Synthesis of the parent and substituted tetracyclic ABCD ring cores of camptothecins via 1-(3-aryl-2-propynyl)-1,6-dihydro-6-oxo-2- pyridinecarbonitriles

Article abstract of DOI:10.1021/ol0620242

A new synthetic pathway to the parent and substituted ABCD ring cores of the camptothecin family of alkaloids was developed. The N-alkylation of 1,6-dihydro-6-oxo-2-pyridinecarbonitrile (2) with 3-bromo-1-phenylpropyne provided 3a using Curran's protocol.

Full text of DOI:10.1021/ol0620242

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4665-4667
Synthesis of the Parent and Substituted
Tetracyclic ABCD Ring Cores of
Camptothecins via 1-(3-Aryl-2-propynyl)-
1,6-dihydro-6-oxo-2-pyridinecarbonitriles
Weixiang Dai, Jeffrey L. Petersen,† and Kung K. Wang*
C. Eugene Bennett Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045
kung.wang@mail.wVu.edu
Received August 16, 2006
ABSTRACT
A new synthetic pathway to the parent and substituted ABCD ring cores of the camptothecin family of alkaloids was developed. The N-alkylation
of 1,6-dihydro-6-oxo-2-pyridinecarbonitrile (2) with 3-bromo-1-phenylpropyne provided 3a using Curran’s protocol. Treatment of 3a with a
catalytic amount of DBU (5 mol %) at 110
°C for 12 h produced indolizino[1,2-b]quinolin-9(11H)-one (6a), the parent ABCD ring core of
camptothecin, in essentially quantitative yield.
The potent antitumor activities of the camptothecin family
of alkaloids have stimulated intense interest in developing
synthetic methods for the parent (20S)-camptothecin (1a) and
related analogues.1 Diverse approaches to the assembly of
the pentacyclic ring structure have been reported.1b The
efforts have borne fruits with the approval of topotecan (1b)
by the FDA for the treatment of ovarian cancer and small-
cell lung cancer2 and irinotecan (1c) for refractory colorectal
cancer.3 Several other camptothecin analogues are also in
various stages of clinical trials.
While the lactone E ring of camptothecins is essential in
targeting DNA topoisomerase I,4 the ABCD ring core can
† To whom correspondence concerning the X-ray structures should be
addressed. Phone: (304) 293-3435, ext 6423. Fax: (304) 293-4904.
E-mail: jeffrey.petersen@mail.wvu.edu.
(1) For recent reviews, see: (a) Wall, M. E.; Wani, M. C. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol.
50, pp 509-536. (b) Du, W. Tetrahedron 2003, 59, 8649-8687.
(2) (a) Ormrod, D.; Spencer, C. M. Drugs 1999, 58, 533-551. (b)
Herzog, T. J. Oncologist 2002, 7 (Suppl. 5), 3-10.
(3) Saltz, L. B. In Colorectal Cancer; Saltz, L. B., Ed.; Humana Press,
Inc.: Totowa, 2002; pp 513-524.
be modified with substituents to promote DNA binding.5 We
recently reported the use of a benzannulated enallene-isoni-
trile for the construction of a dimethylamino-substituted AB-
10.1021/ol0620242 CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/07/2006

CD ring core.6 We now report the use of the chemically more
robust nitrile group to replace the chemically labile isonitrile
group in a conjugated system to produce the parent and
substituted ABCD ring cores in a single cascade sequence.
The synthetic sequence involved the N-alkylation of 2,
readily prepared from either 2-bromo- or 2-chloro-6-meth-
oxypyridine,7 with 3-bromo-1-phenylpropyne using Curran’s
protocol8 to produce 1,6-dihydro-6-oxo-(3-phenyl-2-propy-
nyl)-2-pyridinecarbonitrile (3a) in 86% yield (Scheme 1).
reported previously.10 This process was employed in generat-
ing a benzannulated enyne-allene system for subsequent
transformation to an indeno-fused 4H-quinolizin-4-one.10a
However, initial attempts to use potassium tert-butoxide
resulted in complete consumption of 3a but without the
formation of 6a. Exposure of 3a to triethylamine in 1,2-
dichlorobenzene at 120 °C for 27 h produced only a small
quantity of 6a while large portions of 3a remained unreacted.
The success of DBU in catalyzing the reaction may be
attributed to its stronger basicity than that of triethylamine11
but gentler nature than potassium tert-butoxide.
The involvement of the nitrile group in the apparent
intramolecular hetero-Diels-Alder reaction of 4a is worth
mentioning. Unactivated nitriles are known to be very
resistant to the Diels-Alder reactions.12 However, electron-
deficient nitriles, such as p-toluenesulfonyl cyanide and ethyl
cyanoformate, are good dienophiles, capable of undergoing
Diels-Alder reactions at ambient temperature.12 The nitrile
group in 4a is in conjugation with the 2(1H)-pyridone system,
presumably making it more reactive for the Diels-Alder
reaction. The involvement of an allenic moiety as a part of
the diene component may also enhance the propensity for
the Diels-Alder reaction.13
Scheme 1
The use of the intramolecular hetero-Diels-Alder strategy
as an efficient way to construct the BC rings of camptoth-
ecins has previously been demonstrated in a formal synthesis
of camptothecin involving the cycloaddition reaction between
an N-arylimidate and an unactivated alkyne as a key step.14
The intramolecular cycloaddition reaction between an N-
arylimine and an unactivated alkyne has also found success
in the synthesis of a camptothecin precursor.15 In these two
cases, the heteroatom is on the diene component. Our
approach of using a nitrile group for intramolecular cycload-
dition with an arylallenic moiety is unique in that the
heteroatom is on the dienophile.
Treatment of 3a with a catalytic amount of 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU, 5 mol %) in 1,2-dichlorobenzene
at 110 °C for 12 h produced indolizino[1,2-b]quinolin-9-
(11H)-one (6a),7a,9 the parent ABCD ring core of camptoth-
ecin, in essentially quantitative yield. In the absence of DBU,
no reaction occurred and 3a was recovered. With 1 equiv of
DBU, the reaction was complete within 2 h at 120 °C. Pre-
sumably, the transformation from 3a to 6a involved an initial
1,3-prototropic rearrangement to form the corresponding al-
lenic intermediate 4a. A subsequent intramolecular hetero
Diels-Alder reaction to form 5a followed by a second pro-
totropic rearrangement to regain aromaticity then produced
6a.
An alternative mechanism to the concerted Diels-Alder
reaction in producing 5a may involve a stepwise mechanism
with the formation of biradical 7a from 4a followed by an
intramolecular radical-radical coupling to give 5a (eq 1).
The use of a base, such as potassium tert-butoxide or
sodium hydroxide, to promote the acetylene-allene rear-
rangement of N-substituted propargyl amides has been
There are ample precedents in the literature for the analogous
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Med. Chem. 2002, 45, 5809-5812.
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6647-6652. (b) Grigg, R.; Ko¨ppen, I.; Rasparini, M.; Sridharan, V. Chem.
Commun. 2001, 964-965. (c) Grigg, R.; Loganathan, V.; Sridharan, V.;
Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron 1996, 52,
11479-11502.
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Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58-68. (b) Sundermeier,
M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M.
Chem. Eur. J. 2003, 9, 1828-1836.
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I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019-1028.
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8257 and references therein. (b) Li, W.-T.; Lai, F.-C.; Lee, G.-H.; Peng,
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therein.
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(14) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N. J.;
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Org. Lett., Vol. 8, No. 20, 2006

benzannulated enyne-allene system16 and aza-analogues17
to form the corresponding benzofulvene and related biradicals
under thermal conditions. A similar benzannulated enallene-
nitrile case was also reported,18 although other examples
failed to generate biradicals.19 The use of 8 to generate radical
9 for the radical cyclization reactions was found to be
successful in producing 6a (Scheme 2).7a A radical reaction
Table 1. Synthesis of 1-(3-Aryl-2-propynyl)-1,6-dihydro-6-
oxo-2-pyridinecarbonitriles and Indolizino[1,2-b]quinolin-9-
(11H)-ones
Scheme 2
pathway involving phenyl isonitrile and a 2-pyridonyl radical
was also reported for the construction of the ABCD ring
core.20
By using the propargyl bromides having one or two
methoxyl groups on the phenyl substituent at the alkynyl
terminus and again employing Curran’s protocol for the
N-alkylation with 2, four different 2(1H)-pyridones 3b-e
were obtained (Table 1). Treatment of 3b with 1 equiv of
DBU at 120 °C gave the only possible product 6b within 2
h in essentially quantitative yield. A single product 6c7a was
also derived from 3c. Apparently, the Diels-Alder reaction
or the intramolecular radical-radical coupling step did not
involve the ortho carbon bearing the methoxyl group.
However, in the case of 3d, a mixture of the regioisomers
6d and 6d′14 (4:3) was produced. The structure of 6d was
established by X-ray structure analysis. With an o-methoxy
substituent again present in the case of 3e, a single isomer
6e was obtained.
a Quantitative yields.
sequence also allows easy placement of a variety of substit-
uents on the ABCD ring core.
Acknowledgment. The financial support of the National
Science Foundation (CHE-0414063) is gratefully acknowl-
edged. K.K.W. thanks the National Science Council of
Taiwan, the Republic of China, for a grant to support
sabbatical leave in the Department of Chemistry at the
National Taiwan University. J.L.P. acknowledges the support
(CHE-9120098) provided by the National Science Founda-
tion for the acquisition of a Siemens P4 X-ray diffractometer.
The financial support of the NSF-EPSCoR (1002165R) for
the purchase of a 600 MHz NMR spectrometer is also
gratefully acknowledged.
In conclusion, a new synthetic pathway to the parent and
substituted ABCD ring cores of the camptothecin family of
alkaloids was developed. The need to use only DBU to
induce the cyclization process producing essentially quantita-
tive yields of the cyclized adducts under mild thermal
conditions is particularly attractive. The convergent synthetic
(16) (a) Schmittel, M.; Strittmatter, M.; Vollmann, K.; Kiau, S. Tetra-
hedron Lett. 1996, 37, 999-1002. (b) Schmittel, M.; Strittmatter, M.; Kiau,
S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1843-1845. (c) Schmittel, M.;
Vavilala, C. J. Org. Chem. 2005, 70, 4865-4868.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and 1H and/or 13C NMR spectra
of 3-(2,3-dimethoxyphenyl)-2-propyn-1-ol, 3-bromo-1-aryl-
propynes, 3a-e, and 6a-e; ORTEP drawings of the crystal
structures of 3b, 6a, and 6d; and X-ray crystallographic data
of 3b, 6a, and 6d (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Li, H.; Yang, H.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2004,
69, 4500-4508 and references therein.
(18) Wu, M.-J.; Lin, C.-F.; Chen, S.-H.; Lee, F.-C. J. Chem. Soc., Perkin
Trans. 1 1999, 2875-2876.
(19) (a) Wang, K. K.; Wang, Z.; Sattsangi, P. D. J. Org. Chem. 1996,
61, 1516-1518. (b) Gillmann, T.; Heckhoff, S. Tetrahedron Lett. 1996,
37, 839-840.
(20) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron 1996, 52,
11385-11404.
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