A short synthesis of camptothecin via a 2-fluoro-1,4-dihydropyridine

Article abstract of DOI:10.1039/b007814j

Addition of the enolate derived from isopropyl α-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 7, followed by oxidation-hydrolysis of the resultant 2-fluoro-1,4-dihydropyridine 8b afforded pyridone 9b, from which 20-deoxycampt

Full text of DOI:10.1039/b007814j

A short synthesis of camptothecin via a 2-fluoro-1,4-dihydropyridine
M.-Llu¨ısa Bennasar,* Cec´ılia Juan and Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain.
E-mail: bennasar@farmacia.far.ub.es
Received (in Liverpool, UK) 19th September 2000, Accepted 1st November 2000
First published as an Advance Article on the web
Addition of the enolate derived from isopropyl
a-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoro-
pyridinium triflate 7, followed by oxidation–hydrolysis of
the resultant 2-fluoro-1,4-dihydropyridine 8b afforded pyr-
idone 9b, from which 20-deoxycamptothecin (11), a known
precursor of camptothecin, was synthesized by a radical
cyclization–desulfurization, with subsequent elaboration of
the lactone E ring by chemoselective reduction.
To test the viability of our proposal for the construction of the
pyridone moiety we first applied the nucleophilic addition–
oxidation sequence to the model N-benzyl-2-fluoropyridinium
salt 2 (Scheme 1). Knowing the reluctance of 2-halopyridines to
undergo alkylation with alkyl halides and tosylates,7 2-fluoro-
pyridinium salt 2 was prepared by alkylation of the correspond-
ing 2-fluoropyridine 18 with benzyl triflate. Without isolation,
pyridinium triflate 2 was allowed to react with the enolate
derived from methyl a-(methylsulfanyl)butyrate, which in
related additions had exhibited better C-4 regioselectivity than
the corresponding unsubstituted butyrate enolate.9 Following
our synthetic plan, the resulting 1,4-dihydropyridine adduct 3
was converted into the desired pyridone 410 by oxidation with
DDQ with hydrolysis of the C–F bond. The overall yield of the
three-step sequence from 2-fluoropyridine 1 was 65%.
The application of the above strategy to the synthesis of
camptothecin required starting from the pyridinium salt 7,
which incorporates the 2-bromoquinolyl-3-methyl fragment
needed for the closure of the five-membered C ring. This salt
was obtained by alkylation of 2-fluoropyridine 1 with triflate 6,
prepared from 2-bromo-3-(iodomethyl)quinoline (5).11 Pyr-
idinium triflate 7 was allowed to react as in the above N-benzyl
series with the enolate derived from methyl a-(methylsulfa-
nyl)butyrate and then with DDQ to provide pyridone 9a in 50%
overall yield from 2-fluoropyridine 1. This pyridone already
incorporates all the carbon atoms of the natural product. As
expected, treatment of 9a with tris(trimethylsilyl)silane–AIBN
brought about both a radical arylation12 and desulfurization to
give the key tetracycle 10a in 65% yield (Scheme 2).
Camptothecin and 20-deoxycamptothecin1 are pentacyclic
alkaloids with a pyrrolo[3,4-b]quinoline nucleus fused to a
2-pyridone ring. First isolated by Wall et al. in 1966 from
Camptotheca acuminata,2 camptothecin has recently
re-emerged as one of the most promising agents for cancer
treatment, topoisomerasa I being identified as the intracellular
target for the drug.3 Due to this interesting cytotoxic activity,
camptothecin and its structural derivatives have been the
objective of many total syntheses using
a variety of
approaches.4,5
The construction of the lactone E ring of camptothecin
required the chemoselective reduction of the conjugate ester
rather than the aliphatic one of 10a. This transformation had
already been reported from the diethyl ester analog 10c by
treatment with DIBAL (no details given).5k However, in our
hands, the sequential treatment of 10a with DIBAL–CH2Cl2 at
270 °C or DIBAL–THF at 240 °C and NaBH4 gave the diol 12
as the only isolable product in 80% yield. Neither were we able
to induce this transformation from diethyl ester 10c, prepared in
We present here a new, concise synthesis of (±)-20-deoxy-
camptothecin, a known synthetic precursor of camptothecin.
Our approach involves the convergent construction of a suitably
substituted and functionalized tetracyclic ABCD derivative 10
and the closure of the lactone E ring at the final synthetic step.
For this purpose, we planned to take advantage of the synthetic
potential of 1,4-dihydropyridines generated by nucleophilic
addition of enolates to N-alkyl-3-acylpyridinium salts. In our
previous work6 these dihydropyridines have been further
elaborated to complex polycyclic indole alkaloids either after
acylation of the unsubstituted enamine moiety or via a
dihydropyridinium cation generated by protonation or inter-
action with an electrophile.
For the synthesis of camptothecin we envisaged that, after the
regioselective addition of a butyric ester enolate (the C18–C21
fragment) to an appropriate N-(quinolylmethyl)-2-fluoropyr-
idinium salt, the intermediate 2-fluoro-1,4-dihydropyridine
could undergo a different transformation, namely an oxidation
with concomitant hydrolysis of the C–F bond, leading to a
4-substituted-2-pyridone. Then, the quinoline and pyridone
rings would be connected following the Comins procedure,5d–f
by radical cyclization taking advantage of a bromine atom
present at the 2-position of the quinoline nucleus. A methoxy-
carbonyl substituent at the b-position of the starting pyridinium
would not only increase the electrophilicity of the pyridine ring
in the nucleophilic attack but would also be subsequently
converted to the C-17 oxymethylene group of the alkaloid.
Scheme 1 Model studies. Reagents and conditions: i, BnOTf, Et2O, rt, 10
min; ii, methyl a-(methylsufanyl)butyrate, LDA, THF, 270 °C, then 240
to 210 °C, 1.5 h; iii, DDQ, 3+1 THF–MeOH, rt, 12 h.
DOI: 10.1039/b007814j
Chem. Commun., 2000, 2459–2460
This journal is © The Royal Society of Chemistry 2000
2459

90% yield by transesterification of 10a (EtOH, KF, reflux, 3
days). Diol 12 was also formed as the major product in 75%
yield.
The above results prompted us to differentiate the two ester
groups as in the pioneering Winterfeldt synthesis of camptothe-
cin from a closely related tetracyclic substrate.13 Thus, we
focused our attention on tetracycle 10b, which was prepared by
reaction of pyridinium triflate 7 with the enolate derived from
isopropyl a-(methylsulfanyl)butyrate, followed by DDQ oxida-
tion (50% overall yield from 1) and subsequent radical
cyclization (65% yield). Gratifyingly, treatment of 10b with
DIBAL–hexanes in DME at 270 °C and then with NaBH4 in
isopropanol afforded a 1+1 mixture of the target lactone 11
(20-deoxycamptothecin)5a and lactol 13 (65% yield), which
were easily separated by column chromatography. The conver-
sion of lactol 13 into 11 (65% yield) has recently been
reported.5n Taking into account that 20-deoxycamptothecin
(11) has previously been converted by hydroxylation at C-20
either to racemic (Me2NH, CuCl2, O2, DMF)5a or natural
[(+)-(20S)]-camptothecin [LHDMS, THF, (+)-(2R,8aS)-(cam-
phorylsulfonyl)oxaziridine],5m the above synthesis constitutes a
formal total synthesis of this natural product.
‘Comissionat per a Universitats i Recerca’ (Generalitat de
Catalunya) for Grant 1999SGR00079 and for a fellowship to
C. J.
Notes and references
1 C. R. Hutchinson, Tetrahedron, 1981, 37, 1047.
2 M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail and
G. A. Sim, J. Am. Chem. Soc., 1966, 88, 3888.
3 Y. Fan, J. N. Weinstein, K. W. Kohn, L. M. Shi and Y. Pommier, J. Med.
Chem., 1998, 41, 2216, and references cited therein.
4 For synthetic references up to 1992, see: J. C. Cai and C. R. Hutchinson,
in Indoles, The Monoterpenoid Indole Alkaloids, ed. J. E. Saxton, in The
Chemistry of Heterocyclic Compounds, ed. A. Weissberger and E. C.
Taylor, Wiley, New York, 1983, vol. 25, part 4, p. 753; M. E. Wall and
M. C. Wani, in Monoterpenoid Indole Alkaloids, ed. J. E. Saxton, in The
Chemistry of Heterocyclic Compounds, ed. E. C. Taylor, Wiley,
Chichester, 1994, vol. 25, suppl. to part 4, p. 689.
5 For recent syntheses of camptothecin, see: (a) W. Shen, G. A. Coburn,
W. G. Bornmann and S. J. Danishefsky, J. Org. Chem., 1993, 58, 611;
(b) A. V. Rama Rao, J. S. Yadav and M. Valluri, Tetrahedron Lett.,
1994, 35, 3613; (c) F. G. Fang, S. Xie and M. W. Lowery, J. Org. Chem.,
1994, 59, 6142; (d) D. L. Comins, H. Hong, J. K. Saha and G. Jianhua,
J. Org. Chem., 1994, 59, 5120; (e) D. L. Comins, H. Hoang and G.
Jianhua, Tetrahedron Lett., 1994, 35, 5331; (f) D. L. Comins and J. K.
Saha, Tetrahedron Lett., 1995, 36, 7995; (g) S. Jew, K. Ok, H. Kim,
M. G. Kim, J. M. Kim, J. M. Hah and Y. Cho, Tetrahedron: Asymmetry,
1995, 6, 1245; (h) J. M. D. Fortunak, J. Kitteringham, A. R. Mastrocola,
M. Mellinger, N. J. Sisti, J. L. Wood and Z.-P. Zhuang, Tetrahedron
Lett., 1996, 37, 5683; (i) N. Murata, T. Sugihara, Y. Kondo and T.
Sakamoto, Synlett, 1997, 298; (j) M. A. Ciufolini and F. Roschangar,
Tetrahedron, 1997, 53, 11049; (k) S. P. Chavan and M. S. Venkatraman,
Tetrahedron Lett., 1998, 39, 6745; (l) H. Josien, S.-B. Ko, D. Bom and
D. P. Curran, Chem. Eur. J., 1998, 4, 67; (m) K. Tagami, N. Nakazawa,
S. Sano and Y. Nagao, Heterocycles, 2000, 53, 771; (n) R. T. Brown, L.
Jianli and C. A. M. Santos, Tetrahedron Lett., 2000, 41, 859.
6 For a review, see J. Bosch and M.-L. Bennasar, Synlett, 1995, 587. For
more recent work, see: M.-L.Bennasar, B. Vidal and J. Bosch, J. Org.
Chem., 1997, 62, 3597; M.-L. Bennasar, J.-M. Jime´nez, B. Vidal, B. A.
Sufi and J. Bosch, J. Org. Chem., 1999, 64, 9605.
The above results significantly expand the methodology for
the synthesis of nitrogen compounds based on the addition of
carbon nucleophiles to N-alkyl-3-acylpyridinium salts as they
open new synthetic possibilities for the subsequent elaboration
of the initially formed 1,4-dihydropyridine adducts.
Financial support from the DGICYT, Spain (project PB94-
0214) is gratefully acknowledged. Thanks are also due to the
7 Y. Ban, R. Sakaguchi and M. Nagai, Chem. Pharm. Bull., 1965, 18, 931;
A. P. Dobbs, K. Jones and K. T. Veal, Tetrahedron Lett., 1997, 38, 5833.
See also J. A. Vega, J. J. Vaquero, J. Alvarez-Builla, J. Exquerra and C.
Hamdouchi, Tetrahedron, 1999, 55, 2317.
8 Prepared from 2-fluoropyridine and ClCO2Me according to the
procedure reported by T. Gu¨ngo¨r, F. Marsais and G. Queguiner,
J. Organomet. Chem., 1981, 215, 139.
9 M.-L. Bennasar, E. Zulaica, C. Juan, L. Llauger and J. Bosch,
Tetrahedron Lett., 1999, 40, 3961.
10 All new compounds were fully characterized by spectroscopic analysis
(NMR) and gave satisfactory HRMS and/or combustion data.
11 Prepared by iodine–bromine exchange of 2-bromo-3-(bromomethyl)-
quinoline D. L. Comins, M. F. Baevsky and H. Hong, J. Am. Chem. Soc.,
1992, 114, 10971.
12 For the radical arylation of 2-pyridones, see R. Nadin and T. Harrison,
Tetrahedron Lett., 1999, 40, 4073. See also reference 5e.
13 E. Winterfeldt, T. Korth, D. Pike and M. Boch, Angew. Chem., Int. Ed.
Engl., 1972, 11, 289; K. Krohn and E. Winterfeldt, Chem. Ber., 1975,
108, 3030.
Scheme 2 Synthesis of (±)-20-deoxycamptothecin. Reagents and condi-
tions: i, AgOTf, CH2Cl2, rt, 45 min; ii, CH2Cl2, rt, 1 h; iii, methyl or
isopropyl a-(methylsufanyl)butyrate, LDA, THF, 270 °C, then 240 to
210 °C, 1.5 h; iv, DDQ, 3+1 THF–MeOH, rt, 12 h; v, TTMSS (2 equiv.),
AIBN, C6H6, reflux, 4 h; vi, DIBAL–hexane (3 equiv.), DME, 270 °C, 30
min, then NaBH4, iPrOH, rt, 1 h.
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