A concise synthesis of Pawhuskin A

Article abstract of DOI:10.1021/np800351c

Pawhuskin A is an isoprenylated stilbene that was isolated from Dalea purpurea and reported to have affinity for the opioid receptor in vitro. It has been synthesized through a convergent sequence that joins a prenylated aldehyde with a geranylated phosphonate in a stereoselective Horner-Wadsworth-Emmons condensation to afford the target E olefin isomer. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used to explore its biological activity and to prepare more active analogues.

Full text of DOI:10.1021/np800351c

J. Nat. Prod. 2008, 71, 1949–1952
1949
A Concise Synthesis of Pawhuskin A
Jeffrey D. Neighbors,†,‡ Matthew J. Buller,† Kelly D. Boss,† and David F. Wiemer*,†,‡
Departments of Chemistry and Pharmacology, UniVersity of Iowa, Iowa City, Iowa 52242-1294
ReceiVed June 13, 2008
Pawhuskin A is an isoprenylated stilbene that was isolated from Dalea purpurea and reported to have affinity for the
opioid receptor in Vitro. It has been synthesized through a convergent sequence that joins a prenylated aldehyde with
a geranylated phosphonate in a stereoselective Horner-Wadsworth-Emmons condensation to afford the target E olefin
isomer. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used
to explore its biological activity and to prepare more active analogues.
Early in 2004, Belofsky and co-workers reported the isolation
of several compounds from Dalea purpurea, including three new
isoprenylated stilbenes that they named pawhuskins A-C (Figure
1, 1-3).1 These three compounds were shown to have affinity for
the opioid receptor in bioassays that quantified displacement of 3H-
naloxone from a preparation of rat striatal tissue that included the
R, κ, and µ receptors.2 Our earlier work on synthesis of the
schweinfurthins,3 also doubly prenylated stilbenes, allowed a rapid
synthesis of pawhuskin C.4 Because it bears an acyclic isoprenoid
substituent on just one of the arene rings, pawhuskin C can be
viewed as the simplest member of its family. However, pawhuskin
A is the most active with respect to opioid receptor binding, and
its substitution pattern differs from that of pawhuskin C or the
natural5,6 (e.g., 4 or 5) or synthetic3,7 schweinfurthins.
Within the past few years, it has been recognized that non-
nitrogenous compounds can bind at the opioid receptors and
demonstrate activity or block the binding of active agents.8 The
diterpenoid salvinorin A9 was found to be a κ selective agonist,
and then more recently the pawhuskins have been reported to bind
at opioid receptors, although their specificity has not been estab-
lished. Whether the pawhuskins bind at hitherto unrecognized sites
or bind at known sites in these receptors is not yet clear, and whether
they can serve as agonists or antagonists has not yet been
determined. However, there are compelling needs for new analgesics
for treatment of pain, as well as for compounds that block opiate
binding for use in pharmacological interventions in cases of
stimulant abuse.10
Figure 1. The natural pawhuskins and two related schweinfurthins.
The combination of interesting biological activity and the need
for different protocols for introduction of the isoprenoid substituents
led to an interest in the preparation of this compound. In this paper,
we report an efficient synthesis of pawhuskin A that confirms the
structure assigned to the natural product and paves the way for
exploration of structure-activity relationships.
Retrosynthesis of pawhuskin A (Figure 2) through disconnection
of the central stilbene olefin to intermediates appropriate for
Horner-Wadsworth-Emmons (HWE) condensation leads to either
the aryl aldehyde 6 as the left half and a benzylic phosphonate 7
as the right half, which we chose to pursue, or to the opposite
pairing. The aldehyde 6 could then be recognized in commercial
3,4-dihydroxybenzaldehyde (8), while the phosphonate 7 might be
derived from commercial methyl 3,5-dihydroxybenzoate (9).
In a synthetic sense, preparation of the phosphonate appeared to
require the longer sequence. Initially, conversion of ester 9 to the
protected benzylic alcohol 10 was accomplished by variations on
literature methods (Scheme 1).11 After formation of the TBS ether
Figure 2. Retrosynthesis of pawhuskin A.
* Corresponding author. Tel: 319-335-1365. Fax: 319-335-1270. E-mail:
david-wiemer@uiowa.edu.
† Department of Chemistry.
10, bromination with NBS provided the aryl bromide 11 in good
yield.12 Halogen-metal exchange and reaction with geranyl
‡ Department of Pharmacology.
10.1021/np800351c CCC: $40.75
2008 American Chemical Society and American Society of Pharmacognosy
Published on Web 10/16/2008

1950 Journal of Natural Products, 2008, Vol. 71, No. 11
Scheme 1. Synthesis of Phosphonate 15
Notes
reaction with prenyl bromide afforded the substituted arene 17.
Oxidation of the benzylic alcohol 17 to the corresponding aldehyde
18 occurred readily upon treatment with MnO2. The HWE
condensation of aldehyde 18 and phosphonate 15 was straightfor-
ward, providing the trans-stilbene 19 with no trace of the isomeric
cis product. Hydrolysis of the four MOM groups was accomplished
with CSA in MeOH to afford pawhuskin A (1). While the yield
for this last step is somewhat disappointing, it does reflect cleavage
of four separate protecting groups and is consistent with yields
observed in other such highly protected systems.15 The final product
gave 1H and 13C NMR data identical to those of the natural product.
In conclusion, the natural product pawhuskin A has been prepared
by a convergent sequence ending in formation of the central stilbene
and deprotection of the MOM groups. The required phosphonate
intermediate 15 can be prepared in a straightforward fashion from
the corresponding alcohol 14. This key alcohol 14 was prepared
through two different sequences, a more traditional approach that
required six steps from commercial methyl 3,5-dihydroxybenzoate
and gave the desired product in ∼25% overall yield, and a new
strategy that required only three steps and provided this key
intermediate in ∼33% overall yield (and almost 80% overall yield
based on recovered starting material). By means of this new
sequence, the synthesis reported here should provide sufficient
material to explore the biological properties of pawhuskin A in
more detail and allow synthesis of analogues for more extensive
structure-activity relationship studies.
Experimental Section
General Experimental Procedures. Tetrahydrofuran (THF) and
Et2O were distilled from Na and benzophenone and used immediately,
while CH2Cl2 was distilled from CaH2. Anhydrous DMF was used
directly without further purification. All nonaqueous reactions were done
under an Ar atmosphere, in oven- or flame-dried glassware, and with
magnetic stirring. Flash chromatography was done on silica gel with
Scheme 2. Synthesis of Pawhuskin A
1
an average of 40-63 µm particle size. The H and 13C NMR spectra
were recorded at 300 MHz with CDCl3 as solvent and (CH3)4Si as
internal standard unless otherwise noted. High-resolution and electro-
spray (ES) mass spectra were obtained at the University of Iowa Mass
Spectrometry Facility. The elemental analyses were conducted by
Atlantic Microlab, Inc. (Norcross, GA).
Synthesis of Aryl Bromide 11. To a stirred solution of silyl ether
1015 (5.38 g, 15.7 mmol) in CHCl3 was added NBS (2.82 g, 15.8 mmol)
at room temperature, and the reaction was heated to reflux for 2 h and
then allowed to cool to room temperature. The reaction mixture was
quenched by addition of H2O and extracted into CHCl3. The combined
organic layers were washed twice with H2O, dried (MgSO4), and
concentrated in Vacuo to afford a yellow oil. Final purification by flash
chromatography (17% EtOAc in hexanes) gave aryl bromide 11 as a
clear oil (6.06 g, 92%) having spectral properties identical to the known
compound.12
bromide in the presence of CuBr ·DMS gave the target carbon
skeleton 12 in moderate yield, and treatment of this silyl ether with
TBAF afforded the benzylic alcohol 14. An alternate route to
compound 14 through the resorcinol derivative 13 was explored
and proved significantly more efficient. For this sequence the ester
9 was treated with geraniol and BF3 ·OEt2 to obtain the target carbon
skeleton directly.13 While the yield for this reaction was modest
(35%), a substantial amount of the starting material was recovered
and the yield based on recovered starting material was very
attractive (85%). Subsequent introduction of the MOM groups and
reduction with LiAlH4 proceeded smoothly to afford the benzylic
alcohol 14 in a very direct fashion. Conversion of alcohol 14 to
the corresponding phosphonate 15 also proceeded smoothly through
formation of the mesylate, displacement with NaI, and a final
reaction with P(OEt)3.
tert-Butyl[{2-(2E-3,7-dimethyl-2,6-octadienyl)-3,5-
bis(methoxymethoxy)benzyl}oxy]dimethylsilane (12). To a solution
of aryl bromide 11 (0.52 g, 1.31 mmol) in THF (10 mL) at -78 °C
was added n-BuLi (0.60 mL, 1.44 mmol, 2.4 M hexanes), and the
resulting solution was stirred for 1 h. After CuBr ·DMS (0.30 g, 1.45
mmol) was added and the reaction was stirred for 30 min, geranyl
bromide (0.29 mL, 1.45 mmol) was added and the reaction mixture
was allowed to warm to room temperature and stirred for 10 h. The
reaction was quenched by addition of saturated NH4Cl and extracted
with EtOAc, and the combined organic layers were washed with brine,
dried (MgSO4), and concentrated to afford a yellow oil. Final
purification by column chromatography (8% to 18% EtOAc in hexanes)
1
afforded the geranylated arene 12 (340 mg, 54%) as a clear oil: H
NMR (CDCl3, 300 MHz) δ 6.91 (d, J ) 2.5 Hz, 1H), 6.71 (d, J ) 2.6
Hz, 1H), 5.16 (s, 2H), 5.15 (s, 2H), 5.08-5.02 (m, 2H), 4.69 (s, 2H),
3.47 (s, 3H), 3.46 (s, 3H), 3.28 (d, J ) 6.6 Hz, 2H), 2.08-1.93 (m,
4H), 1.76 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 0.95 (s, 9H), 0.09 (s, 6H);
13C NMR δ 156.1, 155.3, 141.5, 134.6, 131.3, 124.2, 122.8, 120.8,
107.4, 102.0, 94.6, 94.6, 62.6, 56.0, 55.9, 39.7, 26.7, 25.9 (3C), 25.7,
23.9, 18.4, 17.6, 16.1, -5.3(2C); anal. C 67.95%, H 9.71%, calcd for
C27H46O5Si, C 67.74%, H 9.68%.
Synthesis of the complementary benzaldehyde required for the
anticipated HWE condensation is shown in Scheme 2. Commercial
3,4-dihydroxybenzaldehyde (8) was readily converted to the MOM-
protected benzyl alcohol 16.14 After treatment of this alcohol with
excess n-BuLi to induce directed ortho metalation and CuBr·DMS,

Notes
2-[(2E)-3,7-Dimethyl-2,6-octadienyl]-3,5-bis(methoxymethoxy-
Journal of Natural Products, 2008, Vol. 71, No. 11 1951
to triethyl phosphite (1 mL), and the mixture was heated at 100 °C for
10 h. After the solution was allowed to cool to room temperature, the
excess phosphite was removed under high vacuum. The initial yellow
oil was purified by flash chromatography (50% EtOAc in hexanes) to
afford phosphonate 15 (274 mg, 68%) as a clear oil: 1H NMR (CDCl3,
300 MHz) δ 6.70-6.68 (m, 2H), 5.15 (s, 2H), 5.13 (s, 2H), 5.07-5.00
(m, 2H), 4.07-3.98 (m, 4H), 3.46-3.45 (m, 2H), 3.46 (s, 3H), 3.45
(s, 3H), 3.13 (d, JHP ) 22 Hz, 2H), 2.09-1.95 (m, 4H), 1.78 (s, 3H),
1.65 (s, 3H), 1.57 (s, 3H), 1.26 (t, JHP ) 7.0 Hz, 6H); 13C NMR (CDCl3)
δ 155.9, 155.7 (d, JCP ) 3.8 Hz), 134.8, 132.0 (d, JCP ) 9.1 Hz), 131.2,
124.0,124.2, 122.9, 111.4, 102.4 (d, JCP ) 3.7 Hz), 94.6, 94.6, 62.0 (d,
JCP ) 6.17, 2C), 56.0, 55.9, 39.6, 30.4 (d, JCP ) 137 Hz), 26.6, 25.6,
24.6, 17.6, 16.3, 16.3, 16.1; 31P NMR δ 27.3; HRMS (ESI) calcd for
C25H41O7P 484.2590, found 484.2595.
Synthesis of [3,4-Bis(methoxymethoxy)-2-(3-methylbut-2-enyl)phe-
nyl]methanol (17). To a stirred solution of alcohol 164,14 (203 mg,
0.92 mmol) in THF (4 L) was added n-BuLi (0.78 mL of a 2.48 M
solution in hexanes) at 0 °C, and the mixture was stirred for 30 min at
0 °C. To this mixture was added CuBr as its dimethyl sulfide complex
(201 mg, 0.98 mmol), and the reaction was allowed to stir for 30 min
at 0 °C. After prenyl bromide (0.11 mL, 0.98 mmol) was added
dropwise at 0 °C, the mixture was stirred for 2 h at 0 °C, then quenched
by addition of H2O and extracted with Et2O. The combined organic
layers were dried (MgSO4), filtered, and concentrated in Vacuo to afford
a dark yellow oil. The oil was purified by flash chromatography
(15-20% EtOAc in hexanes) to give the prenylated arene 17 as a light
yellow oil (92 mg, 35%): 1H NMR (CDCl3, 300 MHz) δ 7.10 (d, J )
8.4 Hz, 1H), 7.00 (d, J ) 8.4 Hz, 1H), 5.19 (s, 2H), 5.15 (t, J ) 1.5,
1H), 5.11 (s, 2H), 4.60 (s, 2H), 3.59 (s, 3H), 3.54 (s, 1H), 3.52 (d, J )
1.8 Hz, 2H), 3.50 (s, 3H) 1.80 (s, 3H), 1.69 (s, 3H); 13C NMR δ 149.9,
145.3, 135.0, 134.1, 132.4, 125.1, 123.8, 114.3, 99.6, 96.4, 63.6, 57.9,
56.6, 26.0, 25.7, 18.3; anal. C 65.13%, H 8.44%, calcd for C16H24O5,
C 64.84%, H 8.16%.
)benzyl Alcohol (13). The silyl ether 12 (107 mg, 0.23 mmol) was
dissolved in THF (10 mL), and the solution was cooled to 0 °C. To
this solution was added TBAF (0.26 mL, 1.00 M in THF), the reaction
was allowed to warm to room temperature, and after 1.5 h it was
quenched by addition of saturated NH4Cl. After extraction with EtOAc,
the combined organic extract was washed with water and brine, dried
over MgSO4, and concentrated in Vacuo to give a yellow oil. Final
purification by flash chromatography (30% EtOAc in hexanes) gave
the benzylic alcohol 13 (65 mg, 78%): 1H NMR (CDCl3, 300 MHz) δ
6.79 (d, J ) 2.4 Hz, 1H), 6.76 (d, J ) 2.4 Hz, 1H), 5.17 (s, 2H), 5.15
(s, 2H), 5.11-5.02 (m, 2H), 4.64 (s, 2H), 3.47 (s, 3H), 3.47 (s, 3H),
3.38 (d, J ) 6.6 Hz, 2H), 2.08-1.94 (m, 4H), 1.77 (s, 3H), 1.65 (s,
3H), 1.57 (s, 3H); 13C NMR δ 156.2, 155.9, 140.9, 135.1, 131.4, 124.1,
123.4, 122.4, 108.8, 103.0, 94.6, 94.6, 63.3, 56.0, 56.0, 39.7, 26.6, 25.6,
24.1, 17.6, 16.1; HRMS(FAB) calcd for C21H33O5 (M + H)+ 365.2328,
found 365.2319.
Methyl 2-(3,7-Dimethylocta-2,6-dienyl)-3,5-dihydroxybenzoate
(13). To a solution of benzoate 9 (4.00 g, 23.8 mmol) in dioxane (100
mL) was added BF3 ·OEt2 (1.2 mL, 9.5 mmol). The reaction was heated
to 50 °C, and geraniol (2.08 mL, 11.9 mmol) in dioxane (20 mL) was
added dropwise over 50 min. After the reaction was allowed to stir for
an additional 2 h, it was poured into H2O and extracted with Et2O (300
mL). The combined organic fractions were washed with brine, dried
(MgSO4), and concentrated in Vacuo. Final purification by flash column
chromatography (25-35% EtOAc in hexanes) gave the geranylated
compound 13 (1.27 g, 35%) as a light yellow oil as well as recovered
benzoate 9 (2.35 g, 59%): 1H NMR (CDCl3, 300 MHz) δ 6.86 (d, J )
2.7 Hz, 1H), 6.53 (d, J ) 2.7 Hz, 1H), 5.20 (t, J ) 6.6 Hz, 1H),
5.07-5.00 (m, 1H), 4.83 (s, 2H), 3.86 (s, 3H), 3.59 (d, J ) 6.5 Hz,
2H), 2.12-1.99 (m, 4H), 1.78 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H); 13C
NMR δ 169.1, 156.9, 154.9, 138.6, 132.34, 132.31, 124.1, 122.5, 120.5,
109.8, 107.5, 52.6, 40.0, 26.7, 26.1, 26.0, 18.0, 16.5; HRMS m/z
304.1675 (calcd for C18H24O4, 304.1673).
3,4-Bis(methoxymethoxy)-2-(3-methylbut-2-enyl)benzaldehyde (18).
To a stirred solution of benzyl alcohol 17 (116 mg, 0.39 mmol) in
CH2Cl2 (10 mL) was added MnO2 (0.80 g, 7.80 mmol) at 0 °C, and
the resulting mixture was stirred for 22 h while it was allowed to warm
to room temperature. The reaction mixture was filtered through Celite,
and the pad was rinsed with EtOAc, Et2O, hexanes, and MeOH. After
the combined filtrate was concentrated in Vacuo to afford a yellow oil,
final purification by flash chromatography (30% EtOAc in hexanes)
Methyl2-(3,7-Dimethylocta-2,6-dienyl)-3,5-bis(methoxymethoxy)benzoate.
To a solution of compound 13 (272 mg, 0.89 mmol) in acetone (50
mL) was added anhydrous K2CO3 (1.23 g, 8.94 mmol). After the
reaction was allowed to stir for 15 min, MOMCl (0.34 mL, 4.47 mmol)
was added and the solution was heated to 60 °C for 6 h. The reaction
was allowed to cool to room temperature, the acetone was removed in
Vacuo, and EtOAc (100 mL) was added. The solution then was washed
with saturated NH4Cl, H2O, and brine, dried (MgSO4), and finally
concentrated in Vacuo to give the protected ester (348 mg, 99%) as a
1
gave the aldehyde 18 as a pale yellow oil (91 mg, 79%). The H and
13C NMR data were identical to reported data.16
1
yellow oil: H NMR (CDCl3, 300 MHz) δ 7.09 (d, J ) 2.4 Hz, 1H),
Tetra(methoxymethyl)pawhuskin A (19). NaH (as a 60% disper-
sion in mineral oil, 46 mg, 1.15 mmol) and 15-crown-5 (0.03 mL, 0.12
mmol) were dissolved in THF (5 mL), and the solution was cooled to
0 °C. Aldehyde 18 (32 mg, 0.11 mmol) and phosphonate 15 (106 mg,
0.22 mmol) were dissolved in THF (3 mL) and transferred via syringe
to the NaH suspension. The mixture was stirred for 22 h while it was
allowed to warm to room temperature. The reaction mixture was
quenched by addition of H2O (10 mL) and extracted with EtOAc. The
combined organic layers were dried (MgSO4), filtered, and concentrated
in Vacuo to afford a yellow oil. The yellow oil was purified by flash
chromatography (25% EtOAc in hexanes) to afford stilbene 19 as a
yellow oil (44 mg, 63%): 1H NMR (CDCl3, 300 MHz) δ 7.29 (d, J )
8.7 Hz, 1H), 7.10 (s, 2H), 7.02 (d, J ) 8.4 Hz, 1H), 6.93 (d, J ) 2.4
Hz, 1H), 6.74 (d, J ) 2.1 Hz, 1H), 5.21 (s, 2H), 5.18 (s, 2H), 5.17 (s,
2H), 5.15 (t, J ) 1.5 Hz, 1H), 5.13 (t, J ) 0.9 Hz, 1H), 5.11 (s, 2H),
5.05 (tt, J ) 6.6, 1.2 Hz, 1H), 3.60 (s, 3H), 3.56 (d, J ) 6.3 Hz, 2H),
3.51 (s, 3H), 3.49 (s, 3H), 3.48 (s, 3H), 3.45 (d, J ) 6.9 Hz, 2H),
2.05-1.97 (m, 4H), 1.80 (s, 3H), 1.79 (s, 3H), 1.69 (s, 3H), 1.62 (s,
3H), 1.55 (s, 3H); 13C NMR δ 156.3, 156.0, 149.5, 144.8, 138.8, 134.9,
134.7, 132.3, 131.9, 131.6, 128.7, 127.5, 124.6, 123.7, 123.4, 123.2,
122.3, 114.5, 106.9, 103.1, 99.6, 95.4, 95.0, 95.0, 57.9, 56.6, 56.3, 56.3,
40.1, 27.1, 26.2, 25.9, 25.9, 25.0, 18.5, 18.0, 16.7; HRMS calcd for
C37H52O8 (M+) 624.3662, found 624.3657.
6.92 (d, J ) 2.5 Hz, 1H), 5.17 (s, 2H), 5.15 (s, 2H), 5.12 (m, 1H),
5.05 (t, J ) 6.6 Hz, 1H), 3.85 (s, 3H), 3.59 (d, J ) 6.9, 2H), 3.46 (s,
3H), 3.45 (s, 3H), 2.08-1.90 (m, 4H), 1.74 (s, 3H), 1.63 (s, 3H), 1.56
(s, 3H); 13C NMR δ 168.6, 156.6, 155.9, 135.0, 132.4, 131.5, 126.0,
124.6, 123.5, 110.2, 107.1, 94.8 (2C), 56.4, 56.3, 52.4, 40.1, 27.0, 25.9,
25.6, 17.9, 16.5; HRMS m/z 392.2204 (calcd for C22H32O6, 392.2199).
[2-(3,7-Dimethylocta-2,6-dienyl)-3,5-bis(methoxymethoxy)phenyl-
]methanol (14). To a suspension of LiAlH4 (29 mg, 0.75 mmol) in
THF (5 mL) at 0 °C was added the intermediate ester (151 mg, 0.38
mmol) in THF (2 mL) dropwise. The reaction was allowed to stir for
1 h and then quenched by addition of H2O. The reaction mixture was
acidified with 1 M HCl (5 mL) and then diluted with EtOAc, washed
with brine, dried (MgSO4), and concentrated in Vacuo. Final purification
by flash column chromatography (25% EtOAc in hexanes) gave alcohol
14 (130 mg, 94%). Both 1H and 13C NMR data matched those reported
above.
Diethyl
[2-{(2E)-3,7-Dimethyl-2,6-octadienyl}-3,5-bis-
(methoxymethoxy)benzyl]phosphonate (15). Methanesulfonyl chloride
(0.26 mL, 3.4 mmol) was added dropwise to a solution of alcohol 14
(302 mg, 0.83 mmol) and Et3N (0.20 mL 1.4 mmol) in CH2Cl2 (8 mL)
at 0 °C, and the reaction mixture was allowed to warm to room
temperature over 1.5 h, quenched by addition of H2O, and extracted
with EtOAc. The combined organic layers were washed with saturated
NH4Cl and brine, dried (MgSO4), and concentrated in Vacuo. The
resulting residue and NaI (135 mg, 0.90 mmol) were stirred in acetone
(9 mL) for 16 h. This reaction mixture was concentrated in Vacuo to
afford a red solid, which was dissolved in EtOAc. After the resulting
yellow solution was washed once with NaHCO3 and then with Na2S2O3
(10% aqueous) until the color faded, it was washed with brine, dried
(MgSO4), and concentrated in Vacuo. The resulting yellow oil was added
Pawhuskin A (1). To a stirred solution of stilbene 19 (42 mg, 0.06
mmol) was added camphorsulphonic acid (4 mg, 0.02 mmol), in MeOH,
and the mixture was stirred at 55 °C for 24 h. The reaction mixture
was quenched by addition of saturated NH4Cl and extracted with
EtOAc. The combined organic layers were dried (MgSO4), filtered, and
concentrated in Vacuo to afford a yellow oil. Final purification by flash
chromatography (30% EtOAc in hexanes) gave pawhuskin A (1) as a

1952 Journal of Natural Products, 2008, Vol. 71, No. 11
Notes
yellow oil (11 mg, 36%). Both 1H and13C NMR spectra were identical
to published data.1
(7) (a) Mente, N. R.; Wiemer, A. J.; Neighbors, J. D.; Beutler, J. A.; Hohl,
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Acknowledgment. Financial support from the Roy J. Carver
Charitable Trust and from the National Institutes of Health, through a
grant from the National Institute of Environmental Health Sciences (P01
ES012020) and the Office of Dietary Supplements (ODS), and an
Oncology Research Training Award (2 T32 CA79445) through the
Holden Comprehensive Cancer Center, is gratefully acknowledged.
(8) McCurdy, C. R.; Scully, S. S. Life Sci. 2005, 78, 476–484.
(9) (a) Roth, B. L.; Baner, K.; Westkaemper, R.; Siebert, D.; Rice, K. C.;
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