thiaplidiaquinones could stem from hypotaurine addition to
one of two tricyclic pyranoquinones (7, 8), in turn derived from
oxa-6π electrocyclization10 of ortho-quinone methide tautomers
(9, 10) of bis-benzoquinones (11, 12) (Scheme 1).
However, while Carbone et al. constructed bis-benzoqui-
nones 11 and 12 via a Suzuki−Miyaura reaction, we speculated
that such coupling could be achieved simply by allowing
geranylbenzoquinone (13) to tautomerize in the presence of
triethylamine, undergo Michael reaction with another equiv-
alent of quinone, and then follow a cascade of oxidation and
More recently, meroterpenoids bearing a benzo[c]chromene-
7,10-dione skeleton have been reported from geographically
remote species of Aplidium ascidians. In 2005, Fattorusso’s
group isolated thiaplidiaquinones A and B (4, 5) from a
Mediterranean ascidian, Aplidium conicum, determining that
both natural products induced apoptosis in Jurkat cells by a
mechanism involving the intracellular production of reactive
oxygen species.6 In contrast, the related metabolite scabellone B
(6), isolated from a New Zealand collection of Aplidium
scabellum, was found to be a relatively nontoxic antimalarial
Received: November 12, 2012
Published: December 10, 2012
© 2012 American Chemical Society and
American Society of Pharmacognosy
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Note
Geranylbenzoquinone (13) was prepared in a two-step
sequence by reaction of 4-methoxyphenol with geranylbromide
to afford 2-geranyl-4-methoxyphenol,11 oxidation of which with
CAN yielded 1311 (Scheme 3). Initial assessment of the ability
of geranylbenzoquinone to undergo base-induced tautomeriza-
tion and dimerization was performed in an NMR tube,
whereupon addition of Et3N (1 equiv) to a solution of quinone
13 in CDCl3 caused a rapid change in color of the solution
Scheme 1. Retrosynthesis of Thiaplidiaquinones A and B
1
from pale yellow to dark brown, with H NMR spectra of the
reaction mixture indicating rapid consumption of starting
material and the production of a complex mixture. An HSQC
NMR spectrum of the mixture identified the generation of a
new oxymethine fragment, with a correlation observed at δH
6.18, δC 68.4 [cf. scabellone B (6) H-5/C-6 (δH 6.00 (1H, d, J =
9.3 Hz, H-5); δC 67.6)],7 suggestive of successful formation of a
benzo[c]chromene ring system. The reaction between quinone
13 and Et3N (5 equiv) was repeated on a larger scale, with a
short reaction time of 2 min, followed by purification using
silica gel flash column chromatography. The fraction eluting
with 15% MeOH/CH2Cl2 was left exposed to silica gel
overnight, whereupon a further color change, this time from
brown to dark purple, was observed. Further purification of the
purple products yielded 7 and 8 in yields of 5.7% and 2.4%,
respectively (Scheme 3). Albeit with low yields, the biomimetic
transformation of 13 to tricycles 7 and 8 is unprecedented.
High-resolution ESI mass spectrometry assigned the
molecular formula C32H38O4 [M + Na]+ to both 7 and 8,
while detailed analysis of NMR data established the presence of
1-oxygeranyl, geranyl, tetrasubstituted benzene, and 2,3-
disubstituted benzoquinone fragments (see Tables S1 and
S2). Close similarity of the NMR data to those observed for
scabellone B (6),7 also obtained in CDCl3 solvent, gave
confidence that 7 and 8 were indeed isomeric benzo[c]-
chromene-7,10-diones. The most prominent difference be-
tween the two reaction products was the coupling, or lack of it,
for the two benzenoid ring protons. The observation of 3.0 Hz
coupling between H-1 (δH 7.67) and H-3 (δH 6.75) defined the
higher yielding product to be quinone 7, while the lack of scalar
coupling between the two benzenoid protons [δH 7.82 (s, H-1);
δH 6.69 (s, H-4)] of the second reaction product established
their relative disposition as being para, i.e., quinone 8.
spontaneous ring closure to form the more advanced
thiaplidiaquinone precursors 7 and 8 (Scheme 2).
Scheme 2. Tautomerization and Dimerization of
Geranylbenzoquinone
With precursor quinones 7 and 8 in hand, addition of
hypotaurine was undertaken in a manner previously used by us
in the synthesis of the anti-inflammatory ascidian metabolite
ascidiathiazone A.12 Thus an aqueous solution of hypotaurine
(1 equiv) was slowly added to 7 in CH3CN/EtOH at 0 °C and
stirred for 48 h at room temperature (rt). Chromatographic
purification of the reaction product mixture afforded
thiaplidiaquinone A (4) and dioxothiazine regioisomer 14 in
Scheme 3. Synthesis of Pre-thiaplidiaquinones A and B
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Note
Scheme 4. Synthesis of Thiaplidiaquinones A and B
1220, 1037 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.73 (1H, d, J = 8.7
Hz, H-6), 6.68 (1H, d, J = 2.8 Hz, H-3), 6.65 (1H, dd, J = 8.7, 2.8 Hz,
H-5), 5.34−5.28 (1H, m, H-2′), 5.10−5.04 (1H, m, H-6′), 4.80 (1H, s,
OH), 3.75 (3H, s, H3-7), 3.33 (2H, d, J = 7.2 Hz, H2-1′), 2.16−2.10
(2H, m, H2-4′), 2.10−2.05 (2H, m, H2-5′), 1.76 (3H, s, H3-9′), 1.68
(3H, s, H3-8′), 1.60 (3H, s, H3-10′); 13C NMR (CDCl3, 100 MHz) δ
153.8 (C-4), 148.5 (C-1), 138.7 (C-3′), 132.1 (C-7′), 128.3 (C-2),
124.0 (C-6′), 121.6 (C-2′), 116.5 (C-6), 115.8 (C-3), 112.2 (C-5),
55.8 (C-7), 39.8 (C-4′), 30.1 (C-1′), 26.6 (C-5′), 25.8 (C-8′), 17.8
(C-10′), 16.3 (C-9′); (+)-HRESIMS m/z 283.1669 [M + Na]+ (calcd
for C17H24NaO2, 283.1669).
Geranylbenzoquinone (13). A solution of cerium ammonium
nitrate (9.15 g, 0.019 mol) in CH3CN/H2O (1:2, 75 mL) was added
dropwise to a stirred solution of 2-geranyl-4-methoxyphenol (2.18 g,
9.4 mmol) in CH3CN (25 mL) at 0 °C. The mixture was stirred
overnight at 0 °C, then poured into 10% NaCl(aq) (100 mL) and
extracted with Et2O (2 × 50 mL). The organic extract was then dried
(MgSO4), and the solvent removed under reduced pressure.
Purification by silica gel column chromatography (EtOAc/n-hexane,
1:4) gave quinone 13 as a bright yellow oil (1.19 g, 58%): Rf (30%
EtOAc/n-hexane) 0.83; IR (ATR) νmax 2966, 2919, 2859, 1656, 1599,
1297 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.76 (1H, d, J = 10.1 Hz,
H-6), 6.71 (1H, dd, J = 10.1, 2.4 Hz, H-5), 6.55−6.51 (1H, m, H-3),
5.19−5.12 (1H, m, H-2′), 5.11−5.05 (1H, m, H-6′), 3.13 (2H, d, J =
7.2 Hz, H2-1′), 2.14−2.09 (2H, m, H2-4′), 2.09−2.05 (2H, m, H2-5′),
1.70 (3H, s, H3-8′), 1.63 (3H, s, H3-9′), 1.60 (3H, s, H3-10′); 13C
NMR (CDCl3, 100 MHz) δ 188.1 (C-4), 187.7 (C-1), 148.7 (C-2),
140.3 (C-3′), 136.9 (C-6), 136.5 (C-5), 132.5 (C-3), 132.0 (C-7′),
124.0 (C-6′), 117.8 (C-2′), 39.8 (C-4′), 27.5 (C-1′), 26.6 (C-5′), 25.8
(C-8′), 17.8 (C-10′), 16.2 (C-9′); (+)-HRESIMS m/z 267.1359 [M +
Na]+ (calcd for C16H20NaO2, 267.1356).
4-Geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-hydroxy-6H-
benzo[c]chromene-7,10-dione (7) and 3-Geranyl-6-(2,6-dimethyl-
hepta-1,5-dienyl)-2-hydroxy-6H-benzo[c]chromene-7,10-dione (8).
Triethylamine (0.26 mL, 0.19 g, 1.84 mmol) was added dropwise to a
rapidly stirring solution of geranylbenzoquinone (0.09 g, 0.37 mmol)
in CH2Cl2 (10 mL) under an atmosphere of nitrogen. When the
reaction mixture became a dark brown color (approximately 2 min), it
was loaded onto a silica gel chromatography column (CH2Cl2). The
fraction that eluted with 10−15% MeOH/CH2Cl2 was then loaded
onto another silica gel chromatography column (CH2Cl2) and left
exposed to silica overnight. The purple compounds formed were
eluted with CH2Cl2 to yield 4-geranyl-6-(2,6-dimethylhepta-1,5-
dienyl)-2-hydroxy-6H-benzo[c]chromene-7,10-dione (7) as a purple
oil (5.13 mg, 5.7%) and 3-geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-2-
hydroxy-6H-benzo[c]chromene-7,10-dione (8) as a purple oil (2.13
mg, 2.4%):
Compound 7: Rf (CH2Cl2) 0.29; IR (ATR) νmax 3266, 2977, 1643,
1390 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.67 (1H, d, J = 3.0 Hz, H-
1), 6.75 (1H, d, J = 3.0 Hz, H-3), 6.73 (2H, s, H-8, 9), 6.04 (1H, d, J =
9.5 Hz, H-6), 5.32 (1H, d, J = 9.5 Hz, H-1″), 5.25 (1H, t, J = 7.3 Hz,
H-2′), 5.09 (1H, t, J = 6.5 Hz, H-6′), 4.92 (1H, t, J = 6.6 Hz, H-5″),
4.70 (1H, br s, OH), 3.24 (2H, dd, J = 7.3, 3.0 Hz, H2-1′), 2.11−2.05
(2H, m, H2-5′), 2.04−2.00 (2H, m, H2-4′), 2.00−1.97 (2H, m, H2-4″),
1
yields of 21% and 40%, respectively (Scheme 4). H and 13C
NMR data observed for the minor product were in excellent
agreement with those reported for the natural product,6,9 while
data observed for some resonances, in particular H-1 (ΔδH
0.31) and C-6a/C-9/C-10/C-11a (ΔδC 7.9−33), of regio-
siomer 14 were markedly different (see Tables S3 and S4).
Reaction of the second precursor, quinone 8, with hypotaurine
in a similar manner afforded two products, identified as
thiaplidiaquinone B (5) (9.3% yield) and its regioisomer 15
(13%). Once again the spectroscopic data observed for the
reaction minor product agreed very well with the data reported
for the natural product, while those observed for the isomer
were quite different (see Tables S5 and S6).6 The UV−visible
spectra of natural products 4 and 5 were almost super-
imposable, as were those of the regioisomers 14 and 15, but the
two series were markedly different from each other (see Figure
S1), suggesting that this classical spectroscopic technique may
be a useful tool in assigning dioxothiazine regiochemistry in this
compound class.
In conclusion, we have achieved a biomimetic synthesis of
the complex dioxothiazino meroterpenoids thiaplidiaquinones
A and B by base-mediated dimerization of geranylbenzoqui-
none, followed by addition of hypotaurine.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Ultraviolet−visible spectra
were run as MeOH solutions on a UV-2102 PC Shimadzu UV−vis
scanning spectrophotometer. Infrared spectra were recorded using a
Perkin-Elmer Spectrum One Fourier-transform IR spectrometer as a
dry film. 1H and 13C NMR spectra were recorded at 298 K, at 400 and
100 MHz, respectively, or at 600 and 150 MHz, respectively, on
Bruker DRX spectrometers. NMR experiments were run in CDCl3 and
1
were referenced to TMS for H and to the central peak of the CDCl3
signal at 77.16 ppm13 for 13C. Standard Bruker pulse sequences were
utilized. HRMS data were acquired on a Bruker micrOTOF Q II mass
spectrometer. Flash column chromatography was performed using
Davisil silica gel (40−63 μm), while analytical thin-layer chromatog-
raphy was carried out on Merck DC-plastikfolien Kieselgel 60 F254
plates, and products were visualized by UV fluorescence.
2-Geranyl-4-methoxyphenol. Sodium metal (0.71 g, 0.031 mol)
was added portionwise to a solution of 4-methoxyphenol (1.91 g,
0.015 mol) in dry Et2O (65 mL) under a nitrogen atmosphere and
then stirred for 3 h at rt. Geranyl bromide (3.34 g, 3.04 mL, 0.015
mol) was then added dropwise, and the solution heated at reflux for 48
h under nitrogen. After the solution cooled to rt, 10% HCl(aq) (5 mL)
was added, the aqueous layer was extracted with Et2O (2 × 10 mL),
the combined organic layers were washed with water (2 × 50 mL) and
dried (MgSO4), and the solvent was removed under reduced pressure.
Purification by silica gel column chromatography (EtOAc/n-hexane,
1:4) gave 2-geranyl-4-methoxyphenol as a pale yellow oil (2.24 g,
56%): Rf (CH2Cl2) 0.56; IR (ATR) νmax 3352, 2935, 2834, 1506, 1440,
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1.97−1.90 (2H, m, H2-3″), 1.94 (3H, s, H3-8″), 1.68 (3H, s, H3-8′),
1.67 (3H, s, H3-9′), 1.59 (3H, s, H3-10′), 1.58 (3H, s, H3-7″), 1.50
(3H, s, H3-9″); 13C NMR (CDCl3, 100 MHz) δ 187.1 (C-10), 185.2
(C-7), 149.9 (C-2), 147.0 (C-4a), 144.3 (C-2″), 137.2 (C-8/9), 137.0
(C-3′), 135.8 (C-8/9), 134.9 (C-6a), 132.3 (C-4), 131.9 (C-6″), 131.6
(C-7′), 130.5 (C-10a), 124.4 (C-6′), 123.6 (C-5″), 121.6 (C-2′), 120.2
(C-3), 118.4 (C-1″), 117.6 (10b), 112.5 (C-1), 67.3 (C-6), 39.9 (C-
3″), 39.8 (C-4′), 28.2 (C-1′), 26.8 (C-5′), 26.3 (C-4″), 25.8 (C-8′),
25.7 (C-7″), 17.8 (C-10′), 17.8 (C-9″), 17.4 (C-8″), 16.6 (C-9′);
(+)-HRESIMS m/z 509.2645 [M + Na]+ (calcd for C32H38O4Na,
509.2662).
H3-8′), 1.64 (3H, s, H3-9′), 1.59 (3H, s, H3-10′), 1.59 (3H, s, H3-7″),
1.51 (3H, s, H3-9″); 13C NMR (CDCl3, 100 MHz) δ 177.7 (C-12),
177.5 (C-7), 150.4 (C-2), 148.4 (C-4a), 144.8 (C-2″), 143.8 (C-7a),
137.1 (C-3′), 133.6 (C-12a), 132.3 (C-4), 132.0 (C-6″), 131.7 (C-7′),
130.9 (C-6a), 124.3 (C-6′), 123.5 (C-5″), 122.1 (C-3), 121.4 (C-2′),
118.2 (C-1″), 117.5 (C-12b), 113.7 (C-1), 111.4 (C-11a), 67.1 (C-6),
49.2 (C-10), 40.2 (C-9), 39.9 (C-4′), 39.7 (C-3″), 28.2 (C-1′), 26.8
(C-5′), 26.3 (C-4″), 25.8 (C-8′), 25.7 (C-7″), 17.8 (C-9″), 17.8 (C-
10′), 17.4 (C-8″), 16.2 (C-9′); (+)-HRESIMS [M + Na]+ 614.2531
(calcd for C34H41NNaO6S, 614.2547).
Thiaplidiaquinone B (5) and Regioisomer 15. A solution of
hypotaurine (2.55 mg, 0.02 mmol) in H2O (0.15 mL) was added
dropwise to a solution of 3-geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-
2-hydroxy-6H-benzo[c]chromene-7,10-dione (8) (11.39 mg, 0.02
mmol) in CH3CN/EtOH (1:1, 1 mL) at 0 °C. The resulting mixture
was stirred for 2 days, after which H2O (3 mL) was added. The
aqueous solution was then extracted with CH2Cl2 (3 mL × 2) and
dried (MgSO4), and the solvent removed under reduced pressure. The
crude reaction product was purified using silica gel chromatography
(EtOAc/n-hexane, 1:1) to yield thiaplidiaquinone B (5) as a light
purple oil (1.29 mg, 9.3%) and regioisomer 15 as a dark blue oil (1.84
mg, 13%).
Thiaplidiaquinone B (5):. Rf (EtOAc) 0.59; UV (MeOH) λmax (log
ε) 324 (3.00), 362 (sh, 2.84), 558 (2.17) nm; IR (ATR) νmax 3447,
3301, 2928, 1618, 1586, 1424, 1282, 1164, 1122 cm−1; 1H NMR
(CDCl3, 600 MHz) δ 7.69 (1H, br s, H-1), 6.85 (1H, br s, NH-11),
6.69 (1H, br s, H-4), 6.06 (1H, d, J = 9.6 Hz, H-6), 5.31−5.25 (1H, m,
H-1″), 5.31−5.25 (1H, m, H-2′), 5.07 (1H, t, J = 6.7 Hz, H-6′), 4.94
(1H, t, J = 6.5 Hz, H-5″), 4.14−4.07 (2H, m, H2-10), 3.37−3.29 (2H,
m, H2-9), 3.37−3.29 (2H, m, H2-1′), 2.14−2.10 (2H, m H2-5′), 2.10−
2.06 (2H, m, H2-4′), 2.01−1.97 (2H, m, H2-4″), 1.97−1.92 (2H, m,
H2-3″), 1.91 (3H, s, H3-8″), 1.73 (3H, s, H3-9′), 1.69 (3H, s, H3-8′),
1.60 (3H, s, H3-10′), 1.60 (3H, s, H3-7″), 1.51 (3H, s, H3-9″); 13C
NMR (CDCl3, 150 MHz) δ 179.2 (C-12), 175.3 (C-7), 149.0 (C-2),
148.1 (C-4a), 145.4 (C-2″), 143.9 (C-11a), 139.3 (C-3′), 137.5 (C-
6a), 133.1 (C-3), 132.2 (C-7′), 132.0 (C-6″), 127.9 (C-12a), 123.9
(C-6′), 123.7 (C-5″), 120.4 (C-2′), 118.8 (C-4), 116.6 (C-1″), 114.8
(C-12b), 114.3 (C-1), 110.2 (C-7a), 67.7 (C-6), 48.7 (C-9), 40.0 (C-
10), 39.9 (C-3″), 39.8 (C-4′), 29.8 (C-1′), 26.5 (C-5′), 26.1 (C-4″),
25.9 (C-8′), 25.8 (C-7″), 17.9 (C-10′), 17.8 (C-9″), 17.6 (C-8″), 16.4
(C-9′); (+)-HRESIMS m/z 614.2538 [M + Na]+ (calcd for
C34H41NNaO6S, 614.2547).
Compound 8: Rf (CH2Cl2) 0.43; IR (ATR) νmax 3393, 2922, 1647,
1
1423 cm−1; H NMR (CDCl3, 400 MHz) δ 7.82 (1H, s, H-1), 6.72
(2H, s, H-8, 9), 6.69 (1H, s, H-4), 5.99 (1H, d, J = 9.5 Hz, H-6), 5.35
(1H, d, J = 9.5 Hz, H-1″), 5.30 (1H, t, J = 7.1 Hz, H-2′), 5.11−5.05
(1H, m, H-6′), 4.98 (1H, br s, OH), 4.94−4.90 (1H, m, H-5″), 3.33
(2H, dd, J = 7.1, 4.0 Hz, H2-1′), 2.16−2.11 (2H, m, H2-5′), 2.11−2.07
(2H, m, H2-4′), 2.03−1.95 (2H, m, H2-4″), 1.97−1.92 (2H, m, H2-3″),
1.92 (3H, s, H3-8″), 1.73 (3H, s, H3-9′), 1.69 (3H, s, H3-8′), 1.59 (3H,
s, H3-7″), 1.59 (3H, s, H3-10′), 1.50 (3H, s, H3-9″); 13C NMR
(CDCl3, 100 MHz) δ 187.2 (C-10), 185.1 (C-7), 149.2 (C-4a), 149.1
(C-2), 144.0 (C-2″), 139.0 (C-3′), 137.0 (C-8/9), 135.9 (C-8/9),
133.8 (C-6a), 133.4 (C-3), 132.1 (C-7′), 131.9 (C-6″), 130.2 (C-10a),
124.0 (C-6′), 123.7 (C-5″), 120.7 (C-2′), 118.6 (C-4), 118.2 (C-1″),
115.8 (C-10b), 115.1 (C-1), 67.6 (C-6), 39.8 (C-3″), 39.8 (C-4′), 29.7
(C-1′), 26.6 (C-5′), 26.2 (C-4″), 25.8 (C-8′), 25.7 (C-7″), 17.9 (C-
9″), 17.8 (C-10′), 17.4 (C-8″), 16.4 (C-9′); (+)-HRESIMS m/z
509.2649 [M + Na]+ (calcd for C32H38O4Na, 509.2662).
Thiaplidiaquinone A (4) and Regioisomer 14. A solution of
hypotaurine (1.2 mg, 0.01 mmol) in H2O (0.10 mL) was added
dropwise to a solution of 4-geranyl-6-(2,6-dimethylhepta-1,5-dienyl)-
2-hydroxy-6H-benzo[c]chromene-7,10-dione (7) (4.02 mg, 0.01
mmol) in CH3CN/EtOH (1:1, 0.8 mL) at 0 °C. The resulting
mixture was stirred for 2 days, after which H2O (3 mL) was added.
The aqueous solution was then extracted with CH2Cl2 (2 mL × 2) and
dried (MgSO4), and the solvent removed under reduced pressure. The
crude reaction product was purified using silica gel chromatography
(EtOAc/n-hexane, 1:1) to yield thiaplidiaquinone A (4) as a red oil
(1.02 mg, 21%) and regioisomer 14 as a dark blue oil (1.93 mg, 40%).
Thiaplidiaquinone A (4): Rf (EtOAc) 0.63; UV (MeOH) λmax (log
ε) 331 (3.04) nm; IR (ATR) νmax 3304, 2926, 1683, 1622, 1587, 1445,
1348, 1282, 1120 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.54 (1H, br s,
H-1), 6.90 (1H, br s, NH-11), 6.71 (1H, br s, H-3), 6.08 (1H, d, J =
9.5 Hz, H-6), 5.28−5.23 (1H, m, H-1″), 5.23−5.19 (1H, m, H-2′),
5.08 (1H, tt, J = 7.0, 1.4 Hz, H-6′), 4.98−4.87 (1H, m, H-5″), 4.19−
4.04 (2H, m, H2-10), 3.43−3.31 (2H, m, H2-9), 3.28 (1H, dd, J = 15.5,
7.1 Hz, H-1′a), 3.17 (1H, dd, J = 15.5, 7.4 Hz, H-1′b), 2.10−2.04 (2H,
m H2-5′), 2.04−1.99 (2H, m, H2-4′), 1.99−1.96 (2H, m, H2-4″),
1.96−1.92 (2H, m, H2-3″), 1.92 (3H, s, H3-8″), 1.68 (3H, s, H3-8′),
1.66 (3H, s, H3-9′), 1.59 (3H, s, H3-10′), 1.59 (3H, s, H3-7″), 1.50
(3H, s, H3-9″); 13C NMR (CDCl3, 100 MHz) δ 179.3 (C-12), 175.3
(C-7), 149.7 (C-2), 146.2 (C-4a), 145.6 (C-2″), 143.9 (C-11a), 138.8
(C-6a), 137.1 (C-3′), 132.5 (C-4), 131.9 (C-6″), 131.6 (C-7′), 128.2
(C-12a), 124.4 (C-6′), 123.7 (C-5″), 121.4 (C-2′), 120.1 (C-3), 117.0
(C-1″), 116.8 (C-12b), 111.6 (C-1), 110.6 (C-7a), 67.5 (C-6), 48.8
(C-9), 40.1 (C-10), 39.9 (C-4′), 39.9 (C-3″), 28.2 (C-1′), 26.8 (C-5′),
26.3 (C-4″), 25.8 (C-8′), 25.7 (C-7″), 17.8 (C-9″), 17.8 (C-10′), 17.6
(C-8″), 16.3 (C-9′); (+)-HRESIMS [M + Na]+ 614.2536 (calcd for
C34H41NNaO6S, 614.2547).
Regioisomer 15: Rf (50% EtOAc/n-hexane) 0.17; UV (MeOH)
λmax (log ε) 303 (3.17), 370 (3.39), 450 (2.69), 587 (2.68) nm; IR
(ATR) νmax 3457, 3335, 2930, 1659, 1613, 1584, 1552, 1425, 1277,
1
1214, 1123 cm−1; H NMR (CDCl3, 600 MHz) δ 7.98 (1H, s, H-1),
6.67 (1H, br s, NH-8), 6.64 (1H, s, H-4), 5.94 (1H, d, J = 9.4 Hz, H-
6), 5.33 (1H, d, J = 9.4 Hz, H-1″), 5.27 (1H, t, J = 7.0 Hz, H-2′), 5.08
(1H, t, J = 6.8 Hz, H-6′), 4.96−4.91 (1H, br m, H-5″), 4.15−4.05 (2H,
m, H2-9), 3.38−3.33 (2H, m, H2-10), 3.31 (2H, d, J = 7.0 Hz, H2-1′),
2.14−2.09 (2H, m, H2-5′), 2.09−2.04 (2H, m, H2-4′), 2.02−1.96 (2H,
m, H2-4″), 1.96−1.91 (2H, m, H2-3″), 1.88 (3H, s, H3-8″), 1.69 (3H,
s, H3-9′), 1.68 (3H, s, H3-8′), 1.60 (3H, s, H3-7″), 1.60 (3H, s, H3-
10′), 1.51 (3H, s, H3-9″); 13C NMR (CDCl3, 150 MHz) δ 177.9 (C-
12), 177.2 (C-7), 150.7 (C-4a), 149.5 (C-2), 144.4 (C-2″), 143.7 (C-
7a), 138.7 (C-3′), 136.2 (C-3), 133.3 (C-12a), 132.0 (C-7′), 132.0 (C-
6″), 129.5 (C-6a), 124.1 (C-6′), 123.6 (C-5″), 120.4 (C-2′), 118.4 (C-
4), 118.0 (C-1″), 116.0 (C-1), 115.6 (C-12b), 111.3 (C-11a), 67.3 (C-
6), 49.2 (C-10), 40.1 (C-9), 39.9 (C-4′), 39.8 (C-3″), 29.4 (C-1′),
26.6 (C-5′), 26.3 (C-4″), 25.8 (C-8′), 25.8 (C-7″), 17.9 (C-9″), 17.8
(C-10′), 17.4 (C-8″), 16.3 (C-9′); (+)-HRESIMS m/z 614.2529 [M +
Na]+ (calcd for C34H41NNaO6S, 614.2547).
Regioisomer 14: Rf (50% EtOAc/n-hexane) 0.14; UV (MeOH)
λmax (log ε) 304 (3.03), 368 (3.36), 442 (2.54), 575 (2.46) nm; IR
(ATR) νmax 3304, 2970, 1661, 1594, 1571, 1441, 1350, 1282, 1124,
1065 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.82 (1H, d, J = 2.7 Hz, H-
1), 6.78 (1H, d, J = 2.7 Hz, H-3), 6.73 (1H, br s, NH-8), 5.98 (1H, d, J
= 9.4 Hz, H-6), 5.28 (1H, d, J = 9.4 Hz, H-1″), 5.20 (1H, t, J = 7.4 Hz,
H-2′), 5.08 (1H, t, J = 6.4 Hz, H-6′), 4.92 (1H, t, J = 6.1 Hz, H-5″),
4.19−4.05 (2H, m, H2-9), 3.42−3.34 (2H, m, H2-10), 3.23 (1H, dd, J
= 15.8, 7.0 Hz, H-1′a), 3.15 (1H, dd, J = 15.8, 7.3 Hz, H-1′b), 2.11−
2.04 (2H, m, H2-5′), 2.03−1.95 (2H, m, H2-4′), 2.03−1.95 (2H, m,
H2-4″), 1.94−1.91 (2H, m, H2-3″), 1.90 (3H, s, H3-8″), 1.67 (3H, s,
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables of NMR data for 4, 5, 7, 8, 14, and 15, figure of UV
1
spectra of 4, 5, 14, and 15, and copies of H and 13C NMR
spectra for 2-geranyl-4-methoxyphenol, geranylbenzoquinone,
2259
dx.doi.org/10.1021/np300790g | J. Nat. Prod. 2012, 75, 2256−2260

Journal of Natural Products
Note
and compounds 4, 5, 7, 8, 14, and 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Tel: +64 9 373 7599, x 88284. Fax: + 64 9 373 7422. E-mail:
b.copp@auckland.ac.nz.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funding from the University of Auckland. We
thank the late Prof. E. Fattorusso for copies of NMR data of the
natural products, Dr. M. Schmitz for assistance with NMR data
acquisition, and Dr. N. Lloyd for MS data.
DEDICATION
■
This paper is dedicated to the memory of Prof. Ernesto
Fattorusso (1937−2012).
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