Synthesis of indole analogues of the natural schweinfurthins

Article abstract of DOI:10.1021/jo4014244

An interest in the schweinfurthins, natural stilbenes with significant antiproliferative activity, has prompted efforts to prepare a set of indole analogues. To approach the desired compounds through a Horner-Wadsworth-Emmons condensation, new indole derivatives bearing a phosphonomethyl substituent in the B-ring were required. The parent indole system with the necessary substitution pattern was obtained through Stobbe condensation and cyclization. A prenyl substituent was incorporated at the C3 position of a 4,6-disubstituted indole through a highly regioselective electrophilic aromatic substitution reaction, while metalation and alkylation provided the C2-prenylated indole. After introduction of the phosphonate group through classical reactions, the new indole phosphonates were found to undergo the desired condensation with nonracemic aldehydes representing the schweinfurthin left half. This approach provides facile access to new heteroaromatic analogues of the natural schweinfurthins and should be applicable to many other natural stilbenes as well.

Full text of DOI:10.1021/jo4014244

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Article
Synthesis of Indole Analogues of the Natural Schweinfurthins
John G. Kodet, and David F. Wiemer
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4014244 • Publication Date (Web): 19 Aug 2013
Downloaded from http://pubs.acs.org on August 21, 2013
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Synthesis of Indole Analogues of the Natural
Schweinfurthins
John G. Kodet and David F. Wiemer*
Department of Chemistry University of Iowa, Iowa City, Iowa 52242-1294
david-wiemer@uiowa.edu
RECEIVED DATE:
TITLE RUNNING HEAD: Synthetic schweinfurthin indoles.
KEYWORDS. Schweinfurthin, indole, stilbene analogues, phosphonate.
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Table of Contents Graphic:
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OCH3
OCH3
O
O
H
OH
N
HO
H
HO
H
R'
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R
OH
OH
Schweinfurthin F
indole analogues
R = R' = H
R = prenyl; R' = H
R = H; R' = prenyl
Abstract.
An interest in the schweinfurthins, natural stilbenes with significant anti-proliferative
activity, has prompted efforts to prepare a set of indole analogues. To approach the desired
compounds through a Horner-Wadsworth-Emmonds condensation, new indole derivatives
bearing a phosphonomethyl substituent in the B-ring were required. The parent indole system
with the necessary substitution pattern was obtained through a Stobbe condensation and
cyclization. A prenyl substituent was incorporated at the C-3 position of a 4,6-disubstituted
indole through a highly regioselective electrophilic aromatic substitution reaction, while
metalation and alkylation provided the C-2 prenylated indole. After introduction of the
phosphonate group through classical reactions, the new indole phosphonates were found to
undergo the desired condensation with nonracemic aldehydes representing the schweinfurthin
left half. This approach gives facile access to new heteroaromatic analogues of the natural
schweinfurthins, and should be applicable to many other natural stilbenes as well.
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Introduction.
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The schweinfurthins (Figure 1), a small group of rare natural products,1,2 display a novel
pattern of differential activity in the National Cancer Institute’s (NCI) 60 cell line screen. Their
activity pattern suggests that these compounds act on a novel target or through a new
mechanism,1 and thus these compounds can be viewed as potential leads for further drug
development. To alleviate the scarcity of these natural products, to access novel analogues, and
to explore the limits of the pharmacophore, we have undertaken the synthesis of both natural
schweinfurthins and a range of analogues.3-9 After an analysis of new compounds of potential
interest, we considered the possibility of incorporating an indole in the stilbene system. The
indole substructure is so common in both natural products and pharmaceutical agents that it often
is considered a privileged scaffold.10,11 Incorporation of an indole motif might afford analogues
with comparable or improved activity while at the same time increasing bioavailability.12,13
Furthermore, the D-ring resorcinol of the natural schweinfurthins may limit the schweinfurthins’
stability, and proper placement of an indole system might improve the chemical stability as well.
Based on this rationale, synthesis of indole analogues of the schweinfurthins became a goal of
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our program.
OR'
R
O
OH
HO
H
H
n
OH
Schweinfurthin A
1 R = OH, R' = H, n = 2
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
5 R = H, R' = H, n = 2
6 R = H, R' = H, n = 2
Schweinfurthin G
3-Deoxyschweinfurthin A
3-Deoxyschweinfurthin B
Figure 1. Some natural schweinfurthins (1 – 4) and some synthetic analogues (5, 6).
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There are multiple ways that an indole moiety could be superimposed upon the D-ring of
the natural schweinfurthins. The pattern pursued in this study would view the indole nitrogen as
a replacement for one of the resorcinol oxygens, and incorporate the remainder of the indole ring
as a substituent on the position para to the stilbene olefin (Figure 2). These structures would
exploit the known flexibility of the para position to modification with preservation of biological
activity.4,7,8 Furthermore, preparation of intermediates leading to structures 7 and 8 might be
readily modified to allow addition of isoprenoid substituents to the 5-membered ring, via
electrophilic aromatic substitution (which is favored at C-3 of indole itself14 and would lead to
compound 9) or via anion chemistry (which can be directed to C-2 in N-substituted indoles and
would provide compound 10).15,16 Because both compounds 9 and 10 represent modest
deviations from the natural products in terms of the position of the prenyl group both series were
of interest, and a strategy that could diverge to both isomers at a later stage would be particularly
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attractive.
OR
O
H
N
HO
H
OH
7 R = H
8 R = CH3
OCH3
O
H
N
HO
H
R'
9
R = prenyl, R' = H
R
OH
10 R = H, R' = prenyl
Figure 2. First generation indole targets.
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Our foray into schweinfurthin studies began with synthesis of schweinfurthin C,17 and
that early effort established the strategy of a late stage Horner-Wadsworth-Emmons (HWE)
condensation for construction of the trans-stilbene olefin. To take advantage of intermediates
already in hand from previous research, especially the now readily available R,R,R-aldehydes 11
and 12 that carry all of the schweinfurthin stereogenic centers (Scheme 1), would require an
indole phosphonate such as compound 13. Given the vast number of known indoles it was
somewhat surprising to find that apparently only C-218 and C-319 phosphonomethyl compounds
have been prepared. Based on the assumption that phosphonate 13 could be prepared from the
corresponding alcohol 14, which in turn should be available from the ester 15, routes to these
two potential intermediates were considered. The presence of the “benzylic” alcohol of
compound 14 might not be tolerated by many of the classical methods20 for de novo indole
synthesis because of their reliance on acidic conditions, and the recent Kraus indole synthesis
appears to be better suited for preparation of 2-substituted or 2,3-disubstituted compounds.21,22
However, preparation of the substituted indole 15 has been reported through an approach based
on a Stobbe condensation of a succinate diester (17) and 2-pyrrole carboxaldehyde (18) followed
by cyclization of the intermediate acid 16.23 While the initial report did not provide a complete
characterization of the product, a more recent study from the Vedejs labs placed this approach on
a solid foundation and proved that it does afford the desired substitution pattern.24 Therefore we
began an effort to obtain the targeted schweinfurthin analogues with preparation of several
indoles based on this strategy.
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OR
PG
O
7
8
9
O
N
(EtO)2P
+
R'
H
HO
H
R
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O
OMOM
13
11 R = CH3
12 R = MOM
O
H
PG
N
N
RO
HO
R'
R
OH
OMOM
15
14
O
O
O
H
H
N
+
N
H
RO
RO
OR
O
17
18
O
16
OH
Scheme 1. Retrosynthetic analysis.
Results and Discussion.
The Stobbe condensation of diethyl succinate with 2-pyrrole carboxaldehyde (18)
smoothly gave the half ester 19 as expected.24 Without extensive purification, this material was
treated with a mixture of acetic anhydride and acetic acid (6:1) in refluxing toluene to induce
cyclization (Scheme 2). These conditions resulted in formation of the acetate-protected indole
20 (74%) accompanied by small amounts of the indolizine 21 (~1%), also as expected,24 while a
parallel reaction in THF at reflux gave a less favorable product ratio (42% and 19%,
respectively). Attempts to extend this approach to the brominated pyrrole 22, which might be
useful for elaboration of the final products through halogen-metal exchange or cross coupling
reactions,25 were more complex. While the desired half ester 22 was readily prepared by a
Stobbe condensation, treatment of compound 22 under standard cyclization conditions gave only
trace amounts of the desired indole 23 and afforded the indolizine 24 as the major product
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instead. Compound 24 is highly fluorescent and might be useful for synthesis of new types of
fluorescent schweinfurthin analogues.26 However, for the immediate goal, N-protection of the
pyrrole aldehyde would circumvent this issue as observed with N-methyl pyrrole.27 Because
previous syntheses of schweinfurthin analogues employed MOM-protected phenols, the half
ester 25 was prepared by Stobbe condensation of the MOM-protected aldehyde. In this case,
cyclization under the standard conditions afforded only the desired indole product 26. In a
similar sense, after the pyrrole 18 was protected as its MOM derivative 27, cyclization of the
Stobbe product now gave only the desired indole 28. Because a late stage deprotection of the
indole MOM group ultimately proved more difficult than expected (vide infra), pyrrole aldehyde
18 also was protected as its tosyl derivative. However, in this case attempted Stobbe
condensation proved problematic, so introduction of this group at this stage of the sequence was
not pursued further.
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O
O
R
R
N
EtO2C
HO2C
N
EtO
EtO
X
conditions
N
X
X
OAc
OAc
Ac2O, AcOH, toluene
Ac2O, AcOH, THF
Ac2O, KOAc
19 R = H, X = H
22 R = H, X = Br
25 R = MOM, X = Br
27 R = MOM, X = H
20 R = H, X = H (74%)
23 R = H, X = Br (trace)
26 R = MOM, X = Br (79%)
28 R = MOM, X = H (82%)
21 X = H (1%)
24 X = Br (79%)
Ac2O, KOAc
Scheme 2. Cyclization to indoles and indolizines
After hydrolysis of the acetate group of indole 20, treatment of the resulting phenol 29
with NaH and MOMCl in THF gave the desired MOM-protected indole 30 along with a
significant amount of a C-alkylated product, tentatively assigned as the C-5 isomer 31 (Scheme
3). Addition of DMF to the solvent system improved the ratio of desired to undesired product
from ~1.3:1 to ~9:1. Reduction of ester 30 proceeded in quantitative yield, but attempts at
conversion to the phosphonate were somewhat frustrating. The reaction proceeded via the
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corresponding bromide, although the Arbuzov reaction of that bromide with (EtO)3P in refluxing
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toluene gave the desired phosphonate 33 in modest yield.
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O
O
MOMCl
NaH
THF, DMF
R
H
N
N
EtO
EtO
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R'
OR
OR
K2CO3
EtOH
82%
30 R = CH2OCH3, R' = H (79%)
31 R = R' = CH2OCH3 (9%)
20 R = Ac
29 R = H
LiAlH4
99%
0 °C
MOM
1) MsCl, NEt3,
MOM
O
N
N
(EtO)2P
HO
LiBr
2) P(OEt)3
39%
OMOM
33
OMOM
32
NaH, 15-crown-5
69%
12
OR
O
MOM
N
HO
TsOH
MeOH
65%
H
34 R = MOM
35 R = H
OR
Scheme 3. Synthesis and HWE condensation of indole phosphonate 33.
The HWE coupling of the hexahydroxanthene aldehyde 1228 with phosphonate 33
smoothly gave the protected analogue 34. Unfortunately, attempted hydrolysis of the three
MOM groups by treatment with TsOH/MeOH gave compound 35, where both of the phenolic
MOM groups had been cleaved but the indole nitrogen was still protected. Attempts to remove
this remaining MOM group under more vigorous conditions29-31 proved unsuccessful, and gave
only decomposition.
To circumvent this difficult hydrolysis, a new strategy based upon early formation of a
differentially protected indole was explored. Selective MOM protection of the phenol 29 gave
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indole 36 (Scheme 4) and different N-protecting groups then could be introduced easily. For
example, treatment of compound 36 with base and Boc2O gave the carbamate 37, and selective
reduction of the ethyl ester gave the primary alcohol 38 in good yield. Under standard
conditions for formation of the phosphonates (i.e. initial formation of the mesylate followed by
treatment with LiBr and then neat (EtO)3P at reflux), formation of the C-P bond was
accompanied by cleavage of the Boc group32 to afford phosphonate 39 as the major product. The
Boc group was easily re-installed through treatment of phosphonate 39 with Boc2O to give
phosphonate 40, or phosphonate 40 could be obtained more directly from the alcohol 38 in a
reasonable yield (61%) if the Arbuzov reaction were conducted at a lower temperature (~95 °C)
instead of reflux (~165 °C). Alternatively, a tosylate protecting group could be installed through
treatment of indole 36 with TsCl and base, and the intermediate carboxylic acid ester was
reduced selectively to the alcohol 41 in good yield. The tosyl group proved stable to standard
conditions for formation of the phosphonate, and compound 42 was obtained smoothly.
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O
H
MOMCl
DIPEA
N
EtO
29
CH2Cl2
77%
7
8
9
OMOM
36
Boc2O, NaH
87%
1) TsCl, NaH
2) DIBAL
84%
Ts
O
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Boc
N
HO
N
EtO
41
OMOM
OMOM
37
1) MsCl, NEt3, LiBr
2) P(OEt)3, reflux
85%
DIBAL
91%
Boc
Ts
N
O
N
HO
(EtO)2P
OMOM
OMOM
38
42
1) MsCl, NEt3, LiBr
2) P(OEt)3, reflux
1) MsCl, NEt3, LiBr
2) P(OEt)3, 95 °C
R
40 (61%)
O
N
(EtO)2P
OMOM
Boc2O
DMAP
72%
39 R = H (58%)
40 R = Boc (4%)
Scheme 4. Synthesis of new indole phosphonates.
Of the new indole phosphonates 39, 40, and 42, the HWE condensation of compound 39
with an aldehyde representing the schweinfurthin left half would be most advantageous because
it would avoid an N-deprotection step of the product at a later stage. In the limited number of
condensations between an indole phosphonate and an aldehyde, an N-protected indole always
was employed.33-36 Nevertheless, because aldehyde 12 has been used in similar HWE
reactions,3,6,13 condensations were attempted between this aldehyde and phosphonate 39. At best
just trace amounts of a possible stilbene product were observed in this case, even though p-
methoxybenzaldehyde reacted smoothly with phosphonate 39.37 Attempted condensation of
aldehyde 12 with phosphonate 40 also was problematic. In this case, little or no condensation
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was observed and TLC analysis suggested that Boc cleavage had taken place instead.
Fortunately, the HWE condensation of phosphonate 42 with aldehyde 12 at reflux gave a mixture
of stilbene products in very good total yield (Scheme 5). Somewhat to our surprise, analysis of
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1
13
the H and C NMR spectra showed that the major product 43 carried a tosylate as an A-ring
ester, while the minor product 44 did not have an A-ring tosylate, but already had undergone
cleavage of the N-tosyl group. The hindered tosylate ester 43 proved resistant to standard
hydrolysis,38-45 but reduction with LiAlH4
converted the major HWE product (43) to the
46,47
minor product (44) in low yield. Final hydrolysis of the MOM groups gave the stilbene 7, the
first schweinfurthin G analogue that incorporates an indole system.
OMOM
12
NaH
15-crown-5
O
H
+
N
reflux
RO
H
42
LiAlH4
30%
43 R = Ts 67%
44 R = H 22%
OMOM
TsOH
MeOH
58%
OH
O
H
N
HO
H
7
OH
Scheme 5. Synthesis of an indole analogue of schweinfurthin G.
To prepare the analogous schweinfurthin F analogue, phosphonate 42 was allowed to
react with aldehyde 113 and base (Scheme 6). When the reaction was conducted at reflux in
THF, the only stilbene product (56%) again reflected transfer of the tosyl group from the indole
nitrogen to the A-ring alcohol. Treatment of this hindered tosylate ester with LiAlH4 did afford
the free alcohol 46 in modest yield. Compound 46 undergoes hydrolysis of the phenolic MOM
group under standard conditions to afford the schweinfurthin F analogue 8.
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OCH3
11
NaH
15-crown-5
O
H
+
N
reflux
RO
H
56%
42
7
8
9
LiAlH4
43%
45 R = Ts
46 R = H
OMOM
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HCl
MeOH
66%
OCH3
O
H
N
HO
H
8
OH
Scheme 6. Synthesis of an indole analogue of schweinfurthin F.
Because the natural schweinfurthins contain an isoprene chain as a D-ring substituent,
installation of an isoprenoid chain on the indole would afford analogues more closely parallel to
the natural products. Our original plan had been to incorporate this chain in a regiospecific
manner through halogen-metal exchange on a protected indole derived from bromide 26, but this
sequence would become unappealing if the MOM hydrolysis were problematic or the SN2’
product was formed during alkylation with prenyl bromide.48-52 An attractive alternative might
be based on an extension of the methodology of Ganesan,53 which relies upon Zn(OTf)2
activation of an allylic halide to bring about only C-3 alkylation through electrophilic aromatic
substitution. Among the attractive features of the original study, alkylation of indole itself with
prenyl halides generally gave only the C-3 alkylated product, proceeded in ~60% yield, and did
not give the products of SN2’ reaction (i.e. “reversed” prenyl substituents) that are frequently
observed with other methods.48,49 However, it was unclear whether this approach could be
applied to access the substituted indole required here, where both C-6 and C-4 groups that might
impact reactivity were required. In particular, a C-6 ethoxycarbonyl group would add an
electron withdrawing substituent system, while reduction of this group to the corresponding
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alcohol might invite polymerization reactions given the known reactivity of benzyl alcohol under
these conditions.53 Furthermore, a MOM substituent at the C-4 position might compete with an
isoprenoid halide for complexation with the Zn(OTf)2 or introduce a degree of steric hindrance to
the C-3 position. Nevertheless, the brevity of this approach led us to study the process with
indole 36. To our delight, the reaction of indole 36 with prenyl bromide in the presence of
Zn(OTf)2 gave the desired product 47 in 65% yield (Scheme 7). This yield is comparable to
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those obtained on indole itself,53 despite the presence of the B-ring substituents.
O
H
Zn(OTf)2, TBAI
N
DIPEA, Prenyl Br
EtO
36
toluene, CH2Cl2
65%
47 OMOM
1) NaH, TsCl
2) DIBAL, 0 °C
82%
Ts
N
X
OMOM
1) MsCl, NEt3, LiBr
2) P(OEt)3, DMF
48 X = OH
49 X = P(O)(OEt)2
88%
11
NaH, 15-crown-5
0 °C to rt, 2h
OCH3
O
R
N
HO
H
OR'
50 R = Ts, R' = MOM
51 R = H, R' = MOM
NaH, 1:1 iPrOH/THF
44% (2 steps)
TsOH
MeOH
28%
9
R = R' = H
Scheme 7. Synthesis of the prenylated indole schweinfurthin 9.
Once ester 47 was in hand, the remaining steps in the sequence proceeded in a fashion
parallel to those employed for preparation of the earlier analogues. Protection of the indole
nitrogen as the tosylate proceeded smoothly. Then, after selective reduction of the carboxylic
acid ester with DIBAL, the resulting alcohol 48 was readily converted to phosphonate 49. An
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HWE condensation with aldehyde 11 afforded a mixture of N-tosyl intermediate 50 and the free
indole 51. After partial purification, treatment with NaH in a mixture of THF and i-PrOH
afforded only compound 51. Final hydrolysis of the MOM group proceeded in low yield, but did
afford the desired target compound, the schweinfurthin F analogue 9.
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To access compound 10 from an intermediate already in hand, indole 41 was protected as
its silyl ether 52, and then treated with n-BuLi and prenyl bromide. Despite the presence in the
B-ring of two substituents that might participate in directed ortho metallation,54 this sequence
gave a single product identified as the C-2 alkylated indole 53. After deprotection to the alcohol
54, and formation of the phosphonate 55 through standard reactions, condensation of
phosphonate 55 with aldehyde 11 provided a mixture of the new stilbenes 56 and 57. After
partial purification, treatment with 2-propanol and base completed conversion to compound 57,
and final deprotection gave the desired schweinfurthin analogue 10.
Ts
Ts
n-BuLi
Prenyl Br RO
N
N
RO
THF -78 °C
68%
OMOM
OMOM
TBSCl
imid
97%
41 R = H
52 R = TBS
53 R = TBS
54 R = H
TBAF
85%
1) MsCl, NEt3, LiBr
2) P(OEt)3, reflux
90%
Ts
N
O
(EtO)2P
NaH,15-crown-5
0 °C to rt
11
OMOM
55
OMe
O
R
N
HO
H
OMOM
TsOH
MeOH
NaH, 1:1
2-propanol
THF
56 R = Ts
57 R = H
10
68%
37%
(2 steps)
Scheme 8. Synthesis of the prenylated indole schweinfurthin 10.
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In preliminary bioassays, compounds 7–10 were tested for their activity against the SF-
295 cell line, which is one of those more sensitive to the natural schweinfurthins.1 These new
schweinfurthin analogues did show activity in these assays, with EC50’s ranging from ~200 nM
to 2.5 M (Table 1).37 Because the more active compounds show potency comparable to some
of the natural schweinfurthins, preparation of additional indole analogues as well as more
extensive testing in the 60 cell line assay of the National Cancer Institute would be warranted.
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EC50
Compound
(μM)
0.2
2.5
0.2
2.2
7
8
9
10
Table 1. Preliminary bioassays in the SF-295 cell line
In conclusion, we have developed a strategy for synthesis of indole analogues of the
natural schweinfurthins. This effort included preparation of several new indoles by cyclization
after a Stobbe condensation, and ultimately led to preparation of the first indoles bearing a
phosphonomethyl substituent in the indole B-ring. These B-ring phosphonates have been used in
HWE reactions with the complex aldehydes 11 and 12, and undergo these condensations
smoothly as long as the indole nitrogen is securely protected. With a tosyl group on the indole
nitrogen, an unexpected transfer of the tosyl group to an unprotected alcohol was observed.
While this transfer undoubtedly could be avoided through use of an alcohol protecting group,
instead, because this transfer also deprotected the indole nitrogen, the tosylate ester was isolated
and cleaved to the free alcohol, which allowed preparation of indole analogues of the
schweinfurthin G and F cores. These studies also have shown that the Zn(OTf)2 mediated
alkylation of a 4,6-disubstituted indole is a facile way to introduce a prenyl substituent to C-3 of
the indole system, which in turn allowed preparation of a schweinfurthin F analogue complete
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with a side chain. In this more hindered prenyl indole, an HWE condensation at room
temperature did afford the desired stilbene without transfer of the tosyl group, and reductive
cleavage of the N-tosyl group was more efficient. Finally, a C-2 prenylated indole was obtained
through metalation and alkylation of a tosyl indole intermediate, which allows divergent use of
intermediate 35 to obtain either the C-2 or C-3 alkylated compounds. Together these studies
have afforded four new indole analogues (7–10) of the natural schweinfurthins, and they define
procedures that could be used to prepare analogues of many other natural stilbenes including
resveratrol,55 the chiricanines,56 the arachidins and arahypins,57 and the pawhuskins.58 Further
research on the biological activity of the new schweinfurthin analogues is underway, and will be
reported in due course.
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Experimental Section
General Experimental Procedures. THF was freshly distilled from sodium/benzophenone,
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
stirring. All commercial reagents were used without further purification unless otherwise stated.
NMR spectra were recorded at 300 MHz for 1H, and 75 MHz for 13C or higher with CDCl3 as
solvent 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.
2-(1H-Pyrrol-2-ylmethylene)-succinic acid 1-ethyl ester (19). General Procedure for Stobbe
Condensations. According to the procedure of Vedejs24 but in THF (60 mL) instead of benzene,
NaH (4.2 g, 105 mmol, 60% dispersion oil) was added slowly to aldehyde 18 (5.01 g, 52.6
mmol) and diethylsuccinate (13.3 mL, 80.2 mmol) at 0 °C. The reaction mixture was allowed to
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stir overnight and warm to rt. The reaction mixture was cooled to 0 °C, quenched by addition of
water and Et2O was added and then extracted with 5% KOH. The combined aqueous layers
were acidified with HCl (6 M) and extracted with Et2O. The combined organic extracts were
washed with brine, dried (MgSO4), filtered, and the solvent was removed in vacuo to afford acid
19 (11.2 g, 96%) as a red-brown solid: 1H NMR ((CD3)2CO, 400 MHz) δ 10.83 (br s, 1H), 10.63
(br s, 1H), 7.75 (s, 1H), 7.07 – 7.06 (m, 1H), 6.61 – 6.59 (m, 1H), 6.30 – 6.27 (m, 1H), 4.20 (q, J
= 7.1 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H); 13C NMR ((CD3)2CO, 400 MHz) δ 172.4,
168.5, 131.8, 128.8, 123.1, 119.2, 114.4, 111.9, 61.3, 34.4, 14.9; HRMS (TOF MS EI) m/z calcd
for C11H13NO4 (M+) 223.0845, found 223.0851.
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4-Acetoxy-1H-indole-6-carboxylic acid ethyl ester (20) and 5-Acetoxy-indolizine-7-
carboxylic acid ethyl ester (21). To acid 19 (17.1 g, 76.7 mmol) in toluene (800 mL) was
added Ac2O (48 mL, 506 mmol) and glacial AcOH (4.62 mL, 80.5 mmol) and the reaction was
heated to reflux. The next day the reaction mixture was allowed to cool to rt, quenched by
addition of K2CO3 (sat), washed with brine, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification by flash column chromatography (0 to 50% ethyl
acetate in hexanes) afforded indole 20 (14.0 g, 74%) as a light brown solid and indolizine 21
(201 mg, 1%) as a yellow-brown oil. For indole 20: 1H NMR δ 8.98 (br s, 1H), 7.95 (s, 1H),
7.53 (s, 1H), 7.20 – 7.18 (m, 1H), 6.40 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.38 (t, J
= 7.2 Hz, 3H); 13C NMR 169.5, 167.0, 142.8, 136.7, 127.9, 124.8, 124.2, 112.6, 111.8, 99.4,
60.9, 20.9, 14.3. Anal. calcd. for C13H13NO4: C, 63.15; H; 5.30; N, 5.66. Found: C, 62.97; H,
5.31; N, 5.61.
1
For indolizine 21: H NMR δ 8.14 (s, 1H), 7.33 – 7.31 (m, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.90
(dd, J = 3.9, 2.8 Hz, 1H), 6.79 (dd, J = 4.0, 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H),
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1.39 (t, J =7.2 Hz, 3H); 13C NMR 166.9, 165.6, 138.8, 133.4, 120.2, 119.2, 115.7, 110.5, 105.6,
99.0, 60.9, 20.6, 14.3; HRMS (TOF MS EI) m/z calcd for C13H13NO4 (M+) 247.0845, found
247.0849.
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Alternative route to indole 20 and indolizine 21. To acid 19 (1.00 g, 4.48 mmol) in THF was
added Ac2O (5.4 mL, 57.5 mmol) and glacial AcOH (2.2 mL, 5.76 mmol) and the reaction
mixture was heated to reflux. The next day the reaction mixture was allowed to cool to rt,
poured into Et2O and water, washed with NaHCO3 (sat), dried (MgSO4), and filtered, and the
filtrate was concentrated in vacuo. Final purification by flash column chromatography (15% to
50% Et2O in hexanes) afforded indole 20 (461 mg, 42%) and indolizine 21 (212 mg, 19%).
2-(4-Bromo-1H-pyrrol-2-ylmethylene)-succinic acid 1-ethyl ester (22). According to the
general procedure, a solution of 4-bromo-2-pyrrolecarboxaldehyde (502 mg, 2.89 mmol) and
diethyl succinate (0.72 mL, 4.29 mmol) in THF (4 mL) at 0 °C was treated with NaH (266 mg,
6.65 mmol, 60 % dispersion oil). Standard work-up and final purification by flash column
chromatography (30% to 40% ethyl acetate in hexanes) afforded acid 22 (316 mg, 36%) as a
1
light brown solid: H NMR ((CD3)2CO) δ 10.87 (br s, 1H), 7.67 (s, 1H), 7.14 (dd, J = 2.9, 1.4
Hz, 1H), 6.63 – 6.62 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.65 (s, 2H), 1.28 (t, J = 7.1 Hz, 3H); 13C
NMR ((CD3)2CO) δ 172.2, 167.9, 130.7, 129.3, 122.5, 121.5, 115.0, 98.8, 61.3, 34.1, 14.5;
HRMS (TOF MS EI) m/z calcd for C11H12Br NO4 (M+) 300.9950, found 300.9954.
5-Acetoxy-2-bromo-indolizine-7-carboxylic acid ethyl ester (24). To acid 22 (811 mg, 2.68
mmol) in THF was added glacial AcOH (0.19 mL, 3.3 mmol), and Ac2O (3.2 mL 33.8 mmol)
and the solution was heated at reflux overnight. The reaction mixture was then allowed to cool
to rt, quenched by addition of Na2CO3 (sat), and extracted with ethyl acetate. The combined
organic extracts were washed with water and brine, dried (MgSO4), and filtered, and the filtrate
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was concentrated in vacuo. Final purification by flash column chromatography (20% Et2O in
hexanes) afforded indolizine 24 (687 mg, 79%): 1H NMR δ 8.00 (d, J = 1.4 Hz, 1H), 7.32 (dd, J
= 1.5, 0.5 Hz, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.78 (d, J = 1.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H),
2.44 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR δ 166.6, 165.1, 138.1, 133.3, 120.6, 118.6, 110.3,
107.2, 105.4, 99.4, 61.2, 20.6, 14.3. Anal. calcd. for C13H12BrNO4: C, 47.88; H; 3.71; N, 4.29.
Found: C, 48.10; H, 3.73; N, 4.22.
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2-(4-Bromo-1-methoxymethyl-1H-pyrrol-2-ylmethylene)-succinic acid 1-ethyl ester (25).
To 4-bromo-1H-pyrrole-2-carboxaldehyde (1.84 g, 10.6 mmol) in 10:1 THF/DMF (55 mL) at 0
°C was added NaH (525 mg, 7.5 mmol, 60% dispersion oil) and the reaction was allowed to stir
for 5 min. To the resulting solution was added MOMCl (0.97 mL, 12.8 mmol) and the reaction
was allowed to stir for 2 h and then quenched by addition of NH4Cl (sat), diluted with water, and
extracted with Et2O. The combined organic extracts were washed with water and the brine, dried
(MgSO4), and filtered, and the filtrate was concentrated in vacuo. Final purification by flash
column chromatography (25% Et2O in hexanes) afforded the protected aldehyde (1.97 g, 86%)
as a white solid: 1HMR δ 9.53 (d, J = 1.0 Hz, 1H), 7.13 (dd, J = 1.7, 1.0 Hz, 1H), 6.97 (d, J = 1.9
Hz, 1H), 5.62 (s, 2H), 3.31 (s, 3H); 13C NMR δ 179.0, 131.8, 130.1, 125.8, 98.0, 78.4, 56.3;
HRMS (EI) m/z calcd for C7H8BrNO2 (M+) 216.9738, found 216.9740. According to the general
procedure, the MOM-protected bromopyrrole aldehyde (1.01 g, 4.63 mmol) in THF (9 mL) at 0
°C was treated with diethyl succinate (1.2 mL, 1.54 mmol), followed by NaH (310 mg, 7.75
mmol). Standard work-up and final purification by flash column chromatography (25% to 40%
ethyl acetate in hexanes) afforded acid 25 (425 mg, 27%) as a brown-yellow solid: 1H NMR δ
7.77 (s, 1H), 6.92 (d, J = 1.4 Hz, 1H), 6.61 (d, J = 1.1 Hz, 1H), 5.23 (s, 2H), 4.29 (q, J = 7.1 Hz,
2H), 3.68 (s, 2H), 3.26 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR 175.4, 167.6, 128.3, 128.2,
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125.2, 122.1, 116.6, 97.9, 78.1, 61.5, 56.0, 34.0, 14.2. Anal. calcd for C13H16BrNO5: C, 45.10;
H; 4.66; N, 4.05. Found: C, 45.19; H, 4.69; N, 3.93.
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4-Acetoxy-3-bromo-1-methoxymethyl-1H-indole-6-carboxylic acid ethyl ester (26). To acid
25 (1.084 g, 3.13 mmol) in Ac2O (20 mL) was added KOAc (0.49 g, 5.0 mmol) and the reaction
was heated to reflux for 1 h and then allowed to cool to rt. The solution was diluted with ethyl
acetate, washed with Na2CO3 (sat), water, and brine, dried (MgSO4), and filtered, and the filtrate
was concentrated in vacuo. Final purification by flash column chromatography (20% ethyl
acetate in hexanes) afforded indole 26 (911 mg, 79%) as a brown solid: 1H NMR δ 8.14 (d, J =
1.2 Hz, 1H), 7.56 (d, J = 1.2 Hz, 1H), 7.33 (s, 1H), 5.45 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.28 (s,
3H), 2.43 (s, 3H), 1.41 (t, J = 7.1 Hz. 3H); 13C NMR δ 179.9, 166.2, 142.9, 137.1, 130.8, 126.1,
123.1, 115.2, 110.8, 88.2, 77.7, 61.2, 56.4, 21.0 14.4. Anal. calcd for C15H16BrNO5: C, 48.67; H,
4.36; N, 3.78. Found: C, 48.84; H, 4.60; N, 3.58.
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2-(1-Methoxymethyl-1H-pyrrol-2-ylmethylene)-succinic acid 1-ethyl ester (27). A solution
of N-MOM-2-pyrrolecarboxaldehyde (100 mg, 0.72 mmol) and diethyl succinate (145 mg, 0.84
mmol) in THF at 0 °C was treated with KOt-Bu (120 mg, 1.07 mmol). The solution was allowed
to warm to rt overnight and the next day was heated to reflux for one h. The solution was cooled
to 0 °C, quenched by addition of water, diluted with Et2O, and extracted with 5% KOH. The
combined aqueous extracts were acidified (6M HCl) and extracted with Et2O. The combined
organic layers were washed with brine, dried (MgSO4), and filtered, and then the filtrate was
concentrated in vacuo. Final purification by flash column chromatograph (30% ethyl acetate in
hexanes) afforded acid 27 (60 mg, 31%) as a yellow solid: 1H NMR δ 7.87 (s, 1H), 6.93 (dd, J =
2.7, 1.5 Hz, 1H), 6.67 – 6.66 (m, 1H)), 6.29 – 6.27 (m, 1H), 5.29 (s, 2H), 4.29 (q, J = 7.1 Hz,
2H), 3.72 (s, 2H), 3.25 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR δ 176.1, 168.1, 129.3, 127.7,
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126.2, 120.0, 115.6, 110.1, 78.0, 61.3, 55.7, 34.2, 14.2. Anal. calcd for C13H17NO5: C, 58.42; H,
6.41. Found: C, 58.49; H, 6.43.
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4-Acetoxy-1-methoxymethyl-1H-indole-6-carboxylic acid ethyl ester (28). To acid 27 (333
mg, 1.25 mmol) in Ac2O (10 mL) was added KOAc (153 mg, 1.56 mol) and the solution was
heated at reflux until the reaction was complete as judged by TLC analysis. The solution was
allowed to cool to rt and then poured into NaHCO3 (sat) and diluted with Et2O. Once bubbling
had ceased, the aqueous layer was extracted with Et2O and the combined organic extracts were
washed with NaHCO3 (sat), water, and brine, dried (MgSO4), and filtered, and the filtrate was
concentrated in vacuo. Final purification by flash column chromatography (40% ethyl acetate in
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hexanes) afforded indole 28 (298 mg, 82%) as a brown-yellow solid: H NMR δ 8.14 (dd, J =
1.0, 1.0 Hz, 1H), 7.60 (d, J = 1.1 Hz, 1H), 7.31 (d, J = 3.3 Hz, 1H), 6.46 (dd, J = 3.3, 0.8 Hz,
1H), 5.47 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.25 (s, 3H), 2.40 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H);
13C NMR δ 169.0, 166.6, 143.0, 137.2, 131.2, 125.9, 124.9, 113.4, 110.3, 99.7, 77.5, 60.9, 56.0,
22.0, 14.3; HRMS (TOF MS EI) m/z calcd for C15H17NO5 (M+) 291.1107, found 291.1104.
4-Hydroxy-1H-indole-6-carboxylic acid ethyl ester (29). To a solution of acetate 20 (201 mg,
0.81 mmol) in EtOH (20 mL) was added K2CO3 (210 mg, 1.52 mmol) and the resulting mixture
was heated to reflux for 90 min. The reaction mixture was cooled to 0 °C, filtered through celite,
and then concentrated in vacuo. The resulting residue was dissolved in Et2O and extracted with
2N NaOH. The aqueous extracts were acidified and extracted with Et2O, dried (MgSO4), and
filtered, and the filtrate was concentrated in vacuo. Final purification by flash column
chromatography (50% Et2O in hexanes) afforded phenol 29 (136 mg, 82%) as a light brown
solid: 1H NMR (CD3)2CO δ 10.5 (br s, 1H), 8.60 (br s, 1H), 7.76 (dd, J = 1.2, 1.2 Hz, 1H), 7.42
(dd, J = 3.2, 2.5 Hz, 1H), 7.18 (d, J = 1. 3 Hz, 1H), 6.67 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.36
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(t, J = 7.2 Hz, 3H); 13C NMR δ 167.8, 150.9, 138.2, 127.2, 125.5, 122.8, 107.0, 104.5, 100.1,
60.9, 14.7. Anal. calcd for C11H11NO3 : C, 64.38; H, 5.40; N, 6.83. Found: C, 64.39; H, 5.49; N,
6.66.
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4-Methoxymethoxy-1-methoxymethyl-1H-indole-6-carboxylic acid ethyl ester (30) and 4-
methoxymethoxy-1,5-bis-methoxymethyl-1H-indole-6-carboxylic acid ethyl ester (31). To a
stirring suspension of NaH (800 mg, 20 mmol, 60% dispersion in oil) in a 6:1 mixture of THF
and DMF (35 mL) at 0 °C was added indole 29 (1.61 g, 7.86 mmol) as a THF solution. Next
MOMCl (1.5 mL, 20 mmol) was added dropwise and the reaction mixture was allowed to stir for
50 min. The reaction was quenched by addition of water and extracted with Et2O. The
combined organic extracts were dried (MgSO4) and filtered, and the filtrate was concentrated in
vacuo. Final purification by flash column chromatography (25 to 50% Et2O in hexanes) afforded
indoles 30 (1.82 g, 79%) and 31 (227 mg, 9%). For compound 30: 1H NMR δ 7.94 (dd, J = 0.9,
0.9 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 3.3 Hz, 1H), 6.69 (dd, J = 3.2, 0.8 Hz, 1H),
5.47 (s, 2H), 5.38 (s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.55 (s, 3H), 3.25 (s, 3H), 1.44 (t, J = 7.2 Hz,
3H); 13C NMR δ 167.3, 150.0, 137.1, 129.8, 125.4, 124.0, 106.8, 104.6, 100.2, 94.7, 77.4, 60.8,
56.2, 55.9, 14.4. Anal. calcd for C15H19NO5: C, 61.42; H, 6.53; Found: C, 61.59; H, 6.62. For
compound 31: 1H NMR δ 7.82 (d J = 0.6 Hz, 1H), 7.25 (d, J = 3.3 Hz, 1H), 6.68 (dd, J = 3.3, 0.8
Hz, 1H), 5.46 (s, 2H), 5.28 (s, 2 H), 4.93 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 3.39 (s,
3H), 3.22 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR δ 168.4, 150.0, 136.7, 130.1, 126.9, 124.6,
121.1, 109.1, 100.9, 99.5, 77.4, 65.7, 61.0, 58.0, 57.4, 56.0, 14.3. Anal. calcd for C17H23NO6: C,
60.52; H, 6.87; N, 4.15. Found: C, 60.40; H, 7.00; N, 4.00.
(4-Methoxymethoxy-1-methoxymethyl-1H-indol-6-yl)-methanol (32). To ester 30 (668 mg,
2.28 mmol) in THF at 0 °C was added LiAlH4 (190 mg, 5.0 mmol) and the resulting mixture was
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allowed to stir for 2 h. The reaction mixture was then quenched by addition of water, acidified,
and extracted with Et2O. The combined organic extracts were washed with water, dried
(MgSO4), and filtered, and the filtrate was concentrated in vacuo. Final purification by flash
column chromatography (50% ethyl acetate in hexanes) afforded alcohol 32 (566 mg, 99%) as a
white solid: 1H NMR δ 7.17 (s, 1H), 7.09 (d, J = 3.3 Hz, 1H), 6.80 (d, J = 0.9 Hz, 1H), 6.63 (dd,
J = 3.2, 0.7 Hz, 1H), 5.39 (s, 2H), 5.32 (s, 2 H), 4.75 (s, 2H), 3.53 (s, 3H), 3.22 (s, 3H), 2.02 (br
s, 1H); 13C NMR δ 150.7, 137.9, 136.6, 127.3, 119.9, 103.7, 102.8, 99.8, 94.7, 77.5, 66.1, 56.1,
55.8; HRMS (EI) m/z calcd for C13H17NO4 (M+) 251.1158; found 251.1152.
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(4-Methoxymethoxy-1-methoxymethyl-1H-indol-6-ylmethyl)-phosphonic acid diethyl ester
(33). To a solution of alcohol 32 (12 mg, 0.048 mmol) in CH2Cl2 (5 mL) at 0 °C was added
Et3N (0.05 mL, 0.38 mmol) and MsCl (0.02 mL, 0.24 mmol) and the reaction was allowed to
warm to rt. The following day the reaction was quenched by addition of NH4Cl (sat) and
extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (MgSO4),
and filtered, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in
acetone (5 mL) at rt, LiBr (33 mg, 0.38 mmol) was added, and the reaction mixture was allowed
to stir overnight. The following day the reaction mixture was poured into Et2O, 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 vacuo. The resulting
residue was dissolved in P(OEt)3 (0.5 mL) and toluene (3 mL) and the solution was heated at
reflux overnight. The following day the solution was allowed to cool to rt, poured into Et2O, and
then 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 vacuo.
Final purification by flash column chromatography (80% ethyl acetate in hexanes) afforded
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phosphonate 33 (7 mg, 39% yield) as an oil: 1H NMR δ 7.12 (d, J = 3.2 Hz, 1H), 7.07 (dd, J =
3.2 Hz, 1.0 Hz, 1H), 6.75 (dd, J = 1.7, 1.3 Hz, 1H), 6.61 (dd, J = 3.2 Hz, 0.7 Hz, 1H), 5.40 (s,
2H), 5.32 (s, 2H), 4.06 – 3.96 (m, 4H), 3.53 (s, 3H), 3.25 (d, JHP = 21.3 Hz, 2H), 3.23 (s, 3H),
1.26 (td, J = 7.1 Hz, 0.3 Hz, 6H); 13C NMR δ 150.4 (d, JCP = 2.8 Hz) , 138.0 (d, JCP = 3.0 Hz),
127.0 (d, JCP = 1.2 Hz), 126.4 (d, JCP = 9.2 Hz), 119.3 (d, JCP = 2.9 Hz), 106.5 (d, JCP = 5.9 Hz),
105.5 (d, JCP = 7.7 Hz), 99.7 (d, JCP = 1.5 Hz), 94.7, 77.4, 62.0 (d, JCP = 6.6 Hz, 2C), 56.1, 55.8,
34.2 (d, JCP = 138 Hz), 16.3 (d, JCP 6.1 Hz, 2C); 31P NMR  27.4; HRMS (EI) m/z calcd for
C17H26NO6P (M+) 371.1498; found 371.1497.
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5-Methoxymethoxy-7-[2-(4-methoxymethoxy-1-methoxymethyl-1H-indol-6-yl)-vinyl]-
1,1,4a-trimethyl-(2R,4aR,9aR)-2,3,4,4a,9,9a-hexahydro-1H-xanthen-2-ol (34). To a
suspension of NaH (45 mg, 1.13 mol, 60% dispersion in oil) in THF at 0 °C was added
phosphonate 33 (37 mg, 0.10 mmol) as a THF solution followed by aldehyde 1228 (17.6 mg,
0.052 mmol) as a THF solution and the reaction was allowed to warm slowly to rt. The
following day the reaction mixture was quenched by addition of water and extracted with ethyl
acetate. 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
(50 to 70% ethyl acetate in hexanes) afforded stilbene 34 (16 mg, 55%) as an oil: 1H NMR δ 7.24
(s, 1H), 7.16 (d, J = 1.9 Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.03 – 6.97 (m, 4H), 6.62 (d, J = 3.2
Hz, 1H), 5.44 (s, 2H), 5.39 (s, 2H), 5.25 (d, J = 6.5 Hz, 1H), 5.21 (d, J = 6.6 Hz, 1H), 3.57, (s,
3H) 3.55 (s, 3H), 3.47–3.42 (m, 1H), 3.27 (s, 3H), 2.75 – 2.72 (m, 2H), 2.13 – 2.08 (m, 1H), 1.91
– 1.64 (m, 5H), 1.25 (s, 3H), 1.12 (s, 3H), 0.90 (s, 3H); 13C NMR δ 150.8, 146.2, 143.6, 138.2,
133.5, 129.5, 127.7, 127.0,125.5, 123.1, 121.9, 120.1, 113.4, 102.9, 102.5, 100.0, 95.9, 94.8,
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78.0, 77.6, 76.9, 56.2, 56.2, 55.9, 46.8, 38.4, 37.7, 28.3, 27.3, 23.2, 19.9, 14.3; HRMS (EI) m/z
calcd for C32H41NO7 (M+) 551.2883 found 551.2891.
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7-[2-(4-Hydroxy-1-methoxymethyl-1H-indol-6-yl)-vinyl]-1,1,4a-trimethyl-(2R,4aR,9aR)-
2,3,4,4a,9,9a-hexahydro-1H-xanthene-2,5-diol (35). To MOM-protected compound 34 (16
mg, 0.029 mmol) in MeOH (3 mL) was added TsOH (80 mg, 0.42 mmol) and the solution was
allowed to stir at rt. The next day the solution was quenched by addition of NH4Cl (sat), diluted
with water, and extracted with ethyl acetate. The combined organics extracts were washed with
water, dried (MgSO4) and filtered, and the filtrate was concentrated in vacuo. Final purification
by flash column chromatography (50% ethyl acetate in hexanes) afforded the schweinfurthin
analogue 35 (9 mg, 67%) as a yellow oil: 1H NMR (CD3OD) δ 7.16 (d, J = 3.3 Hz, 1H), 7.11 (m,
1H), 6.98 (d, J = 16.0 Hz, 1H), 6.91 (d, J = 16.4 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.77 (d, J =
1.8 Hz, 1H), 6.73 (d, J = 1.0 Hz, 1H), 6.55 (dd, J = 3.3, 0.7 Hz, 1H), 5.47 (s, 2H), 3.40–3.35 (m,
1H), 3.25 (s, 3H), 2.75–2.71 (m, 2H), 2.09–2.04 (m, 1H), 1.85–1.63 (m, 4H), 1.24 (s, 3H), 1.11
(s, 3H), 0.89 (s, 3H); 13C NMR δ 151.6, 147.0, 142.1, 140.1, 134.9, 131.4, 128.6, 128.4, 128.0,
124.0, 120.3, 120.2, 111.1, 103.3, 102.2, 100.5, 78.8, 78.3, 78.2, 56.0, ~49 (obscured by solvent),
39.5, 38.9, 29.0, 27.9, 24.0, 20.3, 14.8; HRMS (EI) m/z calcd for C28H33NO5 (M+) 463.2359
found 463.2353.
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Preparation of 4-Methoxymethoxy-1H-indole-6-carboxylic acid ethyl ester (36). To a
suspension of phenol 29 (1.18 g, 5.74 mmol) in CH2Cl2 (100 mL) at rt was added DIPEA (4.0
mL, 23.0 mmol) and MOMCl (0.7 mL, 9.2 mmol) and the reaction mixture was allowed to stir
overnight. The reaction was quenched by addition of water and extracted with CH2Cl2. 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 (15 to 25% ethyl
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acetate in hexanes) afforded indole 36 (1.10 g, 77%) as a light yellow solid: 1H NMR δ 8.95 (br
s, 1H), 7.89 (dd, J = 1.0, 1.0 Hz, 1H), 7.43 (d, J = 1.1 Hz, 1H), 7.26 (dd, J = 3.1, 2.5 Hz, 1H),
6.69 (m, 1H), 5.38 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.54 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C
NMR δ 167.7, 149.9, 136.5, 126.4, 124.7, 123.0, 108.4, 103.8, 100.0, 94.7, 60.8, 56.2, 14.3.
Anal. calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C, 62.83; H, 6.12; N, 5.42.
4-Methoxymethoxy-indole-1,6-dicarboxylic acid 1-tert-butyl ester, 6-ethyl ester (37). To a
solution of indole 36 (1.00 g, 4.01 mmol) in THF (20 mL) at 0 °C was added NaH (200 mg, 5
mmol, 60% dispersion in oil) and Boc2O (960 mg, 4.40 mmol). An additional aliquot of THF
was added (8 mL) and after 1 h the reaction mixture was quenched by addition of NH4Cl (sat)
and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried
(MgSO4), and filtered, and the solvent was removed in vacuo. Final purification of the resulting
material by flash column chromatography (12.5 to 15% Et2O in hexanes) afforded indole 37
(1.23 g, 87%): 1H NMR δ 8.54 (br s, 1H), 7.67 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 1.2 Hz, 1H), 6.74
(dd, J = 3.7, 0.7 Hz, 1H), 5.36 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 3.53 (s, 3H), 1.70 (s, 9H), 1.41
(t, J = 7.1 Hz, 3H) 13C NMR 167.0, 149.8, 149.4, 135.7, 127.5, 127.4, 125.4, 111.6, 107.5, 104.2,
94.8, 84.4, 60.9, 56.3, 28.1 (3C), 14.4. Anal. calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01.
Found: C, 62.00; H, 6.68; N, 4.02.
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6-Hydroxymethyl-4-methoxymethoxy-indole-1-carboxylic acid tert-butyl ester (38). To
ester 37 (434 mg, 1.24 mmol) in THF (30 mL) at 0 °C was added DIBAL (4.1 mL, 1M in THF).
When judged complete by TLC analysis, the reaction was quenched by addition of NH4Cl (sat),
poured into ethyl acetate, acidified, and then extracted with ethyl acetate. The combined organic
extracts were washed with NaHCO3 (sat) and brine, dried (MgSO4), and filtered, and the filtrate
was concentrated in vacuo. Final purification by flash column chromatography (25% ethyl
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acetate in hexanes) afforded alcohol 38 (345 mg, 91%) as a colorless oil: 1H NMR δ 7.84 (s, 1H),
7.48 (d, J = 3.8 Hz, 1H), 6.93 (d, J = 0.9 Hz, 1H), 6.67 (dd, J = 3.8, 0.7 Hz, 1H), 5.30 (s, 2H),
4.75 (s, 2H), 3.51 (s, 3H), 2.16 (br s, 1H), 1.66 (s, 9H) 13C 150.3, 149.7, 138.7, 136.6, 124.8,
121.0, 108.0, 106.3, 104.1, 94.7, 83.7, 66.0, 56.1, 28.1 (3C). Anal. calcd for C16H21NO5: C,
62.53; H, 6.89; N, 4.56. Found: C, 62.30; H, 7.13; N, 4.56.
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Preparation of (4-Methoxymethoxy-1H-indol-6-ylmethyl)-phosphonic acid diethyl ester
(39) and 6-(Diethoxy-phosphorylmethyl)-4-methoxymethoxy-indole-1-carboxylic acid tert-
butyl ester (40). To LiBr (450 mg, 5.18 mmol) and NEt3 (0.43 mL, 3.09 mmol) in THF at 0 °C
was added the benzylic alcohol 38 (312 mg, 1.02 mmol) as a THF solution. The solution was
stirred for 5 min and then MsCl (0.16 mL, 2.07 mmol) was added dropwise. The reaction
mixture was allowed to stir for 1 h and more LiBr (400 mg, 4.61 mmol) was added. After the
reaction was judged complete by TLC analysis it was quenched by addition of NaHCO3 (sat),
diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed
with brine, dried (MgSO4), and filtered, and the filtrate was concentrated in vacuo. To the
resulting residue was added P(OEt)3 (4 mL) and the solution was heated at reflux overnight. The
next day the solution was allowed to cool to rt and then poured into water and extracted with
ethyl acetate. The organic extracts were washed with brine, dried (MgSO4), and filtered, and the
filtrate was concentrated in vacuo. Final purification by flash column chromatography (50 to
70% ethyl acetate in hexanes) afforded indole phosphonate 40 (18 mg, 4%) as an oil and the
parent indole phosphonate 39 (194 mg, 58%) as an oil.
For phosphonate 39: 1H NMR δ 9.61 (s, 1H), 7.05 (d, J = 2.9 Hz, 1H), 6.99 (t, J = 2.3 Hz, 1H),
6.66 (s, 1H), 6.54, (t, J = 2.2 Hz, 1H), 5.29 (s, 2H), 4.44 – 3.96 (m, 4H), 3.50 (s, 3H), 3.21 (d, JPH
= 21.1 Hz, 2H), 1.24 (t, J = 7.0 Hz, 6H); 13C NMR δ 150.2 (d, JCP = 2.7 Hz), 137.7 (d, JCP = 2.9
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Hz), 124.8 (d, JCP = 9.4 Hz), 123.5, 118.2 (d, JCP = 2.7 Hz), 107.1 (d, JCP = 7.4 Hz), 105.6 (d, JCP
= 5.8 Hz), 98.7, 94.7, 62.1 (d, JCP = 6.8 Hz, 2C), 55.9, 33.9 (d, JCP = 138 Hz), 16.2 (d, JCP = 6.1
Hz, 2C); 31P NMR δ 28.2; HRMS (EI) m/z calcd for C15H22NO5P (M+) 327.1236; found
327.1229.
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Boc protection of phosphonate 39. To phosphonate 39 (194 mg, 0.593 mmol) in CH2Cl2 (10
mL) was added DMAP (8 mg, 0.065 mmol) and Boc2O (150 mg, 0.69 mmol). The reaction was
allowed to stir for 2 h and then checked by TLC analysis. After an additional amount of Boc2O
was added (50 mg, 0.23 mmol), the reaction was allowed to proceed for another hour. The
reaction mixture was quenched by addition of water and extracted with CH2Cl2. The combined
organic extracts were dried (MgSO4), and filtered, and the filtrate was concentrated in vacuo.
Final purification by flash column chromatography (80% ethyl acetate in hexanes) afforded the
Boc-protected indole 40 (183 mg, 72%) with 1H and 13C NMR spectra consistent with material
prepared via the route below.
Preparation of phosphonate 40 at reduced temperature. To alcohol 38 (147 mg, 0.48 mmol)
in THF (10 mL) was added LiBr (250 mg, 2.9 mmol) and NEt3 (0.2 mL, 1.4 mmol), the solution
was cooled to 0 °C, and then was allowed to stir. After 10 min, MsCl (0.08 mL, 2.07 mmol) was
added dropwise and the reaction mixture was allowed to stir for 2 h. The reaction was then
quenched by addition of NH4Cl (sat), diluted with water, and extracted with ethyl acetate. The
combined organic extracts were dried (MgSO4) and filtered, and the filtrate was concentrated in
vacuo. To the residue was added P(OEt)3 and the resulting solution was heated to 95 °C and
allowed to stir overnight. The next day the solution was allowed to cool to rt, and then
concentrated in vacuo. Final purification by flash column chromatography (1.5% EtOH in Et2O)
afforded phosphonate 40 (125 mg, 61%) as an oil: 1H NMR δ 7.78 (br s, 1H), 7.48 (d, J = 3.5
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Hz, 1H), 6.88 (m, 1H), 6.66 (d, J = 3.7 Hz, 1H), 5.30 (s, 2H), 4.09–4.00 (m, 4H), 3.51 (s, 3H),
3.26 (d, JPH = 21.6 Hz, 2H), 1.66, (s 9H), 1.27 (t, J = 7.1 Hz, 6H); 13C NMR δ 150.0 (d, JCP = 2.9
Hz), 149.6, 128.7 (d, JCP = 9.5 Hz), 124.6, 120.3, 110.7 (d, JCP = 7.9 Hz), 108.9 (d, JCP = 5.7 Hz),
104.0 (d, JCP =1.6 Hz), 94.7, 83.6, 62.0 (d, JCP = 6.6 Hz, 2C), 56.3, 34.3 (d, JCP = 138 Hz), 28.1
(3C), 16.3 (d, JCP = 6.3 Hz, 2C); 31P NMR δ 27.3; HRMS (EI) m/z calcd for C20H30NO7P (M+)
427.1760; found 427.1757
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[4-Methoxymethoxy-1-(toluene-4-sulfonyl)-1H-indol-6-yl]-methanol (41). To indole 36 (805
mg, 3.23 mmol) in THF (30 mL) at 0 °C was added NaH (170 mg, 4.2 mmol, 60% dispersion in
oil) followed after 10 min by TsCl (700 mg, 3.61 mmol). After 30 min, DIBAL (1.45 mL, 8.1
mmol) was added and the reaction was allowed to stir for an additional 30 min. It then was
quenched by addition of NH4Cl (sat), poured into ethyl acetate, acidified, and extracted with
ethyl acetate. 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 (50% ethyl acetate in hexanes) afforded benzylic alcohol 41 (1.02 g, 87%
overall yield): 1H NMR ((CD3)2CO) δ 7.84 (d, J = 8.3 Hz, 2H), 7.78 (s, 1H), 7.59 (d, J = 3.6 Hz,
1H), 7.22, (d, J = 8.5 Hz, 2H), 6.99 (s, 1H), 6.81, (dd, J = 3.7, 0.7 Hz, 1H), 5.27 (s, 2H), 4.78 (s,
2H), 4.53 (br s, 1H), 3.41 (s, 3H), 2.23 (s, 3H); 13C NMR δ 151.2, 146.0, 141.8, 136.9, 135.8,
130.7 (2C), 127.5 (2C), 126.0, 121.5, 107.2, 106.7, 105.9, 95.2, 65.0, 56.2, 21.3; HRMS (EI) m/z
calcd for C18H19NO5S (M+) 361.0984; found 361.0992.
[4-Methoxymethoxy-1-(toluene-4-sulfonyl)-1H-indol-6-ylmethyl]-phosphonic acid diethyl
ester (42). To alcohol 41 (118 mg, 0.33 mmol) in THF (10 mL) at 0 °C was added LiBr (226
mg, 2.62 mmol) and NEt3 (0.18 mL, 1.30 mmol). The reaction was allowed to stir for 5 min and
then MsCl (0.06 mL, 0.78 mmol) was added dropwise. The reaction was allowed to warm to rt
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