Addition of ester enolates to N-alkyl-2-fluoropyridinium salts: Total synthesis of (±)-20-deoxycamptothecin and (+)-camptothecin

Article abstract of DOI:10.1021/jo026173j

Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition of α-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts, respectively. Addition of the enolate derived from isopropyl α-(methylsulfanyl)butyrate to N-(quinolylmethyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which (±)-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative (33) provides access to natural (+)-camptothecin (37).

Full text of DOI:10.1021/jo026173j

Ad d ition of Ester En ola tes to N-Alk yl-2-flu or op yr id in iu m Sa lts:
Tota l Syn th esis of (()-20-Deoxyca m p toth ecin a n d
(+)-Ca m p toth ecin
M.-Llu¨ısa Bennasar,* Ester Zulaica, Cec´ılia J uan, Yolanda Alonso, and J oan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona 08028, Spain
bennasar@farmacia.far.ub.es
Received J uly 10, 2002
Several 4-substituted dihydropyridones or 2-pyridones have been prepared by nucleophilic addition
of R-(methylsulfanyl)ester enolates to N-alkyl-2-fluoropyridinium salts, followed by acid hydrolysis
or oxidation with concomitant hydrolysis, of the intermediate 2-fluoro-1,4-dihydropyridine adducts,
respectively. Addition of the enolate derived from isopropyl R-(methylsulfanyl)butyrate to N-(quinolyl-
methyl)-2-fluoropyridinium triflate 21 followed by DDQ treatment gave pyridone 29, from which
(()-20-deoxycamptothecin (31), a known precursor of camptothecin, was synthesized by a radical
cyclization-desulfurization, with subsequent elaboration of the lactone E ring by chemoselective
reduction. A similar sequence starting from the enolate of a chiral 2-hydroxybutyric acid derivative
(33) provides access to natural (+)-camptothecin (37).
In tr od u ction
that could also be of use in alkaloid synthesis. Our initial
efforts in this field were rewarded when we accomplished
a formal synthesis of the indole alkaloid akagerine.8 We
went on to consider the reaction sequence depicted in
Scheme 1. If the regioselective addition of an appropriate
carbon nucleophile (e.g. an ester enolate) to the 4-position
of the ring could be ensured, the intensive functional-
ization of the initially formed 2-fluoro-1,4-dihydropyri-
dine adducts A might give rapid access to dihydro-2-
pyridones B or 2-pyridones C, which bear an R-(alkoxycar-
bonyl)alkyl substituent at the 4-position, either by hy-
drolysis of the C-F bond9 or oxidation with concomitant
hydrolysis, respectively. Compounds B constitute useful
building blocks as they contain two reactive sites (an
enamide double bond10 and a lactam carbonyl group11)
for further functionalization. On the other hand, 2-pyri-
dones C can be recognized as the ring D of the important
The addition of carbon nucleophiles to pyridinium salts
constitutes a classical approach for the formation of C-C
bonds in the synthesis of nitrogen compounds embodying
a partially or totally reduced pyridine ring.1 Over the past
years, we have been actively studying the reaction of
indole-containing enolates with 3-acyl-N-alkylpyridinium
salts as the initial step of a general and versatile method
for the synthesis of indole alkaloids.2,3 The high reactivity
of the resultant 1,4-dihydropyridine adducts4 has allowed
the straightforward construction of complex polycyclic
structures, either by acylation of the unsubstituted
enamine moiety5 or via a dihydropyridinium cation
generated by protonation6 or interaction with an elec-
trophile.5b,7
We envisaged the use of N-alkyl-2-fluoropyridinium
salts in the above methodology as a complementary and
appealing approach to more functionalized compounds
(5) (a) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem. 1995, 60,
4280-4286. (b) Bennasar, M.-L.; Vidal, B.; Bosch, J . J . Org. Chem.
1997, 62, 3597-3609. (c) Bennasar, M.-L.; Vidal, B.; Kumar, R.; La´zaro,
A.; Bosch, J . Eur. J . Org. Chem. 2000, 3919-3925.
(6) (a) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch,
J . J . Org. Chem. 1990, 55, 1156-1168. (b) Bennasar, M.-L.; Zulaica,
E.; J ime´nez, J .-M.; Bosch, J . J . Org. Chem. 1993, 58, 7756-7767. (c)
Bennasar, M.-L.; Zulaica, E.; Ramı´rez, A.; Bosch, J . J . Org. Chem. 1996,
61, 1239-1251. (d) Bennasar, M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch,
J . Tetrahedron 1999, 55, 3117-3128. (e) Bennasar, M.-L.; Zulaica, E.;
Alonso, Y.; Vidal, B.; Va´zquez, J .-T.; Bosch, J . Tetrahedron: Asymmetry
2002, 13, 95-106.
(7) (a) Bennasar, M.-L.; Vidal. B.; Bosch, J . J . Am. Chem. Soc. 1993,
115, 5340-5341. (b) Bennasar, M.-L.; Vidal. B.; Bosch, J . J . Chem.
Soc., Chem. Commun. 1995, 125-126.
(8) Bennasar, M.-L.; J ime´nez, J .-M.; Vidal, B.; Sufi, B. A.; Bosch, J .
J . Org. Chem. 1999, 64, 9605-9612.
(9) For the hydrolysis of the C-F bond in 2-fluoropyridines, see: (a)
Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.; Mallet,
M.; Godard, A.; Que´guiner, G. J . Org. Chem. 1993, 58, 7832-7838.
(b) Comins, D. L.; Saha, J . K. Tetrahedron Lett. 1995, 36, 7995-7998.
(10) For N-acyliminium chemistry on enamides, see: Hiemstra, H.;
Speckamp, W. N. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 2, pp 1047-1082.
* Address correspondence to this author. Phone: 34 934 024 540.
Fax: 34 934 021 896.
(1) For compilations on this subject, see: (a) Bennasar, M.-L.;
Lavilla, R.; Alvarez, M.; Bosch, J . Heterocycles 1988, 27, 789-824. (b)
Comins, D. L.; J oseph, S. P. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds; Pergamon:
London, UK, 1996; Vol. 5, pp 70-78. (c) Comins, D. L.; J oseph, S. P.
In Advances in Nitrogen Heterocycles; Moody, C. J ., Ed.; J AI Press:
London, UK, 1996; Vol. 2, pp 251-294.
(2) For the pioneering use of this reactivity pattern for the construc-
tion of indoloquinolizidine alkaloids, see: Wenkert, E. Pure Appl.
Chem. 1981, 53, 1271-1276. (b) Wenkert, E.; Angell, E. C.; Drexler,
J .; Moeller, P. D. R.; Pyrek, J . S.; Shi, Y.-J .; Sultana, M.; Vankar, Y.
D. J . Org. Chem. 1986, 51, 2995-3000.
(3) For a review, see: Bosch, J .; Bennasar, M.-L. Synlett 1995, 587-
596.
(4) For reviews on the rich chemistry of dihydropyridines, see: (a)
Eisner, U.; Kuthan, J . Chem. Rev. 1972, 72, 1-42. (b) Stout, D.;
Meyers, A. I. Chem. Rev. 1982, 82, 223-243. (c) Sausins, A.; Duburs,
G. Heterocycles 1988, 27, 291-314. (d) Lavilla, R. J . Chem. Soc., Perkin
Trans. 1 2002, 1141-1156.
10.1021/jo026173j CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/25/2002
J . Org. Chem. 2002, 67, 7465-7474
7465

Bennasar et al.
SCHEME 1. 3-Acyl-2-flu or op yr id in iu m Sa lts:
Syn th etic P ossibilities
SCHEME 2
TABLE 1. Rea ction s of 3-Acetyl-2-flu or op yr id in iu m
pyrroloquinoline alkaloid camptothecin. This paper deals
with our work on N-alkyl-2-fluoropyridinium salts based
on the above concepts, and presents as the most signifi-
cant results the concise total syntheses of (()-20-deoxy-
camptothecin12 and natural (+)-camptothecin.
Sa lts 2 w ith Lith iu m En ola tes Der ived fr om Ester s 3 a n d
4
entry
pyridinium salt
ester
productsa (ratio) yield (%)
1
2
3
4
2a
2a
2b
2b
3
4
3
4
5a + 7a (1:1)
6a + 8a (4:1)
5b + 7b (5:1)
6b
60
55
50
55
Resu lts a n d Discu ssion
a
Epimeric mixtures at the ester R carbon.
Syn th esis of 4-[r-(Meth oxyca r bon yl)a lk yl]d ih y-
d r o-2-p yr id on es. The introduction of functionalized
alkyl groups at the 4-position of a pyridine nucleus has
received considerable attention and different nucleophilic
reagents have been tested.13 In a previous work,14 we
have shown that R-(methylsulfanyl)ester enolates smoothly
undergo addition to 3-acyl-N-alkylpyridinium salts, with
higher chemoselectivity and C-4 regioselectivity than
simple ester enolates.15 With the final aim of reaching
4-substituted dihydro-2-pyridones, we then decided to
study the behavior of sulfanylester enolates toward
3-acetyl-2-fluoropyridinium salts 2a and 2b. These salts
were efficiently prepared by alkylation of 3-acetyl-2-
fluoropyridine (1) with methyl or benzyl triflate16 and
immediately treated with the lithium enolates derived
from esters 3 and 4 (Scheme 2). After column chroma-
tography of the crude reaction products, the expected
2-fluorodihydropyridine adducts 5,6 or 7,8 were obtained
in the ratios and yields listed in Table 1.
As can be observed, the addition of the lithium enolate
derived from acetic ester 3 to N-methylpyridinium triflate
2a was not regioselective, leading to a nearly equimo-
lecular mixture of 1,4- and 1,2-dihydropyridines 5a and
7a in 60% yield (entry 1). More satisfactorily, a 4:1
mixture of dihydropyridines 6a and 8a was obtained in
similar yield (55%, entry 2) when the enolate derived
from butyric ester 4 was used as the nucleophile. On the
other hand, N-benzylpyridinium triflate 2b was a more
convenient electrophilic substrate as it led to the respec-
tive 2-fluoro-1,4-dihydropyridines 5b (from 3, entry 3) or
6b (from 4, entry 4) as the major or even only product.
The regioselectivity of the above reactions seems to
depend on steric factors, the desired C-4 attack being
favored by the bulkiness of both the substituent at the
pyridine nitrogen and the enolate.
(11) For the chemistry of lactam-derived vinyl triflates, see: (a) Foti,
C. J .; Comins, D. L. J . Org. Chem. 1995, 60, 2656-2657. (b) Luker,
T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1997, 62, 8131-
8140. (c) Occhiato, E.; Trabocchi, A.; Guarna, A. J . Org. Chem. 2001,
66, 2459-2465.
(12) For a preliminary communication of this part of the work, see:
Bennasar, M.-L.; J uan, C.; Bosch, J . Chem. Commun. 2000, 2459-
2460.
(13) (a) Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang, M.; Steel, P. J .
Org. Lett. 2001, 3, 2807-2809 and references therein. See also: (b)
Raussou, S.; Gosmini, R.; Mangeney, P.; Alexakis, A.; Commerc¸on, M.
Tetrahedron Lett. 1994, 35, 5433-5436. (c) Yamada, S.; Misono, T.;
Ichikawa, M.; Morita, C. Tetrahedron 2001, 57, 8939-8949. (d) Rudler,
H.; Denise, B.; Parlier, A.; Daran, J .-C. Chem. Commun. 2002, 940-
941.
1
The H NMR spectra of 2-fluoro-1,4-dihydropyridines
5a ,b and 6a ,b showed the typical 1,4-dihydropyridine
1
pattern complicated by the H-19F coupling (see Experi-
mental Section). As expected, 5a and 5b were easily
transformed into the respective methyl (2-oxo-1,2,3,4-
tetrahydro-4-pyridyl)acetates 9a and 9b by acid hydroly-
sis of the C-F bond with 1 N HCl, followed by desulfu-
rization with n-Bu3SnH-AIBN. The overall yield of both
transformations was satisfactory (75-80%, Scheme 3).
Similarly, dihydropyridones 10a and 10b were obtained
in good yield by acid hydrolysis of 6a and 6b, respectively
(Scheme 3).
(14) Bennasar, M.-L.; Zulaica, E.; J uan, C.; Llauger, L.; Bosch, J .
Tetrahedron Lett. 1999, 40, 3961-3964.
(15) For the addition of these nucleophiles to N-alkylpyridinium
salts followed by acid-induced cyclization on the indole nucleus, see:
Spitzner, D.; Zaubitzer, T.; Shi, Y. J .; Wenkert, E. J . Org. Chem. 1988,
53, 2274-2278. See also ref 2b.
We assigned the most stable trans relative configura-
tion to 9a ,b and 10a ,b after inspecting their 1H NMR
spectra. It is worth mentioning that these â-dicarbonyl
compounds showed a different tautomeric behavior. Thus,
whereas 9a ,b appeared as a 2:1 mixture of keto and enol
forms, the latter with the enol double bond presumably
(16) Alkylation of 2-halopyridines with alkyl halides and tosylates
a difficult process: (a) Dobbs, A. P.; J ones, K.; Veal, K. T.
is
Tetrahedron Lett. 1997, 38, 5383-5386. (b) Vega, J . A.; Vaquero, J .
J .; Alvarez-Builla, J .; Ezquerra, J .; Hamdouchi, C. Tetrahedron 1999,
55, 2317-2326.
7466 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (()-20-Deoxycamptothecin and (+)-Camptothecin
SCHEME 3a
SCHEME 4. Syn th etic Ap p r oa ch to
Ca m p toth ecin s
a
Key: (a) 1 N HCl, THF, rt, 3 h; (b) n-Bu3SnH-AIBN, C6H6,
reflux, 2 h.
in a Z configuration, 10a ,b were exclusively in the keto
form. It seems reasonable to assume that the predomi-
nance of the keto form increases with the size of the
substituent at the 4-position of the ring, due to A1,3
strain in the enol form with the methyl group at the sp2
carbon.
Syn th esis of Ca m p toth ecin s. Camptothecin and 20-
deoxycamptothecin17 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 Camp-
totheca acuminata,18 camptothecin is an important lead
compound among the anticancer natural products, the
identified intracellular target for the drug being topo-
isomerase I.19 This interesting cytotoxic activity has made
camptothecin and its structural derivatives attractive
objectives for chemical synthesis.20,21
olylmethyl)-2-fluoropyridinium salt and the closure of the
lactone E ring at the final synthetic step (Scheme 4).
Thus, the regioselective addition of the enolate of a
butyric acid derivative (the C18-C21 fragment) to this
2-fluoropyridinium salt, followed by oxidation of the
intermediate 2-fluoro-1,4-dihydropyridine with concomi-
tant hydrolysis of the C-F bond, would lead to a
4-substituted-2-pyridone. Then, the quinoline and pyri-
done rings would be connected by a radical cyclization
taking advantage of a bromine atom present at the
2-position of the quinoline nucleus (Comins pro-
cedure).9b,21d,e,n The one-carbon substituent (Y) at the
â-position of the starting pyridinium salt would be
subsequently converted to the C-17 oxymethylene group
of the alkaloid.
To test the feasibility of our proposal for the construc-
tion of the 2-pyridone moiety we undertook a brief study
of the nucleophilic addition-2-fluorodihydropyridine oxi-
dation sequence starting from model N-benzyl-2-fluoro-
pyridinium salts 12, which bear a variety of one-carbon
substituents at the â-position (Scheme 5, Table 2). The
good C-4 regioselectivity exhibited by R-(methylsulfanyl)-
butyrate 4 toward 2-fluoropyridinium salts 1 made its
use in this sequence particularly attractive. As in the
above 3-acetyl series, 2-fluoropyridinium salts 12 were
easily prepared by benzyl triflate alkylation of the
respective pyridines 11, which, with the exception of
commercially available 11c, were obtained by ortho-
lithiation of 2-fluoropyridine followed by reaction with a
suitable electrophile.22
Our approach to camptothecins is based on the con-
vergent construction of a suitably substituted and func-
tionalized tetracyclic ABCD derivative from an N-(quin-
(17) Hutchinson, C. R. Tetrahedron 1981, 37, 1047-1065.
(18) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail,
A. T.; Sim, G. A. J . Am. Chem. Soc. 1966, 88, 3888-3890.
(19) Fan, Y.; Weinstein, J . N.; Kohn, K. W.; Shi, L. M.; Pommier, Y.
J . Med. Chem. 1998, 41, 2216-2226 and references therein.
(20) For synthetic references up to 1992, see: (a) Cai, J . C.;
Hutchinson In Indoles, The Monoterpenoid Indole Alkaloids; Saxton,
J . E., Ed. In The Chemistry of Heterocyclic Compounds; Weissberger,
A., Taylor, E. C., Eds.; Wiley: New York, 1983; Vol. 25, Part 4, pp
753-781. (b) Wall, M. E.; Wani, M. C. In Monoterpenoid Indole
Alkaloids; Saxton, J . E., Ed. In The Chemistry of Heterocyclic Com-
pounds; Taylor, E. C., Ed.; Wiley: Chichester, UK, 1994; Vol. 25,
Supplement to Part 4, pp 689-713.
(21) For more recent syntheses of camptothecin, see: (a) Shen, W.;
Coburn, G. A.; Bornmann, W. G.; Danishefsky, S. J . J . Org. Chem.
1993, 58, 611-617. (b) Rama Rao, A. V.; Yadav, J . S.; Valluri, M.
Tetrahedron Lett. 1994, 35, 3613-3616. (c) Fang, F. G.; Xie, S.; Lowery,
M. W. J . Org. Chem. 1994, 59, 6142-6143. (d) Comins, D. L.; Hong,
H.; Saha, J . K.; J ianhua, G. J . Org. Chem. 1994, 59, 5120-5121. (e)
Comins, D. L.; Hoang, H.; J ianhua, G. Tetrahedron Lett. 1994, 35,
5331-5334. (f) J ew, S.; Ok, K.; Kim, H.; Kim, M. G.; Kim, J . M.; Hah,
J . M.; Cho, Y. Tetrahedron: Asymmetry 1995, 6, 1245-1248. (g)
Fortunak, J . M. D.; Kitteringham, J .; Mastrocola, A. R.; Mellinger, M.;
Sisti, N. J .; Wood, J . L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37,
5683-5686. (h) Murata, N.; Sugihara, T.; Kondo, Y.; Sakamoto, T.
Synlett 1997, 298-300. (i) Ciufolini, M. A.; Roschangar, F. Tetrahedron
1997, 53, 11049-11060. (j) Chavan, S. P.; Venkatraman, M. S.
Tetrahedron Lett. 1998, 39, 6745-6748. (k) J osien, H.; Ko, S.-B.; Bom,
D.; Curran, D. P. Chem. Eur. J . 1998, 4, 67-83. (l) Tagami, K.;
Nakazawa, N.; Sano, S.; Nagao, Y. Heterocycles 2000, 53, 771-775.
(m) Brown, R. T.; J ianli, L.; Santos, C. A. M. Tetrahedron Lett. 2000,
41, 859-862. (n) Comins, D. L.; Nolan, J . M. Org. Lett. 2001, 3, 4255-
4257. (o) Yabu, K.; Masumoto, S.; Kanai, M.; Curran, D. P.; Shibasaki,
M. Tetrahedron Lett. 2002, 43, 2923-2926.
We first focused our attention on 2-fluoropyridinium
triflates 12a and 12b, whose substitution pattern would
allow access to the C-17 oxymethylene group of camp-
tothecin by reduction. Satisfactorily, only the desired C-4
adduct 14a (mixture of epimers) was isolated from the
reaction of ester 4 with 2-fluoro-3-(methoxycarbonyl)-
pyridinium triflate 12a (entry 1). In contrast, only trace
amounts of 1,4-dihydropyridine 14b were obtained from
3-formylpyridinium triflate 12b (entry 2), probably due
(22) For a recent review on the ortho-metalation of pyridines and
quinolines, see: Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57,
4059-4090.
J . Org. Chem, Vol. 67, No. 21, 2002 7467

Bennasar et al.
SCHEME 5. Mod el Stu d ies
SCHEME 6. Con str u ction of th e
P yr r olo[3,4-b]qu in olin e System a
a
Key: (a) AgOTf, CH2Cl2, rt, 30 min; (b) CH2Cl2, rt, 30 min; (c)
ester 4, LDA, THF, -78 °C, then -30 °C, 1.5 h; (d) DDQ, THF-
MeOH, rt, 4 h; (e) TTMSS (2 equiv), AIBN, C6H6, reflux, 4 h.
The application of the above strategy to the construc-
tion of the pyrrolo[3,4-b]quinoline system of campto-
thecins required starting from pyridinium salts 21 or 22,
which incorporate the 2-bromo-3-quinolylmethyl frag-
ment needed for the closure of the five-membered C ring.
These salts were obtained by alkylation of 2-fluoropy-
ridines 11a or 11c with triflate 20, prepared from
2-bromo-3-(iodomethyl)quinoline (19). The resulting py-
ridinium triflates 21 and 22 were allowed to react as in
the above N-benzyl series with the enolate derived from
methyl ester 4 and then with DDQ to provide pyridones
23 and 24 in 50% and 30% overall yield from 11a and
11c, respectively. Our first attempts to assemble the
desired tetracyclic system by radical cyclization using the
n-Bu3SnH-AIBN conditions reported by Comins21e re-
sulted in premature reductive dehalogenation. However,
satisfactorily, treatment of 23 and 24 with the poorer
hydrogen atom donor tris(trimethylsilyl)silane (TTMSS)23-
AIBN brought about both a radical arylation24 and
desulfurization to give the key tetracycles 25 and 26 in
70% and 65% yield (Scheme 6).
Completion of the pentacyclic system of camptothecin
from diester 25 required the seemingly simple task of
chemoselectively reducing the conjugate rather than the
aliphatic ester so that lactonization to 20-deoxycamp-
tothecin could occur. This reductive route had already
been reported from the diethyl ester analogue 27 by
treatment with DIBAL (no details given).21j However, in
our hands, the sequential treatment of 25 with DIBAL-
CH2Cl2 at -78 °C or DIBAL-THF at -40 °C and NaBH4
gave diol 28 as the only isolable product in 80% yield
(Scheme 7). Neither were we able to induce this trans-
formation from diethyl ester 27, prepared in 90% yield
by transesterification of 25. Diol 28 was also formed as
the major product in 75% yield.
TABLE 2. Rea ction s of 2-F lu or op yr id in iu m Sa lts 12a -e
w ith Lith iu m En ola tes Der ived fr om 4 a n d 13 F ollow ed
by Oxid a tion
pyridinium Li-enolate
pyridone
entry
salt
derived from
adduct
14a
14b (trace)
(overall yield, %)a
1
2
3
12a
12b
12a
4
4
13
16a (65)
15a + 18a 17a (50)
(4:1)
4
5
6
12c
12d
12e
4
4
4
14c
16c (30)
complex mixtures
complex mixtures
a
From the corresponding pyridine 11.
to the low chemoselectivity of the nucleophilic addition.
As expected, treatment of 14a with DDQ in THF-MeOH
resulted in oxidation with concomitant hydrolysis of the
C-F bond to give pyridone 16a in 65% overall yield from
2-fluoropyridine 11a .
We also considered using the enolate derived from
R-(methylsulfanyl)butyramide 13 in order to subse-
quently reach 2-pyridones with a different functional-
ization for the lactonization step. As can be observed in
entry 3, its reaction with 2-fluoropyridinium salt 12a was
less regioselective, leading to a 4:1 mixture of C-4 and
C-6 adducts, 15a and 18a . DDQ treatment of 15a gave
pyridone 17a in 50% overall yield from 11a .
The behavior of pyridinium triflates 12c-e, lacking the
characteristic â-acyl substituent, was also investigated.
We were pleased to observe that 2-fluoro-3-methylpyri-
dinium triflate 12c was electrophilic enough to partici-
pate in the addition-oxidation sequence with ester 4 to
give pyridone 16c (through 14c, not isolated) in 30%
overall yield from 11c. Unfortunately, we were not able
to extend the chemistry outlined above to pyridinium
triflates 12d or 12e, which carry protected hydroxy-
methyl groups with the same oxidation level as C-17 of
camptothecin.
Given the difficulties encountered in the chemoselec-
tive reduction of tetracycles 25 or 27, we decided to tackle
(23) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
(24) For the radical arylation of 2-pyridones, see: (a) Nadin, R.;
Harrison, T. Tetrahedron Lett. 1999, 40, 4073-4076. (b) Orito, K.;
Satoh, Y.; Nishizawa, H.; Harada, R.; Tokuda, M. Org. Lett. 2000, 2,
2535-2537. (c) See also ref 21e.
7468 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (()-20-Deoxycamptothecin and (+)-Camptothecin
SCHEME 7a
SCHEME 9. Syn th esis of (+)-Ca m p toth ecin a
a
Reagents and conditions: (a) KF, EtOH, reflux, 40 h; (b)
DIBAL-CH2Cl2, CH2Cl2, -78 °C or DIBAL-THF, THF, -40 °C,
then NaBH4.
SCHEME 8. Syn th esis of
(()-20-Deoxyca m p toth ecin a
a
Key: (a) LDA, THF, -78 °C, 30 min; (b) 21, -30 °C, 1.5 h; (c)
DDQ, 2:1 THF-MeOH, rt, 4 h; (d) TTMSS (2 equiv), AIBN, C6H6,
reflux, 4 h; (e) DIBAL-CH2Cl2, -78 to -30 °C, 45 min; (f) DIBAL-
CH2Cl2, -78 °C, 30 min; (g) I2, CaCO3, 10:1 MeOH-H2O, rt, 4
days.
synthesis reported here constitutes a formal synthesis
of this natural product.
The success of the above synthesis motivated us to
pursue a more ambitious goal, the total synthesis of
natural (+)-camptothecin, taking advantage of the same
methodology but using the enolate of a chiral 2-hydroxy-
butyric acid derivative in the nucleophilic addition step
to the 2-fluoropyridinium ring.26
The enolate of (2R,5R)-2-tert-butyl-5-ethyl-1,3-diox-
olan-4-one (33),27 derived from (R)-2-hydroxybutyric acid,
was the nucleophile of choice as it had proven to react
with electrophiles (allyl bromide27 and an R,â-unsatur-
ated diester21g) in a highly diastereoselective manner
from the opposite side to the tert-butyl group. We
expected that this enolate would react in the same way
with 2-fluoropyridinium salt 21 to give, after the oxida-
tion step, a 2-pyridone incorporating the stereogenic
center with the desired configuration (20S). The remain-
der of the synthesis would closely parallel the racemic
synthesis, the hydroxyacid moiety28 being reestablished
at the final lactonization step (Scheme 9).21g
a
Key: (a) isopropyl R-(methylsulfanyl)butyrate, LDA, THF, -78
°C, then -30 °C, 1.5 h; (b) DDQ, 2:1 THF-MeOH, rt, 12 h; (c)
TTMSS (2 equiv), AIBN, C6H6, reflux, 4 h; (d) DIBAL-hexane (3
equiv), DME, -70 °C, 15 min, then NaBH4, iPrOH, rt, 30 min.
the problem by differentiating the two ester groups as
in the pioneering Winterfeldt synthesis of camptothecin
from a closely related tetracyclic substrate.25 Thus, we
turned our attention to tetracycle 30 (Scheme 8), which
was prepared by reaction of pyridinium triflate 21 with
the enolate derived from isopropyl R-(methylsulfanyl)-
butyrate, followed by DDQ oxidation (50% overall yield
from 11a ) and subsequent radical cyclization (70% yield).
Gratifyingly, treatment of 30 with DIBAL-hexanes in
DME at -70 °C and then with NaBH4 in 2-propanol
afforded a 1:1 mixture of the target lactone 31 (20-
deoxycamptothecin) and lactol 32 (65% yield), which were
easily separated by column chromatography. The conver-
sion of lactol 32 into 31 (65% yield) by PCC treatment
has recently been reported.21m NMR data of synthetic 31
were identical with those described for this product.21a
Considering that (()-20-deoxycamptothecin (31) has
previously been converted by hydroxylation at C-20 to
either racemic21a,25 or natural (+)-camptothecin21l the
We were pleased to find that the addition of the lithium
enolate of 33 to 2-fluoropyridinium triflate 21 followed
by DDQ oxidation gave pyridone 34 as a single diaste-
reomer (NMR), whose configuration at the C-5 of the
dioxolanone ring was tentatively assigned as S taking
into account the above precedents. The overall yield of
(26) For the use of chiral nucleophiles toward N-alkyl-3-acylpyri-
dinium salts, see: (a) Amann, R.; Arnold, K.; Spitzner, D.; Majer, Z.;
Snatzke, G. Liebigs Ann. 1996, 349-355. (b) See also ref 6e.
(27) Krohn, K.; Hamann, I. Liebigs Ann. 1988, 949-953.
(28) For the development of this concept (“self-reproduction of
chirality”), see: Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984,
40, 1313-1324.
(25) (a) Winterfeldt, E.; Korth, T.; Pike, D.; Boch, M. Angew. Chem.,
Int. Ed. 1972, 11, 289-290. (b) Krohn, K.; Winterfeldt, E. Chem. Ber.
1975, 108, 3030-3042.
J . Org. Chem, Vol. 67, No. 21, 2002 7469

Bennasar et al.
was carried out on SiO2 (silica gel 60, SDS, 0.04-0.06 mm).
Melting points are uncorrected. Unless otherwise indicated,
NMR spectra were recorded in CDCl3 solution at 300 (1H) or
75.4 MHz (13C), using TMS as internal reference. Microanaly-
ses and HRMS were performed by Centro de Investigacio´n y
Desarrollo (CSIC), Barcelona.
3-Acetyl-2-flu or o-1-m eth ylp yr id in iu m Tr iflu or om eth -
a n esu lfon a te (2a ). CF3SO2Me (0.27 mL, 2.5 mmol) was added
to 3-acetyl-2-fluoropyridine (1)30 (0.23 g, 1.65 mmol) at room
temperature under Ar. The resulting mixture was diluted with
dry CH2Cl2 (3 mL) and stirred at room temperature for 10 min.
The white precipitate was filtered and washed with anhydrous
Et2O to give pyridinium triflate 2a , which was immediately
used in the next reaction.
3-Acetyl-1-ben zyl-2-flu or op yr id in iu m Tr iflu or om eth -
a n esu lfon a te (2b). Benzyl bromide (0.26 mL, 2.16 mmol) was
added to a suspension of CF3SO2Ag (0.55 g, 2.16 mmol) in dry
Et2O (2 mL) at room temperature under Ar. A yellow-green
precipitate (AgBr) was formed. The reaction mixture was
filtered over pyridine 1 (0.2 g, 1.44 mmol) and the resulting
suspension was stirred at room temperature for 10 min. The
solvent was removed under an Ar stream to give a white gum,
which was immediately used in the next reaction.
this key transformation was lower (20% from 11a ) than
that observed in the above racemic series. Some varia-
tions of the reaction conditions (temperature, time, base)
were examined, but they did not significantly alter the
yield. Nevertheless, we went on with the next step of the
synthesis, i.e., the intramolecular arylation of 34. This
was accomplished by treatment with TTMSS-AIBN,
providing the desired tetracycle 35 in 65% yield.
The remaining challenge at this point was to find the
right conditions for the lactonization step, which would
now involve the chemoselective reduction of the conju-
gated methoxycarbonyl rather than the dioxolanone
carbonyl group to give a hydroxymethyl derivative, and
the subsequent intramolecular transesterification with
loss of pivalaldehyde. In fact, we did not expect many
difficulties since it had been reported that the sequential
treatment of the 10-methoxy derivative of 35 with DIBAL
in CH2Cl2 (no conditions given), NaBH4, and aqueous
NaOH produced (S)-10-methoxycamptothecin in 70%
yield.21g To our surprise, when tetracycle 35 was treated
with DIBAL in CH2Cl2 at -78 °C for 30 min and then
with NaBH4 we cleanly obtained a single product (65%
yield), which was identified as hexacycle 38 after a
careful inspection of the mono- and bidimensional (HSQC
and HMBC) NMR spectra. The formation of hexacycle
38 was striking as it involved the initial reduction of the
lactone carbonyl group and the subsequent relactoniza-
tion of the initially formed lactol with the intact meth-
oxycarbonyl group.
However, R-hydroxylactol 36, a dihydroderivative of
camptothecin, was the main product (45%) when the
reduction of 35 with DIBAL in CH2Cl2 was effected at a
higher temperature (-30 °C). Lactol 36 was also obtained
when hexacycle 38 was subjected to similar reduction
conditions, thus confirming that the latter was an
intermediate in the transformation of 35 to 36. The
formation of 36 must therefore involve the double reduc-
tion of the C-17 carbonyl group, followed by hemiacetal-
ization with loss of pivalaldehyde. Finally, as expected,
R-hydroxylactol 36 could be converted in 60% yield into
(+)-camptothecin (37) by oxidation with iodine in the
presence of CaCO3.29 Our synthetic (+)-camptothecin,
[R]22D +25 (c 0.2, 4:1 CHCl3-MeOH) (lit.18 [R]22D +31 (4:1
CHCl3-MeOH)), showed NMR spectra and chromato-
graphic behavior identical with an authentic material.
In summary, we have shown that the nucleophilic
addition of ester enolates to 2-fluoropyridinium salts
followed by suitable manipulation of the resultant 2-fluoro-
1,4-dihydropyridine adducts provides a rapid synthetic
entry to highly functionalized and substituted dihydro-
2-pyridones or 2-pyridones. The effectiveness of the
strategy is illustrated in the concise total synthesis of
(()-camptothecin and natural (+)-camptothecin.
Rea ction of P yr id in iu m Tr ifla te 2a w ith th e En ola te
Der ived fr om 3. LDA 1.5 M in cyclohexane (1.33 mL, 2 mmol)
was added under Ar to a solution of acetate 3 (0.22 mL, 2
mmol) in THF (15 mL) cooled at -78 °C, and the resulting
mixture was stirred at -78 °C for 30 min. A suspension of
pyridinium triflate 2a (prepared from 1.65 mmol of 1) in THF
(5 mL) was added, and the mixture was stirred at -30 °C for
1.5 h. The reaction mixture was poured into H2O and extracted
with Et2O. The organic extracts were concentrated and the
resulting residue was chromatographed (7:3 hexanes-AcOEt)
to give a 1:1 mixture of fluorodihydropyridines 5a and 7a (270
mg, 60%). An additional chromatograph (CH2Cl2) allowed the
isolation of pure m eth yl 3-a cetyl-2-flu or o-1-m eth yl-r-(m e-
th ylsu lfa n yl)-1,4-d ih yd r op yr id in e-4-a ceta te (5a , epimeric
1
mixture). Less polar epimer: mp 95 °C (Et2O-hexanes); H
NMR δ 2.14 (s, 3H), 2.36 (d, J ) 7.3 Hz, 3H), 3.09 (d, J ) 2.5
Hz, 3H), 3.45 (d, J ) 3 Hz, 1H), 3.74 (s, 3H), 4.32 (ddd, J )
5.4, 3, 1.6 Hz, 1H), 5.10 (ddd, J ) 7.6, 5.4, 1.8 Hz, 1H), 5.88
(dd, J ) 7.6, 5 Hz, 1H); 13C NMR δ 16.2 (CH3), 30.7 (CH3),
34.3 (CH3), 37.4 (CH), 52.0 (CH3), 55.1 (CH), 90.5 (C), 105.8
(CH), 129.9 (CH), 161.2 (C, J ) 262.5 Hz), 172.4 (C), 193.0
(C). Anal. Calcd for C12H16FNSO3‚1/4H2O: C, 51.88; H, 5.98;
N, 5.04. Found: C, 51.66; H, 6.30; N, 5.10.
Rea ction of P yr id in iu m Tr ifla te 2a w ith th e En ola te
Der ived fr om 4. Operating as above, from pyridinium triflate
2a (prepared from 1.65 mmol of 1) and ester 4 (0.36 mL, 2.5
mmol) a 4:1 mixture of fluorodihydropyridines 6a and 8a (273
mg, 55%) was obtained. An additional column chromatograph
(CH2Cl2) allowed the isolation of pure m eth yl 3-a cetyl-r-
eth yl-2-flu or o-1-m eth yl-r-(m eth ylsu lfa n yl)-1,4-d ih yd r o-
p yr id in e-4-a ceta te (6a , 3:2 epimeric mixture): 1H NMR δ
0.90 and 0.92 (2t, J ) 7.3 Hz, 3H), 1.50, 1.65, 1.85, and 2.03
(4m, 2H), 2.04 and 2.17 (2s, 3H), 2.36 and 2.40 (2d, J ) 7.3
Hz, 3H), 3.11 and 3.13 (2d, J ) 2.4 Hz, 3H), 3.64 and 3.68 (2s,
3H), 4.27 and 4.35 (dd, J ) 8.7 or 8.3, 6.1 Hz, 1H), 5.07 and
5.31 (ddd, J ) 8.3 or 8.7, 7.3, 1.8 Hz, 1H), 5.91 and 6.00 (2dd,
J ) 7.3, 4.3 Hz, 1H); 13C NMR δ 9.1, 9.5 (CH3), 11.3, 13.0 (CH3),
23.6, 24.5 (CH2), 30.5, 30.6 (CH3), 34.1, 34.2 (CH3), 39.8, 40.1
(CH), 51.9, 52.3 (CH3), 63.0, 66.3 (C), 90.1, 90.5 (C), 105.5,
106.9 (CH), 129.3, 130.1 (CH), 159.5, 160.0 (J ) 270 Hz, C),
172.5, 172.8 (C), 193.6, 193.8 (C). Anal. Calcd for C14H20FNSO3‚
3/2H2O: C, 53.65; H, 6.86; N, 4.47. Found: C, 53.52; H, 6.93;
N, 4.79.
Exp er im en ta l Section
Gen er a l P r oced u r es. Reactions courses and product mix-
tures were routinely monitored by TLC on silica gel (precoated
F254 Merck plates). Drying of organic extracts during the
workup of reactions was performed over anhydrous Na2SO4.
Evaporation of the solvents was accomplished under reduced
pressure with a rotatory evaporator. Flash chromatography
Rea ction of P yr id in iu m Tr ifla te 2b w ith th e En ola te
Der ived fr om 3. Operating as above, from pyridinium triflate
2b (prepared from 1.44 mmol of 1) and acetate 3 (0.19 mL,
(29) For similar transformations on tetracyclic DE substructures of
camptothecin, see refs 21c and 21k.
(30) Gu¨ngo¨r, T.; Marsais, F.; Queguiner, G. J . Organomet. Chem.
1981, 215, 139-150.
7470 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (()-20-Deoxycamptothecin and (+)-Camptothecin
1.73 mmol) a 5:1 mixture of fluorodihydropyridines 5b and 7b
(251 mg, 50%) was obtained. An additional column chromato-
graph (1:9 hexanes-CH2Cl2) allowed the isolation of pure
m eth yl 3-a cetyl-1-ben zyl-2-flu or o-r-(m eth ylsu lfa n yl)-1,4-
d ih yd r op yr id in e-4-a ceta te (5b, 4:3 mixture of epimers): 1H
NMR δ 2.09 and 2.12 (2s, 3H), 2.36 and 2.38 (d, J ) 7.4 or 7.1
Hz, 3H), 3.29 and 3.48 (d, J ) 6.3 or 3 Hz, 1H), 3.60 and 3.73
(2s, 3H), 4.19 and 4.34 (2m, 2H), 4.53 and 4.60 (2d, J ) 15.7
Hz, 2H), 5.14 (m, 1H), 5.95 (m, 1H), 7.20-7.50 (m, 5H); 13C
NMR δ 14.6, 16.2 (CH3), 30.7 (CH3), 36.4, 37.6 (CH), 50.8, 50.9
(CH2), 51.8, 52.0 (CH3), 53.9, 54.9 (CH), 90.8, 90.9 (C), 106.4,
106.7 (CH), 127.2, 128.1, 129.0 (CH), 128.0, 128.8 (CH), 135.5,
135.6 (C), 159.5, 160.0 (J ) 270 or 267 Hz, C), 171.1, 172.3
(C), 193.3, 193.6 (C). Anal. Calcd for C18H20FNSO3‚1H2O: C,
59.67; H, 5.96; N, 3.87. Found: C, 59.67; H, 6.12; N, 3.83.
Meth yl 3-Acetyl-1-ben zyl-r-eth yl-2-flu or o-r-(m eth yl-
su lfa n yl)-1,4-d ih yd r op yir id in e-4-a ceta te (6b). Operating
as above, from pyridinium triflate 2b (prepared from 1.44
mmol of 1) and ester 4 (0.25 mL, 1.73 mmol) 2-fluoro-1,4-
dihydropyridine 6b (1:1 epimeric mixture) was obtained after
flash chromatography (8:2 hexanes-AcOEt): 298 mg (55%);
1H NMR δ 0.73 and 0.83 (2t, J ) 7.5 Hz, 3H), 1.22, 1.54, 1.81
and 1.95 (4m, 2H), 1.93 and 2.12 (2s, 3H), 2.30 and 2.37 (2d,
J ) 7.5 Hz, 3H), 3.49 and 3.58 (2s, 3H), 4.25 and 4.33 (dd, J
) 8.7 or 8.1, 6 Hz, 1H), 4.47-4.63 (m, 2H), 5.03 and 5.19 (ddd,
J ) 7.2, 6, and 1.5 or 1.8 Hz, 1H), 5.95 and 6.07 (2dd, J ) 7.2,
4.5 Hz, 1H), 7.20-7.40 (m, 5H); 13C NMR δ 8.8, 9.3 (CH3), 11.5,
12.8 (CH3), 23.5, 24.3 (CH2), 30.5, 30.8 (CH3), 39.8, 40.2 (CH),
50.5, 50.6 (CH2), 51.7, 52.1 (CH3), 61.9, 65.4 (C), 89.7, 89.8 (C),
105.6, 106.6 (CH), 127.4, 127.9, 128.6 (CH), 135.1, 135.2 (C),
158.9 and 160.0 (J ) 265 or 270 Hz, C), 172.1, 172.6 (C), 193.4,
194.0 (C). Anal. Calcd for C20H24FNO3S‚1H2O: C, 61.60; H,
6.56; N, 3.59. Found: C, 61.60; H, 6.34; N, 3.85.
Meth yl 3-Acetyl-1-m eth yl-2-oxo-1,2,3,4-tetr a h yd r op y-
r id in e-4-a ceta te (9a ). A solution of 2-fluoro-1,4-dihydropy-
ridine 5a (0.21 g, 0.76 mmol) in THF (10 mL) and 1 N aqueous
HCl (10 mL) was stirred at room temperature for 3 h. The
reaction mixture was poured into a saturated Na2CO3 solution
and extracted with Et2O. Concentration of the dried extracts
gave a residue that was dissolved in dry benzene (10 mL). The
resulting solution was heated at reflux, and AIBN (catalytic)
and Bu3SnH (0.22 mL, 0.8 mmol) were added. After the
mixture was refluxed for 1 h, Bu3SnH (0.22 mL, 0.8 mmol)
and AIBN (catalytic) were again added and the mixture was
stirred for 1 h. The reaction mixture was poured into H2O and
extracted with Et2O. After concentration of the organic ex-
tracts, the crude product was chromatographed (6:4 hexanes-
AcOEt) to give 9a (2:1 mixture of keto-enol tautomers): 0.14
g (80%); 1H NMR δ (keto form) 2.31 (s, 3H), 2.39 (m, 2H), 3.07
(s, 3H), 3.33 (m, 1H), 3.50 (d, J ) 5.5 Hz, 1H), 3.68 (s, 3H),
5.13 (ddd, J ) 7.8, 4.8, 1 Hz, 1H), 5.97 (dd, J ) 7.8, 1 Hz, 1H);
1H NMR δ (enol form, most significant signals) 2.01 (s, 3H),
3.09 (s, 3H), 3.68 (masked, 1H), 5.91 (d, J ) 7.8 Hz, 1H), 14.23
(s, 1H); 13C NMR (keto form) δ 29.3 (CH3), 30.6, (CH), 34.3
(CH3), 37.3 (CH2), 51.6 (CH3), 59.7 (CH), 108.0 (CH), 129.9
(CH), 171.5 (C), 172.2 (C), 202.8 (C); 13C NMR (enol form) δ
18.1 (CH3), 32.0 (CH), 33.8 (CH3), 42.8 (CH2), 51.8 (CH3), 98.3
(C), 107.3 (CH), 129.2 (CH), 165.5 (C), 169.0 (C), 172.2 (C);
HRMS calcd for C11H15NO4 226.1080 (M + 1), found 226.1079.
Meth yl 3-Acetyl-1-ben zyl-2-oxo-1,2,3,4-tetr a h yd r op y-
r id in e-4-a ceta te (9b). Operating as above, from 2-fluoro-1,4-
dihydropyridine 5b (100 mg, 0.29 mmol) tetrahydropyridine
9b (2:1 mixture of keto-enol tautomers) was obtained after
flash chromatography (7:3 hexanes-AcOEt): 60 mg (75%); 1H
NMR (keto form) δ 2.31 (s, 3H), 2.39 (m, 2H), 3.34 (m, 1H),
3.60 (d, J ) 5 Hz, 1H), 3.66 (s, 3H), 4.63 and 4.73 (2d, J ) 15
Hz, 2H), 5.14 (dd, J ) 7.8 and 5.4 Hz, 1H), 6.00 (d, J ) 7.8
Hz, 1H), 7.20-7.40 (m, 5H); 1H NMR (enol form, most
significant signals) δ 2.04 (s, 3H), 3.67 (s, 3H), 3.67 (masked,
1H), 5.95 (d, J ) 7.8 Hz, 1H); 13C NMR (keto form) δ 29.3
(CH3), 30.6 (CH), 37.1 (CH2), 51.8 (CH2, CH3), 59.9 (CH), 108.4
(CH), 127.4, 127.7, 128.7 (6 CH), 136.8 (C), 171.7 (C), 171.5
(C), 202.6 (C); 13C NMR (enol form, most significant signals) δ
18.3 (CH3), 32.0 (CH), 42.9 (CH2), 51.7 (CH2, CH3), 98.2 (C),
107.8 (CH), 165.2 (C).
Meth yl 3-Acetyl-r-eth yl-1-m eth yl-r-(m eth ylsu lfa n yl)-
2-oxo-1,2,3,4-tetr a h yd r op yr id in e-4-a ceta te (10a ). A solu-
tion of 2-fluoro-1,4-dihydropyridine 6a (150 mg, 0.49 mmol)
in THF (10 mL) and HCl 1 N (10 mL) was stirred at room
temperature for 3 h. The reaction mixture was partitioned
between saturated aqueous Na2CO3 and Et2O, and extracted
with Et2O. The organic extracts were dried and concentrated
and the resulting residue was chromatographed (7:3 hexanes-
AcOEt) to give 10a (1:1 epimeric mixture, 119 mg, 80%). An
additional chromatography (CH2Cl2) allowed the isolation of
the less polar epimer: 1H NMR δ 0.97 (t, J ) 7.4 Hz, 3H),
1.73 (m, 1H), 1.87 (m, 1H), 2.07 (s, 3H), 2.34 (s, 3H), 3.08 (s,
3H), 3.57 (d, J ) 5.9 Hz, 1H), 3.75 (s, 3H), 4.01 (s, 1H), 4.97
(ddd, J ) 7.9, 5.9, 1.4 Hz, 1H), 6.05 (d, J ) 7.9 Hz, 1H); 13C
NMR δ 9.5 (CH3), 12.6 (CH3), 26.1 (CH2), 28.5 (CH3), 34.2
(CH3), 38.0 (CH), 52.2 (CH3), 57.5 (CH), 58.5 (C), 103.9 (CH),
131.6 (CH), 165.3 (C), 172.2 (C), 202.4 (C). Anal. Calcd for
C14H21NSO4‚2/3H2O: C, 53.99; H, 7.23; N, 4.50. Found: C,
54.00; H, 7.17; N, 4.36.
Met h yl 3-Acet yl-1-ben zyl-r-et h yl-r-(m et h ylsu lfa n yl)-
2-oxo-1,2,3,4-tetr a h yd r op yr id in e-4-a ceta te (10b). Operat-
ing as above, tetrahydropyridine 10b (1:1 epimeric mixture)
was obtained from 2-fluoro-1,4-dihydropyridine 6b (0.25 g, 0.66
mmol): 0.21 g (85%); 1H NMR δ 0.90 and 0.98 (2t, J ) 7.2 Hz,
3H), 1.70 (m, 2H), 1.97 and 2.03 (2s, 3H), 2.32 and 2.33 (2s,
3H), 3.38 (d, J ) 5.4 Hz, 1H), 3.56 and 3.72 (2s, 3H), 4.07 (s,
1H), 4.47-4.93 (2m, 2H), 4.96 and 5.05 (ddd, J ) 8.1, 5.7 or
5.4, 1.2 or 1.5 Hz, 1H), 6.09 and 6.10 (2 dd, J ) 8.1, 1.2 Hz,
1H), 7.10-7.20 (m, 5H); 13C NMR δ 8.7, 8.2 (CH3), 11.7, 11.2
(CH3), 25.3, 24.2 (CH2), 27.8 (CH3), 37.4, 37.9 (CH), 48.8, 48.7
(CH2), 51.4, 51.2 (CH3), 56.8, 57.5 (CH), 57.7, 58.7 (C), 103.3,
102.6 (CH), 127.0, 127.4, 127.8 (5 CH), 129.4, 129.0 (CH), 135.3
(C), 164.3, 163.8 (C), 171.4, 170.8 (C), 201.6 (C).
Meth yl 2-F lu or o-3-p yr id in eca r boxyla te (11a ). n-BuLi
(1.6 M in hexane, 6.9 mL, 11 mmol) was added under Ar to a
solution of diisopropylamine (1.6 mL, 11 mmol) in THF (10
mL) cooled at -78 °C, and the mixture was stirred at -78 °C
for 30 min. Then, a solution of 2-fluoropyridine (0.86 mL, 10
mmol) in THF (50 mL) was added, and the mixture was stirred
at the same temperature for 4 h. Methyl chloroformate (0.93
mL, 12 mmol) was added and, after being stirred at -78 °C
for 1 h, the mixture was allowed to rise to room temperature.
The reaction mixture was poured into H2O and extracted with
Et2O. The ethereal extracts were dried and concentrated. Flash
chromatography (9:1 hexanes-Et2O) of the residue gave 11a :
1.2 g (78%); 1H NMR δ 3.97 (s, 3H), 7.35 (m, 1H), 8.40 (m,
2H); 13C NMR δ 52.3 (CH3), 113.2 (C), 121.2 (CH), 142.8 (CH),
151.2 (CH), 161.0 (J ) 244 Hz, C), 163.1 (C). Anal. Calcd for
C7H6FNO2: C, 54.20; H, 3.90; N, 9.03. Found: C, 53.88; H,
3.97; N, 8.90.
2-F lu or o-3-for m ylp yr id in e (11b). Pyridine 11b was pre-
pared from 2-fluoropyridine following a previously reported
procedure.31
2-F lu or o-3-(m eth oxym eth yl)p yr id in e (11d ). 2-Fluoro-3-
(hydroxymethyl)pyridine31a (0.2 g, 1.6 mmol) in THF (2.5 mL)
was added dropwise (over 30 min) to a solution of MeI (0.4
mL, 6.4 mmol) in THF (0.5 mL) in the presence of NaH (55%
in mineral oil, 105 mg, 2.4 mmol). When the addition was
finished, the reaction mixture was poured into H2O and
extracted with Et2O. The ethereal extracts were dried and
concentrated. Flash chromatography (9:1 hexanes-AcOEt)
1
gave 11d : 68 mg (30%); H NMR δ 3.45 (s, 3H), 4.50 (s, 2H),
7.20 (m, 1H), 7.86 (m, 1H), 8.14 (d, J ) 4.8 Hz, 1H).
2-F lu or o-3-[(2-m eth oxyeth oxy)m eth yl]p yr id in e (11e).
DMAP (20 mg, 0.16 mmol), diisopropylethylamine (0.28 mL,
(31) (a) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;
Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446-
2458. (b) Mallet, M. J . Organomet. Chem. 1991, 406, 49-56.
J . Org. Chem, Vol. 67, No. 21, 2002 7471

Bennasar et al.
1.6 mmol), and 2-(methoxyethoxy)methyl chloride (0.2 mL, 1.6
mmol) were added to a solution of 2-fluoro-3-(hydroxymethyl)-
pyridine31a (0.2 g, 1.6 mmol) in dry CH2Cl2 (2 mL), and the
resulting mixture was stirred at room temperature overnight.
The usual workup and flash chromatography (75:25 hexanes-
and the mixture was stirred at room temperature for 4 h.
Extractive workup (Et2O) and flash chromatography (85:15
hexanes-AcOEt) of the crude product gave pyridone 16c: 140
mg (30%); 1H NMR δ 0.84 (t, J ) 7.5 Hz, 3H), 1.97 (s, 3H),
2.00 (s, 3H), 2.10 (q, J ) 7.5 Hz, 2H), 3.75 (s, 3H), 5.10 and
5.17 (2d, J ) 14.5 Hz, 2H), 6.60 (d, J ) 7.5 Hz, 1H), 7.17 (d,
J ) 7.5 Hz, 1H), 7.27-7.36 (m, 5H); 13C NMR δ 8.8 (CH3),
13.4 (CH3), 14.3 (CH3), 28.5 (CH2), 52.4 (CH2), 52.4 (CH2), 59.3
(C), 106.5 (CH), 127.9 (C), 128.0 (CH), 128.5 (CH), 128.8 (CH),
135.0 (C), 132.3 (CH), 145.4 (C), 162.8 (C), 171.4 (C). Anal.
Calcd for C19H23NSO3: C, 66.06; H, 6.71; N, 4.05. Found: C,
65.65; H, 6.55; N, 4.55.
2-Br om o-3-(iod om eth yl)qu in olin e (19). 2-Bromo-3-(bro-
momethyl)quinoline32 (1 g, 3.3 mmol) in dry acetone (10 mL)
was treated vith NaI (1 g, 6.6 mmol), and the resulting mixture
was stirred at room temperature overnight. The solvent was
removed and the residue was partitioned between H2O and
Et2O and extracted with Et2O. The organic extracts were
concentrated and the resultant residue was chromatographed
(9:1 hexanes-AcOEt) to give quinoline 19: 1 g (92%); 1H NMR
δ 4.68 (s, 2H), 7.58 (t, J ) 8.1 Hz, 1H), 7.73 (t, J ) 8.1 Hz,
1H), 7.83 (d, J ) 8,1 Hz, 1H), 8.03 (d, J ) 8.1 Hz, 1H), 8.20 (s,
1H); 13C NMR δ 2.7 (CH2), 126.0 (CH), 126.2 (CH), 126.8 (C),
127.0 (CH), 129.4 (CH), 131.7 (C), 136.1 (CH), 141.6 (C), 146.1
(C).
1-[(2-Br om o-3-q u in olyl)m et h yl]-2-flu or o-3-(m et h oxy-
ca r bon yl)p yr id in iu m Tr ifla te (21). Quinoline 19 (0.18 g,
0.5 mmol) in dry CH2Cl2 (2 mL) was added under Ar to a
solution of CF3SO2Ag (130 mg, 0.5 mmol) in dry CH2Cl2 (0.5
mL). After the solution was stirred at room temperature for
30 min, a yellow precipitate formed (AgI). The reaction mixture
was filtered over 2-fluoropyridine 11a (66 mg, 0.43 mmol) and
the resulting suspension was concentrated to 1 mL ap-
proximately under an Ar stream and then stirred for 30 min.
The solvent was removed under Ar to give a gum, which was
washed with dry Et2O and immediately used in the next
reaction.
1
Et2O) gave 11e: 220 mg (64%); H NMR δ 3.40 (s, 3H), 3.60
and 3.73 (2m, 4H), 7.22 (m, 1H), 7.87 (m, 1H), 8.20 (d, J ) 4.8
Hz, 1H), 4.68 (s, 2H), 4.85 (s, 2H), 7.20 (m, 1H), 7.85 (m, 1H),
8.15 (d, J ) 4.8 Hz, 1H).
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-F lu or o-
p yr id in iu m Tr ifla tes 12a -e. Pyridinium triflates 12a -e
were prepared from pyridines 11a -e and benzyl triflate,
following the procedure described for 2b, and immediately used
in the next reaction.
Meth yl 1-Ben zyl-r-eth yl-3-(m eth oxyca r bon yl)-r-(m e-
th ylsu lfa n yl)-2-oxo-1,2-d ih yd r op yr id in e-4-a ceta te (16a ).
Pyridinium triflate 12a (prepared from 0.97 mmol of 11a ) was
allowed to react with the enolate derived from ester 4 (0.17
mL, 1.2 mmol) as described for the preparation of 2-fluorodi-
hydropyridines 5a and 6a . Workup and flash chromatography
(85:15 hexanes-AcOEt) gave 2-fluoro-1,4-dihydropyridine 14a
(epimeric mixture): 248 mg; 1H NMR δ 0.81 and 0.91 (2t, J )
7.5 Hz, 3H), 1.35, 1.60, 1.90, and 2.08 (4m, 2H), 1.98 and 2.14
(2s, 3H), 3.58, 3.64, 3.70, and 3.74 (4s, 6H), 4.22 (m, 1H), 4.46,
4.47, 4.53, and 4.58 (4d, J ) 15.3 Hz, 2H), 4.99 and 5.08 (2m,
1H), 5.98 and 6.08 (2dd, J ) 7.3 and 4.3 Hz, 1H), 7.20-7.40
(m, 5H). To a solution of dihydropyridine 14a (248 mg, 0.64
mmol) in THF (40 mL) and MeOH (2 mL) was added DDQ
(182 mg, 0.78 mmol) and the mixture was stirred at room
temperature for 5 h. The reaction mixture was poured into
H2O and extracted with Et2O. Concentration of the ethereal
extracts followed by flash chromatography (55:45 hexanes-
AcOEt) gave pyridone 16a : 248 mg (65%); 1H NMR δ 0.89 (t,
J ) 7 Hz, 3H), 1.96 (s, 3H), 2.19 and 2.30 (2m, 2H), 3.75 and
3.84 (2s, 6H), 5.11 and 5.13 (2d, J ) 12 Hz, 2H), 6.60 (d, J )
6.8 Hz, 1H), 7.28 (d, J ) 6.8 Hz, 1H), 7.30-7.36 (m, 5H); 13C
NMR δ 9.3 (CH3), 13.9 (CH3), 29.7 (CH2), 52.3 (CH3), 52.3
(CH2), 59.9 (C), 107.2 (CH), 124.8 (C), 128.0 (CH), 128.5 (CH),
128.8 (CH), 135.0 (C), 136.1 (CH), 148.8 (C), 160.1 (C), 166.5
(2C); HMRS calcd for C20H23NO5S 389.1296, found 389.1286.
1-[(2-Br om o-3-qu in olyl)m eth yl]-2-flu or o-3-m eth ylp yr i-
d in iu m Tr ifla te (22). Operating as above, pyridinium triflate
22 was obtained from quinoline 19 (0.18 g, 0.51 mmol) and
2-fluoro-3-methylpyridine 11c (48 mg, 0.43 mmol).
N,N -Diet h yl-1-b en zyl-r-et h yl-3-(m et h oxyca r b on yl)-
r-(m e t h ylsu lfa n yl)-2-oxo-1,2-d ih yd r op yr id in e -4-a ce t -
a m id e (17a ). Amide 13 (0.17 mL, 1.2 mmol) in anhydrous
THF (10 mL) was allowed to react with LDA (1.2 mmol) at
-78 °C for 30 min and then with pyridinium triflate 12a
(prepared from 0.97 mmol of 11a ) as above. Workup and flash
chromatography (8:2 hexanes-AcOEt) of the residue gave 280
mg of a 4:1 mixture of 2-fluorodihydropyridines 15a and 18a .
An additional chromatography (CH2Cl2) allowed the isolation
of pure 15a (epimeric mixture): 1H NMR δ 0.84 and 0.92 (2t,
J ) 7.5 Hz, 3H), 1.20 (m, 4H), 1.55 (m, 1H), 1.88 and 1.91 (2s,
3H), 3.40 (br s, 4H), 3.69 and 3.74 (2s, 3H), 4.34-4.63 (m, 3H),
5.04 and 5.18 (2t, J ) 6.4 or 6.7 Hz, 1H), 5.99 (m, 1H), 7.20-
7.40 (m, 5H). 2-Fluorodihydropyridine 15a (0.21 g, 0.50 mmol)
in THF (10 mL) and MeOH (3 mL) was allowed to react with
DDQ (136 mg, 0.6 mmol) as above. Workup and flash chro-
matography (6:4 hexanes-AcOEt) gave pyridone 17a : 208 mg
(50%); 1H NMR δ 0.92 (t, J ) 7.5 Hz, 6H), 1.12 (t, 3H), 1.90 (s,
3H), 2.18 (m, 2H), 3.12 and 3.50 (2m, 4H), 3.88 (s, 3H), 5.06
and 5.14 (2d, J ) 14.4 Hz, 2H), 6.27 (d, J ) 7.5 Hz, 1H), 7.19
(d, J ) 7.5 Hz, 1H), 7.26-7.40 (m, 5H); 13C NMR δ 8.8 (CH3),
11.9 (CH3), 12.4 (CH3), 12.6 (CH3), 30.8 (CH2), 41.1 (CH2), 42.3
(CH2), 51.9 (CH2), 52.6 (CH3), 106.3 (CH), 123.9 (C), 128.0 (CH),
128.5 (CH), 128.8 (CH), 135.0 (C), 135.9 (CH), 148.7 (C), 160.0
(C), 166.3 (C), 167.7 (C); HMRS calcd for C23H30N2O4S 430.1933,
found 430.1926.
Meth yl 1-[(2-Br om o-3-qu in olyl)m eth yl]-r-eth yl-3-(m eth -
oxyca r bon yl)-R-(m eth ylsu lfa n yl)-2-oxo-1,2-d ih yd r op yr i-
d in e-4-a ceta te (23). Pyridinium triflate 21 (prepared from
0.43 mmol of pyridine 11a ) was allowed to react with the
enolate derived from ester 4 (0.07 mL, 0.5 mmol) as described
for the preparation of 5a and 6a . After extractive workup
(Et2O) and flash chromatography (8:2 hexanes-AcOEt) a solid
(115 mg) was obtained. To a solution of the above solid in
THF-MeOH (2:1, 7 mL) was added DDQ (56 mg, 0.24 mmol),
and this mixture was stirred at room temperature for 4 h.
Extractive workup and flash chromatography (1:1 hexanes-
AcOEt) gave pyridone 23: 112 mg (50%); 1H NMR δ 0.92 (t, J
) 7.5 Hz, 3H), 1.98 (s, 3H), 2.16 and 2.32 (2m, 2H), 3.76 and
3.84 (2s, 6H), 5.37 (s, 2H), 6.71 (d, J ) 7.2 Hz, 1H), 7.60 (t, J
) 7 Hz, 1H), 7.70 (d, J ) 7.2 Hz, 1H), 7.76 (t, J ) 7 Hz, 1H),
7.85 (d, J ) 8.1 Hz, 1H), 8.01 (d, J ) 8.1 Hz, 1H), 8.23 (s, 1H);
13C NMR δ 9.2 (CH3), 13.7 (CH3), 29.7 (CH2), 52.2 (2 CH3),
52.3 (CH2), 59.8 (C), 107.6 (CH), 124.7 (C), 126.8 (C), 127.4
(CH), 127.6 (CH), 127.7 (C), 128.2 (CH), 128.6 (C), 131.0 (CH),
137.2 (CH), 139.6 (CH), 142.0 (C), 147.5 (C), 149.8 (C), 160.2
(C), 169.7 (C).
Meth yl 2-[(2-Br om o-3-qu in olyl)m eth yl]-r-eth yl-3-m e-
th yl-r-(m eth ylsu lfa n yl)-2-oxo-1,2-d ih yd r op yr id in e-4-a ce-
ta te (24). Operating as in the preparation of pyridone 16c,
pyridone 24 was obtained from pyridinium triflate 22 (pre-
pared from 0.43 mmol of pyridine 11c), ester 4 (0.07 mL, 0.51
mmol), and DDQ (117 mg, 0.51 mmol) after flash chromatog-
raphy (3:2 hexanes-AcOEt): 60 mg (30%); 1H NMR δ 0.88 (t,
Meth yl-1-ben zyl-r-eth yl-3-m eth yl-r-(m eth ylsu lfa n yl)-
2-oxo-1,2-d ih yd r op yr id in e-4-a ceta te (16c). Pyridinium tri-
flate 12c (prepared from 1.35 mmol of 11c) was allowed to
react with the enolate derived from 4 (0.23 mL, 1.6 mmol) as
described for the preparation of 5a and 6a . Anhydrous MeOH
(2 mL) and DDQ (0.37 g, 1.6 mmol) were added at -30 °C,
(32) Comins, D. L.; Baevsky, M. F.; Hong, H. J . Am. Chem. Soc.
1992, 114, 10971-10972.
7472 J . Org. Chem., Vol. 67, No. 21, 2002

Synthesis of (()-20-Deoxycamptothecin and (+)-Camptothecin
J ) 7.5 Hz, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 2.17 (masked, 2H),
3.78 (s, 3H), 5.37 (s, 2H), 6.70 (d, J ) 7.5 Hz, 1H), 7.45 (d, J
) 7.5 Hz, 1H), 7.57 (t, J ) 8.1 Hz, 1H), 7.73 (t, J ) 8.4 Hz,
1H), 7.80 (d, J ) 7.5 Hz, 1H), 8.03 (d, J ) 8.7 Hz, 1H), 8.10 (s,
1H); 13C NMR δ 8.8 (CH3), 13.5 (CH3), 28.5 (CH2), 14.3 (CH3),
52.2 (CH2), 52.4 (CH3), 59.3 (C), 106.9 (CH), 127.0 (C), 127.3
(CH), 127.7 (CH), 128.1 (CH), 128.3 (C), 129.3 (C), 130.6 (CH),
133.0 (CH), 138.6 (CH), 142.4 (C), 146.2 (C), 147.7 (C), 162.9
(C), 171.4 (C). Anal. Calcd for C22H23BrN2O3S‚1/2H2O: C, 54.55;
H, 4.99; N, 5.78. Found: C, 54.37; H, 4.53; N, 6.02.
(C), 148.5 (C), 152.6 (C), 154.7 (C), 161.1 (C); HRMS calcd for
C20H20N2O3 336.1473, found 336.1474.
B: To a solution of tetracycle 25 (25 mg, 0.06 mmol) in THF
(0.5 mL) cooled at -78 °C was added DIBAL (1 M in THF,
0.18 mL, 0.18 mmol) under Ar, and the mixture was stirred
at -78 °C for 1.5 h. The reaction mixture was allowed to rise
to -40 °C and stirred for 10 min. NaBH4 (spatula) and H2O
(1 mL) were added and the mixture was stirred at room
temperature for 30 min. Workup and flash chromatography
as above gave diol 28: 16 mg (80%).
Met h yl r-E t h yl-3-(m et h oxyca r b on yl)-4-oxo-4,6-d ih y-
d r oin d olizin o[1,2-b]qu in olin e-2-a ceta te (25). AIBN (cata-
lytic) and TTMSS (0.03 mL, 0.09 mmol) were added to a heated
(reflux) solution of pyridone 23 (46 mg, 0.09 mmol) in dry
benzene (10 mL). After 2 h at reflux, AIBN (catalytic) and
TTMSS (0.03 mL, 0.09 mmol) were added, and the mixture
was stirred at the same temperature for 2 h. The reaction
mixture was poured into H2O and extracted with Et2O.
Concentration of the organic extracts and flash chromatogra-
phy (9:1 AcOEt-MeOH) of the crude product gave tetracycle
25: 25 mg (70%); 1H NMR δ 0.97 (t, J ) 7.2 Hz, 3H), 1.95 and
2.23 (2 m, 2H), 3.71 (s, 3H), 3.79 (t, J ) 7.5 Hz, 1H), 3.99 (s,
3H), 5.28 (s, 2H), 7.41 (s, 1H), 7.67 (t, J ) 7.2 Hz, 1H), 7.83 (t,
J ) 7 Hz, 1H), 7.94 (d, J ) 8.1 Hz, 1H), 8.23 (d, J ) 8.4 Hz, 1
H), 8.39 (s, 1H); 13C NMR (most significant signals) 12.0 (CH3),
25.6 (CH2), 49.4 (CH), 50.2 (CH2), 52.4 (CH3), 52.7 (CH3), 99.6
(CH), 128.1 (2CH), 129.7 (CH), 130.5 (CH), 131.0 (CH), 172.2
(C).
C: Operating as in the above method A, diol 28 was obtained
from tetracycle 27 (20 mg, 0.05 mmol), DIBAL (1 M in CH2Cl2
0.18 mL, 0.18 mmol), and NaBH4 (catalytic amount): 13 mg,
(75%).
Isop r op yl 1-[(2-Br om o-3-q u in olyl)m et h yl]-r-et h yl-3-
(m et h oxyca r b on yl)-r-(m et h ylsu lfa n yl)-2-oxo-1,2-d ih y-
d r op yr id in e-4-a ceta te (29). Isopropyl 2-(methylsulfanyl)-
buyrate (90 mg, 0.51 mmol) in THF (20 mL) was allowed to
react with LDA (0.5 mmol) at -78 °C for 30 min and then
with pyridinium triflate 21 (prepared from 0.43 mmol of
2-fluoropyridine 11a ) and DDQ as described for the prepara-
tion of pyridone 23. After flash chromatography (1:1 hexanes-
AcOEt) of the crude product pyridone 29 was obtained: 117
1
mg (50%); H NMR δ 0.91 (t, J ) 7.8 Hz, 3H), 1.27 and 1.31
(2d, J ) 6.3 Hz, 6H), 1.98 (s, 3H), 2.15 and 2.30 (2m, 2H), 3.84
(s, 3H), 5.06 (m, J ) 6.3 Hz, 1H), 5.38 (s, 2H), 6.56 (d, J ) 7.5
Hz, 1H), 7.58 (t, J ) 7 Hz, 1H), 7.60 (d, J ) 7.5 Hz, 1H), 7.74
(t, J ) 7 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 1H), 8.01 (d, J ) 8.4 Hz,
1H), 8.22 (s, 1H); 13C NMR δ 9.5 (CH3), 13.9 (CH3), 21.2 (CH3),
21.6 (CH3), 29.7 (CH2), 51.9 (CH2), 52.3 (CH3), 60.2 (C), 69.4
(CH), 107.6 (CH), 125.4 (C), 127.0 (C), 127.4 (CH), 127.9 (CH),
128.0 (CH), 128.5 (C), 130.9 (CH), 136.5 (CH), 139.6 (CH),
142.3 (C), 147.8 (C), 149.3 (C), 160.2 (C), 166.4 (C), 168.4 (C);
HRMS calcd for C25H27BrN2O5S 546.0824, found 546.0793.
Anal. Calcd for C25H27BrN2O5S‚1.5H2O: C, 52.19; H, 5.27; N,
4.87. Found: C, 52.19; H, 5.21; N, 4.94.
Meth yl r-Eth yl-3-m eth yl-4-oxo-4,6-d ih yd r oin d olizin o-
[1,2-b]qu in olin e-2-a ceta te (26). Operating as above, tetra-
cycle 26 was obtained from pyridone 24 (42 mg, 0.09 mmol),
AIBN (catalytic), and TTMSS (2 × 0.03 mL, 0.18 mmol), after
flash chromatography (98:2 AcOEt-MeOH): 20 mg (65%); 1H
NMR δ 0.95 (t, J ) 7.5 Hz, 3H), 1.92 and 2.22 (2 m, 2H), 2.36
(s, 3H), 3.70 (s, 3H), 3.87 (t, J ) 7.6 Hz, 1H), 5.25 (s, 2H), 7.33
(s, 1H), 7.61 (t, J ) 8.1 Hz, 1H), 7.80 (t, J ) 8.4 Hz, 1H), 7.89
(d, J ) 8.1 Hz, 1H), 8.20 (d, J ) 8.4 Hz, 1H), 8.32 (s, 1H); 13
C
Isop r op yl r-Eth yl-3-(m eth oxyca r bon yl)-4-oxo-4,5-d i-
h yd r oin d olizin o[1,2-b]qu in olin e-2-a ceta te (30). Operating
as in the preparation of tetracycles 25 or 26, tetracycle 30 was
obtained from pyridone 29 (46 mg, 0.09 mmol) after flash
chromatography (9:1 AcOEt-MeOH): 25 mg (70%); 1H NMR
δ 0.98 (t, J ) 7.2 Hz, 3H), 1.18 and 1.26 (2d, J ) 6.3 Hz, 6H),
1.95 and 2.20 (2m, 2H), 3.72 (t, J ) 7.5 Hz, 1H), 3.99 (s, 3H),
5.03 (m, J ) 6.3 Hz, 1H), 5.28 (s, 2H), 7.45 (s, 1H), 7.66 (t, J
) 7 Hz, 1H), 7.83 (t, J ) 7 Hz, 1H), 7.93 (d, J ) 8 Hz, 1H),
8.22 (d, J ) 8.2 Hz, 1H), 8.38 (s, 1H); 13C NMR δ 12.0 (CH3),
21.6 (CH3), 21.8 (CH3), 25.6 (CH2), 50.1 (CH), 50.3 (CH2), 52.6
(CH3), 68.8 (CH), 99.7 (CH), 124.7 (C), 127.9 (CH), 128.0 (CH),
128.8 (2C), 129.8 (CH), 130.5 (CH), 130.9 (CH), 146.4 (C), 148.9
(C), 151.3 (C), 152.3 (C), 158.3 (C), 166.5 (C), 171.3 (C); HRMS
calcd for C24H24N2O5 420.1685, found 420.1688.
NMR δ 11.9 (CH3), 12.7 (CH3), 25.1 (CH2), 49.4 (CH), 49.9
(CH2), 52.2 (CH3), 100.1 (CH), 127.3 (CH), 127.9 (C), 127.8
(CH), 128.0 (C), 128.5 (C), 129.5 (CH), 130.1 (CH), 130.7 (CH),
142.4 (C), 147.4 (C), 148.7 (C), 153.2 (C), 161.4 (C), 172.9 (C);
HRMS calcd for C21H20N2O3 348.1473, found 348.1474. Anal.
Calcd for C21H20N2O3‚1.5H2O: C, 66.96; H, 6.19; N, 7.44.
Found: C, 66.68; H, 5.80; N, 7.70.
Dieth yl Ester (27). KF (70 mg, 1.2 mmol) was added to a
solution of tetracycle 25 (25 mg, 0.06 mmol) in dry EtOH (5
mL) and the mixture was heated (reflux) for 40 h. The solvent
was removed and the residue was partitioned between H2O
and AcOEt, then extracted with AcOEt. The organic extracts
were dried and concentrated, and the resulting residue was
chromatographed (99:1 AcOEt-MeOH) to give tetracycle 27:
21j
1
23 mg (90%); H NMR δ 0.97, 1.24, and 1.43 (3 t, J ) 7.2
Red u ction of Diester 30. A solution of diester 30 (15 mg,
0.03 mmol) in DME (2 mL) was added to a cooled (-70 °C)
solution of DIBAL (1 M in hexane, 0.1 mL, 0.1 mmol) in DME
(2 mL), and the resulting solution was stirred at -70 °C for
15 min. The reaction mixture was poured into H2O and
extracted with CH2Cl2. The organic extracts were concentrated
to give a residue, which was disolved in dry 2-propanol (1 mL).
NaBH4 (spatula) was added and the mixture was stirred at
room temperature for 30 min. After extractive workup (CH2-
Cl2) and flash chromatography (AcOEt-MeOH) of the crude
product the following compounds were isolated:
Hz, 9H), 1.95 (m, 1H), 2.22 (m, 2H), 3.75 (t, J ) 7.6 Hz, 1H),
4.16 (m, 2H), 4.48 (q, J ) 7.2 Hz, 2H), 5.30 (s, 2H, 5-H), 7.44
(s, 1H), 7.57 (t, J ) 7.6 Hz, 1H), 7.81 (t, J ) 7.8 Hz, 1H), 7.92
(d, J ) 8.2 Hz, 1H), 8.21 (d, J ) 8.4 Hz, 1H), 8.38 (s, 1H).
Diol 28. A: To a solution of tetracycle 25 (25 mg, 0.06 mmol)
in dry CH2Cl2 (0.5 mL) cooled at -78 °C was added DIBAL (1
M in CH2Cl2 0.18 mL, 0.18 mmol) under Ar, and the mixture
was stirred at -78 °C for 2 h. NaBH4 (spatula) and dry MeOH
(1 mL) were added, and the mixture was stirred at room
temperature for 30 min. The reaction mixture was poured into
H2O and extracted with CH2Cl2. Concentration of the organic
extracts and flash chromatography (98:2 CHCl3-MeOH) of the
(()-20-Deoxyca m p toth ecin (31):21a elution with 99:1 AcO-
Et-MeOH, 3.8 mg (32%); 1H NMR δ 1.09 (t, J ) 7.4 Hz, 3H),
2.09 (m, 2H), 3.62 (t, J ) 6.6 Hz, 1H), 5.29 (s, 2H), 5.39 (d, J
) 16.3 Hz, 1H), 5.57 (d, J ) 16.3 Hz, 1H), 7.19 (s, 1H), 7.66
(dt, J ) 7.5 and 1 Hz, 1H), 7.83 (dt, J ) 6.9 and 1.4 Hz, 1H),
7.93 (d, J ) 7 Hz, 1H), 8.21 (d, J ) 8.4 Hz, 1H), 8.39 (s, 1H).
1
crude product gave 28: 16 mg (80%); H NMR δ 0.89 (t, J )
7.5 Hz, 3H), 1.75 (m, 2H), 3.30 (m, 1H), 3.80 (dd, J ) 10.5 and
9.6 Hz, 1H), 3.98 (dd, J ) 10.5 and 4.8 Hz, 1H), 4.67 and 5.03
(2d, J ) 12.6 Hz, 2H), 5.17 (s, 2H), 7.28 (s, 1H), 7.57 (t, J )
7.8 Hz, 1H), 7.78 (m, 2H), 8.12 (d, J ) 8.4 Hz, 1H), 8.26 (s,
1H); 13C NMR δ 12.0 (CH3), 24.0 (CH2), 45.8 (CH), 49.9 (CH2),
56.5 (CH2), 66.0 (CH2), 99.5 (CH), 127.6 (CH), 127.8 (C), 128.0
(CH), 128.6 (C), 129.3 (CH), 130.3 (CH, C), 130.9 (CH), 144.4
La ctol 32:21m elution with 85:15 AcOEt-MeOH, 3.9 mg
1
(33%); H NMR δ 1.05 (t, J ) 7.4 Hz, 3H), 1.80 (m, 2H), 2.68
(t, J ) 6.6 Hz, 1H), 2.84 (s, 1H), 4.82 (s, 2H), 5.24 (s, 2H), 5.40
J . Org. Chem, Vol. 67, No. 21, 2002 7473

Bennasar et al.
(s, 1H), 7.20 (s, 1H), 7.63 (t, J ) 7,5 Hz, 1H), 7.80 (t, J ) 7 Hz,
1H), 7.91 (d, J ) 8.1 Hz, 1H), 8.20 (d, J ) 9 Hz, 1H), 8.34 (s,
1H).
and 2.25 (2m, 2H, 19-H), 4.61 (s, 1H), 5.36 and 5.12 (2d, J )
15 Hz, 2H, 5-H), 5.66 (s, 1H, 21-H), 7.47 (s, 1H, 14-H), 7.70 (t,
J ) 7.5 Hz, 1H, 10-H), 7.90 (t, J ) 7.5 Hz, 1H, 11-H), 8.05 (d,
J ) 7.5 Hz, 1H, 9-H), 8.35 (d, J ) 7.5 Hz, 1H, 12-H), 8.48 (s,
1H, 7-H); 13C NMR (assignments aided by HSQC and HMBC)
δ 7.5 (C-18), 23.8 (3CH3), 29.4 (C-19), 34.6 (C), 50.9 (C-5), 77.7
(C-20), 96.6 (C-14), 101.0 (C-21), 109.1 (CH), 112.0 (C-16), 128.2
(C-9), 128.5 (C-10), 128.6 (C-6), 129.4 (C-8), 129.8 (C-12), 130.9
(C-11), 131.6 (C-7), 149.0 (C-13), 151.7 (C-3), 151.8 (C-2), 156.8
(C-15), 157.2 (N-CO), 157.5 (C-17); HMRS calcd for C25H24N2O5
432.1685, found 432.1674.
Met h yl 1-[(2-Br om o-3-q u in olyl)m et h yl]-4-[(2R,5S)-2-
ter t-bu tyl-5-eth yl-4-oxo-1,3-d ioxola n -5-yl]-2-oxo-1,2-d ih y-
d r op yr id in e-3-ca r boxyla te (34). Dioxolanone 3327,33 (0.1 g,
0.58 mmol) in THF (13 mL) cooled at -78 °C was allowed to
react with LDA (0.6 mmol) under Ar at -78 °C for 30 min
and then with pyridinium triflate 21 (prepared from 0.54 mmol
of 2-fluoropyridine 11a ) and DDQ as described for the prepa-
ration of pyridone 23. After extractive workup (Et2O) and flash
chromatography (6:4 hexanes-AcOEt) of the crude product
(-)-O,21-Dih yd r oca m p toth ecin (36). DIBAL (1 M in CH2-
Cl2, 0.2 mL, 0.2 mmol) was added to a solution of tetracycle
35 (32 mg, 0.07 mmol) in dry CH2Cl2 (0.6 mL) cooled at -78
°C, and the mixture was allowed to rise to -30 °C (45 min).
Dry MeOH (1 mL) and NaBH4 (catalytic) were added, and the
mixture was stirred at 0 °C for 1 h. The reaction mixture was
quenched with 2 N NaOH. After the solution was stirred at
room temperature for 30 min, 2 N HCl was added to bring
the pH to 4-5, and the mixture was stirred for 30 min. The
reaction mixture was extracted with 99:1 CHCl3-MeOH.
Concentration of the organic extracts and flash chromatogra-
phy (99:1 CHCl3-MeOH) of the residue afforded R-hydroxy-
lactol 36: 11 mg (45%); [R]22D -29 (c 0.2, CHCl3-CH3OH 4:1);
1H NMR (DMSO-d6) δ 0.89 (t, J ) 7.2 Hz, 3H), 1.72 (q, J )
7.2 Hz, 2H), 4.49 and 4.60 (2d, J ) 17 Hz, 2H), 4.96 (s, 1H),
4.99 (br, 1H), 5.22 (s, 2H), 6.75 (br, 1H), 7.36 (s, 1H), 7.67 (t,
J ) 7.5 Hz, 1H), 7.84 (t, J ) 7.5 Hz, 1H), 8.12 (2d, 2H), 8.64
(s, 1H); 13C NMR δ (DMSO-d6) 7.8 (CH3), 32.5 (CH2), 49.7
(CH2), 58.4 (CH2), 70.3 (C), 92.7 (CH), 98.6 (CH), 123.1 (C),
127.3 (CH), 127.8 (C), 128.4 (CH), 128.9 (CH), 129.4 (C),130.1
(CH), 131.3 (CH), 142.8 (C), 147.9 (C), 150.1 (C), 153.0 (C),
157.3 (C).
pyridone 34 was obtained: 59 mg (20%); [R]22 -59 (c 0.6,
D
1
CHCl3); H NMR δ 0.94 (masked, 3H), 0.99 (s, 9H), 2.09 and
2.16 (2m, 2H), 3.87 (s, 3H), 5.16 (s, 1H), 5.28 and 5.39 (2d, J
) 14.7 Hz, 2H), 6.53 (d, J ) 7.8 Hz, 1H), 7.58 (t, J ) 7 Hz,
1H), 7.64 (d, J ) 7.2 Hz, 1H), 7.75 (t, J ) 7 Hz, 1H), 7.84 (d,
J ) 8 Hz, 1H), 8.01 (d, J ) 8 Hz, 1H), 8.26 (s, 1H, 4-H); 13C
NMR δ 8.4 (CH3), 23.6 (3CH3), 31.7 (CH2), 34.7 (C), 52.3 (CH2),
52.6 (CH3), 83.3 (C), 103.1 (CH), 108.2 (CH), 123.9 (C), 127.1
(C), 127.5 (CH), 128.0 (CH), 128.2 (CH), 131.1 (CH), 138.2
(CH), 139.9 (CH), 142.4 (C), 146.3 (C), 147.9 (C), 159.8 (C),
166.4 (C), 170.9 (C); HRMS calcd for C26H27N2O6Br 542.1052,
found 542.1034.
Meth yl 2-[(2R,5S)-2-ter t-Bu tyl-5-eth yl-4-oxo-1,3-d iox-
ola n -5-yl]-4-oxo-4,6-d ih yd r oin d olizin o[1,2-b]qu in olin e-3-
ca r boxyla te (35). A solution of pyridone 34 (66 mg, 0.12
mmol) in dry benzene (10 mL) was allowed to react with
TTMSS (2 × 0.04 mL, 0.24 mmol) and AIBN (catalytic) as
described for the preparation of tetracycle 25. After extractive
workup and flash chromatïgraphy (4:6 hexanes-AcOEt) of the
crude product tetracycle 35 was obtained: 34 mg (60%); [R]22
D
-191 (c 1, CHCl3); 1H NMR δ 1.02 (s, 9H), 1.08 (t, J ) 7.2 Hz,
3H), 2.22 and 2.34 (2m, 2H), 3.93 (s, 3H), 5.22 and 5.27 (2s,
3H), 7.61 (s, 1H), 7.66 (t, J ) 7.2 Hz, 1H), 7.83 (t, J ) 8 Hz,
1H), 7.94 (d, J ) 8.4 Hz, 1H), 8.24 (d, J ) 8.4 Hz, 1H), 8.37 (s,
1H); 13C NMR δ 8.5 (CH3), 23.7 (3CH3), 31.9 (CH2), 34.7 (C),
50.2 (CH2), 52.6 (CH3), 83.3 (C), 97.8 (CH), 108.1 (CH), 122.9
(C), 128.0 (CH), 128.1 (CH, C), 128.6 (C), 130.0 (CH), 130.5
(CH), 130.9 (CH), 146.3 (C), 147.3 (C), 148.9 (C), 151.7 (C),
158.5 (C), 166.6 (C), 171.0 (C); HRMS calcd for C26H26N2O6
462.1790, found 462.1794.
(+)-Ca m p toth ecin (37). To a solution of R-hydroxylactol
36 (7 mg, 0.02 mmol) in MeOH-H2O (0.5 mL, 10:1) were added
iodine (0.46 g, 0.18 mmol) and CaCO3 (4 mg, 0.04 mmol), and
the mixture was stirred at room temperature for 4 days. The
reaction mixture was carefully washed with H2O (5 mL) and
extracted with 99:1 CHCl3-MeOH. Concentration of the
organic extracts and flash chromatography (98:2 CHCl3-
MeOH) of the crude product gave (+)-camptothecin (37): 4 mg
(60%); [R]22 +25 (c 0.2, CHCl3-CH3OH 4:1) (lit.18 [R]22 +31
D
D
Hexa cycle 38. DIBAL (1 M in CH2Cl2, 0.1 mL, 0.1 mmol)
was added under Ar to a solution of tetracycle 35 (32 mg, 0.07
mmol) in dry CH2Cl2 (0.6 mL) cooled at -78 °C. After the
solution was stirred at -78 °C for 15 min, DIBAL (1 M in CH2-
Cl2, 0.1 mL, 0.1 mmol) was added again, and the reaction
mixture was stirred at -78 °C for 15 min. Dry MeOH (1 mL)
and NaBH4 (spatula) were added and the mixture was stirred
at 0 °C for 30 min. The reaction mixture was quenched with
2 N NaOH. After the solution was stirred for 30 min, glacial
acetic acid was added until neutralization and the mixture was
stirred for 30 min. The solvent was removed and the resultant
residue was chromatographed (99:1 CHCl3-MeOH) to give
hexacycle 38: 20 mg (65%); [R]22D -60 (c 0.3, CHCl3); 1H NMR
(400 MHz, biogenetic numbering, assignments aided by HSQC
and HMBC) δ 0.92 (s, 9H), 1.00 (t, J ) 7.5 Hz, 3H, 18-H), 2.15
(CHCl3:CH3OH 4:1)).
Ack n ow led gm en t . Financial support from the
“Ministerio de Ciencia y Tecnolog´ıa” (Spain, project
BQU2000-0785) is gratefully acknowledged. We also
thank the DURSI (Generalitat de Catalunya) for Grant
2001SGR00084 and for a fellowship to C.J . One of us
(Y.A.) also thanks the “Ministerio de Educacio´n, Cultura
y Deporte” for a Grant.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of
compounds 9a , 9b, 10b, 11d , 11e, 16a , 17a , 19, 23, 25, 28,
30-32, and 34-38. This material is available free of charge
via the Internet at http://pubs.acs.org.
(33) Mori, K.; Sasaki, M.; Tamada, S.; Suguro, T.; Masuda, S.
Tetrahedron 1979, 35, 1601-1605.
J O026173J
7474 J . Org. Chem., Vol. 67, No. 21, 2002