Structural reassignment of a marine metabolite from a binaphthalenetetrol to a tetrabrominated diphenyl ether

Article abstract of DOI:10.1021/np300141t

The structure of a reported natural product isolate has been revised from (S)-2,2'-dimethoxy-[1,1'- binaphthalene]-5,5',6,6'-tetraol to a known tetrabrominated diphenyl ether. After total synthesis of the reported binaphthalenetetrol was accomplished via a key reduction of a binaphtho-ortho-quinone, comparison of the physical properties and NMR spectroscopic data of the synthetic material indicated that the structure of the natural product isolate was incorrect. Evaluation of the authentic natural product suggested the structure is a tetrabrominated diphenyl ether, likely 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol.

Full text of DOI:10.1021/np300141t

Article
pubs.acs.org/jnp
Structural Reassignment of a Marine Metabolite from a
Binaphthalenetetrol to a Tetrabrominated Diphenyl Ether
Erin E. Podlesny and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
ABSTRACT: The structure of a reported natural product
isolate has been revised from (S)-2,2′-dimethoxy-[1,1′-
binaphthalene]-5,5′,6,6′-tetraol to a known tetrabrominated
diphenyl ether. After total synthesis of the reported
binaphthalenetetrol was accomplished via a key reduction of
a binaphtho-ortho-quinone, comparison of the physical proper-
ties and NMR spectroscopic data of the synthetic material
indicated that the structure of the natural product isolate was
incorrect. Evaluation of the authentic natural product
suggested the structure is a tetrabrominated diphenyl ether, likely 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol.
of NMR spectroscopic data and the absolute configuration
from the CD spectrum.7 Herein, we describe a total synthesis of
the proposed binaphthalenetetrol natural product, (S)-1.
Together with a reanalysis of the natural product isolate, this
effort supports reassignment as a tetrabrominated diphenyl
ether.
ver the past several years we have developed and
Oeffectively used oxidative asymmetric biaryl coupling to
synthesize axially or helically chiral naphthalene-based natural
products,1 including nigerone,2 cercosporin,3 hypocrellin A,4
and other perylenequinones.5 More recently, we have shown
the value of using axially chiral binaphtho-para-quinones to
synthesize the bisanthraquinone natural product (S)-5,5′-
bisoranjidiol.6 During our study of binaphtho-ortho-quinone-
diols, a new marine natural product was reported that mapped
onto this skeleton: (S)-2,2′-dimethoxy-1,1′-binaphthyl-5,5′,6,6′-
tetraol [(S)-1, Scheme 1]. Isolated in 2007 from an Indonesian
Lendenfeldia sp. sponge,7 this material was reported to
significantly inhibit hypoxia-induced and iron-chelator (1,10-
phenanthroline)-induced activation of the transcription factor
HIF-1 (hypoxia-inducible factor-1) in T47D breast tumor cells.
The published structure of (S)-1 was deduced from the analysis
RESULTS AND DISCUSSION
■
Retrosynthetic analysis of (S)-1 revealed that reduction of
chiral binaphtho-ortho-quinone (S)-2 would readily reveal the
proposed natural product. The biquinone (S)-2, in turn, could
be obtained by selective oxidation of (S)-3. Asymmetric biaryl
coupling of 4 with a dinuclear chiral vanadium catalyst,8
followed by methylation and deprotection, would provide (S)-
3.
Known biaryl (S)-5 was synthesized in 82% yield and 81% ee
(enhanced to 98% ee after trituration) from 4 using chiral
vanadium catalyst 6 (Scheme 2).8 Methylation of (S)-5,
followed by removal of the benzyl protecting groups, provided
intermediates (S)-7 and (S)-3 in 73% and 99% yields,
respectively. Oxidation of binaphthol (S)-3 efficiently provided
binaphtho-ortho-quinone (S)-2 as an orange solid with very
high efficiency (97% yield). A crystal structure of rac-2 secured
our structural assignment (Figure 1). Compound rac-2 was
prepared in the same manner as (S)-2, except the achiral
catalyst VO(acac)2 was used instead of 6 for the biaryl coupling
reaction. Subsequent reduction of (S)-2 with sodium dithionite
produced the desired compound synthetic-1 (Scheme 2).
Surprisingly, both the spectroscopic data and physical
properties of synthetic-1 did not correlate with those reported
for the natural product. The synthetic material was unstable in
Scheme 1. Retrosynthetic Analysis
Received: February 22, 2012
Published: June 12, 2012
© 2012 American Chemical Society and
American Society of Pharmacognosy
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a
1
Scheme 2. Synthesis of Reported Natural Product (S)-1
Table 1. Comparison of H NMR Data for Literature and
Synthetic-1
a
literature
(CDCl3)
synthetic (CDCl3 +
EtOAc)
synthetic (acetone-
d6)
b
position
δH
δH
δH (J in Hz)
3
6.70, br s
7.39, br s
7.16, br s
7.32, br s
7.29, d
8.13, d
6.44, d
6.79, d
6.98, br s
6.31, br s
3.62, s
7.45, d (9.3)
8.25, d (9.3)
6.45, d (9.3)
6.90, d (9.0)
8.00, s
4
7
8
OH
OH
OMe
7.65, s
4.02, s
3.68, s
a
b
Reference 7. See Scheme 2 for numbering.
peaks and the missing phenol signals. There is also a significant
departure between the chemical shifts of synthetic-1 and the
isolated natural product, with all aromatic peaks differing by at
least 0.53 ppm. In addition, the OMe is shifted downfield at
4.02 ppm for literature-1 relative to the synthetic material at
3.62 ppm (Table 1). Due to the instability and solubility
problems, obtaining a satisfactory 13C NMR spectrum in
CDCl3 was difficult. However, the OMe is visible at 56.9 ppm
(Table 2), whereas the OMe for the published material is at
61.5 ppm. The remaining chemical shifts from the 13C NMR
spectrum in acetone-d6 are also quite different.
a
Abbreviations: IBX, o-iodoxybenzoic acid.
Table 2. Comparison of 13C NMR Data for Literature- and
Synthetic-1
a
literature (CDCl3)
synthetic (acetone-d6)
b
position
δC
δC
1
117.4
145.0
118.2
130.2
150.5
138.5
120.2
127.4
119.9
118.5
61.5
120.9
139.0
114.6
122.9
154.3
138.5
117.6
119.2
130.9
122.6
2
3
4
5
6
7
8
9
10
OMe
c
56.7 (56.9)
a
b
c
Reference 7. See Scheme 2 for numbering. Recorded in CDCl3 +
EtOAc.
Figure 1. Crystal structure of binaphtho-ortho-quinone rac-2.
On the basis of the reported HRESIMS data (m/z
378.1105), which suggested a molecular formula of C22H18O6,
and the correlations presented for the NMR spectroscopic data,
the structure originally proposed for 1 appears logical.7
Scrutinizing the data further, however, revealed inconsistencies.
From the analysis of the published 1H−13C HMBC
correlations, two- and three-bond correlations between C-6/
H-7 and C-6/H-8 were not reported (for atom numbering see
Scheme 2).7 After an analysis of the original spectroscopic
data,9 it also appears that there are 13 peaks in the 13C NMR
spectrum rather than the 11 published. These two extra peaks
are very closely associated with peaks at 117.4 and 150.4 ppm.
These inconsistencies prompted us to conduct our own
examination of the natural product isolate.9 The (−)-HRESIMS
spectrum of the metabolite exhibited a cluster of peaks, which
indicates four bromines are present and gives a molecular
formula of C13H8Br4O3 ([M − H]− m/z 526.7119). Moreover,
air and to silica, readily forming perylenequinone upon
standing. In contrast, the natural product was isolated using
silica gel column chromatography (2:1 hexanes−EtOAc).7 In
addition, synthetic-1 was insoluble in CDCl3, the solvent used
to obtain the published NMR spectroscopic data. Due to this
poor solubility, it was necessary to add EtOAc to CDCl3 in
order to obtain a spectrum. A cleaner spectrum was recorded in
acetone-d6. Both the acetone-d6 and CDCl3 spectra show the
expected two pairs of doublets and the two phenol peaks of
synthetic-1 (Table 1).
1
On the other hand, the H NMR data for the reported
natural product (Table 1) are missing both phenol peaks and
lack any of the expected splitting patterns. Analysis of the
original spectrum9 indicates that it was obtained at high
concentration, which could account for the observed broad
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our 13C NMR spectrum was identical to that supplied to us,9
indicating that there are 13 carbons. The H NMR spectrum
also revealed small coupling constants consistent with meta-
protons on an aromatic ring (see Table 3). The COSY
correlation data showed that two spin systems were present,
with H-2 coupled to H-4 and H-10 coupled to H-12 (Table 3).
congeners, such as the binaphtho-ortho-quinones. Oxidatively
sensitive binaphthalenetetrol (S)-1 was efficiently synthesized
from a binaphtho-ortho-quinone intermediate, the structure of
which was confirmed by crystallography. Comparison of the
structural data from this synthetic material shows that the
reported natural product structure is not (S)-2,2′-dimethoxy-
[1,1′-binaphthalene]-5,5′,6,6′-tetraol [(S)-1]. Examination of an
authentic sample of the natural product indicates that it is a
tetrabrominated diphenyl ether.
1
Table 3. NMR Spectroscopic Data for Natural Product
a
Isolate
b
position
δC, type
δH (J in Hz)
HMBC
EXPERIMENTAL SECTION
■
1
150.9, C
119.1, CH
117.5, C
General Experimental Procedures. Infrared spectra were
recorded on either a Jasco FT/IR-480 Plus spectrometer or an
Applied Systems ReactIR 1000. NMR spectra were recorded on 300
and 500 MHz spectrometers. Multiplicity for 1H NMR data is
reported as follows: s = singlet, d = doublet, t = triplet, br = broad, m =
2
6.83, d (2.3)
7.46, d (2.2)
1, 3, 4, 6
3, 6
3
4
130.8, CH
119.2, C
5
1
multiplet. H NMR spectra were referenced to the residual solvent
6
146.2, C
peaks: CDCl3 (7.26 ppm), acetone-d6 (2.05 ppm), and CD3OD (3.31
ppm). 13C NMR spectra were referenced to CDCl3 (77.16 ppm) and
acetone-d6 (29.8 ppm). High-resolution mass spectra were measured
on a Waters LC-TOF mass spectrometer (model LCT-XE Premier).
Enantiomeric excesses were determined using analytical HPLC with
UV detection at 254 nm. An analytical Chiralpak IA column (4.6 mm
× 250 mm, 5 μm) from Daicel was used. All reactions were carried out
under an atmosphere of dry argon, unless otherwise noted. When
necessary, solvents and reagents were dried prior to use. DMF was
distilled from MgSO4. Reactions were all monitored via analytical thin
layer chromatography, and visualization was accomplished with UV
light. Column chromatography was performed with Silicycle SiliaFlash
P60 silica gel (40−63 μm particle size).
7
61.8, CH3
139.3, C
150.6, C
120.2, CH
120.1, C
127.6, CH
117.4, C
4.03, s
6
8
9
10
11
12
13
7.18, d (2.2)
7.35, d (2.2)
8, 9, 11, 12
8, 10, 13
a
Recorded in CDCl3, 500 MHz for H NMR and 125 MHz for 13C
NMR. HMBC correlations indicate the protons in column 3 coupling
to the carbon entry in column 2.
1
b
(S)-6,6′-Bis(benzyloxy)-2,2′-dimethoxy-1,1′-binaphthalene
[(S)-7]. To a solution of (S)-58 (143 mg, 0.29 mmol, 98% ee) at 0 °C
was added NaH (60%, 62.5 mg, 1.56 mmol), followed by MeI (7 μL,
1.1 mmol) after 10 min. After stirring 2 h at room temperature, the
mixture was cooled to 0 °C and quenched with H2O. This mixture was
extracted with EtOAc (×2) and washed several times with H2O,
followed by brine. The organic layer was dried over Na2SO4, filtered,
and concentrated. The residue was chromatographed (20% EtOAc/
hexanes) to afford (S)-7 as a white solid (119 mg, 73%, 98% ee): mp
Interpretation of the HSQC and HMBC data (Table 3)
revealed a tetrabrominated diphenyl ether with the OMe and
OH on separate rings and two bromines on each ring. There
are three correlations missing, but eight possible structures
could be proposed based on the data (see Figure 2).
Comparison of calculated chemical shifts with the observed
13C NMR data (Table 4) of the metabolite highlighted 8 as the
closest match and possible identity of the natural product.
A literature search of the molecular formula revealed a few
tetrabrominated diphenyl ethers (isolated from marine
sponges).10,11 Of the compounds in Figure 2, however, only
8 has been reported. Comparison of the NMR data from this
report and the isolation report7 with the published data for
compound 8 also indicated a reasonable match (Table 5).12
Further suggestive support for this structure is that 8 was
previously isolated from a Palauan collection of another
Lendenfeldia sponge.11,13 Overall, the evidence supports
structure 8 as the identity of the natural product.
1
78−81 °C; IR (film) νmax 2933, 1596, 1504, 1253 cm−1; H NMR
(500 MHz, CDCl3) δ 7.85 (2H, d, J = 9.0 Hz), 7.48 (4H, d, J = 7.4
Hz), 7.42 (2H, d, J = 9.1 Hz), 7.40 (4H, t, J = 7.5 Hz), 7.34 (2H, t, J =
7.3 Hz), 7.27 (2H, d, J = 2.5 Hz), 7.05 (2H, d, J = 9.3 Hz), 7.0 (2H,
dd, J = 9.2 Hz, 2.5 Hz), 5.16 (4H, s), 3.74 (6H, s); 13C NMR (125
MHz, CDCl3) δ 155.4 (C−O × 2), 153.8 (C−O × 2), 137.3 (C × 2),
130.2 (C × 2), 129.7 (C × 2), 128.7 (CH × 4), 128.2 (CH × 2), 128.1
(CH × 2), 127.7 (CH × 4), 127.1 (CH × 2), 120.3 (C × 2), 119.7
(CH × 2), 115.2 (CH × 2), 107.4 (CH × 2), 70.2 (CH2 × 2), 57.3
(OCH3 × 2); HRESIMS m/z 527.2219 [M + H]+ (calcd for
C36H30O4, 527.2222).
(S)-2,2′-Dimethoxy-[1,1′-binaphthalene]-6,6′-diol [(S)-3]. A
solution of (S)-7 (279 mg, 0.529 mmol) in MeOH/THF (11.2 mL)
was evacuated and purged with Ar. To this solution was added Pd/C
In summary, oxidative naphthol coupling was shown to
provide an expeditious entry into more highly oxidized
Figure 2. Possible structures of the natural product isolate.
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a
Table 4. Differences between Observed 13C NMR Data of Natural Product Isolate and Calculated 13C NMR Data of 8−15
ΔδC
position
observed δC
8
9
10
0.5
11
0.5
12
13
14
15
1
150.9
119.1
117.5
130.8
119.2
146.2
61.8
0.5
3.8
0.5
3.8
−6.3
14.3
6
−6.3
14.3
6
−6.3
14.3
6
−6.3
14.3
6
2
3.8
7.8
3.8
7.8
3
7.8
7.8
4
2
2
2
2
17.9
−7.4
−15.3
6
17.9
−7.4
−15.3
6
17.9
−7.4
−15.3
6
17.9
−7.4
−15.3
6
5
5.1
5.1
5.1
5.1
6
−1.7
0.9
−1.7
0.9
−1.7
0.9
−1.7
0.9
7
8
139.3
150.6
120.2
120.1
127.6
117.4
0.9
−4.7
5.6
−20.3
−7.9
4.6
−20.1
−7
5.7
0.9
−4.7
5.6
−20.3
−7.9
4.6
−20.1
−7
5.7
9
−1.5
2.3
−1.5
2.3
10
11
12
13
4.5
4.5
2.1
10.1
−1.6
6.3
9.4
8.3
2.1
10.1
−1.6
6.3
9.4
8.3
0.6
21.2
−9.6
21.2
−9.6
0.6
21.2
−9.6
21.2
−9.6
−1.6
−1.6
a
Chemical shifts were calculated using CambridgeSoft ChemBioDraw.
Table 5. Comparison of NMR Data of Natural Product Isolate with Literature for Compound 8
a
b
c
observed (CDCl3)
original data (CDCl3)
lit. (CDCl3)
lit. (CD3OD)
observed (CD3OD)
position
δC
δH
δC
δH
δC
δH
δH
1
150.9
119.1
117.5
130.8
119.2
146.2
61.8
150.5
118.2
117.4
130.2
119.0
145.0
61.5
152.9
118.0
117.4
129.7
119.8
147.1
61.5
2
6.83
7.46
6.70
7.40
6.53
7.30
6.50
7.39
3
4
5
6
7
4.03
4.01
3.96
3.99
8
139.3
150.6
120.2
120.1
127.6
117.4
138.5
150.5
120.2
119.9
127.4
117.4
140.0
153.6
121.1
120.4
127.1
119.4
9
10
11
12
13
7.18
7.35
7.16
7.33
7.10
7.25
7.13
7.34
a
b
c
Values taken from hard copies of spectra; see SI. Reference 11. Reference 10.
(10 wt %, 104 mg), and the mixture evacuated and purged three times
with H2. After stirring under a hydrogen atmosphere overnight, the
mixture was filtered through Celite with EtOAc and concentrated. The
residue was passed through a short column of silica (30% EtOAc/
hexanes) to afford (S)-3 as a white solid (182 mg, 99%): mp >240 °C
dec; IR (film) νmax 3366, 1598, 1511, 1256 cm−1; 1H NMR (500 MHz,
acetone-d6) δ 8.33 (2H, s), 7.81 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J =
9.0 Hz), 7.23 (2H, d, J = 2.3 Hz), 6.93 (2H, d, J = 9.1 Hz), 6.89 (2H,
dd, J = 9.1 Hz, 2.4 Hz), 3.68 (6H, s); 13C NMR (125 MHz, acetone-
d6) δ 154.3 (C−O × 2), 154.0 (C−O × 2), 131.6 (C × 2), 129.7 (C ×
2), 128.1 (CH × 2), 127.6 (CH × 2), 121.0, 119.5, 115.9, 109.8, 57.0
(OCH3 × 2); HRESIMS m/z 347.1284 [M + H]+ (calcd for
C22H18O4, 347.1283).
141.5 (CH × 2), 135.6 (C × 2), 133.7 (CH × 2), 129.2 (CH × 2),
125.5 (C × 2), 123.3 (C × 2), 112.0 (CH × 2), 56.7 (OCH3);
HRESIMS m/z 375.0877 [M + H]+ (calcd for C22H14O6, 375.0869).
(S)-2,2′-Dimethoxy-[1,1′-binaphthalene]-5,5′,6,6′-tetraol
[(S)-1]. In a separatory funnel, (S)-2 (16 mg, 0.043) was dissolved in
CH2Cl2 (2 mL) and diluted with Et2O (4 mL). Then, an aqueous
solution of Na2S2O4 (40 mg/6 mL) was added. The mixture was
shaken, and additional Na2S2O4 (50 mg) was added, followed by
shaking until a loss of orange color was observed in the organic layer.
After separating the layers, the organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated to afford 1 as an air-
sensitive, off-white solid (98% ee): IR (film) νmax 3375, 2925, 1600,
1518, 1367, 1259, 1095 cm−1; 1H NMR (300 MHz, acetone-d6) Table
1; 13C NMR (125 MHz, acetone-d6) Table 2; compound partially
oxidized during ionization: HRESIMS m/z 375.0863 [M − H]− (calcd
for C22H15O6, 375.0869).
Natural product isolate (tetrabrominated diphenyl ether 8):
IR (film) νmax 3366, 2930, 1569, 1469, 1393, 1255, 1216, 914 cm−1; 1H
NMR (500 MHz, CDCl3 and CD3OD) Tables 3 and 5; 13C NMR
(125 MHz, CDCl3) Table 3; HRESIMS m/z 526.7119 [M − H]−
(calcd for C13H7Br4O3, 526.7129).
X-ray Crystallographic Analysis of rac-2. Crystals of a racemic
sample of 2 were obtained by slow evaporation from CH2Cl2. The X-
ray intensity data were collected at a temperature of 143(1) K on a
Bruker APEXII CCD area detector employing graphite-monochro-
mated Mo Kα radiation (λ = 0.71073 Å). The structure was solved by
direct methods (SHELXS-97). There was a region of disordered
(S)-2,2′-Dimethoxy-[1,1′-binaphthalene]-5,5′,6,6′-tetraone
[(S)-2]. To a solution of (S)-3 (15.4 mg, 0.044 mmol) in 0.8 mL of
DMF was added 2-iodoxybenzoic acid (25.0 mg, 0.089 mmol). The
mixture was stirred for 3 h in the dark. Following this time, the mixture
was diluted with H2O and extracted with EtOAc. The organic layer
was washed with 25% aqueous NaHCO3, dried over Na2SO4, filtered,
and concentrated. The residue was chromatographed (5%−10%
EtOAc/CH2Cl2) to afford (S)-2 as an orange solid (16.2 mg, 97%):
mp 190 °C dec; [α]25 −42.1 (c 0.054, 98% ee, CH2Cl2); UV
D
(CH2Cl2) λmax (log ε) 388 (6.91), 270 (6.88); IR (film) νmax 2927,
1
2850, 1661, 1568, 1468, 1274 cm−1; H NMR (500 MHz, CDCl3) δ
8.29 (2H, d, J = 8.7 Hz), 7.10 (2H, d, J = 8.7 Hz), 6.97 (2H, d, J = 10.4
Hz), 6.34 (2H, d, J = 10.4 Hz), 3.86 (6H, s); 13C NMR (125 MHz,
CDCl3) δ 181.2 (CO × 2), 177.7 (CO × 2), 163.2 (C−O × 2),
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solvent for which a reliable disorder model could not be devised; the
X-ray data were corrected for the presence of disordered solvent using
SQUEEZE. Refinement was by full-matrix least-squares based on F2
using SHELXL-97. All reflections were used during refinement. Non-
hydrogen atoms were refined anisotropically, and hydrogen atoms
were refined using a riding model. The crystallographic data for rac-2
have been deposited at the Cambridge Crystallographic Data Centre
with the deposition number 883203. Copies of the data can be
obtained, free of charge, on application to the Director, CCDC, 12
Union Road, Cambridge CB21EZ, UK [fax: +44(0)-1233-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
Wu, Z.-J.; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo, S.-W.; Cun, L.-F.;
Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 13927−13938. (c) Takizawa,
S.; Katayama, T.; Sasai, H. Chem. Commun. 2008, 4113−4122.
(d) Takizawa, S.; Katayama, T.; Somei, H.; Asano, Y.; Yoshida, T.;
Kameyama, C.; Rajesh, D.; Onitsuka, K.; Suzuki, T.; Mikami, M.;
Yamataka, H.; Jayaprakash, D.; Sasai, H. Tetrahedron 2008, 64, 3361−
3371. (e) Takizawa, S.; Katayama, T.; Kameyama, C.; Onitsuka, K.;
Suzuki, T.; Yanagida, T.; Kawai, T.; Sasai, H. Chem. Commun. 2008,
1810−1812.
1
(9) Copies of the original H and 13C NMR spectra and a sample of
the natural product isolate were kindly provided by Dr. Nagle (see ref
7).
(10) Norton, R. S.; Croft, K. D.; Wells, R. J. Tetrahedron 1981, 37,
2341−2349.
ASSOCIATED CONTENT
* Supporting Information
1D and 2D NMR spectra and crystallographic data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
(11) Hattori, T.; Konno, A.; Adachi, K.; Shizuri, Y. Fisheries Sci. 2001,
67, 899−903.
(12) Observed 1H and 13C NMR chemical shifts appear to be
concentration dependent.
(13) Compound 8 was reported from the sponge Phyllospongia
dendyi. This sponge has been taxonomically reclassified as Lendenfeldia
dendyi: Bergquist, P. R. New Zeal. J. Zool. 1980, 7, 443−503.
AUTHOR INFORMATION
Corresponding Author
*Tel: (215)-898-3048. E-mail: marisa@sas.upenn.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
E.E.P. gratefully acknowledges the National Institutes of Health
for both a Ruth L. Kirschstein National Research Service Award
(F31-GM093515) and Chemistry-Biology Interface (T32-
GM071339) predoctoral fellowships. Financial support for
this work was also provided by the National Science
Foundation (CHE-0911713). Partial instrumentation support
was provided by the NIH for MS (1S10RR023444) and NMR
(1S10RR022442) and by the NSF for an X-ray diffractometer
(CHE 0840438). The invaluable assistance of Dr. P. Carroll in
obtaining the crystal structure and of Dr. G. Furst and Dr. J. Gu
(all of the University of Pennsylvania) for obtaining the 2D
NMR data is gratefully acknowledged. We also thank Dr. D.
Nagle (University of Mississippi) for providing copies of the
original 1H and 13C NMR spectra and for providing a sample of
the natural product isolate.
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