Total synthesis of pareitropone via radical anion coupling

Article abstract of DOI:10.1021/ol1017849

A concise (9-step) synthesis of the tropoloisoquinoline alkaloid pareitropone has been achieved starting from 2-bromoisovanillin. The key step features oxidative cyclization of a readily available phenolic nitronate for the convenient construction of the fused tropone ring. This work underscores the synthetic utility of intramolecular oxidative coupling reactions of phenolic nitronates.

Full text of DOI:10.1021/ol1017849

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3954-3956
Total Synthesis of Pareitropone via
Radical Anion Coupling
Suk-Koo Hong,† Hyeonjeong Kim,† Youngran Seo,† Sang Hyup Lee,‡
Jin Kun Cha,*,§ and Young Gyu Kim*,†
Department of Chemical and Biological Engineering, Seoul National UniVersity,
Seoul, 151-744, Republic of Korea, College of Pharmacy, Duksung Women’s
UniVersity, Seoul, 132-714, Republic of Korea, and Department of Chemistry,
Wayne State UniVersity, Detroit, Michigan 48202
jcha@chem.wayne.edu; ygkim@snu.ac.kr
Received July 30, 2010
ABSTRACT
A concise (9-step) synthesis of the tropoloisoquinoline alkaloid pareitropone has been achieved starting from 2-bromoisovanillin. The key
step features oxidative cyclization of a readily available phenolic nitronate for the convenient construction of the fused tropone ring. This
work underscores the synthetic utility of intramolecular oxidative coupling reactions of phenolic nitronates.
Pareitropone (1), isolated from the roots of Cissampelos pareira
(Menispermaceae), was reported to display the most potent
cytotoxicity (against P388 cells) among a small family of
naturally occurring tropoloisoquinolines.1 These alkaloids are
structurally similar to the mitotic inhibitor colchicine. Although
deceptively simple, they pose considerable synthetic challenges.
Among a small number of total syntheses documented in the
literature,2-4 there has been only one synthesis of 1 by
Feldman, which features an elegant application of alkynyl-
iodonium chemistry.5 Prompted by the scarcity and promis-
ing bioactivity of 1, we report herein its concise synthesis.6
Extension of the [4 + 3] oxyallyl cycloaddition approach
would require furan 2, which differs from a previously
utilized cycloaddition substrate in the substitution pattern,
for the regioselective installation of the tropone (Scheme 1).4c
Instead of developing a new route to 2, we decided to pursue
an alternate approach based on oxidative cyclization of
phenolic nitronates, which had been developed by Kende.7
Kende’s elegant method for preparing fused tropones features
radical anion coupling of 4 and subsequent norcaradiene
rearrangement of the presumed intermediate 3a. This ap-
proach could provide an efficient and scalable route to the
target alkaloid under mild conditions.
† Seoul National University.
‡ Duksung Women’s University.
(5) (a) Feldman, K. S.; Cutarelli, T. D. J. Am. Chem. Soc. 2002, 124,
11600. (b) Feldman, K. S.; Cutarelli, T. D.; Di Florio, R. J. Org. Chem.
2002, 67, 8528.
§ Wayne State University.
(1) Morita, H.; Takeya, K.; Itokawa, H. Bioorg. Med. Chem. Lett. 1995,
5, 597.
(6) Hong, S.-K.; Kim, H.; Seo, Y.; Kim, H.-T.; Kim, G. J.; Lee, S. H.;
Cha, J. K.; Kim, Y. G. Synthetic Studies toward Pareitropone. Abstracts of
Papers, 239th National Meeting of the American Chemical Society, San
Francisco, CA; American Chemical Society: Washington, DC, 2010; ORGN
124.
(2) (a) Banwell, M. G.; Ireland, N. K. J. Chem. Soc., Chem. Commun.
1994, 591. (b) Boger, D. L.; Takahashi, K. J. Am. Chem. Soc. 1995, 117,
12452
(3) For a review of colchicine syntheses: Graening, T.; Schmalz, H.-G.
Angew. Chem., Int. Ed. 2004, 43, 3230
.
.
(7) (a) Kende, A. S.; Koch, K. Tetrahedron Lett. 1986, 27, 6051 Cf. (b)
Leboff, A.; Carbonnelle, A.-C.; Alazard, J.-P.; Thal, C.; Kende, A. S.
Tetrahedron Lett. 1987, 28, 4163. (c) Kende, A. S.; Koch, K.; Smith, C. A.
J. Am. Chem. Soc. 1988, 110, 2210.
(4) (a) Lee, J. C.; Jin, S.-j.; Cha, J. K. J. Org. Chem. 1998, 63, 2804.
(b) Lee, J. C.; Jin, S.; Cha, J. K. Tetrahedron 2000, 56, 10175. (c) Lee,
J. C.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 3243
.
10.1021/ol1017849  2010 American Chemical Society
Published on Web 08/10/2010

the Pomeranz-Fritsch method.2b,4c,11 Thus, reductive ami-
nation of 9 with aminoacetaldehyde dimethylacetal and
subsequent tosylation of 10 delivered the ring-closure
substrate 11 in good yield. Cyclization of 11 by the action
of 2,4-dinitrobenzenesulfonic acid gave the desired isoquino-
line 12 in 68% yield, whereas the use of 6 M HCl produced
the corresponding desilylated phenol. The next task was the
introduction of the requisite nitromethyl group onto the
isoquinoline ring, which proved to be challenging. After
considerable experimentation, an attractive solution was
found in a slight modification of Yadav’s procedure.12
Addition of nitromethane to 12 took place in the presence
of 3-butyn-2-one to yield the Reissert-type adduct 13 in 88%
yield. Desilylation of 13 furnished the phenol 14 to set the
stage for the Kende cyclization.
Scheme 1. Retrosynthetic Analysis
The Kende annulation for the preparation of a fused tropone
was first implemented in model studies (15 f 16 f 17 in
Scheme 3).13,14
Our synthesis began with O-methylation of 58 (97%) to
give known 2-bromoveratraldehyde (7). The Suzuki coupling
of 7 with 89 gave the biaryl adduct 9 in quantitative yield
(Scheme 2).10 The isoquinoline ring was next installed by
Scheme 3. Model Study of Radical Anion Coupling
Scheme 2. Preparation of Cyclization Substrate 14
Similarly, exposure of a solution of 14 in 1 M aqueous
KOH to an excess amount of K3Fe(CN)6 resulted in oxidative
cyclization and concomitant removal of the butenone moiety
to afford the spiro dienone 18 in 76% yield (Scheme 4). With
18 in hand, the final conversion to the tropone only remained.
(8) (a) Commercially available. (b) Prepared from bromination of
isovanillin (6): Herny, T. A.; Sharp, T. M. J. Chem. Soc. 1930, 2279. (c)
Hazlet, S. E.; Brotherton, R. J. J. Org. Chem. 1962, 27, 3253
.
(9) Aitken, D. J.; Faure, S.; Roche, S. Tetrahedron Lett. 2003, 44, 8827
.
(10) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457
.
(11) Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981,
37, 3977
.
(12) Yadav, J. S.; Reddy, B. V. S.; Yadav, N. N.; Gupta, M. K. Synthesis
2009, 7, 1131.
(13) Compound 15 was prepared from 9 by standard methods in good
yield.
(14) Although Kende and Koch employed dilute base (0.01 M KOH),7a
a 1 M KOH solution was used for the generation of the requisite phenolic
nitronate in the present work due to the solubility issue. A complex reaction
mixture was observed when a 0.01 M KOH solution was used for cyclization
of 14.
Org. Lett., Vol. 12, No. 17, 2010
3955

TMSOTf or TMSCl. Additionally, in situ trapping of the
Michael adduct as a silylenol ether (e.g., 3b) would help
drive the reaction toward electrocyclic ring opening rather
than the retro-Michael reaction. Treatment of 18 with an
excess of TMSOTf indeed afforded pareitropone (1) in
excellent (80%) yield.16 The spectral data (1H, 13C NMR,
and UV spectra, along with HRMS) of the final target were
in excellent agreement with those reported in the literature.1,5
Scheme 4. Completion of a Total Synthesis of 1
In conclusion, a concise synthesis of pareitropone (1) has
been achieved from commercially available 2-bromoisovan-
illin in 9 steps and 30% overall yield. The brevity is made
possible by the under-utilized oxidative cyclization of
phenolic nitronates. SAR studies of 1 will be reported in
due course.
Acknowledgment. Y.G.K. would like to thank BK-21
program, Research Center for Energy Conversion and
Storage, Agency for Defense Development, Honam Petro-
chemicals, and Samsung Electronics for financial support.
J.K.C. thanks the National Institutes of Health (GM35956)
for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data (1H NMR, 13C NMR, and HRMS)
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
In marked contrast to clean conversion of 16 to 17, reaction
of 18 with DBU was unsatisfactory and gave only poor (up
to 15%) yields of 1. Other bases, such as triethylamine,
morpholine, N-methylmorpholine, etc., were screened, but
none were effective. We hypothesized that the chief hurdles
arose from the energetically unfavorable cyclopropane
formation due to the high strain present in 19, coupled with
inauspicious competition of norcaradiene rearrangement of
3a with the retro-Michael reaction.15 A possible solution was
devised to promote the conjugate addition by the use of
OL1017849
(15) For a related competition between ring opening and retro-Michael,
see: Iwata, C.; Yamada, M.; Shinoo, Y.; Kobayashi, K.; Okada, H. J. Chem.
Soc., Chem. Commun. 1977, 888.
(16) (a) Interestingly, TMSOTf alone was more effective than the use
of TMSOTf and Et3N. The latter conditions gave 1 in 50% yield. (b)
Subsequent to electrocyclic ring opening of 3b, the loss of “TMSONO”
would be more likely than that of “HONO” in the presence of an excess of
TMSOTf.
3956
Org. Lett., Vol. 12, No. 17, 2010