Synthesis and structure activity relationships of schweinfurthin indoles

Article abstract of DOI:10.1016/j.bmc.2014.02.043

As part of a program to explore the biological activity of analogues of the natural schweinfurthins, a set of compounds has been prepared where an indole system can be viewed as a substitution for the resorcinol substructure of the schweinfurthin's D-ring. Twelve of these schweinfurthin indoles have been prepared and evaluated in the 60 cell line screen of the National Cancer Institute. While a range of activity has been observed, it is now clear that schweinfurthin indoles can demonstrate the intriguing pattern of activity associated with the natural stilbenes. In the best cases, these indole analogues display both potency and differential activity across the various cell lines comparable to the best resorcinol analogues.

Full text of DOI:10.1016/j.bmc.2014.02.043

Bioorganic & Medicinal Chemistry 22 (2014) 2542–2552
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure activity relationships of schweinfurthin
indoles
John G. Kodet a, John A. Beutler b, David F. Wiemer a,
⇑
a Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
b Molecular Targets Laboratory, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
As part of a program to explore the biological activity of analogues of the natural schweinfurthins, a set of
compounds has been prepared where an indole system can be viewed as a substitution for the resorcinol
substructure of the schweinfurthin’s D-ring. Twelve of these schweinfurthin indoles have been prepared
and evaluated in the 60 cell line screen of the National Cancer Institute. While a range of activity has been
observed, it is now clear that schweinfurthin indoles can demonstrate the intriguing pattern of activity
associated with the natural stilbenes. In the best cases, these indole analogues display both potency
and differential activity across the various cell lines comparable to the best resorcinol analogues.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 15 January 2014
Revised 11 February 2014
Accepted 19 February 2014
Available online 6 March 2014
Keywords:
Schweinfurthin
Indole
Stilbene analogues
SAR
1. Introduction
to an interest in compounds where the entire D-ring was replaced
with an indole motif.
Extracts of the plant Macaranga schweinfurthii1–3 and other
Macaranga species4–6 have yielded a small set of natural stilbenes
referred to collectively as the schweinfurthins. The tetracyclic
members of this family, represented by schweinfurthins A (1), B
(2), F (3), and G (4) (Fig. 1), have shown intriguing results in the
National Cancer Institute’s 60 cell line screen, including potent
anti-proliferative effects, good differential activity, and a pattern
of activity against different cell types that suggests a novel mecha-
nism of action. While efforts to secure more material from the nat-
ural source have met with limited success, a program to synthesize
these natural products has been more rewarding. Our synthesis ef-
forts have determined the absolute stereochemistry of the natural
products,7 provided access to most of the tetracyclic examples in
the correct natural stereochemistry,8–11 and afforded a host of ana-
logues designed to gather information on structure-activity rela-
tionships12–15 and to afford fluorescent16 or biotinylated17 probes.
From the results of these studies it is now clear that: (a) the C-3 hy-
droxyl group is not essential for activity; (b) compounds with a free
phenol at C-5 show greater activity than the corresponding meth-
oxy compounds, although both are active; (c) methylation of one
D-ring phenol improves chemical stability but does not diminish
activity greatly; and, (d) the para position on the D-ring is tolerant
of a variety of substituents. Integration of all of these factors led us
The indole system is found in an enormous variety of natural
products and many bioactive agents, and it is sometimes consid-
ered to be a privileged scaffold for drug development.18,19 If one
were to view the indole nitrogen as a replacement for one D-ring
phenol, analogues to schweinfurthin F (or G) could take on the gen-
eral structure 5 (or 6, Fig. 2). Given the inherent flexibility for
substituents at the para position noted above, isoprenoid substitu-
ents might be appended at either of the two positions on the
5-membered ring (as shown in structures 7 and 8). If such target
compounds were to be prepared through a late-stage formation
of the central olefin, as has been the case with so many of the
schweinfurthins, then advanced intermediates bearing the
OR'
13
R
10a
8a
O
4
1
5
8
4a
9a
2'
4'
3'
8'
5'
6'
OH
HO
H
12
1'
2''
3''
11
H
n
OH
1 R = OH, R' = H, n = 2
Schweinfurthin A
2 R = OH, R' = CH3, n = 2 Schweinfurthin B
3 R = H, R' = CH3, n = 1 Schweinfurthin F
4 R = H, R' = H, n = 1
Schweinfurthin G
⇑
Corresponding author. Tel.: +1 319 335 1365.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
Figure 1. Some natural schweinfurthins.
http://dx.doi.org/10.1016/j.bmc.2014.02.043
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.

J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2543
OR1
O
R2
R2
Ts
OHC
N
N
N
HO
(EtO)2(O)P
R3
H
R4
5 R1 = R2 = R3 = R4 = R5 = H
OR5
OR5
10
OMOM
6 R1 = CH3; R2 = R3 = R4 = R5 = H
9
7 R1 = CH3; R3 = prenyl; R2 = R4 = R5 = H
8 R1 = CH3; R4 = prenyl; R2 = R3 = R5 = H
Figure 2. Intermediates for assembly of schweinfurthin indoles.
O
R1
N
1) Et3N, LiBr, MsCl
H
N
Zn(OTf)2, TBAI
DIPEA , C10H17Br
Ts
N
O
2) P(OEt)3, DMF
R
EtO
(EtO)2P
70%
62%
OMOM
OMOM
OMOM
11
12 R = CO2Et; R1 = H
1) NaH, TsCl
2) DIBALH, 0 °C
71%
OCH3
14
13 R = CH2OH; R1 = Ts
O
NaH, 15-crown-5
53%
HO
CHO
H
OCH3
OCH3
O
15
O
TsOH, MeOH
36%
H
N
R
N
HO
HO
H
H
18
OH
OMOM
LiAlH4, 0 °C to rt
78%
16 R = Ts
17 R = H
Scheme 1. Synthesis of a geranylated schweinfurthin indole.
substitution pattern of structures 9 or 10 would be attractive.
While there are many routes to various indoles,20 strategies for
preparation of the desired substitution pattern are much more
limited. We recently reported preparation21,22 of compound 9
through a variation of the procedures refined by Vedejs.23 This
specific intermediate was used to assemble indoles 5 and 6, and
similar phosphonate intermediates were used to make compounds
7 and 8.21,22 In this manuscript, we report the preparation of
complementary aldehydes of the general structure 10, synthesis
of a variety of methylated analogues, and the biological activity
of twelve of these schweinfurthin indoles in the NCI’s 60 cell line
screen.
OCH3
O
H
N
HO
H
6
OH
H
N
CH3
CH3
N
N
OCH3
OH
OCH3
20
21
19
2. Chemical synthesis
Figure 3. Mono- and dimethylated schweinfurthin indole targets.
Most of the new compounds prepared here can be viewed as
analogues of schweinfurthin F (3)5 or 3-deoxyschweinfurthin B14
which carries a geranyl group on the D-ring in place of the prenyl
group of schweinfurthin F. This choice was made as a compromise
between synthetic expediency and the known activity of these par-
ent compounds. The first of the new compounds prepared was the
geranylated indole 18 (Scheme 1). Reaction of the MOM-protected
compound 1121 with geranyl bromide gave the 3-geranyl deriva-
tive 12, as expected from the parallel reaction of prenyl bromide.22
After protection of the indole nitrogen (12) through reaction with
tosyl chloride, reduction with DIBALH gave the primary alcohol
13, and conversion to the phosphonate 14 proceeded under stan-
dard conditions. An HWE condensation with aldehyde 1514,8 gave
the desired stilbene 16 as a single E-olefin isomer,24 and removal
of the tosyl group by treatment with LiAlH4 gave the free indole
17. Hydrolysis of the MOM group gave the target compound 18
in modest yield.
Because methylation of one D-ring phenol improves the chem-
ical stability of the schweinfurthins, determination of the impact of
methylation in the indole subsystem was the next objective. With
compound 6 already in hand, the two isomeric monomethyl com-
pounds 19 and 20, as well as the dimethyl compound 21, became
the next targets (Fig. 3).
Preparation of the O-methyl compound 19 began with treat-
ment of compound 22 with K2CO3 and limited methyl iodide to ob-
tain the methyl ether 23 (Scheme 2). Protection of the indole
nitrogen and reduction gave the expected alcohol 24 smoothly,
and this product could be converted to the phosphonate 25 under
standard conditions. An HWE condensation with aldehyde 15 and
in situ cleavage of the tosyl group gave the first of the methylated
analogues, compound 19.
Preparation of the N-methyl compound 20 began in a similar
fashion (Scheme 3). Treatment of the MOM protected indole 11

2544
J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
O
O
Ts
N
H
N
H
N
1) NaH, TsCl
K2CO3, CH3I
HO
EtO
EtO
2) DIBALH, 0 °C
DMF, 0 °C
73%
81%
OCH3
22
23
24
OH
OCH3
1) Et3N, LiBr, MsCl
2) P(OEt)3, DMF
75%
OCH3
Ts
N
O
O
R
N
(EtO)2P
NaH, 15-crown-5
THF, 0 °C
15
+
HO
H
OCH3
OCH3
NaOiPr, iPrOH
THF, 39% (2 steps)
25
26 R = Ts
19 R = H
Scheme 2. Synthesis of an O-methyl schweinfurthin indole.
CH3
N
CH3
N
1) NaH, CH3I
OHC
2) LiAlH4
MnO2
80%
HO
11
81%
OMOM
27
OMOM
28
OCH3
O
O
NaH, 15-crown-5
71%
P(OEt)2
MOMO
H
29
OCH3
OCH3
O
TsOH
MeOH
CH3
N
O
CH3
N
HO
H
51%
MOMO
H
20
OH
30
OMOM
Scheme 3. Synthesis of an N-methyl schweinfurthin indole.
O
1) LiAlH4
2) MnO2
CH3
N
CH3
N
with base and methyl iodide gave the expected product 27. How-
ever, after attempted conversion of compound 27 to the corre-
sponding phosphonate proved difficult, the complementary HWE
condensation was pursued. Therefore compound 27 was oxidized
to the corresponding aldehyde 28 and phosphonate 297 was used
to assemble the central olefin. This HWE condensation proceeded
smoothly to afford the desired stilbene 30. Treatment of this com-
pound with TsOH in methanol under standard conditions gave the
desired stilbene 20.
A similar strategy was employed to prepare the dimethyl com-
pound 21 (Scheme 4). Complete methylation of indole 22 was fol-
lowed by a standard reduction–oxidation sequence on indole 31 to
obtain aldehyde 32. Because hydrolysis of the MOM group from the
C-2 alcohol had proven slow with compound 30, phosphonate 29
was treated with TsOH/EtOH to remove the MOM group prior to
the HWE condensation. Reaction of aldehyde 32 with phosphonate
33 proceeded in modest yield, but gave the desired target 21
directly.
NaH, CH3I
81%
OHC
EtO
22
84%
OCH3
O
OCH3
32
31
OCH3
O
P(OEt)2
RO
H
NaH
15-crown-5
51%
29 R = MOM
33 R = H
TsOH, EtOH
85%
OCH3
O
CH3
N
HO
H
21
OCH3
To allow a second comparison of the impact of hydrogen (5),
prenyl, and geranyl substituents in an O-methyl series, compounds
38 and 43 were prepared (Scheme 5). For the geranyl series, reac-
tion of indole 23 with geranyl bromide in the presence of
Scheme 4. Synthesis of an N,O-dimethyl schweinfurthin indole.
gave the geranylated target 38 in modest yield. Preparation of
the prenyl analogue proceeded through a parallel series of reac-
tions in comparable yields, through intermediates 39, 40, and 41.
In this case, after the HWE condensation of compounds 41 and
15, deprotection was conducted without isolation of the interme-
diate 42, to afford the prenyl compound 43.
25
Zn(OTf)2 gave the geranylated indole 34. After introduction of
the tosyl protecting group, reduction of the ester gave the primary
alcohol 35. In this series, formation of the phosphonate 36 pro-
ceeded smoothly under standard conditions, and condensation
with aldehyde 15 gave the desired stilbene 37. Final deprotection

J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2545
O
O
H
N
H
N
Ts
N
Zn(OTf)2, TBAI
DIPEA, RBr
1) NaH, TsCl
2) DIBALH
EtO
EtO
HO
R
R
OCH3
OCH3
23
OCH3
34 R = geranyl (53%)
39 R = prenyl (59%)
35 R = geranyl (64%)
40 R = prenyl (76%)
1) Et3N, LiBr, MsCl
2) P(OEt)3
OCH3
NaH
O
Ts
N
O
15-crown-5
R'
N
(EtO)2P
HO
15
H
R
OCH3
R
OCH3
36 R = geranyl (81%)
41 R = prenyl (84%)
NaOiPr, iPrOH
37 R = geranyl; R' = Ts
38 R = geranyl; R' = H
42 R = prenyl; R' = Ts
43 R = prenyl; R' = H
THF, 22% (two steps)
NaOiPr, iPrOH
THF, 38% (two steps)
Scheme 5. Synthesis of geranyl and prenyl-substituted schweinfurthin indoles.
OMOM
OMOM
O
1) Et3N, LiBr, MsCl
2) P(OEt)3
O
O
P(OEt)2
OH
OR
MOMO
MOMO
H
H
90%
44
45
NaH
15-crown-5
32
42%
O
CH3
N
RO
H
OCH3
46 R = MOM
47 R = H
TsOH
MeOH/THF
60%
Scheme 6. Synthesis of a C-5 hydroxy schweinfurthin indole.
OMOM
Ts
N
O
aldehyde (Scheme 7). To exclude the possibility of tosyl transfer
to an A-ring hydroxyl group,21 the protected aldehyde 4811 was
used. This HWE condensation proceeded smoothly and the result-
ing stilbene was treated with base in situ to remove the tosyl group
and afford compound 49. Final hydrolysis of the MOM protecting
groups gave the desired analogue 50.
With this set of new compounds complete, these eight schwein-
furthin indoles (18–21, 38, 43, 47, and 50), together with the four
previously prepared (5–8), were examined for their biological
activity in the 60 cell line assay.
O
(EtO)2P
+
MOMO
CHO
H
OCH3
48
41
1) NaH, 15-crown-5
2) NaOiPr, THF/iPrOH
51%
(overall)
OR
O
H
N
RO
H
3. Biological results and discussion
TsOH, MeOH
62%
OCH3
49 R = MOM
50 R = H
Twelve indole schweinfurthins were tested in the 60 cell line
bioassay. Each compound maintains the hexahydroxanthene A-B-
C ring system found in the natural products schweinfurthin F (3)
and G (4), along with the R,R,R-stereochemistry, to focus on the im-
pact of the indole substructure on bioactivity. Key aspects of the
data generated through these assays are summarized in Table 1.
Because the set of assay data is quite substantial, any number of
comparisons might be made, but some central conclusions are
summarized below.
Compound 5 can be considered parallel to schweinfurthin G
with a 4-hydroxyindole system replacing the resorcinol unit found
in the natural material, while compound 6 bears the same relation-
ship to schweinfurthin F. As shown in Table 1, both compounds
showed significant activity in the 60 cell line screen, with mean
Scheme 7. Synthesis of a C-5 hydroxy E-ring prenyl schweinfurthin indole.
Finally, because the C-ring phenols tend to be more active that
the corresponding methoxy compounds in other schweinfurthin
studies, two analogues of schweinfurthin G (4) were prepared
(47 and 50). For the first of these targets (Scheme 6), the tricyclic
alcohol 44 was converted to the phosphonate 45.8 Condensation
with aldehyde 32 gave the desired stilbene, and final hydrolysis
of the A-ring MOM group gave the desired phenol 47.
Because phosphonate 41 already was in hand, compound 50
was prepared from the right half phosphonate and a left half

2546
J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
Table 1
Activity of schweinfurthin indoles in the NCI 60 cell line screen
Compd
NSC#
R1
R2
R3
R4
R5
Mean GI50 (nM)
GI50 range (log10 units)
n
SF-295 GI50 (nM)
5
6
7
8
18
19
20
21
38
43
47
50
3
750658
750655
752116
752816
750656
751060
752115
752114
751061
754492
752817
754493
740544
744343
H
H
H
H
H
H
H
CH3
CH3
H
H
H
Prenyl
H
H
H
H
H
H
H
H
CH3
H
CH3
CH3
CH3
CH3
CH3
570
3.29
2.02
3.08
3.00
3.19
2.41
2.63
2.61
2.54
2.38
3.00
3.26
2.79
3.12
2a
2a
2a
2a
1
89
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
1020
3160
390
1620
380
1260
1260
1070
430
450
580
780
110
230
290
<21b
110
55
H
H
H
H
H
H
H
H
H
Prenyl
Geranyl
H
H
H
Geranyl
Prenyl
H
1
2a
2a
1
760
170
200
48
H
CH3
H
2a
2a
2a
2a
2a
<12b
<23b
<36b
10
H
Prenyl
Schweinfurthin F
Schweinfurthin G
4
a
Data represents the average of two independent experiments.
In one experiment the GI50 was below the lowest concentration tested (10 nM).
b
GI50’s of 570 and 1020 nM (vs 110 and 780 nM for schweinfurthin
G and F, respectively) as well as differential activity of 3.29 and
2.02 log10 units (vs 3.12 and 2.79). Visual inspection of the activity
profiles was consistent with schweinfurthin-like activity, given
that the CNS and leukemia subpanels were particularly sensitive
while the ovarian subpanel was relatively resistant. Perhaps more
importantly, comparison of the mean GI50 data from all the tested
cell lines with a Pearson correlation shows good correlations to the
natural schweinfurthins. The activity of compound 5, which carries
a C-ring hydroxyl group, correlates very well with schweinfurthin
G (0.83), while the activity of compound 6, which bears a C-ring
methoxy group, correlates nearly as well with schweinfurthin F
(0.61). This confirms that the new indoles demonstrate schwein-
furthin-like behavior, and indicates that modification of the
right-half resorcinol to an indole motif is a well-tolerated change.
The early results summarized above encouraged efforts to pre-
pare additional analogues, including some with isoprenoid side
chains that more closely resemble natural schweinfurthins. Com-
pound 7 bears a prenyl substituent at C-2 of the indole ring, while
compound 8 carries a prenyl substituent at C-3 and compound 18
carries a geranyl substituent at the same site. All three compounds
showed differential activity of three log10 units or more, and their
activity correlated well with that of the natural schweinfurthins.
However, compound 8 showed the greatest potency, with a mean
GI50 of 390 nM.
valid comparator and Table 1 includes the GI50 values for the
SF-295 cell line, as run within the NCI 60 screen. This is a hu-
man-derived glioblastoma cell line, and one of those most sensitive
to the schweinfurthins. In this set of 12 compounds, four (8, 43, 47,
and 50) displayed mean GI50 values of 50 nM or less against this
specific cell line, values that are comparable to those of schwein-
furthins F and G.
4. Conclusions
A number of new schweinfurthin indoles have been prepared,
including compounds that bear geranyl or prenyl groups at C-2 or
C-3 of the indole system, as well as compounds that have been
selectively methylated on the indole nitrogen or a phenolic
hydroxyl group. Twelve such compounds have been tested for
biological activity in the NCI’s 60 cell line screen and all of them
showed activity. The best compounds display GI50s comparable
to those of the natural schweinfurthins, show a range of activity
of ꢀ3 orders of magnitude between the most sensitive and the most
resistant cell lines, and display a schweinfurthin-like pattern
of activity that suggest they possess a similar mechanism of
action. Taken together, these data suggest that an indole moiety
is a viable replacement for the resorcinol-based D-ring of the
natural schweinfurthins.
In past studies we have shown that monomethylation of the D-
ring resorcinol increased chemical stability with a minimal impact
on potency.7,13 Therefore, we prepared the O- and N-methylindoles
as shown in compounds 19 and 20, as well as the N-,O-dimethyl
compound 21. All three compounds showed activity in the 60 cell
5. Experimental section
5.1. General experimental conditions
Tetrahydrofuran was freshly distilled from sodium/benzophe-
none, while CH2Cl2 and Et3N were freshly distilled from CaH2. All
reactions in non-aqueous solvents were conducted in oven dried
glassware under a positive pressure of argon with magnetic stir-
ring. All commercial reagents were used without further purifica-
tion unless otherwise stated. NMR spectra were recorded at
300 MHz for 1H, and 75 MHz for 13C or higher with CDCl3 as solvent
line screen, but only compound 19 had a mean GI50 below 1 lM. To
explore this activity further, both the 3-geranyl (38) and 3-prenyl
(43) derivatives of compound 19 were prepared and tested for
their activity. Both of these compounds showed activity but only
the prenyl compound 43 displayed a sub-micromolar mean GI50
.
Finally, because the C-ring hydroxyl group of schweinfurthin G
appears to confer somewhat greater activity than the C-ring meth-
oxy group of schweinfurthin F, and this pattern was observed again
with compounds 5 and 6, the C-ring phenols 47 and 50 were pre-
pared. Both compounds showed sub-micromolar mean GI50’s and
differential activity of more than three orders of magnitude. Addi-
tion of the C-3 prenyl substituent to the indole system in this case
does not appear to enhance substantially either the potency or the
differential activity in this pairwise comparison.
and (CH3)4Si (1H, 0.00 ppm) or CDCl3 13C, 77.0 ppm) as internal
(
standards unless otherwise noted. High resolution mass spectra
were run with magnet detection unless another method is noted.
Elemental analyses were performed by a commercial facility.
5.2. Geranylated indole 12
To indole 1121 (1.11 g, 4.44 mmol), TBAI (820 mg, 2.22 mmol),
and Zn(OTf)2 (968 mg, 2.66 mmol) in toluene (15 mL) at rt was
added DIPEA (0.86 mL, 4.88 mmol) and the reaction mixture was
Mean GI50 values provide a useful comparison of these indole
schweinfurthins, and differential activity is a useful indication of
selective activity. However, activity in a single cell line also is a

J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2547
allowed to stir for 15 min. Geranyl bromide (481 mg, 2.22 mmol)
was added dropwise, the reaction was allowed to proceed for 3 h
and then quenched by addition of NH4Cl (satd) and extracted with
Et2O. The combined organic layers were washed with H2O, dried
(Na2SO4), concentrated, and purified by column chromatography
(17.5–20% EtOAc in hexanes) to afford geranylated indole 12
(524 mg, 62%) as a colorless oil along with recovered starting mate-
rial 11 (553 mg): 1H NMR d 8.72 (br s, 1H), 7.81 (d, J = 0.9 Hz, 1H),
7.35 (d, J = 0.9 Hz, 1H), 6.96–6.95 (m, 1H), 5.51–5.46 (m, 1H), 5.35
(s, 2H), 5.14–5.10 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.67 (d, J = 7.1 Hz,
2H), 3.53 (s, 3H), 2.16–2.03 (m, 4H), 1.72 (s, 3H), 1.68 (s, 3H), 1.60
(s, 3H) 1.38 (t, J = 7.1 Hz, 3H); 13C NMR d 167.7, 151.3, 137.3, 135.1,
131.2, 124.3, 124.3, 123.9, 123.5, 121.2, 116.4, 108.3, 102.6, 94.1,
60.7, 56.1, 39.6, 26.6, 25.6, 25.2, 17.6, 15.9, 14.3. Anal. Calcd for
108.9 (d, JCP = 5.6 Hz), 108.7 (d, JCP = 7.7 Hz), 94.3, 61.9 (d, JCP = 6.7 -
Hz, 2C), 56.0, 39.5, 34.1 (d, JCP = 138.1 Hz), 26.5, 25.5, 25.4, 21.3,
17.5, 16.2 (d, JCP = 6.0 Hz, 2C), 15.9; 31P NMR d 26.9; HRMS (EI)
calcd for C32H44NO7PS (M+) 617.2576; found 617.2562.
5.5. Indole 16
To phosphonate 14 (84 mg, 0.14 mmol) and aldehyde 158
(32 mg, 0.10 mmol) in THF (5 mL) at rt was added NaH (60 mg,
1.50 mmol, 60% dispersion in oil) followed by 15-crown-5 (3 drops).
The reaction mixture was allowed to stir for 90 min, then quenched
by addition of Na2CO3 (satd), and extracted with EtOAc. The com-
bined organic extracts were washed with brine, dried (MgSO4),
and filtered, and then concentrated in vacuo. Final purification by
flash column chromatography (35–40% EtOAc in hexanes) afforded
compound 16 (53%, 43 mg): 1H NMR d 7.75–7.73 (m, 3H), 7.21 (d,
J = 8.0 Hz, 2H), 7.11 (s, 1H), 7.04–7.02 (m, 3H), 6.94–6.93 (m, 1H),
6.91–6.90 (m, 1H), 5.44–5.40 (m, 1H), 5.28, (s, 2H), 5.15–5.11 (m,
1H), 3.93 (s, 3H), 3.53–3.51 (m, 2H), 3.51 (s, 3H), 3.46–3.42 (m,
1H), 2.75–2.73 (m, 2H), 2.33 (s, 3H), 2.17–2.08 (m, 5H), 1.92–1.60
(m, 5H), 1.70 (s, 3H), 1.69 (s, 3H), 1.62 (s, 3H), 1.27 (s, 3H), 1.12
(s, 3H), 0.91 (s, 3H); 13C NMR d 152.0, 149.0, 144.6, 142.7, 137.5,
136.7, 135.7, 135.3, 131.5, 129.7 (2C), 128.9, 128.5, 126.7, 126.7
(2C), 124.1, 123.1, 122.6, 122.1, 121.7, 120.5, 120.3, 106.9, 105.9,
104.8, 94.3, 78.0, 77.0, 56.2, 56.0, 46.8, 39.7, 38.4, 37.7, 28.3, 27.3,
26.6, 25.7, 25.6, 23.1, 21.5, 19.8, 17.7, 16.1, 14.2; HRMS (EI) calcd
for C46H57NO7S (M+) 767.3856; found 767.3853.
C23H31NO4: C, 71.66; H, 8.11; N, 3.63. Found: C, 71.43; H, 8.19, N,
3.77.
5.3. Alcohol 13
To indole 12 (397 mg, 1.04 mmol) in THF at 0 °C was added NaH
(55 mg, 1.38 mmol, 60% dispersion in oil) and the solution was al-
lowed to stir for 10 min. Tosyl chloride (235 mg, 1.23 mmol) was
added and the solution was allowed to warm to rt. When the reac-
tion was judged complete by TLC analysis the reaction mixture was
cooled to 0 °C, then DIBALH (0.54 mL, 2.63 mmol) was added. After
30 min the solution was quenched by addition of NH4Cl (satd),
poured into EtOAc, acidified, and extracted with EtOAc. The com-
bined organic extracts were washed with Na2CO3 (satd), brine,
dried (MgSO4), and filtered, and then concentrated in vacuo. Final
purification by flash column chromatography (35% EtOAc in hex-
anes) afforded benzylic alcohol 13 (366 mg, 71%) as an oil: 1H
NMR d 7.70 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.15 (d, J = 8.2 Hz,
2H), 7.13 (s, 1H), 6.86 (s, 1H), 5.44–5.39 (m, 1H), 5.22 (s, 2H),
5.14–5.10 (m, 1H), 4.71 (s, 2H), 3.53 (d, J = 7.0 Hz, 2H), 3.47 (s,
3H), 2.31–2.29 (m, 4H), 2.14–2.05 (m, 4H), 1.69–1.68 (m, 6H),
1.61 (s, 3H); 13C NMR d 151.9, 144.6, 139.1, 137.1, 136.6, 135.3,
131.5, 129.7 (2C), 126.6 (2C), 124.1, 122.7, 121.9, 121.7, 120.3,
106.0, 105.8, 94.2, 65.5, 56.1, 39.6, 26.6, 25.6, 25.5, 21.4, 17.6,
16.1. Anal. Calcd for C28H35NO5S: C, 67.58; H, 7.09; N, 2.81. Found:
C, 67.81; H, 7.19, N, 2.83.
5.6. Indole 17
To the schweinfurthin analogue 16 (43 mg, 0.056 mmol) in THF
(5 mL) at 0 °C was added LiAlH4 (45 mg, 1.06 mmol) and then the
mixture was allowed to warm to rt. The following day, the reaction
mixture was quenched by addition of NH4Cl (satd), poured into
H2O, and extracted with EtOAc. The combined organic extracts
were washed with water and brine, dried (MgSO4), and filtered
and the filtrate was concentrated in vacuo. Final purification by
flash column chromatography (30–40% EtOAc in hexanes) afforded
indole 17 (27 mg, 78%) as a light yellow oil: 1H NMR d 7.92 (br s,
1H), 7.07–7.06 (m, 1H), 7.02 (d, J = 16.2 Hz, 1H), 6.95 (d,
J = 16.3 Hz, 1H), 6.92, (d, J = 0.7 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H),
6.87 (d, J = 1.4 Hz, 1H), 6.81–6.80 (m, 1H), 5.53–5.47 (m, 1H), 5.36
(s, 2H), 5.16–5.10 (m, 1H), 3.90 (s, 3H), 3.64 (d, J = 7.3 Hz, 2H)
3.57 (s, 3H), 3.45–3.40 (m, 1H), 2.74–2.71 (m, 2H), 2.11–2.04, (m,
6H), 1.89–1.84 (m, 2H), 1.72 (d, J = 0.6 Hz, 3H), 1.72–1.57 (m, 2H),
1.69 (d, J = 0.8 Hz, 3H), 1.60 (s, 3H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89
(s, 3H); 13C NMR d 152.2, 148.9, 142.3, 138.6, 135.0, 133.0, 131.3,
129.4, 127.6, 126.7, 124.4, 123.8, 122.6, 121.0, 120.2, 117.6, 116.7,
106.9, 103.8, 100.9, 94.3, 78.1, 77.0, 56.0, 56.0, 46.8, 39.8, 38.4,
37.7, 28.3, 27.3, 26.7, 25.7, 25.5, 23.2, 19.8, 17.7, 16.0, 14.3; HRMS
(EI) calcd for C39H51NO5 (M+) 613.3767; found 613.3754.
5.4. Phosphonate 14
To alcohol 13 (366 mg, 0.74 mmol) in THF (20 mL) was added
LiBr (510 mg 5.87 mmol) and Et3N (0.41 mL, 2.94 mmol) and the
solution was cooled to 0 °C. After 20 min, MsCl (0.14 mL, 1.8 mmol)
was added dropwise. The reaction was allowed to stir and slowly
warm to rt. When complete by TLC analysis it was quenched by
addition of NaHCO3 (satd) and extracted with Et2O. The organic
layers were washed with brine, dried (MgSO4), and filtered, and
the filtrate was concentrated in vacuo. The resulting residue was
dissolved in DMF (3 mL) and P(OEt)3 (0.4 mL) was added and the
solution was heated at reflux overnight. The next day the solution
was allowed to cool to rt, then poured into water, and extracted
with EtOAc. The organic layer was washed with brine, dried
(MgSO4), and concentrated in vacuo. Final purification by flash col-
umn chromatography (2.5% EtOH in Et2O) afforded phosphonate
14 (320 mg, 70%) as a light yellow oil: 1H NMR d 7.74 (d,
J = 8.3 Hz, 2H), 7.59–7.58 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.09 (d,
J = 1.1 Hz, 1H), 6.82–6.80 (m, 1H), 5.43–5.38 (m, 1H), 5.23 (s, 2H),
5.15–5.11 (m, 1H), 4.06–3.95 (m, 4H), 3.52 (d, J = 7.2 Hz, 2H),
3.47 (s, 3H), 3.22 (d, JPH = 21.5 Hz, 2H), 2.32 (s, 3H), 2.14–2.07 (m,
4H), 1.70 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H) 1.25 (t, J = 7.1 Hz, 6H);
13C NMR d 151.6 (d, JCP = 2.8 Hz) 144.4, 137.1 (d, JCP = 2.9 Hz),
136.5, 135.3, 131.4, 129.6 (2C), 129.2 (d, JCP = 9.3 Hz), 126.7 (2C),
124.0, 122.7 (d, JCP = 1.6 Hz), 121.7, 121.6, 119.7 (d, JCP = 3.2 Hz),
5.7. Analogue 18
To the protected indole 17 (21 mg, 0.034 mmol) in MeOH
(2 mL) was added TsOH (40 mg, 0.21 mmol) in two proportions
3 h apart, and the solution was allowed to stir. The next day the
solution was quenched by addition of NaHCO3 (satd), diluted with
H2O and extracted with EtOAc. The combined organics extracts
were washed with brine, dried (MgSO4), and filtered, and the fil-
trate was concentrated in vacuo. Final purification by flash column
chromatography (50% EtOAc in hexanes) afforded schweinfurthin
analogue 18 (7 mg, 36%) as a light yellow oil: 1H NMR (CD3OD) d
6.96–6.93 (m, 3H), 6.92–6.91 (m, 1H), 6.85–6.84 (m, 1H), 6.73 (d,
J = 0.9 Hz, 1H), 6.61–6.60 (m, 1H), 5.54–5.49 (m, 1H), 5.16–5.11
(m, 1H), 3.61 (d, J = 7.1 Hz, 2H), 3.38–3.33 (m, 1H), 3.25 (s, 3H),

2548
J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2.74–2.71 (m, 2H), 2.15–2.01 (m, 5H), 1.83–1.59 (m, 4H), 1.72 (s,
3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.22 (s, 3H), 1.09 (s, 3H), 0.87 (s,
3H); 13C NMR (CD3OD) d 153.2, 150.1, 143.2, 140.7, 135.4, 133.6,
132.1, 131.4, 129.2, 126.9, 125.8, 125.6, 124.0, 121.8, 121.4,
118.0, 116.6, 108.0, 103.8, 101.4, 78.7, 77.1, 56.4, ꢀ49⁄, 40.9,
39.5, 38.9, 29.0, 27.9, 27.7, 26.4, 26.0, 24.1, 20.2, 17.8, 16.1, 14.9;
HRMS (EI) calcd for C37H47NO4 (M+) 569.3505 found 569.3504.
⁄Obscured by solvent.
to rt and poured into Et2O, washed with H2O, brine, dried (MgSO4),
and filtered and then the filtrate was concentrated in vacuo. Final
purification by flash column chromatography (2.5–3% MeOH in
Et2O) afforded phosphonate 25 (529 mg, 75%) as a light yellow so-
lid: 1H NMR d 7.75 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 2.9 Hz, 1H), 7.42
(dd, J = 3.7, 1.3 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 3.6 Hz,
1H), 6.65 (s, 1H), 4.03–3.93 (m, 4H), 3.88 (s, 3H), 3.25 (d, JHP = 21.5 -
Hz, 2H), 2.33 (s, 3H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR d 152.8 (d,
JCP = 2.8 Hz), 144.8, 136.0 (d, JCP = 3.1 Hz), 135.3, 129.7 (2C), 129.4
(d, JCP = 9.2 Hz), 126.7 (2C), 124.8 (d, JCP = 1.7 Hz), 120.0 (d,
JCP = 3.3 Hz), 107.7 (d, JCP = 7.9 Hz), 106.0 (d, JCP = 1.7 Hz), 105.6
(d, JCP = 5.7 Hz), 62.1 (d, JCP = 6.7 Hz, 2C), 55.4, 34.4 (d, JCP = 138.3 -
Hz), 21.4, 16.3 (d, JCP = 5.9 Hz, 2C); 13P d 26.2; HRMS (EI) calcd for
C21H26NO6PS (M+) 451.1218; found 451.1216.
5.8. Preparation of the methylated indole 23 and the
dimethylated indole 31
Following Vedejs23 procedure, to phenol 22 (1.05 g, 5.12 mmol)
in DMF (28 mL) was added K2CO3 (2.12 g, 15.4 mmol), the reaction
mixture was cooled to 0 °C, and after 20 min MeI (0.32 mL,
5.12 mmol) was added dropwise. The reaction was maintained at
0 °C overnight, then quenched by addition of 1 M HCl and extracted
with Et2O. The combined organic extracts were washed with brine,
dried (MgSO4), filtered, and then concentrated in vacuo. Final purifi-
cation by flash column chromatography (20–25% EtOAc in hexanes)
afforded methoxyindole 23 (824 mg, 73%) as a white solid: 1H NMR d
8.66 (br s, 1H), 7.85 (t, J = 0.9 Hz, 1H), 7.26 (dd, J = 3.3, 2.5 Hz, 1H),
7.22 (d, J = 1.0 Hz, 1H), 6.70–6.68 (m, 1H), 4.40 (q, J = 7.1 Hz, 2H),
4.00 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR d 167.8, 152.7, 136.2,
125.9, 124.9, 122.3, 107.5, 100.2, 99.9, 60.8, 55.4, 14.4; HRMS (EI)
calcd for C12H13NO3 (M+) 219.0895; found 219.0904.
Also recovered was the dimethylated indole 31 (31 mg, 3%) as a
white solid: 1H NMR d 7.77 (t, J = 0.9 Hz, 1H), 7.21 (d, J = 1.0 Hz,
1H), 7.11 (d, J = 3.0 Hz, 1H), 6.60 (dd, J = 3.1, 0.8 Hz, 1H), 4.41 (q,
J = 7.1 Hz, 2H), 4.01 (s, 3H), 3.83 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H);
13C NMR d 167.7, 152.7, 137.1, 130.3, 124.4, 122.7, 105.8, 99.6,
98.7, 60.8, 55.4, 33.2, 14.5; HRMS (EI) calcd for C13H15NO3 (M+)
233.1052; found 233.1056.
5.11. Schweinfurthin analogue 19
To aldehyde 15 (40 mg, 0.13 mmol) and phosphonate 25
(72 mg, 0.16 mmol) in THF (1.2 mL) was added NaH (50 mg,
1.25 mmol, 60% dispersion in oil) and 15-crown-5 (3 drops). After
1 h the reaction was quenched by addition of NH4Cl (satd) and ex-
tracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), filtered, and then concentrated in vacuo.
Purification by flash column chromatography (35% EtOAc in hex-
anes) afforded a mixture of tosyl protected indole 26 and the free
indole 19 (36 mg). The resulting mixture in THF (5 mL) was added
dropwise to a solution of NaH (115 mg, 2.88 mmol, 60% dispersion
in oil) in 2-propanol (2 mL). The solution was allowed to stir over-
night and then quenched by addition of H2O and extracted with
EtOAc. The combined organic layers were washed with brine, dried
(MgSO4), and filtered, and the filtrate was concentrated in vacuo.
Final purification by flash column chromatography (40% EtOAc in
hexanes) afforded schweinfurthin analogue 19 (23 mg, 39% for 2
steps) as a colorless oil: 1H NMR d 8.17 (br s, 1H), 7.12–7.10 (m,
2H), 7.06 (d, J = 16.3, Hz, 1H), 6.99 (d, J = 16.3 Hz, 1H), 6.91–6.89
(m, 2H), 6.74 (s, 1H), 6.63 (t, J = 2.4 Hz, 1H), 4.02 (s, 3H), 3.91 (s,
3H), 3.44 (dd, J = 11.6, 4.0 Hz, 1H), 2.76–2.73 (m, 2H), 2.16–2.11
(m, 1H), 1.90–1.56 (m, 5H), 1.27 (s, 3H), 1.11 (s, 3H), 0.90 (s, 3H);
13C NMR d 153.5, 149.1, 142.5, 137.6, 133.3, 129.6, 128.0, 127.0,
123.3, 122.8, 120.4, 118.7, 107.1, 103.5, 100.4, 97.9, 78.2, 56.2,
55.5, 47.0, 38.6, 37.8, 28.5, 27.5, 23.4, 20.0, 14.4; HRMS (EI) calcd
for C28H33NO4 (M+) 447.2410; found 447.2413.
5.9. Benzylic indole alcohol 24
To indole 23 (436 mg, 1.99 mmol) in THF (10 mL) at 0 °C was
added NaH (100 mg, 2.5 mmol, 60% dispersion in oil), followed
by TsCl (430 mg, 2.25 mmol). Once the reaction was judged com-
plete by TLC analysis, DIBALH (1.07 mL, 6.0 mmol) was added
dropwise. After 1 h the reaction mixture was quenched by addition
of NH4Cl (satd), diluted with EtOAc, acidified with 1 M HCl to dis-
solve the solids, and extracted with EtOAc. The combined organic
extracts were washed with NaHCO3 (satd), brine, dried (MgSO4),
and filtered, and then the filtrate was concentrated in vacuo. Final
purification by flash column chromatography (35% EtOAc in hex-
anes) afforded alcohol 24 (533 mg, 81%) as a white solid: 1H
NMR d 7.72 (d, J = 8.4, Hz, 2H), 7.57 (s, 1H), 7.43 (d, J = 3.6 Hz,
1H), 7.16 (d, J = 8.5 Hz, 2H), 6.72 (dd, J = 3.7, 0.8 Hz, 1H), 6.67 (s,
1H), 4.74 (s, 2H), 3.85 (s, 3H), 2.32 (br s, 1H), 2.29 (s, 3H); 13C
NMR d 153.0, 144.9, 139.2, 135.8, 135.0, 129.8 (2C), 126.7 (2C),
124.9, 120.4, 105.9, 104.7, 102.7, 65.8, 55.3, 21.4; HRMS (EI) calcd
for C17H17NO4S (M+) 331.0878; found 331.0873.
5.12. Alcohol 27
To indole 11 (202 mg, 0.81 mmol) in THF (10 mL) at 0 °C was
added NaH (49 mg, 1.2 mmol, 60% dispersion in mineral oil) fol-
lowed after 5 min by MeI (0.06 mL, 0.96 mmol), and the reaction
mixture was allowed to stir for 2 h. After LiAlH4 (92 mg,
2.42 mmol) was added, the reaction mixture was allowed to stir
for 1 h and then quenched with NH4Cl (satd) and extracted with
EtOAc. The combined organic extracts were washed with brine,
dried (MgSO4), and filtered, and the filtrate was concentrated in va-
cuo. Final purification by flash column chromatography (40% EtOAc
in hexanes) afforded benzylic alcohol 27 (146 mg, 81%, 2 steps) as a
light yellow solid: 1H NMR d 6.96 (s, 1H), 6.91 (d, J = 3.2 Hz, 1H),
6.70 (s, 1H), 6.53 (d, J = 3.1 Hz, 1H), 5.27 (s, 2H), 4.69 (s, 2H), 3.65
(s, 3H), 3.48 (s, 3H), 2.68 (br s 1H); 13C NMR d 150.3, 138.1,
135.7, 127.8, 118.9, 102.6, 102.2, 97.9, 94.4, 65.8, 56.0, 32.8; HRMS
(EI) calcd for C12H15NO3 (M+) 221.1052; found 221.1042.
5.10. Phosphonate 25
To benzylic alcohol 24 (517 mg, 1.56 mmol) in THF (15 mL) was
added LiBr (1.09 g, 12.5 mmol) and the solution was cooled to 0 °C.
Next Et3N (0.87 mL, 6.2 mmol) and, after 10 min, MsCl (0.36 mL,
1.73 mmol) were added and the reaction mixture was allowed to
stir for 2.5 h. The reaction mixture was quenched by addition of
NH4Cl (satd) and extracted with Et2O. The combined organic layers
were washed with brine, dried (MgSO4), and filtered, and then the
filtrate was concentrated in vacuo. After the resulting oil was dis-
solved in DMF (6 mL) and P(OEt)3 (2 mL) was added, the solution
was heated at reflux. The next day the reaction was allowed to cool
5.13. Aldehyde 28
To alcohol 27 (73 mg, 0.33 mmol) in CH2Cl2 (10 mL) at rt was
added MnO2 (430 mg, 4.9 mmol) and the resulting mixture was
allowed to stir for 4 h, then filtered through celite, and washed with

J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2549
EtOAc. The solvent was removed in vacuo to afford aldehyde 28
(58 mg, 80%) as a light yellow solid: 1H NMR d 9.98 (s, 1H), 7.55
(s, 1H), 7.27 (s, 1H), 7.19 (d, J = 2.9 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H),
5.38, (s, 2H), 3.85 (s, 3H), 3.54 (s, 3H); 13C NMR d 192.2, 150.7,
137.4, 131.8, 131.7, 124.8, 108.5, 102.0, 99.2, 94.5, 56.2, 33.2; HRMS
(EI) calcd for C12H13NO3 (M+) 219.0895; found 219.0889.
to warm to rt over 50 min. It was then quenched by addition by
NH4Cl (satd) and extracted with EtOAc. The combined organic lay-
ers were washed with brine, dried (MgSO4), and filtered, and the
solvent was removed in vacuo. The resulting residue was then dis-
solved in CH2Cl2 (10 mL) and MnO2 (315 mg, 3.62 mmol) was
added. After the reaction mixture was allowed to stir for 4 h, it
was filtered through celite and the solvent was removed in vacuo
to afford aldehyde 32 (38 mg, 84%, for 2 steps) as a light yellow so-
lid: 1H NMR d 9.98 (s, 1H), 7.48 (s, 1H), 7.17 (d, J = 2.9 Hz, 1H), 7.05
(s, 1H), 6.64 (d, J = 2.7 Hz, 1H), 4.00 (s, 3H), 3.85 (s, 3H); 13C NMR d
192.2, 153.5, 137.0, 132.0, 131.4, 124.2, 109.3, 99.4, 97.1, 55.4,
5.14. Stilbene 30
To aldehyde 28 (11 mg, 0.05 mmol) and phosphonate 29
(27 mg, 0.06 mmol) in THF (1.5 mL) at rt was added NaH (40 mg,
1.0 mmol, 60% dispersion in oil). After the reaction mixture was al-
lowed to stir for 6 h, it was quenched by addition of NH4Cl (satd)
and then extracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4), filtered, and the filtrate was
concentrated in vacuo. Final purification by flash column chroma-
tography (50% Et2O in hexanes) afforded stilbene 30 (19 mg, 71%)
as a light yellow oil: 1H NMR d 7.11 (d, J = 16.1 Hz, 1H), 7.10 (s,
1H), 7.01 (d, J = 16.2 Hz, 1H), 7.00 (s, 1H), 6.98 (d, J = 3.1 Hz, 1H),
6.92 (s, 1H), 6.89 (s, 1H), 6.56 (d, J = 3.0 Hz, 1H), 5.39 (s, 2H), 4.78
(d, J = 6.9 Hz, 1H), 4.66 (d, J = 6.9 Hz, 1H), 3.92 (s, 3H), 3.72 (s,
3H), 3.57 (s, 3H), 3.42 (s, 3H), 3.29 (dd, J = 11.5, 4.0 Hz, 1H), 2.74–
2.71 (m, 2H), 2.17–2.12 (m, 1H), 1.87–1.57 (m, 4H), 1.25 (s, 3H),
1.10 (s, 3H), 0.92 (s, 3H); 13C NMR d 150.7, 148.9, 142.3, 138.4,
132.7, 129.3, 128.2, 127.7, 126.8, 122.6, 120.2, 119.5, 106.7,
102.3, 101.5, 98.4, 96.1, 94.8, 84.0, 76.9, 56.1, 55.7, 55.6, 47.0,
38.2, 37.6, 33.0, 29.7, 25.3, 23.1, 19.8, 15.1; HRMS (EI) calcd for
33.2; HRMS (EI) calcd for
189.0787.
C
11H11NO2 (M+)189.0790; found
5.18. Phosphonate 33
To phosphonate 298 (81 mg, 0.17 mmol) in EtOH (3 mL) was
added TsOH (80 mg, 0.42 mmol) and the reaction flask was
wrapped in foil. The reaction mixture was allowed to stir for
2 days, then quenched by addition of NaHCO3 (satd), and extracted
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and filtered, and then concentrated in vacuo. Final
purification by flash column chromatography (3% EtOH in Et2O)
afforded phosphonate 33 (62 mg, 85%) as a colorless oil: 1H NMR
d 6.66–6.65 (m, 1H), 6.64–6.62 (m, 1H), 4.07–3.99 (m, 4H), 3.83
(s, 3H), 3.39 (dd, J = 11.5, 3.9 Hz, 1H), 3.05 (d, JHP = 21.1 Hz, 2H),
2.69–2.66 (m, 2H), 2.13–2.09 (m, 1H), 1.90–1.59 (m, 5H), 1.26 (t,
J = 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H), 1.22 (s, 3H), 1.08 (s, 3H),
0.86 (s, 3H); 13C NMR d 148.6 (d, JCP = 3.1 Hz), 141.5 (d, JCP = 3.6 -
Hz), 122.7 (d, JCP = 7.5 Hz), 122.6 (d, JCP = 3.1 Hz), 122.0 (d,
JCP = 9.2 Hz), 111.8 (d, JCP = 5.9 Hz), 77.9, 77.7, 62.1 (d, JCP = 6.8 Hz),
62.0 (d, JCP = 6.7 Hz), 46.6, 38.3, 37.6, 33.1 (d, JCP = 138.1 Hz), 28.2,
27.3, 23.0, 19.7, 16.4 (d, JCP = 6.1 Hz), 16.4 (d, JCP = 6.2 Hz), 14.2;
31P NMR d 27.1; HRMS (EI) calcd for C22H35O6P (M+) 426.2171
found 426.2177.
C
32H41NO6 (M+) 535.2934; found 535.2919.
5.15. Indole 20
To stilbene 30 (19 mg 0.035 mmol) in a 1:1 mixture of THF and
MeOH (2 mL) was added TsOH (30 mg, 0.16 mmol) and the result-
ing solution was allowed to stir at rt overnight. It was then
quenched by addition of NaHCO3 (satd) and extracted with EtOAc.
The combined organic layers were washed with brine, dried
(MgSO4), and filtered and then concentrated in vacuo. Final purifi-
cation by flash column chromatography (40% EtOAc in hexanes)
afforded analogue 20 (8 mg, 51%) as a light yellow oil: 1H NMR d
7.05 (d, J = 16.1 Hz, 1H), 7.00 (s, 1H), 6.98 (d, J = 3.1 Hz, 1H), 6.97
(d, J = 16.5 Hz, 1H), 6.91 (s, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 6.50 (d,
J = 3.1 Hz, 1H), 5.24 (br s, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.44 (dd,
J = 11.6, 3.8 Hz, 1H), 2.75–2.72 (m, 2H), 2.17–2.11 (m 1H), 1.90–
1.55 (m, 5H), 1.25 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); 13C NMR d
148.9, 148.9, 142.3, 138.8, 132.9, 129.3, 128.2, 127.5, 127.0,
122.6, 120.3, 117.8, 106.6, 101.6, 101.5, 97.4, 78.0, 56.0, 46.7,
38.4, 37.6, 33.1, 29.7, 28.2, 27.3, 19.8, 14.3; HRMS (EI) calcd for
5.19. Analogue 21
To phosphonate 33 (31 mg, 0.073 mmol) and aldehyde 32
(12 mg, 0.063 mmol) in THF (1 mL) was added NaH (40 mg,
1.0 mmol, 60% dispersion in oil) and 15-crown-5 (1 drop). The
solution was allowed to stir overnight, then quenched by addition
of NH4Cl (satd) and finally extracted with EtOAc. The combined or-
ganic extracts were washed with brine, dried (MgSO4), and filtered,
and the filtrate was concentrated in vacuo. Final purification by
flash column chromatography (45% EtOAc in hexanes) afforded
analogue 21 (15 mg, 51%) as a yellow oil: 1H NMR d 7.11 (d,
J = 16.1 Hz, 1H), 7.04–6.99 (m, 2H), 6.96 (d, J = 3.2 Hz, 1H), 6.93
(d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.5 Hz, 1H), 6.75 (s, 1H), 6.55 (d,
J = 2.9 Hz, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.79 (s, 3H), 3.44 (dd,
J = 11.7, 4.0 Hz, 1H), 2.75–2.72 (m, 2H), 2.17–2.12 (m, 1H), 1.90–
1.60 (m, 5H), 1.27 (s, 3H), 1.11 (s, 3H), 0.90 (s, 3H); 13C NMR d
153.3, 148.9, 142.3, 138.3, 132.6, 129.4, 128.0, 127.9, 126.6,
122.6, 120.2, 118.8, 106.7, 101.8, 98.5, 97.2, 78.0, 77.0, 56.0, 55.3,
46.7, 38.4, 37.6, 33.1, 28.3, 27.4, 23.2, 19.8, 14.3; HRMS (EI) calcd
for C29H35NO4 (M+) 461.2566; found 461.2569.
C
28H33NO4 (M+) 447.2410; found 447.2422.
5.16. N,O-Dimethylindole 31
To indole 22 (500 mg, 2.43 mmol) in a mixture of THF and DMF
(5:1) at 0 °C was added NaH (224 mg, 5.6 mmol, as a 60% disper-
sion in oil), followed after 20 min by MeI (0.34 mL, 5.35 mmol).
The reaction was allowed to stir for 3 h, then quenched by addition
of NH4Cl (satd), and finally extracted with EtOAc. The combined or-
ganic extracts were washed with brine, dried (MgSO4), filtered and
the filtrate was concentrated in vacuo. Final purification by flash
column chromatography (20% EtOAc in hexanes) afforded indole
31 (460 mg, 81%) as a white solid with 1H and 13C NMR spectra
identical to those of material obtained above.
5.20. Geranyl indole 34
According to the procedure of Zhu and Ganesan,25 to indole 23
(824 mg, 3.76 mmol), TBAI (663 mg, 1.80 mmol), and Zn(OTf)2
(745 mg, 2.05 mmol) were allowed to react in a mixture of toluene
(16 mL), and CH2Cl2 (2 mL) and DIPEA (0.66 mL, 3.76 mmol). After
stirring for 15 min, geranyl bromide (371 mg, 1.71 mmol) was
added dropwise and after an additional 2.5 h the reaction mixture
was quenched by addition of NH4Cl (satd) and finally extracted
5.17. Aldehyde 32
To indole 31 (54 mg, 0.24 mmol) in THF (5 mL) at 0 °C was
added LiAlH4 (28 mg, 0.73 mmol), and the reaction was allowed

2550
J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
with EtOAc. The combined organic layers were washed with brine,
dried (MgSO4), and filtered and then concentrated in vacuo. Final
purification by flash column chromatography (17% EtOAc in hex-
anes) afforded the geranylated indole 34 (325 mg, 53%) as a color-
less oil along with recovered starting indole (436 mg): 1H NMR d
8.18 (br s, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.15 (d, J = 1.0 Hz, 1H),
6.94–6.93 (m, 1H), 5.49–5.44 (m, 1H), 5.15–5.10 (m, 1H), 4.39 (q,
J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.64 (d, J = 7.2 Hz, 2H), 2.14–2.04 (m,
4H), 1.71 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H);
13C NMR d 167.7, 154.5, 137.1, 135.3, 131.3, 124.7, 124.7, 123.5,
123.2, 120.9, 117.2, 107.4, 99.8, 60.7, 55.3, 39.7, 26.7, 25.7, 25.3,
17.7, 16.0, 14.4; HRMS (EI) calcd for C22H29NO3 (M+) 355.2147;
found 355.2152.
5.23. Geranylated stilbene 37
To phosphonate 36 (100 mg, 0.17 mmol) and aldehyde 15
(40 mg, 0.13 mmol) in THF (1.0 mL) at 0 °C was added NaH
(60 mg, 1.0 mmol, 60% oil dispersion) and 15-crown-5 (1 drop).
When the aldehyde had disappeared as judged by TLC, the reaction
was quenched by addition of NH4Cl (satd), and extracted with
Et2O. The combined organic extracts were dried (MgSO4), and fil-
tered, and then concentrated in vacuo. Final purification by flash
column chromatography (30% EtOAc in hexanes) afforded ana-
logue 37 (37 mg, 38%) as an oil which was used directly in the next
step: 1H NMR d 7.73 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 0.9 Hz, 1H), 7.20
(d, J = 8.1 Hz, 2H), 7.09 (t, J = 1.1 Hz, 1H), 7.04–7.03 (m, 2H), 6.94–
6.93 (m, 1H), 6.91–6.90 (m, 1H), 6.79 (s, 1H), 5.42–5.37 (m, 1H),
5.15–5.11 (m, 1H), 3.93 (s, 3H), 3.90, (s, 3H), 3.51–3.42 (m, 3H),
2.76–2.73 (m, 2H), 2.17–2.04 (m, 5H), 1.91–1.82 (m, 3H), 1.75–
1.59 (m, 11H), 1.27 (s, 3H), 1.11 (s, 3H), 0.90 (s, 3H); 13C NMR d
154.6, 149.0, 144.6, 142.7, 137.5, 136.6, 135.7, 135.4, 131.5, 129.7
(2C), 128.9, 128.2, 127.0, 126.7 (2C), 124.2, 123.5, 122.7, 121.8,
121.7, 120.5, 120.0, 106.9, 105.4, 101.4, 78.0, 77.1, 56.0, 55.2,
46.8, 39.7, 38.4, 37.7, 28.3, 27.3, 26.6, 25.7, 25.6, 23.2, 21.5, 19.8,
17.7, 16.0, 14.3.
5.21. Benzylic alcohol 35
To indole 34 (325 mg, 0.91 mmol) in THF (10 mL) at 0 °C was
added NaH (44 mg, 1.1 mmol, 60% dispersion in oil) followed by
TsCl (183 mg, 0.96 mmol). When the reaction was judged complete
by TLC, DIBALH (0.53 mL, 2.97 mmol) was added dropwise. After
an additional h the solution was quenched by addition of NH4Cl
(satd), diluted with EtOAc, acidified with 1 M HCl to dissolve the
solids, and finally extracted with EtOAc. The combined organic lay-
ers were washed with NaHCO3 (satd), brine, dried (MgSO4), and fil-
tered and then concentrated in vacuo. Final purification by flash
column chromatography (35% EtOAc in hexanes) afforded alcohol
35 (273 mg, 64%) as a colorless oil: 1H NMR d 7.68 (d, J = 8.4 Hz,
2H), 7.54 (s, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.09 (s, 1H), 6.62 (s, 1H),
5.41–5.37 (m, 1H), 5.15–5.11 (m, 1H), 4.71 (s, 2H), 3.79 (s, 3H),
3.50 (d, J = 7.0 Hz, 2H), 2.74 (br s, 1H), 2.26 (s, 3H), 2.14–2.04 (m,
4H), 1.67 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H); 13C NMR d 154.6,
144.5, 139.0, 136.9, 136.5, 135.2, 131.4, 129.6 (2C), 126.5 (2C),
124.0, 123.1, 121.7, 121.4, 119.8, 104.8, 102.8, 65.6, 55.1, 39.6,
26.5, 25.6, 25.5, 21.3, 17.6, 15.9; HRMS (EI) calcd for C27H33NO4S
(M+) 467.2130; found 467.2135.
5.24. Analogue 38
Stilbene 37 (37 mg, 0.05 mmol) in THF (2 mL) was added to a
solution of NaH (150 mg, 3.75 mmol, 60% dispersion in oil) in 2-
propanol (2 mL) and the solution was allowed to stir overnight.
The reaction mixture was then quenched by addition of H2O and
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), filtered, and then concentrated in vacuo.
Final purification by flash column chromatography (45% EtOAc in
hexanes) afforded schweinfurthin analogue 38 (17 mg, 58%, or
22% over two steps from compound 36) as a colorless oil: 1H
NMR d 7.91 (br s, 1H), 7.02–6.99 (m, 3H), 6.91–6.90 (m, 1H).
6.88–6.87 (m, 1H), 6.78 (s, 1H), 6.68 (s, 1H), 5.50–5.46 (m, 1H),
5.16–5.12 (m, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.63 (d, J = 7.2 Hz,
2H), 3.46–3.41 (m, 1H), 2.75–2.71 (m, 2H), 2.16–2.06 (m, 5H),
1.90–1.61 (m, 14H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); 13C
NMR d 155.0, 148.9, 142.3, 138.4, 135.0, 132.9, 131.3, 129.5,
127.9, 126.5, 124.5, 123.8, 122.6, 120.6, 120.2, 117.2, 117.0,
106.9, 103.3, 97.4, 78.0, 56.0, 55.1, 46.8, 39.8, 38.4, 37.7, 28.3,
27.4, 26.8, 25.7, 25.5, 23.2, 19.8, 17.7, 16.0, 14.3; HRMS (EI) calcd
for C38H49NO4 (M+) 583.3662; found 583.3672.
5.22. Phosphonate 36
To benzylic alcohol 35 (269 mg, 0.58 mmol) in THF (10 mL) was
added LiBr (400 mg, 4.60 mmol) and the solution was cooled to
0 °C. Next Et3N (0.32 mL, 2.3 mmol) followed after 10 min by MsCl
(0.13 mL, 1.73 mmol) were added, and the reaction mixture was al-
lowed to stir for 2 h. The reaction mixture was then quenched by
addition of NH4Cl (satd) and extracted with Et2O. The combined or-
ganic extracts were washed with brine, dried (MgSO4), and filtered,
and the filtrate was concentrated in vacuo. The resulting oil was
dissolved in P(OEt)3 (2 mL) and heated at reflux. The next day
the reaction was allowed to cool to rt, then poured into Et2O,
washed with H2O, brine, dried (MgSO4), and filtered, and finally
the filtrate was concentrated in vacuo. Final purification by flash
column chromatography (2.5–3% MeOH in Et2O) afforded phos-
phonate 36 (273 mg, 81%) as a colorless oil; 1H NMR d 7.71 (d,
J = 8.4 Hz, 2H), 7.50 (dd, J = 3.0, 1.1 Hz, 1H), 7.19 (d, J = 8.4 Hz,
2H), 7.07–7.06 (m, 1H), 6.62–6.61 (m, 1H), 5.41–5.36 (m, 1H),
5.15–5.11 (m, 1H), 4.02–3.96 (m, 4H), 3.84 (s, 3H), 3.49 (d,
J = 7.2 Hz, 2H), 3.23 (d, JPH = 21.4 Hz, 2H), 2.33 (s, 3H), 2.14–2.05
(m, 4H), 1.70 (d, J = 0.8 Hz, 3H), 1.67 (d, J = 1.0 Hz, 3H), 1.62 (s,
3H), 1.24 (t, J = 7.1 Hz, 6H); 13C NMR d 154.3 (d, JCP = 3.0 Hz),
144.4, 137.0 (d, JCP = 3.1 Hz), 136.5, 135.4, 131.4, 129.6 (2C),
129.1 (d, JCP = 9.1 Hz), 126.6 (2C), 124.1, 123.1 (d, JCP = 1.6 Hz),
121.6, 121.4 (d, JCP = 1.3 Hz), 119.3 (d, JCP = 3.2 Hz), 107.8 (d,
JCP = 7.9 Hz), 105.8 (d, JCP = 5.5 Hz), 62.1 (d, JCP = 6.6 Hz, 2C), 55.2,
39.6, 34.3 (d, JCP = 138.1 Hz), 26.6, 25.6, 25.5, 21.4, 17.6, 16.3 (d,
JCP = 5.9 Hz, 2C), 16.0; 13P NMR d 26.2; HRMS (EI) calcd for C31H42-
NO6PS (M+) 587.2470; found 587.2481.
5.25. Prenylated indole 39
To indole 23 (388 mg, 1.77 mmol), TBAI (360 mg, 0.98 mmol),
and Zn(OTf)2 (436 mg, 1.2 mmol) in a 5:1 mixture of toluene and
CH2Cl2 (12 mL) at rt was added DIPEA (0.38 mL, 2.2 mmol) and
the reaction mixture was allowed to stir for 10 min. Prenyl bro-
mide (126 mg, 0.88 mmol) was added dropwise. After 2 h the reac-
tion mixture was quenched by addition of NH4Cl (satd) and
extracted with EtOAc. The combined organic extracts were washed
with H2O, dried (MgSO4), and filtered, and the filtrate was concen-
trated in vacuo. Final purification by flash column chromatography
(10–15% EtOAc in hexanes) afforded prenylated indole 39 (209 mg,
59%) along with recovered indole 23 (149 mg) as expected based
on the literature precedent:25 1H NMR d 8.31 (br s, 1H), 7.74 (d,
J = 1.0 Hz, 1H), 7.15 (d, J = 0.5 Hz, 1H), 6.94–6.93 (m, 1H), 5.47–
5.42 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.63 (d,
J = 7.2 Hz, 2H), 1.75 (s, 3H), 1.72 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H);
13C NMR d 167.8, 154.4, 137.1, 131.5, 124.6, 123.7, 123.2, 120.8,
117.1, 107.4, 99.8, 60.7, 55.3, 25.7, 25.4, 17.7, 14.4; HRMS (EI) calcd
for C17H21NO3 (M+) 287.1521; found 287.1523.

J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
2551
5.26. Alcohol 40
indole 43 (13.5 mg, 38% for two steps) as a light yellow oil: 1H
NMR d 7.90 (br s, 1H), 7.03 (d, J = 16.0 Hz, 1H), 7.01 (s, 1H), 6.96
(d, J = 16.2 Hz, 1H), 6.91–6.90 (m, 1H), 6.88–6.87 (m, 1H), 6.79–
6.78 (m, 1H), 6.68 (s, 1H) 5.49–5.44 (m, 1H), 3.97 (s, 3H), 3.90 (s,
3H), 3.61 (d, J = 7.2 Hz, 2H), 3.46–3.41 (m, 1H), 2.75–2.72 (m,
2H), 2.17–2.10 (m, 1H), 1.91–1.59 (m, 5H), 1.75 (s, 3H), 1.73 (s,
3H), 1.26 (s, 3H), 1.11 (s, 3H), 0.89 (s, 3H); 13C NMR d 155.0,
148.9, 142.3, 138.3, 132.9, 131.2, 129.5, 127.9, 126.5, 124.0,
122.6, 120.5, 120.2, 117.2, 117.0, 106.9, 103.3, 97.4, 78.1, 77.0,
56.0, 55.1, 46.8, 38.3, 37.7, 28.3, 27.3, 25.8, 25.6, 23.3, 19.8, 17.7,
To a solution of indole 39 (18 mg, 0.06 mmol) in THF (3 mL) at rt
was added NaH (5 mg, 0.13 mmol, 60% dispersion oil) and the reac-
tion mixture was allowed to stir for 10 min. After TsCl (15 mg,
0.08 mmol) was added, the solution was stirred for 2 h and then
DIBALH (0.05 mL, 0.44 mmol) was added dropwise. After an addi-
tional 30 min, the reaction was quenched with NH4Cl (satd),
poured into EtOAc, acidified with 1 M HCl, and extracted with
EtOAc. The combined organic extracts were washed with NaHCO3
(satd), and brine, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification by flash column chroma-
tography (35% EtOAc in hexanes) afforded the benzylic alcohol 40
(19 mg, 76%): 1H NMR d 7.70 (d, J = 8.1 Hz, 2H), 7.53 (s, 1H), 7.15 (d,
J = 8.3 Hz, 2H), 7.10 (s, 1H), 6.64 (s, 1H), 5.39–5.35 (m, 1H), 4.72 (s,
2H), 3.82 (s, 3H), 3.49 (d, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.76 (s, 3H),
1.68 (s, 3H); 13C NMR d 154.7, 144.6, 139.0, 136.9, 135.2, 132.9,
129.7 (2C), 126.6 (2C), 123.1, 121.8, 121.5, 119.8, 104.9, 102.9,
65.7, 55.2, 25.7, 25.6, 21.4, 17.7; HRMS (EI) calcd for C22H25NO4S
(M+) 399.1504; found 399.1508.
14.3; HRMS (EI) calcd for
515.3040.
C
33H41NO4 (M+) 515.3036; found
5.29. Phosphonate 45
Through a variation of our earlier procedure, alcohol 448
(204 mg, 0.66 mmol) in THF (10 mL) at 0 °C was treated with LiBr
(400 mg, 4.6 mmol) and Et3N (0.37 mL, 2.65 mmol), and then after
5 min MsCl (0.13 mL, 1.65 mmol) was added. After 90 min, the
reaction mixture was quenched by addition of water and extracted
with Et2O. The combined organic extracts were washed with brine,
dried (MgSO4), and filtered, and the filtrate was concentrated in va-
cuo. The resulting residue was dissolved in P(OEt)3 (3 mL) and the
solution was heated to reflux overnight. The next day the solution
was allowed to cool to rt and then concentrated in vacuo. Final
purification by flash column chromatography (2% EtOH in Et2O)
afforded phosphonate 45 (297 mg, 90%) as an oil whose 1H and
13C NMR spectra were consistent with those from previously pre-
pared materials.8
5.27. Phosphonate 41
To alcohol 40 (102 mg, 0.25 mmol) in THF (5 mL) at 0 °C was
added LiBr (133 mg, 1.53 mmol) and Et3N (0.11 mL, 0.79 mmol).
The solution was stirred for 5 min, MsCl (0.05 mL, 0.65 mmol)
was added dropwise, and the reaction was allowed to warm to
rt. After 2 h it was quenched by addition of NH4Cl (satd), extracted
with Et2O, dried (MgSO4), and filtered, and the filtrate was concen-
trated in vacuo. To the resulting residue was added P(OEt)3 (2 mL)
and the solution was heated to 130 °C and allowed to stir over-
night. The next day the solution was allowed to cool to rt and
the solvent was removed in vacuo. Final purification by flash col-
umn chromatography (2% EtOH in Et2O) afforded indole phospho-
nate 41 (111 mg, 84%) as a colorless oil: 1H NMR d 7.72 (d,
J = 8.4 Hz, 2H), 7.50 (d, JHP = 2.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H),
7.07 (d, J = 1.1 Hz, 1H), 6.62 (s, 1H), 5.40–5.34 (m, 1H), 4.06–3.92
(m, 4H), 3.84 (s, 3H), 3.48 (d, J = 7.1 Hz, 2H), 3.23 (d, JHP = 21.5 Hz,
2H), 2.32 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H);
13C NMR d 154.3 (d, JCP = 2.9 Hz), 144.4, 136.9 (JCP = 2.9 Hz),
135.2, 132.9, 129.7 (2C), 129.1 (d, JCP = 9.8 Hz), 126.7 (2C), 123.1
(d, JCP = 1.7 Hz), 121.7, 121.3 (d, JCP = 1.6 Hz), 119.3 (d, JCP = 3.2 Hz),
107.8 (d, JCP = 7.8 Hz), 105.8 (d, JCP = 5.6 Hz), 62.0 (d, JCP = 2.9 Hz,
2C), 55.2, 34.2 (d, JCP = 138.2 Hz), 25.7, 25.6, 21.4, 17.7, 16.3 (d,
JCP = 6.0 Hz, 2C); 31P NMR d 26.2; HRMS (EI) calcd for C26H34NO6PS
(M+) 519.1844; found 519.1843.
5.30. Stilbene 46
To aldehyde 32 (15 mg, 0.08 mmol) and phosphonate 45
(48 mg, 0.10 mmol) in THF (3 mL) at 0 °C was added NaH (40 mg,
1.0 mmol, 60% dispersion oil) and 15-crown-5 (2 drops) and the
reaction mixture was allowed to warm to rt. The following day
the reaction mixture was quenched by addition of NH4Cl (satd)
and extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and filtered, and the filtrate
was concentrated in vacuo. Final purification by flash column chro-
matography (20% EtOAc in hexanes) afforded stilbene 46 (18 mg,
42%) as a light yellow oil: 1H NMR d 7.17 (d, J = 1.7 Hz, 1H), 7.08
(d, J = 16.8 Hz, 1H), 7.03 (s, 1H), 6.99 (d, J = 16.4 Hz, 1H), 6.98 (d,
J = 1.4 Hz, 1H), 6.94 (d, J = 3.1 Hz, 1H), 6.73 (s, 1H), 6.54 (d,
J = 2.9 Hz, 1H), 5.25 (d, J = 6.7 Hz, 1H), 5.21 (d, J = 6.5 Hz, 1H),
4.78 (d, J = 6.9 Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 4.01 (s, 3H), 3.78
(s, 3H), 3.55 (s, 3H), 3.41 (s, 3H), 3.29 (dd, J = 11.5, 3.9 Hz, 1H),
2.75–2.72 (m, 2H), 2.13–1.97 (m, 2H), 1.80–1.57 (m, 3H), 1.26 (s,
3H), 1.10 (s, 3H), 0.91 (s, 3H); 13C NMR d 153.3, 146.2, 143.6,
138.3, 132.7, 129.6, 128.2, 127.8, 126.4, 123.2, 121.7, 118.9,
113.4, 101.8, 98.5, 97.3, 96.2, 95.9, 84.0, 76.9, 56.2, 55.6, 55.3,
47.1, 38.3, 37.7, 33.0, 27.3, 25.3, 23.2, 19.9, 15.1; HRMS (EI) calcd
for C32H41NO6 (M+) 535.2934; found 535.2933.
5.28. Analogue 43
To phosphonate 41 (45 mg, 0.089 mmol) and aldehyde 15
(21 mg, 0.069 mmol) in THF (1 mL) at 0 °C was added NaH
(40 mg, 1.0 mmol, 60% dispersion oil) and 15-crown-5 (2 drops).
The reaction mixture was allowed to stir for 45 min, then
quenched by addition of NH4Cl (satd), and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
(MgSO4), and filtered, and then the filtrate was concentrated in va-
cuo. Purification by flash column chromatography (20–50% EtOAc
in hexanes) afforded a mixture of protected and unprotected in-
doles (26 mg). This mixture was treated with NaOi-Pr in THF
(3 mL), generated in situ from NaH (160 mg, 4 mol, 60% dispersion
oil) and i-PrOH, and the reaction mixture was allowed to stir over-
night. The next day the reaction mixture was quenched by addition
of H2O and extracted with EtOAc. The combined organic extracts
were washed with water and brine, dried (MgSO4), and filtered,
and the filtrate was concentrated in vacuo. Final purification by
flash column chromatography (45% EtOAc in hexanes) afforded
5.31. Analogue 47
To the MOM-protected analogue 46 (18 mg, 0.034 mmol) in 1:1
MeOH/THF (0.8 mL) protected from ambient light was added TsOH
(50 mg, excess) and the resulting solution was allowed to stir over-
night. The reaction mixture was quenched by addition of NH4Cl
(satd) and extracted with EtOAc. The combined organic layers were
washed with brine, dried (MgSO4), and filtered and the filtrate was
concentrated in vacuo. Final purification by flash column chroma-
tography (50% EtOAc in hexanes) afforded analogue 47 (9 mg, 60%)
as a light green oil: 1H NMR d 7.08 (d, J = 16.2 Hz, 1H), 7.02 (s, 1H),
7.00–6.95 (m, 2H), 6.94 (d, J = 3.0 Hz, 1H), 6.82 (d, J = 1.5 Hz, 1H),

2552
J. G. Kodet et al. / Bioorg. Med. Chem. 22 (2014) 2542–2552
6.73 (s, 1H), 6.54 (d, J = 2.6 Hz, 1H), 5.46 (br s, 1 OH), 4.01 (s, 3H),
3.78 (s, 3H), 3.45 (dd, J = 11.3, 4.0 Hz, 1H), 2.74–2.70 (m, 2H), 2.06–
2.01 (m, 1H), 1.91–1.60 (m, 4H), 1.55 (br s, 1 OH), 1.26 (s, 3H), 1.12
(s, 3H), 0.90 (s, 3H); 13C NMR d 153.3, 145.2, 139.7, 138.4, 132.7,
130.3, 128.3, 127.9, 126.5, 122.0, 119.2, 118.9, 119.4, 101.8, 98.5,
97.3, 77.9, 77.9, 55.3, 47.2, 38.5, 37.7, 33.0, 28.2, 27.3, 22.7, 20.2,
120.5, 119.2, 117.2, 117.1, 109.4, 103.4, 97.4, 77.9, 77.8, 55.1,
47.2, 38.5, 37.7, 28.2, 27.3, 25.8, 25.6, 22.7, 20.2, 17.7, 14.3; HRMS
(EI) calcd for C32H39NO4 (M+) 501.2879; found 501.2881.
Acknowledgments
14.3; HRMS (EI) calcd for
447.2404.
C
28H33NO4 (M+) 447.2410; found
We thank the UI Graduate College for a Presidential Fellowship
(to J.G.K.). This research was supported in part by the Intramural
Research Program of NIH, National Cancer Institute, Center for Can-
cer Research. Financial support from the Roy J. Carver Charitable
Trust as a Research Program of Excellence is gratefully acknowl-
edged. We thank the Developmental Therapeutics Program, NCI,
for the 60-cell testing.
5.32. Stilbene 49
To phosphonate 41 (45 mg, 0.089 mmol) and aldehyde 4811
(25.7 mg, 0.068 mmol) in THF (3 mL) at 0 °C was added NaH
(50 mg, 1.25 mmol, 60% dispersion oil) and 15-crown-5 (2 drops).
The reaction was allowed to warm to rt and then allowed to stir
for 4 h. To the reaction mixture was added 2-propanol (3 mL)
and NaH (40 mg, 1.0 mmol, 60% dispersion oil) and the solution
was allowed to stir. After 20 h the reaction was quenched by addi-
tion of NaHCO3 (satd) and extracted with EtOAc. The combined or-
ganic extracts were washed with brine, dried (MgSO4), and filtered,
and the filtrate was concentrated in vacuo. Final purification by
flash column chromatography (40% EtOAc in hexanes) afforded in-
dole 49 (20 mg, 51% for 2 steps) as a light yellow oil: 1H NMR d 7.89
(br s, 1H), 7.15 (d, J = 1.4 Hz, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 6.98–
6.97 (m, 2H), 6.78 (d, J = 1.1 Hz, 1H), 6.68 (s, 1H), 5.49–5.44 (m,
1H), 5.25 (d, J = 6.6 Hz, 1H), 5.20 (d, J = 6.6 Hz, 1H), 4.78 (d,
J = 6.9 Hz, 1H), 4.65 (d, J = 6.9 Hz, 1H), 3.97 (s, 3H), 3.61 (d,
J = 7.2 Hz, 2H), 3.55 (s, 3H), 3.41 (s, 3H), 3.29 (dd, J = 11.6, 3.9 Hz,
1H), 2.75–2.71 (m, 2H), 2.13–1.94 (m, 2H), 1.75–1.55 (m, 3H),
1.75 (s, 3H), 1.73 (s, 3H), 1.26 (s, 3H), 1.10 (s, 3H), 0.91 (s, 3H);
13C NMR d 155.0, 146.2, 143.6, 138.3, 132.9, 131.2, 129.6, 128.0,
126.3, 124.7, 123.3, 121.7, 120.5, 117.2, 117.0, 113.4, 103.4, 97.4,
96.2, 95.9, 84.0, 76.9, 56.2, 55.6, 55.1, 47.1, 38.3, 37.7, 27.4, 25.8,
25.6, 25.3, 23.2, 19.9, 17.7, 14.3; HRMS (EI) calcd for C36H47NO6
(M+) 589.3403; found 589.3416.
Supplementary data
Supplementary data (NMR spectra and complete bioassay data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmc.2014.02.043.
References and notes
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. Klausmeyer, P.; Van, Q. N.; Jato, J.; McCloud, T. G.; Beutler, J. A. J. Nat. Prod. 2010,
73, 479.
4. Thoison, O.; Hnawia, E.; Gueritte-Voegelein, F.; Sevenet, T. Phytochemistry
1992, 31, 1439.
5. Yoder, B. J.; Cao, S. G.; Norris, A.; Miller, J. S.; Ratovoson, F.; Razafitsalama, J.;
Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I. J. Nat. Prod. 2007, 70,
342.
6. van der Kaaden, J. E.; Hemscheidt, T. K.; Mooberry, S. L. J. Nat. Prod. 2001, 64,
103.
7. 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.
8. Mente, N. R.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2008, 73, 7963.
9. Topczewski, J. J.; Neighbors, J. D.; Wiemer, D. F. J. Org. Chem. 2009, 74, 6965.
10. Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2011, 76, 909.
11. Topczewski, J. J.; Wiemer, D. F. Tetrahedron Lett. 2011, 52, 1628.
12. Neighbors, J. D.; Topczewski, J. J.; Swenson, D. C.; Wiemer, D. F. Tetrahedron
Lett. 2009, 50, 3881.
5.33. Analogue 50
13. Topczewski, J. J.; Callahan, M. P.; Kodet, J. G.; Inbarasu, J. D.; Mente, N. R.;
Beutler, J. A.; Wiemer, D. F. Bioorg. Med. Chem. 2011, 19, 7570.
14. Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org. Chem. 2005, 70, 925.
15. 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.
16. Topczewski, J. J.; Kuder, C. H.; Neighbors, J. D.; Hohl, R. J.; Wiemer, D. F. Bioorg.
Med. Chem. 2010, 18, 6734.
17. Ulrich, N. C.; Kuder, C. H.; Hohl, R. J.; Wiemer, D. F. Bioorg. Med. Chem. Lett.
2010, 20, 6716.
To protected analogue 49 (12.2 mg, 0.021 mmol) was added 1:1
THF/MeOH (2 mL) and TsOH (35 mg, 0.18 mmol) and the reaction
mixture was allowed to stir overnight. The next day the reaction
mixture was quenched by addition of NH4Cl (satd) and extracted
with EtOAc. The combined organic extracts were washed with
brine, dried (MgSO4), and filtered, and the filtrate was concentrated
in vacuo. Final purification by flash column chromatography (25–
50% EtOAc in hexanes) afforded analogue 50 (6.4 mg, 62%) as an
oil: 1H NMR d 7.89 (br s, 1H), 7.01 (d, J = 16.1 Hz, 1H), 7.00 (s,
1H), 6.97 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 16.2 Hz, 1H), 6.80–6.78
(m, 2H), 6.67 (s, 1H), 5.49–5.44 (m, 2H), 3.97 (s, 3H), 3.61 (d,
J = 7.2 Hz, 2H), 3.45 (dd, J = 11.2, 4.0 Hz, 1H), 2.78–2.63 (m, 2H),
2.06–2.00 (m, 1H), 1.93–1.58 (m, 5H), 1.75 (s, 3H), 1.73 (s, 3H),
1.25 (s, 3H), 1.12 (s, 3H), 0.89 (s, 3H); 13C NMR d 155.0, 145.2,
139.7, 138.3, 132.9, 131.2, 130.3, 128.2, 126.4, 124.1, 122.0,
18. Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.; Arya, P. Chem.
Rev. 2009, 109, 1999.
19. Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
20. Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195.
21. Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2013, 78, 9291.
22. Kodet, J. G., Ph. D. Thesis, University of Iowa, 2010.
23. Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69, 6945.
24. Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F. J. Org. Chem. 1999, 64, 8718.
25. Zhu, X. W.; Ganesan, A. J. Org. Chem. 2002, 67, 2705.