Synthesis-driven mapping of the dictyodendrin alkaloids

Article abstract of DOI:10.1016/j.tet.2009.06.058

The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparat

Full text of DOI:10.1016/j.tet.2009.06.058

Tetrahedron 65 (2009) 6519–6534
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis-driven mapping of the dictyodendrin alkaloids
Philipp Buchgraber, Mathias M. Domostoj, Bodo Scheiper, Conny Wirtz, Richard Mynott,
*
Jo¨rg Rust, Alois Fu¨rstner
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As
such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-
marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like compounds that
hinges on the formation of their indole subunit by reductive cyclization of appropriate keto-amide
precursors mediated by low valent titanium. It is shown that the underlying concept can be extended
from the synthesis of heterocycles to the preparation of phenol and aniline derivatives using oxo-acid,
oxo-nitrile or oxo-lactam derivatives as the substrates; such arene formations can even be carried out in
cascade. Exploratory studies into the closure of the B-ring of the dictyodendrins with the aid of elec-
trophilic reagents such as Ph3PAuCl/AgSbF6 or Iþ revealed the bias of these polycyclic heteroarenes to
undergo unusual skeletal rearrangements. It is demonstrated that the individual dictyodendrins and
analogues are capable of cleaving double stranded DNA under oxidative conditions, provided that they
exhibit at least one unprotected phenol group in their periphery.
Received 17 March 2009
Received in revised form 15 June 2009
Accepted 15 June 2009
Available online 21 June 2009
Dedicated to Professor Larry E. Overmann,
the 2008 recipient of the Tetrahedron Prize,
with admiration and respect
Keywords:
Alkaloids
DNA
Gold
Indoles
Ó 2009 Elsevier Ltd. All rights reserved.
Telomerase
Titanium
1. Introduction
Therefore, the dictyodendrin alkaloids 1–5 isolated from the
sponge Dictyodendrilla verongiformis deserve attention as they
Telomeric DNA that protects chromosomes at both ends is
shortened in each round of cell division through replication-de-
pendent sequence loss.1 This process constitutes an internal clock
of aging which is counteracted in cancer cells by the action of tel-
omerase, an enzyme with inverse transcriptase properties. The fact
that telomerase is over-expressed in >85% of all malignant tumors
but largely silent in healthy tissue suggests that this enzyme con-
stitutes a selective tumor marker and may hence serve as molecular
target for a new generation of cancer drugs with improved thera-
peutic windows.1,2
Chemotherapy based on telomerase inhibition, however, is
confronted with the problem that it may take many rounds of cell
division before the growing tumor becomes affected. Therefore it is
particularly important that any drug candidate not only shows high
potency and selectivity, but also exhibits minimal toxicity even in
combination with other drugs and is not subject to export from the
cells by multidrug resistance (MDR) mechanisms.2
were claimed to be the first marine natural products with telo-
merase inhibitory activity (100% inhibition at a concentration of
50 m
g mLꢀ1) (Scheme 1).3,4 Unfortunately however, no further
information on the bioassays used nor on other relevant phar-
maceutical properties of these compounds were disclosed.
Even though the dictyodendrins are rather unusual from the
structural viewpoint, many distantly related pyrrole alkaloids are
known that exhibit promising biological activity profiles (for se-
lected examples, see Scheme 2).5 In the case of storniamide 11,
for example, it was shown that the inherent cytotoxicity of the
compound can be largely switched off by methylation of the
peripheral hydroxy groups. Moreover, compound 12 representing
the permethylated storniamide core was reported to reverse
multidrug resistance and was even found capable of hyper-
sensitizing the human colon cancer cell line HTC116/VM46 to-
wards vincristine and doxorubicin.6 If a similar profile could be
grafted onto dictyodendrin descendants while maintaining or
even increasing the reported telomerase inhibitory capacity,
such derivatives might become candidates for preclinical
development.
Small molecule telomerase inhibitors that meet these stringent
criteria and that may hence qualify as lead compounds are rare.
Any such endeavor requires a secured supply of material. To
this end, we reported the first and so far only total synthesis of
three members of this family of natural products.7,8 As part of
* Corresponding author. Tel.: þ49 208 306 2342; fax: þ49 208 306 2994.
E-mail address: fuerstner@kofo.mpg.de (A. Fu¨ rstner).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.058

6520
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
OSO3Na
NH
OH
OH
OSO3Na
HO
MeO
N
HO
OH
HO
HO
NH
MeO
O
MeOOC
O
OH
O
MeO
N
N
N
O
O
MeO
X
OMe
OH
OH
HO
HO
Lamellarin A (8, X = OH) Lukianol A (10)
Lamellarin C (9, X = H)
OH
OH
Dictyodendrin A (1)
OH
Dictyodendrin B (2)
HO
OH
OH
OH
HO
OSO3Na
NH
OSO3Na
NH
HO
HO
HO
H
H
N
N
N
O
O
O
O
O
N
N
HO
OH
Storniamide A (11)
OH
OH
HO
OH
HO
OH
Dictyodendrin E (5)
OR
OH HO
OH
MeO
OMe
OMe
OMe
MeO
Dictyodendrin C (3, R = H)
Dictyodendrin D (4, R = SO3Na)
MeO
O
O
OSO3Na
NH
OSO3Na
HO
MeO
OMe
HO
N
N
O
O
NH
O
O
OH
HO
MeOOC
HO
O
O
N
N
HO
12
OH
Purpurone (13)
OMe
Scheme 2. Selected examples of related pyrrole alkaloids of marine origin.
OH
OH
HO
OH
OH
a reasonable scale, it seemed worthwhile to explore alternative
strategies to close the B-ring.
7
6
To probe various electrophile-induced cyclization modes, pyr-
role 17a (R¼Me) was prepared by adaptation of the established
route and then converted into amide 19 on treatment with the very
sensitive acid chloride 18 (Scheme 3).18 Exposure of 19 to low-
valent titanium19,20 prepared by reduction of TiCl3 with KC8 in DME 15
afforded indole 20, which turned out to be rather unstable and
could therefore be isolated in only 59% yield. Gratifyingly, however,
reaction of this product with catalytic amounts of (Ph3P)AuCl and
AgSbF6 in CH2Cl2 at 0 ꢁC resulted in the almost instantaneous clo-
sure of the missing B-ring.21,22 The constitution of the resulting
permethylated dictyodendrin analogue 21 was confirmed by ex-
tensive NMR investigations, amongst which the 15N,1H-HMBC ex-
periments turned out to be particularly informative (see
Experimental section). The structure assignment was later con-
firmed by single crystal structure analysis (Fig. 1).
Scheme 1. Structures of the dictyodendrins and related compounds.
a longstanding program dealing with bioactive pyrrole alka-
loids,7,9–12 we set out to map these interesting pyrrolocarbazole
derivatives more systematically. Outlined below are some of the
synthetic aspects of this venture in ‘diverted total synthesis’,13,14
which led to a collection of over 30 dictyodendrin-inspired ‘natural
product like’ compounds; at the same time, our study provides
insights into the unusual reactivity of these highly condensed,
electron rich heteroarenes. While a detailed biochemical profiling
of the individual products is pending, we describe here their pre-
viously unknown ability to cleave double stranded DNA under ox-
idative conditions.
21 shows a peculiar behavior upon exposure to Lewis acids.
Specifically, attempts at Friedel–Crafts acylation with 4-methoxy-
benzoyl chloride in the presence of SnCl4 failed to afford any of the
desired ketone, but instead led to clean isomerization of the
starting material with formation of compound 24 (Scheme 4). TiCl4
and BF3$Et2O trigger this unusual migration of the aryl substituent
with similar efficiency.23 It is believed that this rearrangement
commences with attack of the Lewis acid to the C-3 position of 21.
The resulting iminium cation 22 then reacts with the adjacent
arene ring to form the Wheland-type complex 23, which, upon
2. Results and discussion
2.1. Electrophilic closure of the B-ring
Our total synthesis of 2, 3 and 5 used a common building block,
which was formed by a titanium-induced reductive keto-amide
coupling reaction15–17 followed by a photochemical 6
p-electro-
cyclization/aromatization cascade.7 Even though the latter trans-
formation was high yielding and could be performed on

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6521
OMe
O
Cl
O
NO2
O
NO2
O
NX2
18
OR
OR
[a]
OR
OMe
[b]
[d]
N
MeO
15
14a R = Me
b R = iPr
16 X = O
17 X = H
[c]
OMe
MeO
OMe
OMe
NH
OMe
NH
MeO
MeO
D
C
O
HN
O
OMe
[e]
[f]
B
A
N
N
N
19
20
21
OMe
OMe
MeO
OMe
OMe
Scheme 3. (a) 4-Methoxybenzaldehyde, NaOMe, MeOH, reflux, 77% (R¼Me), 74% (R¼i-Pr); (b) (i) NaH, TosMIC, THF, ꢀ30 ꢁC; (ii) p-MeOC6H4CH2CH2Br, reflux, 90% (R¼Me), 83%
(R¼i-Pr); (c) Pd/C, H2 (1 atm), EtOAc, 84% (R¼Me), or: Fe powder, aq HCl, EtOH, 96% (R¼i-Pr); (d) 18, CH2Cl2, ꢀ30 ꢁC, 70%; (e) TiCl3/2KC8, DME, reflux, 59%; (f) (Ph3P)AuCl (5 mol %),
AgSbF6 (5 mol %), CH2Cl2, 0 ꢁC, 67%.
O4
OMe
NH
C27
OMe
NH
MeO
C26
C25
C24
C31
C22
C23
C18
C28
C29
Cl4Sn
C5
C21
C20
C16
C37
C6
[a]
N2
C4
C3
3
O2
C17
C30
MeO
N
N
C10
C7
C8
C11
C12
C13
O1
C36
C19
C9
C38
C32
C33
OMe
OMe
C35
C34
O3
C1
C2
C14
N1
22
21
OMe
OMe
C15
Figure 1. Molecular structure of compound 21 in the solid state. Anisotropic dis-
placement parameters are shown at the 50% probability level.
OMe
NH
OMe
NH
SnCl4
N
MeO
collapse, engenders the observed 3/2 shift of the aryl group
driven by the relief of the strain resulting from the peri-interaction
of the migrating aryl group in the starting material 21.
N
2
MeO
The sensitivity of polycyclic arenes of the dictyodendrin series
also surfaced in attempted cyclizations of 20 with various Xþ
sources. Whereas treatment with either I2/K2CO3 or ICl led to in-
stantaneous decomposition, the use of [I(pyridine)2]BF4 24 afforded
two isomeric iodides (Scheme 5). The major product was shown by
X-ray crystallography to be the expected 12-iodo derivative 25
(Fig. 2), but the constitution of the byproduct was established only
after extensive NMR investigations.
OMe
OMe
24
23
OMe
OMe
Scheme 4. Attempted Friedel–Crafts acylation of 21 induces a 3/2 aryl shift: (a)
p-MeOC6H4COCl, SnCl4, 1,2-dichloroethane, reflux, 64%.
The NMR data allow one fragment consisting of ring A and its
substituents and another of rings C, D, and part of B together with
their substituents to be identified; they showed that the iodide
must definitely be on ring B. The connectivities determined by
HMBC spectra (13C,1H and 15N,1H) revealed no significant differ-
ences from those determined for the major product 25. However,
not all the connectivities in the center of the core can be de-
termined using HMBC spectra because correlations corresponding
to those from H-12 in 24 are missingdin particular, the connec-
tivities in ring B to the ring junction AB are not defined. Thus, these
data are also consistent with the orientation of the pyrrole A-ring in
27 relative the remainder of the core being the ‘reverse’ of that in 25.
This structural assignment was nicely confirmed by the observed
NOEs (Scheme 5).
This unexpected outcome may be rationalized by assuming that
activation of the alkyne in 20 by the Iþ equivalent engenders two
competing cyclization modes. Whereas the regular 6-endo process
leads to the expected product 25, a 5-endo cyclization gives rise to
iminium cation 26, which generates 27 by a subsequent Wagner–
Meerwein-like rearrangement. Though unusual, this process
follows the reactivity pattern that is also expressed in the acid
catalyzed aryl shift described above (21/24).

6522
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
OMe
precursors with the aid of low-valent titanium. Even though tita-
MeO
nium-mediated oxo-ester coupling reactions per se are known in
the literature,19,25,26 it seems that such transformations have never
been used for the formation of substituted phenol derivatives.27
To probe this new entry into phenol derivatives, two suitable
model compounds were prepared by Suzuki reaction28 of 28 with
29 and 32 with 33, respectively (Scheme 6, for the preparation of
the building blocks, see the Experimental section). Gratifyingly, the
resulting keto-esters 30 and 34 underwent productive ring closure
when exposed to low-valent titanium in the presence of excess
pyridine to buffer the reaction mixture. In both cases the corre-
sponding free phenols 31a and 35a (R¼H) were formed as the
major products.
NH
5-endo
6-endo
N
[a]
[a]
20
OMe
OMe
OMe
NH
OMe
MeO
MeO
NH
12
I
I
I
Cl
O
O
N
B
N
N
O
OEt
O
25
29
26
OMe
OMe
[a]
OMe
28
OMe
OMe
OMe
nOe
EtO
MeO
OR
Cl
O
MeO
OMe
NH
Cl
O
MeO
[b]
D
N
N
C
I
N
A
12
OMe
B
I
NH
OMe
H
N
H
H
H
OMe
H
H
30
OMe
OMe
31a R = H
b R = Et
OMe
OMe
27
OMe
Scheme 5. (a) [I(pyridine)2]BF4, TfOH, CH2Cl2, ꢀ60 ꢁC, 67% (25 and 27).
Ph
O
O
Br
33
B
O
O
C17
O17
I1
Ph
Ph
O
[c]
N
OMe
N
OMe
C13
N15
C14
C12
C11
C10
C1
C16
32
34
C25
O27
C27
C26
C24
C2
C9
C8
C7
C6
35a R = H
b R = Me
C21
[d]
C23
C22
C36
C3
C35
OR
N
C31
O37
C39
C34
N4
C42
Scheme 6. (a) Pd(PPh3)4 (5 mol %), K3PO4, 1,4-dioxane, 100 ꢁC, 36%; (b) TiCl3/2KC8,
DME, pyridine, reflux, 79% (31a/31b¼25:1); (c) Pd(PPh3)4 (5 mol %), K3PO4, 1,4-di-
oxane, 100 ꢁC, 92%; (d) TiCl3/2KC8, DME, pyridine, reflux, 89% (35a/35b¼5:1).
C43
C5
C41
C47
C32
C33
C40
C37
C44
Based on these promising results, the investigation into arene
ring formation by reductive coupling was extended to other un-
conventional substrate types. As can be seen from the results
compiled in Scheme 7, various biaryl derivatives bearing a ketone
and either a free carboxylic acid, acyl fluoride, amide, lactam or
nitrile cleanly reacted to the corresponding substituted phenan-
threne derivatives when exposed to low-valent titanium, in-
dependent of whether it is generated from TiCl3 and KC8 or via the
operationally more convenient ‘instant procedure’ (TiCl3/Zn,
without pre-reduction);15 notably, product 41 closely resembles
the aristolactam alkaloids (Fig. 3).29 Collectively, these results show
that the formation of substituted aromatic rings provides sufficient
C46
O47
C45
Figure 2. Molecular structure of compound 25 in the solid state. Anisotropic dis-
placement parameters are shown at the 50% probability level.
2.2. Reductive closure of the B-ring and non-canonical
McMurry-type reactions
Next, we investigated if the B-ring of the dictyodendrin core
could be forged by reductive oxo-ester cyclization. This plan was
inspired by the remarkable efficiency with which the indole sub-
unit of these targets could be generated from suitable keto-amide

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6523
polycarbonyl derivative with excess titanium–graphite in refluxing
DME for 40 min gave the desired carbazole 51 in 54% yield. If the
reaction was quenched prematurely after only 25 min, indole 50 was
the only product that could be isolated from the mixture (70%). Al-
though these results show that polycarbonyl derivatives are ame-
nable to chemo- and regioselective coupling cascades,32 it becomes
evident that reductive indole formation is considerably faster than
the subsequent closure of the phenol ring. For the latter process to
occur, the ortho,ortho0-disubstituted biaryl unit in, e.g., 50 must be-
come planar, with the two carbonyl groups on the same side, before
productive C–C-bond formation can occur; the barrier inherent to
this rotation probably translates into a kinetic handicap.
X
OH
O
[a]
O
or [b]
MeO
OMe
36 a (X = OH)
b (X = F)
37
[c]
c (X = NH2)
NH2
O
[c]
N
O
MgCl
MeO
B
MeO
OMe
MeO
44
38
39
MeO
O
N
B
MgCl
O
N
O
[a]
H
O
O
H
45
OMe
MeO
OMe
Br
41
40
[a]
47
46
S
S
OMe
OMe
OH
OH
O
[b]
O
O
NHR
N
H
O
O
O
O
MeO
OMe
[b,c]
42
43
[g]
[e,f]
Scheme 7. (a) TiCl3/2KC8, DME, reflux, 89% (36a/37), 85% (36b/37); 86% (40/41);
(b) TiCl3, Zn, DME, reflux, 86% (36a/37), 90% (36b/37), 85% (42/43); (c) (i) TiCl3,
Zn, DME, reflux; (ii) ETDA workup, 58% (36c/39), 90% (38/39).
OMe
OMe
O3
48a R = Boc
48b R = H
49
C41
[d]
C45
C42
C40
C46
C51
MeO
C43
H
N2
N
O
C44
O
C39
C56
C55
C54
C31
C38
C37
C36
NH
OR
C57
O4
C32
C52
C53
C33
C34
C35
51a (R = H)
b (R = Me)
50
OMe
OMe
Figure 3. Molecular structure of compound 41 in the solid state. Anisotropic dis-
placement parameters are shown at the 50% probability level.
Scheme 8. (a) 45, Pd(OAc)2 (1 mol %), S-Phos (2 mol %), DMF/THF, 110 ꢁC; (b) N-Boc-2-
bromoaniline, MeLi, THF, 78 ꢁC, then tert-BuLi, 63% (over both steps); (c) TPAP
(5 mol %), NMO, MS 3 Å, CH2Cl2, 88%; (d) aq HCl, EtOH, reflux, quant.; (e) MeOOC-
C(O)Cl, pyridine, CH2Cl2, ꢀ20 ꢁC, 93%; (f) CrO3, HOAc, 93%; (g) TiCl3/2KC8, DME, reflux,
25 min: 50 (70%)þ51 (3%); 40 min: 51 (a/b¼9:1, 54%).
driving force for highly ‘non-canonical’ McMurry reactions19 which
involve functional groups that were previously considered inert
toward low-valent titanium.30
2.3. McMurry cascade
2.4. Peripheral modifications
Since the results summarized above had shown that the B- as
well as the C-ring of the dicytodendrin core can be formed in a re-
ductive mode, an attempt was made to combine these trans-
formations into a one-pot cyclization cascade. This requires four
different carbonyl groups in close proximity to engage into two well
orchestrated coupling events effected by the very same reagent.
This concept was probed by the model study shown in Scheme 8.
Chemoselective benzylation of 2-bromo benzaldehyde 46 via the 9-
MeO-9-BBN variant31 of the Suzuki coupling afforded product 47,31
which was readily transformed into compound 49. Treatment of this
In addition to the dictyodendrin analogues mimicking the
condensed pyrrolocarbazole core of the natural products, several
derivatives with
a formally open B-ring were prepared for
biological testing (53–56). Their syntheses were straightforward,
requiring nothing but acylation of the common pyrrole precursor
17b (R¼i-Pr)7 followed by treatment of the resulting oxo-amide
derivatives 52 with TiCl3/2KC8 under standard conditions. Although
not fully optimized, the yields were good to excellent in all cases
but one, showing the robustness of this reductive approach to
indoles (Scheme 9).

6524
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
OMe
show that the presence of Cu(2þ) is essential for triggering such
oxidative stress. Dictyodendrin C, in sulfated (3) or unsulfated form
(65),7 also shows an appreciable effect (Fig. 4, lane 7 and Fig. 5, lane
10). Importantly, however, no noticeable DNA cleavage was exerted
by their fully protected congeners 57 and 59 (lanes 5 and 8).
R
O
HN
O
OiPr
N
52
a R = CH=CHC6H4OMe
b R = CH2CH2C6H4OMe
c R = C6H4OMe
MeO
d R = Me
OiPr
NH
OiPr
MeO
MeO
NH
OSO3Na
OiPr
NH
OMe
HO
MeO
N
N
NH
53
54
O
N
OMe
N
OMe
OMe
OMe
OH
OH
OMe
HO
HO
MeO
HO
OiPr
NH
OiPr
NH
MeO
MeO
57
5
OH
OMe
OSO3Na
NH
N
N
NH
OMe
O
O
O
N
N
55
56
OMe
OMe
OH
OH
HO
Scheme 9. Dictoydendrin analogues with formally cleaved B-ring generated by re-
ductive cyclization of keto-amides 52a–d. Reagents and conditions: TiCl3/2KC8, DME,
reflux, 53 (73%), 54 (20%), 55 (89%), 56 (77%).
58
3
OH
OH
OiPr
NH
OMe
OSO3Na
MeO
HO
O
3. Investigation of the DNA-cleaving Properties
NH
OH
Together with the samples of the natural products themselves
and their immediate precursors, our synthesis campaign afforded
more than 30 dictyodendrin-like compounds for biological in-
vestigations. Whereas a detailed profiling of the individual prod-
ucts is still in progress, the preliminary data indicate a low inherent
toxicity of prototype members of the series against HeLa as well as
HepG2 cancer cells. This constitutes an important prerequisite for
possible monitoring of cancer growth inhibition by downregulation
of telomerase activity.
O
N
N
OMe
OH
MeO
59
HO
OMe
OH
2
Previous investigations from this laboratory had shown that
polyhydroxylated pyrroles can induce single- and even double
strand cleavage in supercoiled plasmid DNA under oxidative con-
ditions.10,33,34 As the dictyodendrins are supposed to target DNA, it
was appropriate to study whether they are also able to damage this
bio-macromolecule in a similar fashion. The gel depicted in Figure 4
illustrates this property and establishes a strong correlation be-
tween observed DNA damage and the peripheral methylation
pattern of the compounds. Specifically, dictyodendrin B (2, lane 9)
and E (5, lane 4),7 as well as the dictyodendrin E analogue 58 devoid
of the sulfate moiety (lane 6)7 relax the supercoiled plasmid DNA of
Figure 4. Agarose gel electrophoresis showing the extent of DNA cleavage by different
dictyodendrins and derivatives thereof in the presence of Cu(OAc)2 and BuNH2 after an
incubation time of 1.5 h at 37 ꢁC. Lane 1: DNA marker (500 base pairs molecular weight
difference); lane 2: native DNA (band I: supercoiled DNA; band II: nicked DNA (single
strand cleavage)); lane 3: linear DNA produced by cleavage of the parent DNA with the
restriction endonuclease Xho I (band III); lane 4: DNAþcompound 5þCuIIþBuNH2; lane
5: DNAþcompound 57þCuIIþBuNH2; lane 6: DNAþcompound 58þCuIIþBuNH2; lane 7:
DNAþcompound 3þCuIIþBuNH2; lane 8: DNAþcompound 59þCuIIþBuNH2; lane 9:
DNAþcompound 2þCuIIþBuNH2; lane 10: DNAþcompound 5 without CuIIþBuNH2;
lane 11: DNA marker (500 base pairs molecular weight difference).
This conclusion was confirmed by the gel depicted in Figure 5,
wherein selected analogues were screened. Even compound 63,7 in
which all but one of the phenolic groups are methylated, still
constitutes a potent DNA damaging agent in combination with
Cu(2þ) (lane 7), whereas all fully protected compounds are devoid
the bacteriophage F
X174 (form I) within 1.5 h at 37 ꢁC to the nicked
form II in the presence of Cu(OAc)2 and n-butylamine; even small
amounts of linear DNA (form III) generated by double strand
cleavage are visible. As expected, comparison of lanes 9 and 10

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6525
agents indicated and transferred under Ar: THF, Et2O, 1,4-dioxane
(Mg/anthracene), CH2Cl2, Et3N, CH3CN, DMSO,(CaH2), hexane, tol-
uene, 1,4-dioxane, DME (Na/K), DMF (Desmodur 15, dibutyl tin
dilaurate), MeOH, EtOH (Mg). Flash chromatography (FC): Merck
silica gel 60 (230–400 mesh) or CombiFlash (Teledyne Isco). NMR:
Spectra were recorded on Bruker DPX 300, AMX 300, AV 400 and
DMX 600 spectrometers in the solvents indicated; chemical shifts
(d) are given in ppm relative toTMS, coupling constants (J) in Hz. The
R
solvent signals were used as references and the chemical shifts
converted to the TMS scale (CDCl3: dCh77.0 ppm; residual
CHCl3: dHh7.26 ppm; CD2Cl2: dCh53.8 ppm; residual CHDCl2:
dHh5.32 ppm; CD3OD dCh49.0 ppm; residual CHD2OD:
dHh3.30 ppm; acetone-d6: dCh29.8 ppm; residual acetone-d5:
dHh2.05 ppm, C6D6: dCh128.0 ppm; residual C6D5H: dHh7.15 ppm;
DMSO-d6: dCh39.5 ppm; residual DMSO-d5: dHh2.49 ppm). 15N
NMR spectra were calibrated against external CH3NO2. The coupling
constants (J) were not averaged. The proton spectra of the para-di-
substituted phenyl groups are of AA0XX0 spin systems. The splitting
of signals of greatest intensity is quoted as the value of the coupling
MeO
HN
OiPr
O
MeO
O
NH
N
OMe
N
17b R = H
OMe
MeO
R =
O
3
5
0
constant J(AX), assuming that J(AX ) is zero. Where indicated, the
signal assignments are unambiguous; the numbering scheme is
arbitrary and shown in the inserts. The assignments are based upon
1D and 2D spectra recorded using the following pulse sequences
from the Bruker standard pulse program library: DEPT; COSY (cosygs
and cosydqtp); HSQC (invietgssi) optimized for 1JC,H¼145 Hz; HMBC
OMe
60
61
MeO
OMe
OR1
NH
OMe
OH
NH
MeO
HO
n
(inv4gslplrnd) for correlations via JC,H; HSQC-TOCSY (invietgsml)
using an MLEV17 mixing time of 120 ms; IR: Magna IR750 (Nicolet)
~
or Spectrum One (Perkin–Elmer) spectrometer, wavenumbers ð
n
Þ in
O
cmꢀ1; MS (EI): Finnigan MAT 8200 (70 eV), ESI-MS: ESQ3000
(Bruker), accurate mass determinations: Bruker APEX III FT-MS (7 T
magnet) or Mat 95 (Finnigan). Melting points: Bu¨chi melting point
apparatus B-540 (corrected). Elemental analyses: H. Kolbe, Mu¨l-
heim/Ruhr. All commerciallyavailable compounds (Fluka, Lancaster,
Aldrich) were used as received. For the preparation of compounds 2,
3, 5, 15b–17b and 57–65, see Ref. 7.
O
N
N
OMe
OH
OR2
OH
62 R1 = iPr, R2 = Me
63 R1 = H, R2 = Me
64 R1 = iPr, R2 = H
65
4.1.1. (2E)-3-Methoxy-2-nitrophenyl-3-(4-methoxyphenyl)-2-
propenone (15a, R¼Me)
Sodium (161 mg, 7.00 mmol) was dissolved in MeOH (10 mL)
before p-methoxybenzaldehyde (2.50 mL, 21.2 mmol) and ketone
14a (2.70 g, 14.2 mmol) were added. The mixture was stirred at
70 ꢁC for 2 h before it was slowly cooled to ambient temperature.
The resulting precipitate was filtered off, successively washed with
water (20 mL) and MeOH (20 mL), and dried under high vacuum to
give chalcone 15a as a pale yellow solid (3.42 g, 77%); mp¼151–
Figure 5. Agarose gel electrophoresis showing the extent of DNA cleavage by different
dictyodendrins analogues in the presence of Cu(OAc)2 and BuNH2 after an incubation
time of 1.5 h at 37 ꢁC; band I: supercoiled DNA; band II: nicked DNA (single strand
cleavage); band III: linear DNA produced by cleavage of the parent DNA with the
restriction endonuclease Xho I; lane 1: DNA marker (500 base pairs molecular
weight difference); lane 2: native DNA; lane 3: linear DNA (band III); lane 4:
DNAþcompound 60þCuIIþBuNH2; lane 5: DNAþcompound 61þCuIIþBuNH2; lane 6:
DNAþcompound 62þCuIIþBuNH2; lane 7: DNAþcompound 63þCuIIþBuNH2; lane 8:
DNAþcompound 17bþCuIIþBuNH2; lane 9: DNAþcompound 64þCuIIþBuNH2; lane 10:
DNAþcompound 65þCuIIþBuNH2.
152 ꢁC; 1H NMR (300 MHz, CDCl3):
d
¼7.57–7.50 (m, 4H), 7.28–7.26
(m, 2H), 7.01–6.90 (m, 3H), 3.96 (s, 3H), 3.85 (s, 3H); 13C NMR
(75 MHz, CDCl3):
d¼189.6, 162.2, 151.5, 147.1, 134.3, 131.5, 130.6,
126.8, 121.5, 120.4, 115.4, 114.5, 56.8, 55.4; IR (film): 3007, 2939,
2841, 1663, 1642, 1587, 1571, 1539, 1511, 1475, 1454, 1436, 1306,
1292, 1258, 1173, 1026, 852, 830, 794 cmꢀ1; MS (EI): m/z (%): 313
(17) [Mþ], 177 (14), 161 (10), 135 (35), 121 (100), 90 (11), 76 (18), 65
(8); HRMS (EI) m/z: calcd for C17H15NO5þNa [(MþNa)þ]: 336.0847,
found: 336.0850.
of any appreciable activity. This strong correlation with the nucle-
ase-like activity can be rationalized by assuming a Cu(2þ)-medi-
ated oxidation of the phenol to the corresponding o-quinone with
concomitant release of H2O2 which, in turn, undergoes metal-
assisted cleavage to diffusible oxygen radicals as the ultimately
DNA-damaging agents.35 In any case, we conclude that the natu-
rally occurring dictyodendrins and synthetic analogues are
endowed with potent DNA cleavage properties, but that these can
be effectively switched off by per-alkylation of the peripheral
phenolic sites.
4.1.2. (3-Methoxy-2-nitrophenyl){4-(4-methoxyphenyl)-1-[2-(4-
methoxyphenyl)ethyl]1H-pyrrol-3-yl}methanone (16a, R¼Me)
A solution of tosylmethylisocyanide (TosMIC, 1.76 g, 9.00 mmol)
and chalcone 15a (1.42 g, 4.50 mmol) in THF (20 mL) was added to
a stirred suspension of NaH (0.65 g, 27 mmol) in dry THF (10 mL) at
ꢀ30 ꢁC. The mixture was stirred at ꢀ30 ꢁC for 1 h and at ambient
temperature for 2 h. After completion of the reaction, 2-bro-
moethyl-4-methoxybenzene (3.87 g, 18.0 mmol) was introduced
and the mixture refluxed for 2 h. For work up, the reaction was
quenched with water (20 mL) and the product extracted with
EtOAc (3ꢂ20 mL). The combined organic layers were washed with
4. Experimental
4.1. General
All reactions were carried out under Ar in flame-dried glassware.
The solvents used were purified by distillation over the drying

6526
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
brine and dried over Na2SO4. Evaporation of the solvent followed by
flash chromatography of the residue (EtOAc/hexanes, 1:1) afforded
pyrrole 16a as a pale yellow solid (1.98 g, 90%); mp¼61–62 ꢁC; 1H
NMR (300 MHz, CDCl3): 7.36–7.26 (m, 3H), 7.04 (m, 1H), 6.93 (m,
2H), 6.88 (m, 1H), 6.81–6.77 (m, 4H), 6.73 (d, J¼2.3 Hz, 1H), 6.55 (d,
J¼2.3 Hz, 1H), 3.96 (t, J¼6.9 Hz, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.74 (s,
(d, J¼15.7 Hz, 1H), 7.44 (d, J¼8.7 Hz, 2H), 7.36 (d, J¼8.6 Hz, 2H), 7.09
(dd, J¼8.0, 7.8 Hz, 1H), 7.02–6.95 (m, 4H), 6.92 (d, J¼2.5 Hz, 1H),
6.89–6.78 (m, 6H), 6.57 (d, J¼2.5 Hz, 1H), 6.37 (d, J¼15.6 Hz, 1H),
4.54 (sept, J¼6.0 Hz, 1H), 4.02 (t, J¼7.1 Hz, 2H), 3.81 (s, 3H), 3.79 (s,
3H), 3.78 (s, 3H), 2.98 (t, J¼7.1 Hz, 2H), 1.33 (d, J¼6.1 Hz, 6H); 13C
NMR (100 MHz, CDCl3):
d
¼190.5, 164.3, 160.8, 158.5, 158.3, 152.1,
3H), 2.92 (t, J¼6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d
¼186.1,
141.0, 137.0, 131.5, 129.7, 129.7, 129.7, 129.4, 127.7, 127.3, 127.1, 125.7,
125.3, 122.0, 121.2, 121.0, 118.6, 116.2, 114.1, 114.1, 113.4, 71.3, 55.3,
55.2, 55.2, 51.8, 36.9, 22.1; IR (KBr): 3251, 3119, 2974, 2933, 2835,
1675, 1629, 1603, 1577, 1513, 1464, 1248, 1174, 1112, 1033, 921, 827,
778 cmꢀ1; MS (EI) m/z (%): 644 (61) [Mþ], 484 (18), 467 (31), 363
(47), 334 (12), 321 (10), 176 (9), 161 (100), 135 (22), 121 (9), 105 (5);
HRMS (ESI) calcd for C40H40N2O6þNa [(MþNa)þ]: 667.2779, found:
667.2776.
158.3, 158.2, 151.0, 139.3, 136.0, 131.0, 130.9, 129.7, 129.6, 129.4,
126.8, 126.5, 121.6, 121.0, 120.3, 114.4, 113.9, 113.1, 56.5, 55.0, 51.7,
36.6; IR (KBr): 3122, 3001, 2940, 2837, 1644, 1610, 1577, 1536, 1514,
1503, 1473, 1453, 1382, 1289, 1247, 1179, 1035, 834, 790 cmꢀ1; MS
(EI): m/z (%): 486 (100) [Mþ], 335 (9), 322 (20), 264 (11), 189 (8), 160
(13), 121 (57), 105 (12), 77 (9); HRMS (EI) m/z: calcd for
C28H26N2O6þNa [(MþNa)þ]: 509.1688, found: 509.1684.
4.1.3. (2-Amino-3-methoxyphenyl){4-(4-methoxyphenyl)-1-[2-(4-
methoxyphenyl)ethyl]1H-pyrrol-3-yl}methanone (17a, R¼Me)
Compound 16a (5.20 g,10.7 mmol) was added to a suspension of
Pd/C (10% w/w, 2.27 g) in EtOAc (30 mL) and the resulting mixture
was stirred under an atmosphere of H2 until TLC control indicated
complete consumption of the substrate. For work up, the catalyst
was filtered off through a short pad of silica which was carefully
rinsed with EtOAc, the combined filtrates were evaporated and the
residue was purified by flash chromatography (hexanes/EtOAc, 2:1)
to give product 17a as a yellow solid (4.12 g, 84%); mp¼56–57 ꢁC;
4.1.6. Amide 52b
Prepared analogously from 17b as a colorless foam (84%); 1H
NMR (300 Hz, CDCl3):
d¼7.72 (br s, 1H), 7.38 (d, J¼9.0 Hz, 2H), 7.13–
6.80 (m, 12H), 6.76 (d, J¼8.6 Hz, 2H), 6.60 (d, J¼2.3 Hz, 1H), 4.52
(sept, J¼6.0 Hz, 1H), 4.03 (dd, J¼7.3, 7.0 Hz, 2H), 3.80 (s, 3H), 3.80 (s,
3H), 3.75 (s, 3H), 3.00 (t, J¼7.1 Hz, 2H), 2.92–2.81 (m, 2H), 2.56–2.45
(m, 2H), 1.31 (d, J¼6.0 Hz, 6H); 13C NMR (75 MHz, CDCl3):
¼190.4,
d
170.4 (br), 158.6, 158.3, 157.9, 152.1, 137.5 (br), 133.1, 131.5, 129.8,
129.7, 129.6, 129.2, 127.2, 127.1, 125.5 (br), 125.3, 121.8, 121.2, 121.0,
115.8, 114.1, 113.8, 113.4, 71.1, 55.2, 55.2, 55.2, 51.8, 38.6 (br), 36.9,
30.7, 22.1; IR (KBr): 3251, 3121, 3030, 2974, 2933, 2834, 1683, 1632,
1612, 1579, 1549, 1513, 1464, 1384, 1300, 1246, 1178, 1034, 921, 828,
779 cmꢀ1; MS (EI) m/z (%): 646 (100) [Mþ], 587 (6), 484 (12), 467
(16), 441 (7), 363 (48), 339 (32), 321 (31), 292 (11), 280 (8), 186 (16),
178 (19), 162 (15), 135 (31), 121 (78), 105 (9); HRMS (ESI) calcd for
C40H42N2O6þNa [(MþNa)þ]: 669.2935, found: 669.2936. Anal.
Calcd for C40H42N2O6 (646.8): C 74.28, H 6.55, N 4.33; found: C
74.17, H 6.63, N 4.24.
1H NMR (300 MHz, CDCl3):
d
¼7.29 (m, 2H), 7.12 (dd, J¼8.1, 1.2 Hz,
1H), 6.92 (m, 2H), 6.83–6.75 (m, 5H), 6.60 (dd, J¼10.2, 2.3 Hz, 2H),
6.43 (dd, J¼8.0, 7.9 Hz, 1H), 6.05 (s, 2H), 3.92 (t, J¼6.8 Hz, 2H), 3.76
(s, 3H), 3.72 (s, 3H), 3.71 (s, 3H), 2.89 (t, J¼6.8 Hz, 2H); 13C NMR
(75 MHz, CDCl3):
d
¼193.0, 158.2, 157.8, 146.7, 140.4, 129.5, 129.4,
129.0, 128.2, 127.3, 126.3, 125.0, 121.7, 120.2, 119.8, 113.7, 113.5, 113.3,
112.1, 55.4, 54.9, 54.9, 51.3, 36.7; IR (film): 3484, 3358, 3120, 3033,
3000, 2935, 2835, 1613, 1582, 1543, 1513, 1453, 1440, 1246, 1224,
1178, 1036, 833, 776, 745 cmꢀ1; MS (EI): m/z (%): 456 (53) [Mþ], 335
(100), 307 (14), 212 (5), 186 (9), 162 (8), 121 (19), 91 (4); HRMS (EI)
m/z: calcd for C28H29N2O4 [(MþH)þ]: 457.2127, found: 457.2126.
4.1.7. Amide 52c
Prepared analogously from 17b as a colorless foam (91%); 1H
NMR (400 MHz, CDCl3):
d
¼8.55 (br s, 1H), 7.78 (d, J¼8.8 Hz, 2H),
4.1.4. Compound 19
7.34 (d, J¼8.8 Hz, 2H), 7.09 (dd, J¼8.3, 7.3 Hz, 1H), 7.04–6.95 (m,
4H), 6.94 (d, J¼2.3 Hz, 1H), 6.88 (d, J¼8.8 Hz, 2H), 6.82 (d, J¼8.6 Hz,
2H), 6.81 (d, J¼8.4 Hz, 2H), 6.55 (d, J¼2.3 Hz, 1H), 4.53 (sept,
J¼6.1 Hz, 1H), 4.00 (t, J¼7.1 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.79
(s, 3H), 2.96 (t, J¼7.1 Hz, 2H), 1.31 (d, J¼6.1 Hz, 6H); 13C NMR
Chloro-N,N-2-trimethylpropenylamine (1.0 mL, 7.6 mmol)18
was added to a solution of 3-(4-methoxyphenyl)-2-propynoic acid
(689 mg, 3.90 mmol) in CH2Cl2 (8 mL) and the resulting mixture
stirred for 2 h. Because of the instability of the resulting acid
chloride 18, amine 17a (880 mg, 1.93 mmol) was directly added to
this mixture at ꢀ30 ꢁC and stirring continued for 15 min at this
temperature. At this point, pyridine (1 mL) was introduced and the
mixture allowed to reach ambient temperature. After 1 h, the re-
action was quenched with water (10 mL), the aqueous layer was
extracted with EtOAc (3ꢂ10 mL), the combined organic phases
were dried (MgSO4) and evaporated, and the residue was purified
by flash chromatography (hexanes/EtOAc,1:1) to afford amide 19 as
a beige solid (829 mg, 70%); mp¼115–116 ꢁC; 1H NMR (400 MHz,
CDCl3): 8.40 (s, 1H), 7.44–7.36 (m, 4H), 7.16 (t, J¼8.0 Hz, 1H), 7.04–
6.95 (m, 4H), 6.85–6.95 (m, 7H), 6.58 (m, 1H), 4.00 (m, 2H), 3.88 (s,
(100 MHz, CDCl3):
d
¼190.8, 165.0, 162.2, 158.6, 158.2, 152.0, 136.6,
131.3, 129.7, 129.6, 129.4, 127.3, 127.2, 127.0, 126.4, 125.0, 122.4,
121.3, 120.9, 116.5, 114.1, 113.6, 113.4, 71.4, 55.4, 55.2, 55.2, 51.8, 36.9,
22.1; IR (KBr): 3422, 3122, 2974, 2933, 2835, 1677, 1640, 1607, 1513,
1249, 1032, 834, cmꢀ1; MS (EI): m/z (%): 618 (44) [Mþ], 497 (12),
467 (26), 307 (5), 135 (100), 107 (6), 77 (6); HRMS (ESI) calcd for
C38H38N2O6þNa [(MþNa)þ]: 641.2622, found: 641.2614. Anal. Calcd
for C38H38N2O5 (618.7): C 73.77, H 6.19, N 4.53; found: C 73.58, H
6.16, N 4.45.
4.1.8. Amide 52d
3H), 3.78 (s, 9H), 2.95 (m, 2H); 13C NMR (100 MHz, CDCl3):
d¼190.1,
Prepared analogously from 17b as a colorless foam (90%); 1H
160.9, 158.5, 158.3, 154.2, 134.3, 131.8, 129.6, 129.5, 127.0, 127.0,
126.3, 123.4, 121.9, 121.2, 121.0, 114.0, 113.4, 112.1, 82.7, 56.1, 55.2,
55.1, 51.8, 36.8, 19.1; IR (film): 3006, 2936, 2837, 2206, 1768, 1713,
1645, 1604, 1580, 1512, 1464, 1441, 1286, 1249, 1168, 1033, 834,
752 cmꢀ1; MS (EI) m/z (%): 614 (100) [Mþ], 582 (11), 482 (88), 453
(39), 361 (24), 334 (36), 306 (10), 238 (6), 176 (28), 159 (58), 135
(52), 121 (29); HRMS (EI) m/z: calcd for C38H34N2O6þNa
[(MþNa)þ]: 637.2314, found: 637.2302.
NMR (300 MHz, CDCl3):
d¼7.75 (br s, 1H), 7.38 (d, J¼8.8 Hz, 2H),
7.12–7.03 (m, 1H), 7.03–6.90 (m, 4H), 6.89–6.80 (m, 5H), 6.60 (d,
J¼2.5 Hz,1H), 4.53 (sept, J¼6.1 Hz,1H), 4.01 (t, J¼7.1 Hz, 2H), 3.80 (s,
3H), 3.79 (s, 3H), 2.98 (t, J¼7.1 Hz, 2H), 1.99 (s, 3H), 1.33 (d, J¼6.1 Hz,
6H); 13C NMR (75 MHz, CDCl3):
d
¼190.4, 168.4, 158.5, 158.3, 152.2,
137.6, 131.6, 129.7, 129.6, 129.6, 127.1, 127.0, 125.5, 125.3, 121.7, 121.1,
121.0, 115.9, 114.1, 113.3, 71.1, 55.2, 55.1, 51.8, 36.8, 23.2, 22.0; IR
(KBr): 3260 (br), 3121, 2975, 2934, 2835, 1683, 1635, 1613, 1513,
1503, 1464, 1384, 1246, 1033, 832, 778 cmꢀ1; MS (EI) m/z (%): 526
(100) [Mþ], 467 (37), 441 (8), 405 (7), 363 (31), 321 (26), 307 (19),
292 (8), 186 (16), 135 (23), 121 (17), 105 (6); HRMS (ESI) calcd for
C32H34N2O5þNa [(MþNa)þ]: 549.2360, found: 549.2365.
4.1.5. Amide 52a
Prepared analogously from 17b as a pale yellow solid (81%);
mp¼164–165 ꢁC; 1H NMR (400 MHz, CDCl3):
¼8.11 (br s, 1H), 7.55
d

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6527
4.1.9. Representative procedure for the synthesis of cyclization
precursors via Suzuki coupling: preparation of compound 30
13C NMR (100 MHz, CDCl3):
d
¼161.3, 136.2, 131.4, 127.1, 126.7, 123.6,
121.7, 112.0, 66.2, 52.1; IR (KBr): 3310, 2949, 2845, 1699, 1691, 1508,
1434, 1334, 1255, 1205, 770, 742 cmꢀ1; MS (EI): m/z (%): 301 (94)
[Mþ], 269 (100), 241 (8), 215 (8), 114 (53), 88 (17), 62 (8); HRMS
(ESI) calcd for C10H8INO2þNa [(MþNa)þ]: 323.9492, found:
323.9490. Anal. Calcd for C10H8INO2 (301.1): C 39.89, H 2.68, N 4.65;
found: C 39.98, H 2.74, N 4.61.
6
5
4
1
O
7
3
2
8
9
O
11
Cl
10
O
18
13
14
17
4.1.11. Methyl 3-iodo-1-methyl-1H-indole-2-carboxylate
20
21
N
19
16
25
15
Methyl 3-iodo-1H-indole-2-carboxylate (500 mg, 1.66 mmol)
was added in small portions to a suspension of NaH (59.9 mg,
2.50 mmol) in DMF (3.3 mL) at 0 ꢁC. After the evolution of hydrogen
24
26
22
OMe
23
27
28
had ceased, MeI (210 mL, 3.37 mmol) was introduced and the
29
resulting mixture stirred for 1 h at ambient temperature. Addition
of water (15 mL) precipitated the crude material which was filtered
off and washed with water. Recrystallization from Et2O afforded the
title compound as a white solid (390 mg, 74%); mp¼74–75 ꢁC; 1H
OMe
30
A mixture of iodide 28 (546 mg, 1.00 mmol), boronic ester 29
(530 mg, 2.02 mmol),36 dry K3PO4 (850 mg, 4.00 mmol), and
Pd(PPh3)4 (116 mg, 0.100 mmol) in 1,4-dioxane (5 mL) was stirred
at 100 ꢁC for 22 h. Sodium hydroxide (41.3 mg, 1.03 mmol) and eth-
anol (0.83 mL) were added and the mixture was stirred for 1 h un-
til GC/MS indicated complete hydrolysis of excess boronic ester 29.
At this point, water (30 mL) was added, the aqueous layer was
extracted with EtOAc (3ꢂ20 mL), the combined organic phases
were washed with aq satd NH4Cl and brine, dried (Na2SO4), filtered
and evaporated, and the residue was purified by flash chromato-
graphy (EtOAc/hexanes, 1:10/1:5) to provide compound 30 as
an orange foam (201 mg, 36%). 1H NMR (600 MHz, CDCl3):
NMR (300 MHz, CDCl3):
d
¼7.57 (ddd, J¼8.1, 1.1, <1 Hz, 1H), 7.40
(ddd, J¼8.3, 6.7, 1.2 Hz, 1H), 7.34 (ddd, J¼8.5, 1.0, 0.9 Hz, 1H), 7.27–
7.20 (m, 1H), 4.07 (s, 3H), 3.99 (s, 3H); 13C NMR (75 MHz, CDCl3):
d
¼161.8,139.0,130.3,128.8,126.1,124.0,121.5,110.4, 66.6, 51.6, 33.0;
IR (KBr): 3017, 2949, 2837, 1706, 1501, 1461, 1433, 1371, 1221, 1160,
1105, 744 cmꢀ1; MS (EI) m/z (%): 315 (100) [Mþ], 284 (17), 256 (6),
215 (7), 158 (10), 129 (13), 114 (9), 89 (15); HRMS (ESI) calcd for
C11H10INO2þNa [(MþNa)þ]: 337.9648, found: 337.9650. Anal. Calcd
for C11H10INO2 (315.1): C 41.93, H 3.20, N 4.45; found: 41.80, H 3.20;
N 4.42.
d
¼7.72 (dd, J¼7.7, 1.5 Hz, 1H, H-5), 7.68 (d, J¼8.9 Hz, 2H, H-20),
4.1.12. Compound 32
A solution of indole methyl 3-iodo-1-methyl-1H-indole-2-car-
boxylate, pinacolborane (140 mL, 0.965 mmol), Et3N (270 mL,
7.36 (dd, J¼2.0, 0.4 Hz, 1H, H-12), 7.31 (dd, J¼8.8, <1 Hz, 1H, H-
15), 7.26 (dd, J¼8.8, 2.0 Hz, 1H, H-14), 7.21 (td, J¼7.5, 1.5 Hz, 1H,
H-7), 7.17 (td, J¼7.6, 1.5 Hz, 1H, H-6), 7.06–7.04 (m, 1H, H-8), 7.01
(d, J¼8.6 Hz, 2H, H-27), 6.69 (d, J¼8.7 Hz, 2H, H-28), 6.55 (d,
J¼8.9 Hz, 2H, H-21), 4.70 (ddd, J¼14.4, 8.3, 6.7 Hz, 1H, H-24a),
4.54 (ddd, J¼14.4, 8.4, 6.3 Hz, 1H, H-24b), 4.18 (dq, J¼10.8, 7.1 Hz,
1H, H-2a), 4.10 (dq, J¼10.8, 7.1 Hz, 1H, H-2b), 3.72 (s, 3H, H-23),
3.68 (s, 3H, H-30), 3.08 (ddd, J¼13.8, 8.2, 6.3 Hz, 1H, H-25a), 3.02
(ddd, J¼13.7, 8.2, 6.8 Hz, 1H, H-25b), 1.09 (t, J¼7.1 Hz, 3H, H-1);
1.91 mmol) and [(dppf)PdCl2]$CH2Cl2 (15.8 mg, 0.193 mmol) in 1,4-
dioxane (3.2 mL) was stirred for 8.5 h at 100 ꢁC. For work-up, the
mixture was diluted with EtOAc (20 mL), the combined organic
phases were washed with water, aq satd NH4Cl (2ꢂ10 mL), and
brine (2ꢂ10 mL), dried over Na2SO4 and evaporated, and the resi-
due was purified by flash chromatography (hexanes/EtOAc, 8:1) to
give compound 32 as colorless crystals (177 mg, 88%); mp¼91–
13C NMR (150 MHz, CDCl3):
d¼188.6 (C-18), 167.8 (C-3), 163.2 (C-
92 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼7.87 (dt, J¼8.1, 1.0 Hz, 1H),
7.40–7.30 (m, 2H), 7.17 (ddd, J¼8.0, 6.3, 1.6 Hz, 1H), 4.02 (s, 3H), 3.92
(s, 3H), 1.43 (s, 12H); 13C NMR (100 MHz, CDCl3):
¼163.1, 139.6,
22), 158.3 (C-29), 135.8 (C-16), 134.0 (C-17), 133.9 (C-9), 133.0
(C-8), 132.5 (C-20), 131.5 (C-4), 131.1 (C-7), 130.8 (C-19), 130.2 (C-
26), 129.9 (C-5), 129.8 (C-27), 127.5 (C-11), 127.0 (C-6), 126.3
(C-13), 125.1 (C-14), 121.6 (C-10), 120.2 (C-12), 114.0 (C-28), 112.9
(C-21), 111.5 (C-15), 61.1 (C-2), 55.3 (C-23), 55.1 (C-30), 46.4 (C-
24), 36.0 (C-25), 13.9 (C-1); 15N NMR (60.8 MHz, CDCl3, CH3NO2):
d
131.0, 124.7, 123.4, 120.9, 110.1, 83.5, 51.6, 31.7, 25.0; IR (KBr): 3054,
2978, 2945, 1711, 1611, 1528, 1469, 1388, 1300, 1250, 1226, 1144,
1108, 978, 858, 745 cmꢀ1; MS (EI) m/z (%): 315 (100) [Mþ], 257 (81),
242 (59), 214 (22), 198 (72), 184 (80), 171 (23), 156 (21), 115 (25);
HRMS (ESI) calcd for C17H22BNO4þNa [(MþNa)þ]: 338.1534, found:
338.1531. Anal. Calcd for C17H22BNO4 (315.2): C 64.78, H 7.04, N
4.44; found: C 64.71, H 6.95, N 4.35.
d¼ꢀ242.7; IR (film): 3062, 2957, 2935, 2837, 1719, 1634, 1598,
1573, 1512, 1475, 1464, 1354, 1286, 1251, 1164, 1110, 1067, 1032,
965, 843, 824, 800, 779, 765, 722 cmꢀ1; MS (EI) m/z (%): 567 (37)
[Mþ], 446 (21), 433 (19), 400 (12), 362 (13), 360 (38), 134 (35),
121 (100), 91 (6), 77 (8); HRMS (ESI) calcd for C34H30ClNO5þNa
[(MþNa)þ]: 590.1705, found: 590.1708. Anal. Calcd for
C34H30ClNO5 (568.1): C 71.89, H 5.32, N 2.47; found: C 69.48, H
5.42, N 2.40.
4.1.13. Compound 34
A mixture containing compound 32 (300 mg, 0.952 mmol), 2-
bromo benzophenone (33, 379 mg, 1.45 mmol), anhydrous K3PO4
(612 mg, 2.88 mmol) and Pd(PPh3)4 (54.2 mg, 46.9 mmol) in 1,4-
dioxane (4.8 mL) was stirred at 100 ꢁC for 7.5 h. For work up, the
mixture was diluted with EtOAc (30 mL) before it was washed with
water and brine (15 mL each), the organic layer was dried over
Na2SO4 and evaporated, and the residue purified by flash chro-
matography (hexanes/EtOAc, 10:1) to give product 34 as a white
solid (323 mg, 92%); mp¼118–119 ꢁC; 1H NMR (400 MHz, CDCl3):
4.1.10. Methyl 3-iodo-1H-indole-2-carboxylate
KOH (884 mg, 24.5 mmol) was added to solution of methyl in-
dole-2-carboxylate (853 mg, 4.87 mmol) in DMF (4.5 mL) at 0 ꢁC
and the resulting mixture was stirred for 10 min before a solution of
iodine (1.30 g, 5.12 mmol) in DMF (5.2 mL) was added over 7 min.
Stirring was continued for 1.5 h at this temperature before the
mixture was poured into aq satd NH4Cl (50 mL) and Na2S2O3
(50 mL) to precipitate the product. The solid material was filtered
off, washed with water (10 mL) and dried under high vacuum to
give the title compound as an off-white powder (1.29 g, 88%);
d
¼7.70 (ddd, J¼7.6, 1.5, 0.5 Hz, 1H), 7.62 (td, J¼7.6, 1.5 Hz, 1H), 7.54–
7.46 (m, 2H), 7.43–7.39 (m, 1H), 7.37–7.33 (m, 2H), 7.29 (ddd, J¼8.5,
6.9, 1.2 Hz, 1H), 7.21–7.14 (m, 3H), 7.09 (ddd, J¼8.0, 6.9, 1.1 Hz, 1H),
7.00–6.94 (m, 1H), 3.82 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼198.4, 162.3, 140.1, 138.1, 137.8, 134.3, 131.6, 131.4, 130.2,
mp¼156–157 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼9.45 (br s, 1H),
129.0,128.7,127.1,127.1,126.9,125.5,125.2,122.6,121.6,120.8,109.8,
51.4, 31.7; IR (film): 3396, 3291, 3058, 3031, 2953, 1709, 1658, 1599,
7.60–7.55 (m, 1H), 7.43–7.34 (m, 2H), 7.28–7.20 (m,1H), 4.00 (s, 3H);

6528
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
1537, 1467, 1440, 1333, 1318, 1287, 1264, 1247, 1200, 1111, 968, 945,
935, 920, 808, 766, 746, 708 cmꢀ1; MS (EI) m/z (%): 369 (34) [Mþ],
310 (100); HRMS (ESI) calcd for C24H19NO3þNa [(MþNa)þ]:
392.1257, found: 392.1254. Anal. Calcd for C24H19NO3 (369.4): C
78.03, H 5.18, N 3.79; found: C 77.94, H 5.24, N 3.70.
132.5, 130.8, 130.3, 130.0, 129.2, 128.2, 128.0, 122.2, 113.3, 55.4, 23.7;
IR (film): 3452, 3016, 2970, 2947, 2841, 1768, 1738, 1706, 1655, 1595,
1575, 1436, 1378, 1253, 1151, 1004, 929, 739 cmꢀ1; MS (EI) m/z (%):
371 (24) [Mþ], 236 (100), 207 (6), 157 (6), 135 (32), 77 (6); HRMS
(ESI) calcd for C23H17NO4þNa [(MþNa)þ]: 394.1050, found:
394.1051.
The following compounds were prepared analogously:
4.1.14. Acid 36a
4.1.19. Acid fluoride 36b
Off-white foam; 1H NMR (400 MHz, CDCl3):
d¼7.84 (d, J¼9.1 Hz,
Cyanuric fluoride (0.53 mL, 6.2 mmol) was added dropwise to
a solution of acid 36a (407 mg, 1.22 mmol) in CH2Cl2 (12 mL) and
pyridine (110 m
L, 1.36 mmol) at 0 ꢁC. The mixture was stirred at
ambient temperature for 3 h before the reaction was quenched
with water (5 mL) and the mixture diluted with CH2Cl2 (10 mL). The
organic phase was washed several times with water until it became
clear, dried (Na2SO4), filtered, and evaporated to provide the title
compound as a colorless oil (382 mg, 93%). 1H NMR (400 MHz,
2H), 7.80–7.76 (m, 1H), 7.56–7.44 (m, 3H), 7.39–7.30 (m, 3H), 7.08–
7.04 (m, 1H), 6.90 (d, J¼8.8 Hz, 2H), 3.85 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d¼189.4, 170.2, 164.5, 140.4, 139.3, 137.6, 133.4, 132.7, 130.9,
130.8, 130.6, 129.7, 129.2, 129.1, 128.6, 128.0, 127.3, 113.9, 55.6; IR
(film): 3012, 2970, 2840, 1737, 1724, 1689, 1649, 1593, 1574, 1508,
1366, 1253, 1229, 1217, 1150, 1023, 929, 844, 749 cmꢀ1; MS (EI) m/z
(%): 332 (8) [Mþ], 287 (100), 271 (5), 197 (26), 181 (5), 152 (8), 135
(23), 107 (5) 77 (8); HRMS (ESI) calcd for C21H16O4þNa [(MþNa)þ]:
355.0941, found: 355.0941. Anal. calcd for C21H16O4 (332.3): C
75.89, H 4.85; found: C 75.77, H 4.82.
CDCl3):
7.43 (m, 4H), 7.41–7.36 (m, 1H), 7.35–7.29 (m, 2H), 6.82 (d, J¼8.8 Hz,
2H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼7.94 (dd, J¼7.8, 1.3 Hz, 1H), 7.69 (d, J¼8.8 Hz, 2H), 7.56–
d
¼195.9, 163.5, 156.6
(d, JCF¼347 Hz), 144.1 (d, JCF¼4.4 Hz), 139.6, 138.3, 133.7, 132.5, 132.2
(d, JCF¼2.9 Hz), 131.9 (d, JCF¼1.8 Hz), 130.4, 130.1, 129.9, 128.8, 127.8,
127.6, 123.9 (d, JCF¼57.6 Hz), 113.4, 55.4; 19F NMR (282 MHz, CDCl3,
4.1.15. Acid 42
White foam; 1H NMR (400 MHz, CDCl3):
d
¼7.67 (d, J¼8.8 Hz,
2H), 7.56–7.35 (m, 5H), 6.96 (d, J¼4.8 Hz, 1H), 6.74 (d, J¼8.8 Hz, 2H),
3.76 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼196.2,166.2,163.4,147.8,
CFCl3):
d
¼30.1; IR (film): 3062, 2965, 2936, 2841, 1814, 1654, 1598,
d
1575, 1509, 1315, 1290, 1258, 1229, 1177, 1152, 1023, 998, 930, 847,
755 cmꢀ1; MS (EI): m/z (%): 334 (30) [Mþ], 287 (100), 199 (7), 170
(11), 135 (58), 77 (12); HRMS (ESI) calcd for C21H15FO3þNa
[(MþNa)þ]: 357.0897, found: 357.0901.
139.2, 134.9, 132.5, 132.4, 131.3, 130.6, 130.0, 129.7, 128.5, 127.6,
127.2, 113.3, 55.4; IR (film): 3600 (br), 1658, 1598, 1509, 1421, 1293,
1259, 1152, 933, 847, 785, 766 cmꢀ1; MS (EI) m/z (%): 338 (39) [Mþ],
293 (100), 203 (99), 187 (8), 135 (52), 92 (13), 77 (20); HRMS (ESI)
calcd for C19H14O4SþNa [(MþNa)þ]: 361.0505, found: 361.0505.
Anal. Calcd for C19H14O4S (338.4): C 67.44, H 4.17; found: C 67.32, H
4.22.
4.1.20. 2-(4-Methoxybenzyl)benzaldehyd (47)
A solution of p-methoxybenzylmagnesium chloride (0.55 M in
THF, 24.0 mL 13.2 mmol) was added over 10 min to a solution of 9-
MeO-9-BBN (1.80 mL, 13.4 mmol) in THF (25 mL) at ꢀ78 ꢁC. Once
the addition was completed, the mixture was stirred at ambient
temperature for 30 min before the resulting solution of borate 45
was diluted with DMF (100 mL) and degassed by two freeze–thaw
cycles. Aldehyde 46 (1.50 mL, 12.9 mmol) was added, followed
by Pd(OAc)2 (29.1 mg, 0.130 mmol) and S-Phos (106 mg,
0.258 mmol),37 and the resulting mixture was stirred at 110 ꢁC for
5 h until GC/MS indicated complete conversion of the substrate.
The mixture was diluted with tert-butyl methyl ether (200 mL), the
organic layer was washed with water (200 mL) and brine
(3ꢂ100 mL), dried (Na2SO4), filtered and evaporated. The residue
was purified by flash chromatography (EtOAc/hexanes, 1:20) to
provide the title compound as a pale yellow oil (2.28 g, 78%) Even
though some boron impurities were visible by 1H NMR, the mate-
rial was used in the next reaction without further purification. 1H
4.1.16. Amide 36c
Yellow solid; mp¼158–163 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼7.89 (d, J¼8.8 Hz, 2H), 7.70 (dd, J¼7.8, 0.8 Hz, 1H), 7.54–7.31 (m,
6H), 7.23–7.18 (m, 1H), 6.96 (d, J¼9.1 Hz, 2H), 6.93 (d, J¼7.6 Hz, 1H),
5.37–5.19 (br s, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼197.5, 171.5, 164.3, 141.0, 138.2, 136.3, 133.1, 131.0, 130.3, 129.7,
129.5, 128.7, 128.3, 128.0 (2C), 127.9, 126.9, 113.9, 55.6; IR (film):
3333 (br), 3184 (br), 3059, 3962, 2931, 2840, 1666, 1646, 1593, 1575,
1509, 1317, 1305, 1293, 1256, 1151, 931, 754, 730 cmꢀ1; MS (EI): m/z
(%): 331 (<1) [Mþ], 287 (69) [MþꢀCONH2], 196 (100), 135 (10);
HRMS (ESI) calcd for C21H17NO3þNa [(MþNa)þ]: 354.1101, found:
354.1103. Anal. Calcd for C21H17NO3 (331.4): C 76.12, H 5.17, N 4.23;
found: C 76.04, H 5.11, N 4.05.
4.1.17. Compound 38
NMR (400 MHz, CDCl3):
d
¼10.27 (s, 1H), 7.85 (dd, J¼7.7, 1.4 Hz, 1H),
Yellow solid; mp¼119–120 ꢁC; 1H NMR (400 MHz, CDCl3):
7.52 (td, J¼7.5, 1.5 Hz, 1H), 7.40 (td, J¼7.5, <1 Hz, 1H), 7.28–7.24 (m,
1H), 7.06 (d, J¼8.7 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 4.39 (s, 2H), 3.77
d
¼7.68 (d, J¼8.8 Hz, 2H), 7.62 (ddd, J¼7.4, 7.3, 2.0 Hz, 1H), 7.60–
7.51 (m, 3H), 7.51–7.48 (m, 1H), 7.48–7.43 (m, 1H), 7.35–7.32 (m,
(s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼192.4, 158.1, 143.5, 133.9,
1H), 7.29 (td, J¼7.6, 1.3 Hz, 1H), 6.82 (d, J¼8.8 Hz, 2H), 3.81 (s, 3H);
133.9, 132.4, 131.9, 131.5, 129.7, 126.9, 114.0, 55.2, 37.1; IR (film):
2932, 2835, 2753, 1696, 1611, 1599, 1511, 1301, 1247, 1178, 1035, 843,
818, 773, 755 cmꢀ1; MS (EI) m/z (%): 226 (100) [Mþ], 209 (95), 195
(35), 181 (12), 178 (13), 165 (45), 152 (23), 121 (11), 118 (37), 90 (31),
77 (12), 51 (7); HRMS (ESI) calcd for C15H14O2þNa [(MþNa)þ]:
249.0886, found: 249.0888.
13C NMR (100 MHz, CDCl3):
d¼196.0, 163.5, 144.3, 139.5, 137.4,
132.9, 132.4, 132.1, 131.0, 130.6, 130.3, 130.1, 129.1, 128.4, 127.7,
118.2, 113.5, 112.1, 55.4; IR (film): 3061, 2966, 2936, 2840, 2225,
1656, 1597, 1575, 1509, 1468, 1436, 1420, 1291, 1259, 1177, 1151,
1027, 930, 846, 761 cmꢀ1; MS (EI) m/z (%): 313 (38) [Mþ], 177 (6),
151 (7), 135 (100), 107 (6), 92 (9), 77 (12); HRMS (ESI) calcd for
C21H15NO2þNa [(MþNa)þ]: 336.0995, found: 336.0995. Anal. Calcd
for C21H15NO2 (313.3): C, 80.49, H 4.82, N 4.47; found: C 80.33, H
4.92, N 4.41.
4.1.21. Compound 48a
MeLi (1.64 M in Et2O, 9.0 mL, 14.8 mmol) was added over 7 min
to a solution of N-(tert-butoxycarbonyl)-2-bromoaniline (4.01 g,
14.7 mmol) in THF (75 mL) at ꢀ78 ꢁC and the mixture was stirred
for 15 min. tert-BuLi (2.87 M in pentanes, 10.0 mL, 28.7 mmol) was
then added dropwise and the mixture was stirred for 80 min before
a solution of aldehyde 47 (2.27 g, 10.0 mmol) in THF (25 mL) was
added over 25 min. The resulting mixture was stirred for 25 min
before the reaction was carefully quenched with water (10 mL) at
4.1.18. Compound 40
Yellow solid; mp¼159–161 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼7.73–7.66 (m, 3H), 7.62–7.47 (m, 5H), 7.45–7.40 (m, 1H), 6.78 (d,
J¼8.8 Hz, 2H), 3.81 (s, 3H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼196.0, 168.0, 167.8, 160.4, 139.0, 139.0, 136.3, 136.2, 133.1, 132.6,

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6529
ꢀ78 ꢁC and the mixture allowed to reach ambient temperature. The
4.1.23. Compound 49
mixture was diluted with brine (100 mL), the aqueous phase was
extracted with tert-butyl methyl ether (3ꢂ100 mL), the combined
organic layers were dried (Na2SO4), filtered, and evaporated, and
the residue was purified by flash chromatography (EtOAc/hexanes,
1:12/1:3þ1% Et3N) to provide tert-butyl-2-(hydroxy(2-(4-
methoxybenzyl)phenyl)methyl)phenylcarbamate as a white foam
MeO2CCOCl (350
m
L, 3.80 mmol) was added to a solution of
aniline 48b (996 mg, 3.14 mmol) in CH2Cl2 (30 mL) and pyridine
(1.3 mL, 16.1 mmol) at ꢀ20 ꢁC and the resulting mixture was stirred
for 30 min before the reaction was quenched with water (60 mL).
The product was extracted with CH2Cl2 (3ꢂ40 mL), the combined
organic layers were dried (Na2SO4) and evaporated, and the residue
was purified by flash chromatography (EtOAc/hexanes, 1:2) to
provide the corresponding amide as a white foam (1.18 g, 93%). 1H
(3.41 g, 63%). 1H NMR (400 MHz, CDCl3):
d
¼7.76 (d, J¼7.9 Hz, 1H),
7.57 (d, J¼7.3, 1.8 Hz, 1H), 7.36–7.24 (m, 4H), 7.14 (dd, J¼7.2, 1.6 Hz,
1H), 6.98–6.90 (m, 3H), 6.83 (dd, J¼7.7,1.6 Hz,1H), 6.77 (d, J¼8.8 Hz,
1H), 6.77 (d, J¼8.8 Hz, 2H), 6.06 (br s, 1H), 3.79 (br s, 2H), 3.76 (s,
NMR (600 MHz, CDCl3):
d¼8.71 (dd, J¼8.4,1.0 Hz,1H), 7.59–7.55 (m,
1H), 7.43 (td, J¼7.5, 1.5 Hz, 1H), 7.31–7.23 (m, 5H), 7.03 (ddd, J¼7.9,
7.4, 1.1 Hz, 1H), 6.85 (d, J¼8.8 Hz, 2H), 6.63 (d, J¼8.7 Hz, 2H), 4.00 (s,
3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
¼158.0, 153.8, 139.7,
138.4, 137.0, 132.5, 132.1, 130.7, 129.6, 128.7, 128.1, 128.0, 126.9,
126.8, 123.9, 122.6, 114.0, 80.5, 70.4, 55.2, 37.8, 28.3; IR (film): 3391,
2978, 2933, 2835, 1726, 1704, 1611, 1588, 1512, 1450, 1392, 1368,
1302, 1246, 1159, 1026, 837, 759, 739 cmꢀ1; MS (EI): m/z (%): 401 (2)
[(MꢀH2O)þ], 345 (100), 300 (71), 269 (28), 237 (25), 225 (28), 208
(75), 165 (20), 121 (12), 57 (99), 41 (26), 29 (16); HRMS (ESI) calcd
for C26H29NO4þNa [(MþNa)þ]: 442.1989; found: 442.1987.
3H), 3.94 (s, 2H), 3.68 (s, 3H); 13C NMR (150 MHz, CDCl3):
d¼202.2,
160.7, 157.9, 154.8, 140.1, 139.1 (2C), 134.9, 134.3, 131.9, 130.7, 130.4,
130.2, 128.2, 125.9, 123.9, 123.6, 120.8, 113.7, 55.1, 53.9, 38.5; IR
(film): 3232, 3064, 3007, 2954, 2909, 2836, 1765, 1737, 1714, 1642,
1582, 1602, 1523, 1512, 1450, 1437, 1292, 1255, 1163, 1034, 936, 838,
765 cmꢀ1; MS (EI) m/z (%): 403 (38) [Mþ], 385 (100), 325 (36), 316
(26), 300 (38), 236 (10), 224 (11), 208 (75), 197 (14), 194 (10), 181
(15), 165 (17), 152 (13), 146 (14); HRMS (ESI) calcd for C24H22NO5
[(MþH)þ]: 404.1492, found: 404.1491. Anal. calcd for C24H21NO5
(403.4): C 71.45, H 5.25, N 3.47; found: C 71.35, H 5.36, N 3.39.
A solution of CrO3 (345 mg, 3.45 mmol) in acidic acid (2.7 mL)
and water (1.6 mL) was added to a solution of this amide (499 mg,
1.24 mmol) in acidic acid (12.4 mL) and the resulting mixture stir-
red for 7 h before water (50 mL) was introduced and the product
extracted with EtOAc (2ꢂ40 mL). The combined organic phases
were washed with brine, dried (Na2SO4) and evaporated, and the
residue was purified by flash chromatography (EtOAc/hexanes,
1:1.5/1:0) to provide compound 49 as an off-white solid (477 mg,
TPAP (141 mg, 0.402 mmol)38 was added to a mixture contain-
ing this alcohol (3.39 g, 8.07 mmol), carefully dried NMO (1.42 g,
12.1 mmol, dried by aceotropic distillation with toluene and drying
in high vacuum) and molecular sieves 3 Å (6.7 g) in CH2Cl2
(160 mL), and the resulting suspension was stirred for 3 h at am-
bient temperature. For work-up, the mixture was adsorbed on sil-
ica, which was loaded on top of a flash column packed with silica.
The product was eluted with EtOAc/hexanes (1:10), giving com-
pound 48a as a colorless oil which solidified on standing (2.96 g,
88%); mp¼78–81 ꢁC; 1H NMR (400 MHz, CDCl3):
¼10.72 (br s, 1H),
d
8.46 (dd, J¼8.6, 1.0 Hz, 1H), 7.48 (ddd, J¼7.5, 7.4, 1.7 Hz, 1H), 7.42–
7.37 (m, 1H), 7.28–7.23 (m, 2H), 7.20 (dd, J¼8.0, 1.6 Hz, 2H), 6.94 (d,
J¼8.8 Hz, 2H), 6.85–6.80 (m, 1H), 6.70 (d, J¼8,6 Hz, 2H), 3.93 (s, 2H),
93%); mp¼135–136 ꢁC; 1H NMR (400 MHz, CDCl3):
¼12.0 (br s,
d
1H), 8.55 (d, J¼8.3 Hz, 1H), 7.70–7.58 (m, 4H), 7.56–7.49 (m, 3H),
7.36 (dd, J¼7.8, 1.5 Hz, 1H), 7.08–7.03 (m, 1H), 6.81 (d, J¼8.8 Hz, 2H),
3.71 (s, 3H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3):
d¼202.2, 158.0,
153.1, 142.4, 139.8, 139.7, 135.0, 134.6, 132.2, 130.5, 130.2, 130.0,
127.9, 125.7, 122.1, 120.5, 119.0, 113.8, 80.7, 55.2, 38.2, 28.3; IR (film):
3275, 3065, 2978, 2932, 2835, 1730, 1636, 1605, 1581, 1512, 1448,
1392, 1367, 1249, 1150, 832, 753 cmꢀ1; MS (EI): m/z (%): 417 (21)
[Mþ], 361 (52), 317 (50), 299 (97), 224 (100), 208 (56), 181 (21), 165
(12), 152 (10), 120 (11), 57 (54), 41 (17); HRMS (ESI) calcd for
C26H27NO4þNa [(MþNa)þ]: 440.1832, found: 440.1837. Anal. Calcd
for C26H27NO4 (417.5): C 74.80, H 6.52, N 3.35; found: C 74.65, H
6.41, N 3.28.
3.96 (s, 3H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼200.0,194.7,
163.6, 160.5, 154.4, 140.4, 139.5, 138.2, 134.7, 133.5, 132.2, 130.8,
130.7, 130.3, 129.6, 128.9, 124.9, 123.8, 120.8, 113.7, 55.4, 53.8; IR
(film): 3456, 3282, 2971, 2864, 1734, 1641, 1598, 1582, 1524, 1451,
1421, 1366, 1301, 1291, 1269, 1257, 1229, 1217, 1150, 1113, 937,
762 cmꢀ1; MS (EI) m/z (%): 417 (26) [Mþ], 358 (61), 250 (100), 135
(20), 77 (6); HRMS (ESI) calcd for C24H19NO6þNa [(MþNa)þ]:
440.1105, found: 440.1104. Anal. Calcd for C24H19NO6 (417.4): C
69.06, H 4.59, N 3.36; found: C 68.94, H 4.51, N 3.28.
4.1.22. 2-Amino-20-(4-methoxybenzyl)benzophenone (48b)
4.1.24. Representative procedure for reductive carbonyl coupling
reactions. Preparation of indole 20
A suspension of 48a (2.88 g, 6.91 mmol) in ethanol (30 mL)
and aq HCl (2 M, 30 mL) was refluxed for 1.5 h. The resulting
yellow solution was cooled to 0 ꢁC before aq NaOH (2 M, 35 mL)
was added. The mixture was extracted with tert-butyl methyl
ether (3ꢂ100 mL) and the combined organic phases where
washed with brine (20 mL), dried (Na2SO4) and evaporated to
provide the title compound as a yellow oil which was used
without further purification (2.24 g, quant.). 1H NMR (600 MHz,
CAUTION: KC8 is pyrophoric and must be handled with care under
Ar! Dry DME (30 mL) was carefully added to a mixture of TiCl3
(301 mg, 1.95 mmol) and KC8 (527 mg, 3.90 mmol)39 at 0 ꢁC under
Ar and the resulting suspension was refluxed for 1.5 h. A solution of
ketoamide 19 (150 mg, 0.24 mmol) in dry DME (5 mL) was then
introduced and the mixture was refluxed until TLC indicated
complete conversion of the substrate (ca. 1.5 h). After reaching
ambient temperature, the mixture was filtered through a plug of
Celite layered on silica, which was carefully rinsed with EtOAc/
toluene (1:1, 120 mL), and the combined filtrates were evaporated.
Purification of the residue by flash chromatography (EtOAc/hex-
anes, 1:4) yielded indole 20 as a pale yellow solid (83 mg, 59%). 1H
NMR (400 MHz, C6D6): 8.11 (s, 1H), 7.50 (m, 2H), 7.36 (m, 2H), 7.33
(m, 1H), 6.98 (t, J¼7.9 Hz, 1H), 6.87 (m, 1H), 6.80 (m, 2H), 6.75–6.70
(m, 4H), 6.64–6.62 (m, 3H), 6.42 (m, 1H), 3.57 (t, J¼7.1 Hz, 2H), 3.43
(s, 3H), 3.31 (s, 3H), 3.24 (s, 3H), 3.18 (s, 3H), 2.67 (t, J¼7.1 Hz, 2H);
CDCl3):
d
¼7.34 (ddd, J¼7.6, 7.2, 1.8 Hz, 1H), 7.27–7.22 (m, 3H),
7.20 (dq, J¼7.8, 0.5 Hz, 1H), 7.15 (dd, J¼8.1, 1.3 Hz, 1H), 7.00 (d,
J¼8.7 Hz, 2H), 6.73 (d, J¼8.7 Hz, 2H), 6.68 (dd, J¼8.3, 0.7 Hz, 1H),
6.48 (ddd, J¼8.1, 7.1, 1.1 Hz, 1H), 6.42–6.28 (br s, 2H), 3.88 (s, 2H),
3.73 (s, 3H); 13C NMR (150 MHz, CDCl3):
d
¼201.1, 157.9, 151.1,
140.5, 139.1, 134.9, 134.7, 132.5, 130.2, 130.1, 129.2, 127.3, 125.6,
118.5, 116.7, 115.5, 113.7, 55.2, 38.0; IR (film): 3472, 3343, 3061,
3024, 2997, 2954, 2929, 2849, 2835, 1724, 1616, 1582, 1547, 1511,
1478, 1450, 1301, 1248, 1035, 934, 840, 754 cmꢀ1; MS (EI) m/z (%):
317 (86) [Mþ], 299 (69), 266 (8), 224 (100), 209 (20), 181 (28),
165 (12), 152 (12), 120 (19), 92 (11), 65 (9); HRMS (ESI) calcd for
C21H19NO2þNa [(MþNa)þ]: 340.1308, found: 340.1305. Anal.
Calcd for C21H19NO2 (317.4): C 79.47, H 6.03, N 4.41; found: C
79.33, H 6.09, N 4.32.
13C NMR (100 MHz, C6D6):
d
¼160.0, 159.0, 158.1, 146.0, 133.3, 130.8,
130.3, 130.0, 129.7, 128.9, 127.4, 125.0, 122.0, 120.6, 119.1, 118.7, 116.9,
116.1, 114.7, 114.6, 114.3, 114.3, 114.1, 103.5, 94.0, 82.4, 54.9, 54.8,
54.7, 54.6, 51.5, 37.4; IR (film): 3342, 3000, 2957, 2934, 2836, 2206,
1606, 1578, 1546, 1512, 1462, 1441, 1289, 1248, 1177, 1095, 1031, 832,

6530
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
785 cmꢀ1; MS (EI) m/z (%): 582 (100) [Mþ], 461 (17), 448 (15), 446
(10); HRMS (EI) m/z: calcd for C38H34N2O4: 582.2518; found:
582.2523.
(hexanes/EtOAc, 10:1/2:1) as a beige solid; mp¼216–219 ꢁC; 1H
NMR (400 MHz, CDCl3):
d¼8.85 (d, J¼8.1 Hz, 1H), 8.63 (d, J¼8.1 Hz,
1H), 7.71–7.46 (m, 9H), 7.42 (ddd, J¼8.0, 6.9, 1.0 Hz, 1H), 7.35 (ddd,
J¼8.3, 7.0, 1.2 Hz, 1H), 4.29 (s, 3H), 3.56 (s, 3H); 13C NMR (100 MHz,
4.1.25. Representative procedure for reductive arene syntheses via
the ‘instant method’: preparation of compound 39
CDCl3):
d
¼144.5, 140.9, 136.6, 132.1, 131.4, 130.0, 129.2, 128.2, 127.7,
127.3, 126.9, 125.6, 124.4, 123.6, 123.0, 123.0, 122.0, 120.1, 117.3,
109.4, 61.5, 31.5; IR (KBr): 3060, 3029, 2957, 2930, 2828, 1610, 1577,
1554, 1519, 1498, 1476, 1379, 1294, 1262, 1080, 1005, 769, 745,
702 cmꢀ1; MS (EI) m/z (%): 337 (100) [Mþ], 322 (17), 307 (12), 294
(29), 278 (13), 153 (7), 139 (5); HRMS (EI) calcd for C24H19NO:
337.1367; found: 337.1465. Anal. Calcd for C24H19NO (337.4): C
85.43, H 5.68, N 4.15; found: C 80.91, H 5.45, N 3.60.
A suspension containing nitrile 38 (46.6 mg, 0.149 mmol), TiCl3
(334 mg, 2.17 mmol) and zinc dust (288 mg, 4.40 mmol) in DME
(15 mL) was stirred under reflux until TLC showed complete con-
sumption of the substrate. For work up, the filtrate was evaporated,
the residue suspended in EtOAc (20 mL) and the suspension vig-
orously stirred with a solution of Na4EDTA (1 M in water, 20 mL) for
20 min. The mixture was extracted with EtOAc (2ꢂ20 mL), the
combined organic phases were washed with brine, dried (Na2SO4),
filtered, and evaporated, and the residue was purified by flash
chromatography (EtOAc/hexanes, 1:6) to provide aniline 39 as
a white solid (40.0 mg, 90%); mp¼175–176 ꢁC (Ref. 40: 179–181 ꢁC);
4.1.29. 10-(4-Methoxyphenyl)phenanthren-9-ol (37)
Mp¼198–199 ꢁC; 1H NMR (400 MHz, CDCl3):
¼8.75 (m, 1H),
d
8.68 (d, J¼8.1 Hz, 1H), 8.42–8.39 (m, 1H), 7.75–7.65 (m, 2H), 7.53–
7.43 (m, 3H), 7.41 (d, J¼8.7 Hz, 2H), 7.16 (d, J¼8.7 Hz, 2H), 5.52 (s,
1H NMR (400 MHz, CDCl3):
d
¼8.79–8.76 (m, 1H), 8.67–8.63 (m, 1H),
1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼159.9, 146.4, 132.9,
7.98–7.95 (m, 1H), 7.73–7.64 (m, 2H), 7.47–7.38 (m, 2H), 7.36–7.32
132.7, 131.0, 127.1, 126.8, 126.6, 126.4, 126.1, 125.4, 125.0, 123.9,
123.0, 122.6, 122.5, 116.9, 115.3, 55.4; IR (KBr): 3480, 3074, 3025,
2966, 2937, 2839, 1605, 1596, 1509, 1494, 1449, 1296, 1246, 1208,
1184, 1072, 1021, 854, 763, 727 cmꢀ1; MS (EI) m/z (%): 300 (100)
[Mþ], 285 (7), 271 (8), 257 (9); HRMS (EI) calcd for C21H16O2:
300.1150, found: 300.1147. Anal. Calcd for C21H16O2 (300.4): C
83.98, H 5.37; found: C 83.88, H 5.31.
(m, 3H), 7.13 (d, J¼8.8 Hz, 2H), 4.04 (br, 2H), 3.93 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d
¼159.1, 137.0, 133.5, 132.3, 130.6, 129.7, 126.7,
126.5, 126.5, 125.8, 125.2, 125.1,123.3,123.1,122.4,121.6,117.8,114.9,
55.3; IR (KBr): 3441, 3363, 3073, 3004, 2953, 2898, 2833, 1622,
1605, 1588, 1573, 1508, 1493, 1433, 1398, 1283, 1245, 1175, 1103,
1031, 844, 814, 755, 723 cmꢀ1; MS (EI): m/z (%): 299 (100) [Mþ], 284
(15), 254 (10), 239 (7); HRMS (EI) calcd for C21H17NO: 299.1310;
found: 299.1308. The analytical data are consistent with those
previously reported.41
4.1.30. Compound 41
Yellow solid; recrystallization from EtOAc provided a crystal
The following products were prepared analogously:
suitable for X-ray structure analysis; mp¼156–157 ꢁC; 1H NMR
(400 MHz, CDCl3):
d
¼8.63 (d, J¼7.8 Hz, 1H), 8.58 (dd, J¼8.1, 0.8 Hz,
4.1.26. Compound 31a
1H), 8.13 (dd, J¼7.1, 0.5 Hz, 1H), 7.84 (dd, J¼8.0, 7.2 Hz, 1H), 7.58–
7.44 (m, 3H), 7.36 (d, J¼8.8 Hz, 2H), 7.07 (d, J¼8.6 Hz, 2H), 3.94 (s,
White solid; mp >165 ꢁC (decomp.); 1H NMR (400 MHz, CDCl3):
d
¼8.70 (d, J¼8.3 Hz, 1H), 8.50 (d, J¼2.0 Hz, 1H), 8.40 (dd, J¼8.3,
3H), 2.95 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼168.6, 159.7, 135.7,
0.8 Hz, 1H), 7.56 (ddd, J¼8.3, 7.1, 1.3 Hz, 1H), 7.51 (ddd, J¼8.2, 6.9,
1.0 Hz, 1H), 7.45 (d, J¼8.6 Hz, 2H), 7.34 (dd, J¼8.6, 2.0 Hz, 1H), 7.28
(d, J¼8.7 Hz, 1H), 7.15 (d, J¼8.6 Hz, 2H), 6.73 (d, J¼8.8 Hz, 2H), 6.66
(d, J¼8.8 Hz, 2H), 5.46 (s, 1H), 4.00–3.90 (m, 5H), 3.77 (s, 3H), 2.65–
134.4, 132.2, 128.7, 127.4, 127.4, 127.1, 126.8, 126.3, 125.9, 125.3,
123.6, 122.8, 119.3, 113.9, 55.4, 28.6; IR (KBr): 2943, 2834, 1702,
1638, 1624, 1605, 1512, 1475, 1454, 1295, 1247, 1020, 841, 760,
717 cmꢀ1; MS (EI) m/z (%): 339 (100) [Mþ], 294 (5); HRMS (ESI)
calcd for C23H17NO2þNa [(MþNa)þ]: 362.1151, found: 362.1151.
Anal. Calcd for C23H17NO2 (339.4): C 81.40, H 5.05, N 4.13; found: C
81.34, H 5.10, N 4.06.
2.55 (m, 2H); 13C NMR (100 MHz, CDCl3):
d¼160.6, 158.3, 149.4,
138.0, 137.2, 132.8, 130.0, 129.7, 129.4, 127.9, 125.6, 124.9, 124.6,
123.7, 123.0, 122.8, 122.6, 120.7, 120.2, 115.6, 113.8, 110.1, 109.1, 108.7,
55.5, 55.3, 45.6, 34.5; IR (film): 3515, 3068, 3030, 3003, 2954, 2933,
2835, 1622, 1608, 1576, 1512, 1305, 1247, 1217, 1176, 1150, 1032, 873,
822, 761 cmꢀ1; MS (EI) m/z (%): 507 (100) [Mþ], 386 (61), 351 (91),
135 (7). Anal. Calcd for C32H26ClNO3 (508.0): C 75.66, H 5.16, N 2.76;
found: C 75.56, H 5.20, N 2.71.
4.1.31. Compound 43
Mp¼202–204 ꢁC; 1H NMR (400 MHz, CDCl3):
d
¼8.33 (d,
J¼8.1 Hz, 1H), 8.02 (d, J¼5.3 Hz, 1H), 7.64 (d, J¼5.3 Hz, 1H), 7.54–
7.44 (m, 2H), 7.43–7.36 (m, 3H), 7.15 (d, J¼8.3 Hz, 2H), 5.56 (s, 1H),
3.93 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼159.9,145.5,137.6,132.7,
4.1.27. Compound 31b
132.5, 128.3, 126.5, 125.7, 125.6, 125.3, 123.7, 123.7, 122.4, 116.5,
115.2, 55.4; IR (KBr): 3467, 3100, 3068, 3029, 2966, 2937, 2839,
1607, 1555, 1513, 1476, 1450, 1441, 1245, 1211, 1182, 1020, 838, 767,
734 cmꢀ1; MS (EI): m/z (%): 306 (100) [Mþ], 291 (11), 234 (6); HRMS
(EI) calcd for C19H14O2S: 306.0715, found: 306.0712. Anal. Calcd for
C19H14O2S (306.4): C 74.48, H 4.61; found: 74.36, H 4.53.
Formed as minor by-product during the titanium-mediated
cyclization of oxo-ester 30; this compound can be separated form
the major product 31a by flash chromatography using hexanes/
EtOAc (4:1) as the eluent. White solid; mp¼148–152 ꢁC; 1H NMR
(400 MHz, CDCl3):
d
¼8.76 (d, J¼8.3 Hz, 1H), 8.56 (d, J¼1.3 Hz, 1H),
8.28 (d, J¼8.3 Hz, 1H), 7.79–7.72 (m, 1H), 7.57–7.45 (m, 3H), 7.42–
7.32 (m, 2H), 7.09 (d, J¼8.6 Hz, 2H), 6.74–6.62 (m, 4H), 4.08–3.99
(m, 2H), 3.94 (s, 3H), 3.84–3.70 (m, 5H), 2.65–2.53 (m, 2H), 1.14 (t,
J¼7.2 Hz, 3H); IR (KBr): 3069, 2932, 2835, 1610, 1569, 1512, 1471,
4.1.32. Compound 50
Formed as a yellow foam by cyclization of 49 after a reaction
time of 25 min; 1H NMR (400 MHz, CDCl3):
d¼8.79 (br s, 1H),
1447, 1348, 1303, 1286, 1246, 1176, 1096, 1078, 1033, 822, 764 cmꢀ1
;
MS (EI) m/z (%): 535 (79) [Mþ], 414 (8), 385 (100), 350 (13),135 (29);
HRMS (ESI) calcd for C34H30ClNO3þNa [(MþNa)þ]: 558.1806;
found: 558.1813.
7.68–7.64 (m, 1H), 7.60 (td, J¼7.5, 1.5 Hz, 1H), 7.55–7.41 (m, 5H),
7.28–7.20 (m, 2H), 7.08 (ddd, J¼8.1, 6.3, 1.5 Hz, 1H), 6.55 (d,
J¼8.8 Hz, 2H), 3.72 (s, 3H), 3.69 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
¼196.5, 162.8, 161.9, 140.4, 135.4, 132.9, 131.7, 131.6, 130.5,
4.1.28. Compound 35b
129.9, 129.0, 128.3, 127.4, 125.7, 123.3, 122.4, 121.7, 120.9, 112.7,
111.5, 55.4, 51.3; IR (film): 3330, 3059, 2951, 2839, 1700, 1649,
1596, 1575, 1508, 1479, 1452, 1443, 1420, 1330, 1315, 1291, 1246,
1176, 1148, 930, 844, 730 cmꢀ1; MS (EI) m/z (%): 385 (58) [Mþ],
326 (100), 310 (11), 282 (6), 250 (10), 135 (30), 77 (5); HRMS (ESI)
The crude product consists of a w5:1 mixture of phenol 35a and
methyl ether 35b which could not be separated by flash chroma-
tography. This mixture was reacted with MeI and NaH in DMF to
generate pure 35b, which was isolated by flash chromatography

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6531
calcd for C24H19NO4þNa [(MþNa)þ]: 408.1206, found: 408.1211.
(100 MHz, CD2Cl2):
d
¼159.2, 158.8, 157.7, 144.3, 134.3, 132.7, 131.1,
Anal. Calcd for C24H19NO4 (385.4): C 74.79, H 4.97, N 3.63; found:
C 74.62, H 4.87, N 3.73.
130.1, 129.7, 128.6, 128.0, 127.4, 126.3, 124.7, 122.1, 120.3, 118.8,
114.7, 114.2, 114.1, 113.7, 112.8, 108.9, 104.7, 70.8, 55.6, 55.5, 55.4,
52.0, 37.7, 22.5; IR (KBr): 3422 (br), 3033, 2973, 2933, 2834, 1612,
1577, 1534, 1512, 1493, 1452, 1441, 1248, 1178, 1115, 1034, 832,
784 cmꢀ1; MS (EI) m/z (%): 586 (100) [Mþ], 544 (8), 423 (14), 135
(5); HRMS (ESI) calcd for C38H38N2O4þNa [(MþNa)þ]: 609.2724,
found: 609.2717.
4.1.33. Compound 51a
Formed as a pale yellow solid by cyclization of 49 after a reaction
time of 40 min; mp >228 ꢁC (decomp.); 1H NMR (400 MHz, DMSO-
d6):
d
¼11.60 (br s,1H), 8.97–8.95 (m,1H), 8.71 (d, J¼8.1 Hz,1H), 8.56
(d, J¼8.1 Hz, 1H), 7.69 (d, J¼8.1 Hz, 1H), 7.50 (ddd, J¼8.1, 6.8, 1.0 Hz,
1H), 7.45–7.39 (m, 2H), 7.35–7.25 (m, 4H), 7.13 (d, J¼8.6 Hz, 2H),
4.1.37. Compound 56
3.87 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d¼158.5, 140.4, 138.6,
Colorless foam; 1H NMR (400 MHz, CD2Cl2):
d
¼8.12 (br s, 1H),
132.6, 130.7, 129.7, 128.0, 125.6, 125.6, 125.1, 123.8, 123.6, 123.3,
122.6, 121.4, 119.8, 119.6, 114.7, 114.0, 112.0, 55.1; IR (KBr): 3426,
3059, 3014, 2964, 2935, 2836, 1607, 1535, 1512, 1453, 1326, 1286,
1256, 1243, 1174, 1116, 1026, 828, 761, 748 cmꢀ1; MS (EI) m/z (%):
339 (100) [Mþ], 324 (6), 267 (6); HRMS (ESI) calcd for
C23H17NO2þNa [(MþNa)þ]: 362.1151, found: 362.1157. Anal. Calcd
for C23H17NO2 (339.4): C 81.40, H 5.05, 4.13; found: C 81.31, H 5.11, N
4.05. Small amounts of the corresponding methyl ether 51b were
formed as a by-product which analyzed as follows: 1H NMR
7.12 (d, J¼8.8 Hz, 2H), 7.09 (d, J¼8.6 Hz, 2H), 6.88–6.83 (m, 4H), 6.82
(d, J¼2.4 Hz, 1H), 6.69 (d, J¼8.8 Hz, 2H), 6.61–6.55 (m, 2H), 4.72
(sept, J¼6.1 Hz, 1H), 4.13 (t, J¼7.2 Hz, 2H), 3.79 (s, 3H), 3.72 (s, 3H),
3.09 (t, J¼7.2 Hz, 2H), 2.05 (s, 3H), 1.42 (d, J¼6.1 Hz, 6H); 13C NMR
(100 MHz, CD2Cl2):
d
¼158.9, 157.8, 143.8, 131.8, 131.2, 131.1, 130.1,
130.1, 128.2, 127.0, 124.3, 121.8, 119.8, 118.7, 114.7, 114.3, 113.9, 112.3,
108.9, 103.9, 70.6, 55.6, 55.5, 51.9, 37.7, 22.5, 12.4; IR (KBr): 3386,
3032, 2973, 2932, 2834, 1611, 1576, 1545, 1513, 1501, 1462, 1245,
1033, 833, 781 cmꢀ1; MS (EI) m/z (%): 494 (100) [Mþ], 452 (12), 373
(6), 331 (27), 135 (5); HRMS (ESI) calcd for C32H34N2O3þNa
[(MþNa)þ]: 517.2462, found: 517.2454.
(400 MHz, CDCl3):
d
¼8.78 (d, J¼9.3 Hz, 1H), 8.67 (br s, 1H), 8.58 (d,
J¼7.8 Hz,1H), 7.74 (d, J¼8.3 Hz,1H), 7.66–7.60 (m, 2H), 7.51–7.34 (m,
5H), 7.09 (d, J¼8.6 Hz, 2H), 3.93 (s, 3H), 3.64 (s, 3H); IR (KBr): 3374,
3057, 3002, 2958, 2935, 2835, 1607, 1531, 1512, 1455, 1370, 1289,
1244, 1174, 1032, 1003, 834, 766, 750, 743 cmꢀ1; MS (EI) m/z (%):
353 (100) [Mþ], 338 (26), 310 (12), 307 (21), 295 (6), 161 (7); HRMS
(ESI) calcd for C24H19NO2þNa [(MþNa)þ]: 376.1308; found:
376.1307.
4.1.38. Compound 21
H
n
OMe
J
N,H
MeO
H
N
4.1.34. Compound 53
δ
N = -272.1 ppm
Pale yellow solid; 1H NMR (400 MHz, CD2Cl2):
d
¼8.40 (br s, 1H),
δ
N = -240.1 ppm
H
7.22 (d, J¼8.8 Hz, 2H), 7.17 (d, J¼8.8 Hz, 2H), 7.10 (d, J¼8.6 Hz, 2H),
6.88–6.81 (m, 8H), 6.76 (d, J¼16.7 Hz, 1H), 6.70–6.61 (m, 4H), 4.76
(sept, J¼6.1 Hz, 1H), 4.16 (t, J¼7.1 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H),
3.66 (s, 3H), 3.11 (t, J¼7.1 Hz, 2H), 1.46 (d, J¼6.1 Hz, 6H); 13C NMR
H
N
H
H
OMe
(100 MHz, CD2Cl2):
d
¼159.6, 158.9, 158.0, 144.1, 133.0, 131.2, 131.0,
130.6, 130.1, 129.7, 128.6, 128.3, 127.7, 125.4, 124.4, 122.5, 120.2,
119.2, 117.3, 114.4, 114.3, 114.1, 113.9, 113.1, 113.0, 105.5, 70.8, 55.6,
55.6, 55.5, 52.0, 37.7, 22.5; IR (KBr): 3431 (br), 3032, 2973, 2931,
2834, 1605, 1576, 1545, 1513, 1462, 1248, 1175, 1114, 1032, 957, 929,
832, 784 cmꢀ1; MS (EI) m/z (%): 612 (100) [Mþ], 449 (5), 135 (8), 121
(9); HRMS (ESI) calcd for C40H40N2O4þNa [(MþNa)þ]: 635.2880,
found: 635.2881.
OMe
AgSbF6 (50 mg, 5 mol %) was added to a solution of (Ph3P)AuCl
(70 mg, 5 mol %) in CH2Cl2 (40 mL) at 0 ꢁC and the resulting mixture
stirred at this temperature for 10 min before a solution of com-
pound 20 (180 mg, 0.3 mmol) in CH2Cl2 (10 mL) was introduced. Af-
ter stirring for 2 min, the mixture was filtered through a pad of
silica, the filtrate was evaporated, and the residue purified by flash
chromatography (hexanes/EtOAc, 5:1) to give product 21 as a pale
yellow solid (120 mg, 67%). 1H NMR (600 MHz, acetone-d6):
4.1.35. Compound 54
Yellow solid; 1H NMR (400 MHz, CD2Cl2):
d
¼7.96 (br s, 1H), 7.09
(d, J¼8.8 Hz, 2H), 7.06 (d, J¼8.6 Hz, 2H), 6.93 (d, J¼8.6 Hz, 2H), 6.87–
6.74 (m, 7H), 6.68 (d, J¼8.8 Hz, 2H), 6.60–6.54 (m, 1H), 6.39 (d,
J¼2.3 Hz, 1H), 4.68 (sept, J¼6.1 Hz,1H), 4.10 (t, J¼7.1 Hz, 2H), 3.75 (s,
3H), 3.75 (s, 3H), 3.70 (s, 3H), 3.06 (t, J¼7.1 Hz, 2H), 2.80–2.72 (m,
2H), 2.68–2.60 (m, 2H), 1.39 (d, J¼6.1 Hz, 6H); 13C NMR (100 MHz,
d
¼10.27 (s, 1H, NH), 7.51 (m, 2H, H-23), 7.39 (m, 2H, H-28), 7.31
(s, 1H, H-12), 7.11 (s, 1H, H-1), 7.07 (m, 2H, H-24), 7.02 (m, 2H, H-
29), 6.76 (d, J¼7.8 Hz, 1H, H-8), 6.69 (m, 2H, H-19), 6.65 (m, 2H,
H-18), 6.64 (m, 1H, H-7), 6.32 (d, J¼7.8 Hz, 1H, H-6), 3.99 (m, 2H,
H-15), 3.95 (s, 3H, H-32), 3.89 (s, 3H, H-31), 3.88 (s, 3H, H-26),
3.70 (s, 3H, H-21), 2.58 (m, 2H, H-16); 13C NMR (150 MHz, ace-
CD2Cl2):
d¼158.9, 158.8, 157.9, 143.9, 135.5, 134.0, 131.2, 131.1, 130.1,
130.0, 129.7, 128.3, 127.0, 124.4, 122.0, 119.8, 118.6, 114.5, 114.3, 114.1,
113.9, 112.5, 109.1, 104.2, 70.7, 55.5, 55.5, 55.5, 51.9, 37.7, 34.7, 29.1,
22.5; IR (KBr): 3443 (br), 3031, 2973, 2932, 2834, 1611, 1576, 1545,
1512, 1454, 1246, 1177, 1115, 1034, 832, 782 cmꢀ1; MS (EI) m/z (%):
614 (100) [Mþ], 493 (82), 451 (26), 329 (11), 135 (26), 121 (16), 105
(5); HRMS (ESI) calcd for C40H42N2O4þNa [(MþNa)þ]: 637.3037,
found: 637.3034.
tone-d6):
d
¼160.3 (C-25), 159.8 (C-30), 159.2 (C-20), 146.4 (C-9),
136.2 (C-11), 134.5 (C-22), 132.7 (C-28), 131.9 (C-23), 131.3 (C-27),
131.2 (C-17), 130.7 (C-10), 130.5 (C-18), 130.2 (C-1), 129.5 (C-14),
126.8 (C-13), 124.9 (C-5), 123.9 (C-3), 118.6 (C-7), 118.1 (C-6), 117.9
(C-2), 114.8 (C-4), 114.4 (C-24), 114.3 (C-19), 114.1 (C-29), 110.6 (C-
12), 104.6 (C-8), 55.7 (C-31), 55.7 (C-32), 55.7 (C-26), 55.4 (C-21),
51.1 (C-15), 37.4 (C-16); 15N NMR (60.8 MHz, acetone-d6): ꢀ240.1,
ꢀ272.1 ppm; IR (KBr): 2997, 2959, 2917, 1849, 1610, 1574, 1547,
1513, 1503, 1462, 1441, 1417, 1246, 1175, 1032, 837 cmꢀ1; MS (EI)
m/z (%): 582 (100) [Mþ], 461 (73), 446 (11), 430 (23), 121 (7);
HRMS (EI) m/z: calcd for C38H35N2O4 [(MþH)þ]: 583.2596; found:
583.259.
4.1.36. Compound 55
Yellow solid; 1H NMR (400 MHz, CD2Cl2):
d
¼8.41 (br s, 1H), 7.41
(d, J¼8.8 Hz, 2H), 7.09–7.01 (m, 4H), 6.93–6.76 (m, 7H), 6.67–6.62
(m, 1H), 6.58 (d, J¼8.8 Hz, 2H), 6.50 (d, J¼2.4 Hz, 1H), 4.76 (sept,
J¼6.1 Hz, 1H), 4.11 (t, J¼6.9 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.67
(s, 3H), 3.04 (t, J¼6.9 Hz, 2H), 1.45 (d, J¼6.1 Hz, 6H); 13C NMR

6532
P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
4.1.39. Compound 24
(600 MHz, acetone-d6):
d
¼9.01 (s, 1H, NH), 7.40 (m, 2H, H-23), 7.38
(m, 2H, H-28), 7.17 (m, 2H, H-24), 7.14 (s, 1H, H-1), 7.04 (m, 2H, H-
29), 6.84 (d, J¼7.8 Hz, 1H), 6.82 (m, 2H, H-18), 6.75 (m, 2H, H-19),
6.71 (dd, J¼7.8, 8.2 Hz, 1H, H-7), 6.24 (d, J¼8.2 Hz, 1H, H-6), 3.99
(s, 3H, H-32), 3.94 (s, 3H, H-26), 3.91 (s, 3H, H-31), 3.77 (m, 2H,
H-15), 3.73 (s, 3H, H-21), 2.70 (m, 2H, H-16); 13C NMR (150 MHz, ac-
31
O
30
29
28
19
18
17
etone-d6):
d
¼160.8 (C-25), 160.0 (C-30), 159.3 (C-20), 146.4 (C-9),
20
O
27
16
1
2
3
6
7
138.7 (C-11), 137.0 (C-27), 136.0 (C-22), 132.8 (C-28), 132.8 (C-23),
131.2 (C-17), 131.0 (C-1), 130.7, 130.6 (C-14, C-18), 130.1 (C-13),
129.7 (C-10), 125.8 (C-5), 123.7 (C-3), 119.8 (C-7), 118.4 (C-6), 117.5
(C-2), 114.8 (C-4), 114.7 (C-24), 114.4 (C-19), 114.2 (C-29), 105.4 (C-
8), 81.4 (C-12), 55.9 (C-32), 55.8 (C-26), 55.7 (C-31), 55.4 (C-21),
50.6 (C-15), 37.8 (C-16); IR (film): 2962, 1571, 1511, 1454, 1401,
1357, 1316, 1258, 1241, 1170, 1014, 797, 729, 657 cmꢀ1; MS (EI): m/z
(%): 708 (100) [Mþ], 587 (19), 460 (28), 445 (6), 300 (5), 254 (10),
135 (8); HRMS (EI) m/z: calcd for C38H33IN2O4þNa [(MþNa)þ]:
731.1382, found: 731.1386.
21
N
15
5
4
8
14
22
9
13
10
25
N
H
11
O
12
O
32
23
26
24
A solution of substrate 21 (11 mg, 2
mmol) and SnCl4 (2 mL,
2.1
m
mol) in 1,2-dichloroethane (1.5 mL) was stirred at 80 ꢁC for
2 h. The reaction was diluted with CH2Cl2 (5 mL) before it was
quenched at ambient temperature with satd aq NaHCO3 (5 mL). A
standard extractive work up followed by flash chromatography
(EtOAc/hexanes, 1:4) of the crude material afforded compound 24
as a colorless solid (7 mg, 64%). 1H NMR (600 MHz, acetone-d6):
4.1.41. Compound 27
d¼10.28 (s, 1H, NH), 7.91 (d, J¼7.8 Hz, 1H, H-6), 7.62 (m, 2H, H-
21
23), 7.48 (m, 2H, H-28), 7.29 (s, 1H, H-12), 7.15 (m, 1H, H-7), 7.14
(m, 1H, H-2), 7.11 (m, 2H, H-24), 7.06 (m, 2H, H-29), 6.94 (d,
J¼7.8 Hz, 1H, H-8), 6.56 (m, 2H, H-19), 6.29 (m, 2H, H-18), 4.02
(m, 5H, H-15, H-32), 3.90 (s, 3H, H-26), 3.87 (s, 3H, H-31), 3.66 (s,
3H, H-21), 2.19 (m, 2H, H-16); 13C NMR (150 MHz, acetone-d6):
160.5 (C-30), 160.2 (C-25), 159.1 (C-20), 146.9 (C-9), 144.2 (C-1),
135.9 (C-11), 134.8 (C-22), 131.8 (C-23), 131.7 (C-28), 131.1 (C-17),
131.0 (C-14), 130.6 (C-10), 130.1 (C-18), 127.2 (C-13), 126.9 (C-27),
125.5 (C-5), 124.6 (C-3), 119.9 (C-7), 114.7 (C-29), 114.6 (C-6), 114.5
(C-24), 114.4 (C-4), 114.3 (C-19), 110.1 (C-12), 105.3 (C-8), 102.7 (C-
2), 55.8 (C-26), 55.8 (C-32), 55.7 (C-31), 55.3 (C-21), 48.2 (C-15),
36.0 (C-16); IR (film): 2950, 2925, 2899, 2832, 1609, 1577, 1512,
1457, 1439, 1421, 1281, 1244, 1175, 1083, 1030, 834, 793, 753,
734 cmꢀ1; MS (EI) m/z (%): 582 (96) [Mþ], 461 (100), 430 (22),
121 (6); HRMS (EI) calcd for C38H35N2O4 [(MþH)þ]: 583.2596,
found: 583.2591.
32
8
MeO
20
9
OMe
7
6
10
19
5
4
NH
11
15
17
16
18
3
N
14
13
I
12
22
1
2
23
27
28
29
24
25
30
OMe
OMe
26
31
1H NMR (600 MHz, acetone-d6):
d
¼9.22 (s, 1H, NH), 8.03 (d,
J¼8.3 Hz, 1H, H-6), 7.24 (dd, J¼8.1 Hz, 1H, H-7), 7.09 (m, 2H, H-
18), 7.07 (d, J¼7.9 Hz, 1H, H-8), 6.90 (s, 1H, H-1), 6.87 (m, 2H, H-
23), 6.85 (m, 2H, H-19), 6.63 (m, 2H, H-28), 6.56 (m, 2H, H-24),
6.46 (m, 2H, H-29), 5.05 (d, J¼7.5 Hz, 2H, H-15), 4.09 (s, 3H, H-
32), 3.77 (s, 3H, H-21), 3.74 (s, 3H, H-26), 3.71 (s, 3H, H-31), 3.28
4.1.40. Compounds 25 and 27
(d, J¼7.5 Hz, 2H, H-16); 13C NMR (150 MHz, acetone-d6):
¼159.8
d
(C-25), 159.5 (C-20), 158.2 (C-30), 147.1 (C-9), 139.0 (C-13), 138.8
(C-11), 135.5 (C-22), 132.7 (C-23), 132.1 (C-14), 131.5 (C-28), 131.0
(C-17), 130.8 (C-18), 129.5 (C-10), 129.4 (C-27), 128.1 (C-1), 123.9
(C-5), 123.2 (C-3), 121.2 (C-7), 119.9 (C-2), 116.4 (C-6), 114.7 (C-19),
113.3 (C-24), 113.2 (C-29), 108.2 (C-4), 105.7 (C-8), 77.9 (C-12),
56.1 (C-32), 55.5 (C-21), 55.4 (C-26), 55.4 (C-31), 52.4 (C-15), 37.8
(C-16); IR (film): 2950, 2925, 2832, 1607, 1565, 1511, 1462, 1454,
1400, 1364, 1318, 1284, 1243, 1173, 1103, 1062, 1033, 827, 804, 778,
721 cmꢀ1; HRMS (EI) m/z: calcd for C38H33IN2O4þNa [(MþNa)þ]:
731.1382, found: 731.1386.
32
8
31
9
OMe
7
6
MeO
30
10
5
4
29
NH
27
11
3
28
12
2
1
I
14 13
22
N
15
23
16
24
25
17
18
19
OMe
26
20
OMe
4.2. DNA cleavage assay
21
Trifluoromethanesulfonic acid (15
solution of [I(pyridine)2]BF4 (67 mg, 0.18 mmol) in CH2Cl2
m
L, 0.16 mmol) was added to
A solution of purified scDNA (2
mL of a stock solution containg
a
ca. 400 X174 RF1 DNA, purchased from MBI Fermentas
m
g mLꢀ1) [
F
(3.5 mL) and the resulting mixture was stirred for 15 min at ambi-
ent temperature before it was cooled to ꢀ40 ꢁC. A solution of com-
pound 20 (87 mg, 0.15 mmol) in CH2Cl2 (2.5 mL) was introduced
and stirring continued for 30 min before the mixture was allowed
to reach ambient temperature. The reaction was quenched with
aq satd Na2S2O3 (5 mL), the organic layer was washed with water,
dried (MgSO4) and evaporated, and the residue was purified by
flash chromatography (hexanes/EtOAc, 4:1) to give a mixed fraction
containing products 25 and 27 (71 mg, 67%). Analytically pure sam-
ples were obtained by preparative HPLC which showed the follow-
ing analytical and spectroscopic properties: Compound 25: 1H NMR
GmbH, St. Leon-Rot, Germany; the EDTA contained in the com-
mercial sample was removed according to the Qiaex II protocol for
desalting and concentrating DNA by using a Qiaex II Gel Extraction
Kit] was incubated at 37 ꢁC for 1.5 h with the respective dictyo-
dendrin derivative (2
of a 1 mM stock solution), n-butylamine (2
solution), aq NaCl (3 L of a 0.5 mM stock solution) in water
(complemented to give a total volume of 20 L). The mixture was
mL of a 2 mM stock solution), Cu(OAc)2 (2
mL
mL of a 20 mM stock
m
m
quenched with loading buffer (BioRad laboratories) and the DNA
resolved by electrophoresis (Powerpac 300, BioRad) (85 V, 1 h) on
a 0.8% agarose gel (containing ethidium bromide) in tris/boronic

P. Buchgraber et al. / Tetrahedron 65 (2009) 6519–6534
6533
3. Warabi, K.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Org. Chem. 2003,
68, 2765–2770.
acid buffer (BioRad). The bands detected by UV were analyzed and
processed using the Bio Doc II software (Biometra).
4. Compound 6 and 7 are obviously closely related to the dictyodendrins. These
metabolites were isolated from a different Dictyodendrilla species and reported to
be aldose reductase inhibitors, cf: Sato, A.; Morishita, T.; Shiraki, T.; Yoshioka, S.;
Horikoshi, H.; Kuwano, H.; Hanzawa, H.; Hata, T. J. Org. Chem.1993, 58, 7632–7634.
5. (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264–287; (b)
Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005, 17, 411–445; (c) Bailly, C. Curr.
Med. Chem.: Anti-Cancer Agents 2004, 4, 363–378 and literature cited therein.
6. (a) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc.
1999, 121, 54–62; (b) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.; Jin,
Q. J. Org. Chem. 2000, 65, 2479–2483; (c) Chou, T.-C.; Guan, Y.; Soenen, D. R.;
Danishefsky, S. J.; Boger, D. L. Cancer Chemother. Pharmacol. 2005, 56, 379–390;
(d) Soenen, D. R.; Hwang, I.; Hedrick, M. P.; Boger, D. L. Bioorg. Med. Chem. Lett.
2003, 13, 1777–1781; (e) Quesada, A. R.; Garcia Gra´valos, M. D.; Ferna´ndez
Puentes, J. L. Br. J. Cancer 1996, 74, 677–682.
4.3. X-ray crystal structure analysis of 21
2(C38H34N2O4)$C4H8O2, Mr¼1253.45 g molꢀ1
, colorless plate,
crystal size 0.24ꢂ0.21ꢂ0.04 mm, monoclinic, space group P21/n,
a¼19.1139(2) Å, b¼16.5476(2) Å, c¼20.7068(3) Å,
b
¼96.5220(10)ꢁ,
V¼6506.95(14) Å3, T¼100 K, Z¼4, Dcalcd¼1.279 g cm3,
¼0.71073 Å,
l
m
(Mo
K
a
)¼0.084 mmꢀ1
, semi-empirical absorption correction
(Tmin¼0.95, Tmax¼1.00), Nonius KappaCCD diffractometer,
3.01<
reflections, 12,819 reflections with I>2
rect methods and refined by full-matrix least-squares against F2 to
q
<30.97ꢁ, 94,787 measured reflections, 20,639 independent
(I), structure solved by di-
s
7. (a) Fu¨rstner, A.; Domostoj, M. M.; Scheiper, B. J. Am. Chem. Soc. 2006,128, 8087–8094;
(b) Fu¨rstner, A.; Domostoj, M. M.;Scheiper, B. J. Am. Chem. Soc. 2005,127,11620–11621.
8. For studies towards the dictyodendrins, see: Ayats, C.; Soley, R.; Albericio, F.;
R1¼0.080 [I>2 (I)], wR2¼0.118, 857 parameters, H atoms riding,
s
´
Alvarez, M. Org. Biomol. Chem. 2009, 7, 860–862.
S¼0.997, residual electron density 0.6/ꢀ0.4 e Åꢀ3
.
9. Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 50, 6637–6641.
10. Fu¨rstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58, 6373–6380.
11. Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582–3603.
4.4. X-ray crystal structure analysis of 25
12. (a) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817–2825; (b)
Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W. J. Org. Chem. 1999, 64, 8275–8280;
(c) Fu¨rstner, A.; Krause, H. J. Org. Chem. 1999, 64, 8281–8286; (d) Fu¨ rstner, A.;
Radkowski, K.; Peters, H. Angew. Chem., Int. Ed. 2005, 44, 2777–2781.
13. Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329–8351.
14. For recent case studies on ‘diverted total synthesis’ from this laboratory, see: (a)
Fu¨rstner, A.; Nevado, C.; Waser, M.; Trembley, M.; Chevrier, C.; Teply´, F.; Aı¨ssa, C.;
Moulin, E.; Mu¨ller, O. J. Am. Chem. Soc. 2007,129, 9150–9161; (b) Fu¨rstner, A.; Kirk,
D.; Fenster, M. D. B.; Aı¨ssa, C.; De Souza, D.; Nevado, C.; Tuttle, T.; Thiel, W.; Mu¨ller,
O. Chem.dEur. J. 2007, 13,135–149; (c) Fu¨rstner, A.; De Souza, D.; Turet, L.; Fenster,
M. D. B.; Parra-Rapado, L.; Wirtz, C.; Mynott, R.; Lehmann, C. W. Chem.dEur. J. 2007,
13, 115–134; (d) Fu¨rstner, A.; Flu¨gge, S.; Larionov, O.; Takahashi, Y.; Kubota, T.;
Kobayashi, J. Chem.dEur. J. 2009, 15, 4011–4029; (e) Fu¨rstner, A.; Kattnig, E.; Kelter,
G.; Fiebig, H.-H. Chem.dEur. J. 2009, 15, 4030–4043.
15. (a) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215–
5229; (b) Fu¨rstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991–6010.
16. For applications of this methodology, see: (a) Ding, F.; Zhang, Y.; Qu, B.; Li, G.;
Farina, V.; Lu, B. Z.; Senanayake, C. H. Org. Lett. 2008, 10, 1067–1070; (b) Jones,
C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2007, 72, 7968–7973; (c) Hu,
W.; Guo, Z.; Chu, F.; Bai, A.; Yi, X.; Cheng, G.; Li, J. Biooorg. Med. Chem. 2003, 11,
1153–1160; (d) Fan, X.; Zhang, Y. Tetrahedron 2003, 59, 1917–1923; (e) Fan, X.-S.;
Zhang, X.-Y.; Zhang, Y.-M. Chin. J. Chem. 2003, 21, 336–338; (f) see also: Jeong,
H. J.; Yoon, U. Y.; Jang, S. H.; Yoo, U.-A.; Kim, S. N.; Truong, B. T.; Shin, S. C.; Yoon,
Y.-J.; Singh, O. M.; Lee, S.-G. Synlett 2007, 1407–1410; (g) Katritzky, A. R.; Ji, Y.;
Fang, Y.; Prakash, I. J. Org. Chem. 2001, 66, 5613–5615; (h) Banerji, A.; Nayak, S.
K. J. Chem. Soc., Chem. Commun. 1990, 150–151.
C
38H33IN2O4, Mr¼708.56 g molꢀ1, colorless plate, crystal size
0.07ꢂ0.05ꢂ0.02 mm, monoclinic, space group P21/c, a¼10.09510(10) Å,
b¼23.1367(3) Å, c¼13.7023(2) Å,
b
¼92.9810(10)ꢁ, V¼3196.08(7) Å3,
T¼100 K, Z¼4, Dcalcd¼1.473 g cm3,
l
¼0.71073 Å,
m
(Mo K
a
)¼1.046 mmꢀ1
,
semi-empirical absorption correction (Tmin¼0.99, Tmax¼1.00), Non-
ius KappaCCD diffractometer, 2.98<
reflections, 10,167 independent reflections, 8026 reflections with
q
<30.97ꢁ, 86,412 measured
I>2s(I), structure solved by direct methods and refined by full-
matrix least-squares against F2 to R1¼0.039 [I>2
(I)], wR2¼0.088,
s
415 parameters, H atoms riding, S¼1.048, residual electron density
3.0/ꢀ1.0 e Åꢀ3
.
4.5. X-ray crystal structure analysis of 41
C
23H17NO2, Mr¼339.38 g molꢀ1
, yellow block, crystal size
0.13ꢂ0.12ꢂ0.12 mm, triclinic, space group Pꢀ1, a¼6.76770(10) Å,
b¼9.6890(2) Å, c¼27.6343(6) Å,
a
¼96.5490(10)ꢁ,
b
¼95.2090(10)ꢁ,
g
¼108.0680(10)ꢁ, V¼1696.11(6) Å3, T¼100 K, Z¼4, Dcalcd¼1.329
g cm3,
l¼0.71073 Å,
m
(Mo K
a
)¼0.085 mmꢀ1, semi-empirical ab-
17. (a) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468–4475; (b)
Fu¨ rstner, A.; Ernst, A. Tetrahedron 1995, 51, 773–786; (c) Fu¨rstner, A.; Ernst, A.;
Krause, H.; Ptock, A. Tetrahedron 1996, 52, 7329–7344; (d) Fu¨rstner, A.; Jumbam,
D. N.; Seidel, G. Chem. Ber. 1994, 127, 1125–1130; (e) Fu¨rstner, A.; Jumbam, D. N.
J. Chem. Soc., Chem. Commun. 1993, 211–212.
sorption correction (Tmin¼0.72, Tmax¼0.86), Nonius KappaCCD dif-
fractometer, 2.92<
q
<33.16ꢁ, 40,537 measured reflections, 12,778
(I), structure
independent reflections, 9803 reflections with I>2
s
18. Preparation of 18 required the use of chloro-N,N,2-trimethylpropenylamine,
whereas oxalyl chloride afforded only Z-3-chloroacrylic acid. For the prepara-
tion of the chloroenamine reagent, see: Devos, A.; Remion, J.; Frisque-Hesbain,
A.-M.; Colens, A.; Ghosez, L. J. Chem. Soc., Chem. Commun. 1979, 1180–1181.
19. McMurry, J. E. Chem. Rev. 1989, 89, 1513–1524.
solved by direct methods and refined by full-matrix least-squares
against F2 to R1¼0.066 [I>2
(I)], wR2¼0.199, 473 parameters, H
s
atoms riding, S¼1.056, residual electron density 0.8/ꢀ1.0 e Åꢀ3
.
CCDC 719,450–719,652 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.ca.ac.uk/data_request/cif.
´
20. Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. 1996, 35, 2442–2469.
21. Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449.
22. For the formation of polycyclic arenes by
p-acid catalyzed reactions of alky-
nylated substrates, see: (a) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002, 67,
6264–6267; (b) Mamane, V.; Hannen, P.; Fu¨rstner, A. Chem.dEur. J. 2004, 10,
4556–4575; (c) Fu¨ rstner, A.; Kennedy, J. W. J. Chem.dEur. J. 2006, 12, 7398–
7410; (d) Fu¨rstner, A.; Mamane, V. Chem. Commun. 2003, 2112–2113.
23. Brønsted acids have not been tested.
Acknowledgements
24. Barluenga, J.; Gonza´lez, J. M.; Campos, P. J.; Asensio, G. Angew. Chem., Int. Ed.
Engl. 1988, 27, 1546–1547.
Generous financial support by the MPG, the Alexander-von-
Humboldt Foundation (postdoc fellowship to M.M.D.) and the
25. McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983, 105, 1660–1661.
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M.; Kushida, T.; Kitami, S.; Oda, M. J. Chem. Soc., Chem. Commun. 1987, 1607–
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Trans. 1 1988, 1729–1734; (d) Li, W.; Li, Y.; Li, Y. Synthesis 1994, 678–680; (e) Li,
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´
Fonds der Chemischen Industrie (Kekule stipend to B.S.) is grate-
fully acknowledged. We thank Mrs. H. Krause for performing the
gel electrophoresis experiments and Dr. C.W. Lehmann for super-
vising the crystal structure analyses.
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