Concise synthesis of (±)-Rhazinilam through direct coupling

Article abstract of DOI:10.1021/ol052033v

(Chemical Equation Presented) A concise synthesis of rhazinilam through direct, palladium-catalyzed, intramolecular coupling is described.

Full text of DOI:10.1021/ol052033v

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5207-5209
Concise Synthesis of (
through Direct Coupling
±)-Rhazinilam
Alfred L. Bowie, Jr., Chambers C. Hughes, and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
trauner@cchem.berkeley.edu
Received August 23, 2005
ABSTRACT
A concise synthesis of rhazinilam through direct, palladium-catalyzed, intramolecular coupling is described.
Transition-metal-catalyzed cross-couplings have emerged as
one of the most powerful tools in synthesis.1 Common logic
holds that one coupling partner bears a functional group
permitting oxidative addition, whereas the other component
engages in transmetalation, e.g., as a stannane, borate,
organocopper, organomagnesium, or organozinc species.
However, over recent years it has transpired that certain
nucleophilic arenes can engage in cross-couplings without
the need for prior functionalization as an organometallic
species. Although these formal Heck couplings to arenes have
been occasionally described,2 the generality of this concept
has not been widely recognized. With the advent of new
catalysts and the systematic exploration of conditions this
perception has changed, and numerous inter- and intramo-
lecular examples for this reactivity have been recently
reported.3
a few steps. Recently, Fagnou reported an approach to
allocolchicine (6) based on the direct intramolecular coupling
of aryl chloride 4 to afford biphenyl derivative 5.5
We now wish to report an exceptionally concise synthesis
of (()-rhazinilam (Figure 1) that further demonstrates the
synthetic power of direct couplings to nucleophilic (hetero)-
arenes.
Rhazinilam (7)6a,b and its congener rhazinal (8)6c have
attracted considerable attention in both the biological and
synthetic communities.7 Similar to taxol and vincristine,
rhazinilam was found to interfere with tubulin polymerization
dynamics, making it a promising starting point for the
development of anticancer agents.
(3) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Okazawa, T.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286. (c) Sezen, B.; Sames,
D. J. Am. Chem. Soc. 2003, 125, 5274. (d) Glover, B.; Harvey, K. A.; Liu,
B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301. (e) Park,
C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org.
Lett. 2004, 6, 1159. (f) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou,
K. J. Am. Chem. Soc. 2004, 126, 9186.
In 2002, we described the application of “direct” pal-
ladium-catalyzed biaryl coupling in the total synthesis of a
natural product, the IL-8 inhibitor frondosin B (3) (Scheme
1).4 Intramolecular coupling of benzofuranyl triflate 1 gave
tetracycle 2, which was converted to the natural product in
(4) (a) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41,
1569 (erratum: Angew. Chem., Int. Ed. 2002, 41, 2227). (b) Hughes, C.
C.; Trauner, D. Tetrahedron 2004, 60, 9675.
(1) For reviews on this topic, see: (a) Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New
York, 2004. (b) Hassa, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire,
M. Chem. ReV. 2002, 102, 1359.
(2) (a) Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317. (b)
Burwood, M.; Davies, B.; Diaz, I.; Grigg, R.; Molina, P.; Sridharan, V.;
Hughes, M. Tetrahedron Lett. 1995, 36, 9053.
(5) LeBlanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849.
(6) (a) Linde, H. H. A. HelV. Chim. Acta 1965, 48, 1822. (b) Abraham,
D. J.; Rosenstein, R. D.; Lyon, R. L.; Fong, H. H. S. Tetrahedron Lett.
1972, 13, 909. (c) Kam, T.-S.; Tee, Y.-M.; Subramaniam, G. Nat. Prod.
Lett. 1998, 12, 307.
(7) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. Mini-ReV. Org. Chem. 2004,
1, 333.
10.1021/ol052033v CCC: $30.25
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Published on Web 10/14/2005

synthesis of rhazinilam by Smith (Scheme 2).8 A high-
Scheme 1. Direct Couplings in Total Synthesis
Scheme 2. Preparation of Compound 15
yielding nucleophilic substitution of the tosyl group by the
sodium salt of 2-carbomethoxy pyrrole (10) gave N-alkylated
pyrrole 11. Upon treatment with aluminum chloride, 11
underwent intramolecular Friedel-Crafts alkylation to afford
indolizine carboxylic acid 12, bearing the quaternary ste-
reocenter. Coupling of 12 with 2-iodoaniline (13) under
Mukaiyama’s conditions12 afforded amide 14, the X-ray
structure of which is displayed in Supporting Information.
Protection of the amide as a methoxymethyl (MOM) deriva-
tive then gave key intermediate 15.
The stage was now set for the implementation of the direct
coupling (Scheme 3). After extensive screening of ligands
and metal sources, we found the conditions recently described
by Fagnou3f to be superior to all other methods. Heating of
15 with 10 mol % of Buchwald’s “DavePhos” ligand (16)13
and Pd(OAc)2 in the presence of a base resulted in the clean
formation of the strained, nine-membered lactam 19 in 47%
yield. Other conditions gave little or no intended product
and usually resulted in simple deiodination of the aryl ring.
Mechanistically, the key cyclization reaction proceeds
through intramolecular nucleophilic attack of the pyrrole
moiety onto the Pd(II) center in 17, followed by deproto-
nation, as first suggested by Miura.3a Reductive elimination
of Pd(0) from complex 18 then results in formation of the
biaryl bond. The electron-rich ligand 16 may facilitate not
Synthetically, the molecule poses interesting challenges
due to the presence of a strained nine-membered lactam ring
incorporating a biaryl moiety and a quaternary stereocenter.
Following a “classical” synthesis by Smith more than 30
years ago,8 rhazinilam has recently gained prominence as a
playground for the development of new synthetic methodol-
ogy. Sames reported an asymmetric approach based on
intramolecular platinum(II)-mediated C-H activation,9 whereas
Magnus used the conversion of a lactam to a pyrrole via a
thiophenyl imine as a key step.10 The synthesis of rhazinal11a
and biologically active analogues of rhazinilam11b based on
intermolecular Suzuki couplings have also been reported.
Our synthesis starts with the easily accessible, racemic
γ-lactone 9, which was featured before in the first total
(8) Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973,
14, 5179.
(9) Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900.
(10) Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647.
(11) (a) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.;
Hamel, E.; Verdier-Pinard, P. Org. Biomol. Chem. 2003, 1, 296. (b) Dupont,
C.; Gue´nard, D.; Thal, C.; Thoret, S.; Gue´ritte, F. Tetrahedron Lett. 2000,
41, 5853.
(12) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707.
(13) Harris, M. C.; Geis, O.; Buckwald, S. L. J. Org. Chem. 1999, 64,
6019.
Figure 1.
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Org. Lett., Vol. 7, No. 23, 2005

by treatment of 19 with a large excess of boron trichloride
at low temperature.14 This afforded ester 20, which was
identical in all respects to the immediate rhazinilam precursor
obtained in a previous synthesis.9 Accordingly, saponification
of the ester moiety, followed by decarboxylation, gave the
natural product 7 as a racemate.
Scheme 3. Key Coupling and Total Synthesis of Rhazinilam
In conclusion, we have developed a highly efficient
synthesis of rhazinilam that features the formation of a
strained nine-membered ring through intramolecular coupling
to an unactivated pyrrole.15 Future work will focus on the
asymmetric synthesis of 7 and 8 and the development of
ortho-palladation/direct coupling strategies16 for the synthesis
of these natural products and related biologically active
molecules.
Acknowledgment. This work was supported by a Cali-
fornia Cancer Research Coordinating Committee grant
(CRCC 1-D108O5-37849). C.C.H. thanks Roche Biosciences
for a predoctoral fellowship. Financial support by Eli Lilly,
Glaxo Smith Kline, Amgen, Merck, and AstraZeneca is
gratefully acknowledged. We thank Dr. Frederick J. Hol-
lander and Dr. Allen G. Oliver for the crystal structure
determination of compound 14.
only oxidative addition but also the formation of a more
reactive cationic palladium(II) species by dissociation of the
halide.
Importantly, the MOM amide protecting group proved
crucial for the success of this cyclization, since with the free
amide we only observed deiodination. This could be due to
reluctance of the palladium(II) complex 21, which can be
expected to form in the presence of a base, to undergo the
coupling.
The removal of the MOM protecting group, however,
proved to be a considerable challenge, presumably due to
the sensitivity of the pyrrole moiety. After careful optimiza-
tion, we found that this transformation could be achieved
Supporting Information Available: Spectroscopic and
analytical data for compounds 11, 12, 14 (including X-ray;
CCDC 285045), 15, 19, and 20. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL052033V
(14) Nicolaou, K. C.; Chen, David Y.-K.; Huang, X.; Ling, T.; Bella,
M.; Snyder, S. A. J. Am. Chem. Soc. 2004, 126, 12888.
(15) For another recent example of the participation of a pyrrole in
palladium-catalyzed cyclizations, see: Garg, K. N.; Caspi, D. D.; Stoltz,
B. M., J. Am. Chem. Soc. 2004, 126, 9552.
(16) Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046.
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