Cycloaddition studies directed toward the strychnos alkaloid minfiensine

Article abstract of DOI:10.1016/j.tetlet.2008.12.088

The thermolysis of several imidofuranyl carbamates delivers products derived from an intramolecular [4+2]-cycloaddition reaction. In the case of the ortho-azido aryl carbamate 13, the preferred path proceeds by an electrocyclization of a nitrene intermedi

Full text of DOI:10.1016/j.tetlet.2008.12.088

Tetrahedron Letters 50 (2009) 3145–3147
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Tetrahedron Letters
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Cycloaddition studies directed toward the strychnos alkaloid minfiensine
*
Drew R. Bobeck, Stefan France , Carolyn A. Leverett, Fernando Sánchez-Cantalejo, Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The thermolysis of several imidofuranyl carbamates delivers products derived from an intramolecular
[4+2]-cycloaddition reaction. In the case of the ortho-azido aryl carbamate 13, the preferred path pro-
ceeds by an electrocyclization of a nitrene intermediate to produce a 3-substituted indole. Attempts to
reduce the azido group resulted in a novel intramolecular aza-Wittig reaction with the neighboring imido
group.
Received 8 December 2008
Revised 16 December 2008
Accepted 17 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Cascade reactions where the conversion of a starting material to
a product that then becomes a substrate for the next reaction are
highly desirable not only due to their elegance, but also because
of their efficiency and economy in terms of reagent consumption
and purification.1–3 These multistep, one-pot procedures are often
accompanied by dramatic increases in molecular complexity.4–6
For the past several years, our research group has been investigat-
ing the intramolecular [4+2]-cycloaddition/rearrangement cascade
of 2-amidofurans (IMDAF) as a strategy for the synthesis of hexa-
hydroindolinone alkaloids.7 Our recently completed syntheses of
( )-erysotramidine,8 ( )-lycoricidine,9 and ( )-strychnine10 nicely
demonstrate the utility of this cascade process for the construction
of various alkaloids. On the basis of our earlier work, we felt that
we could also use this methodology for the synthesis of the strych-
nos alkaloid minfiensine (1). This unusual alkaloid was isolated
from the African plant Strychnos minfiensis by Massiot and cowork-
ers in 1989, and possesses a highly challenging pentacyclic ring
framework.11 The 1,2,3,4-tetrahydro-9a,4a-iminoethano-carbazole
core (2) represents the defining feature of minfiensine and this
tetracyclic framework can also be found in a number of related
akuammiline alkaloids.12,13 While two total syntheses of minfie-
nine have already been reported,14 beginning with Overman’s
brilliant synthesis in 2005,15 only a few successful methods to pre-
pare the tetracyclic sub-ring have been described to date.16
We reasoned that minfiensine (1) might be assembled by
employing the domino cycloaddition/rearrangement cascade7 of
2-amidofuran 3 as outlined in Scheme 1. The synthetic plan we
had in mind for minfiensine involves generation of the E-ring of es-
ter 7 by a palladium catalyzed intramolecular enolate coupling17 of
the tethered vinyl iodide 6 as was recently carried out in our syn-
thesis of strychnine.10 We envisioned the formation of 6 as coming
about by cyclization of the anilino group (or its equivalent) onto
the N-acyliminium ion present in 5, which we intended to generate
by the protonation of the 3a-aryl-2,3,3a,4-tetrahydro-1H-indol-
5(6H)-one 4b. The formation of 4b should occur by an IMDAF
cycloaddition reaction of amidofuran 3b (X = NH2) followed by a
subsequent rearrangement of the initially formed [4+2]-oxabicy-
clic adduct.7 It should be noted that our group had previously
reported on the thermal cascade reaction of furanyl carbamate
3a (X = H), which cleanly afforded cycloadduct 4a in 85% yield,
thereby providing good precedent for the key cycloaddition step
in the proposed scheme.18
As the goal of our initial efforts, we chose to examine the ther-
mal chemistry of the nitro-aryl substituted carbamate 3c (X = NO2)
in order to test the proposed methodology. Our intention was to
reduce the nitro functionality to the corresponding amino group
either in the starting amidofuran (i.e., 3c?3b) or else in the result-
ing rearranged cycloadduct (i.e., 4c?4b). We were surprised to dis-
cover, however, that heating a sample of 3c at 200 °C for 3 days
gave no sign of any product derived from a [4+2]-cycloaddition
reaction and only the starting carbamate was recovered. We were
able to cleanly reduce 3c into 3b using some conditions reported
by Heathcock19 (Cu(acac)2); NaBH4/EtOH). However, as was the
case with the nitro system, the thermolysis of 3b at 200 °C only
resulted in recovered starting material. One possible explanation
that might account for the lack of reactivity of these systems is that
the presence of a substituent group in the ortho position causes an
unfavorable steric interaction with the furan ring in the reactive
‘Diels–Alder conformation’ thereby diminishing the overall rate of
the IMDAF cycloaddition.
OH
9a
4a
2
3
N
N
N
N
H
H
H
Me
2; 9a,4a-iminoethano-carbazole
1; minfiensine
* Corresponding author. Tel.: +1 404 727 0283; fax: +1 404 727 6629.
E-mail address: chemap@emory.edu (A. Padwa).
Present address: Department of Chemistry, Georgia Institute of Technology,
901 Atlantic Drive, Atlanta, GA 30322-0400, United States.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.088

3146
D. R. Bobeck et al. / Tetrahedron Letters 50 (2009) 3145–3147
OH
CO2Me
O
N
N
N
N
H
N
EtO2C
N
EtO2C
Me
I
6
Me
Me
7
1; minfiensine
X
X
NH2
O
H2C
O
O
+
N
N
N
CO2Et
CO2Et
CO2Et
5
²
3a; X = H
4a; X = H
85%
3b; X = NH2
3c; X = NO2
4b; X = NH2
4c; X = NO2
Scheme 1.
In earlier studies, we had demonstrated that conformation ef-
fects can have a dramatic impact on the rate of the IMDAF reaction
of amido-substituted furans.20 Specifically, the incorporation of an
imido carbonyl group in the tether that joins the dienophile and
azido group could be easily reduced. We found, however, that
heating a sample of 13 in refluxing toluene produced only the 3-
substituted indole 15 with no signs of an IMDAF cycloadduct being
present in the crude reaction mixture. Apparently, loss of nitrogen
from azide 13 followed by an electrocyclization22 to give 14 and
then indole 15 by a 1,5-hydrogen shift proceeds at a faster rate
than the IMDAF cycloaddition.
furan moieties results in a conformation where the
p-bond and
the furan ring are in closer proximity, thereby facilitating the
cycloaddition reaction relative to the simpler amine system. An
example that illustrates this marked rate difference is seen in the
thermal chemistry of carbamate 8 versus imidofuran 9. Heating a
sample of 8 at 200 °C for 10 h gave no sign of any product derived
from a [4+2]-cycloaddition. In sharp contrast, 9 gave 10 in 90% iso-
lated yield when heated at 100 °C for 2 h. In this case, the initially
formed Diels–Alder cycloadduct underwent ring opening and a
subsequent loss of water to produce the aromatized product 10
(Scheme 2).
In an attempt to exploit this conformational facilitating effect,
we first opted to study the IMDAF reaction of the o-bromo substi-
tuted imidofuranyl carbamate 11. We found that the intramolecu-
lar cycloaddition behavior of 11 in response to the presence of a
C@O group in the tether was striking. Thus, the thermolysis of 11
at 150 °C in toluene afforded 2,5-dioxohexahydro-1H-indole 12
in 90% isolated yield (Scheme 3). Unfortunately, all of our efforts
to convert the bromo group into an amino functionality using
Buchwald/Hartwig amination procedures21 failed.
To avoid this competitive cyclization problem, we decided to
first reduce the azido group to the corresponding amine. A stan-
dard method for azide reduction involves its reaction with triphen-
ylphosphine which leads to the formation of the corresponding
iminophosphorane (i.e., 16). In the presence of water, hydrolysis
generally occurs quite rapidly to produce the primary amine and
triphenylphosphine oxide (Staudinger reduction).23 However, with
the above system, iminophosphorane 16 preferred to react with
the adjacent imido carbonyl group in an aza-Wittig manner24 to
deliver dihydroquinoline 17, which then tautomerized to the more
stable quinoline 18 (Scheme 4). Although amides are not tradition-
ally used as the carbonyl coupling partner for intramolecular aza-
Wittig reactions, there are a number of reports in the literature
describing the use of this reaction for the synthesis of various
nitrogen containing heterocycles24,25
.
In conclusion, we have tested a strategy for the eventual con-
struction of the 9a,4a-iminoethano-carbazole framework of minf-
iensine using the IMDAF rearrangement cascade of 2-
imidofurans. Furanyl carbamates with carbonyl groups in the
tether provided the desired cycloaddition product. Those lacking
the carbonyl group failed to cyclize. We now plan to find an alter-
nate set of conditions to reduce the o-azido group of carbamate 13
and explore its conversion to the key 5-oxo-hexahydro-1H-indole
intermediate. Further progress toward the total synthesis of minf-
iensine (1) is ongoing in this laboratory and will be reported in due
time.
Nevertheless, armed with this promising result, we set out to
explore the cycloaddition chemistry of the related o-azido furanyl
carbamate 13 as we thought that the relatively small and linear
CO2Et
N
200 ºC
10 h
No Cycloaddition
O
CH2
8
CO2Et
N
Br
Br
100 ºC
2 h
H2C
150 ºC
O
O
O
O
O
N
O
CO2Et
N
N
CH2
CO2Et
O
CO2Et
12; 90%
9
11
10 (90%)
Scheme 2.
Scheme 3.

D. R. Bobeck et al. / Tetrahedron Letters 50 (2009) 3145–3147
3147
CO2Et
CO2Et
N3
N
N
O
O
²
H2C
O
O
O
O
N
H
N
N
CO2Et
14
15
13
Ph3P, H2O
CH3
CH2
N
Ph3P
N
H2C
CO2Et
CO2Et
O
N
N
O
N
N
O
O
CO2Et
16
18
17
Scheme 4.
13. Anthoni, U.; Christophersen, C.; Nielson, P. H.. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1999; Vol. 13, pp
163–236.
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Chem. Soc. 2008, 130, 5368; (b) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew.
Chem., Int. Ed. 2008, 47, 3618.
Acknowledgments
We appreciate the financial support provided by the National
Science Foundation (CHE-0742663). F.C.S. wishes to thank the
Fundación Ramón Areces and the Universidad de Granada, Spain,
for funds to allow for a short research leave at Emory University.
15. Dounay, A. B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127,
10186.
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J.; Sapi, J.; Laronze, J. Y.; Royer, D.; Toupet, L. Synlett 1992, 601.
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Bonjoch, J. Adv. Synth. Catal. 2004, 346, 1646; (e) Solé, D.; Urbaneja, X.; Bonjoch,
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