Total synthesis of chaetominine

Article abstract of DOI:10.1021/ol802155n

(Figure Presented) An efficient, asymmetric synthesis of the cytotoxic natural product chaetominine was achieved in 14 steps. The strategy employs a copper(I)-mediated cyclization reaction as a key step to install the abc-tricyclic ring system, which was

Full text of DOI:10.1021/ol802155n

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5027-5030
Total Synthesis of Chaetominine
Mathieu Toumi, Franc¸ois Couty, Je´rome Marrot, and Gwilherm Evano*
Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles
Saint-Quentin en YVelines, 45, aVenue des Etats-Unis, 78035 Versailles Cedex, France
eVano@chimie.uVsq.fr
Received September 15, 2008
ABSTRACT
An efficient, asymmetric synthesis of the cytotoxic natural product chaetominine was achieved in 14 steps. The strategy employs a copper(I)-
mediated cyclization reaction as a key step to install the abc-tricyclic ring system, which was further elaborated by diastereoselective oxidation
and reduction reactions. This effort also documents the first example of an oxidative rearrangement yielding to homochiral spirocyclic
pyrrolidinyloxindoles.
(-)-Chaetominine 1 (Figure 1) was isolated in 2006 by Tan
and co-workers from the solid-substrate culture of Chaeto-
showed that chaetominine was highly potent against human
leukemia K562 (21 nM) and colon cancer SW1116 (28 nM)
cell lines with IC50 values smaller than the ones of 5-fluo-
rouracil, which is one of the most frequently prescribed
anticancer drugs.
Due to its intriguing molecular architecture and its potential
as a lead compound for anticancer drugs, chaetominine has
attracted immediate interest from the synthetic community.
This culminated in a total synthesis by the Snider group,3
who smartly adapted their elegant synthesis of related
alkaloids, the fumiquinazolines.4
Herein, we describe an efficient synthesis of (-)-chaeto-
minine as part of our ongoing studies of cyclic peptide
alkaloids and copper-mediated cyclizations.5
Our synthetic plan for the synthesis of (-)-chaetominine
is shown in Scheme 1. We envisioned the exocyclic
quinazolinone would be installed at the end of the synthesis
starting from a phthalimide-protected precursor by using
Figure 1. Structures of (-)-chaetominine and kapakahine B.
mium sp. IFB-E015, an endophytic fungus on apparently
healthy Adenophora axilliflora leaves.1 A unique feature of
this compact modified tripeptide is its strained tetracyclic
framework which is only encountered in seven other
metabolites, the kapakahines.2 In vitro cytotoxic assays
(2) (a) Yeung, B. K. S.; Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida,
W. Y.; Scheuer, P. J.; Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168. (b)
Nakao, Y.; Kuo, J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett.
2003, 5, 1387.
(3) Snider, B. B.; Wu, X. Org. Lett. 2007, 9, 4913.
(4) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545.
(5) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003. (c) Toumi, M.; Couty, F.; Evano, G. Synlett 2008, 29.
(1) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.; Ding, H.; Xu, C.; Zhu,
H. L.; Tan, R. X. Org. Lett. 2006, 8, 5709.
10.1021/ol802155n CCC: $40.75
Published on Web 10/11/2008
2008 American Chemical Society

The synthesis of the precursor for the copper-catalyzed
cyclization (Scheme 2) started with protection of D-tryp-
tophan 6 by reaction with phthalic anhydride in refluxing
pyridine followed by EDC-mediated coupling with alanine
methyl ester. In order to install suitable functionalities for
the cyclization reaction, the indole nitrogen was first
selectively protected as a carbamate using phase-transfer
conditions to give fully protected dipeptide 9. Mercuration
with mercury trifluoroacetate followed by workup with
potassium iodide and reaction with iodine then allowed for
a clean regioselective introduction of the iodide at C2 of the
indole ring and set the stage for the key cyclization step.4,7
As expected, the cyclization proved to be challenging due
to the formation of the six-membered ring, which involves
formation of an intermediate seven-membered ring metal-
lacycle, as well as the known low reactivity of hindered and/
or acyclic secondary amides toward copper-mediated ami-
dation. Selected examples of conditions assayed are shown
in Table 1. After considerable experimentation, we eventually
Scheme 1. Retrosynthetic Analysis of (-)-Chaetominine
Table 1. Optimization of Cyclization Conditions
Snider’s strategy. To access the γ-lactam moiety in 1 together
with the installation of its last stereocenter, we expected that
a diastereoselective reduction of the imine in 3 would
generate an amine that would hopefully react with the ester
to give the corresponding lactam. The hydroxy imine 3 could
be obtained by a substrate-controlled diastereoselective
epoxidation of 4 followed by opening of the epoxide by the
secondary amine. In this synthetic plan, the first key issue
to be adressed is, therefore, the formation of tetrahydropy-
rido[2,3-b]indole 4. Disconnection at the C2-N16 bond
reveals iodo amide 5, where the use of a copper-mediated
cyclization reaction would enable formation of the tricyclic
ring system.6 This precursor 5 would itself be obtained from
D-tryptophan 6 and L-alanine 7. We expected that the use of
a phthalimide protecting group for the exocyclic amine would
allow for good levels of stereoselectivity during the instal-
lation of the oxygenated stereocenter together with masking
the amine that could interfere during the copper-mediated
cyclization.
a No reaction. b Degradation of starting material.
Scheme 2. Synthesis of Cyclization Precursor 5
found that this reaction was best effected using a combination
of copper iodide, trans-N,N′-dimethylcyclohexane-1,2-di-
amine, and potassium phosphate at 110 °C in toluene.8,9
Using these conditions, cyclized compound 10 could be
isolated in 64% yield, without epimerization and along with
(6) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (c)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(d) Evano, G.; Blanchard, N.; Toumi, M. Chem. ReV. 2008, 108, 3054
.
(7) Mingoia, Q. Gazz. Chim. Ital. 1930, 60, 509
.
(8) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421
.
(9) Coste, A.; Toumi, M.; Wright, K.; Razafimahale´o, V.; Couty, F.;
Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841
.
5028
Org. Lett., Vol. 10, No. 21, 2008

Scheme 3. Formation of the Tetracyclic Core
30% of reduced product 9 that could be resubmitted to the
iodination-cyclization sequence (Table 1, entry 5).
While this system turned out to be quite similar to the
one we used for the synthesis of pyrroloindoles starting from
related 2-iodotryptophan derivatives,9 the presence of an
acyclic secondary amide and the formation of a six-
membered ring required the use of a more efficient ligand
in this case. Another striking difference is the proportion of
reduction products which could be minimized for the
formation of a five-membered ring but could not be
completely avoided in this case. This combination, however,
proved to be the most efficient one, and all other ligands,
bases, and solvent systems gave inferior results. Other metals
such as palladium(0)10 (Table 1, entry 6) or iron(III)11 (Table
1, entry 7) proved to be completely inefficient cyclization
promoters.
Having useful quantities of tricyclic precursor 10 in hand,
we next turned our attention to the installation of the two
remaining stereocenters as well as the formation of the
γ-lactam (Scheme 3). To this end, a diastereoselective
epoxidation of 10 was first envisioned. Upon reaction with
DMDO at low temperature in dichloromethane, we were
delighted to note that 10 was smoothly oxidized and
furnished a single compound which we expected to be
epoxide 11. Upon closer inspection, it however turned out
that epoxide 11 was indeed formed within the reaction
mixture but immediately underwent a rearrangement yielding
spirolactam 12 as a single stereoisomer. Its structure and
stereochemistry could be ascertained by X-ray diffraction
after removal of the Cbz protecting group. This unprec-
edented rearrangement probably involves ring opening of the
epoxide and migration of the amide at the benzylic posi-
tion.12,13
Even if the oxidative rearrangement of 10 to spiro-oxindole
12 clearly is a quite interesting transformation, it did seriously
compromise the formation of the tetracyclic ring system of
chaetominine. In order to avoid this rearrangement, we
decided to carry out the oxidation on a deprotected indole.
Indeed, the presence of the secondary amine in 4 allowed
for a clean isomerization of the intermediate amino epoxide
14 to hydroxy imine 3 before the undesired rearrangement
could occur. Simple treatment of 4 with DMDO at -85 °C
for 45 min allowed for the isolation of 94% of hydroxy imine
3 with complete diastereoselectivity. Steric interactions
between the bulky phthalimide and DMDO in the spiro
transition state usually invoked for related oxidations might
account for the high level of diastereoselectivity observed
in this epoxidation.14
Elaboration of the tetracyclic core then proceeded easily
(Scheme 3). Reaction of imine 3 with sodium cyanoboro-
hydride and acetic acid in methanol at room temperature
provided compound 15 as a single diastereoisomer, most
certainly through assistance of the free hydroxyl group.15
This compound, however, proved to be relatively unstable
upon purification on silica gel since it was isolated as a
mixture with a newly formed compound which gratifyingly
turned out to be the γ-lactam 16. Pleased by this most
(10) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525.
(14) (a) Murray, R. W.; Singh, M.; Williams, B. L.; Moncrieff, H. M.
J. Org. Chem. 1996, 61, 1830. (b) Yang, D.; Jiao, G.-S.; Yip, Y.-C.; Wong,
M.-K. J. Org. Chem. 1999, 64, 1635. (c) Ouchi, H.; Mihara, Y.; Takahata,
H. J. Org. Chem. 2005, 70, 5207.
(11) Correa, A.; Elmore, S.; Bolm, C. Chem.sEur. J. 2008, 14, 3527.
(12) For oxidation of indoles with DMDO followed by epoxide opening/
alkyl shift, see: (a) Zhang, X.; Foote, C. S. J. Am. Chem. Soc. 1993, 115,
8867. (b) Adam, W.; Ahrweiler, M.; Peters, K.; Schmiedeskamp, B. J. Org.
Chem. 1994, 59, 2733.
(15) An equilibration of the trans isomer to the more stable cis isomer
through opening of the aminal might also account for the high level of
selectivity observed in this reduction. Basic AM1 calculations (MOPAC)
show a difference in energy of ca. 10 kcal·mol-1 between the two
isomers.
(13) For oxidation with DMDO followed by epoxide opening/oxygen
shift, see: Konno, F.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. J. Org.
Chem. 2006, 71, 9818.
Org. Lett., Vol. 10, No. 21, 2008
5029

encouraging result, we tried to promote this lactamization
by simply stirring the crude product 15 with silica gel in a
mixture of dichloromethane, acetone, and ethanol together
with small amounts of ammonia. Using these conditions, the
desired tetracyclic compound 16, whose stereochemistry was
ascertained by NOESY experiments, could be isolated in
90% yield over the last two steps.
Scheme 4. Completion of the Synthesis of (-)-Chaetominine
To avoid interaction of the free alcohol in 16 during the
final steps of the synthesis, it was protected as a silyl ether
by reaction with TESOTf and 2,6-lutidine in dichlo-
romethane. Deprotection of the phthalimide proved to be an
especially challenging task because of epimerization at the
amino acid stereocenters and opening of the sensitive
γ-lactam.16 After considerable experimentation, it was found
that treatment with hydrazine hydrate in a mixture of THF
and ethanol cleanly cleaved the phthalimide and left the
newly formed γ-lactam intact, affording free amine 17 in
58% overall yield (two steps). This material proved to be
identical in all respects to Snider and Wu’s intermediate.3
Installation of the quinazolinone using their three-step
sequence (reaction with isatoic anhydride and triethyl ortho-
formate followed by TES deprotection) finally provided
synthetic (-)-chaetominine 1 in 54% over the last three steps.
In summary, we have developed an efficient synthesis of
(-)-chaetominine in 14 steps and 10% overall yield starting
from D-tryptophan and L-alanine as building blocks. Notable
features of our synthetic approach include an efficient
copper(I)-mediated cyclization of a sensitive, highly substi-
tuted iodotryptophanylalanine derivative. This effort also
documents the first example of a diastereoselective oxidative
rearrangement yielding highly substituted spirocyclic pyr-
rolidinyloxindoles. This oxidation could be controlled to
access either tetrahydropyrido[2,3-b]indole or spirocyclic
compounds by simply changing the protecting groups. The
convergent approach reported here should be easily applied
to the synthesis of analogues for further biological testing,
which will be reported in due time.
Acknowledgment. We thank the CNRS and the ANR
(project ProteInh) for financial support. M.T. acknowledges
the Ministe`re de la Recherche for a graduate fellowship. We
thank Mr. Vincent Steinmetz (Institut Lavoisier de Versailles)
for his helpful assistance with mass spectrometry analyses.
Supporting Information Available: Experimental pro-
1
cedures, characterization, and copies of H and 13C NMR
spectra for all for all intermediates and chaetominine.
Chaetominine spectral data compared to reported data and
X-ray structure of 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) Snider and Wu noted that the γ-lactam in chaetominine was readily
opened by simple heating in methanol. See ref 3 for details.
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Org. Lett., Vol. 10, No. 21, 2008