Biomimetic approach to perophoramidine and communesin via an intramolecular cyclopropanation reaction

Article abstract of DOI:10.1021/ol0607138

Starting from tryptamine 4 and isatin 5, a biomimetic approach to the pentacyclic substructure 1 of perophoramidine and communesin was developed. The key steps were to create a stable three/six bicyclic system 2 on the 2,3-double bond of an indole derivative 3 by an intramolecular cyclopropanation, followed by ring opening of the resulting cyclopropane ring with the in situ generated amine group of an aniline.

Full text of DOI:10.1021/ol0607138

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2187-2190
Biomimetic Approach to
Perophoramidine and Communesin via
an Intramolecular Cyclopropanation
Reaction
Jun Yang, Hao Song, Xue Xiao, Jue Wang, and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug
Targeting, West China School of Pharmacy, and National Key Laboratory of
Biotherapy, Sichuan UniVersity, Chengdu 610041, PRC
yanshuqin@yahoo.com
Received March 23, 2006
ABSTRACT
Starting from tryptamine 4 and isatin 5, a biomimetic approach to the pentacyclic substructure 1 of perophoramidine and communesin was
developed. The key steps were to create a stable three/six bicyclic system 2 on the 2,3-double bond of an indole derivative 3 by an intramolecular
cyclopropanation, followed by ring opening of the resulting cyclopropane ring with the in situ generated amine group of an aniline.
Indole alkaloids form an important class of natural products
that have been studied extensively by chemists interested in
synthesis because of their intriguing structures and exhibited
biological activities. Recently, two indole alkaloids, pero-
phoramidine1 and communesin,2 with novel molecular skel-
etons were isolated from ascidian Perophora namei and a
strain of Penicillium sp., respectively. Both indole alkaloids
have a similar polycyclic system containing two vicinal
quaternary centers with relatively inverted stereochemistry
at the 4-position of the part-saturated quinoline moiety.
The structural novelty and complexity of these indole
alkaloids, along with their anticancer activities, have attracted
intense synthetic interest over the last five years. A few
modeling studies for constructing part of the polycyclic ring
system were attempted through a halogen-selective tandem
Heck carbonylation reaction3 and a hetero Diels-Alder
reaction between an indole moiety and an aza-o-xylylene
intermediate,4 which led to the first total synthesis of
perophoramidine.5
(1) For an isolation and anticancer activity study of perophoramidine,
see: Verbitski, S. M.; Mayne, C. L.; Davis, R. A. J. Org. Chem. 2002, 67,
7124.
(2) For an isolation and anticancer activity study of communesin, see:
(a) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.;
Christophersen, C. J. Nat. Prod. 2005, 68, 258. (b) Jadulco, R.; Edrada, R.
A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P.
J. Nat. Prod. 2004, 67, 78. (c) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry,
S. L.; Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640. (d) Ratnayake, A.
S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem.
2001, 66, 8717. (e) D’Amours, D.; Sallmann, F. R.; Dixit, V. M.; Poirier,
G. G. J. Cell Sci. 2001, 114, 3771. (f) Numata, A.; Takahashi, C.; Ito, Y.;
Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.;
Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355.
(3) Artman, G. D.; Weinreb, S. M. Org. Lett. 2003, 5, 1523.
(4) (a) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. (b) May, J.
A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203.
(5) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068.
10.1021/ol0607138 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/19/2006

In exploration of a new synthetic approach to perophora-
midine and communesin, we report here a biomimetic
approach to the pentacyclic substructure 1, shared by both
alkaloids, via intramolecular cyclopropanation, followed by
nucleophilic ring opening of the resulting activated cyclo-
propane ring with an in situ generated amine group of aniline
(Scheme 1) as key steps.6 The synthetic strategy is based on
functional group at the side chain, provided mainly the C-H
substitution product at the 2-position of indole rather than
yielding a cyclopropane ring. The C-2 substitution products
were formed as a result of ring collapse to relieve ring strain
of a spiro fused three/four or three/five bicyclic system. It
is reasonable to expect that the ring strain of a three/six
bicyclic system in 2 should be lower than that of the three/
four and three/five bicyclic systems and in turn allow the
three/six bicyclic system’s survival from the reaction.9 To
realize the unprecedented reaction of installing a stable
cyclopropane ring on the 2,3-double bond of 3-substituted
indole, the availability of diazo 3 became the key point
needed to be addressed first.
Scheme 1
Scheme 2
the hypothesis that these alkaloids have a biosynthetic origin
from tryptamine and isatin.
By examining the retrosynthetic plan as outlined in
Scheme 1, the feasibility of this type of biomimetic approach
will most likely rely on the key step of creating a cyclopro-
pane ring from the 2,3-double bond of indole 3. Although
numerous papers reported the metal-catalyzed diazoalkane
decomposition to prepare a cyclopropane ring from a variety
of substrates,7 a literature search found only a few examples
describing the cyclopropanation reactions on indoles.8 In-
termolecular cyclopropanation of indole with a carbene could
generate a stable cyclopropane ring on the 2,3-double bond
of indole, but intramolecular cyclopropanation of 3-substi-
tuted indole, with a γ-diazoketone or δ-diazoketo ester
As described in Scheme 2, starting with isatin 5, azido
acid 6 was prepared in 84% yield through a three-step, one-
pot procedure by modifying the literature procedures.10
Treatment of 6 with p-toluenesulfonyl-hydrazine in hot acetic
acid provided hydrazone 7 in 81% yield. The stable acyl
chloride 8 was easily obtained in 71% yield by reaction of
7 with thionyl chloride at 80 °C for 1 h in benzene, followed
by recrystallization from benzene after removing excess
thionyl chloride. Treatment of N,N′-disubstituted tryptamines
4a and 4b with 2 equiv of NaH in THF, respectively,
followed by dropwise addition of 8 (2 equiv) in THF at 0
(6) Intramolecular opening of activated cyclopropane by amine was first
reported by Danishefsky. See: Danishefsky, S. Acc. Chem. Res. 1979, 12,
66.
(7) Doyle, M. P.; Mckervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York,
1998.
(8) (a) Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
4277. (b) Jung, M. E.; Slowinski, F. Tetrahedron Lett. 2001, 42, 6835. (c)
Salim, M.; Capretta, A. Tetrahedron 2000, 56, 8063. (d) Dhanak, D.;
Kuroda, R.; Reese, C. B. Tetrahedron Lett. 1987, 28, 1827. (e) Wenkert,
E.; Alonso, M. E.; Gottlieb, H. E.; Sanchez, E. L. J. Org. Chem. 1977, 42,
3945. (f) Ashmore, J. W.; Radlick, P. C.; Helmkamp, G. K. Synth. Commun.
1976, 6, 399. (g) Welstead, W. J.; Stauffer, H. F.; Sancilio, L. F. J. Med.
Chem. 1974, 17, 544.
(9) A stable spiro fused three/seven bicycle system was found in indole
alkaloid lundurines. See: (a) Kam, T. S.; Lim, K. H.; Yoganathan, K.;
Hayashi, M.; Komiyama, K. Tetrahedron 2004, 60, 10739. (b) Kam, T. S.;
Yoganathan, K.; Chuah, Ch. H. Tetrahedron Lett. 1995, 36, 759.
(10) (a) Hall, J. H.; Patterson, E. J. Am. Chem. Soc. 1967, 89, 5856. (b)
Snyder, H. R.; Thompson, C. B.; Hinman, R. L. J. Am. Chem. Soc. 1952,
74, 2009.
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Org. Lett., Vol. 8, No. 10, 2006

°C gave amides 9a and 9b in 72% and 68% yields. For
achieving a successful condensation of 4 with 8, the second
amine functional group in 4 had to be deprotonated first
because decomposition of 8 occurred when 8 was directly
added into a solution of NaH. Condensation of 4 with 8 in
the presence of an organic base such as Et3N, DMAP, or
DBU was unsuccessful. The diazos 3a and 3b were prepared
in 55% and 50% yields by treatment of the purified 9a and
9b with Et3N for 24 h in CH2Cl2, respectively. Attempts to
combine the above two steps of amidation and diazo
formation into a one-pot procedure (from 8 to 3) were not
feasible under a variety of reaction conditions. Because
diazos 3a and 3b were not stable enough on heating and
under strong base conditions, long time storage of both 3a
and 3b is not recommended.
by oxidation of the sodium enolate of 1a or 1a′ followed by
a retroaldol reaction.
It is interesting to note that ring opening of the cyclopro-
pane ring by the in situ generated aniline provided 1a and
1a′ with retention of stereochemistry at C-2 of the indole. A
rationale for the observed stereochemistry is that an indo-
lenium intermediate 12 is first formed by collapse of the
cyclopropane ring (Scheme 4). Aromatic isomerization of
Scheme 4
With diazo 3a in hand, our attention then turned to
installing a cyclopropane ring on the 2,3-double bond of the
indole core by copper-catalyzed intramolecular cyclopropa-
nation (Scheme 3). As anticipated, diazo decomposition of
Scheme 3
12 leading to intermediate 13, followed by stereoselective
nucleophilic attack of the negative nitrogen in 13 at C-2 from
the bottom of the indolenium plane, affords intermediate 14.
Nonstereospecific protonation of 14 provides two isomers
1a and 1a′. The stereochemistry in 1a and 1a′ was secured
by proton NOEDs experiments. In the NOEDs experiments,
the correlation between the amido R-proton and the bisaminal
proton in 1a and the correlation between the bisaminal proton
and the methylene proton in 1a′ were observed.
Similarly, when diazo 3b was treated with 1 mol % of
CuOTf in CH2Cl2, an inseparable mixture of 2b in a 1.3:1
ratio was isolated in 85% yield (Scheme 5). With a cumyl
protecting group on the amido nitrogen in 3b rather than a
benzyl protecting group, a C-C insertion reaction of carbene
on the phenyl ring was totally avoided.
3a in the presence of 1 mol % of CuOTf in CH2Cl2 yielded
the stable cyclopropane intermediate 2a in 58% yield as an
inseparable mixture of diastereoisomers in a 5.5:1 ratio and
the C-C insertion compound 10 as a byproduct in 21% yield.
Reduction of the azide group with NaBH4 in THF, followed
by ring opening of the cyclopropane ring by the in situ
generated amine, provided the pentacyclic substructure 1a
as the major isomer in 81% yield and the minor isomer 1a′
in 10% yield. The kinetic product 1a was then isomerized
completely to its thermodynamically stable isomer 1a′ under
a strong base condition and upon heating. Thus, treatment
of 1a with 2 equiv of NaH in THF at 50 °C gave 1a′ in 92%
yield and 11 in 3% yield. Compound 11 was probably formed
Reduction of 2b with NaBH4 gave the pentacyclic products
1b and 1b′ in 93% yield. Interestingly, upon removing both
Boc and cumyl groups in 1b and 1b′ using 40% of TFA in
CH2Cl2 at room temperature, the thermodynamically stable
isomer 1c was isolated as the sole product in 90% yield.
The stereochemistry of 1c with a trans relationship between
the bisaminal proton and the amido R-proton was confirmed
by an NOEDs experiment. In the NOEDs experiment, the
Org. Lett., Vol. 8, No. 10, 2006
2189

In summary, starting from tryptamine and isatin, we have
developed a biomimetic approach to the pentacyclic sub-
structures 1a′ and 1b′ of perophoramidine and communesin
via an intramolecular cyclopropanation as a key step.
Synthetic effort directed toward the total syntheses of these
indole alkaloids is currently underway.
Scheme 5
Acknowledgment. We thank Professor Martin E. Kue-
hne, Department of Chemistry, University of Vermont, for
helpful discussions. We gratefully acknowledge financial
support from NSFC (No. 20372048), Ministry of Education
(NCET and RFDP), and Sichuan Province Government (No.
04ZQ026-011).
Supporting Information Available: Experimental de-
1
tails, H and 13C NMR spectra of 1-4 and 6-9, DEPT,
COSY, HMBC, HMQC, and NOEDs NMR spectra of 1a′,
1c, and 2a. This material is available free of charge via the
Internet at http://pubs.acs.org.
correlation between the bisaminal proton and the methylene
proton was observed.
OL0607138
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