Relevance of the C-5 position to schweinfurthin induced cytotoxicity

Article abstract of DOI:10.1016/j.bmc.2011.10.034

The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have little impact on other cell lines even at microm

Full text of DOI:10.1016/j.bmc.2011.10.034

Bioorganic & Medicinal Chemistry 19 (2011) 7570–7581
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Relevance of the C-5 position to schweinfurthin induced cytotoxicity
Joseph J. Topczewski a, Michael P. Callahan a, John G. Kodet a, Jery D. Inbarasu a, Nolan R. Mente a,
John A. Beutler b, David F. Wiemer a,
⇑
a Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA
b Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The schweinfurthins are an intriguing group of anti-proliferative agents that display low nanomolar
activities against several cell types, including the human-derived glioblastoma cell line SF-295, but have
little impact on other cell lines even at micromolar concentrations. This activity has inspired the synthe-
sis of seven of the natural schweinfurthins, all with the correct absolute stereochemistry, and a variety of
analogues designed to probe different facets of the pharmacophore. Reported herein is the synthesis of
several new schweinfurthin analogues varied at the C-5 position along with data on their biological activ-
ity in the NCI 60 cell-line assay.
Received 21 August 2011
Revised 5 October 2011
Accepted 10 October 2011
Available online 19 October 2011
Keywords:
Schweinfurthins
Apoptosis
Ó 2011 Elsevier Ltd. All rights reserved.
Cytotoxic
Anti-proliferative
Bioassay
1. Introduction
of one D-ring phenol11 (Fig. 1, ‘tolerant’), and especially incorpora-
tion of substituents at the para position of the D-ring, including
In 1998 the structures of schweinfurthins A and B (1 and 2,
Fig. 1) were reported as part of the National Cancer Institute’s
(NCI) search for anti-proliferative agents with new mechanisms
of action. These compounds were isolated from an extract of
Macaranga schweinfurthii through bioassay guided fractionation,1
and subsequently were subjected to the NCI 60 cell-line screen.
This assay revealed a unique pattern of activity which does not
correlate to any known mechanism of cell growth inhibition. Sev-
eral cell lines were particularly sensitive to the schweinfurthins,
including the human glioblastoma line SF-295, while other cell
lines (e.g., the lung cancer line A549) were only marginally affected
even at elevated doses. These observations led to the hypothesis
that further exploration of the schweinfurthins might uncover a
new target for treatment of specific malignancies, especially for
conditions with poor clinical prognoses such as glioblastoma
multiforme.
hydrogen or an alkyl, allyl, prenyl, or geranyl group (‘highly
tolerant’).12–15 Conversely, modification of other regions resulted
in a significant loss of activity, including a cis-fused A/B system,16
a cis-stilbene or a saturated linkage,13 and simultaneous methyla-
tion of both D-ring phenols (Fig. 1, ‘intolerant’).11
Investigations of the schweinfurthin mechanism17 have re-
vealed that schweinfurthin A can phenocopy the tumor suppressor
Unexplored
R'
5
Tolerant
R
O
B
Tolerant
OH
Intolerant
A
C
Highly
Tolerant
HO
2
H
D
Intolerant
H
n
At this time seven of the eleven natural schweinfurthins1–4 have
been synthesized, including specifically schweinfurthins A (1),5
B
OH
(2),6 C,7 E (3),6 F (4),8 and G (5),8 as well as vedelianin9 (6). Our
group also has synthesized numerous schweinfurthin analogues
and in the process has gained considerable knowledge of the
schweinfurthin pharmacophore. Several portions of the schwein-
furthin structure have shown tolerance to modification, including
the presence or absence of a hydroxyl group at C-3,10 methylation
Intolerant
Schweinfurthin A 1 R = OH, R' = OH, n = 2
Schweinfurthin B 2 R = OH, R' = OCH3, n = 2
Schweinfurthin E 3 R = OH, R' = OCH3, n = 1
Schweinfurthin F 4 R = H, R' = OCH3, n = 1
Schweinfurthin G 5 R = H, R' = OH, n = 1
Vedelianin
6 R = OH, R = OH, n = 1
⇑
Corresponding author.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
Figure 1. Key schweinfurthins and current understanding of the pharmacophore.
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.10.034

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7571
NF1 in CNS and peripheral nervous system tumor cell lines,17a
although a proximate target has not yet been identified conclu-
sively. Recent work by the Shair group has implicated oxysterol
binding proteins in the action of schweinfurthins and other appar-
ently similar natural products, but the evidence for schweinfur-
aldehydes (Scheme 1). The first aldehyde prepared carried only a
hydrogen substituent at C-5. To pursue this compound, protection
of the previously reported arene 718 as the TBS ether afforded com-
pound 8, which was epoxidized under Shi conditions19 to obtain
the nonracemic compound 9. Removal of the silyl group in epoxide
9 afforded the phenol 10, and subsequent treatment with BF3ꢀOEt2
brought about cyclization to afford the hexahydroxanthene 11 in
very good yield. After reduction of this methyl ester to the benzylic
alcohol 12, oxidation with MnO2 gave the parent aldehyde 13.
While aldehyde 13 underwent direct bromination at the C-5 posi-
tion in modest yield (23%), a longer sequence provided the MOM-
protected bromide 18 in much better yield. Thus, bromination of
the methyl ester 11 in methylene chloride and acetic acid provided
a mixture of bromides 14 and 15, but cleavage of the acetate could
be accomplished in near-quantitative yield. After protection of the
hydroxyl group of compound 14 through reaction with MOMCl,
reduction provided the benzylic alcohol 17 and a final oxidation
with MnO2 gave the desired aldehyde 18. This aldehyde was con-
densed with a ‘right-half’ phosphonate (vide infra) that was also
MOM-protected, so a separate step was not required for the even-
tual removal of the C-2 MOM group.
A substantial number of important drugs bear a fluorine substi-
tuent, at least in part because fluorine’s electronic properties are
significantly different from hydrogen but its size is sufficiently
similar that there is minimal potential for introduction of
unfavorable steric interactions in a mono-fluoro compound.20 To
prepare a C-5 fluorinated schweinfurthin analogue, synthesis of
the requisite aldehyde began with ester 19, obtained in three steps
from commercial 3-fluoro-4-hydroxybenzoic acid (esterification,
bromination and protection as the MOM acetal).21 After this ester
was reduced to alcohol 20 it was converted to the methyl ether
thins is less compelling than for OSW-1 and cephalostatin 1.17b
A
recent study more specific to the schweinfurthins found that the
synthetic analogue 3-deoxyschweinfurthin B had a pronounced
impact on isoprenoid homeostasis,17c but more work is clearly
needed before the mechanism(s) will be understood in any detail.
An increased understanding of the pharmacophore has allowed
synthesis of schweinfurthins for use as fluorescent12,14 or biotinyl-
ated15 probes that may allow more specific determination of the
basis of schweinfurthins’ cellular activity. However, one region of
the schweinfurthin structure that, until now, has remained rela-
tively unexplored is the C-5 position. Within the natural family,
this position has been found only as a free phenol or a methoxy
group, with the free phenol typically 2–4 fold more potent. Given
this difference in potency, it appeared to be worthwhile to explore
the effect that various substituents at the C-5 position might have
on activity. Reported herein is the synthesis of a small set of C-5
modified schweinfurthins with an evaluation of their relative
activity in the NCI’s 60 cell-line assay.
2. Synthesis
Our strategy for schweinfurthin synthesis is based on a late
stage Horner–Wadsworth–Emmons (HWE) condensation between
an aryl aldehyde, usually representing the hexahydroxanthene side
of the target, and a benzylic phosphonate.10 To use this approach to
obtain C-5 analogues required preparation of several key
Shi
epoxidation
RO
O
RO
BF3·OEt2
O
50%
OCH3
OCH3
94%
HO
R
H
O
O
11 R = CO2CH3
12 R = CH2OH
13 R = CHO
7 R = H
8 R = TBS
TBSCl
imid, 95%
LiAlH4, 100%
MnO2, 90%
TBAF
100%
9
R = TBS
10 R = H
Br
Br
Br
Br2, CH2Cl2
AcOH
MOMCl
DIPEA
O
O
O
MnO2
81%
11
82%
RO
CO2CH3
MOMO
R
MOMO
CHO
H
H
H
14 R = H (36%)
15 R = Ac (52%)
16 R = CO2CH3
17 R = CH2OH
DIBAL-H
92%
18
K2CO3, CH3OH
96%
F
F
F
F
n-BuLi, CuBr·DMS
Shi
epoxidation
MOMO
MOMO
MOMO
Br
O
geranyl bromide
BF3·OEt2
O
17%
57%
54%
R
HO
R
H
22
19 R = CO2CH3
20 R = CH2OH
21 R = CH2OCH3
OCH3
23
OCH3
LiAlH4, 90%
NaH, CH3I
76%
24 R = CH2OCH3
25 R = CHO
DDQ, 90%
R'
SCH3
SCH3
n-BuLi, CuBr·DMS
MOMO
MOMO
O
BF3·OEt2
epoxygeranyl bromide
O
51%
38%
HO
R
H
29
OR
OCH3
30 R = CH2OCH3
31 R = CHO
DDQ, 76%
26 R = H, R' = H
27 R = CH3, R' = H
NaH, CH3I, 81%
n-BuLi, (CH3S)2, 44%
28 R = CH3, R' = SCH3
Scheme 1. Synthesis of four intermediate aldehydes for the ‘left half’ of the schweinfurthins.

7572
J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
21 via a standard Williamson synthesis. Halogen metal exchange
and reaction of the resulting aryl lithium intermediate with gera-
nyl bromide provided compound 22 in low yield. Application of a
Shi epoxidation furnished epoxide 23 in moderate yield and good
enantiomeric excess. Cyclization of this epoxide afforded the hexa-
hydroxanthene 24. The benzyl methyl ether has been utilized as a
latent benzaldehyde in other schweinfurthin syntheses,5,8 and in
this specific case DDQ oxidation provided aldehyde 25 cleanly in
a single step from the methyl ether 24.
A slightly different approach based on sequential and selective
directed ortho metallation was employed to gain access to the
C-5 methylthio schweinfurthin analogue. In this case, after alcohol
26 was converted to the methyl ether 27, deprotonation with
n-BuLi followed by treatment with (CH3S)2 provided the thio-
methyl ether 28. A second ortho metallation and copper-mediated
coupling with the known22 epoxide of geranyl bromide provided
epoxide 29. Cyclization to compound 30 proceeded in reasonable
yield, and DDQ oxidation of the benzyl methyl ether provided alde-
hyde 31 smoothly without detectable oxidation of the thiomethyl
group.
We also prepared compounds with carbon-containing substitu-
ents at C-5 (Scheme 2). During the course of these studies, the ben-
zyl alcohol 32 became available through a cascade cyclization
terminated by electrophilic aromatic substitution.5 Treatment of
compound 32 with DDQ preferentially oxidized the benzyl methyl
ether in the presence of the free benzyl alcohol to provide aldehyde
33, corroborating previous observations on the regioselectivity of
this oxidation.5 Protection of the benzyl alcohol as a TBS ether
afforded aldehyde 34 for use as a partner in HWE reactions.
The right half of the new schweinfurthin analogues was pre-
pared as shown in Scheme 3. Directed ortho metallation of alcohol
3523 occurred upon exposure to multiple equivalents of n-BuLi, and
subsequent reaction with geranyl bromide afforded the expected
geranylated arene 38 in 47% yield.24 This approach presumably in-
OR
R
OMOM
n-BuLi, CuBr
geranyl bromide
OMOM
OCH3
OCH3
TBAF
35 R = H
36 R = TBS
TBSCl
imid, 84%
37 R = OTBS
38 R = OH
39 R = P(O)(OEt)2
40%(2 steps)
MsCl, TEA
NaI, P(OEt)3
100%
Scheme 3. Synthesis of phosphonate 39.
volves formation of an intermediate dianion, and was more effi-
cient than the 34% overall yield if alcohol 35 was protected as
the TBS ether 36, alkylated to obtain compound 37, and then
deprotected to afford alcohol 38. Conversion of benzyl alcohol 38
to the phosphonate 39 was conducted by a classical Arbuzov reac-
tion25 after formation of the mesylate and iodide. This provided
phosphonate 39 which was used as an HWE coupling partner
throughout this series.
With phosphonate 39 and a set of aldehydes now available,
stilbene formation was accomplished by standard HWE olefination
(Table 1). Treatment of the new aldehydes 13, 18, 25, 31, and 34, as
well as the known aldehydes 40,5 41,8 and 42,10 with phosphonate
39 and base provided stilbenes 43–50 in moderate to high yield.
Hydrolysis of the MOM acetals 43–49 was accomplished by
exposure to methanolic p-TsOH to provide schweinfurthin
analogues 51–57.
The benzylic C-5 position of compound 50 allowed the possibil-
ity of further elaboration and this intermediate was exploited to
obtain several additional analogues. After cleavage of the silyl
ether through treatment with TBAF, several analogues were ob-
tained through straightforward reactions of the resulting benzyl
alcohol 58 (Scheme 4). Exposure of alcohol 58 to MnO2 resulted
in aldehyde 60. Further oxidation of this intermediate with sodium
chlorite26 provided the carboxylic acid 61, while reductive amina-
tion of aldehyde 60 with NaCNBH3 and dimethylamine resulted in
the tertiary amine 62. The D-ring MOM group of compound 58
could be removed via hydrolysis to afford schweinfurthin 59, but
this reaction proceeded in low yield. Given this disappointing yield,
and because MOM groups might be cleaved in vivo during cellular
assays, hydrolysis of the other MOM acetals in this small set was
not pursued pending the results of bioassays on two representative
OR'
O
HO
R
H
32 R = CH2OCH3, R' = H
33 R = CHO, R' = H
34 R = CHO, R' = TBS
DDQ
TBSCl, imid
70% (2 steps)
Scheme 2. Synthesis of C-5 alkyl compounds.
Table 1
HWE condensations and subsequent hydrolysis
R
P(O)(OEt)2
R
O
OCH3
O
HWE
+
OCH3
HO
CHO
HO
H
H
OMOM
R' = MOM
TsOH
OR'
R' = H
Entry
RCHO
R =
HWE (% Yield)
Stilbene
Hydrolysis (% Yield)
Schwein.
R =
1
2
3
4
5
6
7
8
13
18a
25
31
40
41
42
34
H
Br
F
66
54
53
74
50
77
90
36
43
44a
45
46
47
48
49
50
53
92
77
40
41
61
92
51
52
53
54
55
56
57
H
Br
F
SCH3
CH2OCH3
OMOM
OCH3
CH2OTBS
SCH3
CH2OCH3
OH
OCH3
a
In this series, the aldehyde and stilbene bear a C-2 MOM group that is cleaved in the final hydrolysis.

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7573
sured by the mean GI50 values. The difference in activity is even
more striking if one considers just the sensitive SF-295 and insen-
sitive A549 cell lines. For these two cell lines, compound 56 was
more than 30-fold more potent against SF-295 cells than against
A549 cells, while compound 57 showed only about 13-fold great-
er activity in the SF-295 assay. A lesser differential activity also is
observed in the full 60 cell-line data for compound 57 versus
compound 56 (1.58 versus 2.84).
R
O
OCH3
HO
H
OR'
50 R = CH2OTBS, R' = MOM
58 R = CH2OH, R' = MOM
59 R = CH2OH, R' = H
By some measures, compound 57 also is an interesting com-
pound: it has a relatively low mean GI50 (1.67 lM) and shows a
TBAF, 95%
TsOH, 17%
MnO2, 98%
13-fold difference in activity between the SF-295 and A549 cells.
However, perhaps the most surprising compound is the benzyl
alcohol 58. As noted above, because attempted hydrolysis of the
D-ring MOM group in compound 58 was accompanied by exten-
sive decomposition, both compounds 58 and 60 were submitted
for this assay with the D-ring MOM group still in place. Thus there
are two points of difference between compounds 58 and 57 which
complicates any direct comparison of their biological activity.
Nevertheless, the fact that compound 58 displays potency compa-
rable to compound 57 and high differential activity (2.56 log units
in the 60 cell assay) is intriguing. If one assumes that the D-ring
MOM group is lost after cell uptake, the resulting compound would
be simply isomeric to compound 56 at C-5 and it is nearly equiva-
lent in mean GI50. However compound 58 may be significantly
more stable to metabolism. Because ortho quinone formation in
the C-ring would require extensive metabolism with any carbon
substituent at C-5, it may be worthwhile to explore other schwein-
furthin analogues that include a C-5 hydroxymethyl group.
60 R = CHO, R' = MOM
61 R = CO2H, R' = MOM
62 R = CH2N(CH3)2, R' = MOM
NaCNBH3,
HN(CH3)2, 32%
NaClO2, 100%
Scheme 4.
members of this group, the alcohol 58 and the corresponding alde-
hyde 60.
3. Biological results and discussion
Nine of these new schweinfurthin analogues have been submit-
ted to the NCI’s 60 cell-line screen,27 compounds 51–58, and 60.
The current protocol for this assay requires initial testing at a sin-
gle dose, and then the more active compounds are subjected to the
full 5-dose assay. Of these nine schweinfurthins, compounds 52
and 55 did not pass the single dose assay with a level of activity
sufficient to justify the full screen. Given the substantial size of
the bromide substituent, it may not be surprising that compound
52 showed little activity, but the limited activity of the fluoride
55 was disappointing. This may suggest that a C-5 substituent
capable of hydrogen bond donation is important to activity, or that
the limited ability of fluorine28 to serve as hydrogen bond acceptor
diminishes activity.
4. Conclusions
In conclusion, several C-5 modified schweinfurthin analogues
have been prepared through new variations on the strategies that
have been used to prepare the natural products in this family.
These syntheses required sequences of varied length and gave var-
ied yields, but averaged 11 linear steps and proceeded in an aver-
age yield of ꢁ5%. Of the nine schweinfurthin analogues synthesized
for this study and tested in the NCI 60 cell assay, only compounds
56 and 58 have in vitro potency comparable to schweinfurthin A
(1),1 although most of them show selectivity for inhibition of
CNS tumor cell growth. From these studies, it appears that the phe-
nol group at C-5 is one structural feature that preserves both good
potency and a high differential activity. Perhaps surprisingly,
incorporation of a hydroxymethyl group at this position also led
Five of the compounds that did pass this test carried one phe-
nol and one methoxy substituent in the D-ring, and these five
compounds displayed a range of activity (Table 2). Compound
56 was the most potent, with a mean GI50 of 0.47 lM, and this
compound also showed the greatest difference in activity be-
tween the most and least sensitive cell lines (2.84 log units).
Reflecting the same trend as the natural products schweinfurthin
A and B, introduction of a methyl ether at the C-5 position (i.e.,
compound 57) resulted in about a 3-fold loss of potency as mea-
Table 2
Activity of schweinfurthin analogues in the NCI 60 cell line screen27
R
O
OCH3
HO
H
OR'
Entry
Schweinfurthin
R =
R’ =
Mean GI50
(l
M)
Differential (log units)
SF-295 GI50
(l
M)
A-549 GI50 (lM)
1
2
3
4
5
6
7
51a
53a
54a
56b
57a
58b
60a
H
F
H
H
H
H
H
MOM
MOM
10.15
6.23
7.95
0.47
1.67
1.66
6.30
1.56
1.40
1.58
2.84
1.58
2.56
2.46
1.66
5.01
3.80
0.022
0.19
0.15
1.20
13.2
2.14
6.03
0.72
2.45
1.41
7.8
SCH3
OH
OCH3
CH2OH
CHO
a
Duplicate wells were run for each of these compounds in one assay.
Duplicate wells were run for each of these compounds in each of two independent assays and the average value is given in this table.
b

7574
J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
to an analogue with good activity. Thus the contribution of the C-5
substituent may be more reliant on its ability to undergo hydrogen
128.9, 122.8, 122.5, 117.9, 64.2, 58.4, 51.9, 36.3, 28.5, 27.4, 25.7
(3C), 24.9, 18.7, 18.3, 16.3, ꢂ3.7 (2C). Anal. Calcd for C24H38O4Si:
C, 68.86; H, 9.15. Found C, 69.09; H, 9.19.
bonding than on its electronic effect on the extended
p system. It is
now apparent that preservation of a C-5 substituent capable of H-
bonding will be important during studies that probe other aspects
of the schweinfurthin pharmacophore. Furthermore, the activity
observed for compound 58, despite the presence of a D-ring
MOM acetal, suggests that this group is biodegradable upon cell
uptake and/or that there is more flexibility to substituents at this
position than previously recognized. Thus it is reasonable to con-
clude that there is still more to be learned about the activity of syn-
thetic compounds modeled upon the natural schweinfurthins, and
further studies in this vein will be forthcoming.
5.4. Phenol 10
To a solution of epoxide 9 (459 mg, 1.1 mmol) in THF (20 mL) at
rt was added TBAF (1 M in THF, 2.2 mL, 2.2 mmol). After 3 h, the
reaction was quenched by addition of water. The resulting solution
was extracted with ether, dried (MgSO4), and concentrated in va-
cuo. Final purification by column chromatography (10–15% EtOAc
in hexanes) afforded phenol 10 (333 mg, 100%) as an oil: 1H NMR d
7.81–7.77 (m, 2H), 6.84–6.81 (m, 1H), 5.36 (td, J = 7.1, 1.4 Hz, 1H),
3.87 (s, 3H), 3.38 (d, J = 6.9 Hz, 2H), 2.74 (t, J = 6.2 Hz, 1H), 2.29–
2.12 (m, 2H), 1.77 (s, 3H), 1.71–1.64 (m, 2H), 1.29 (s, 3H), 1.27 (s,
3H); 13C NMR d 167.3, 158.7, 137.0, 131.8, 129.6, 127.2, 122.2,
122.0, 115.4, 64.4, 58.9, 51.9, 36.4, 29.1, 27.2, 24.8, 18.7, 16.2. Anal.
Calcd for C18H24O4: C, 71.03; H, 7.95. Found C, 70.73; H, 7.96.
5. Experimental procedures and methods
5.1. General experimental conditions
Tetrahydrofuran was freshly distilled from sodium/benzophe-
none, while methylene chloride was distilled from calcium hydride
prior to use. All other reagents and solvents were purchased from
commercial sources and used without further purification. All reac-
tions in nonaqueous solvents were conducted in flame-dried glass-
ware under a positive pressure of argon and with magnetic stirring.
All NMR spectra were obtained at 300 MHz for 1H, and 75 MHz for
13C with CDCl3 as solvent, and (CH3)4Si (1H, 0.00 ppm) or CDCl3
5.5. Hexahydroxanthene 11
To a solution of epoxide 10 (353 mg, 1.16 mmol) in CH2Cl2
(125 mL) at ꢂ78 °C was added BF3ꢀOEt2 (0.73 mL, 5.76 mmol). After
6 min, the reaction was quenched by addition of triethylamine
(TEA, 1.5 mL). Water was added, the resulting solution was ex-
tracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo.
Purification by column chromatography (25% EtOAc in hexanes)
(
13C, 77.0 ppm) as internal standards unless otherwise noted. The
afforded compound 11 (332 mg, 94%) as a white solid: ½a D26:4
ꢄ
31P chemical shifts were reported in ppm relative to 85% H3PO4
(external standard). High resolution mass spectra were obtained
at the University of Iowa Mass Spectrometry Facility. Silica gel
(60 Å, 0.040–0.063 mm) was used for flash chromatography.
+66.8 (c 7.3, CHCl3, 93% ee by HPLC); 1H NMR d 7.82 (d,
J = 1.8 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 6.77 (d, J = 8.4 Hz,
1H), 3.87 (s, 3H), 3.44 (dd, J = 11.3, 4.2 Hz, 1H), 2.82–2.66 (m,
2H), 2.03 (dt, J = 12.4, 3.3 Hz, 1H), 1.92–1.54 (m, 5H), 1.23 (s, 3H),
1.11 (s, 3H), 0.89 (s, 3H); 13C NMR (CDCl3) d 167.1, 157.3, 131.9,
129.2, 121.7, 117.0, 77.9, 76.7, 51.8, 46.7, 38.4, 37.6, 28.2, 27.3,
22.9, 20.0, 14.3; 13C NMR (75.5 MHz, acetone-d6) d 167.4, 158.7,
132.9, 129.9, 123.6, 122.8, 118.0, 78.8, 78.0, 52.2, 48.0, 39.5, 38.9,
29.4, 28.1, 23.9, 20.6, 15.2. Anal. Calcd for C18H24O4: C, 71.03; H,
7.95. Found C, 70.82; H, 8.10.
5.2. Silyl ether 8
To a solution of phenol 7 (1.86 g, 6.4 mmol) in CH2Cl2 (200 mL)
was added imidazole (2.19 g, 32.2 mmol), followed by TBSCl
(1.15 g, 7.7 mmol) in one portion at 0 °C. The solution was allowed
to stir for 12 h, and then the reaction was quenched by addition of
water. The resulting solution was extracted with CH2Cl2, dried
(MgSO4), and concentrated in vacuo. Purification by column chro-
matography (1–5% EtOAc in hexanes) produced ester 8 as an oil
(2.46 g, 95%): 1H NMR d 7.83 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.4,
2.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.34–5.29 (m, 1H), 5.14–5.09
(m, 1H), 3.86 (s, 3H), 3.32 (d, J = 6.8 Hz, 2H), 2.12–2.01 (m, 4H),
1.69 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.02 (s, 9H), 0.26 (s, 6H);
13C NMR d 167.2, 157.8, 136.7, 132.5, 131.4, 129.6, 128.8, 124.3,
122.9, 122.0, 117.9, 51.8, 39.8, 28.5, 26.7, 25.7 (3C), 25.7, 18.3,
17.7, 16.3, ꢂ3.7 (2C). Anal. Calcd for C24H38O3Si: C, 71.59; H,
9.51. Found C, 71.44; H, 9.58.
5.6. Hexahydroxanthene 12
To a solution of ester 11 (108 mg, 0.4 mmol) in THF (20 mL) at
0 °C was added LiAlH4 (74 mg, 2.0 mmol). After 2 h, the reaction
was quenched by addition of H2O, acidified (pH 2), extracted into
ethyl acetate, dried (MgSO4), and concentrated in vacuo to afford
alcohol 12 (98 mg, 100%) as a white solid: 1H NMR d 7.10–7.06
(m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 4.58 (s, 2H), 3.41 (dd, J = 11.5,
4.4 Hz, 1H), 2.72 (br d, 1H), 2.69 (d, J = 3.9 Hz, 1H), 2.00 (dt,
J = 12.3, 3.2 Hz, 1H), 1.88–1.82 (m, 1H), 1.80–1.50 (m, 4H), 1.25
(br s, 1H), 1.21 (s, 3H), 1.09 (s, 3H), 0.88 (s, 3H); 13C NMR d
152.8, 132.3, 129.0, 126.6, 122.0, 117.1, 78.0, 76.5, 65.3, 46.9,
38.4, 37.8, 28.3, 27.4, 23.1, 19.9, 14.3. Anal. Calcd for C17H24O3: C,
69.84; H, 8.27. Found C, 70.16; H, 7.92.
5.3. Epoxide 9
To a solution of ester 8 (879 mg, 2.2 mmol), CH2Cl2 (6 mL),
CH3CN (3 mL), EtOH (3 mL), and aqueous buffer (2 M K2CO3,
4 ꢃ 10ꢂ3 M EDTA, 12 mL), and the Shi catalyst (140 mg, 0.5 mmol)
was added H2O2 (30% wt. in H2O, 1.2 mL, 10.6 mmol) via syringe
pump (0.14 mL/h) at ꢂ10 °C. After 17 h, the reaction was quenched
by addition of Na2SO3. The resulting solution was extracted with
ether, dried (MgSO4), and concentrated in vacuo. Final purification
by column chromatography (2–5% EtOAc in hexanes) provided
recovered ester 8 (318 mg, 36%) and epoxide 9 (459 mg, 50%) as
oils: 1H NMR d 7.81 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.4 Hz,
1H), 6.79 (d, J = 8.2 Hz, 1H), 5.38–5.33 (m, 1H), 3.86 (s, 3H), 3.33
(d, J = 6.9 Hz, 2H), 2.72 (t, J = 6.4 Hz, 1H), 2.28–2.09 (m, 2H),
1.77–1.56 (m, 2H), 1.71 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H), 1.01 (s,
9H), 0.26 (s, 6H); 13C NMR d 167.1, 157.8, 135.8, 132.2, 131.4,
5.7. Aldehyde 13
To a solution of diol 12 (98 mg, 0.35 mmol) in CH2Cl2 (25 mL) at
rt was added MnO2 (812 mg, 8.22 mmol). After 2 h, the reaction
was diluted, filtered through a pad of celite, and the filtrate was
concentrated in vacuo. Final purification by crystalization (hex-
anes) afforded aldehyde 13 (78 mg, 90%) as white needles: 1H
NMR d 9.83 (s, 1H), 7.64–7.61 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H),
3.45 (d, J = 12.0 Hz, 1H), 2.79–2.75 (m, 2H), 2.07–2.02 (m, 1H),
1.92–1.60 (m, 5H), 1.25 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); 13C
NMR d 191.0, 158.9, 132.2, 129.7, 129.2, 122.5, 117.7, 78.0, 77.8,

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7575
46.6, 38.4, 37.6, 28.2, 27.3, 22.9, 20.1, 14.3; HRMS (EI) m/z calcd for
17H22O3 (M+) 274.1570, found 274.1579.
1.22 (s, 3H), 1.08 (s, 3H), 0.89 (s, 3H); 13C NMR d 149.5, 133.2,
129.9, 127.9, 123.7, 111.3, 96.2, 84.0, 77.7, 64.6, 55.7, 47.1, 38.2,
37.4, 27.4, 25.2, 23.4, 20.0, 15.1; HRMS (EI) m/z calcd for
C
5.8. C5-Bromo hexahydroxanthene 14
C
19H27O4Br (M+) 398.1093, found 398.1093.
Method A: To a flask containing unsubstituted hexahydroxanth-
ene 11 (107 mg, 0.4 mmol), glacial acetic acid (1 mL), and CH2Cl2
(35 mL) was added Br2 (0.02 mL, 0.4 mmol) in CH2Cl2 (1 mL) drop-
wise at room temperature. The solution was allowed to stir for
24 h, and then the reaction was quenched by addition of Na2SO3.
Water was added and the product was extracted into CH2Cl2, dried
(MgSO4), and concentrated under reduced pressure. Final purifica-
tion by flash chromatography produced bromide 14 as a white so-
lid (48 mg, 36%): 1H NMR d 8.03 (d, J = 2.1 Hz, 1H), 7.76 (d,
J = 2.2 Hz, 1H), 3.88 (s, 3H), 3.44 (dd, J = 11.4, 4.1 Hz, 1H), 2.78–
2.75 (m, 2H), 2.17–2.10 (m, 1H), 1.94–1.55 (m, 5H), 1.24 (s, 3H),
1.11 (s, 3H), 0.88 (s, 3H); 13C NMR d 166.0, 154.0, 132.5, 130.7,
123.1, 122.4, 111.2, 79.0, 77.7, 52.1, 46.5, 38.4, 37.3, 28.1, 27.3,
5.11. Brominated aldehyde 18
To a flask containing benzyl alcohol 17 (76 mg, 0.2 mmol) in
methylene chloride (52 mL) was added MnO2 (88% precipitated ac-
tive, 315 mg, 3.2 mmol). The mixture was allowed to stir for 3.25 h
and then the reaction was quenched by filtration through celite. Fi-
nal purification by flash chromatography produced aldehyde 18
(61 mg, 81%) as a white solid: ½a D26:4
ꢄ
+75.9 (c 0.61, CHCl3, 96% ee
by HPLC); 1H NMR d 9.71, (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.51 (d,
J = 1.6 Hz, 1H), 4.71 (d, J = 7.1 Hz, 1H), 4.58 (d, J = 7.1 Hz, 1H),
3.34 (s, 3H), 3.22 (dd, J = 11.7, 4.3 Hz, 1H), 2.77–2.65 (m, 2H),
2.07 (dt, J = 12.7, 3.2 Hz, 1H), 2.01–1.45 (m, 4H), 1.20 (s, 3H), 1.03
(s, 3H), 0.84 (s, 3H); 13C NMR d 189.8, 155.5, 132.8, 130.8, 129.7,
123.9, 112.3, 96.2, 83.7, 79.4, 55.7, 46.8, 38.3, 37.2, 27.4, 25.2,
23.3, 20.3, 15.1. Anal. Calcd for C19H25O4Br: C, 57.44; H, 6.34. Found
C, 57.54; H, 6.37.
23.3, 20.2, 14.3; HRMS (EI) m/z calcd for
C
18H23O4Br (M+)
382.0780, found 382.0777. In addition the acetate-protected com-
pound 15 was isolated as a white solid (78 mg, 52%): 1H NMR d
8.04 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 4.66 (dd, J = 11.5,
3.9 Hz, 1H), 3.88 (s, 3H), 2.78–2.75 (m, 2H), 2.18–1.37 (m, 5H),
2.09 (s, 3H), 1.37 (s, 3H), 1.00 (s, 3H), 0.96 (s, 3H); 13C NMR d
170.6, 165.9, 153.9, 132.5, 130.6, 122.8, 122.5, 111.3, 79.0, 78.5,
52.0, 46.6, 37.4, 37.0, 27.2, 24.6, 23.1, 21.2, 20.2, 15.4; HRMS (EI)
m/z calcd for C20H25O5Br (M+) 424.0886, found 424.0889.
Method B: To a flask containing acetate 15 (76 mg, 0.2 mmol),
and CH3OH (10 mL) was added potassium carbonate (137 mg,
1.0 mmol) at room temperature. The solution was allowed to stir
for 6 h, the CH3OH was removed in vacuo and then the reaction
was quenched by addition of NH4Cl. The product was extracted
into CH2Cl2, dried (MgSO4), and concentrated under reduced pres-
sure. Final purification by flash chromatography produced the bro-
mide 14 as a white solid (66 mg, 96%).
5.12. Benzyl alcohol 20
To a solution of ester 19 (254 mg, 0.9 mmol) in THF (3 mL) at
0 °C was added LiAlH4 (35 mg, 0.9 mmol). After 20 min, the reac-
tion was quenched by slow addition of saturated NH4Cl. The result-
ing solution was extracted with ether, dried (MgSO4), and
concentrated in vacuo. Final purification by column chromatogra-
phy afforded alcohol 20 (208 mg, 90%) as a colorless oil: 1H NMR
d 7.26–7.23 (m, 1H), 6.97 (dd, JHF = 11.3 Hz, J = 2.0 Hz, 1H), 5.09
(s, 2H), 4.50 (s, 2H), 3.56 (s, 3H), 2.68 (br s, 1H); 13C NMR d 156.0
(d, JCF = 254 Hz), 141.1 (d, JCF = 14.0 Hz), 138.7 (d, JCF = 7.0 Hz),
126.5 (d, JCF = 2.3 Hz), 117.8 (d, JCF = 3.4 Hz), 114.3 (d, JCF = 21.2 Hz),
98.9 (d, JCF = 5.6 Hz), 63.5, 57.8; 19F NMR (280 MHz, CDCl3) d
ꢂ125.8. Anal. Calcd for C9H10O3BrF: C, 40.93; H, 3.82. Found C,
41.17; H, 3.85.
5.9. MOM-protected bromide 16
To a flask containing alcohol 14 (174 mg, 0.5 mmol), and CH2Cl2
(10 mL) was added DIPEA (0.5 mL, 2.9 mmol) followed by MOMCl
(0.08 mL, 1.1 mmol) at room temperature. The solution was al-
lowed to stir for 24 h, and then the reaction was quenched by addi-
tion of water. The product was extracted into CH2Cl2, dried
(MgSO4), and concentrated under reduced pressure. Final purifica-
tion by flash chromatography produced 16 as a yellow oil (185 mg,
82%): 1H NMR d 8.03 (d, J = 1.8 Hz, 1H), 7.76–7.75 (m, 1H), 4.78 (d,
J = 6.9 Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 3.88 (s, 3H), 3.41 (s, 3H), 3.28
(dd, J = 11.7, 4.1 Hz, 1H), 2.80–2.68 (m, 2H), 2.12 (dt, J = 12.8,
3.3 Hz, 1H), 2.05–1.97 (m, 1H), 1.85–1.51 (m, 3H), 1.25 (s, 3H),
1.09 (s, 3H), 0.90 (s, 3H); 13C NMR d 166.0, 154.0, 132.5, 130.7,
123.2, 122.4, 111.2, 96.2, 83.7, 78.9, 55.7, 52.0, 46.8, 38.2, 37.3,
27.4, 25.2, 23.3, 20.2, 15.1; HRMS (EI) m/z calcd for C20H27O5Br
(M+) 426.1042, found 426.1051.
5.13. Benzyl ether 21
To a solution of benzyl alcohol 20 (198 mg, 0.7 mmol) in THF
(5 mL) at 0 °C was added NaH (60% wt. in mineral oil, 35 mg,
0.9 mmol) followed by iodomethane (0.06 mL, 1.0 mmol). After
10 h, the reaction was quenched by addition of water, the resulting
solution was extracted with ether, dried (MgSO4), and concen-
trated in vacuo. Final purification by column chromatography (8%
EtOAc in hexanes) afforded ether 21 (158 mg, 76%) as an oil: 1H
NMR d 7.25–7.24 (m, 1H), 6.98 (dd, JHF = 11.1 Hz, J = 2.0 Hz, 1H),
5.11 (s, 2H), 4.29 (s, 2H), 3.56 (s, 3H), 3.31 (s, 3H); 13C NMR d
155.9 (d, JCF = 250 Hz), 141.4 (d, JCF = 13.4 Hz), 136.1 (d,
JCF = 6.7 Hz), 127.3 (d, JCF = 3.5 Hz), 117.8 (d, JCF = 3.5 Hz), 115.1
(d, JCF = 20.9 Hz), 99.0 (d, JCF = 6.1 Hz), 72.9 (d, JCF = 1.8 Hz), 58.3,
57.8 (d, JCF = 1.7 Hz); 19F NMR (280 MHz, CDCl3) d ꢂ126.1. Anal.
Calcd for C10H12BrF O3: C, 43.03; H, 4.33. Found C, 42.87; H, 4.33.
5.10. Benzyl alcohol 17
5.14. Geranylated arene 22
To a flask containing ester 16 (185 mg, 0.4 mmol) and THF
(10 mL) was added DIBAL-H (2.2 mL, 5.2 mmol) at 0 °C. The solu-
tion was allowed to stir for 3 h, and then the reaction was
quenched by addition of saturated NH4Cl. The product was ex-
tracted into ether, dried (MgSO4), and concentrated under reduced
pressure. Final purification by flash chromatography produced
alcohol 17 (158 mg, 92%): 1H NMR d 7.36 (d, J = 1.8 Hz, 1H), 7.04
(d, J = 1.8 Hz, 1H), 4.77 (d, J = 7.1 Hz, 1H), 4.65 (d, J = 6.6 Hz, 1H),
4.56 (s, 2H), 3.41 (s, 3H), 3.28 (dd, J = 11.4, 4.2 Hz, 1H), 2.72 (d,
J = 9.5 Hz, 2H), 2.09 (dt, J = 12.6, 3.0 Hz, 1H), 1.95–1.43 (m, 5H),
To a solution of ether 21 (153 mg, 0.6 mmol) in THF (10 mL) at
ꢂ78 °C was added n-BuLi (0.27 mL, 0.6 mmol). After 10 min,
CuBrꢀDMS (136 mg, 0.7 mmol) was added. After an additional
30 min, geranyl bromide (0.11 mL, 0.6 mmol) was added and after
an additional 1 h, the reaction was quenched by addition of water.
The resulting solution was extracted with ether, dried (MgSO4),
and concentrated in vacuo. Final purification by column chroma-
tography afforded arene 22 (31 mg, 17%) as an oil: 1H NMR d
6.94–6.79 (m, 2H), 5.21 (t, J = 7.2 Hz, 1H), 5.04 (s, 2H), 5.04–5.00

7576
J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
(m, 1H), 4.28 (s, 2H), 3.51 (s, 3H), 3.34–3.27 (m, 2H), 3.30 (s, 3H),
2.09–1.84 (m, 4H), 1.63 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H); 13C
NMR d 155.3 (d, JCF = 247 Hz), 141.7 (d, JCF = 10.8 Hz), 136.8,
136.7, 134.4 (d, JCF = 6.9 Hz), 131.5, 124.2, 124.0 (d, JCF = 2.9 Hz),
122.0, 113.6 (d, JCF = 20.6 Hz), 99.1 (d, JCF = 6.0 Hz), 73.9 (d,
JCF = 1.1 Hz), 58.2, 57.4 (d, JCF = 1.0 Hz), 39.7, 28.3 (d, JCF = 2.5 Hz),
27.6, 25.7, 17.7, 16.2; 19F NMR (280 MHz, CDCl3): d ꢂ130.6; HRMS
(EI) m/z calcd for C20H29O3F (M+) 336.2102, found 336.2106.
5.18. Ether 27
To a solution of alcohol 2629 (2.66 g, 15.8 mmol) in THF (50 mL)
at 0 °C was added NaH (750 mg, 18.8 mmol, 60% dispersion oil).
After 30 min, MeI (1.09 mL, 17.5 mmol) was added dropwise and
the reaction mixture was allowed to stir overnight. The reaction
was quenched by the addition of NH4Cl (sat), and extracted with
EtOAc. The combined organic extracts were washed with brine,
dried (MgSO4), filtered, and concentrated in vacuo. Final purifica-
tion by flash column (15–40% ethyl acetate in hexanes) afforded
arene 27 (2.34 g, 81%) as a colorless oil: 1H NMR d 7.25 (d,
J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.38 (s, 2H),
3.46 (s, 3H), 3.35 (s, 3H); 13C NMR d 156.7, 131.5, 129.1 (2C),
116.0 (2C), 94.3, 74.1, 57.7, 55.8; HRMS (ESI+) calcd for C10H14O3
(M+) 182.0943, found 182.0949.
5.15. (R)-Epoxide 23
To a solution of benzyl ether 22 (30 mg, 0.1 mmol) in CH2Cl2
(1 mL), CH3CN (0.5 mL), EtOH (0.5 mL), aqueous buffer (2 M
K2CO3, 4 ꢃ 10ꢂ3
M EDTA, 2 mL), and Shi catalyst (24 mg,
0.1 mmol) at 0 °C, H2O2 (30% wt. in H2O, 0.05 mL, 0.44 mmol)
was added over 2 h. After an additional 45 min the reaction was
quenched by addition of Na2SO3. The resulting solution was ex-
tracted with CH2Cl2, dried (MgSO4), and concentrated in vacuo.
Final purification by column chromatography afforded epoxide
23 (17 mg, 54%) as an oil: 1H NMR d 6.91–6.82 (m, 2H), 5.26 (t,
J = 7.1 Hz, 1H), 5.04 (s, 2H), 4.23 (s, 2H), 3.51 (s, 3H), 3.34 (d,
J = 7.1 Hz, 2H), 3.30 (s, 3H), 2.64 (t, J = 6.3 Hz, 1H), 2.29–1.86 (m,
4H), 1.66 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H); 13C NMR d 155.3 (d,
JCF = 246 Hz), 141.7 (d, JCF = 12.4 Hz), 136.5 (d, JCF = 1.8 Hz),
135.8, 134.5 (d, JCF = 7.4 Hz), 124.0 (d, JCF = 2.8 Hz), 122.6, 113.6
(d, JCF = 20.4 Hz), 99.1 (d, JCF = 6.5 Hz), 73.9 (d, JCF = 1.9 Hz), 64.1,
58.4, 58.2, 57.5, 36.4, 28.4, 27.4, 24.9, 18.8, 16.2; 19F NMR
(280 MHz, CDCl3) d ꢂ130.6; HRMS (EI) m/z calcd for C20H29O3F
(M+) 352.2051, found 352.2048.
5.19. Thiol Ether 28
To a solution of arene 27 (2.34 g, 12.8 mmol) in THF (60 mL) at
0 °C was added n-BuLi (6.0 mL, 2.2 M in hexanes) and after 5 min
dimethyldisulfide (1.23 mL, 14 mmol) was added dropwise. After
5 h the reaction mixture was quenched by addition of NH4Cl
(sat), extracted with EtOAc, washed with brine, dried (MgSO4),
and filtered, and the filtrate was concentrated in vacuo. Final puri-
fication by flash column chromatography (13% EtOAc in hexanes)
afforded 28 (1.29 g, 44%) as an oil: 1H NMR d 7.13 (s, 1H), 7.04
(m, 2H), 5.22 (s, 2H), 4.38 (s, 2H), 3.49 (s, 3H), 3.36 (s, 3H), 2.43
(s, 3H); 13C NMR d 153.2, 132.2, 128.2, 125.2, 125.2, 113.9, 94.7,
74.1, 57.5, 56.0, 14.4; HRMS (EI+) m/z calcd for C11H16O3S (M+)
228.0820, found 228.0822.
5.16. 5-Fluoro-hexahydroxanthene 24
5.20. Epoxide 29
To a solution of epoxide 23 (16 mg, 0.05 mmol) in CH2Cl2 (6 mL)
at ꢂ78 °C was added BF3ꢀOEt2 (0.03 mL, 0.2 mmol). After 6 min, the
reaction was quenched by addition of TEA. Water was added and
the product was extracted into CH2Cl2, dried (MgSO4), and concen-
trated in vacuo. Final purification by column chromatography (20%
EtOAc in hexanes) produced hexahydroxanthene 24 (8 mg, 57%) as
a white solid: 1H NMR (400 MHz, CDCl3) d 6.91–6.85 (m, 2H), 4.33
(s, 2H), 3.44 (dd, J = 11.3, 6.9 Hz, 1H), 3.38 (s, 3H), 2.79–2.66 (m,
2H), 2.12–1.58 (m, 5H), 1.25 (s, 3H), 1.11 (s, 3H), 0.88 (s, 3H); 13C
To a solution of arene 28 (829 mg, 3.63 mmol), in THF (15 mL)
at to 0 °C was added n-BuLi (1.6 mL, 3.68 mmol). After 1 h, the
solution was cooled to ꢂ20 °C and CuBrꢀDMS (784 mg, 3.81 mmol)
was added. After an additional 1 h, epoxygeranyl bromide22
(887 mg, 3.93 mmol) was added dropwise as a THF solution
(2 mL). After 2 h, the reaction mixture was quenched by addition
of NH4Cl (sat), diluted with water and extracted with EtOAc. The
combined organic extracts were washed with water, brine, dried
(MgSO4), filtered, and then concentrated in vacuo. Final purifica-
tion by column chromatography (15% EtOAc in hexanes) afforded
epoxide 29 (522 mg, 38%) as a light yellow oil: 1H NMR d 6.99 (d,
J = 2.0 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 5.36 (m, 1H), 5.03 (s, 2H),
4.37 (s, 2H), 3.63 (s, 3H), 3.43 (d, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.71
(t, J = 6.2 Hz, 1H), 2.43 (s, 3H), 2.04 (m, 2H), 1.73 (s, 3H), 1.69–
1.62 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H); 13C NMR d 151.6, 135.4,
134.8, 134.8, 132.6, 125.9, 123.1, 123.0, 99.2, 74.3, 64.0, 58.2,
58.0, 57.6, 36.3, 28.4, 27.3, 24.7, 18.6, 16.1, 14.8; HRMS (EI) m/z
calcd for C21H32O4S (M+) 380.2120, found 380.2127.
NMR (100 MHz, CDCl3)
d 151.8 (d, JCF = 246 Hz), 141.0 (d,
JCF = 11.3 Hz), 129.4 (d, JCF = 5.6 Hz), 124.4 (d, JCF = 2.8 Hz), 124.0
(d, JCF = 2.8 Hz), 113.4 (d, JCF = 18.3 Hz), 77.9, 74.1 (d, JCF = 1.5 Hz),
58.1, 46.7, 38.4, 37.5, 28.3, 27.3, 23.0, 22.9, 19.8, 14.3; 19F NMR
(CDCl3)
308.1789, found 308.1782.
d
ꢂ136.9; HRMS (EI) m/z calcd for C18H25O3F (M+)
5.17. 5-Fluorinated aldehyde 25
To a solution of methyl ether 24 (7 mg, 0.02 mmol) in CH2Cl2
(1.0 mL) and water (0.1 mL) at rt was added DDQ (12 mg,
0.05 mmol). After 4 h, the reaction was quenched by addition of
saturated NaHCO3. The resulting solution was extracted with
CH2Cl2, dried (MgSO4), and concentrated in vacuo. Final purifica-
tion by radial chromatography (40% EtOAc in hexanes) produced
aldehyde 25 (6 mg, 90%) as a film: 1H NMR (400 MHz, CDCl3) d
9.81 (d, JHF = 1.9 Hz, 1H), 7.45–7.42 (m, 2H), 3.47 (dd, J = 11.7,
4.0 Hz, 1H), 2.88–2.75 (m, 2H), 2.17–1.58 (m, 5H), 1.30 (s, 3H),
1.14 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d 189.9 (d,
JCF = 2.0 Hz), 152.0 (d, JCF = 249 Hz), 147.3 (d, JCF = 11.0 Hz), 128.4
(d, JCF = 5.2 Hz), 127.8 (d, JCF = 2.6 Hz), 124.6 (d, JCF = 2.6 Hz),
113.7 (d, JCF = 19.5 Hz), 78.8, 77.5, 46.3, 38.3, 37.1, 28.0, 27.1,
22.7, 19.9, 14.1; 19F NMR (CDCl3) d ꢂ134.7. HRMS (EI) m/z calcd
for C17H21O3F (M+) 292.1477, found 292.1478.
5.21. Hexahydroxanthene 30
To a solution of epoxide 29 (207 mg, 0.54 mmol) in CH2Cl2
(136 mL) at ꢂ78 °C was added BF3ꢀOEt2 (0.40 mL, 3.3 mmol). After
10 min, the reaction was quenched by addition of TEA (0.3 mL), al-
lowed to warm to room temperature, and the solvent was removed
in vacuo. Final purification by flash column chromatography (25–
30% EtOAc in hexanes) gave hexahydroxanthene 30 (93 mg, 51%)
as an oil: 1H NMR d 6.93 (d, J = 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz,
1H), 4.34 (s, 2H), 3.40–3.35 (m, 1H), 3.74 (s, 3H), 2.71–2.68 (m,
2H), 2.40 (s, 3H), 2.09–2.04 (m, 1H), 1.87–1.77 (m, 2H), 1.71–1.57
(m, 3H), 1.21 (s, 3H), 1.07 (s, 3H), 0.86 (s, 3H); 13C NMR d 149.6,
129.6, 126.3, 126.2, 123.6, 121.2, 77.9, 77.2, 74.6, 57.9, 46.8, 38.3,

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7577
37.5, 28.2, 27.2, 23.1, 19.9, 14.6, 14.2; HRMS (EI) m/z calcd for
19H28O3S (M+) 336.1759, found 336. 1750.
tracted into CH2Cl2, dried (MgSO4), and concentrated under re-
duced pressure. Final purification by flash chromatography
produced the silyl ether 36 as an oil (2.40 g, 84%): 1H NMR NMR
d 6.62–6.57 (m, 2H), 6.49–6.48 (m, 1H), 5.15 (s, 2H), 4.68 (s, 2H),
3.78 (s, 3H), 3.47 (s, 3H), 0.94 (s, 9H), 0.10 (s, 6H); 13C NMR d
160.9, 158.5, 144.4, 106.2, 105.2, 101.2, 94.7, 65.0, 56.2, 55.5,
26.2 (3C), 18.6, -5.0 (2C); HRMS (EI) m/z calcd for C16H28O4Si
(M+) 312.1757, found 312.1753.
C
5.22. Aldehyde 31
To a solution of methyl ether 30 (84 mg, 0.25 mmol) in a 9:1
mixture of CH2Cl2 and H2O (10 mL) at rt was added DDQ (79 mg,
0.35 mmol). After 20 min, the reaction was quenched by the addi-
tion of NaHCO3 (sat.), diluted with water and extracted with
CH2Cl2. The combined organic layers were washed with brine,
dried (MgSO4), filtered, and concentrated in vacuo to afford alde-
hyde 31 (61 mg, 76%) as a white solid: 1H NMR d 9.82 (s, 1H),
7.48 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 1.1 Hz, 1H), 3.45 (dd, J = 11.2,
3.6 Hz, 1H), 2.80–2.76 (m, 2H), 2.45 (s, 3H), 2.16–2.10 (m, 1H),
1.94–1.81 (m, 2H), 1.76–1.56 (m, 3H), 1.27 (s, 3H), 1.12 (s, 3H),
0.90 (s, 3H); 13C NMR d 190.9, 155.2, 130.0, 129.5, 128.9, 123.6,
121.5, 79.1, 77.9, 46.7, 38.5, 37.5, 28.3, 27.4, 23.1, 20.4, 14.4,
14.4; HRMS (EI) m/z calcd for C18H24O3S (M+) 320.1446, found
320.1447.
5.26. Geranylated benzyl alcohol 38
To a flamed dried Schlenk flask under argon, ether (30 mL) was
added via syringe followed by TMEDA (3.8 mL, 25 mmol) and n-
BuLi (12 mL, 29 mmol, 2.4 M solution in hexanes) and this solution
was cooled to 0 °C. Compound 35 (2.97 g, 12.6 mmol) was dis-
solved in ether (20 mL) and transferred via cannula to the reaction
vessel, which gave a white precipitate. After 20 min, solid CuI
(2.64 g, 13.8 mmol) was added in one portion leading to an imme-
diate color change to black. The resulting mixture was allowed to
stir for 20 min and then geranyl bromide (3.3 mL, 16.3 mmol)
was added dropwise over a 10 min period. The reaction mixture
was allowed to stir for 4 h, and then was quenched by addition
of water. The product was extracted into diethyl ether, dried
(MgSO4), and concentrated under reduced pressure. Final purifica-
tion by column chromatography (30% EtOAc in hexanes) produced
alcohol 38 (1.98 g, 47%) as an oil: 1H NMR d 6.72 (s, 1H), 6.61 (s,
1H), 5.20–5.06 (m, 1H), 5.18 (s, 2H), 5.06–5.04 (m, 1H), 4.63 (s,
2H), 3.82 (s, 3H), 3.46 (s, 3H), 3.36 (d, J = 6.9 Hz, 2H), 2.05–2.00
(m, 2H), 1.96–1.91 (m, 2H), 1.77 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H);
13C NMR d 158.3, 155.6, 139.9, 134.6, 131.1, 124.4, 122.6, 118.6,
105.6, 103.3, 94.4, 65.6, 55.9, 55.7, 39.8, 26.7, 25.6, 22.3, 17.6,
16.0; HRMS (EI) m/z calcd for C20H30O4 (M+) 334.2144, found
334.2141.
5.23. Aldehyde 33
To a solution of methyl ether 325 (350 mg, 1.1 mmol), in CH2Cl2/
water (10:1) at rt was added DDQ (320 mg, 1.4 mmol). After
15 min, the reaction was quenched by addition of brine and NaH-
CO3. The resulting solution was extracted with CH2Cl2, and the
combined organic extracts were washed with a small amount of
water followed by brine. After the organic phase was dried
(MgSO4) and concentrated in vacuo, aldehyde 33 was obtained as
a faintly yellow wax that was used without further purification:
1H NMR d 9.76 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 2.0 Hz,
1H), 5.26 (s, 1H), 4.64 (d, J = 13.2 Hz, 1H), 4.60 (d, J = 13.6 Hz,
1H), 3.38 (dd, J = 11.4, 4.2 Hz, 1H), 2.79–2.67 (m, 2H), 2.34 (br,
1H), 2.04–1.99 (m, 1H), 1.87–1.57 (m, 4H), 1.20 (s, 3H), 1.07 (s,
3H), 0.85 (s, 3H); 13C NMR d 191.2, 156.2, 131.3, 129.6, 128.6,
127.7, 122.2, 78.4, 77.5, 60.7, 46.4, 38.3, 37.5, 27.9, 27.1, 22.7,
20.2, 14.2; HRMS (EI) m/z calcd for C18H24O4 (M+) 304.1675, found
304.1668.
5.27. Phosphonate 39
To a solution of alcohol 38 (1.00 g, 3.0 mmol) in CH2Cl2
(200 mL) at 0 °C was added TEA (1.70 mL, 12.2 mmol), followed
by MsCl (0.93 mL, 12.0 mmol). After 20 h, the reaction was
quenched by addition of saturated NH4Cl. The resulting solution
was extracted with CH2Cl2, dried (MgSO4), and concentrated in va-
cuo to yield the intermediate mesylate as an oil which was used
without further purification.
To a solution of the crude intermediate mesylate in acetone
(11 mL) in a foil-wrapped flask at rt was added sodium iodide
(1.81 g, 12.1 mmol). After 30 min, the reaction was concentrated
in vacuo. The residue was diluted with water and the resulting
solution was extracted with ether, dried (MgSO4), and concen-
trated in vacuo to yield the intermediate iodide as a yellow oil,
which was used without further purification.
To a flask containing the intermediate iodide, triethylphosphite
(1.1 mL, 12.1 mmol) was added at rt. The solution was heated to
62 °C, and after 16 h the reaction was quenched by addition of
water. The resulting solution was extracted with ethyl acetate,
dried (MgSO4), and concentrated in vacuo. Final purification by col-
umn chromatography afforded phosphonate 39 (1.36 g, 100% for 3
steps) as a colorless oil: 1H NMR d 6.65–6.64 (m, 1H), 6.55–6.54 (m,
1H), 5.19–5.14 (m, 1H), 5.16 (s, 2H), 5.09–5.04 (m, 1H), 4.08–4.00
(m, 4H), 3.81 (s, 3H), 3.45 (s, 3H), 3.33 (d, J = 7.1 Hz, 2H), 3.10 (d,
JHP = 21.5 Hz, 2H), 2.07–1.91 (m, 4H), 1.75 (s, 3H), 1.65 (s, 3H),
1.57 (s, 3H), 1.26 (t, J = 7.0 Hz, 6H); 13C NMR d 158.0, 155.5,
134.6, 131.2, 130.0, 124.5, 122.7, 118.0 (d, JCP = 3.9 Hz), 108.7 (d,
JCP = 6.6 Hz), 106.4 (d, JCP = 6.1 Hz), 94.4, 62.1 (d, JCP = 7.4 Hz, 2C),
55.9, 55.8, 39.8, 34.0 (d, JCP = 138.2 Hz), 26.7, 25.7, 22.2, 17.7,
16.4 (d, JCP = 6.1 Hz, 2C), 16.0; 31P NMR d 27.1; HRMS (EI) m/z calcd
for C24H39O6P (M+) 454.2486, found 454.2471.
5.24. Silyl Ether 34
To a solution of alcohol 33, in CH2Cl2 at rt was added TBSCl
(485 mg, 3.2 mmol) followed by imidazole (394 mg, 5.8 mmol).
After 45 min, the reaction was quenched by addition of water.
The resulting solution was extracted with CH2Cl2, and the com-
bined organic extracts were washed with a small amount of water
followed by brine. After which the organic phase was dried
(MgSO4) and concentrated in vacuo. Final purification by column
chromatography (30% EtOAc in hexanes) afforded aldehyde 34
(321 mg, 70% over 2-steps) as a colorless oil: 1H NMR (CDCl3) d
9.82 (s, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 4.70
(d, J = 14.4 Hz, 1H), 4.62 (d, J = 14.1 Hz, 1H), 3.40 (dd, J = 11.4,
3.9 Hz, 1H), 2.77–2.72 (m, 2H), 2.07–2.00 (m, 1H), 1.89–1.62 (m,
4H), 1.20 (s, 3H), 1.09 (s, 3H), 0.94 (s, 9H), 0.87 (s, 3H), -0.11 (s,
6H); 13C NMR d 191.5, 155.3, 130.1, 130.0, 128.6, 127.4, 121.6,
77.9, 77.6, 59.7, 46.4, 38.3, 37.5, 28.0, 27.1, 25.9 (3C), 22.8, 20.2,
18.4, 14.2, ꢂ5.4 (2C); HRMS (EI) m/z calcd for C24H38O4Si (M+ꢂtBu)
362.1869, found 362.1861.
5.25. Silyl ether 36
To a flask containing benzyl alcohol 35 (1.81 g, 9.2 mmol) and
CH2Cl2 (150 mL) was added imidazole (3.19 g, 46.9 mmol), fol-
lowed by TBSCl (1.61 g, 10.7 mmol) at room temperature. The solu-
tion was allowed to stir for 9 h, and then the reaction was
quenched by addition of saturated NH4Cl. The product was ex-

7578
J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
5.28. Stilbene 43
138.2, 136.5, 131.7, 130.1, 128.7, 127.1, 126.8, 126.6, 123.7,
123.3, 121.5, 114.6, 111.6, 106.9, 101.2, 77.8, 77.7, 55.6, 46.6,
39.5, 38.2, 37.3, 28.1, 27.1, 26.2, 25.5, 23.2, 22.1, 19.9, 17.5, 16.0,
14.0; HRMS (EI) m/z calcd for C35H45O4Br (M+) 608.2503, found
608.2498.
Under the general conditions for HWE condensations (vide in-
fra), the reaction of aldehyde 13 (36 mg, 0.1 mmol), phosphonate
39 (31 mg, 0.1 mmol), and NaH (60% wt. in mineral oil, 34 mg,
0.9 mmol) provided stilbene 43 as a white solid (49 mg, 66%): 1H
NMR (400 MHz, CDCl3) d 7.26–7.25 (m, 1H), 6.99–6.86 (m, 4H),
6.74 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 5.22 (s, 2H), 5.20–5.18 (m,
1H), 5.07 (t, J = 6.7 Hz, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 3.43 (dd,
J = 11.8, 4.6 Hz, 1H), 3.37 (d, J = 7.0 Hz, 2H), 2.76–2.66 (m, 2H),
2.07–1.48 (m, 9H), 1.78 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.23 (s,
3H), 1.11 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.1,
155.6, 152.7, 136.5, 134.4, 131.0, 129.2, 127.7, 127.2, 126.3,
125.4, 124.3, 122.5, 121.8, 118.6, 117.1, 105.2, 102.4, 94.4, 77.9,
76.5, 55.8, 55.6, 46.7, 39.7, 38.2, 37.6, 28.1, 27.2, 26.6, 25.5, 22.9,
22.3, 19.8, 17.5, 15.9, 14.1; HRMS (EI) m/z calcd for C37H50O5
(M+) 574.3660, found 574.3651.
5.32. 5-Fluoro stilbene 45
Under the general conditions for HWE reactions, aldehyde 25
(6 mg, 0.02 mmol), phosphonate 39 (10 mg, 0.02 mmol), and
NaH (60% wt. in mineral oil, 5 mg, 0.1 mmol), and purification
by column chromatography (25% EtOAc in hexanes) provided stil-
bene 45 as a white solid (6 mg, 53%): 1H NMR (400 MHz, CDCl3) d
7.11–6.70 (m, 6H), 5.23 (s, 2H), 5.23–5.19 (m, 1H), 5.08 (t,
J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.51 (s, 3H), 3.46 (dd, J = 11.1,
3.6 Hz, 1H), 3.38 (d, J = 6.9 Hz, 2H), 2.81–2.68 (m, 2H), 2.13–1.60
(m, 9H), 1.78 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H), 1.28 (s, 3H),
1.13 (s, 3H), 0.91 (s, 3H); 13C NMR (CDCl3) d 158.1, 155.7, 151.9
(d, JCF = 244 Hz), 140.9 (d, JCF = 10.3 Hz), 136.0, 134.5, 131.0,
129.0 (d, JCF = 8.3 Hz), 127.5, 126.8 (d, JCF = 2.3 Hz), 125.3, 124.3,
122.8 (d, JCF = 2.3 Hz), 122.4, 119.0, 111.0 (d, JCF = 19.0 Hz),
105.3, 102.6, 94.3, 77.7, 77.3, 55.8, 55.6, 46.6, 39.6, 38.2, 37.3,
28.1, 27.1, 26.6, 25.5, 22.8, 22.3, 19.7, 17.5, 15.9, 14.1; 19F NMR
5.29. Schweinfurthin analogue 51
Under general conditions for the removal of MOM-ethers from
protected stilbenes (vide infra), stilbene 53 (33 mg, 0.1 mmol)
was treated with methanol (0.3 mL) and p-TsOHꢀH2O (56 mg,
0.3 mmol) for 2.5 h to provide analogue 51 as
a
clear oil
(CDCl3)
592.3566, found 592.3574.
d
ꢂ136.8; HRMS (EI) m/z calcd for C37H49O5F (M+)
(16 mg, 53%): 1H NMR (400 MHz, CDCl3) d 7.25–6.61 (m, 7H),
5.33 (br s, 1H), 5.25 (t, J = 7.0 Hz, 1H), 5.07 (t, J = 6.7 Hz, 1H),
3.87 (s, 3H), 3.47–3.42 (m, 3H), 2.80–2.68 (m, 2H), 2.18–1.55
(m, 10H), 1.82 (s, 3H), 1.69 (s, 3H), 1.60 (s, 3H), 1.24 (s, 3H),
1.13 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) d 157.8,
155.5, 152.8, 138.1, 136.9, 131.7, 129.1, 128.0, 127.7, 126.0,
125.4, 123.7, 121.8, 121.6, 117.1, 114.3, 106.7, 101.1, 77.9, 77.0,
55.6, 46.7, 39.5, 38.2, 37.6, 28.1, 27.2, 26.3, 25.5, 22.9, 22.1,
19.8, 17.5, 16.0, 14.1; HRMS (EI) m/z calcd for C35H46O4 (M+)
530.3398, found 530.3399.
5.33. 5-Fluoro schweinfurthin analogue 53
Under the general conditions for MOM hydrolysis, stilbene 45
(6 mg, 0.01 mmol), methanol (0.6 mL), and p-TsOHꢀH2O (12 mg,
0.1 mmol) were allowed to react for 24 h. Final purification by
column chromatography provided analogue 53 as a white solid
(4 mg, 72%): 1H NMR (400 MHz, CDCl3) d 7.09 (dd, J = 12.1,
1.7 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 16.3 Hz, 1H), 6.84 (d,
J = 16.3 Hz, 1H), 6.64 (d, J = 1.3 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H),
5.34 (br s, 1H), 5.27–5.23 (m, 1H), 5.09–5.05 (m, 1H), 3.87 (s,
3H), 3.48–3.42 (m, 3H), 2.82–1.84 (m, 11H), 1.82 (s, 3H), 1.69
(s, 3H), 1.60 (s, 3H), 1.27 (s, 3H), 1.13 (s, 3H), 0.90 (s, 3H); 13C
NMR (CDCl3) d 157.8, 155.6, 151.9 (d, JCF = 243 Hz), 141.0 (d,
JCF = 11.3 Hz), 138.2, 136.5, 131.7, 129.0 (d, JCF = 7.5 Hz), 127.1,
127.1 (d, JCF = 2.3 Hz), 124.3 (d, JCF = 1.6 Hz), 123.7, 122.9 (d,
JCF = 2.1 Hz), 121.5, 114.6, 111.0 (d, JCF = 19.2 Hz), 106.8, 101.2,
77.7, 77.3, 55.6, 46.6, 39.5, 38.2, 37.3, 28.1, 27.1, 26.3, 25.5,
22.8, 22.1, 19.7, 17.5, 15.9, 14.1; 19F NMR (CDCl3) d ꢂ136.8;
5.30. C-5 Bromostilbene 44
Under the general conditions for HWE condensations, the reac-
tion of aldehyde 18 (60 mg, 0.2 mmol), phosphonate 39 (72 mg,
0.2 mmol), and NaH (60% wt. in mineral oil, 33 mg, 0.8 mmol)
provided stilbene 44 as a white solid (57 mg, 54%): ½a D26:4
ꢄ
+64.2
(c 0.25, CHCl3, 96% ee by HPLC); 1H NMR d 7.46 (d, J = 1.9 Hz,
1H), 7.10 (d, J = 1.6 Hz, 1H), 6.82–6.79 (m, 3H), 6.62 (s, 1H),
5.15 (s, 2H), 5.12 (t, J = 7.0 Hz, 1H), 5.00 (t, J = 6.4 Hz, 1H), 4.71
(d, J = 6.9 Hz, 1H), 4.58 (d, J = 7.0 Hz, 1H), 3.79 (s, 3H), 3.42 (s,
3H), 3.35 (s, 3H), 3.30 (d, J = 7.0 Hz, 1H), 3.22 (dd, J = 11.6,
4.1 Hz, 1H), 2.81 (d, J = 9.5 Hz, 2H), 2.06–1.36 (m, 9H), 1.70 (s,
3H), 1.57 (s, 3H), 1.50 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H), 0.83 (s,
3H); 13C NMR d 158.2, 155.8, 149.5, 136.2, 134.7, 131.2, 130.3,
128.8, 127.6, 127.0, 126.5, 124.5, 123.6, 122.6, 119.1, 111.7,
105.4, 102.7, 96.2, 94.5, 83.9, 77.9, 56.0, 55.7, 55.7, 47.1, 38.8,
38.2, 37.3, 27.4, 26.7, 25.7, 25.2, 23.4, 22.5, 20.1, 17.6, 16.1,
15.1; HRMS (EI) m/z calcd for C39H53O6Br (M+) 696.3027, found
696.3098.
HRMS (EI) m/z calcd for
C
35H45O4F (M+) 548.3304, found
548.3299.
5.34. Stilbene 46
Under the general conditions for HWE condensations, aldehyde
31 (23 mg, 0.07 mmol), phosphonate 39 (40 mg, 0.09 mmol), THF
(0.7 mL), and NaH (50 mg, 1.25 mmol, 60% dispersion oil) were al-
lowed to react for 18 h. Final purification by flash column chroma-
tography (25% EtOAc in hexanes) afforded stilbene 46 (33 mg, 74%)
as a colorless oil; 1H NMR d 7.11 (d, J = 1.7 Hz, 1H), 7.07 (d,
J = 1.6 Hz, 1H), 6.96 (d, J = 16.3 Hz, 1H), 6.92–6.88 (m, 2H), 6.71
(s, 1H), 5.23 (s, 2H), 5.23–5.18 (m, 1H), 5.09–5.05 (m, 1H), 3.87
(s, 3H), 3.50 (s, 3H), 3.43 (dd, J = 11.5, 3.8 Hz, 1H), 3.37 (d,
J = 7.0 Hz, 2H), 2.74–2.70 (m, 2H), 2.45 (s, 3H), 2.11–1.57 (m,
10H), 1.78 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H), 1.24 (s, 3H), 1.10 (s,
3H), 0.88 (s, 3H); 13C NMR d 158.3, 155.8, 149.8, 136.5, 134.6,
131.1, 129.5, 127.7, 126.8, 126.6, 124.7, 124.4, 122.6, 122.0,
121.4, 118.9, 105.4, 102.6, 94.5, 77.8, 77.5, 55.9, 55.7, 46.8, 39.8,
38.4, 37.5, 28.2, 27.3, 26.7, 25.6, 23.1, 22.4, 20.0, 17.6, 16.0, 14.8,
14.2 HRMS (EI) m/z calcd for C38H52O5S (M+) 620.3535, found
620.3536.
5.31. 5-Bromoschweinfurthin analogue 52
Under the general conditions for removal of MOM-acetals, the
reaction of stilbene 44 (10 mg, 0.01 mmol), methanol (1.5 mL),
and p-TsOHꢀH2O (11 mg, 0.06 mmol) for 96 h provided analogue
52 as a white solid (8 mg, 92%): ½a D26:4
ꢄ
+29.2 (c 0.27, CHCl3, 96%
ee by HPLC); 1H NMR (400 MHz, CDCl3) d 7.53–6.60 (m, 6H), 5.33
(br s, 1H), 5.25 (t, J = 6.6 Hz, 1H), 5.07 (t, J = 6.6 Hz, 1H), 3.87 (s,
3H), 3.48–3.38 (m, 3H), 2.79–2.70 (m, 2H), 2.14–1.35 (m, 10H),
1.82 (s, 3H), 1.69 (s, 3H), 1.60 (s, 3H), 1.25 (s, 3H), 1.12 (s, 3H),
0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) d 157.8, 155.6, 149.4,

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7579
5.35. Schweinfurthin analogue 54
temperature and stirred for 16 h, it was quenched by addition of
water and extracted with EtOAc. The combined organic extracts
were washed with water and brine, dried (MgSO4), concentrated
in vacuo to a yellow liquid, and purified by flash column chroma-
tography (2:1 hexanes/EtOAc) to afford stilbene 48 (57 mg, 77%)
Under general conditions for MOM hydrolysis, stilbene 46
(16.5 mg, 0.03 mmol), methanol (1.5 mL), and TsOH (25 mg,
0.13 mmol) were allowed to react for 18 h. Final purification by
column chromatography (25% EtOAc in hexanes) afforded ana-
logue 54 (6 mg, 40%) as an off-white solid: 1H NMR d 7.11 (d,
J = 1.5 Hz, 1H), 7.06 (d, J = 1.4 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H),
6.86 (d, J = 16.2 Hz, 1H), 6.64 (d, J = 1.1 Hz, 1H), 6.60 (d, J = 1.0 Hz,
1H), 5.26–5.23 (m, 1H), 5.08–5.04 (m, 1H), 3.86 (s, 3H), 3.47–3.41
(m, 3H), 2.74–2.71 (m, 2H), 2.45 (s, 3H), 2.10–2.03 (m, 4H), 1.90–
1.63 (m, 5H), 1.81 (s, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.24 (s, 3H),
1.11 (s, 3H), 0.89 (s, 3H); 13C NMR (CDCl3) d 158.0, 155.8, 153.0,
138.3, 137.2, 131.9, 129.3, 128.2, 127.9, 126.2, 125.6, 123.9,
122.0, 121.8, 117.4, 114.5, 106.9, 101.3, 78.1, 77.2, 55.8, 46.9,
39.8, 38.4, 37.8, 30.3, 28.3, 27.4, 26.5, 25.7, 23.1, 22.3, 20.0, 17.7,
16.2, 14.3; HRMS (EI) m/z calcd for C36H48O4S (M+) 576.3273, found
576.3279.
as a colorless oil: ½a D26:4
ꢄ
+38.4 (c 3.74, CHCl3); 1H NMR d 7.13 (d,
J = 1.8 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 15.9 Hz, 1H),
6.90–6.86 (m, 1H), 6.86 (s, 1H), 6.71 (s, 1H), 5.25–5.18 (m, 5H),
5.07 (t, J = 6.6 Hz,1H), 3.86 (s, 3H), 3.54 (s, 3H), 3.49 (s, 3H), 3.42
(dd, J = 11.4, 3.9 Hz, 1H), 3.39 (d, J = 6.9 Hz, 2H), 2.74 (s, 1H), 2.71
(d, J = 2.7 Hz, 1H), 2.15–2.05 (m, 1H), 2.00–1.80 (m, 5H), 1.78 (s,
3H), 1.75–1.70 (m, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.24 (s, 3H),
1.10 (s, 3H), 0.88 (s, 3H); 13C NMR d 158.4, 155.9, 146.3, 143.9,
136.6, 134.7, 131.3, 129.2, 127.9, 126.9, 124.6, 123.3, 122.8,
122.1, 118.9, 113.6, 105.5, 102.7, 96.0, 94.6, 78.1, 77.1, 56.3, 56.1,
55.8, 46.9, 39.9, 38.5, 37.9, 28.4, 27.4, 26.8, 25.8, 23.3, 22.6, 20.0,
17.8, 16.2, 14.4; HRMS (EI+) m/z calcd for C39H54O7 (M+)
634.3870, found 634.3876.
5.36. 5-Methoxymethyl stilbene 47
5.39. 3-Deoxy-5’-O-methylschweinfurthin A (56)
Under the general conditions for HWE condensations, aldehyde
40 (26 mg, 0.1 mmol), phosphonate 39 (42 mg, 0.1 mmol), and
NaH (60% wt. in mineral oil, 48 mg, 1.2 mmol) were allowed to re-
act. Final purification by column chromatography provided stil-
5.39.1. General Procedure for MOM hydrolysis
To a solution of stilbene 48 (54 mg, 0.09 mmol) in MeOH
(10 mL) was added TsOH (80 mg, 0.47 mmol) at room temperature
and the solution was stirred for 23 h. The reaction was quenched
by addition of NaHCO3 (sat.) and extracted with EtOAc. The organic
extracts were washed with H2O and brine, dried (MgSO4), and con-
centrated in vacuo to afford a yellow oil. Final purification by flash
column chromatography (2:1 hexanes/EtOAc) gave compound 56
bene 47 (26 mg, 50%) as a solid: ½a D26:4
ꢄ
+31.1 (c 0.30, CHCl3, 81%
ee by HPLC); 1H NMR d 7.30 (d, J = 1.6 Hz, 1H), 7.11 (d, J = 1.6 Hz,
1H), 6.89–6.64 (m, 4H), 5.15 (s, 2H), 5.19–5.10 (m, 1H), 5.02–4.97
(m, 1H), 4.38 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.37 (s, 3H), 3.35–
3.38 (m, 3H), 2.67–2.63 (m, 2H), 2.02–1.75 (m, 5H), 1.70 (s, 3H),
1.57 (s, 3H), 1.50 (s, 3H), 1.14–1.13 (m, 4H), 1.13 (s, 3H), 1.03 (s,
3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d 158.2, 155.8,
150.4, 136.7, 134.6, 131.2, 128.9, 128.0, 127.0, 126.5 (2C), 124.5,
124.5, 122.7, 121.7, 118.7, 105.4, 102.6, 94.5, 78.1, 76.7, 69.2,
58.5, 56.0, 55.7, 46.8, 39.9, 38.7, 37.7, 28.3, 27.3, 26.8, 25.7, 23.1,
22.7, 20.2, 17.7, 16.1, 14.3; HRMS (EI) m/z calcd for C39H54O6
(M+) 618.3922, found 618.3922.
(29 mg, 61%) as a white solid: ½a D26:4
ꢄ
+44.7 (c 1.84, CH3OH); 1H
NMR (CD3OD) d 6.89 (d, J = 16.2, 1H), 6.83 (d, J = 1.8 Hz, 1H), 6.79
(d, J = 16.2, 1H), 6.73 (s, 1H), 6.58 (s, 2H), 5.19 (t, J = 7.2 Hz, 1H),
5.05 (t, J = 6.9 Hz, 1H), 3.81 (s, 3H), 3.37–3.33 (m, 1H), 3.31–3.28
(m, 2H), 2.70–2.67 (m, 2H), 2.05–2.00 (m, 2H), 1.95–1.90 (m, 2H),
1.82–1.78 (m, 2H), 1.78 (s, 3H), 1.70–1.65 (m, 3H), 1.61 (s, 3H),
1.55 (s, 3H), 1.21 (s, 3H), 1.08 (s, 3H), 0.86 (s, 3H); 13C NMR
(CD3OD) d 159.9, 156.9, 147.0, 142.2, 137.8, 134.8, 131.9, 130.9,
128.9, 127.6, 125.5, 124.5, 123.9, 120.6, 117.1, 111.1, 107.1,
101.6, 78.7, 78.2, 56.1, 48.6, 41.0, 39.5, 38.9, 29.0, 27.9, 27.8,
25.9, 24.0, 23.1, 20.3, 17.7, 16.2, 14.9; HRMS (EI+) m/z calcd for
C35H46O5 (M+) 546.3345, found 546.3340.
5.37. 5-Methoxymethyl schweinfurthin analogue 55
Under the general conditions for MOM hydrolysis, stilbene 47
(34 mg, 0.1 mmol), methanol (3.0 mL), and p-TsOHꢀH2O (59 mg,
0.3 mmol) were allowed to react for 14 h. Purification by radial
chromatography (20% EtOAc in hexanes) afforded analogue 55
5.40. Stilbene 49
(13 mg, 41%) as an oil: ½a D26:4
ꢄ
+40.0 (c 0.68, CHCl3, 81% ee by HPLC);
Under the general conditions for HWE condensations, aldehyde
42 (98 mg, 0.32 mmol), phosphonate 39 (172 mg, 0.38 mmol), and
NaH (130 mg, 3.2 mmol, 60% in oil) were allowed to react in THF
(6.2 mL) for 15 h. Final purification by column chromatography
(1:1 hexanes/ethyl acetate) afforded stilbene 49 (175 mg, 90%) as
a yellow oil: 1H NMR (CDCl3) d 7.00–6.72 (m, 6H), 5.23 (s, 2H),
5.23–5.21 (m, 1H), 5.08 (t, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.87 (s,
3H), 3.50 (s, 3H), 3.46–3.37 (m, 3H), 2.73 (d, J = 9.2 Hz, 2H), 2.17–
1.51 (m, 10H), 1.78 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.26, (s, 3H),
1.11 (s, 3H), 0.89 (s, 3H);13C NMR (CDCl3) d 158.2, 155.8, 148.9,
142.5, 136.5, 134.6, 131.1, 128.9, 128.0, 126.6, 124.4, 122.59,
122.56, 120.5, 118.7, 106.8, 105.3, 102.5, 94.4, 77.9, 77.1, 55.94,
55.92, 55.7, 46.7, 39.8, 38.3, 37.6, 28.2, 27.3, 26.7, 25.6, 23.1,
22.4, 19.8, 17.6, 16.0, 14.2; HRMS (ESI) m/z calcd for C38H52O6
(M+) 604.3764, found 604.3754.
1H NMR (CDCl3) d 7.31–7.01 (m, 2H), 6.90 (d, J = 16.3 Hz, 1H), 6.80
(d, J = 16.3 Hz, 1H), 6.58–6.46 (m, 2H), 5.29 (br s, 1H), 5.21–5.11
(m, 1H), 5.00–4.97 (m, 1H), 4.38 (s, 2H), 3.78 (s, 3H), 3.37 (s, 3H),
3.34 (d, J = 6.7 Hz, 2H), 2.73–2.58 (m, 2H), 2.09–1.40 (m, 11H),
1.73 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H), 1.13 (s, 3H), 1.03 (s, 3H),
0.81 (s, 3H); 13C NMR (CDCl3) d 157.8, 155.5, 150.3, 138.1, 137.0,
131.7, 128.7, 128.1, 126.9, 126.3, 125.9, 124.3, 123.7, 121.6,
121.5, 114.2, 106.7, 101.1, 77.9, 77.0, 69.0, 58.3, 55.6, 46.6, 39.5,
38.2, 37.5, 28.1, 27.1, 26.3, 25.5, 22.9, 22.1, 20.0, 17.5, 16.0, 14.1;
HRMS (EI) m/e calcd for
573.3560.
C
37H49O5 (MꢂH)ꢂ 573.3580, found
5.38. Stilbene 48
5.38.1. General procedure for HWE condensations
To a suspension of NaH (85 mg, 60% oil dispersion, 2.1 mmol)
and 15–crown-5 (0.01 mL, 0.05 mmol) in THF (10 mL) at 0 °C was
added a solution of phosphonate 39 (65 mg, 0.14 mmol) in THF
(1.5 mL). The resulting mixture was stirred for 0.5 h. and aldehyde
41 (39 mg, 0.12 mmol) in THF (0.5 mL) was then added to the
cooled solution. After the reaction was allowed to warm to room
5.41. 3-Deoxy-schweinfurthin B analogue 57
Under the general conditions for MOM hydrolysis, stilbene 49
(80 mg, 0.13 mmol), MeOH (35 mL), and p-TsOH (75 mg,
0.42 mmol) were allowed to react for 4 days. Final purification by
column chromatography (1:1 hexanes/ethyl acetate) afforded

7580
J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
compound 57 (68 mg, 92%) as a yellow oil: 1H NMR (CDCl3) d 7.00–
6.60 (m, 6H), 5.28–5.24 (m, 1H), 5.07–5.05 (m, 1H), 3.89 (s, 3H),
3.86 (s, 3H), 3.43–3.37 (m, 3H), 2.73 (d, J = 9.2 Hz, 2H), 2.17–1.51
(m, 10H), 1.80 (s, 3H), 1.68 (s, 3H), 1.59 (s, 3H), 1.26, (s, 3H), 1.11
(s, 3H), 0.88 (s, 3H); 13C NMR (CDCl3) d 158.0, 155.6, 148.8,
142.5, 137.7, 136.8, 131.7, 128.9, 128.2, 126.3, 123.9, 122.6,
121.9, 120.5, 114.7, 106.79, 106.77, 101.2, 77.9, 77.0, 55.94, 55.7,
46.7, 39.7, 38.3, 37.6, 28.2, 27.3, 26.4, 25.6, 23.1, 22.2, 19.8, 17.6,
16.1, 14.2; HRMS (ESI) m/z calcd for C36H48O5 (M+) 560.3502, found
560.3481.
(m, 2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.25 (s, 3H), 1.11 (s, 3H), 0.89
(s, 3H); HRMS (EI) m/z calcd for C36H48O5 (M+) 560.3502, found
560.3508.
5.45. Aldehyde 60
To a solution of alcohol 58 (50 mg, 0.10 mmol) in CH2Cl2 at rt
was added activated MnO2 (250 mg, 2.3 mmol). After 22 h at rt,
the solution was diluted with ethyl acetate, filtered through celite,
and concentrated in vacuo which afforded aldehyde 60 (49 mg,
98%) as a yellow oil: 1H NMR (CDCl3) d 10.41 (s, 1H), 7.78 (s, 1H),
7.47 (s, 1H), 6.96 (s, 2H), 6.87 (s, 1H), 6.70 (s, 1H), 5.20 (s, 2H),
5.19 (m, 1H), 5.06 (m, 1H), 3.86 (s, 3H), 3.49 (s, 3H), 3.44 (dd,
J = 11.4, 3.4 Hz, 1H), 3.37 (d, J = 6.8 Hz, 2H), 2.77–2.73 (m, 2H),
2.08–1.82 (m, 8H), 1.77 (s, 3H), 1.74–1.70 (m, 2H), 1.64 (s, 3H),
1.50 (s, 3H), 1.28 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); 13C NMR (CDCl3)
d 189.9, 158.2, 155.8, 155.6, 136.0, 134.6, 133.6, 131.1, 129.2,
128.0, 126.6, 124.4, 124.4, 123.8, 123.7, 122.5, 119.2, 105.4,
102.7, 94.5, 78.0, 77.7, 55.9, 55.7, 46.5, 39.7, 38.4, 37.4, 28.1,
27.2, 26.7, 25.6, 22.9, 22.4, 20.2, 17.6, 16.0, 14.2; HRMS (EI) m/z
calcd for C38H50O6 (M+) 602.3607, found 602.3616.
5.42. Stilbene 50
Under the general conditions for HWE condensations, aldehyde
34 (320 mg, 0.76 mmol) phosphonate 39 (560 mg, 1.23 mmol), and
KHMDS (0.5 M in toluene, 5 mL, 2.5 mmol) were allowed to react
in THF (10 mL) for 10 min. Final purification by column chromatog-
raphy (30% EtOAc in hexanes) afforded stilbene 50 (195 mg, 36%)
as a colorless oil: 1H NMR (CDCl3) d 7.44 (d, J = 0.8 Hz, 1H), 7.14
(d, J = 1.6 Hz, 1H), 6.96 (d, J = 16.0 Hz, 1H), 6.90 (J = 16.0 Hz, 1H),
6.86 (d, J = 0.8 Hz, 1H), 6.71 (d, J = 0.8 Hz, 1H), 5.23 (s, 2H), 5.20
(t, J = 6.8 Hz, 1H), 5.07 (t, J = 6.8 Hz, 1H), 4.70 (d, J = 13.6 Hz, 1H),
4.63 (d, J = 13.6 Hz, 1H), 3.87 (s, 3H), 3.50 (s, 3H), 3.43 (dd,
J = 11.6, 4.4 Hz, 1H), 3.37 (d, J = 6.8 Hz, 2H), 2.73–2.70 (m, 2H),
2.06–1.84 (m, 8H), 1.78 (s, 3H), 1.72–1.68 (m, 2H), 1.65 (s, 3H),
1.57 (s, 3H), 1.20 (s, 3H), 1.10 (s, 3H), 0.98 (s, 9H), 0.88 (s, 3H), –
0.13 (s, 6H); 13C NMR d 158.2, 155.8, 149.6, 136.8, 134.6, 131.2,
129.4, 128.8, 128.4, 126.3, 126.3, 124.4, 123.4, 122.7, 121.1,
118.6, 105.3, 102.6, 94.5, 78.0, 76.5, 60.2, 56.0, 55.7, 46.8, 39.8,
38.3, 37.8, 28.2, 27.3, 26.7, 26.0, 25.7 (3C), 23.0, 22.4, 20.1, 18.5,
17.6, 16.0, 14.2, –5.2 (2C); HRMS (EI) m/z calcd for C44H66O6Si
(M+) 718.4629, found 718.4631.
5.46. Acid 61
To a solution of aldehyde 60 (17 mg, 0.028 mmol) in (CH3)3COH
(1 mL) at rt was added 2-methyl-2-butene (0.3 mL). Dropwise
addition of NaH2PO4 (40 mg) and NaClO2 (34 mg, 0.38 mmol) as
an aqueous solution (0.3 mL) resulted in a darkening of the reac-
tion solution. After 45 min, the reaction was quenched by addition
of 1 N HCl. The resulting solution was extracted with ethyl acetate,
and the combined organic phases were washed with brine, dried
(MgSO4), and concentrated in vacuo to afford acid 61 (18 mg,
100%) as a yellow oil: 1H NMR (CDCl3) d 8.23 (d, J = 2.4 Hz, 1H),
7.55 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 16.8 Hz, 1H), 7.05 (d,
J = 16.6 Hz, 1H), 6.97 (d, J = 0.8 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H),
5.30 (s, 2H), 5.27 (m, 1H), 5.15 (t, J = 5.1 Hz, 1H), 3.95 (s, 3H),
3.58 (s, 3H), 3.56 (m, 1H), 3.45 (d, J = 7.2 Hz, 2H), 2.92–2.87 (m,
2H), 2.20–1.88 (m, 8H), 1.85 (s, 3H), 1.81–1.74 (m, 2H), 1.72 (s,
3H), 1.65 (s, 3H), 1.44 (s, 3H), 1.23 (s, 3H), 1.00 (s, 3H); 13C NMR
(CDCl3) d 165.7, 158.3, 155.9, 151.1, 135.8, 134.7, 132.8, 131.2,
130.9, 129.5, 129.1, 126.0, 124.4, 123.4, 122.5, 119.5, 117.4,
105.6, 102.9, 94.6, 81.3, 77.2, 56.0, 55.7, 46.4, 39.8, 38.5, 37.5,
28.0, 27.1, 26.7, 25.6, 22.9, 22.4, 20.3, 17.6, 16.0, 14.2; HRMS (EI)
m/z calcd for C38H50O7 (M+) 618.3557, found 618.3560.
5.43. Alcohol 58
To a solution of silyl ether 50 (195 mg, 0.27 mmol) in THF at rt
was added TBAF (0.5 mL, 1 M in THF, 0.5 mmol). After 4 h, the reac-
tion was quenched by addition of water, the resulting solution was
extracted with ethyl acetate, and the combined organic phases
were washed with brine. The organic phase was dried (MgSO4)
and concentrated in vacuo, which provided nonracemic alcohol
58 (193 mg, 100% yield, 89% ee by HPLC) as a colorless oil: 1H
NMR (CDCl3) d 7.27 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H),
6.97 (d, J = 16.0 Hz, 1H), 6.92 (d, J = 16.0 Hz, 1H), 6.84 (s, 1H),
6.71 (s, 1H), 5.23 (s, 2H), 5.22 (m, 1H), 5.08 (t, J = 6.2 Hz, 1H),
4.66 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 3.87 (s, 3H),
3.50 (s, 3H), 3.40–3.37 (m, 3H), 2.75–2.64 (m, 2H), 2.08–1.95 (m,
5H), 1.86–1.80 (m, 2H), 1.79 (s, 3H), 1.75–1.67 (m, 3H), 1.66 (s,
3H), 1.58 (s, 3H), 1.22 (s, 3H), 1.10 (s, 3H), 0.88 (s, 3H); 13C NMR
(CDCl3) d 158.1, 155.7, 150.5, 136.5, 134.4, 130.9, 129.0, 128.7,
127.7, 127.2, 126.6, 124.3, 124.2, 122.6, 121.8, 118.7, 105.3,
102.6, 94.4, 77.6, 77.1, 61.8, 55.8, 55.6, 46.7, 39.7, 38.2, 37.7,
28.0, 27.2, 26.6, 25.6, 22.8, 22.4, 20.1, 17.5, 15.9, 14.2; HRMS (EI)
m/z calcd for C38H52O6 (M+) 604.3764, found 604.3751.
5.47. Amine 62
Aldehyde 60 (7.5 mg, 0.012 mmol) was dissolved in dimethyl-
amine (2 M solution in THF, 1 mL, 2 mmol) at rt and molecular
sieves were added. After 2 h, additional dimethylamine (1 mL,
2 mmol) was added along with AcOH (0.05 mL). After an additional
5 h, NaBH(OAc)3 (58 mg, 0.4 mmol) was added in one portion. After
15 h, the reaction was quenched by addition of 1 N NaOH. The
resulting solution was extracted with ethyl acetate, and the com-
bined organic phases were washed with brine, dried (Na2SO4),
and concentrated in vacuo. Final purification by preparative thin
layer chromatography on a base-washed plate (75% EtOAc and
5% TEA in hexanes) afforded amine 62 (2.5 mg, 33%) as a colorless
oil: 1H NMR (CDCl3) d 7.34 (s, 1H), 7.30 (s, 1H), 6.95 (s, 2H), 6.86 (s,
1H), 6.70 (s, 1H), 5.22 (s, 2H), 5.19 (m, 1H), 5.05 (m, 1H), 3.88 (s,
3H), 3.64 (s, 2H), 3.50 (s, 3H), 3.44 (dd, J = 11.4, 7.6 Hz, 1H), 3.36
(d, J = 7.6 Hz, 2H), 2.76–2.73 (m, 2H), 2.59 (s, 6H), 2.06–2.03 (m,
6H), 1.97–1.88 (m, 2H), 1.81 (s, 3H), 1.73–1.68 (m, 2H), 1.67 (s,
3H), 1.59 (s, 3H), 1.24 (s, 3H), 1.11 (s, 3H), 0.90 (s, 3H); 13C NMR
(CDCl3) d 159.4, 156.9, 152.6, 137.3, 135.7, 132.2, 130.6, 130.3,
129.9, 129.7, 128.7, 128.6, 128.0, 125.5, 123.7, 120.2, 106.6,
5.44. Schweinfurthin analogue 59
Under the general conditions for MOM hydrolysis, stilbene 58
(14 mg, 0.025 mmol), methanol (1 mL), and p-TsOHꢀH2O (68 mg,
0.37 mmol) were allowed to react for 24 h to provide analogue
59 (2 mg, 17%) as a white solid after purification by thin layer chro-
matography (50% EtOAc in hexanes): 1H NMR (CDCl3) d 7.26 (s,
1H), 7.18 (s, 1H), 6.95 (d, J = 16.0 Hz, 1H), 6.86 (d, J = 16.0 Hz,
1H), 6.63 (s, 1H), 6.60 (s, 1H), 5.23 (m, 1H), 5.06 (m, 1H), 4.67 (d,
J = 12.4 Hz, 1H), 4.60 (d, J = 12.4 Hz, 1H), 3.85 (s, 3H), 3.46–3.40
(m, 3H), 2.76 (m, 2H), 2.09–1.88 (m, 8H), 1.80 (s, 3H), 1.75–1.70

J. J. Topczewski et al. / Bioorg. Med. Chem. 19 (2011) 7570–7581
7581
8. Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2008, 73, 7963.
9. Topczewski, J. J.; Wiemer, D. F. Tetrahedron Lett. 2011, 52, 1628.
10. Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org. Chem. 2005, 70, 925.
11. Neighbors, J. D.; Salnikova, M. S.; Beutler, J. A.; Wiemer, D. F. Bioorg. Med. Chem.
2006, 14, 1771.
103.8, 95.6, 78.9, 78.2, 71.6, 57.0, 56.8, 48.0, 43.9, 40.9 (2C), 39.5,
38.9, 29.3, 28.4, 27.8, 26.7, 24.3, 23.5, 21.3, 18.7, 17.1, 15.4; HRMS
(EI) m/z calcd for C40H57NO5 (M+) 631.4237, found 631.4232.
12. Kuder, C. H.; Neighbors, J. D.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med. Chem. 2009,
17, 4718.
Acknowledgements
13. Ulrich, N. C.; Kodet, J. G.; Mente, N. R.; Kuder, C. H.; Beutler, J. A.; Hohl, R. J.;
Wiemer, D. F. Bioorg. Med. Chem. 2010, 18, 1676.
14. Topczewski, J. J.; Kuder, C. H.; Neighbors, J. D.; Hohl, R. J.; Wiemer, D. F. Bioorg.
Med. Chem. 2010, 18, 6734.
15. Ulrich, N. C.; Kuder, C. H.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med. Chem. Lett.
2010, 20, 6716.
16. Neighbors, J. D.; Topczewski, J. J.; Swenson, D. C.; Wiemer, D. F. Tetrahedron
Lett. 2009, 50, 3881.
17. (a) Turbyville, T. J.; Gürsel, D.; Tuskan, R. G.; Walrath, J. C.; Lipshultz, C. A.;
Lockett, S.; Wiemer, D. F.; Beutler, J. A.; Reilly, K. M. Mol. Cancer Ther. 2010, 9,
1234; (b) Burgett, A. W. G.; Poulsen, T. B.; Wangkanont, K.; Anderson, D. R.;
Kikuchi, C.; Shimada, K.; Okubo, S.; Mimaki, Y.; Kuroda, M.; Murphy, J. P.;
Schwalb, D. J.; Petrella, E. C.; Cornella-Taracido, I.; Schirle, M.; Tallarico, J. A.;
Shair, M. D. Nat. Chem. Biol. 2011, 7, 639; (c) Holstein, S. A.; Kuder, C. H.; Tong,
H.; Hohl, R. J. Lipids 2011, 46, 907.
We thank the ACS Division of Medicinal Chemistry for support
in the form of a predoctoral fellowship (to J.J.T.), the University of
Iowa Department of Chemistry for a Shriner Fellowship (to J.J.T.),
the UI Graduate College for a Presidential Fellowship (to J.G.K.),
and the Iowa Center for Research by Undergraduates for a summer
fellowship (to J.D.I.). This research was supported in part by the
Intramural Research Program of NIH, National CancerInstitute,
Center for Cancer Research. Financial support from the Roy J. Car-
ver Charitable Trust as a Research Program of Excellence is grate-
fully acknowledged.
18. Blunt, S. B.; Chen, T.-B.; Wiemer, D. F. J. Nat. Prod. 1998, 61, 1400.
19. Shi, Y. Acc. Chem. Res. 2004, 37, 488.
Supplementary data
20. O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
21. (a) Kline, T.; Andersen, N. H.; Harwood, E. A.; Bowman, J.; Malanda, A.; Endsley,
S.; Erwin, A. L.; Doyle, M.; Fong, S.; Harris, A. L.; Mendelsohn, B.; Mdluli, K.;
Raetz, C. R. H.; Stover, C. K.; Witte, P. R.; Yabannavar, A.; Zhu, S. J. Med. Chem.
2002, 45, 3112; (b) Hagiwara, A.; Ikenogami, T.; Kurihara, K.; Taniguchi, T.;
Takahashi, M.; Ida, A. PCT Int. Appl. (2006), WO 2006043510 A1 20060427.
22. Neighbors, J. D.; Mente, N. R.; Boss, K. D.; Zehnder, D. W., II; Wiemer, D. F.
Tetrahedron Lett. 2008, 49, 516.
Supplementary data (NMR spectra and complete bioassay data)
associated with this article can be found, in the online version, at
doi:10.1016/j.bmc.2011.10.034.
References and notes
23. Mente, N. R.; Wiemer, A. J.; Neighbors, J. D.; Beutler, J. A.; Hohl, R. J.; Wiemer, D.
F. Bioorg Med. Chem. Lett. 2007, 17, 911.
1. Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat. Prod. 1998, 61,
1509.
2. Beutler, J. A.; Jato, J.; Cragg, G. M.; Boyd, M. R. Nat. Prod. Lett. 2000, 14, 399.
3. Yoder, B. J.; Cao, S.; Norris, A.; Miller, J. S.; Ratovoson, F.; Razafitsalama, J.;
Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I. J. Nat. Prod. 2007, 70,
342.
4. Thoison, O.; Hnawia, E.; Gueritte-Voegelein, F.; Sevenet, T. Phytochemistry 1992,
31, 1439.
5. Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2011, 76, 909.
6. Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2009, 74, 6965.
7. Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem. 1999, 64, 8718.
24. Neighbors, J. D.; Salnikova, M. S.; Wiemer, D. F. Tetrahedron Lett. 2005, 46, 1321.
25. Battacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415.
26. (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175; (b) Bal, B. S.;
Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091.
27. (a) Shoemaker, R. H. Nat. Rev. Cancer 2006, 6, 813; Additional details about this
screen can be found at http://dtp.nci.nih.gov/screening.html.
28. Carosati, E.; Sciabola, S.; Cruciani, G. J. Med. Chem. 2004, 47, 5114.
29. Takatori, K.; Nishihara, M.; Nishiyama, Y.; Kajiwara, M. Tetrahedron 1998, 54,
15861.