Synthetic studies towards dendridine A: Synthesis of hemi-dendridine A acetate by Fischer indolization

Article abstract of DOI:10.1016/j.tetlet.2012.05.029

A short synthesis of hemi-dendridine A acetate has been accomplished. The synthesis is based on a modified Fischer indolization that represents a rare example of the single-step synthesis of a 7-oxytryptamine from an ortho-oxygenated phenylhydrazine. The synthetic route required developing an efficient synthesis of N-acetyl-2-pyrroline, the key coupling partner for the modified Fischer indolization. Some interesting chemistry associated with the abnormal Fischer indolization has been uncovered, whereby two molecules of the phenylhydrazine substrate combined along the abnormal reaction pathway, affording an unusual N-phenylindoleamine product.

Full text of DOI:10.1016/j.tetlet.2012.05.029

Tetrahedron Letters 53 (2012) 3623–3626
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies towards dendridine A: synthesis of hemi-dendridine A acetate
by Fischer indolization
⇑
Emily M. Boyd, Jonathan Sperry
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A short synthesis of hemi-dendridine A acetate has been accomplished. The synthesis is based on a mod-
ified Fischer indolization that represents a rare example of the single-step synthesis of a 7-oxytryptamine
from an ortho-oxygenated phenylhydrazine. The synthetic route required developing an efficient
synthesis of N-acetyl-2-pyrroline, the key coupling partner for the modified Fischer indolization. Some
interesting chemistry associated with the abnormal Fischer indolization has been uncovered, whereby
two molecules of the phenylhydrazine substrate combined along the abnormal reaction pathway, afford-
ing an unusual N-phenylindoleamine product.
Received 12 March 2012
Revised 25 April 2012
Accepted 3 May 2012
Available online 12 May 2012
Keywords:
Dendridine A
Bisindole
Ó 2012 Elsevier Ltd. All rights reserved.
Abnormal Fischer indolization
Alkaloid
Tryptamine
Upon surveying an Okinawan marine sponge Dictyodendrilla sp.,
Kobayashi and co-workers isolated dendridine A (1), an optically
inactive, C2-symmetrical bis-tryptamine alkaloid with a rare 4,40-
bisindole moiety (Scheme 1).1 The only other natural compounds
possessing this heterocyclic motif are a series of serotonin derived
antioxidants2 and the biopolymer eumelanin.3
In order to investigate extensively the proposed biomimetic
synthesis, our first task was to establish an efficient route to syn-
thetically useful quantities of a suitably protected hemi-dendridine
A and our initial attempts are outlined in Scheme 2. Commercially
available 4-bromo-2-fluoro-1-nitrobenzene (3) was subjected to a
regioselective SNAr reaction with the anion of benzyl alcohol,
In an approach that likely mimics the construction of this natu-
ral product in nature, a biomimetic synthesis of 1 was planned
using a late-stage oxidative phenolic homocoupling4,5 of 5-bro-
mo-7-hydroxytryptamine (2), which we have termed as hemi-den-
dridine A. Herein, we report our initial studies towards this goal
that has culminated in a short synthesis of hemi-dendridine A
acetate.
BnOH
MgBr
NaH, THF
Br
THF
Br
0 C - r.t
°
-40 °C, 3 h
3 h
61%
NO2
31%
NO2
F
3
OBn
4
POCl3
DMF
OH
MeNO2
H
7'
NH4OAc
reflux
1 h
NH2
N
CHO
0 - 60 °C
1 h
Br
Br
5'
Br
biomimetic
[O]
3
Br
5
H2N
4'
N
H
88%
75%
4
NH2
N
H
Br 5
OBn
N
H
OBn
7
5
6
N
OH
7
H
hemi-dendridine A
OH
dendridine A
NO2
NH2
2
1
Br
Br
x
Scheme 1. Dendridine A and proposed biomimetic synthesis.
N
H
see text
N
H
8
OBn
7
OBn
⇑
Corresponding author.
E-mail address: j.sperry@auckland.ac.nz (J. Sperry).
Scheme 2. Unsuccessful approach.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.029

3624
E. M. Boyd, J. Sperry / Tetrahedron Letters 53 (2012) 3623–3626
NH2
debromination of the indole ring. Using in situ generated
Br
BH3ꢀTHF,10 a reagent that had previously been successful in our
hands,7 resulted in an intractable mixture of products
(Scheme 2).
i) Fischer
Br
NHNH2
ii) deprotection
OMe
9
N
H
Unperturbed by these negative results, an alternative strategy
was sought. A modified Fischer indolization was considered, an
idea that was initially avoided due to the propensity of ortho-oxy-
genated phenylhydrazines to form the so-called ‘abnormal prod-
ucts’ arising from ipso-substitution during the sigmatropic
rearrangement.11,12 Nonetheless, our focus turned to this route
OH
hemi-dendridine A
10
N
2
Ac
Scheme 3. Planned Fischer route.
and
a variant of the Fischer indole synthesis reported by
Holzapfel13 seemed appealing, whereby the direct synthesis of
Br
i. NaNO2 Br
ii. SnCl2
71%
tryptamines is achieved from phenylhydrazines and N-acyl-2-pyrr-
olines in
a
single-step.14 Pursuing this approach, the two
NH2
NHNH2
.HCl
components required were disubstituted phenylhydrazine 9 and
N-acetyl-2-pyrroline (10) (Scheme 3). Commercially available 4-
bromo-2-methoxyaniline (11) was subjected to a diazotization–
reduction sequence, furnishing the desired phenylhydrazine 9 as
its hydrochloride salt.15 N-Acetyl-2-pyrroline 10 was accessed
from pyrrolidine using the reported modification13 of the original
procedure.16 However, replicating the reported yield for this step
was not possible in our hands, an observation that has been re-
corded by other research groups17 (Scheme 4). Due to this issue,
a more efficient and reliable route to 10 was sought.
OMe
OMe
11
9
i. Na2S2O8
NaOH, AgNO3
ii. AcCl, iPr2NEt
N
H
<7%
N
(ref13 35%)
Ac
10
Scheme 4. Synthesis of indolization substrates 9 and 10.
The ring-closing metathesis (RCM) of N,N’-diallylacetamide
(12)18 to N-acetyl-3-pyrroline (13) is often employed to gauge
the efficiency of new metathesis catalysts.19 Furthermore, since
the isomerization of 13 is known20 to provide N-acetyl-2-pyrroline
(10), it was envisaged combining both of these reactions into one
synthetic pathway would provide a straightforward synthesis of
10. Indeed, it was discovered that the transformation of 12 into
10 could be accomplished in one-pot. When the RCM of 12 was
complete (1 h), the reaction mixture was concentrated, then added
Grubbs II
RuClH(CO)(PPh3)3
(3 mol%)
(0.7 mol%)
PhMe
rt, 1 h
110 °C, 13.5 h
N
N
N
80%
Ac
Ac
Ac
one-pot
from 12
12
13
10
Scheme 5. One-pot synthesis of N-acetyl-2-pyrroline (10).
21
to a sealed tube containing RuClH(CO)(PPh3)3 and heated to
affording 4. Bartoli indolization6 of 4 gave 5-bromo-7-benzyloxyin-
dole (5) in moderate yield. Straightforward Vilsmeier formylation
gave 6 which underwent facile Henry reaction with nitromethane
giving 7, setting the stage for a key reduction that would afford the
desired tryptamine 8.
Our group has previously encountered difficulties in
successfully forming brominated tryptamines by reduction of their
corresponding nitroalkenes7 and indeed, this was again the case
when attempting the reduction of 7 to 8, with lithium aluminium
hydride8 and various hydrogenation conditions9 causing extensive
130 °C for 13.5 h, gratifyingly affording 10 in excellent yield from
readily available N,N’-diallylacetamide (12) (Scheme 5). This ap-
proach provided synthetically useful quantities of 10 and offers
significant advantages over the existing literature procedure.13,17
With gram quantities of 9 and 10 secured, the key Fischer ind-
olization could be attempted (Scheme 6). Upon subjecting N-acet-
yl-2-pyrroline (10) and a slight excess of phenylhydrazine 9 to
standard Fischer reaction conditions, three products were formed.
The major product was gratifyingly confirmed as the desired trypt-
amine 14 arising from the normal Fischer indolization pathway. To
Br
N
NHNH2
.HCl
Ac
OMe
10
9
(1.3 equiv.)
EtOAc-H2O
AcOH
70 °C, 30 min
NHAc
NHAc
Br
NHAc
Br
Br
N
NH
+
+
N
H
N
H
OMe
OMe
16
19%
abnormal pathway
15
1%
abnormal pathway
14
Br
55%
normal pathway
Scheme 6. Fischer indolization.

E. M. Boyd, J. Sperry / Tetrahedron Letters 53 (2012) 3623–3626
3625
raphy. We thank Professor Chris Moody (University of Nottingham)
for helpful discussions.
Supplementary data
Supplementary data (experimental details for the preparation
of N-acetyl-2-pyrroline (10) and hemi-dendridine A acetate (17),
along with relevant spectra) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.05.029.
References and notes
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Figure 1. X-ray crystal structure of 16.25
NHAc
NHAc
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product synthesis, see: (a) Bringmann, G.; Ledermann, A.; Francois, G.
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Scheme 7. Synthesis of hemi-dendridine A acetate (17).
the best of our knowledge, this is only the second example report-
ing the synthesis of a tryptamine from an ortho-oxygenated phen-
ylhydrazine in a single step.14g,22 The abnormal Fischer pathway
was also operating in this case, as concluded by the isolation of
trace amounts of deoxygenated tryptamine 15.23 The third com-
pound could not be identified by spectroscopy alone and confirm-
ing its assignment as N-phenylindoleamine 1624 was only possible
when X-ray crystals became available (Fig. 1). It can be assumed
that the unusual N-phenylindoleamine 16 results from a second
equiv of phenylhydrazine 9 being incorporated along the abnormal
Fischer pathway. All attempts to reduce the yield of abnormal
products 15 and 16 by altering the reaction conditions and/or vary-
ing the ratio of substrates 9 and 10 were unsuccessful.
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moval of the methoxy group under Lewis acidic conditions, with
starting material recovered in all cases. After much investigation,
demethylation of tryptamine 14 could be accomplished in accept-
able yield using thiophenol and potassium carbonate in NMP at
elevated temperature,26 furnishing 7-hydroxytryptamine 17
(Scheme 7). It was found that dimerization of 17 did not occur
spontaneously upon oxidation in air, implying that some enzy-
matic assistance may be involved in nature’s synthesis of these
compounds. The oxidative phenolic coupling of hemi-dendridine
A acetate (17) is currently under investigation in our laboratory.
In conclusion, a short route to hemi-dendridine A acetate (17)
has been accomplished using a modified Fischer indolization, pro-
viding sufficient quantities of material to investigate extensively
the oxidative phenolic homocoupling. We have also reported an
efficient synthesis of N-acetyl-2-pyrroline (10) from N,N-diallylac-
etamide (12) using a one-pot RCM-isomerization sequence, along
with some interesting observations relating to the abnormal
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The University of Auckland is acknowledged for financial assis-
tance. We thank Tania Groutso and Peter Boyd for X-ray crystallog-

3626
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