Total synthesis of (±)-goniomitine via a formal nitrile/donor- acceptor cyclopropane [3 + 2] cyclization

Article abstract of DOI:10.1021/ol702376j

(Chemical Equation Presented) The total synthesis of (±)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available δ-valerolactam. A synthetic highlight includes the first application of a formal [3 + 2] cycloaddition between a highly functionalized nitrile and a donor-acceptor cyclopropane to prepare an indole nucleus. The use of a microwave reactor is shown to greatly improve the reaction times for two steps.

Full text of DOI:10.1021/ol702376j

ORGANIC
LETTERS
2008
Vol. 10, No. 2
157-159
Total Synthesis of (
Formal Nitrile/Donor
Cyclopropane [3
±)-Goniomitine via a
−Acceptor
+
2] Cyclization
Christian L. Morales and Brian L. Pagenkopf*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, N6A 5B7 Canada
bpagenko@uwo.ca
Received September 29, 2007
ABSTRACT
The total synthesis of (
δ
±
)-goniomitine has been accomplished in 17 linear steps with 5.2% overall yield starting from commercially available
-valerolactam. A synthetic highlight includes the first application of a formal [3 2] cycloaddition between a highly functionalized nitrile and
acceptor cyclopropane to prepare an indole nucleus. The use of a microwave reactor is shown to greatly improve the reaction times
+
a donor
−
for two steps.
The indole alkaloid (-)-goniomitine 1 (Figure 1) is a member
of the aspidosperma family of natural products, many of
this has culminated in one total synthesis by Takano and
co-workers.3 Additionally, several goniomitine analogues
including bisindoles have been prepared,4 some of which
show weak cytotoxicity (IC50 ) 7.1 mM) toward L1210
leukemia cells in culture.4d
In recent years, we have developed dipolar cycloaddition
reactions of donor-acceptor (DA) cyclopropanes with nitriles
for the synthesis of pyrroles5 and have expanded such
methodology to encompass a wide variety of annelation
partners such as pyridines,6 indoles,7 and other dipolaro-
philes.8,9 The pyrrole synthesis is most easily executed when
Figure 1. (-)-Goniomitine.
(3) Takano, S.; Sato, T.; Inomata, K.; Ogasawara, K. Chem. Commun.
1991, 462-464.
(4) (a) Hashimoto, C.; Husson, H.-P. Tetrahedron Lett. 1988, 29, 4563-
4566. (b) Lewin, G.; Schaeffer, C.; Lambert, P. H. J. Org. Chem. 1995,
60, 3282-3287. (c) Lewin, G.; Schaeffer, C. Nat. Prod. Lett. 1995, 7, 227-
234. (d) Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Leonce,
S.; Pierre, A.; Atassi, G. Heterocycles 2000, 53, 2353-2356.
(5) (a) Yu, M.; Pagenkopf, B. L. J. Am. Chem. Soc. 2003, 125, 8122-
8123. (b) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099-5101. (c)
Yu, M.; Pantos, G. D.; Sessler, J. L.; Pagenkopf, B. L. Org. Lett. 2004, 6,
1057-1059.
(6) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang,
J.; Yu, M.; Pagenkopf, B. L. AdV. Synth. Catal. 2006, 8, 4379-4382.
(7) Bajtos, B.; Yu, M.; Zhao, H; Pagenkopf, B. L. J. Am. Chem. Soc.
2007, 129, 9631-9634.
which have been targets of total synthesis because of their
interesting structures and biological activities.1 Goniomitine
was isolated in 1987 from the root bark of Gonioma
malagasy by Husson and co-workers,2 and its unique
structure has attracted the attention of several groups, and
(1) Saxton, J. E. The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 1998: Vol. 51, Chapter 1.
(2) Randriambola, L.; Quirion, J.-C.; Kan-Fan, C.; Husson, H.-P.
Tetrahedron Lett. 1987, 28, 2123-2126.
10.1021/ol702376j CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/18/2007

the nitrile can be used as solvent, but this can present obvious
disadvantages with expensive or less accessible nitriles. In
this regard, we illustrate here through the total synthesis of
(()-goniomitine that a high-value synthetic nitrile can be
an effective reaction partner even when used as the limiting
reagent in the annelation reaction. Additionally, this work
clearly shows for the first time the utility of the DA
cyclopropane/nitrile annelation reaction for the synthesis of
a functionalized indole.10
Scheme 2. Synthesis of Nitrile 4
Retrosynthetic analysis suggested that reaching indole 2,
an intermediate in the Takano synthesis, would be an ideal
target for a formal synthesis of goniomitine (Scheme 1). The
Scheme 1. Retrosynthetic Analysis
yield by enolization of 10 with LDA in THF followed by
alkylation with THP ether 11. The cyano substituent was
introduced through a three-step sequence involving THP
hydrolysis (cat. TsOH, MeOH, 90%), formation of chloride
14 with methanesulfonyl chloride (MsCl, Et3N, CH2Cl2), and
displacement of the intermediate halide with sodium cyanide
in DMSO (70% over two steps). The reaction was more
conveniently performed without loss in yield by heating the
reaction to 130 °C in a microwave reactor with MeCN as
solvent. Attempts to secure nitrile 4 directly by alkylation
of lactam 10 with acrylonitrile or 3-halopropionitrile (chloro,
bromo, and iodo) gave low yields and complex mixtures,
even after pretreatment of the lithium enolate with MgBr2
or ZnCl2. However, reaction of 10 with a mixture of ZnCl2,
TMSOTf, and Et3N (30 min, 0 °C) followed by addition of
acrylonitrile gave 4 in 38% yield. Curiously, isolation of the
silyl ether and subsequent reaction with acrylonitrile in the
presence of various Lewis acids was less effective. For large
scale work, the three-step sequence was preferred.
With nitrile 4 at hand, the stage was set for the critical
cycloaddition between it and DA cyclopropane 5 (Scheme
3). Gratifyingly, after some straightforward optimization, the
tetrahydroindole adduct 15 was secured in 74% yield on 10
g scale (by reaction of nitrile 4 (1.0 equiv), cyclopropane 5
(2.9 equiv), and Me3SiOTf (1.05 equiv) in EtNO2 (2.7 M)
at -30 °C). Catalytic oxidation of tetrahydroindole 15 with
palladium on carbon in refluxing mesitylene gave indole 16
in an excellent 98% yield. Catalysis of the oxidation with
palladium hydroxide gave similar results, but the use of
manganese oxide or DDQ as the oxidant resulted in lower
yields. Together, these steps illustrate the power of the formal
[3 + 2] nitrile/DA cyclopropane annelation methodology to
prepare functionalized indoles in a straightforward and
efficient manner.
indole 2 can be derived from tetrahydroindole 3 by an oxi-
dation state adjustment of the aromatic ring and installation
of a keying ester group insertion at C3. The tetrahydroindole
intermediate 3 will in turn be accessed in a convergent
fashion by the formal [3 + 2] cycloaddition reaction between
nitrile 4 and known DA cyclopropane 5.5b A plausible
mechanistic pathway for this key step likely involves the
nitrilium ion intermediate 7 formed in a Ritter-like process
by attack on the oxocarbenium ion 6. The reversible nature
of the nitrile addition is supported by the divergent stereo-
chemical outcomes of allylation reactions11 and nitrile
annelations5a of carbohydrate-derived cyclopropyl lactones.
The synthesis of nitrile 4 began with the one-pot alkylation
and N-benzylation of commercially available δ-valerolactam
9 to produce the known lactam 1012 (Scheme 2). Creation
of the quaternary center of lactam 12 was achieved in 92%
The C3 ester side chain, an artifact of the cycloaddition
methodology, can in principle serve as an intermediate for
constructing the hydroxyethyl side chain in the natural
product. In practice, it was found more convenient to remove
the ester through decarboxylation and subsequently build the
hydroxyethyl group. The decarboxylation was achieved by
heating 16 to reflux in a mixture of NaOH, EtOH, and water
(8) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099-5101.
(9) (a) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321-347. (b)
Gnad, F.; Reiser, O. Chem. ReV. 2003, 103, 1603-1624. (c) Reissig, H.
Y.; Zimmer, R. Chem. ReV. 2003, 103, 1151-1196.
(10) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045-1075.
(11) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 4639-4640.
(12) Suh, Y.-G.; Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo,
B.-A.; Kim, H.-S. Angew. Chem., Int. Ed. 1999, 38, 3545-3547.
158
Org. Lett., Vol. 10, No. 2, 2008

Scheme 3. Formal Synthesis
Scheme 4. Completion of the Synthesis
followed by reduction of the intermediate imine with NaBH4.
The cyanomethyl group was transformed into the C3
hydroxyethyl side chain by sequential reduction of the nitrile
20 with DIBAL and then NaBH4 (44%, two steps). Finally,
the natural product (()-goniomitine (1) was obtained by
epimerization of the trans ring fusion in 21 to the cis with
catalytic p-TsOH in MeOH and Et3N. The 1H NMR spectra
of synthetic 1 obtained from acid-catalyzed isomerization
matched that of the natural product, and a 13C NMR spectrum
was identical to one from the work of Takano and co-
workers.
In summary, the total synthesis of (()-goniomitine was
achieved in 17 steps from commercially available δ-valero-
lactam with an overall yield of 5.2%. This constitutes the
shortest total synthesis of (()-goniomitine reported to date.
The highlights of the synthesis include the first application
of a formal [3 + 2] cycloaddition between nitriles and DA
cyclopropanes in total synthesis and the use of microwave-
assisted reactions in order to shorten reaction times.
(75% yield).13 Under these conditions, the decarboxylation
reaction required 3 days for completion, but when heated
under microwave conditions at 150 °C, the reaction was
completed in 3 h in the same yield. Debenzylation of 17
revealed the secondary lactam 2, a synthetic intermediate
common to the Takano synthesis, and constitutes a formal
synthesis of goniomitine. To complete the total synthesis,
the plan was to proceed along the pathway described by
Takano, the next steps of which involve a sequential
Mannich/amine methylation reaction followed by displace-
ment with sodium cyanide to give 18. However, we obtained
only trace amounts of 18 using this sequence.
The same series of reactions for installing the C3 hydroxy-
ethyl side chain was found to be more successful when
applied to the benzyl-protected lactam 17 (Scheme 4), and
the cyanomethyl group was introduced without difficulty to
give 19 in 70% over three steps. After the homologation,
the N-benzyl group was cleanly removed in 97% yield with
sodium in ammonia/THF to give 18, whereas several high-
pressure hydrogenation reactions failed.14 The reaction time
for this debenzylation proved to be critical in order to avoid
elimination of the nitrile to give the C3 methyl indole.15 The
successful deprotection of 19 to give 18 again merged the
sequence back into the synthetic stream pioneered by Takano.
The final four steps of the total synthesis were duplicated
without incident. Specifically, construction of the tetracyclic
core was achieved by dehydration of lactam 18 with POCl3
Acknowledgment. We thank NSERC, the donors of the
American Chemical Society Petroleum Research fund, and
the University of Western Ontario for financial assistance.
We thank Prof. Kohei Inomata of Tohoku Pharmaceutical
University and Prof. Yoshiharu Iwabuchi of Tohoku Uni-
versity for providing copies of the NMR spectra for both
synthetic and natural goniomitine. We thank Mr. Jian Wang
and Ms. Barbora Bajtos for helpful discussions.
Supporting Information Available: General experimen-
tal procedures and characterization of all new compounds,
copies of NMR spectra, and copies of NMR from the
isolation and Takano synthesis of goniomitine. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Mohan, B.; Nagarathnam, D.; Vedachalam, M.; Srinivasan, P. C.
Synthesis 1985, 188-190.
(14) Heureux, N.; Wouters, J.; Marko, I. E. Org. Lett. 2005, 7, 5245-
5248.
(15) Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125,
2400-2401.
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