Catalytic selective cyclizations of aminocyclopropanes: Formal synthesis of aspidospermidine and total synthesis of goniomitine

Article abstract of DOI:10.1002/anie.201001853

(Figure Presented) Mild control: Selective cyclization of aminocyclopropanes at either the N1 or C3 position of an indole ring was achieved by tuning the reaction conditions (see scheme). This strategy was applied to the formal synthesis of aspidospermidi

Full text of DOI:10.1002/anie.201001853

Angewandte
Chemie
DOI: 10.1002/anie.201001853
Alkaloids
Catalytic Selective Cyclizations of Aminocyclopropanes: Formal
Synthesis of Aspidospermidine and Total Synthesis of Goniomitine**
Filippo De Simone, Jꢀrg Gertsch, and Jꢁrꢂme Waser*
Polyheterocyclic structures are present in most natural and
synthetic molecules with important biological activity.[1]
Therefore, the discovery of new efficient cyclization reactions
is important to access natural products and to explore a broad
range of complex scaffolds with potentially enhanced bioac-
tivity.[2] We have recently reported the first catalytic formal
homo-Nazarov cyclization of vinyl cyclopropyl ketones for
the synthesis of cyclohexenones (Scheme 1a).[3] In contrast to
the well-established Nazarov cyclization of divinyl ketones to
conditions developed in our work allowed us to apply our
method to several unprecedented heterocyclic structures, but
the scope of the reaction was limited by the required presence
of an electron-rich aromatic group to stabilize the formed
carbocationic intermediate A.
A heteroatom should also be able to stabilize the formed
carbocation, as demonstrated by the rich chemistry of donor–
acceptor cyclopropanes.[6] Aminocyclopropanes in particular
may lead to the fused aminocyclohexane core of numerous
biologically relevant alkaloids (R1 = N in Scheme 1). Cycliza-
tion of an acyl indole substituted aminocyclopropane 1 would
constitute a general entry into the Aspidosperma alkaloids,
such as aspidospermidine (2; Scheme 1b). The tetracyclic
core obtained in the cyclization is present not only in the
Aspidosperma family, but also in more complex natural
products such as vinblastine and vincristine, which are front-
line drugs in cancer therapy.[7] Although the combination of
synthetically challenging structures and potential medical
applications has resulted in a large number of successful total
syntheses of aspidospermidine in the past,[8] the development
of more general and flexible synthetic approaches is still
required to access new analogues. Herein, we report the first
example of the formal homo-Nazarov cyclization of amino-
cyclopropanes and its application in the formal total synthesis
of aspidospermidine (2). Additionally, we demonstrate how a
simple modification in reaction conditions leads to the
scaffold of goniomitine (3), an indole alkaloid isolated from
the tree Gonioma malagasy,[9] starting from aminocyclopro-
pane 1. In contrast to the Aspidosperma scaffold, the
goniomitine ring system is unique in natural products, and
only two total syntheses have been reported so far.[9b,c] Based
on our cyclization strategy, an efficient total synthesis of
goniomitine (3) was accomplished and we present herein the
first study of its bioactivity, revealing significant cytotoxicity
against several cancer cell lines, including vinblastine and
taxol-resistant P-glycoprotein (Pgp, MDR-1) overexpressing
cells.
Scheme 1. Formal homo-Nazarov reaction and applications in the
synthesis of polyheterocyclic natural products. Cbz= benzyloxycar-
bonyl.
give cyclopentenones,[4] examples of homo-Nazarov cycliza-
tions are rare and require stoichiometric amounts of strong
Lewis acids or high temperatures.[5] The mild catalytic
[*] F. De Simone, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique
Fꢀdꢀrale de Lausanne, EPFL SB ISIC LCSO
BCH 4306, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9700
E-mail: jerome.waser@epfl.ch
Homepage: http://isic.epfl.ch/lcso
We began our research by examining the cyclization of the
simple model system 4 containing the aminocyclopropane
derived from the unsubstituted tetrahydropyridine ring and a
N-methylindole (Scheme 2).[10] Our standard conditions
developed for the catalytic homo-Nazarov cyclization were
highly successful and the reaction occurred in 90% yield with
high diastereoselectivity for the cis-fused product 5.[11] This
result demonstrated that carbamates were also excellent
activating groups for the cyclization reaction.
Encouraged by this promising result, we then synthesized
the ethyl-substituted cyclopropane 12 required for the core of
the Aspidosperma alkaloids (Scheme 3). The synthesis of
carboxylic acid 10 was accomplished using a slightly modified
Prof. Dr. J. Gertsch
Institute of Biochemistry and Molecular Medicine
Bꢁhlstrasse 28, 3012 Bern (Switzerland)
[**] The EPFL is acknowledged for financial support. Letitzia Gullifa
(EPFL) is acknowledged for the preparation of the starting material,
Dr. Rosario Scopelliti (EPFL) for the X-ray studies, Dr. Markus
Wartmann (Novartis AG) and Dr. Stefanie Krꢂmer (ETH Zurich) for
the gift of cancer cells, and Prof. Brian L. Pagenkopf (University of
Western Ontario) for a copy of the original NMR data for
goniomitine (3). The collaboration between J.W. and J.G. was
initiated with the support of COST CM0804 (Chemical Biology with
Natural Products).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001853.
Angew. Chem. Int. Ed. 2010, 49, 5767 –5770
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5767

Communications
Scheme 2. Model study for the cyclization of aminocyclopropane 4.
Ts =4-toluenesulfonyl.
Scheme 4. Coupling of N-carboxylated indoles.
interest in using carbon dioxide as protecting/directing group
lies in its easy removal, which occurs upon aqueous workup.
However, its use has been limited to simple substrates.[16] We
were therefore pleased to observe that the coupling proce-
dure proceeded in moderate to good yields, leading directly to
indoles 1a–c. This approach was highly convergent and
allowed the easy variation of coupling partners for the
synthesis of analogues.
The obtained product 1a was submitted to the standard
conditions for the homo-Nazarov cyclization. We were
surprised to observe the formation of two different products.
The two compounds were identified as the desired product
15a resulting from cyclization at the C3 position of indole, and
the compound 16a obtained from attack upon the N1
position. The cyclic products were isolated in 74% yield and
the ratio of 15a to 16a was 1.6:1 (Table 1, entry 1). To increase
Scheme 3. Synthesis and cyclization of aminocyclopropane 12.
Reagents and conditions: a) nBuLi, CbzCl, EtI, THF, À788C, 67%;
b) NaBH4, MeOH; c) H2SO4, THF, 93% overall; d) (CuOTf)2·C7H8,
N2CHCO2Et, CH2Cl2, 76% (d.r. 1:1); e) BF3·Et2O, CH2Cl2; f) NaOH
H2O/THF/EtOH (1:1:3), 91% overall; e) DMTMM, NMM, THF,
MeNHOMe·HCl, 93%; h) N-methylindole, nBuLi, tBuOK, THF, 48%;
i) TsOH, MeCN, quant; j) H2, Pd/C, quant. DMTMM=4-(4,6-dimeth-
oxy-1,3,5-triazin-2-yl)methylmorpholinium chloride, NMM=N-methyl-
morpholine, THF=tetrahydrofuran.
À
the selectivity for C C cyclization, we examined several
Brønsted and Lewis acids as catalysts (entries 1–4). The use of
soft Lewis acids instead of Brønsted acids allowed the desired
formation of 15a as a pure diastereoisomer (entries 2 and 3).
Softer, milder Lewis acids could potentially exert an influence
on the formation of the acyl iminium intermediate and favor
procedure of Grieco and Kaufman.[12] d-Valerolactam (7) was
Cbz protected and alkylated in one pot. Reduction and
dehydratation led to dehydropiperidine 8. Enamide 8 was
converted into aminocyclopropane 9 by cyclopropanation
using CuOTf as the catalyst.[13] The low diastereoselectivity
observed in the cyclopropanation reaction is inconsequential,
as the diastereomeric mixture of esters equilibrated to the
exo isomer in the presence of BF3.[12] The exo ester obtained
was hydrolyzed to obtain 10 as a pure diastereoisomer.
The choice of DMTMM[14] to convert the sensitive
cyclopropane 10 into the Weinreb amide 11 in good yield
was crucial. The coupling reaction between amide 11 and 2-
lithiated N-methylindole afforded the precursor 12 of the
homo-Nazarov reaction. To our delight, our catalytic con-
ditions for the cyclization gave the tetracyclic core of
Aspidosperma alkaloids as a single diastereoisomer 13 after
removal of the Cbz protecting group.
The high diastereoselectivity observed is an important
advantage of the formal homo-Nazarov cyclization. Other
approaches based on aminocyclopropanes in intermolecular
Friedel–Crafts reactions used for the synthesis of Aspido-
sperma alkaloids proceeded with low selectivity.[8d] If an
enantioselective cyclopropanation method can be developed,
an asymmetric synthesis will become possible.[15]
Table 1: Cyclization of aminocyclopropanes 1.
Entry R (1)
Catalyst
Solvent 15/16
Yield
[%]
1
2
3
4
5
6
7
8
H (1a)
H (1a)
TsOH
Cu(OTf)2
MeCN 1.6:1[a]
MeCN 8:1[b]
74
n.d.[c]
n.d.
91
H
H
H
H
H
H
H
Pd(CH3CN)4(BF4)2 MeCN 11:1[b]
Cu(OTf)2
TsOH
TsOH
TsOH
TsOH
TsOH
MeCN 7:1[a]
MeNO2 1.3:1[b]
n.d.
THF
polymers[b] n.d.
CH2Cl2 1:18[b]
toluene 1:16[b]
CH2Cl2 1:21[a]
CH2Cl2 1:22[a]
MeCN 8:1[a]
CH2Cl2 1:20[a]
MeCN 8:1[a]
n.d.
n.d.
89
92
88
9
10
11
12
13
4-OMe (1b) TsOH
4-OMe
5-OMe (1c) TsOH
5-OMe
Cu(OTf)2
86
95
Cu(OTf)2
[a] Yields and ratios determined from products isolated after purifica-
tion. Reaction run with 1a–c (40–100 mg, 90–250 mmol) and 15–
For the synthesis of aspidospermidine (2) an indole having
an unprotected NH moiety was required. Therefore, we
investigated the use of bis-lithiated N-carboxy indoles for the
addition reaction to the Weinreb amide 11 (Scheme 4).[16] The
25 mol% catalyst, and at
a concentration of 0.025m. [b] Ratios
1
calculated by integration of peaks in the H NMR spectra of the crude
reaction mixture. Reaction carried out on a 10 mg (25 mmol) scale at a
concentration of 0.025m. [c] n.d.=not determined.
5768
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5767 –5770

Angewandte
Chemie
the reaction at the softer C3 position of the indole ring.
Deprotection of 15a gave the free amine, concluding the
successful formal total synthesis of aspidospermidine (2), as
this intermediate had already been reported by Wenkert and
Hudlicky.[8d,17]
alcohol gave goniomitine (3) in 77% overall yield from 17.[21]
The total synthesis of (Æ )-goniomitine (3) was accomplished
in a longer linear sequence of 13 steps (5 purifications by
column chromatography) with an overall yield of 11%.
Somewhat surprisingly, we were unable to find any studies
about the bioactivity of goniomitine (3). In a first biological
assessment we therefore investigated the cytotoxicity of this
natural product. Preliminary results are highly promising as
goniomitine displays nanomolar antiproliferative effects in
several tumor cell lines (Table 2). Interestingly, unlike taxol
and vinblastine, which are approximately 100-fold less
effective in cells overexpressing P-gp (not shown), goniomi-
tine did not lose its effect in the resistant MDR-1-MDCK cell
line.
The N-cyclization product 16a was also highly interesting,
as it corresponded to the tetracyclic skeleton of goniomitine
(3). When considering the rarity of this scaffold, the limited
number of synthetic approaches,[9b,c] and the absence of any
study on its bioactivity, we found it worthwhile to optimize the
formation of the N1-cyclization product 16a. We hypothe-
sized that the use of a less polar solvent for the cyclization
reaction could enhance the reactivity of the iminium inter-
mediate and favor a fast attack on the harder N1 position.
Indeed, a strong influence of solvents upon the cyclization
was observed in the presence of Brønsted acids (Table 1,
entries 5–8). We were delighted to isolate the goniomitine
scaffold 16a in high yield and excellent selectivity using
dichloromethane and toluene sulfonic acid as catalyst
(entry 9).
Cyclizations involving (acyl)iminium ions are important
tools in the synthesis of alkaloids.[18] Examples involving a
possible competition between N1 and C3 cyclization are rare,
and it is difficult to control the regioselectivity and stereose-
lectivity of these reactions.[19] The ring-opening of amino-
cyclopropanes constitutes a new method for the generation of
acyl iminium ions and the high level of control on the regio-
and stereoselectivity observed is unprecedented. To gain a
first impression for the generality of the method, two methoxy
indole analogues, 1b and 1c, were examined, as similar
electron-rich indoles are frequently encountered in natural
products. Again, high yields and control of regioselectivity
were achieved in these cases (Table 1, entries 10–13).
To finish the total synthesis of goniomitine (3) starting
from 16a, it would be necessary to introduce the lateral chain
at C3 in the presence of the sensitive aminal functionality. To
avoid this difficult task, we envisaged a more convergent
approach starting from the cyclization precursor 1d
(Scheme 5). Indole 1d was obtained from tryptophol by
TIPS protection, carboxylation, lithiation, and then addition
to the Weinreb amide 11.[20] The cyclopropane 1d was cyclized
in the presence of a catalytic amount of TsOH, affording the
tetracyclic core 17 of goniomitine (3) in 93% yield. The
carbonyl group was reduced to the alcohol and acetylated.
The acetate and the benzyl carbamate were cleaved in one
step through hydrogenolysis. Deprotection of the primary
Table 2: Antiproliferative activity of goniomitine.
Cell lines
IC50 [nm][a]
A549
MCF-7
HCT116
PC-3M
MDCK
205Æ27
239Æ13
281Æ29
159Æ24
247Æ10
381Æ17
MDR-1-MDCK
[a] IC50 values for inhibition of human tumor cell growth; A549 (lung),
MCF-7 (breast), HCT-116 (colon), PC-3M (prostate), MDCK (canine
kidney). MDR-1-MDCK is a human P-glycoprotein 170 (P-gp170)-over-
expressing multidrug-resistant cell line.[22]
In conclusion, we have demonstrated the versatility of
aminocyclopropanes as (acyl)iminium precursors for intra-
molecular cyclizations. The reaction proceeded under mild
conditions and control of the regioselectivity was possible by
the right choice of catalyst and solvent. The power of the
methodology has been demonstrated in the efficient formal
total synthesis of aspidospermidine (2) and the total synthesis
of goniomitine (3). First studies on the bioactivity of
goniomitine revealed its relatively potent cytotoxicity (anti-
proliferative effect; IC50 = 150–400 nm) against several tumor
cell lines. Preliminary data show that this natural product
disrupts the microtubule network (not shown). Therefore,
goniomitine is a potential new anticancer lead structure. In
the future, the high convergence of our synthetic approach
will allow access a large number of analogs of goniomitine (3)
for structure–activity relationship studies. Applications of
aminocyclopropanes as iminium precursors for other types of
cyclization or addition reactions as well as the development of
asymmetric cyclopropanation methods for enamides are
currently under investigation in our laboratory and the results
of this work will be reported in due course.
Received: March 29, 2010
Published online: June 8, 2010
Scheme 5. Total synthesis of goniomitine (3). Reagents and condi-
tions: a) TsOH, CH2Cl2, 93%; b) NaBH4, MeOH; c) Ac2O, pyridine;
d) Pd/C, H2, EtOH; e) TBAF, THF, 77% overall. TBAF=tetra-n-butyl-
ammonium fluoride, TIPS=triisopropylsilyl.
Keywords: alkaloids · antitumor agents · cyclization ·
heterocycles · regioselectivity
.
Angew. Chem. Int. Ed. 2010, 49, 5767 –5770
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5769

Communications
Takano, T. Sato, K. Inomata, K. Ogasawara, J. Chem. Soc. Chem.
Commun. 1991, 462; c) C. L. Morales, B. L. Pagenkopf, Org.
Lett. 2008, 10, 157; Analogs studies: d) C. Hashimoto, H. P.
Husson, Tetrahedron Lett. 1988, 29, 4563; e) G. Lewin, C.
Schaeffer, Nat. Prod. Lett. 1995, 7, 227; f) G. Lewin, C. Schaeffer,
P. H. Lambert, J. Org. Chem. 1995, 60, 3282; g) G. Lewin, C.
Schaeffer, R. Hocquemiller, E. Jacoby, S. Leonce, A. Pierre, G.
Atassi, Heterocycles 2000, 53, 2353.
[1] a) A. F. Pozharskii, A. R. Katritsky, A. T. Soldatenkov in
Heterocycles in Life and Society: An Introduction to Heterocyclic
Chemistry and Biochemistry and the Role of Heterocycles in
Science Technology, Medicine and Agriculture, Wiley-VCH,
Weinheim, 1997; b) J. Clardy, C. Walsh, Nature 2004, 432, 829.
[2] S. M. Ma in Handbook of Cyclization Reactions, Wiley-VCH,
Weinheim, 2009.
[3] F. De Simone, J. Andres, R. Torosantucci, J. Waser, Org. Lett.
2009, 11, 1023.
[10] See the Supporting Information for the synthesis of 4.
[11] The cis stereochemistry was determined by two-dimensional
NMR experiments. See the Supporting Information for details.
[12] P. A. Grieco, M. D. Kaufman, J. Org. Chem. 1999, 64, 7586.
[13] R. Beumer, C. Bubert, C. Cabrele, O. Vielhauer, M. Pietzsch, O.
Reiser, J. Org. Chem. 2000, 65, 8960.
[4] a) I. N. Nazarov, I. I. Zaretskaya, Izv. Akad. Nauk SSSR Ser.
Khim. 1941, 211; For reviews, see: b) K. L. Habermas, S. E.
Denmark, T. K. Jones, Org. React. 1994, 45, 1 – 158; c) A. J.
Frontier, C. Collison, Tetrahedron 2005, 61, 7577; d) H. Pellissier,
Tetrahedron 2005, 61, 6479; e) M. A. Tius, Eur. J. Org. Chem.
2005, 2193; f) W. Nakanishi, F. G. West, Curr. Opin. Drug
Discovery Dev. 2009, 12, 732.
[5] a) W. S. Murphy, S. Wattanasin, Tetrahedron Lett. 1980, 21, 1887;
b) W. S. Murphy, S. Wattanasin, J. Chem. Soc. Perkin Trans. 1
1981, 2920; c) W. S. Murphy, S. Wattanasin, J. Chem. Soc. Perkin
Trans. 1 1982, 1029; d) O. Tsuge, S. Kanemasa, T. Otsuka, T.
Suzuki, Bull. Chem. Soc. Jpn. 1988, 61, 2897; e) V. K. Yadav,
N. V. Kumar, Chem. Commun. 2008, 3774.
[6] a) H. U. Reissig, R. Zimmer, Chem. Rev. 2003, 103, 1151; b) M.
Yu, B. L. Pagenkopf, Tetrahedron 2005, 61, 321; c) F. De Simone,
J. Waser, Synthesis 2009, 3353.
[7] a) S. E. Malawista, H. Sato, K. G. Bensch, Science 1968, 160, 770;
b) B. Gigant, C. G. Wang, R. B. G. Ravelli, F. Roussi, M. O.
Steinmetz, P. A. Curmi, A. Sobel, M. Knossow, Nature 2005, 435,
519; c) F. Gueritte, J. Fahy, The Vinca Alkaloids, Anticancer
Agents from Natural Products (Eds.: D. J. C. Newman, G. M.
Kingston), Taylor & Francis, London, 2005.
[8] For a few selected examples, see: a) G. Stork, J. E. Dolfini, J.
Am. Chem. Soc. 1963, 85, 2872; b) J. P. Kutney, N. Abdurahm, P.
Lequesne, E. Piers, I. Vlattas, J. Am. Chem. Soc. 1966, 88, 3656;
c) T. Gallagher, P. Magnus, J. C. Huffman, J. Am. Chem. Soc.
1982, 104, 1140; d) E. Wenkert, T. Hudlicky, J. Org. Chem. 1988,
53, 1953; e) R. Iyengar, K. Schildknegt, J. Aube, Org. Lett. 2000,
2, 1625; f) M. A. Toczko, C. H. Heathcock, J. Org. Chem. 2000,
65, 2642; g) S. A. Kozmin, T. Iwama, Y. Huang, V. H. Rawal, J.
Am. Chem. Soc. 2002, 124, 4628; h) L. A. Sharp, S. Z. Zard, Org.
Lett. 2006, 8, 831; i) C. Sabot, K. C. Guerard, S. Canesi, Chem.
Commun. 2009, 2941.
[14] 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-N-methylmorpholinium
chloride.
[15] For a review on metal-catalyzed enantioselective cyclopropana-
tion reactions, see: a) H. Pellissier, Tetrahedron 2008, 64, 7041.
Highly selective methods for enamide substrates have not yet
been reported. Alternatively, the kinetic resolution of amino-
cyclopropane esters can also be envisaged.[13]
[16] A. R. Katritzky, K. Akutagawa, Tetrahedron Lett. 1985, 26, 5935.
[17] The structure of deprotected 15a was definitively confirmed by
X-ray diffraction studies on the corresponding hydrochloride
salt; see the Supporting Information.
[18] B. E. Maryanoff, H. C. Zhang, J. H. Cohen, I. J. Turchi, C. A.
Maryanoff, Chem. Rev. 2004, 104, 1431.
[19] a) A. Jackson, N. D. V. Wilson, A. J. Gaskell, J. A. Joule, J.
Chem. Soc. C 1969, 2738; b) P. Forns, A. Diez, M. Rubiralta, J.
Org. Chem. 1996, 61, 7882; c) M. Amat, M. Perez, N. Llor, C.
Escolano, F. J. Luque, E. Molins, J. Bosch, J. Org. Chem. 2004, 69,
8681; d) S. Cutri, A. Diez, M. Bonin, L. Micouin, H. P. Husson,
Org. Lett. 2005, 7, 1911.
[20] See the Supporting Information.
[21] The data contained in the 400 MHz 1H NMR spectra of
goniomitine (3) were identical to those of natural[9a] and
synthetic[9b,c] goniomitine. The obtained values for 13C NMR
spectra fitted perfectly with the reported values for synthetic
goniomitine, but small differences were apparent when com-
pared with natural goniomitine. A comparison of the spectra is
provided in the Supporting Information.
[22] See the Supporting Information for more details. See also: J.
Gertsch, F. Feyen, A. Bꢀtzberger, B. Gerber, B. Pfeiffer, K. H.
Altmann, ChemBioChem 2009, 10, 2513.
[9] Isolation: a) L. Randriambola, J. C. Quirion, C. Kanfan, H. P.
Husson, Tetrahedron Lett. 1987, 28, 2123; Total syntheses: b) S.
5770
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 5767 –5770