Synthesis and structure-activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity

Article abstract of DOI:10.1016/j.bmc.2005.10.025

The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common

Full text of DOI:10.1016/j.bmc.2005.10.025

Bioorganic & Medicinal Chemistry 14 (2006) 1771–1784
Synthesis and structure–activity studies of schweinfurthin
B analogs: Evidence for the importance of a D-ring hydrogen
bond donor in expression of differential cytotoxicity
Jeffrey D. Neighbors,a,b Maya S. Salnikova,a John A. Beutlerc and David F. Wiemera,b,
*
aDepartment of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
bDepartment of Pharmacology, University of Iowa, Iowa City, IA 52242-1294, USA
cMolecular Targets Development Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21701, USA
Received 2 September 2005; revised 14 October 2005; accepted 17 October 2005
Available online 14 November 2005
Abstract—The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop
structure–activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a com-
mon left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penulti-
mate Horner–Wadsworth–Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half
of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity pro-
files of these new compounds in the National Cancer InstituteÕs 60 cell-line anticancer screen is described. Several of these analogs
displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of ꢀ103 across the various cell
lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system
for differential cytotoxicity.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
shown to have cytotoxic activity similar to that of schw-
einfurthin A (1).2
The schweinfurthins are a small set of natural stilbenes
isolated from the African tree Macaranga schweinfurthii
at the National Cancer Institute (NCI) in the late
1990s.1 These compounds were isolated through bioas-
say-guided fractionation as part of the Developmental
Therapeutics Program at NCI, and three of the four
were found to have significant and differential cytoto-
xicity in the NCIÕs 60 cell-line anticancer screen.
Schweinfurthin A (1) and schweinfurthin B (2, Fig. 1)
presented mean GI50Õs of 0.36 and 0.81 lM, respectively,
but the more sensitive cell lines were affected by nano-
molar concentrations, while the more resistant cell lines
tolerated micromolar levels. Schweinfurthin D (4) was
found to be equipotent with schweinfurthin B (2),1b
while the fourth member of this family, schweinfurthin
C (3), lacks the hexahydroxanthene system and dis-
played negligible cytotoxicity in initial screens. Vedelia-
nin (5), a closely related natural product, has been
The NCI has developed a bioinformatics algorithm
known as COMPARE to identify correlations between
patterns of cytotoxic activity in its 60 cell-line assay.3
Compounds which act on the same molecular target
typically display a high degree of correlation across
the various cell lines and subpanels of the screen. The
schweinfurthins were particularly potent inhibitors of
CNS, renal, leukemia, and some breast cancer cell lines,
while many ovarian, melanoma, and lung cancer lines
were resistant. The specific pattern was not correlated
to any compound in the NCI standard agents database
by COMPARE analysis; this may indicate that these
compounds act via a novel cellular pathway or target.4
However, we noted that the pattern of cell growth inhi-
bition was strongly correlated to the cephalostatins,
which also act at an as yet unknown target.5 While con-
siderably less potent than the most active cephalostatins,
where mean GI50Õs as low as ꢀ1 nM are known, the
schweinfurthins are much more amenable to synthetic
manipulation.6 We have postulated that these two classes
of compounds may act through a common pathway,
Keywords: Schweinfurthin; Stilbene; Cytotoxic; 60-Cell assay.
*
Corresponding author. Tel.: +319 335 1365; fax: +319 335
1270; e-mail: david-wiemer@uiowa.edu
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.10.025

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J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
OR
HO
HO
O
OH
H
1 Schweinfurthin A R = H
2 Schweinfurthin B R = CH3
OH
OH
HO
OH
3 Schweinfurthin C
OCH3
O
OH
HO
OH
HO
H
OH
4 Schweinfurthin D
OH
OH
HO
HO
O
OH
H
5 Vedelianan
OH
Figure 1. The schweinfurthin family and related natural products.
though not necessarily at the same point. All compara-
tive studies of schweinfurthins and cephalostatins to
date have found similar effects on cell morphology, time
course of cell death, and a lack of effect on the cell cycle.
Because of their intriguing activity as well as our ongo-
ing interest in chemotherapeutic chemistry7 and preny-
lated aromatics in general,8 an effort to explore the
activity of some schweinfurthin analogs was initiated.
We hoped to identify themes in structure–activity
relationships within the schweinfurthin class which
could be used to design probes of the postulated molec-
ular target responsible for growth inhibition in sensitive
cell lines.
Emmons (HWE) olefination (Fig. 2). This allows maxi-
mum convergence and facilitates introduction of chang-
es in the right-half architecture. Early work on the
simplest member of the family, schweinfurthin C, re-
quired synthesis of the right-half phosphonate 69 which
also could serve as a synthon for schweinfurthins A and
B. We targeted schweinfurthin B to derive the C-ring,
including the methoxy group, from vanillin (8). Two
routes that use cationic cascade cyclizations to effect for-
mation of the A- and B-rings of the tricyclic system have
been explored (Fig. 3). The first such process employed a
phenylselenide substituent (i.e., compound 910) to direct
a diastereoselective cascade,8 ultimately leading to tricy-
clic olefin 10. After some experimentation, a pathway
involving a more biomimetic cyclization11 of epoxide
11 was found to afford tricyclic aldehyde 12.12 The epox-
ide 11 is available via an AD-mix a oxidation as an
enantioenriched mixture with 68% ee, and all of the ana-
logs synthesized here have similar enantiopurity.
Our synthetic strategy involves a late stage introduction
of the central stilbene olefin via a Horner–Wadsworth–
OCH3
HO
HO
O
OH
To complete synthesis of a tetracyclic schweinfurthin,
aldehyde 12 was condensed with the natural right-half
synthon, phosphonate 6. Final deprotection of the
resulting stilbene afforded 3-deoxyschweinfurthin B
(13), and this compound has shown biological activity
comparable to that of the natural product (vide infra).
Thus, the opportunity to explore the effect of right-half
modifications on the bioactivity and physical properties
of the schweinfurthins was presented. Such studies also
might help to overcome a tendency toward oxidation
noted during the isolation of the natural products and
presumed to result from the resorcinol moiety. Finally,
H
2 Schweinfurthin B
OH
O
OCH3
P(OEt)2
RO
RO
O
OMOM
H
H
O
OMOM
6
7
Figure 2. The HWE strategy.

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1773
OCH3
OCH3
OCH3
RO
HO
HO
H
C6H5Se
OH
O
OH
9
O
11
OR
8
OCH3
OCH3
O
O
H
H
HO
H
H
O
O
12
10
OCH3
O
B
C
A
OH
HO
H
D
13
OH
Figure 3. Previous synthetic work.
and most importantly, preparation of a series of analogs
might allow identification of a position to introduce
functionality for construction of affinity reagents or
fluorescent analogs that would be useful in mechanism
of action studies.13
is comparable to those where the benzylic alcohol was
protected, and this strategy leads to considerable savings
in time and materials. Subsequent introduction of the
phosphonate via Arbuzov reaction of the iodide, itself
the result of displacement of the mesylate, smoothly
gave the desired benzylic phosphonate 16 in 4 steps
and 16% overall yield. Modified HWE coupling15 of
phosphonate 16 with aldehyde 12 afforded the desired
dimethoxy-3-deoxyschweinfurthin B (17) in modest
yield.
2. Chemical synthesis
Dimethoxy-3-deoxyschweinfurthin B (17) was selected
as the first target of these studies, in order to block the
potential of phenolic hydroxyls to become hydrogen
bond donors. A path to the requisite phosphonate 16
commenced with the commercial alcohol 14 (Scheme
1). Alkylation of this alcohol by treatment with 2–3
equivalents of strong base and subsequent reaction of
the presumed dianion intermediate with geranyl bro-
mide gave the geranylated arene 15 in modest yield.14
While modest in this case, the yield from this approach
Through very similar chemistry the phosphonates 20
and 21, that both lack the geranyl chain, were prepared
(Scheme 2). Thus, the methoxymethyl-protected benzyl-
ic alcohols 1816 and 1917 were subjected to a three-step
protocol including preparation of the mesylates, conver-
sion to the corresponding iodides, and Arbuzov reac-
tions. The desired phosphonates 20 and 21 were
isolated in satisfactory yields.
OCH3
OCH3
HO
R
nBuLi, TMEDA, CuBr·DMS
geranyl bromide, -20 oC
40%
OCH3
OCH3
15 R = OH
14
1) MsCl, TEA
2) NaI, acetone
3) P(OEt)3, reflux
16 R = P(O)(OEt)2
40% 3 steps
OCH3
37%
OCH3
NaH, 12, 15-Cr-5, THF
0 oC to rt
O
O
OCH3
O
HO
HO
H
H
H
17
12
OCH3
Scheme 1.

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J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1) MsCl, TEA
2) NaI, acetone
3) P(OEt)3
the silyl ether-protecting group and afford benzylic alco-
R
hol 24. A series of three steps parallel to those used in
preparation of compound 16 was employed to convert
alcohol 24 to phosphonate 26 in excellent yield.
R
HO
(EtO)2P
O
R'
R'
20 R = OMOM, R' = OMOM 54%
21 R = OMOM, R' = H 83%
Difluorophosphonate 29, in which the phenolic groups
are replaced by fluorine, was synthesized from the com-
mercial alcohol 27 (Scheme 4). Treatment of this alcohol
under the optimized directed ortho metalation (DoM)
conditions, and alkylation of the resulting dianion,
afforded the arene 28 in moderate yield. A two-step reac-
tion sequence involving transformation into the benzylic
bromide and Arbuzov reaction with triethylphosphite
gave the desired phosphonate 29.
18 R = OMOM, R' = OMOM
19 R = OMOM, R' = H
Scheme 2.
The phosphonate 26 (Scheme 3), which lacks both of the
resorcinol hydroxyl groups while retaining the geranyl
chain, was obtained by alkylation of the organolithium
reagent derived by halogen metal exchange of known
aryl bromide 22.18 The resulting geranylated arene 23
was then allowed to react with fluoride ion to remove
To obtain phosphonate 35, which carries a terminal
primary hydroxyl group, the requisite allyl bromide
nBuLi, geranyl bromide
TBSO
-78 oC
TBSO
70%
Br
22
23
TBAF
R
77%
24 R = OH
1) MsCl, TEA
2) NaI, acetone
25 R = I (78% 2 steps)
26 R= P(O)(OEt)2 (97%)
P(OEt)3, reflux
Scheme 3.
F
F
nBuLi, TMEDA, CuBr·DMS
geranyl bromide, -20 oC
HO
R
53%
F
F
1) PBr3
28 R = OH
27
2) P(OEt)3, reflux
(60% 2 steps)
29 R = P(O)(OEt)2
Scheme 4.
HO
Br
OTBDPS
PBr3
OTBDPS
30
1) KH, 0 o
2) nBuLi, TMEDA, CuBr·DMS
31, -20 oC
31
C
OMOM
R
18
OTBDPS
43% (2 steps from 30)
OMOM
1) MsCl, TEA
32 R = OH
TBAF
96%
2) NaI, acetone
33 R = I (77% 2 steps)
34 R= P(O)(OEt)2 (92%)
P(OEt)3, reflux
OMOM
(EtO)2P
O
OH
OMOM
35
Scheme 5.

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1775
OCH3
OCH3
R
O
NaH, 15C5
(EtO)2P
O
+
R
O
HO
R"
HO
H
H
R'
20,21,26,29,35,36
H
R"
12
37-42
R'
Scheme 6.
groups (Scheme 7, Table 2) and afford the desired com-
pounds 43–45.
Table 1. HWE coupling reactions
Phosphonate
R
R0
R00
Stilbene Yield (%)
20
21
26
29
35
36
OMOM OMOM
H
H
37
38
39
40
91
62
55
85
60
90
OMOM
H
H
F
3. Biological data and discussion
H
F
C
C
C
10H17
10H17
OMOM OMOM
H
10H16OH 41
42
Synthetic 3-deoxyschweinfurthin B has been tested in
the 60 cell-line assay and was found to have activity very
much comparable to that of the natural products (mean
GI50 = 0.74 lM). Even more importantly the differential
activity across the cell lines was correlated with the nat-
ural schweinfurthin B (correlation coefficient = 0.75,
Fig. 4), suggesting that the synthetic compound was
operating at the same, and as yet unknown, molecular
or cellular target.
H
H
31 was synthesized from the known silyl ether 3019 by
treatment with PBr3. The benzylic alcohol 18 (Scheme
5) then was treated with KH followed by DoM and
alkylation with the allylic bromide 31 to afford arene
32. The standard sequence of transformations, from
the benzylic alcohol to the iodide followed by displace-
ment with triethylphosphite, gave the protected
phosphonate 34. This was subjected to reaction with
TBAF under standard conditions to effect removal of
the silyl ether and afford the desired phosphonate 35
in excellent yield.
The seven new analogs (17, 39, 40, and 42–45) were
tested in the NCI 60 cell-line cytotoxicity screen. Every
compound tested showed some cytotoxic effects (Table
3), with mean GI50Õs ranging from 42 lM for the diflu-
oro analog 40, to 1.0 lM for the analog with the termi-
nal primary hydroxyl group, compound 45. While the
mean GI50 values suggest weakly toxic compounds,
the more sensitive cell lines were affected at nanomolar
levels, and the unique pattern of schweinfurthin activity
was observed in several of the analogs. The schweinfurthins
are effective over 3 orders of magnitude in concentra-
tion, with the most sensitive cells including the CNS-
derived lines SF-295, SNB-75, and U-251, while the
entire lung, colon, and ovarian panels show very little
sensitivity.
With a representative group of phosphonates in hand,
exploration of the required HWE couplings was initiat-
ed. Phosphonates 20, 21, 26, 29, and 35, and the com-
mercial phosphonate 36 were allowed to react with
aldehyde 12 (Scheme 6, Table 1) under conditions paral-
lel to those employed to synthesize dimethoxy-3-deoxy-
schweinfurthin B (17, vide supra). These reactions
afforded the expected stilbenes 37–42 in moderate to
excellent yields. These HWE couplings have been found
reliable in the presence of the unprotected A-ring
hydroxyl group, thus avoiding potentially problematic
protection/deprotection sequences. Finally, the stilbenes
37, 38, and 41 were treated with camphorsulfonic acid
(CSA) in methanol20 to free the phenolic hydroxyl
Our initial hypothesis was that the basis for differential
activity resided within the left half of the structure.
The dimethoxy derivative 17 was targeted with the
expectation that it would be more stable than the parent
resorcinols but still retain the cytotoxic profile of the
family. Unfortunately, this proved not to be the case,
since dimethoxy-3-deoxyschweinfurthin B (17) was
ꢀ10-fold less cytotoxic than the parent 3-deoxyschwein-
furtin B. More intriguing was the differential cytotoxic-
ity displayed by this analog. While some differential
activity across the tested cell lines was observed, the pat-
tern was not as well correlated with the natural product
(correlation coefficient = 0.42 vs 2) as was that of 3-
deoxyschweinfurthin B (correlation coefficient = 0.75
vs 2, Table 3). Clearly this result shows that methylation
of the phenols is not well tolerated, but these findings
also raise a question of how these groups function.
OCH3
O
CSA, MeOH
37, 38, or 41
R
HO
H
43-45
R"
R'
Scheme 7.
Table 2. Removal of MOM ether protecting groups
Protected stilbene
R
R0
OH OH
OH
OH OH
R00
Product Yield (%)
37
38
41
H
H
43
44
93
63
42
To probe the activity of a compound without H-bond
acceptors in the D-ring, the difluorinated compound
40 was tested. This compound was found to have the
H
C
10H16OH 45

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J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
Leukemia and Lymphoma
Lung
Colon
CNS
Melanoma
Overian
Renal
Prostate
Breast
Schweinfurthin B
3-deoxyschweinfurthin B
Figure 4. Mean graph comparison of 3-deoxyschweinfurthin B (13) and schweinfurthin B (2). Deviations from the mean in log units against each cell
line measured in the NCI 60 cell-line assay at the GI50 level, data are presented so that positive deviations indicate more potent cytotoxicity.
Approximate regions of several subpanels are indicated. Complete 60 cell-line data are presented in the Supplemental material.
Table 3. Cytotoxic activity of the schweinfurthin analogs and the correlation matrix for the 60 cell-line assay, both at the GI50 level
Compound
1
13
2
45
44
17
43
42
39
40
Mean GI50 (lM) Range at GI50 (log units)
1
13
2
1.00
0.75
0.91
0.74
0.64
0.46
0.38
0.31
0.12
0.40
0.74
0.79
1.0
3.14
2.63
3.08
2.39
1.94
2.52
2.41
1.20
0.79
1.63
1.00
0.75
0.80
0.65
0.39
0.50
0.31
0.01
1.00
45
44
17
43
42
39
40
0.78 1.00
0.72 0.62
0.42 0.34
0.46 0.42
0.29 0.50
1.00
0.18 1.00
0.45 0.42 1.00
0.25 0.15 0.24 1.00
3.8
6.6
7.8
15
19
0.05 0.15 ꢁ0.08 0.34 0.10 0.30 1.00
ꢁ0.07 ꢁ0.05 ꢁ0.17 0.02 ꢁ0.08 0.08 0.04 0.00 0.59 1.00 42
Pearson correlation coefficients were calculated based on comparisons of common cell lines for each pair of compounds. The range represents the
differential in log10 units between the least and most sensitive cell lines in the experiment.
weakest antitumor activity of all the analogs tested so
far, as well as a lack of correlation to the activity of
the natural products (correlation coefficient = ꢁ0.17 vs
2). The results of these two assays highlight the impor-
tance of this right-half substructure to differential activ-
ity. A further test of this theory involved compounds 39
and 42, both of which lack both of the resorcinol oxy-
gens. The compounds show very weak cytoxicity (mean
GI50Õs of 19 and 15 lM, respectively) and virtually no
differential cytotoxicity (i.e., a ꢀ10-fold concentration
differential between most and least sensitive cell lines,
also reflected in the poor correlation to compound 2).
probe for studies aimed at elucidation of their cellular
target(s). As a first step toward deciphering the role of
the geranyl chain it seemed appropriate to test whether
or not simple deletion of this substructure would affect
the activity.
Compound 43, which lacks the geranyl chain, was
shown to be ꢀ10 times less active (mean GI50 = 7.8 lM)
than 3-deoxyschweinfurthin B (13). It does however
show a modest degree of correlation in its pattern of dif-
ferential activity (correlation coefficient = 0.46 vs 2) with
the natural product. This result supports installation of
other motifs at this position to identify an affinity probe.
Compound 43 still shows the same propensity for degra-
dation as other stilbenes bearing the resorcinol hydroxyl
groups. Because a formal deletion of one of the D-ring
hydroxyl groups might be expected to improve stability,
the phenol 44 was tested and found to be twofold more
cytotoxic than resorcinol 43 (mean GI50 = 3.8 lM).
Even more importantly, phenol 44 was found to have
differential activity highly correlated with that of the
natural product (correlation coefficient = 0.72).
Once the importance of the phenolic hydrogen was
clear, implicating this substructure as a hydrogen bond
donor, it was intriguing to ascertain the requirements
for the geranyl chain. Schweinfurthin D (4), which
shows cytotoxicity similar to that of schweinfurthin B
(2), possesses a hydrated terminal olefin that would seem
to indicate a region with some tolerance to modification.
This would be of crucial importance in efforts to attach
an active schweinfurthin to an affinity reagent or other

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1777
Leukemia and Lymphoma
Lung
Colon
CNS
Melanoma
Overian
Renal
Prostate
Breast
3-deoxyschweinfurthin B
Allylic alcohol 45
Figure 5. Mean graph comparison of 3-deoxyschweinfurthin B (13) and allylic alcohol 45. Deviations from the mean in log units against each cell line
measured in the NCI 60 cell-line assay at the GI50 level, data are presented so that positive deviations indicate more potent cytotoxicity. Complete 60
cell line data are available in the Supplemental material.
Based on these results at least one of the D-ring hydrox-
yl groups appeared to be crucial to activity, whereas the
geranyl chain clearly was amenable to some modifica-
tion. In order to test our hypothesis that the terminus
of the geranyl system could be used as a point of attach-
ment to some form of affinity reagent, it would be nec-
essary to append a reactive functional group to this
position. This was realized in the analog 45 which con-
tains an allylic alcohol at the trans position of the gera-
nyl chain terminus, and this compound showed very
good activity (Fig. 5). It was nearly as potent (mean
GI50 = 1.0 lM) as schweinfurthin B or 3-deoxyschwein-
furthin B, and its activity was highly correlated to the
natural product (correlation coefficient = 0.78 vs 2)
and the 3-deoxy analog (0.80). Of special interest, com-
pound 45 shows activity at nanomolar levels against the
leukemia-derived RPMI-8226 and the renal-derived 786-
0 cell lines (3.2 and 17 nM, respectively), which suggests
that it may be a useful mechanistic probe in these lines.
of cytotoxins. Further work in these areas will be
disclosed in due course.
5. Experimental
5.1. General experimental conditions
THF was freshly distilled from sodium/benzophenone,
while CH2Cl2 and Et3N were freshly distilled from
CaH. All reactions in non-aqueous solvents were con-
ducted in oven-dried glassware under positive pressure
of argon, with magnetic stirring. Methanesulfonyl chlo-
ride was purchased commercially and distilled from
P2O5. NMR spectra were recorded at 300 MHz for
1H, and 75 MHz for 13C with CDCl3 as solvent and
(CH3)4Si (1H) or CDCl3 (13C, 77.0 ppm) as internal
standards unless otherwise noted. Correlation coeffi-
cients were calculated using Excel with the Pearson
method excluding data points for cell lines which were
not present for both compounds being compared. High
resolution mass spectra were obtained at the University
of Iowa Mass Spectrometry Facility. Elemental analyses
were performed at an outside facility.
4. Conclusions
The schweinfurthins offer a rare opportunity in the field
of cytotoxic natural products. Their profile of activity
across the NCI 60 cell-line assay indicates these agents
may act at a novel and as yet untapped mechanism of
action against the susceptible tumor cell lines. The cur-
rent studies encourage further study of these compounds
by making available synthetic analogs with high activity
and more favorable chemical properties than the natural
products. The discovery of highly correlated activity in
the phenol analog 44 should lead to much less labile
schweinfurthins and to more predictable supplies of
these agents for the next stages of testing. Synthetic ana-
log 45, which displays highly correlated and potent
activity, may be suitable for attachment of affinity re-
agents to probe the mechanism of action of this family
5.2. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-
phenyl]-methanol (15)
nBuLi (0.87 mL, 2.15 M in hexanes) was added drop-
wise to a solution of benzylic alcohol 14 (105 mg,
0.62 mmol) and TMEDA (0.28 mL, 1.9 mmol) in THF
(10 mL) at ꢁ20 °C. After the solution was stirred at
ꢁ20 °C for 1 h, CuBr as its DMS complex (255 mg,
1.24 mmol) was added in one portion and the solution
was stirred for 1 h at ꢁ20 °C. Geranyl bromide
(0.15 mL, 0.76 mmol) in THF (5 mL) was added via syr-
inge and the reaction mixture was stirred for 2 h at
ꢁ20 °C. The reaction was quenched by addition of

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J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1 N NH4Cl, the aqueous layer was neutralized to pH 7
with 1 N HCl, and this layer was extracted with EtOAc.
The combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo. Final purifi-
cation of the residue by flash chromatography (20%
EtOAc in hexanes) afforded alcohol 15 (76 mg, 40%)
was quenched with water, extracted (ether), and the
combined organic layers were washed with brine. The
residual organic layer was dried (MgSO4) and concen-
trated in vacuo to give a yellow oil. Final purification
by column chromatography (50% EtOAc in hexanes)
afforded the target schweinfurthin analog 17 (6.4 mg,
37%) as a clear oil: 1H NMR d 6.95–6.88 (m, 4H),
6.67 (s, 2H), 5.19 (t, J = 6.8 Hz, 1H), 5.07 (t,
J = 5.7 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 6H), 3.46–3.44
(m, 2H), 3.36–3.33 (m, 1H), 2.75–2.72 (m, 2H), 2.21–
1.75 (m, 9H), 1.77 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H),
1.27 (s, 3H), 1.10 (s, 3H), 0.89 (s, 3H); HREIMS calcd
for C37H50O5 (M+) 574.3658, found 574.3651.
1
as a clear oil. H NMR d 6.54 (s, 2H), 5.17–5.12 (tm,
J = 7.1 Hz, 1H), 5.07–5.02 (tm, J = 6.9 Hz, 1H), 4.63
(s, 2H), 3.80 (s, 6H), 3.31 (d, J = 7 Hz, 2H), 2.04–1.89
(m, 4H), 1.74 (s, 3H), 1.63 (s, 3H), 1.55 (s, 3H); 13C
NMR d 160.3 (2C), 141.8, 136.8, 133.2, 126.6, 124.8,
119.9, 104.7 (2C), 68.0, 57.9 (2C), 41.9, 28.9, 27.8,
24.2, 19.8, 18.1. Anal. Calcd for C19H28O3: C, 74.96;
H, 9.27. Found: C, 74.82; H, 9.34.
5.5. (3,5-Bis-Methoxymethoxy-benzyl)-phosphonic acid
diethyl ester (20)
5.3. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-dimethoxy-
benzyl]-phosphonic acid diethyl ester (16)
Methanesulfonyl chloride (1.4 mL, 18.1 mmol) was add-
ed dropwise to a stirred solution of alcohol 18 (881 mg,
3.9 mmol) and Et3N (2.2 mL 15.76 mmol) in CH2Cl2
(150 mL). The solution was stirred for 2 h at 0 °C. The
reaction mixture was allowed to warm to rt over 5 h,
quenched by addition of water, and extracted with
EtOAc. The combined organic layers were washed with
NH4Cl (sat), brine, dried (MgSO4), and concentrated in
vacuo. The yellow residue was treated with NaI (2.33 g,
15.6 mmol) in acetone (20 mL) for 24 h at rt. The reac-
tion mixture was concentrated in vacuo to a red solid,
which was dissolved in EtOAc. After the resulting yel-
low solution was washed once with NaHCO3 and then
with Na2S2O3 until the color faded, it was extracted with
ether and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. Final purification
of the residue by flash chromatography (30% EtOAc
in hexanes) afforded compound iodide (1.12 g, 84%) as
Methanesulfonyl chloride (0.15 mL, 1.94 mmol) was
added dropwise to a solution of alcohol 15 (181 mg,
0.59 mmol) and Et3N (0.3 mL 1.9 mmol) in CH2Cl2
(5 mL), and the solution was stirred for 2 h at 0 °C.
The reaction mixture was allowed to warm to rt over
5 h, quenched by addition of H2O, and extracted with
EtOAc. The combined organic layers were washed with
NH4Cl (sat), brine, dried (MgSO4), and concentrated in
vacuo. The resulting residue and NaI (310 mg,
2.06 mmol) were stirred in acetone (8 mL) for 24 h.
The reaction mixture was concentrated in vacuo to af-
ford a red solid, which was dissolved in EtOAc. After
the resulting yellow solution was washed once with
NaHCO3 and then with Na2S2O3 until the color faded,
it was extracted with ether and the combined organic
layers were dried (MgSO4) and concentrated in vacuo.
The resulting yellow oil was added to triethyl phosphite
(1.5 mL) and the mixture was heated at 100 °C for 20 h.
After the solution was allowed to cool to rt, it was
poured into ether (5 mL). The mixture wasextracted with
ether, dried (MgSO4), and concentrated in vacuo. The ini-
tial yellow oil was purified by flash chromatography (50%
EtOAc in hexanes) to afford phosphonate 16 (73 mg,
40%) as a light yellow oil: 1H NMR d 6.49 (d,
J = 2.4 Hz, 2H), 5.18–5.13 (tm, J = 7.3 Hz, 1H), 5.07–
5.02 (tm, J = 6.8 Hz, 1H), 4.09–3.98 (m, 4H), 3.80 (s,
6H), 3.31 (d, J = 7.0 Hz, 2H), 3.11 (d, JPH = 21.5 Hz,
2H), 2.06–1.94 (m, 4H), 1.82 (s, 3H), 1.68 (s, 3H), 1.56
(s, 3H), 1.27 (tm, J = 7.0 Hz, 6H); 13C NMR d 160.9 (d,
JCP = 3.1 Hz, 2C), 137.5, 134.1, 132.9 (d, JCP = 9.0 Hz),
127.5, 125.7 (d, JCP = 2.9 Hz), 120.1 (d, JCP = 3.4 Hz),
108.6 (d, JCP = 6.7 Hz, 2C), 65.1 (d, JCP = 6.7 Hz, 2C),
58.7 (2C), 42.8, 37.1 (d, JCP = 137.3 Hz), 29.7, 28.6,
24.9, 20.6, 19.4 (d, JCP = 6.0 Hz, 2C), 18.9; 31P NMR d
+26.4; HRMS (EI) calcd for C23H37O5PNa [M++Na],
447.2276; found 447.2265.
1
a yellow oil: H NMR d 6.73 (d, J = 2.2 Hz, 2H), 6.63
(t,J = 2.2 Hz, 1H), 5.2 (s, 4H), 4.4 (s, 2H), 3.5 (s, 6H);
13C NMR d 158.5 (2C), 141.5, 110.3 (2C), 104.7, 94.7
(2C), 56.3 (2C), 5.5; HRMS (EI) calcd for C11H15O4I
[M+], 338.0015; found 338.0016. A stirred solution of
this iodide (1.11 g, 3.3 mmol) in triethyl phosphite
(2.5 mL) was heated at reflux for 9 h, then it was allowed
to cool to rt and poured into ether (8 mL). The resulting
mixture was extracted with ether, dried (MgSO4), and
concentrated in vacuo. Final purification of the residue
by flash chromatography (gradient, 30–80% EtOAc in
hexanes) afforded phosphonate 20 (734 mg, 64%) as a
1
light yellow oil: H NMR d 6.58–6.55 (m, 3H), 5.06 (s,
4H), 3.97 (m, 4H), 3.39 (s, 6H), 3.01 (d, JPH = 21.6 Hz,
2H), 1.20 (tm, J = 7.1 Hz, 6H); 13C NMR d 158.2 (d,
JCP = 3.2 Hz, 2C), 133.8 (d, JCP = 8.8 Hz), 111.2 (d,
JCP = 6.5 Hz, 2C), 103.5 (d, JCP = 3.4 Hz), 94.4 (2C),
62.1 (d, JCP = 6.6 Hz, 2C), 55.9 (2C), 33.9 (d,
JCP = 138.1 Hz), 16.3 (d, JCP = 6.1 Hz, 2C); 31P NMR
d +25.7. Anal. Calcd for C15H25O7P: C, 51.72; H,
7.23. Found: C, 51.55; H, 7.27.
5.4. Dimethoxy-3-deoxyschweinfurthin B (17)
A solution of phosphonate 16 (20 mg, 0.04 mmol) and
aldehyde 12 (10 mg, 0.03 mmol) in THF (1.5 mL) was
added to a suspension of NaH (29 mg, 0.71 mmol,
60% suspension in oil) and 15C5 (4 lL, 22 nmol) in
THF (2.5 mL) at 0 °C. The resulting mixture was al-
lowed to come to rt and stir for 20 h. The solution
5.6. (3-Methoxymethoxy-benzyl)-phosphonic acid diethyl
ester (21)
Methanesulfonyl chloride (1.0 mL, 12.9 mmol) was add-
ed dropwise to a solution of alcohol 19 (500 mg,
2.97 mmol) and Et3N (0.5 mL 3.6 mmol) in CH2Cl2

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1779
(10 mL), and the solution was stirred for 2 h at 0 °C. The
reaction mixture was allowed to warm to rt over 5 h,
quenched by addition of H2O, and extracted with
EtOAc. The combined organic layers were washed with
NH4Cl (sat), brine, dried (MgSO4), and concentrated in
vacuo. The resulting yellow residue was treated with
NaI (1 g, 3.6 mmol) in acetone (15 mL) for 24 h at rt.
This reaction mixture was concentrated in vacuo to af-
ford a red solid, which was dissolved in EtOAc. After
the resulting yellow solution was washed once with
NaHCO3 and then with Na2S2O3 until the color faded,
it was extracted with ether and the combined organic
layers were dried (MgSO4) and concentrated in vacuo.
The resulting yellow oil was added to triethyl phosphite
(4 mL) and the solution was heated at 100 °C for 20 h.
After the solution was allowed to cool to rt, it was
poured into ether (10 mL). The mixture was extracted
with ether, dried (MgSO4), and concentrated in vacuo.
The initial yellow oil was purified by flash chromatogra-
phy (50% EtOAc in hexanes) to afford phosphonate 21
(2.56 g, 7.14 mmol) in THF (20 mL). The solution was
stirred for 2 h at 0 °C and then was allowed to warm
to rt over 5 h. The reaction was quenched by addition
of NH4Cl (sat) and extracted with EtOAc. The com-
bined organic layers were washed with brine, dried
(MgSO4), and concentrated in vacuo. Final purification
of the residue by flash chromatography (20% EtOAc in
hexanes) afforded compound 24 (1.35 g, 77%) as a light
1
yellow oil: H NMR d 7.28–7.24 (m, 2H), 7.18–7.15 (m,
2H), 5.35–5.30 (tm, J = 7.2 Hz, 1H), 5.12–5.08 (tm,
J = 6.7 Hz, 1H), 4.63 (s, 2H), 3.35 (d, J = 7.3 Hz, 2H),
2.12–2.02 (m, 4H), 1.70 (s, 1H exchanges with D2O),
1.70 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H); 13C NMR d
141.6, 138.5, 136.5, 131.7, 128.7 (2C), 127.4 (2C),
124.4, 123.1, 65.4, 39.9, 34.1, 26.8, 26.0, 17.9, 16.3;
HRMS (EI) calcd for C17H24O [M+], 244.1827; found
244.1832.
5.9. 1-(3,7-Dimethyl-octa-2,6-dienyl)-4-iodomethyl-
benzene (25)
1
(709 mg, 83%) as a light yellow oil: H NMR d 7.20
(tr, J = 7.9 Hz, 1H), 7.08–6.89 (m, 3H), 5.17 (s, 2H),
Methanesulfonyl chloride (1.8 mL, 23.3 mmol) was add-
ed dropwise to a stirred solution of alcohol 24 (1.27 g,
5.22 mmol) and Et3N (3 mL 21.5 mmol) in CH2Cl2
(20 mL) at 0 °C over 2 h. The reaction mixture was al-
lowed to warm to rt over 5 h. After the reaction was
quenched by addition of water, it was extracted with
EtOAc. The combined organic layers were washed with
NH4Cl (sat), brine, dried (MgSO4), and concentrated in
vacuo. The resulting yellow residue was treated with
NaI (3.51 g, 23.4 mmol) in acetone (20 mL) at rt for
24 h. The reaction mixture was concentrated in vacuo
to afford a red solid, which was dissolved in EtOAc.
After the resulting solution was washed once with NaH-
CO3 and then with Na2S2O3 until the color faded, the
aqueous layer was extracted with ether and the com-
bined organic layers were dried (MgSO4) and concen-
trated in vacuo. Final purification of the residue by
flash chromatography (20% EtOAc in hexanes) afforded
4.15–3.97 (m, 4H), 3.44 (s, 3H), 3.11 (d, JPH = 21.6 Hz,
157.1
2H), 1.27–1.22 (m, 6H); 13C NMR
d
(d, JCP = 3.2 Hz), 132.9 (d, JCP = 8.9 Hz), 129.2 (d,
JCP = 3.1 Hz), 123.1 (d, JCP = 6.5 Hz), 117.5 (d,
JCP = 6.5 Hz), 114.5 (d, JCP = 3.5 Hz), 94.1, 61.8 (d,
JCP = 6.7 Hz, 2C), 55.6, 33.4 (d, JCP = 137.2 Hz), 16.1
(d, JCP = 6.0 Hz, 2C); 31P NMR d +25.8. Anal. Calcd
for C13H21O5P: C, 54.16; H, 7.34. Found: C, 53.98; H,
7.35.
5.7. tert-Butyl-[4-(3,7-dimethyl-octa-2,6-dienyl)-
benzyloxy]-dimethyl-silane (23)
nBuLi (7.90 mL, 2.5 M in hexane, 19.8 mmol) was add-
ed dropwise to a stirred solution of aryl bromide 22
(3.13 g, 10.4 mmol) in THF (15 mL) over 15 min at
ꢁ78 °C. The reaction mixture was allowed to stir for
2 h at ꢁ78 °C. Geranyl bromide (2.5 mL, 12.6 mmol)
was added dropwise and the reaction mixture was stir-
red for 2 h at ꢁ78 °C. The reaction mixture was allowed
to warm to rt, quenched by addition of H2O, and then
extracted with ether. The combined organic layers were
washed with NH4Cl (sat), brine, dried (MgSO4), and
concentrated in vacuo. Final purification of the residue
by flash chromatography (hexanes) afforded compound
1
compound 25 (1.44 g, 78%) as a yellow oil: H NMR d
7.30–7.24 (m, 2H), 7.11–7.08 (m, 2H), 5.35–5.30 (tm,
J = 7.2 Hz, 1H), 5.14–5.09 (tm, J = 6.6 Hz, 1H), 4.47
(s, 2H), 3.33 (d, J = 7.2 Hz, 2H), 2.14–2.03 (m, 4H),
1.71 (s, 6H), 1.61 (s, 3H); 13C NMR d. 141.9 (2C),
136.8, 131.7, 129.0 (2C), 128.9 (2C), 124.4, 122.8, 39.9,
34.1, 26.8, 26.0, 17.9, 16.3, 6.4; HRMS (EI) calcd for
C17H23 [M+ꢁI], 227.1800; found 227.1801.
1
23 (2.61 g, 70%) as a light yellow oil: H NMR d 7.24–
7.19 (m, 2H), 7.14–7.12 (m, 2H), 5.43–5.38 (tm,
J = 7.4 Hz, 1H), 5.20–5.15 (tm, J = 7.5 Hz, 1H), 4.77
(s, 2H), 3.41 (d, J = 7.4 Hz, 2H), 2.19–2.09 (m, 4H),
1.77 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H), 1.01 (s, 9H),
0.16 (s, 6H); 13C NMR d. 140.6, 140.0, 136.3, 131.6,
128.4 (2C), 126.4 (2C), 124.5, 123.4, 65.1, 39.9, 34.1,
26.8, 26.2 (3C), 25.9, 18.6, 17.9, 16.3, ꢁ5.0 (2C). Anal.
Calcd for C23H38OSi: C, 77.01; H, 10.68. Found: C,
77.08; H, 10.69.
5.10. Diethyl[4-(3,7-dimethyl-octa-2,6-dienyl)-
benzyl]phosphonate (26)
A stirred solution of iodide 25 (1.35 g, 3.82 mmol) in tri-
ethyl phosphite (25 mL) was heated at reflux for 4 h and
then allowed to cool to rt. Excess triethyl phosphite was
removed by vacuum distillation and the resulting yellow
oil was purified by flash chromatography (30% EtOAc
in hexanes) to afford phosphonate 26 (1.34 g, 97%) as
1
a light yellow oil: H NMR d 7.22–7.18 (m, 2H), 7.12–
5.8. [4-(3,7-Dimethyl-octa-2,6-dienyl)-phenyl]-methanol
(24)
7.09 (m, 2H), 5.33–5.29 (tm, J = 7.2 Hz, 1H), 5.11–5.08
(tm, J = 6.6 Hz, 1H), 4.06–4.00 (m, 4H), 3.32 (d,
J = 7.2 Hz, 2H), 3.11 (d, JPH = 21.3 Hz, 2H), 2.12–2.05
(m, 4H), 1.69 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.24
(t, J = 7.2 Hz, 6H); 13C NMR d 140.6 (d, JCP = 3.8 Hz),
TBAF (26.0 mL, 1.0 M in THF, 26.0 mmol) was added
dropwise to a stirred solution of protected alcohol 23

1780
J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
136.5, 131.7, 129.8 (d, JCP = 6.5 Hz, 2C), 128.9 (d,
JCP = 9.3 Hz), 128.7 (d, JCP = 3.1 Hz, 2C), 124.5,
123.1, 62.2 (d, JCP = 6.8 Hz, 2C), 39.9, 34.4, 32.6 (d,
JCP = 138.2 Hz), 26.8, 26.0, 17.9, 16.6 (d, JCP = 6.1 Hz,
2C), 16.3; 31P NMR d +26.6. Anal. Calcd for
C21H33O3P: C, 69.21; H, 9.13. Found: C, 69.09; H, 9.16.
132.0–131.6 (m), 131.7, 124.3, 120.7, 116.0 (td,
JCF = 20.3 Hz, JCP = 3.5 Hz), 112.9–112.5 (m, 2C), 65.5
(d, JCP = 6.75 Hz, 2C), 39.8, 33.5 (dd, JCP = 139.2 Hz,
JCF = 1.9 Hz), 26.7, 25.9, 21.4 (t, JCF = 1.7 Hz), 17.9,
16.6 (d, JCP = 6.00 Hz, 2C), 16.1; 31P NMR d +24.8 (t,
JPF = 2.3 Hz). Anal. Calcd for C21H31F2O3P: C, 62.99;
H, 7.80. Found: C, 63.22; H, 7.98.
5.11. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-
phenyl]-methanol (28)
5.13. {4-[8-(tert-butyl-diphenyl-silanyloxy)-3,7-dimethyl-
octa-2,6-dienyl]-3,5-bis-methoxymethoxy-phenyl}-metha-
nol (32)
A solution of benzylic alcohol 27 (67 mg, 0.46 mmol)
and TMEDA (0.21 mL, 1.4 mmol) in THF (10 mL)
was cooled to ꢁ20 °C. After nBuLi (0.64 mL, 2.15 M
in hexanes) was added dropwise and the solution was
stirred at ꢁ20 °C for 1 h, CuBr as its DMS complex
(192 mg, 0.93 mmol) was added in one portion and the
solution was stirred for 1 h at ꢁ20 °C. A solution of ger-
anyl bromide (0.11 mL, 0.55 mmol) in THF (5 mL) was
added to the reaction mixture via syringe at ꢁ20 °C and
the solution was stirred for 2 h. The reaction was
quenched by addition of 1 N NH4Cl, the aqueous layer
was neutralized to pH 7 with 1 N HCl, and then was
extracted with EtOAc. The combined organic layers
were washed with brine, dried (MgSO4) and concentrat-
ed in vacuo. Purification by flash chromatography (20%
EtOAc in hexanes) afforded alcohol 28 (68 mg, 53%) as
PBr3 (0.7 mL, 7.4 mmol) was added dropwise to a solu-
tion of alcohol 30 (521 mg, 1.27 mmol) in ether (10 mL)
and the solution was stirred for 7 h at 0 °C. The reaction
mixture was poured into ice water, extracted with ether,
and washed with brine. The combined organic layer was
dried (MgSO4) and concentrated in vacuo to give a yellow
residue, bromide 31. A solution of benzylic alcohol 18
(305 mg, 1.34 mmol) in THF (5 mL) was added to a stir-
red suspension of KH (87 mg, 2.2 mmol) in THF (10 mL)
and the reaction mixture was stirred for 1 h at 0 °C. After
TMEDA (0.4 mL, 2.7 mmol) was added, the solution was
cooled to ꢁ20 °C, then nBuLi (1.87 mL, 2.15 M in hex-
anes) was added dropwise and the solution was stirred
at ꢁ20 °C for 1 h. CuBr as its DMS complex (556 mg,
2.7 mmol) was added in one portion and the solution
was stirred for 1 h at ꢁ20 °C. Bromide 31 in THF
(5 mL) was added to the reaction mixture via syringe at
ꢁ20 °C. After 2 h, the reaction was quenched by addition
of 1 N NH4Cl, and the aqueous layer was neutralized to
pH 7 with 1 N HCl and extracted with EtOAc. The com-
bined organic layer was washed with brine, dried
(MgSO4), and concentrated in vacuo. Final purification
by flash chromatography (20% EtOAc in hexanes) affor-
ded compound 32 (341 mg, 43% from alcohol 30) as a
1
a clear oil: H NMR d 6.91–6.83 (dm, JHF = 7.5 Hz,
2H), 5.23–5.19 (tm, J = 7.3 Hz, 1H), 5.08–5.03 (tm,
J = 6.8 Hz, 1H), 4.65 (d, J = 5.6 Hz, 2H, becomes a sin-
glet at D2O wash), 3.36 (d, J = 7.2 Hz, 2H), 2.07–1.96
(m, 4H), 1.75 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H); 13C
NMR d 161.6 (dd, JCF = 246.9, 9.6 Hz, 2C), 141.2 (t,
JCF = 9.0 Hz), 136.8, 131.7, 124.3, 120.7, 116.4 (t,
JCF = 20.9 Hz), 109.4 (dd, JCF = 26.6, 8.9 Hz, 2C),
54.4 (t, JCF = 2.1 Hz), 39.8, 26.7, 25.9, 21.5 (t,
JCF = 2.5 Hz), 17.9, 16.2; HRMS (EI) calcd for
C17H22F2O [M+], 280.1639; found 280.1639.
1
clear oil: H NMR d 7.70–7.67 (m, 4H), 7.43–7.35 (m,
6H), 6.79 (s, 2H), 5.43–5.39 (tm, J = 7.0 Hz, 1H), 5.26–
5.19 (m, 5H), 4.62 (s, 2H), 4.03 (s, 2H), 3.47 (s, 6H),
3.40 (d, J = 9 Hz, 2H), 2.19–1.96 (m, 4H), 1.81 (s, 3H),
1.59 (s, 3H), 1.06 (s, 9H); 13C NMR d 156.0 (2C), 140.2,
135.8 (4C), 134.8, 134.2 (2C), 134.1, 129.7 (2C), 127.8
(4C), 124.6, 122.9, 119.6, 106.7 (2C), 94.6 (2C), 69.3,
65.7, 56.2 (2C), 39.8, 27.1 (3C), 26.4, 22.8, 19.5, 16.3,
13.7. Anal. Calcd for C37H50O6Si: C, 71.81; H, 8.14.
Found: C, 71.72; H, 7.98.
5.12. [4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-
benzyl]-phosphonic acid diethyl ester (29)
PBr3 (0.03 mL, 0.32 mmol) was added dropwise to a
solution of alcohol 28 (180 mg, 0.64 mmol) in ether
(10 mL) and the solution was stirred for 7 h at 0 °C.
The reaction mixture was poured into ice water, extract-
ed with ether, and washed with brine. The combined
organic layer was dried (MgSO4) and concentrated in
vacuo. The resulting yellow oil was added to triethyl
phosphite (3 mL) and sodium iodide (62 mg,
0.41 mmol), and the mixture was heated at 100 °C for
30 h. After this solution was allowed to cool to rt, it
was poured into ether (10 mL) and washed with sodium
thiosulfate. The mixture was extracted with ether, dried
(MgSO4), and concentrated in vacuo. The initial yellow
oil was purified by flash chromatography (gradient, 30–
80% EtOAc in hexanes) to afford phosphonate 29
5.14. tert-Butyl-[8-(4-iodomethyl-2,6-bis-methoxymeth-
oxy-phenyl)-2,6-dimethyl-octa-2,6-dienyloxy]-diphenylsi-
lane (33)
Methanesulfonyl chloride (0.1 mL, 1.3 mmol) was add-
ed dropwise to a stirred solution of alcohol 32
(364 mg, 0.62 mmol) and Et3N (0.2 mL 1.4 mmol) in
CH2Cl2 (5 mL), and the solution was stirred for 2 h at
0 °C. The reaction mixture was allowed to warm to rt
over 5 h, quenched by addition of H2O, and extracted
with EtOAc. The combined organic layers were washed
with NH4Cl (sat) and brine, dried (MgSO4), and concen-
trated in vacuo. The resulting yellow residue was al-
lowed to react with NaI (132 mg, 0.886 mmol) in
acetone (8 mL) for 24 h at rt. The reaction mixture
was concentrated in vacuo to afford a red solid, which
1
(153 mg, 60%) as a light yellow oil: H NMR d 6.84–
6.77 (m, 2H), 5.22–5.17 (tm, J = 6.4 Hz, 1H), 5.08–5.03
(tm, J = 6.9 Hz, 1H), 4.11–4.00 (m, 4H), 3.35–3.32 (dm,
J = 7.2 Hz, 2H), 3.11–3.04 (dm, JPH = 21.7 Hz, 2H),
2.07–1.92 (m, 4H), 1.74 (s, 3H), 1.65 (s, 3H), 1.58 (s,
3H), 1.31–1.24 (tm, J = 7.1 Hz, 6H); 13C NMR d 161.4
(ddd, JCF = 245.7, 10.0 Hz, JCP = 3.5 Hz, 2C), 136.8,

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1781
was dissolved in EtOAc. After the resulting yellow solu-
tion was washed once with NaHCO3 and then with
Na2S2O3 until the color faded, it was extracted with
ether and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. Final purification
by flash chromatography (30% EtOAc in hexanes) affor-
ded the iodide 33 (347 mg, 77%) as a yellow oil: 1H
NMR d 7.77–7.72 (m, 4H), 7.49–7.38 (m, 6H), 6.84 (s,
2H), 5.48–5.44 (tm, J = 6.6 Hz, 1H), 5.29–5.19 (tm,
J = 6.0 Hz, 1H), 5.20 (s, 4H), 4.43 (s, 2H), 4.08 (s,
2H), 3.50 (s, 6H), 3.41 (d, J = 7.1 Hz, 2H), 2.30–2.01
(m, 4H), 1.85 (s, 3H), 1.63 (s, 3H), 1.11 (s, 9H); 13C
NMR d 155.8 (2C), 138.1, 135.7 (4C), 134.9, 134.1
(2C), 134.0, 129.7 (2C), 127.8 (4C), 124.5, 122.6, 120.2,
108.6 (2C), 94.6 (2C), 69.2, 56.2 (2C), 39.8, 27.0 (3C),
26.3, 22.9, 19.5, 16.3, 13.7, 6.7; HRMS (EI) calcd for
C37H49IO5Si [M+], 728.2394; found 728.2395.
1.73 (s, 3H), 1.53 (s, 3H), 1.24 (trm, J = 6.8 Hz, 6H);
13C NMR d 155.8 (d, JCP = 3.4 Hz, 2C), 135.1, 134.1,
130.4 (d, JCP = 9.1 Hz), 125.9, 123.4, 119.1 (d,
JCP = 3.9 Hz), 109.9 (d, JCP = 6.6 Hz, 2C), 94.7 (2C),
68.9, 62.3 (d, JCP = 6.7 Hz, 2C), 56.2 (2C), 39.5, 34.0
(d, JCP = 138.3 Hz), 26.1, 22.7, 16.6 (d, JCP = 6.1 Hz,
2C), 16.2, 13.8; 31P NMR d +26.2; HRMS (EI) calcd
for C25H41O8P [M+], 500.2539; found 500.2531.
5.17. 7-[2-(3,5-Bis-methoxymethoxy-phenyl)-vinyl]-5-
methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-
xanthen-2-ol (37)
To a stirred suspension of NaH (30 mg, 1.3 mmol) and
15C5 (5 lL, 3 mol %) in THF (5 mL) were added phos-
phonate 20 (25 mg, 0.12 mol) and aldehyde 12 (20 mg,
0.066 mmol) at 0 °C. The reaction mixture was allowed
to warm to rt over 10 h. The reaction was quenched
by addition of water and extracted with EtOAc. After
the combined organic layers were washed with brine,
dried (MgSO4), and concentrated in vacuo, final purifi-
cation by flash chromatography (50% EtOAc in hex-
anes) afforded compound 37 (30 mg, 91%) as a clear
oil: 1H NMR d 7.00 (d, J = 17.1 Hz, 1H), 6.90–6.85
(m, 5H), 6.64 (t, J = 2.1 Hz, 1H), 5.20 (s, 4H), 3.90 (s,
3H), 3.51 (s, 6H), 3.46–3.42 (m, 1H), 2.76–2.74 (m,
1H), 2.73-2.71 (m, 1H), 2.17–2.11 (m, 1H), 1.91–1.81
(m, 2H), 1.75–1.54 (m, 2H), 1.27 (s, 3H), 1.12 (s, 3H),
0.90 (s, 3H); 13C NMR d 158.7 (2C), 149.2, 143.0,
140,1, 129.6, 128.9, 126.2, 122.8, 120.9, 107.8 (2C),
107.3, 104.1, 94.7 (2C), 78.2, 77.3, 55.3 (2C), 56.2,
46.9, 38.6, 37.9, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS
(EI) calcd for C29H38O7 [M+], 498.2618; found 498.2608.
5.15. {4-[8-(tert-Butyl-diphenyl-silanyloxy)-3,7-dimethyl-
octa-2,6-dienyl]-3,5-bis-methoxymethoxy-benzyl}-phos-
phonic acid diethyl ester (34)
A solution of iodide 33 (68 mg, 0.093 mmol) and sodium
iodide (39 mg, 0.26 mmol) in triethyl phosphite (1.5 mL)
was heated at 100 °C for 20 h, allowed to cool to rt, and
poured into ether (5 mL). The resulting mixture was
extracted with ether, dried (MgSO4), and concentrated
in vacuo. The initial yellow oil was purified by flash
chromatography (50% EtOAc in hexanes) to afford
phosphonate 34 (63.5 mg, 92%) as a light yellow oil:
1H NMR d 7.70–7.67 (m, 4H), 7.42–7.34 (m, 6H), 6.70
(d, JHP = 2.3 Hz, 2H), 5.42–5.39 (tm, J = 5.7 Hz, 1H),
5.21–5.17 (trm, J = 7.0 Hz, 1H), 5.17 (s, 4H), 4.10–4.00
(m, 6H), 3.45 (s, 6H), 3.37 (d, J = 7.0 Hz, 2H), 3.09 (d,
JPH = 21.5 Hz, 2H), 2.14–1.95 (m, 4H), 1.80 (s, 3H),
1.58 (s, 3H), 1.28 (trm, J = 7.08 Hz, 6H), 1.06 (s, 9H);
13C NMR d 155.8 (d, JCP = 3.2 Hz, 2C), 135.8 (4C),
134.7, 134.1 (2C), 134.0, 130.5 (d, JCP = 9.0 Hz), 129.7
(2C), 127.7 (4C), 124.7, 123.0, 118.9 (d, JCP = 3.9 Hz),
109.8 (d, JCP = 6.6 Hz, 2C), 94.6 (2C), 69.2, 62.3 (d,
JCP = 6.7 Hz, 2C), 56.2 (2C), 39.8, 34.1 (d,
JCP = 138.3 Hz), 27.0 (3C), 26.5, 22.7, 19.5, 16.6 (d,
JCP = 5.8 Hz, 2C), 16.3, 13.6; 31P NMR d +26.2. Anal.
Calcd for C41H59O8PSi: C, 66.64; H, 8.05. Found: C,
66.58; H, 8.32.
5.18. 5-Methoxy-7-[2-(3-methoxymethoxy-phenyl)-vinyl]-
1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-
ol (38)
To a stirred suspension of NaH (27 mg, 0.68 mmol) and
15C5 (5 lL, 3 mol %) in THF were added phosphonate
21 (50 mg, 0.173 mmol) and aldehyde 12 (20 mg,
0.066 mmol) at 0 °C, and the reaction mixture was al-
lowed to warm to rt over 10 h. The reaction was quenched
by addition of water and extracted with EtOAc. The com-
bined organic layers were washed with brine, dried
(MgSO4), and concentrated in vacuo. Final purification
of the residue by flash chromatography (50% EtOAc in
hexanes) afforded compound 38 (18 mg, 62%) as a clear
5.16. [4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-3,5-
bis-methoxymethoxy-benzyl]-phosphonic acid diethyl
ester (35)
1
oil: H NMR d 7.29–6.87 (m, 8H), 5.21 (s, 2H), 3.90 (s,
3H), 3.51 (s, 3H), 3.46–3.39 (m, 1H), 2.74–2.72 (m, 2H),
2.16–1.59 (m, 5H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s,
3H); 13C NMR d 157.8, 149.2, 142.9, 139.5, 129.8,
129.3, 129.0, 126.3, 122.9, 120.9, 120.3, 115.3, 113.9,
107.2, 94.7, 78.2, 77.3, 56.3, 46.9, 38.6, 37.9, 29.9, 28.5,
27.6, 23.4, 20.1, 14.5; HRMS (ES+) calcd for C27H34O5
(M+H)+, 439.2484; found 439.2475.
TBAF (0.3 mL, 1 M in THF, 0.3 mmol) was added to a
solution of phosphonate 34 (55.1 mg, 0.075 mmol) in
THF (3 mL) and the solution was stirred for 3 h at rt.
The reaction was quenched by addition of water and
EtOAc, and then extracted with EtOAc. The combined
organic layer was washed with brine, dried (MgSO4),
and concentrated in vacuo. Final purification of the res-
idue by flash chromatography (gradient, 60–100%
EtOAc in hexanes) afforded compound 35 (36 mg,
96%) as a clear oil: 1H NMR d 6.66 (broad s, 2H),
5.30–5.24 (m, 1H), 5.13–5.06 (m, 5H), 4.04–3.97 (m,
4H), 3.83 (s, 2H), 3.42 (s, 6H), 3.32 (d, J = 7.0 Hz,
2H), 3.04 (d, JPH = 21.5 Hz, 2H), 2.07–1.95 (m, 4H),
5.19. 7-{2-[4-(3,7-Dimethyl-octa-6,7-dienyl)-phenyl]-vi-
nyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-hexahy-
dro-1H-xanthen-2-ol (39)
To a suspension of NaH (64 mg, 1.6 mmol, 60% in min-
eral oil) in THF (17 mL) at 0 °C was added a mixture of

1782
J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
phosphonate 26 (56 mg, 0.15 mmol) and aldehyde 12
(28 mg, 0.09 mmol) in THF (3 mL). After 5 min, 15C5
(10 lL) was added and the reaction mixture was allowed
to warm to rt and stir for 19 h. Water was added and the
mixture was extracted with ethyl acetate. The combined
organic phase was washed with brine and dried
(MgSO4). Concentration in vacuo afforded a yellow oil
and final purification by column chromatography
(50% EtOAc in hexanes) gave the stilbene 39 (26 mg,
quenched by addition of water and extracted with
EtOAc. The combined organic layers were washed with
brine, dried (MgSO4), and concentrated in vacuo. Puri-
fication of the resulting oil by flash chromatography
(50% EtOAc in hexanes) afforded compound 41
(20.5 mg, 60%) as a clear oil: 1H NMR d 6.99–6.87
(m, 6H), 5.37–5.33 (tm, J = 6.0 Hz, 1H), 5.24–5.18 (m,
5H), 3.95 (s, 2H), 3.91 (s, 3H), 3.52–3.39 (m, 9H),
2.74–2.72 (m, 1H), 2.72–2.70 (m, 1H), 2.17–1.98 (m,
5H), 1.90–1.57 (m, 10H), 1.26 (s, 3H), 1.12 (s, 3H),
0.90 (s, 3H); 13C NMR d 156.1 (2C), 149.2, 142.8,
137.0, 134.9, 134.4, 129.1, 128.6, 126.6, 126.2, 123.3,
122.8, 120.8, 119.7, 107.1, 106.3 (2C), 94.8 (2C), 78.3,
77.4, 69.2, 56.2 (2C), 47.0, 39.6, 38.6, 37.9, 28.5, 27.6,
26.3, 23.4, 22.9, 20.1, 16.3, 14.5, 14.3, 13.9; HRMS
(EI) calcd for C39H54O8 [M+], 650.3819; found 650.3812.
1
55%) as a clear oil: H NMR d 7.40 (m, 2H), 7.16 (m,
2H), 6.95–6.94 (m, 2H), 6.89–6.88 (m, 2H), 5.34 (td,
J = 7.3, 1.0 Hz, 1H), 5.11 (t, J = 6.7 Hz, 1H), 3.89 (s,
3H), 3.43 (dd, J = 11.7, 4.0 Hz, 1H), 3.35 (d,
J = 7.3 Hz, 2H), 2.74–2.71 (m, 2H), 2.16–2.04 (m, 5H),
1.90–1.81 (m, 2H), 1.80–1.70 (m, 2H), 1.71 (s, 3H),
1.69 (s, 3H), 1.61 (s, 3H), 1.25 (s, 3H), 1.10 (s, 3H),
0.90 (s, 3H); 13C NMR d 148.9, 142.5, 140.9, 136.3,
135.2, 131.4, 129.1 (2C), 128.6, 127.8, 126.2, 126.2
(2C), 124.2, 122.8, 122.6, 120.4, 106.9, 78.0, 77.0, 56.0,
46.7, 39.7, 38.4, 37.6, 33.9, 28.3, 27.3, 26.6, 25.7, 23.1,
19.8, 17.7, 16.1, 14.3; HREIMS calcd for C35H46O3
(M+) 514.3447; found 514.3447.
5.22. 5-Methoxy-1,1,4a-trimethyl-7-styryl-2,3,4,4a,9,9a-
hexahydro-1H-xanthen-2-ol (42)
To a suspension of NaH (26 mg, 1 mmol) and 15C5
(5 lL, 3 mol %) in THF (5 mL) were added phospho-
nate 36 (25 mg, 0.12 mmol) and aldehyde 12 (15.8 mg,
0.05 mmol) at 0 °C, and the reaction mixture was stirred
for 10 h at rt. The reaction was quenched by addition of
water and extracted with EtOAc. The combined organic
layers were washed with brine, dried (MgSO4), and con-
centrated in vacuo. Final purification of the residue by
flash chromatography (35% EtOAc in hexanes) afforded
5.20. 7-{2-[4-(3,7-Dimethyl-octa-2,6-dienyl)-3,5-difluoro-
phenyl]-vinyl}-5-methoxy-1,1,4a-trimethyl-2,3,4,4a,9,9a-
hexahydro-1H-xanthen-2-ol (40)
To a stirred suspension of NaH (30 mg, 1.3 mmol) and
15C5 (5 lL, 3 mol %) in THF (5 mL) were added phos-
phonate 29 (71 mg, 0.177 mmol) and aldehyde 12
(20 mg, 0.066 mmol) at 0 °C and the solution was al-
lowed to warm to rt over 10 h. The reaction was
quenched by addition of water and then was extracted
with EtOAc. The combined organic layers were washed
with brine, dried (MgSO4), and concentrated in vacuo.
Final purification of the residue by flash chromatogra-
phy (50% EtOAc in hexanes) afforded compound 40
(30.9 mg, 85%) as a clear oil: 1H NMR d 6.99–6.79
(m, 6H), 5.26–5.22 (tm, J = 7.0 Hz, 1H), 5.09–5.04 (tm,
J = 6.8 Hz, 1H), 3.9 (s, 3H), 3.47–3.42 (m, 1H), 3.37–
3.35 (dm, J = 7.2 Hz, 2H), 2.77–2.74 (m, 1H), 2.73–
2.70 (m, 1H), 2.18–1.82 (m, 7H), 1.76 (s, 3H), 1.72–
1.69 (m, 2H), 1.65 (s, 3H), 1.58 (s, 3H), 1.27 (s, 3H),
1.09 (s, 3H), 0.90 (s, 3H); 13C NMR d 163.4–160.0
(dd, JCF = 241.8 Hz, JCF = 9.8 Hz, 2C), 149.3, 143.4,
137.9, 136.8, 131.7, 130.5, 124.5 (t, JCF = 9.5 Hz),
124.3, 123.0, 121.1, 120.8, 115.9 (t, JCF = 23.4 Hz),
110.0, 108.7 (dd, JCF = 26.6 Hz, JCF = 8.6 Hz, 2C),
107.3, 78.2, 77.4, 56.3, 47.0, 39.8, 38.6, 37.9, 28.5, 27.6,
26.7, 25.8, 23.4, 21.6 (t, JCF = 2.0 Hz), 20.1, 17.8, 16.2,
14.5; HRMS (EI) calcd for C35H44O3F2 [M+],
550.3259; found 550.3256.
1
compound 42 (17 mg, 90%) as a clear oil: H NMR d
7.50–7.47 (m, 2H), 7.37–7.34 (m, 2H), 7.26–7.20 (m,
1H), 6.98 (d, J = 8.5 Hz, 2H), 6.91–6.87 (m, 2H), 3.90
(s, 3H), 3.46–3.41 (m, 1H), 2.77–2.75 (m, 1H), 2.72-
2.68 (m, 2H), 2.16–2.11 (m, 1H), 1.90–1.81 (m, 2H),
1.74–1.55 (m, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s,
3H); 13C NMR d 149.2, 142.9, 137.9, 129.2, 128.9
(2C), 128.8, 127.4, 126.5, 126.4 (2C), 122.9, 120.8,
107.2, 78.2, 77.3, 56.3, 47.0, 38.6, 37.9, 28.5, 27.6, 23.4,
20.1, 14.5; HRMS (EI) calcd for C25H30O3 [M+],
378.2195; found 378.2195.
5.23. 5-[2-(7-Hydroxy-4-methoxy-8,8,10a-trimethyl-
5,7,8,8a,9,10a-hexahydro-6H-xanthen-2-yl)-vinyl]-ben-
zene-1,3-diol (43)
To a stirred solution of stilbene 37 (30 mg, 0.06 mmol)
in methanol (5 mL) was added CSA (20 mg, 0.09 mmol)
and the solution was allowed to stir 10 h at 50 °C. The
reaction mixture was allowed to cool to rt, concentrated
in vacuo, and the residue was dissolved in EtOAc and
water. The mixture was extracted with ether, washed
with brine, dried (MgSO4), and concentrated in vacuo.
Final purification of the residue by flash chromatogra-
phy (60% EtOAc in hexanes) afforded compound 43
5.21. 7-{2-[4-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-
3,5-bis-methoxymethoxy-phenyl]-vinyl}-5-methoxy-
1,1,4a-trimethyl-2,3,4,4a,9, 9a-hexahydro-1H-xanthen-2-
ol (41)
1
(23 mg, 93%) as a clear oil: H NMR (CDCl3/CD3OD)
d 7.06–6.88 (m, 4H), 6.58 (d, J = 2.0 Hz, 2H), 6.31 (t,
J = 2.0 Hz, 1H), 3.97 (s, 3H), 3.75–3.68 (m, 1H), 2.96–
2.81 (m, 2H), 2.20–1.68 (m, 5H), 1.33 (s, 3H), 1.16 (s,
3H), 0.97 (s, 3H); 13C NMR (CDCl3/CD3OD) d 157.7
(2C), 148.3, 142.0, 139,4, 128.8, 128.0, 125.9, 122.3,
120.3, 106.6, 104.3 (2C), 101.2, 77.0, 76.7, 55.1, 46.9,
37.8, 37.2, 27.2, 26.2, 22.5, 18.9, 13.4; HRMS (EI) calcd
for C25H30O5 [M+], 410.2093; found 410.2093.
To a suspension of NaH (12 mg, 0.3 mmol) and 15C5
(5 lL, 3 mol %) in THF (5 mL) were added phospho-
nate 35 (34 mg, 0.068 mmol) and aldehyde 12 (16 mg,
0.053 mmol) at 0 °C, and the reaction mixture was al-
lowed to warm to rt over 10 h. The reaction was

J. D. Neighbors et al. / Bioorg. Med. Chem. 14 (2006) 1771–1784
1783
5.24. 7-[2-(3-Hydroxy-phenyl)-vinyl]-5-methoxy-1,1,4a-
trimethyl-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (44)
Supplementary data
1
Supporting Information Available: H and 13C NMR
spectra for compounds 16, 17, 24, 25, 28, 33, 35, and
37–45, a table of elemental analyses, and complete assay
data from the 60 cell line screen for compounds 17, 39,
40, and 42–45 can be found here. This material is avail-
able free of charge via the Internet. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.bmc.2005.10.025.
CSA (17 mg, 0.073 mmol) was added to a stirred solu-
tion of stilbene 38 (16 mg, 0.036 mmol) in methanol
(5 mL) and the reaction mixture was allowed to stir
for 15 h at rt. The reaction mixture was concentrated
in vacuo and the residue was dissolved in EtOAc and
water. The mixture was extracted with ether, the organic
layer was washed with brine, dried (MgSO4), and con-
centrated in vacuo. Purification of the residue by flash
chromatography (60% EtOAc in hexanes) afforded com-
1
pound 44 (9 mg, 63%) as a clear oil: H NMR d 7.26–
References and notes
7.19 (m, 1H), 7.06–6.85 (m, 6H), 6.73–6.70 (m, 1H),
5.05 (s, 1H, exchangeable with D2O), 3.83 (s, 3H),
3.46–3.43 (m, 1H), 2.75–2.66 (m, 2H), 2.18–1.61 (m,
5H), 1.49 (br. s, 1H, exchangeable with D2O), 1.26 (s,
3H), 1.11 (s, 3H), 0.89 (s, 3H); 13C NMR d 156.1,
149.2, 142.9, 139.6, 130.0, 129.4, 129.0, 126.1, 122.9,
120.9, 119.3, 114.4, 112.9, 107.2, 78.3, 77.4, 56.2, 46.9,
38.6, 37.8, 28.5, 27.6, 23.4, 20.1, 14.5; HRMS (EI) calcd
for C25H30O4 (M+H+), 395.2222; found 395.2237.
1. (a) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd,
M. R. J. Nat. Prod. 1998, 61, 1509–1512; (b) Beutler, J. A.;
Jato, J.; Cragg, G. M.; Boyd, M. R. Nat. Prod. Lett. 2000,
14, 399–404.
2. Thoison, O.; Hnawia, E.; Gueritte-Voegelein, F.; Sevenet,
T. Phytochemistry 1992, 31, 1439–1442.
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Friend, S. H.; Fornace, A. J., Jr.; Kohn, K. W.; Fojo, T.;
Bates, S. E.; Rubinstein, L. V.; Anderson, N. L.;
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Cancer Res. 2003, 63, 8869–8876.
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5.25. 2-(8-Hydroxy-3,7-dimethyl-octa-2,6-dienyl)-5-[2-(7-
hydroxy-4-methoxy-8,8,10a-trimethyl-5,7,8,8a,9,10a-
hexahydro-6H-xanthen-2-yl)-vinyl]-benzene-1,3-diol (45)
CSA (20 mg, 0.09 mmol) was added to a stirred solution
of stilbene 41 (17 mg, 0.026 mmol) in methanol (5 mL)
and the reaction mixture was allowed to stir for 15 h
at 50 °C. The reaction mixture was allowed to cool to
rt and concentrated in vacuo, and the residue was dis-
solved in EtOAc and water. The mixture was extracted
with ether, the organic layer was washed with brine,
dried (MgSO4), and concentrated in vacuo. Purification
of the residue by flash chromatography (80% EtOAc in
hexanes) afforded compound 45 (6 mg, 42%) as a clear
1
oil: H NMR d 6.94–6.73 (m, 4H), 6.49 (s, 2H), 5.40
(s, 2H, exchangeable with D2O), 5.31–5.29 (m, 2H),
4.01 (s, 2H), 3.89 (s, 3H), 3.45–3.43 (m, 3H), 2.74–2.72
(m, 1H), 2.72–2.70 (m, 1H), 2.37–2.12 (m, 5H), 1.91–
1.57 (m, 10H), 1.46 (s, 1H, exchangeable with D2O),
1.26 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); 13C NMR d
155.2 (2C), 149.2, 142.9, 139.2, 137.6, 136.5, 129.0
(2C), 125.8, 125.0, 122.9, 122.7, 120.8, 112.6, 107.2,
106.4 (2C), 78.1, 69.1, 56.2, 47.0, 39.4, 38.6, 37.9, 28.4,
27.6 (2C), 25.1, 23.4, 22.7, 20.1, 15.8, 14.5, 13.9; HRMS
(EI) calcd for C35H46O6 [M+], 561.3216; found 561.3214.
7. (a) Holstein, S. A.; Cermak, D. M.; Wiemer, D. F.; Lewis,
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We thank Domenic Scudiero and the Developmental
Therapeutics Program, NCI, for 60-cell testing. Finan-
cial support from the Breast Cancer Research Program
(DAMD17-01-1-0276 and DAMD17-02-1-0423), the
University of Iowa Graduate College, and an Oncology
Research Training Award from the Holden Comprehen-
sive Cancer CenterÕs Institutional National Research
Service Award (2 T32 CA79445-05) is gratefully
acknowledged. This research was supported in part by
the Intramural Research Program of the NIH, National
Cancer Institute, Center for Cancer Research.
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