Practical asymmetric synthesis of (S)-4,ethyl-7,8-dihydro-4-hydroxy-1H- pyrano[3,4-f]indolizine-3,6,10(4H)-trione, a key intermediate for the synthesis of Irinotecan and other camptothecin analogs

Article abstract of DOI:10.1021/jo970173f

A practical asymmetric synthesis of (S) 4-ethyl-7,8-dihydro-4-hydroxy- 1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1), a versatile intermediate for the synthesis of camptothecin analogs, was developed. Commercially available citrazinic acid is converted in four steps into the 2-chloro-6- methoxypyridine 5. An ortho-directed metalation followed by reaction with a formamide produces an aldehyde with the required 2,3,4,6-substituted pyridine (6) with high regioselectivity. After refunctionalization of the aldehyde, the chloropyridine is converted into an ester by a facile palladium-mediated carbonylation reaction. Wittig reaction and racemic osmylation produce the diol 16 which is resolved by an efficient lipase resolution to an ee > 99%, and a one-pot recycle of the unwanted diol enantiomer was developed. A series of high-yielding oxidation and deprotection steps convert (S)-16 into the pyridone 25, which is then converted into 1 with an ee > 99.6%.

Full text of DOI:10.1021/jo970173f

6588
J . Org. Chem. 1997, 62, 6588-6597
P r a ctica l Asym m etr ic Syn th esis of
(S)-4-Eth yl-7,8-d ih yd r o-4-h yd r oxy-1H-p yr a n o[3,4-f]in d olizin e-
3,6,10(4H)-tr ion e, a Key In ter m ed ia te for th e Syn th esis of
Ir in oteca n a n d Oth er Ca m p toth ecin An a logs
Kevin E. Henegar,* Scott W. Ashford, Ted A. Baughman, J ohn C. Sih, and Rui-Lin Gu
Chemical Process Research and Development, Pharmacia & Upjohn, 7000 Portage Road,
Kalamazoo, Michigan 49001
Received J anuary 30, 1997X
A practical asymmetric synthesis of (S) 4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-
3,6,10(4H)-trione (1), a versatile intermediate for the synthesis of camptothecin analogs, was
developed. Commercially available citrazinic acid is converted in four steps into the 2-chloro-6-
methoxypyridine 5. An ortho-directed metalation followed by reaction with a formamide produces
an aldehyde with the required 2,3,4,6-substituted pyridine (6) with high regioselectivity. After
refunctionalization of the aldehyde, the chloropyridine is converted into an ester by a facile
palladium-mediated carbonylation reaction. Wittig reaction and racemic osmylation produce the
diol 16 which is resolved by an efficient lipase resolution to an ee > 99%, and a one-pot recycle of
the unwanted diol enantiomer was developed. A series of high-yielding oxidation and deprotection
steps convert (S)-16 into the pyridone 25, which is then converted into 1 with an ee > 99.6%.
In tr od u ction
Irinotecan1 (CPT-11) was licensed by Pharmacia &
Upjohn from Yakult Honsha and recently approved by
the FDA for the treatment of refractory colorectal cancer.
Irinotecan is an analog of the natural product campto-
thecin, whose structure was reported in 1966 by Wall and
co-workers.2 Although camptothecin has potent antitu-
mor activity, it has serious problems with solubility and
toxicity, and irinotecan is one of a number of analogs
developed to circumvent these problems.3 Irinotecan
functions as the soluble prodrug for the active metabolite
SN-38, and both SN-38 and camptothecin function as
inhibitors of the enzyme topoisomerase I, which plays an
important role in DNA replication. Biological aspects of
CPT-11 have recently been reviewed.4
Irinotecan has been prepared from natural campto-
thecin in five chemical steps and about 20% overall yield.1
Although this synthesis provides a direct route to irino-
tecan, the reliance on scarce natural camptothecin and
other operational problems caused us to evaluate the
preparation of irinotecan by total synthesis. Many
syntheses of camptothecin have been reported, most
dating from the early to mid 1970’s. Three reviews cover
the older syntheses,5 which are generally racemic and
would be difficult to adapt for large scale synthesis. With
the renewed interest in camptothecin analogs several
new or improved syntheses have been published, but
these approaches would either be impractical for large
scale synthesis of enantiomerically pure irinotecan or
were unavailable for our use for patent reasons.6
One of the most efficient means of assembling the
camptothecin ring system is through a Friedlander
condensation,7 a reaction used in various forms in a
number of published camptothecin syntheses. Extensive
work has been done by Wall and co-workers and at
Daiichi Pharmaceutical to develop a chiral synthesis of
camptothecin and analogs using (4S)-4-ethyl-7,8-dihydro-
4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione (1)
as a key intermediate (Scheme 1). 1 has been used
extensively to produce camptothecin and numerous
analogs.3b,c,6c A synthesis of racemic 1 was reported by
Wall8 based on chemistry originally developed by Chinese
X Abstract published in Advance ACS Abstracts, August 15, 1997.
(1) Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.;
Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. Chem. Pharm.
Bull. 1991, 39, 1446-1454.
(2) 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.
(3) (a) Kingsbury, W. D.; Boehm, J . C.; J akas, D. R.; Holden, K. G.;
Hecht, S. M.; Gallagher, G.; Caranfa, M. J .; McCabe, F. L.; Faucette,
L. F.; J ohnson, R. K.; Hertzberg, R. P. J . Med. Chem. 1991, 34, 98-
107. (b) Wall, M. E.; Wani, M. C.; Nicholas, A. W.; Manikumar, G.;
Tele, C.; Moore, L.; Truesdale, A.; Leitner, P.; Besterman, J . M. J . Med.
Chem. 1993, 36, 2689-2700. (c) Luzzio, M. J .; Besterman, J . M.;
Emerson, D. L.; Evans, M. G.; Lackey, K.; Leitner, P. L.; McIntyre,
G.; Morton, B.; Myers, P. L.; Peel, M.; Sisco, J . M.; Sternbach, D. D.;
Tong, W.-Q.; Truesdale, A.; Uehling, D. E.; Vuong, A.; Yates, J . J . Med.
Chem. 1995, 38, 395-401.
(5) (a) Hutchinson, C. R. Tetrahedron 1981, 37, 1047-1065. (b)
Schultz, A. G. Chem. Rev. 1973, 73, 385-405. (c) Shamma, M.; St.
Georgiev, V. J . Pharm. Sci. 1974, 63, 163-183.
(4) Camptothecins: New Anticancer Agents; Potsmeil, M., Pinedo,
H., Eds.; CRC Press: Boca Raton, 1995.
S0022-3263(97)00173-4 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Key Intermediate for Irinotecan Synthesis
J . Org. Chem., Vol. 62, No. 19, 1997 6589
Sch em e 1
Sch em e 2a
researchers9 and procedures for the resolution of racemic
1 via the diastereomeric R-methylbenzylamides were
published by Wall6a and by Tagawa and co-workers at
Daiichi.6b This synthesis starts with inexpensive materi-
als but several steps present problems, especially for
large scale preparations. In addition, the synthesis is
limited by the inefficient resolution to prepare enantio-
merically enriched material because there are no simple
1 equiv of tetramethylammonium chloride at 120 °C
under atmospheric pressure.12 In the absence of a
quarternary ammonium chloride, product formation oc-
curs only under sealed tube conditions.13
methods for recycling the undesired enantiomer.
A
second variation of this synthesis uses an alkylation of a
chiral amide; this modification overcomes the limitations
of the resolution but uses stoichiometric amounts of
Conversion of 2,6-dichloroisonicotinic acid into the
ethyl ketone 3 was done in 84% yield by reaction with 3
equiv of ethylmagnesium chloride in THF at -40 °C,
quenching the excess Grignard reagent first with methyl
formate before an aqueous acidic workup. Use of this
protocol essentially eliminates the formation of the
tertiary alcohol byproduct. The ketone 3 was then
converted into the nicely crystalline ethylene ketal 4 in
99% yield by reaction with ethylene glycol and TMS
chloride.14 Ketal 4 was efficiently desymmetrized by
reaction with sodium methoxide in refluxing methanol
to give compound 5 in 89% isolated yield as a low melting
solid.15 Under these conditions less than 1% of the 2,6-
dimethoxy compound is formed, although it can be made
the exclusive product if the reaction is run at higher
temperatures and for longer times.
expensive N-tosyl-(R)-proline as the chiral auxiliary.6c
A
third modification using a Sharpless asymmetric dihy-
droxylation has also been reported but gives 1 with an
enantiomeric excess of only 84%.10 Given the continued
interest in preparing additional camptothecin analogs
and our need for a scaleable total synthesis of irinotecan,
we have developed a practical synthesis of the key
intermediate 1 with high enantiomeric purity.
Resu lts a n d Discu ssion
The starting material for the synthesis (Scheme 2) is
citrazinic acid, which is commercially available in bulk.11
This was converted into 2,6-dichloroisonicotinic acid (2)
in 78% yield by reaction with phosphorus oxychloride and
Following the approach used in the Comins’ campto-
thecin synthesis,6e introduction of an aldehyde substitu-
ent adjacent to the methoxy group was done using an
ortho-directed metalation.16 Cooperative effects in di-
rected metalation reactions are well known and there are
a number of examples of metalations of alkoxypyri-
dines,6e,g,h,17 but there is little precedent for selective
reactions with substrates such as 5 having a C-4 sub-
stituent. We found that a high degree of site-selectivity
(6) Leading references: (a) Wani, M. C.; Nicholas, A. W.; Wall, M.
E. J . Med. Chem. 1987, 30, 2317-2319. (b) Terasawa, H.; Sugimori,
M.; Ejima, A.; Tagawa, H. Chem. Pharm. Bull. 1989, 37, 3382-3385.
(c) Ejima, A.; Terasawa, H.; Sugimori, M.; Tagawa, H. J . Chem. Soc.,
Perkin Trans. 1 1990, 27-31. (d) Curran, D. P.; Liu, H. J . Am. Chem.
Soc. 1992, 114, 5863-5864. (e) Comins, D. L.; Baevsky, M. F.; Hong,
H. J . Am. Chem. Soc. 1992, 114, 10971-10972. (f) Shen, W.; Coburn,
C. A.; Bornmann, W. G.; Danishefsky, S. J . J . Org. Chem. 1993, 58,
611-617. (g) Comins, D. L.; Hong.; H., Saha, J . K.; J ianhua G. J . Org.
Chem. 1994, 59, 5120-5121. (h) Comins, D. L.; Hong.; H., J ianhua,
G. Tetrahedron Lett. 1994, 35, 5331-5334. (i) Fang, F. G.; Xie, S.;
Lowery, M. W. J . Org. Chem. 1994, 59, 6142-6143. (j) Curran, D. P.;
Ko, S.-B.; J osien, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2683-
2684. (k) Comins, D. L.; Saha, J . K. Tetrahedron Lett. 1995, 36, 7995-
7998. (l) 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. (m) Ciufolini, M. A.; Roschanger, F. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1692-1694.
(12) Schroetter, E.; Schick, H.; Niedrich, H.; Oehme, P.; Piesche, L.
German (East) Pat. DD 154,538; Chem. Abstr. 1982, 97, 216024.
(13) (a) Baizer, M. E.; Dub, M.; Gister, S.; Steinberg, N. G. J . Am.
Pharm. Soc. 1956, 45, 478-480. (b) Levelt, W. H.; Wibalt, J . P. Rec.
Trav. Chem. 1929, 44, 466.
(14) Chan, T. H.; Brook, M. A.; Chaly, T. Synthesis 1983, 203-205.
(15) For related selective displacements of halopyridines: (a) Testa-
ferri, L.; Tieco, M.; Tingoli, M.; Bartoli, D.; Massoli, A. Tetrahedron
1985, 41, 1371-1384. (b) Murata, N.; Sugihara, T.; Kondo, Y.;
Sakamoto, T. Synlett 1997, 298-300.
(7) Cheng, C.-C.; Yan, S.-J . Organic Reactions; J . Wiley: New York,
1982; vol. 28, pp 37-202.
(8) (a) Wani, M. C.; Ronman, P. E.; Lindley, J . T.; Wall, M. E. J .
Med. Chem. 1980, 23, 554-560. (b) Wani, M. C.; Nicholas, A. W.;
Natschke, S. M.; Wall, M. E. J . Med. Chem. 1986, 29, 1553-1555.
(9) (a) Chem. Abstr. 1976, 84, 122100. (b) Sci. Sin. [Engl. Ed.] 1978,
21, 87.
(10) J ew, S.-s.; Ok, K.-d.; Kim, H.-j,; Kim, M. G.; Kim, J . M.; Hah,
J . M.; Cho, Y.-s. Tetrahedron: Asymmetry 1995, 6, 1245-1248.
(11) Citrazinic acid was purchased from Yorkshire Chemical for $60/
kg.
(16) Snieckus, V. Chem. Rev. 1990, 90, 879-933.
(17) (a) Winkle, M. R.; Ronald, R. C. J . Org. Chem. 1982, 47, 2101-
2108. (b) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29,
773-776. (c) Trecourt, F.; Mallet, M.; Marsais, F.; Queguiner, G. J .
Org. Chem. 1988, 53, 1367-1371. (d) Comins, D. L.; Killpack, M. O.
J . Org. Chem. 1990, 55, 69-73. (e) Hong., H.; Comins, D. L. J . Org.
Chem. 1996, 61, 391-392.

6590 J . Org. Chem., Vol. 62, No. 19, 1997
Henegar et al.
Sch em e 3a
followed by treatment with HCl or NaOH to regenerate
the aldehyde, eliminating the need for a chromatography.
Reaction of 8 with benzyl bromide and potassium tert-
butoxide in THF gave benzyl ether 9 in 99% yield.
Alcohol 8 was also converted into 10 (methyl iodide/
potassium tert-butoxide), which was dechlorinated (NiCl2/
LAH)18 to give 11. The observed coupling constant of 5.4
Hz for the C-5 and C-6 splitting confirms the regiochemi-
cal assignment of compounds 6 and 8.
Palladium-catalyzed carbonylation of the chloropyri-
dine 9 provides an efficient method for C-6 functional-
ization. Aryl chlorides generally have low reactivity in
palladium insertion reactions but insertion complexes of
palladium and nickel with 2-chloropyridine have been
isolated and simple 2-chloropyridines are known to
undergo palladium-catalyzed reactions,19 although pal-
ladium-catalyzed carbonylation reactions of 2-chloropyr-
idines have not been reported. Compound 9 was smoothly
carbonylated by reaction with carbon monoxide, pal-
ladium acetate (0.25 mol %), 1,3-bis(diphenylphosphino)-
propane (DPPP, 0.25 mol %), 1-propanol, and potassium
acetate in DMF at 90 °C. The reaction proceeds under
low carbon monoxide pressure (15 psi or less) with
1-propanol chosen as the alcohol since its boiling point
allows the reaction to be run at atmospheric pressure.
Isolated yield of ester 12 after purification was 89%.
Deketalization of 12 with 50% trifluoroacetic acid at
room temperature gave the ketone 13 in 98% yield.
Conditions of the subsequent Wittig reaction to form 14
required optimization to suppress formation of the diene
overreaction product 15.20 The optimized base/solvent
combination is KHMDS and DMF at 0 °C, which gave
14 in 92% with diene levels less than 3%. On a small
scale, the noncrystalline intermediates 9, 12, 13, and 14
were purified by chromatography but on larger scale the
crude products were used without purification.
for deprotonation adjacent to either the chloro or methoxy
substituent is attainable by appropriate choice of the base
and solvent. Deprotonation of 5 with an alkyllithium
followed by reaction with DMF yields aldehydes 5 and
6. Use of nonpolar solvents induces deprotonation ad-
jacent to the methoxy group, and reaction with n-
butyllithium in heptane at 0 °C gives 95:5 selectivity in
favor of 6 after reaction of the anion with DMF. For
larger scale reactions, DMF was replaced with the more
heptane-soluble N-formylpiperidine. With polar solvents
or coordinating additives the selectivity is reversed;
deprotonation with sec-butyllithium in THF at -40 °C
gives 90:10 selectivity in favor of 7. Reactions in all cases
were accompanied by 10-20% unreacted starting mate-
rial and various products arising from butyl substitution
at C-2, C-6, or at both positions.
Conversion of the olefin into the racemic diol21 16 was
done with 1 mol % osmium tetraoxide and 3 equiv of
trimethylamine N-oxide dihydrate in anhydrous tert-
butanol at 45 °C.23 Addition of water beyond that
contained in the trimethylamine N-oxide dihydrate caused
reactions to stall at about 60% completion. Diol 16 was
Separation of the desired aldehyde 6 from the regio-
isomer 7 and other byproducts was done by chromatog-
raphy on small scale, a separation more easily done after
reduction to the alcohol 8 (Scheme 3) with sodium
borohydride. Alcohol 8 was obtained in 71% overall yield
from 5 (87% corrected for recovered 5). On larger scale
6 was purified by crystallization from heptane or by
formation of the crystalline bisulfite addition product
(18) Ashby, E. C.; Lin, J . J . J . Org Chem. 1978, 43, 1263-1265.
(19) (a) Isobe, K.; Kawaguchi, S. Heterocycles 1981, 16, 1603-1612.
(b) Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984, 936-
938. (c) Isobe, K.; Nanjo, K.; Nakamura, Y.; Kawaguchi, S. Bull. Chem.
Soc. J pn. 1986, 59, 2141-2149. (d) Sato, N.; Hayakawa, A.; Takeuchi,
R. J . Heterocycl. Chem. 1990, 27, 503-506.
(20) Uijttewaal, A. P.; J onkers, F. L.; van der Gen, A. Tetrahedron
Lett. 1975, 1439-1442.

Synthesis of Key Intermediate for Irinotecan Synthesis
J . Org. Chem., Vol. 62, No. 19, 1997 6591
Sch em e 4a
obtained in 78% yield in lab scale runs after crystalliza-
tion from THF-heptane, with an additional 14% yield
of product recoverable from the mother liquors by chro-
matography. Two large scale (>100 kg) pilot runs for
this step gave the product in a total yield of 92%.
Resolution of 16 was done by acetylation with isopro-
penyl acetate catalyzed by Amano PS-30 lipase im-
mobilized on Celite. The acetylation was taken to 60%
conversion, and the (S)-diol 18 was separated from the
acetylated product 19 by either chromatography or by
crystallization; in this case, chromatography gave better
recovery and ee of isolated product than crystallization.
Yield of (S)-diol 1824 with ee > 99% as determined by
chiral HPLC was 38% (76% of theoretical). The reaction
rate significantly increased when the PS-30 was im-
mobilized with Celite 521 (1:1 by weight). For compari-
son, 20-25% conversion of diol to ester was normally
observed after one day at room temperature with im-
mobilized lipase, while commercial PS-30 gave <5% ester
formation in the same time. Butyric anhydride, succinic
anhydride, vinyl acetate, and isopropenyl acetate were
examined as acylating agents. The poorest result was
obtained with butyric anhydride (ees 79% and eep 67%, c
) 54%, enantiomeric ratio E25 ) 12). Vinyl acetate and
succinic anhydride afforded similar results: vinyl acetate
ees 93% and eep 85% at c ) 52%, E ) 45, and succinic
anhydride ees 90% and eep 82% at c ) 53%, E ) 30. Even
though the use of succinic anhydride would be advanta-
geous for the separation of the hemisuccinate from the
unreacted and desired (S)-diol starting material by acid-
base extraction, the lipase reaction was too slow for
practical usefulness. Isopropenyl acetate and vinyl ac-
etate could be used interchangeably in the reaction.
The best reaction conditions were found to be slurry-
to-slurry reaction conditions at room temperature (100
g 16/250 mL MTBE, equal weight immobilized PS-30
catalyst, 1 equiv isopropenyl acetate). Under these
conditions the reaction took 2 days to reach 60% comple-
tion; with a homogeneous solution of 16 the reaction took
4 days to reach the same conversion. The lipase reaction
could be accelerated by performing the reaction at 40-
50 °C without detrimental effect on ee, and the recovered
catalyst was reused several times without major loss in
activity.
An efficient procedure for the recycle of the acetylated
byproduct 19 from the lipase resolution was developed
(Scheme 4). Direct racemization or inversion of the (R)-
enantiomer is expected to be a difficult process based on
the known chemistry of camptothecin and analogs;
procedures exist for the inversion of the hydroxyl stere-
ochemistry in related compounds but the yields are low,6b
and elimination of the hydroxyl group to form 14 directly
is not expected to be a facile process.8a The acetylated
byproducts 19 (primarily R) from the lipase resolution
were transesterified with 1-propanol and a catalytic
amount of potassium tert-butoxide at room temperature.
The resulting (R)-diol mixture 20 was reacted with DMF
dimethylacetal to give 21 as a mixture of stereoisomers;
heating 21 with acetic anhydride yielded 14.26 Overall
chemical yield was >90% for the three-step process,
which was done in one pot without isolation or purifica-
tion of the intermediates.
Conversion of the (S)-diol 18 into the pyridone 25 was
done in four high yielding steps (Scheme 5). The primary
alcohol was oxidized to the aldehyde 22 in 95% yield by
sodium hypochlorite catalyzed by TEMPO,27 carefully
limiting the amount of sodium hypochlorite used to
minimize oxidative cleavage of the aldehyde. Hydroge-
nation of the benzyl ether gave the lactol 23 as essentially
a single diastereomer in 96% yield by crystallization from
methanol. Alternatively, 23 can be isolated by crystal-
lization from heptane/THF in 91.7% yield; this crystal-
lization removes impurities that may form in the Tempo
oxidation and upgrades the ee from >99% to >99.8% as
determined by chiral HPLC assay. A second TEMPO
(21) Preliminary experiments were done with asymmetric dihy-
droxylations22 on the dimethyl analog 17. Reaction with 1 mol %
potassium osmate and 1 mol % DHQD2-phthal required 48 h to go to
>90% completion and gave diol product with an ee of 68% (Henegar,
K. E.; Baughman, T. A., unpublished results). In view of our require-
ment for an ee > 99% for the final product and time constraints,
optimization of the asymmetric dihydroxylation was deferred in favor
of a lipase resolution of the racemic diol to establish the enantiomeric
purity.
(22) (a) Crispino, G. A.; J eong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu,
D.; Sharpless, K. B. J . Org. Chem. 1993, 58, 3785-3786, and references
cited in this paper. (b) Crispino, G. A.; Makita, A.; Wang, Z.-M.;
Sharpless, K. B. Tetrahedron Lett. 1994, 35, 543-546.
(23) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 1973-1976.
(24) Assignment of the absolute stereochemistry of this intermediate
was done by conversion into 1 and comparison of the sign of the specific
rotation with published values from material of known absolute
stereochemistry. Determination of enantiomeric purity of the diol 16
and of later intermediates was made by chiral HPLC analysis.
(25) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294-7299.
(26) (a) Hanessian, S.; Bargiotti, A.; LaRue, M. Tetrahedron Lett.
1978, 737-740. (b) Eastwood, F. W.; Harrington, K. J .; J osan, J . S.;
Pura, J . L. Tetrahedron Lett. 1970, 5223-5224.
(27) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J . Org. Chem.
1987, 52, 2559-2562. TEMPO and 4-acetoxy-TEMPO were used
interchangeably for the oxidations of 17 and 22.

6592 J . Org. Chem., Vol. 62, No. 19, 1997
Henegar et al.
Sch em e 5a
Sch em e 6a
detection 0.2%); precursors 23 and 25 had ee > 99.8%
(limits of detection 0.1%). Further confirmation of enan-
tiomeric purity was obtained after conversion into irino-
tecan.
Irinotecan was made from 1 in three steps (Scheme
6). Reaction of 1 with 2-amino-5-hydroxypropiophenone
(27)29 yields the intermediate phenol SN-38, not normally
isolated and difficult to manipulate due to its poor
solubility in most common organic solvents. Conversion
of SN-38 into irinotecan was then done using the pub-
lished procedure1 by reaction with 4-piperidinopiperidine-
carbamyl chloride followed by purification and salt
formation to give irinotecan in 70% overall yield from 1,
identical to material obtained from Yakult Honsha.
Analysis of this material by chiral HPLC showed the
enantiomeric purity to be >99.8% (R enantiomer detec-
tion limit 0.1%).
oxidation converted the lactol into the lactone 24 (95%
yield) and reaction of 24 with TMS-I, generated in situ
from TMS-Cl and sodium iodide in acetonitrile,6e,28 gave
the pyridone 25 in 89% yield after crystallization from
EtOAc-MTBE. Enantiomeric purity of the pyridone was
determined by chiral HPLC to be >99.8%.
Con clu sion
The synthesis described produces (S)-1, a valuable
intermediate for the synthesis of camptothecin and
analogs, with an ee > 99.6% in 18 chemical steps and
6.4% overall yield on a laboratory scale, uncorrected for
recovery of unreacted 5 or recycle of 19. The synthesis
starts with inexpensive, readily available materials and
is operationally simple to perform. Enantiomeric purity
is established with an efficient lipase resolution and only
one chromatography is required. The chemistry de-
scribed was scaled up successfully with minimal modi-
fications; the initial piloting gave >35 kg of 26 in 6.3%
overall yield with eight isolated intermediates.
Annulation of the cyclopentanone ring was done with
tert-butyl acrylate (10 equiv) and cesium carbonate (2
equiv) in DMSO at 50 °C to give 26, isolated as the
crystalline solvate with toluene (1:1) in 75% yield. The
product exists entirely in the enol form. Deesterification
and decarboxylation of 26 was done in toluene with TFA
as the acidic catalyst to give (S)-1 in 95% yield as a
crystalline solid. Purification of 1, if necessary, can be
done by crystallization from methylene chloride-ethyl
acetate, but the product is unstable to silica and cannot
readily be purified by chromatography. Establishment
of absolute stereochemistry of 1 was done by comparison
of its measured rotation with the values reported in the
literature for material of known stereochemistry (see
Experimental Section). Chiral HPLC analysis of 1
showed no detectable R enantiomer (ee > 99.6%, limit of
Exp er im en ta l Section
Materials were used as received from commercial suppliers.
Melting points were determined on an automatic melting point
determination instrument. Optical rotations were determined
(29) Giovannini, E.; Rosales, J .; de Souza, B. Helv. Chem. Acta 1971,
54, 2111-2113. Material used here was prepared from 2-nitro-5-
hydroxybenzaldehyde (five steps) or from p-anisidine (one step)
(Baughman, T. A.; Hewitt, B. D.; Henegar, K. E., unpublished results).
(30) Tagawa, H.; Terasawa, H.; Ejima, A. Eur. Pat. Appl. 114231,
1986.
(28) (a) Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R. J .
Org. Chem. 1979, 44, 1247-1251. (b) J ung, M. E.; Lyster, M. A. J .
Org. Chem. 1977, 42, 3761-3763. (c) Morita, T.; Okamoto, Y.; Sakurai,
H. J . Chem. Soc., Chem. Commun. 1978, 874-875.

Synthesis of Key Intermediate for Irinotecan Synthesis
J . Org. Chem., Vol. 62, No. 19, 1997 6593
with a Rudolph Autopohl III polarimeter using a 10 cm path
length cell. Infared spectra were recorded, as noted, in KBr
for solid samples (2 mg sample/200 mg KBr) or as thin films
for oils. Microanalyses were performed by Structural and
Medicinal Chemistry (Pharmacia and Upjohn). MTBE refers
to methyl tert-butyl ether. All silica used was 230-400 mesh.
2,6-Dich lor o-4-p yr id in eca r boxylic Acid (2). Citrazinic
acid (152.0 g, 0.98 mol) and Me4NCl (107.71 g, 1.02 mol) were
suspended in POCl3 (450 g, 273 mL, 2.9 mol) and heated in a
130 °C bath. When the internal temperature reached 75 °C
the solids dissolved with a slight exotherm to yield a clear
brown solution. The reaction mixture was heated at 130 °C
for 18 h and then heated to 145 °C for 2 h. After cooling to rt,
the mixture was poured onto 2 kg of ice and stirred for 2 h.
The resulting solids were filtered and dried and then stirred
with 1.5 L of EtOAc and filtered to remove insoluble material
(primarily citrazinic acid). The organic solution was dried over
Na2SO4 and evaporated to yield 146.9 g (78%) of a light brown
solid: mp 203.8-204.7 °C, (lit.12 mp. 205-207 °C); IR (KBr)
64.8, 106.2, 109.2, 113.8, 148.3, 157.3, 163.9; MS (FAB) m/ e
244, 246 ([M + H]+), 101. HRMS (FAB) m/ e calcd for C11H15
-
ClNO3: ([M + H]+) 244.0740; found: ([M + H]+), 244.0743.
Anal. Calcd for C11H14ClNO3: C, 54.22; H, 5.79; Cl, 14.55; N,
5.75. Found: C, 54.30; H, 6.01; Cl, 14.40; N, 5.73.
6-Ch lor o-4-(2-eth yl-1,3-d ioxola n -2-yl)-2-m eth oxy-3-p yr -
id in eca r boxa ld eh yd e (6) a n d 6-Ch lor o-4-(2-eth yl-1,3-d i-
oxola n -2-yl)-2-m et h oxy-3-p yr id in em et h a n ol (8). Com-
pound 5 (73.05 g, 0.299 mol) was dissolved in 1400 mL of
heptane and cooled to -10 °C. A solution of n-BuLi in hexanes
(235 mL, 0.588 mol) was added over 10 min, keeping the
internal temperature <5 °C. The turbid orange solution was
stirred at 0 °C for 30 min after completion of the butyllithium
addition and then cooled to -30 °C. N-Formylpiperidine (66.0
mL, 0.588 mol) was added, and the mixture was allowed to
warm to 0 °C and stirred for 1 h. The deep red mixture was
quenched by the addition of 600 mL of 1 N HCl, the phases
were separated, and the aqueous phase was extracted with
MTBE (2 × 250 mL). A portion of the combined organic phases
was concentrated and chromatographed on silica with 4:1
heptane/EtOAc to yield a sample of 6.
1723 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 2 H); 13
C
NMR (75 MHz, DMSO-d6) δ 122.9, 144.6, 150.1, 163.7; MS (CI)
m/ e 192, 194 (M‚+), 165, 167, 148, 150, 131, 133, 114, 116.
1-(2,6-Dich lor o-4-p yr id in yl)-1-p r op a n on e (3). Com-
pound 2 (6.6 g, 34 mmol) was mixed with 82 mL of THF and
the mixture cooled to -40 °C. Ethylmagnesium chloride in
THF (52 mL, 104 mmol) was added over 15 min, keeping the
internal reaction temperature less than -30 °C. The resulting
dark brown mixture was allowed to warm to 0 °C and stirred
at 0 °C for 1 h. The reaction mixture was recooled to -25 °C,
and 3.2 mL (52 mmol) of methyl formate was added. After 15
min at -25 °C, 20 mL of 6 M HCl was added and the mixture
was allowed to warm to rt. The phases were separated, and
the lower aqueous phase was extracted with THF (3 × 10 mL).
The combined THF phases were washed twice with a mixture
of 15 mL of 1 N NaOH and 15 mL of saturated aqueous NaCl
and then once with 15 mL of saturated aqueous NaCl solution.
The organic phase was dried over Na2SO4 and then concen-
trated to an oil. Toluene (50 mL) was added, the mixture was
concentrated to an oil, and the process was repeated to yield
6.01 g (84%) of a clear brown oil which crystallized under
vacuum: mp 61.1-62.4 °C; IR (KBr) 1700 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.17 (t, J ) 7.1 Hz, 3 H), 2.88 (q, J ) 6.6 Hz,
2 H), 7.61 (s, 2 H); 13C NMR (75 MHz, CDCl3) δ 7.5, 32.6, 120.9,
147.7, 151.8, 197.1; MS (EI) m/ e 203, 205 (M‚+), 174, 176, 146,
148, 110, 85, 76, 60, 50. Anal. Calcd for C8H7Cl2NO: C, 47.09;
H, 3.46; Cl, 34.75; N, 6.86. Found: C, 46.97; H, 3.39; Cl, 34.39;
N, 6.84.
2,6-Dich lor o-4-(2-eth yl-1,3-d ioxola n -2-yl)p yr id in e (4).
Ketone 3 (90.2 g, 0.44 mol), ethylene glycol (650 mL), and
TMSCl (140 mL, 1.1 mol) were stirred at rt. White crystals
gradually formed in the mixture. After about 12 h the reaction
had gone to completion. The reaction was neutralized by the
addition of 1 L of 1 N NaOH solution and extracted with 1:1
EtOAc/heptane (3 × 250 mL). The organic extracts were
combined, dried over Na2SO4, and evaporated. The crystalline
residue was dried under high vacuum to yield 109.71 g (100%)
of the product: mp 94.0-95.0 °C; 1H NMR (300 MHz, CDCl3)
δ 0.80 (t, J ) 7.4 Hz, 3 H), 1.78 (q, J ) 7.4 Hz, 2 H), 3.72 (t,
J ) 7.0 Hz, 2 H), 3.99 (t, J ) 7.0 Hz, 2 H), 7.27 (s, 2 H); 13C
NMR (75 MHz, CDCl3) δ 7.4, 32.8, 65.1, 108.9, 120.3, 150.6,
158.0; MS (EI) m/ e 218, 220 (M‚+), 174, 176, 110, 101, 85, 76,
57. Anal. Calcd for C10H11Cl2NO2: C, 48.41; H, 4.47; Cl, 28.58;
N, 5.65. Found: C, 48.41; H, 4.55; Cl, 28.55; N, 5.65.
To the combined organic phases were added 250 mL of
water, 8.3 g (0.029 mol) of n-Bu4NCl, and 11.3 g (0.29 mol) of
NaBH4. The mixture was vigorously stirred at rt for 18 h.
Acetone (20 mL) was added, and the mixture was stirred at rt
for 30 min. The aqueous phase was removed, and the organic
phase was washed once with 500 mL of water. The organic
phase was evaporated to an oil and chromatographed on 800
g of silica using 4:1(v/v) hexane/EtOAc to yield 57.30 g (71%)
of 8 as a white solid and 15.0 g (20%) of 5.
6-Ch lor o-4-(2-eth yl-1,3-d ioxola n -2-yl)-2-m eth oxy-3-p yr -
id in eca r boxa ld eh yd e (6): mp 57.6-60.4 °C; IR (KBr) 1709
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.96 (t, J ) 9.0 Hz, 3 H),
2.03 (q, J ) 9.0 Hz, 2 H), 3.75 (m, 2 H), 4.00 (m, 2 H), 4.00 (s,
3 H), 7.13 (s, 1 H), 10.44 (s, 1 H); 13C NMR (75 MHz, CDCl3)
δ 7.3, 33.3, 54.8, 64.8, 109.7, 114.7, 117.2, 150.8, 157.5, 161.7,
190.8; MS (FAB) m/ e 272, 274 ([M + H]+), 254, 101. HRMS
(FAB) m/ e calcd for C12H17ClNO4: ([M + H]+) 272.0689;
found: ([M + H]+), 272.0695. Anal. Calcd for C12H16ClNO4:
C, 53.05; H, 5.19; Cl, 13.05; N, 5.16. Found: C, 53.43; H, 5.31;
Cl, 12.76; N, 5.09.
6-Ch lor o-4-(2-eth yl-1,3-d ioxola n -2-yl)-2-m eth oxy-3-p yr -
id in em eth a n ol (8): mp 46.8-48.8 °C; IR (KBr) 3500 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.84 (t, J ) 7.5 Hz, 3 H), 1.87 (q,
J ) 7.0 Hz, 2 H), 3.74 (m, 2 H), 3.92 (s, 3 H), 3.97 (m, 2 H),
4.72 (s, 1 H), 7.05 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.5,
33.0, 54.5, 56.7, 65.0, 110.2, 114.5, 119.1, 147.4, 154.5, 163.0;
MS (EI) m/ e 273 (M
‚+), 244, 228, 210, 200, 101, 57. Anal.
Calcd for C12H16ClNO4: C, 52.66; H, 5.89; Cl, 12.95; N, 5.12.
Found: C, 52.74; H, 5.66; Cl, 12.93; N, 5.18.
6-Ch lor o-4-(2-e t h yl-1,3-d ioxola n -2-yl)-2-m e t h oxy-3-
[(p h en ylm eth oxy)m eth yl]p yr id in e (9). Alcohol 8 (503.98
g, 1.841 mol) was dissolved in 1330 mL of THF, and 1200 g of
t-BuOK solution in THF (2.09 mol, 20 wt %) was added,
keeping the internal temperature less than 30 °C. The
mixture was stirred for 30 min and then benzyl bromide (230.0
mL, 2.117 mol) was added, keeping the internal temperature
less than 30 °C. After completion of the benzyl bromide
addition, the mixture was stirred at 20-30 °C for 1 h. Aqueous
Me2NH solution (38 mL, 40 wt %) was added, and the mixture
was stirred at 20-30 °C for 30 min. A 276 mL volume of 1 N
HCl and 2 L of EtOAc were added, and the phases were
separated. The organic phase was washed with water (3 × 1
L) and evaporated to give 663.5 g (99.3%) of 9 as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 0.75 (t, J ) 7.4 Hz, 3 H),
1.82 (q, J ) 7.4 Hz, 2 H), 3.61 (m, 2 H), 3.82 (s, 3 H), 3.85 (m,
2 H), 4.48 (s, 2 H), 4.57 (s, 2 H), 6.97 (s, 1 H), 7.23 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 7.5, 33.0, 54.5, 62.83, 64.7, 73.2,
110.1, 114.8, 116.4, 127.5, 127.8, 128.2, 138.4, 147.9, 155.6,
163.7; MS (EI) m/ e 363 (M‚+), 272, 254, 228, 210, 101, 91. Anal.
Calcd for C19H22ClNO4: C, 62.72; H, 6.09; Cl, 9.74; N, 3.85.
Found: C, 62.88; H, 6.12; Cl, 9.72; N, 4.14.
6-Ch lor o-4-(2-eth yl-1,3-d ioxola n -2-yl)-2-m eth oxyp yr i-
d in e (5). Compound 4 (57.5 g, 0.23 mol) was dissolved in 170
mL of MeOH. NaOMe solution in MeOH (80 mL, 0.35 mol,
25 wt %) was added and the mixture heated to reflux for 20 h.
After cooling to rt, 250 mL of water and 200 mL of CH2Cl2
were added. The aqueous phase was extracted with CH2Cl2
(2 × 200 mL). The organic phases were combined, dried over
MgSO4, filtered, and concentrated to an amber oil which
crystallized upon seeding to yield 50.43 g (89%) of 5 as a light
1
yellow solid: mp 48.1-49.0 °C; H NMR (300 MHz, CDCl3) δ
6-Ch lor o-4-(2-e t h yl-1,3-d ioxola n -2-yl)-2-m e t h oxy-3-
(m eth oxym eth yl)p yr id in e (10). Alcohol 8 (0.980 g, 3.6
mmol), 2.8 g of t-BuOK solution in THF (5 mmol, 20 wt %),
and 10 mL of THF were stirred at rt for 10 min. CH3I (0.31
0.88 (t, J ) 7.4 Hz, 3 H), 1.85 (q, J ) 7.5 Hz, 2 H), 3.78 (t, J
) 6.9 Hz, 2 H), 3.93 (s, 3 H), 4.02 (t, J ) 7.1 Hz, 2 H), 6.73 (s,
1 H), 6.98 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.6, 32.5, 54.0,

6594 J . Org. Chem., Vol. 62, No. 19, 1997
Henegar et al.
mL, 5 mmol) was added, causing the immediate formation of
a white precipitate. After 10 min, 10 mL of saturated aqueous
NH4Cl solution was added. The aqueous phase was extracted
with 10 mL of ether. The organic phases were combined, dried
over Na2SO4, and evaporated to yield 1.026 g (99%) of 10 as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.75 (t, J ) 7.5 Hz,
3 H), 1.80 (q, J ) 7.5 Hz, 2 H), 3.28 (s, 3 H), 3.64 (m, 2 H),
3.82 (m, 3 H), 3.87 (2, 2 H), 4.46, (s, 2 H), 6.96 (s, 1 H); 13C
NMR (75 MHz, CDCl3) δ 7.4, 33.0, 54.5, 58.6, 64.7, 64.8, 110.1,
114.8, 116.3, 147.8, 155.5, 163.6; MS (EI) m/ e 287 (M‚+), 258,
242, 214, 184, 101.
6-Meth oxy-4-(1-m eth ylen epr opyl)-5-[(p h en ylm eth oxy)-
m eth yl]-2-p yr id in eca r boxylic Acid , P r op yl Ester (14).
Methyltriphenylphosphonium bromide (2.14 g, 6.0 mmol) was
dissolved in 15 mL of DMF and stirred at 0 °C. Potassium
bis(trimethylsilyl)amide solution in toluene (10 mL, 5.0 mmol)
was added, and the yellow solution with suspended white
solids was stirred at 0 °C for 10 min. A solution of ketone 13
(1.48 g, 4.0 mmol) in 5 mL of THF was added all at once, giving
a deep red color that rapidly faded to brown. The mixture was
stirred at 0 °C for 10 min. Additional ylide solution was added
until all of the 12 was consumed. The reaction was quenched
by the addition of 10 mL of 1 N HCl. MTBE (20 mL) was
added, the phases were separated, and the aqueous phase was
extracted with MTBE (2 × 20 mL). The combined organic
phases were washed with water (3 × 20 mL), dried over
Na2SO4, and evaporated to a volume of about 15 mL. The
solution was chromatographed on 20 g of silica with 4:1
hexane/EtOAc to yield 1.39 g of 14 (92%) as a light yellow oil:
4-(2-E t h yl-1,3-d ioxola n -2-yl)-2-m et h oxy-3-(m et h oxy-
m eth yl)p yr id in e (11). Ether 10 (0.166 g, 0.6 mmol) and 0.18
g (1.6 mmol) of anhydrous NiCl2 were stirred with 5 mL of
THF and cooled to -40 °C. LAH solution (2 mL, 2 mmol) in
THF was added, causing gas evolution and the immediate
formation of a black precipitate. The mixture was stirred and
allowed to warm to rt. After 3 h, 10 mL of saturated aqueous
NH4Cl solution was added. The mixture was filtered over
Celite to remove black solids. The aqueous phase was ex-
tracted with 10 mL of ether, and the combined organic phases
were dried over Na2SO4. Evaporation yielded 0.127 g (83.6%)
of 10 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.78 (t,
J ) 7.5 Hz, 3 H), 1.84 (q, J ) 7.4 Hz, 2 H), 3.32 (s, 3 H), 3.62-
3.67 (m, 2 H), 3.18-3.91 (m, 2 H), 3.86 (s, 3 H), 4.54 (s, 2 H),
6.94 (d, J ) 5.4 Hz, 1 H), 7.95 (d, J ) 5.4 Hz, 1 H); 13C NMR
(75 MHz, CDCl3) δ 7.5, 33.1, 53.8, 58.6, 64.3, 65.3, 110.3, 115.3,
117.7, 146.0, 152.5, 163.9; MS (EI) m/ e 253 (M‚+), 224, 208,
180, 150, 101.
1
IR (film) 1740, 1718 cm-1; H NMR (300 MHz, CDCl3) δ 0.85
(m, 6 H), 1.59 (m, 2 H), 2.20 (q, J ) 7.4 Hz, 2 H), 3.89 (s, 3 H),
4.12 (t, J ) 6.7 Hz, 2 H), 4.33 (s, 2 H), 4.42 (s, 2 H), 4.89 (s, 1
H), 5.06 (s, 1 H), 7.17 (m, 5 H), 7.35 (s, 1 H); 13C NMR (75
MHz, CDCl3) δ 10.4, 12.1, 22.0, 30.2, 53.9, 63.8, 67.0, 73.0,
114.7, 118.7, 121.4, 127.6, 127.9, 128.3, 138.2, 144.5, 147.6,
155.3, 163.1, 165.2; MS (FAB) m/ e 370 ([M + H]+), 340, 278,
262, 220, 190, 160, 91. HRMS (FAB) m/ e calcd for C22H27
-
NO4: ([M + H]+) 370.2018; found: ([M + H]+), 370.2017. Anal.
Calcd for C22H26NO4: C, 71.52; H, 7.37; N, 3.79. Found:
C,71.74; H, 7.28; N, 3.87.
The above chromatography also yielded 0.028 g (2.2%) of
the diene 15 as a light yellow oil: 1H NMR (300 MHz, CDCl3)
δ 1.06 (t, J ) 7.35 Hz, 3 H), 2.21 (s, 3 H), 2.40 (q, J ) 7.35 Hz,
2 H), 4.04 (s, 3 H), 4.55 (s, 2 H), 4.62 (s, 2 H), 5.06 (s, 1 H),
5.22 (s, 1 H), 5.27 (s, 1 H), 6.02 (s, 1 H), 6.87 (s, 1 H), 7.31-
7.42 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 12.1, 20.2, 29.4,
30.4, 53.3, 63.9, 72.7, 112.5, 113.6, 115.2, 115.9, 127.4, 127.6,
127.9, 128.2, 138.6, 142.5, 148.7, 154.3, 155.1, 162.0; MS (EI)
m/ e 323 (M‚+), 232, 216, 204, 202, 91.
4-(2-Eth yl-1,3-dioxolan -2-yl)-6-m eth oxy-5-[(ph en ylm eth -
oxy)m et h yl]-2-p yr id in eca r b oxylic Acid , P r op yl E st er
(12). Compound 9 (66.45 g, 183 mmol), Pd(OAc)2 (2.05 g, 9.13
mmol), DPPP (4.14 g, 10.0 mmol), K2CO3 (37.86 g, 274 mmol),
n-PrOH (665 mL), and DMF (332 mL) were charged to a flask.
The flask was purged with nitrogen and then with carbon
monoxide. The mixture was vigorously stirred and heated to
90 °C under an atmosphere of carbon monoxide (15 psi) for
about 16 h. The reaction was cooled and vented. The solids
were removed by filtration through Celite, and the Celite was
washed with 350 mL of THF. The combined filtrates and
washing were concentrated to a volume of about 400 mL.
Water (700 mL) and MTBE (700 mL) were added. The
aqueous phase was separated and extracted with 350 mL of
MTBE. The combined MTBE solutions were extracted with
water (4 × 350 mL), dried over Na2SO4, and evaporated.
Chromatography on 600 g of silica with 80:20 (v/v) heptane/
EtOAc yielded 68.03 g (89%) of 12 as a faintly orange oil: IR
(film) 1736 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J ) 7.4
Hz, 3 H), 0.98 (t, J ) 7.4 Hz, 3 H), 1.77 (m, 2 H), 1.93 (q, J )
7.4 Hz, 2 H), 3.71 (m, 2 H), 3.94 (m, 2 H), 3.99 (s, 3 H), 4.26 (t,
J ) 6.7 Hz, 2 H), 4.59 (s, 2 H), 4.74 (s, 2 H), 7.29 (m, 5 H),
7.82 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.5, 10.4, 22.0, 33.1,
54.1, 63.1, 64.7, 67.0, 73.3, 110.3, 117.0, 122.1, 127.5, 128.0,
128.2, 138.4, 144.7, 153.6, 163.9, 165.3; MS (EI) m/ e 415 (M‚+),
386, 324, 306, 280, 262, 101, 91. Anal. Calcd for C23H29NO6:
C, 66.49; H, 7.04; N, 3.37. Found: C, 66.65; H, 7.70; N, 3.42.
4-[1-Hyd r oxy-1-(h yd r oxym eth yl)p r op yl]-6-m eth oxy-5-
[(ph en ylm eth oxy)m eth yl]-2-pyr idin ecar boxylic Acid, P r o-
p yl Ester (16). Olefin 14 (100.0 g, 0.271 mol), Me3NO-2H2O
(90.24 g, 0.81 mmol), OsO4 (0.68 g, 2.7 mmol), and t-BuOH
(300 mL) were charged to a flask. The mixture was heated to
40 °C for 24 h and then cooled to 20-25 °C. Water (300 mL)
and sodium bisulfite (110 g) were added, and the mixture was
stirred for 30 min at rt. The mixture was extracted with
EtOAc (4 × 200 mL). The combined organic phases were
stirred with 100 g of magnesol for 1 h, and then the slurry
was filtered over 50 g of magnesol. The filtrates were
concentrated to an oil. Toluene (200 mL) and heptane (800
mL) were added, and the mixture was allowed to crystallize
at -20 °C for 18 h. The solids were filtered, washed with 200
mL heptane, and dried to yield 83.51 g of white solids.
Concentration of the mother liquors yielded an additional 3.21
g of white solids. The dark mother liquors were chromato-
graphed on about 500 g of silica with 2:1 heptane/EtOAc to
yield 13.75 g of product. Total yield of 16: 100.47 g, 92%: mp
97.5-101.0 °C; IR (KBr) 3448, 1715 cm-1; 1H NMR (300 MHz,
CDCl3) δ 0.74 (t, J ) 7.4 Hz, 3 H), 1.03 (t, J ) 7.4 Hz, 3 H),
1.80 (m, 4 H), 3.69 (d, J ) 11.2 Hz, 1 H), 3.86 (d, J ) 11.2 Hz,
1 H), 4.01 (s, 3 H), 4.31 (t, J ) 6.7 Hz, 2 H), 4.88 (d, J ) 10.7
Hz, 1 H), 4.96 (d, J ) 10.7 Hz, 1 H), 7.33 (m, 5 H), 7.64 (s, 1
H); 13C NMR (75 MHz, CDCl3) δ 7.5, 10.4, 22.0, 31.7, 54.2,
62.9, 67.1, 70.9, 72.7, 80.1, 117.8, 122.2, 128.0, 128.4, 137.1,
144.7, 155.8, 163.2, 165.2; MS (FAB) m/ e 404, ([M + H]+), 296,
278, 250, 222, 190, 162, 91. HRMS (FAB) m/ e calcd for
C22H29NO6: ([M + H]+) 404.2073; found: ([M + H]+), 404.2076.
Anal. Calcd for C22H29NO6: C, 65.48; H, 7.25; N, 3.47.
Found: C, 65.76; H, 7.28; N, 3.49.
6-Meth oxy-4-(1-oxopr opyl)-5-[(ph en ylm eth oxy)m eth yl]-
2-p yr id in eca r boxylic Acid , P r op yl Ester (13). Ketal 12
(68.02 g, 163.7 mmol) was dissolved in 384 mL of 50% aqueous
TFA, and the mixture was stirred at rt for 21 h. Water (880
mL) was added, and the mixture was extracted with EtOAc
(2 × 500 mL). The organic phases were combined and washed
with water (2 × 500 mL) and then neutralized with saturated
aqueous NaHCO3 solution. The organic phase was dried over
Na2SO4 and evaporated to yield 59.86 g (98.4%) of 13 as a light
yellow oil: IR (film) 1715 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.96 (m, 6 H), 1.72 (m, 2 H), 2.68 (q, J ) 7.2 Hz, 2 H), 3.96 (s,
3 H), 4.23 (t, J ) 6.7 Hz, 2 H), 4.42 (s, 2 H), 4.58 (s, 2 H), 7.24
(m, 5 H), 7.48 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.5, 10.4,
22.0, 36.2, 54.1, 63.8, 67.2, 73.6, 115.5, 121.5, 127.9, 128.0,
128.2, 128.4, 137.3, 144.9, 151.0, 161.3, 164.5; MS (FAB) m/ e
(S)-4-[1-Hydr oxy-1-(h ydr oxym eth yl)pr opyl]-6-m eth oxy-
5-[(p h en ylm eth oxy)m eth yl]-2-p yr id in eca r boxylic Acid ,
P r op yl Ester (17). Racemic diol 16 (100 g, 0.25 mol) and 100
g of PS-30 catalyst (Pseudomonas cepaica lipase immobilized
on equal weight of Celite 521) were suspended in 2.5 L of
MTBE. Isopropenyl acetate (75 mL, 0.68 mol) was added, and
372 ([M + H]+), 280, 264, 91. HRMS (FAB) m/ e calcd for C21
-
H26CNO5: ([M + H]+) 372.1811; found: ([M + H]+), 372.1809.
Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77.
Found: C, 67.70; H, 6.69; N, 4.03.

Synthesis of Key Intermediate for Irinotecan Synthesis
J . Org. Chem., Vol. 62, No. 19, 1997 6595
the mixture was stirred at rt for 48 h, when HPLC analysis
showed <2% R alcohol. MTBE (1 L) was added, and the
mixture was heated to 35-40 °C. The catalyst was removed
by filtration, washed with 300 mL of MTBE, and saved for
reuse. The combined filtrate and washing were evaporated
to an oil and redissolved in 200 mL of CH2Cl2. The solution
was chromatographed on 600 g of silica eluting first with 4:1
heptane/EtOAc and then with 1:1 heptane/EtOAc. Evapora-
tion of the product containing fractions yielded 38 g (76% of
theory) of 18 as a white solid (>99% ee by HPLC): mp 99.0-
overall from 19, as determined by quantitative HPLC weight
% assay with chromatographically purified 14 as reference.
1H NMR analysis showed the main impurity to be toluene.
(S)-4-(1-F or m yl-1-h yd r oxyp r op yl)-6-m eth oxy-5-[(p h en -
ylm eth oxy)m eth yl]-2-p yr id in eca r boxylic Acid , P r op yl
Ester (22). (S)-Diol 18 (0.565 g, 1.4 mmol), 4-acetoxy-TEMPO
(0.006 g, 0.028 mmol), KBr (0.0167 g, 0.14 mmol), and NaHCO3
(0.0153 g, 0.182 mmol) were charged to a flask. CH2Cl2 (7 mL)
and water (1 mL) were added, and the mixture was cooled to
0 °C. A solution of NaOCl (1.6 mL, 0.95 M) was added via
syringe pump over about 40 min. At the end of this addition
the reaction was quenched by the addition of 1 mL of 5% (w/
v) aqueous sodium metabisulfite solution. The aqueous phase
was separated and extracted with CH2Cl2 (2 × 5 mL). The
combined organic phases were dried over Na2SO4 and evapo-
100.1 °C; [R]25 ) +4.08° (c 1.0, CHCl3); IR (KBr) 3450, 1716
D
cm-1; H NMR (300 MHz, CDCl3) δ 0.74 (t, J ) 7.4 Hz, 3 H),
1
1.03 (t, J ) 7.4 Hz, 3 H), 1.80 (m, 4 H), 3.69 (d, J ) 11.2 Hz,
1 H), 3.86 (d, J ) 11.2 Hz, 1 H), 4.01 (s, 3 H), 4.31 (t, J ) 6.7
Hz, 2 H), 4.88 (d, J ) 10.7 Hz, 1 H), 4.96 (d, J ) 10.7 Hz, 1 H),
7.33 (m, 5 H), 7.64 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.5,
10.4, 22.0, 31.7, 54.2, 62.9, 67.1, 70.9, 72.7, 80.1, 117.8, 122.2,
128.0, 128.4, 137.1, 144.7, 155.8, 163.1, 165.2; MS (FAB) m/ e
404 ([M + H]+), 296, 278, 250, 222, 162, 91. Anal. Calcd for
rated to yield 0.601 g (100%) of 22 as a brown syrup: [R]25
)
D
+30.8° (c 0.65, CH2Cl2); IR (film) 1719 cm-1 1H NMR (300
;
MHz, CDCl3) δ 0.91 (t, J ) 7.5 Hz, 3 H), 1.03 (t, J ) 7.5 Hz,
3 H), 1.83 (m, 2 H), 2.10 (m, 2 H), 4.02 (s, 3H), 4.35 (t, J ) 6.6
Hz, 2 H), 4.55 (s, 2 H), 4.68 (d, J ) 11.7 Hz, 1 H), 4.87 (d, J )
11.7 Hz, 1 H), 7.35 (m, 5 H), 7.78 (s, 1 H), 9.62 (s, 1 H); 13C
NMR (75 MHz, CDCl3) δ 7.2, 10.4, 22.0, 29.7, 54.3, 63.2, 67.2,
73.1, 82.4, 117.4, 122.5, 128.2, 128.5, 136.7, 145.0, 150.5, 162.9,
164.9, 200.1; MS (FAB) m/ e 402 ([M + H]+), 384, 372, 294,
C
22H29NO6: C, 65.48; H, 7.25; N, 3.47. Found: C, 65.52; H,
7.35; N, 3.50. Chiral HPLC: Chiralpak AD column (4.6 mm
× 25 cm); 90:10 hexane/IPA; 1 mL/min; 295 nm; (S)-19, 8.1
min; (R)-19, 8.5 min; (S)-18, 15.1 min; (R)-18, 16.7 min.
The above chromatography also yielded 67.75 g (60%) of
m on oa ceta te 19 as a viscous, slightly yellow oil: 1H NMR
(300 MHz, CDCl3) δ 0.81 (t, J ) 7.4 Hz, 3 H), 1.05 (t, J ) 7.4
Hz, 3 H), 1.81 (s, 3 H) 1.77-2.0 (m, 4 H), 4.04, (s, 3 H), 4.25
(d, J ) 11.3 Hz, 1 H), 4.33 (t, J ) 6.7 Hz, 2 H), 4.40 (d, J )
11.3 Hz, 1 H), 4.55 (s, 2 H), 5.01 (s, 2 H), 5.26 (s, 1 H), 7.28-
7.38 (m, 5 H), 7.56 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.2,
10.3, 20.4, 22.0, 32.2, 54.1, 62.9, 67.1, 71.9, 72.4, 78.5, 117.5,
122.6, 122.8, 127.9, 128.3, 137.3, 144.7, 155.1, 163.1, 165.0,
170.6; MS (CI) m/ e 446 ([M + H]+), 404, 340, 266.
Recycle of 19 To Yield 6-Meth oxy-4-(1-m eth ylen ep r o-
p yl)-5-[(p h en ylm et h oxy)m et h yl]-2-p yr id in eca r b oxylic
Acid , P r op yl Ester (14). Monoacetate 19 (100.0 g, 0.224
mol), CH2Cl2 (100 mL), n-PrOH (200 mL), and t-BuOK (0.8 g)
were stirred at rt for 4 h. Removal of the acetate was complete
at this time. The solution was distilled to dryness under
vacuum, toluene (300 mL) was added, and the mixture was
distilled to dryness. Toluene (300 mL) was again added, and
the mixture was distilled to dryness under vacuum to yield
crude 20 as a yellow solid (95.8 g), identified by comparison
with 16 by HPLC.
265, 238, 206, 178, 91. HRMS (FAB) m/ e calcd for C22H28
-
NO6: ([M + H]+) 402.1916; found: ([M + H]+), 402.1924. Anal.
Calcd for C22H27NO6: C, 65.82; H, 6.78; N, 3.49. Found: C,
65.56; H, 6.72; N, 3.5. Chiralpak AD column (4.6 mm × 25
cm); 90:10 hexane/IPA; 1 mL/min, 295 nm; (S)-22, 12.3 min;
(R)-22, 13.9 min.
(S)-4-E t h yl-3,4-d ih yd r o-3,4-d ih yd r oxy-8-m et h oxy-1H-
p yr a n o[3,4-c]p yr id in e-6-ca r b oxylic Acid , P r op yl E st er
(23). a . Isola tion F r om Meth a n ol. Aldehyde 22 (2.62 g,
6.6 mol) was dissolved in 30 mL of MeOH and stirred with
10% Pd/C (0.26 g) under an atmosphere of hydrogen (15 psi)
at rt. After 96 h the reaction was complete. The catalyst was
removed by filtration through Celite and washed with 10 mL
of MeOH. Evaporation of the combined filtrate and washing
yielded 1.97 g (96%) of 23 as a white solid: mp 126.5-131.1
°C; [R]25 ) -65.1° (c 1.0, CHCl3); IR (KBr) 1740, 1716 cm-1
;
D
1H NMR (300 MHz, CDCl3) δ 0.84 (t, J ) 7.5 Hz, 3 H), 0.95 (t,
J ) 7.4 Hz, 3 H), 1.73 (m, 4 H), 3.89 (s, 3 H), 4.24 (t, J ) 6.7
Hz, 2 H), 4.57 (d, J ) 17.2 Hz, 1 H), 4.73 (d, J ) 17.2 Hz, 1H),
7.86 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 7.5, 10.4, 21.9, 31.7,
53.7, 58.3, 67.0, 70.7, 93.3, 116.6, 120.4, 143.5, 149.0, 158.5,
165.3; MS (EI) m/ e 311, (M‚+), 265, 252, 236, 224, 209, 194,
179, 166, 57. Anal. Calcd for C15H22NO6: C, 57.68; H, 7.10;
N, 4.48. Found: C, 57.29; H, 6.91; N, 4.44. Chiralpak AD
column (4.6 mm × 25 cm); 90:10 hexane/IPA; flow rate 1 mL/
min; 295 nm detector; (S)-23, 10.2 min; (R)-23, 19.9 min.
The entire crude diol 20 was dissolved in 400 mL of THF.
DMF dimethyl acetal (45 mL, 0.337 mol) and p-TSA-H2O (2.0
g) were added, and the solution was heated under reflux for
30 min. THF was then distilled under atmospheric pressure
until 200 mL of distillate had been collected. DMF dimethyl
acetal (10 mL) and THF (200 mL) were then added, and
distillation under atmospheric pressure was continued until
200 mL of distillate had been collected. Reaction was complete
at this point, and the mixture was distilled under vacuum to
b. Isola tion by Cr ysta lliza tion fr om THF -MTBE.
Aldehyde 22 (12.5 kg, 31.17 mol) was dissolved in 60 L of
MeOH and stirred with 1.5 kg of 5% Pd/C (50% water wet)
under 45 psi hydrogen, maintaining the internal temperature
<45 °C. The reaction was complete in 2 h. The catalyst was
removed by filtration and washed with 20 L of MeOH. The
combined filtrate and washing were distilled under vacuum
to a volume of 30 L. Heptane (83 L) and THF (22.1 L) were
added, and the mixture was heated to 45 °C for 30 min to
dissolve the solids. The solution was cooled to 20-25 °C for 1
h and then to -25 °C. The solids were filtered, washed with
50 L of heptane, and dried at 40 °C. Yield of 23 was 8.89 kg
(91.7%) as a white crystalline solid. Properties of this product
were identical to those of previously characterized material.
Starting material 22 assayed at >99% ee, product 23 assayed
at >99.8% ee.
(S)-4-E t h yl-3,4-d ih yd r o-4-h yd r oxy-8-m et h oxy-3-oxo-
1H-p yr a n o[3,4-c]p yr id in e-6-ca r boxylic Acid , P r op yl Es-
ter (24). A solution of lactol 23 (1.94 g, 6.2 mmol) in 37 mL
of CH2Cl2 was stirred at 0 °C with a solution of TEMPO (0.04
g, 0.25 mmol), NaHCO3 (0.081 g, 0.96 mmol), and KBr (0.088
g, 0.74 mmol) in 3 mL of water. NaOCl solution (12 mL,
approximately 12 wt %) was added dropwise over 30 min.
Sodium bisulfite (1.0 g) was added to destroy the excess
NaOCl. The aqueous phase was extracted with 10 mL of
1
yield crude 21 as an oil: (mixture of diastereomers) H NMR
(300 MHz, CDCl3) δ 0.81 (q, J ) 7.4 Hz, 3 H), 1.05 (t, J ) 7.4
Hz, 3 H), 1.77-1.99 (m, 4 H), 2.34 and 2.47 (s, total of 6 H),
4.07 (s, 3 H), 4.12 (s, 1 H), 4.34 (t, J ) 6.6 Hz, 2 H), 4.40-4.52
(m, 2 H), 4.65 (s, 2 H) 5.41 and 5.61 (s, total of 1 H), 7.28-
7.39 (m, 5 H), 7.92 and 8.00 (s, total of 1 H); 13C NMR (75
MHz, CDCl3) δ 8.2, 8.2, 10.3, 22.0, 32.8, 34.0, 36.9, 37.0, 54.0,
63.3, 67.0, 73.5, 73.9, 83.3, 84.3, 112.4, 116.6, 117.0, 120.3,
127.8, 128.0, 128.3, 137.7, 144.7, 144.9, 154.4, 155.6, 163.6,
163.8, 165.2.
The entire crude DMF acetal 21 was heated with 200 mL
of Ac2O at 100 °C for 16 h. After cooling to about 50 °C the
light yellow solution was added in three portions to 200 mL
of water. The mixture was stirred for 30 min, then extracted
with toluene (1 × 200 mL and 1 × 100 mL). The combined
toluene extracts were washed with 100 mL of saturated
aqueous NaCl solution and then stirred with 10 g of silica.
The toluene slurry was filtered over 20 g of silica and the silica
washed with 100 mL of 95:5 toluene/EtOAc. The combined
filtrates and washing were evaporated to yield 80.1 g of a clear
honey-colored oil; contained weight of 14 was 64.4 g, 90.1%

6596 J . Org. Chem., Vol. 62, No. 19, 1997
Henegar et al.
CH2Cl2, and the combined organic phases were washed once
with 10 mL of water and dried over Na2SO4. The solvent was
evaporated to yield 1.90 g of 24 (99%) as a colorless oil that
(S)-4-Eth yl-4-h yd r oxy-7,8-d ih yd r o-1H-p yr a n o[3,4-f]in -
d olizin e-3,6,10(4H)-tr ion e (1). Ester 26 toluene solvate
(70.3 g, 0.153 mol) was dissolved in 1400 mL of toluene and
140 mL of TFA and heated at 110 °C for 2 h. The solution
was cooled and concentrated under vacuum to about 350 mL.
EtOAc (1 L) was added, and the mixture was cooled to -20
°C. Filtration yielded 37.92 g (93.4%) of 1 as a light brown
crystalline solid: mp 177.1-178.3 °C; (lit.6a mp 169-170 °C;
lit.6b mp 176-177 °C; lit.6c mp 170-171 °C; lit.32 mp 172-174
°C); [R]25D ) +119.57° (c 1.0, CHCl3); (lit.6b [R]25D ) +120.6° (c
solidified on standing: mp 93.8-94.6 °C; [R]25 ) +57.6° (c
D
0.83, CH2Cl2); IR (KBr) 1736 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.88 (t, J ) 7.5 Hz, 3 H), 0.97 (t, J ) 7.6 Hz, 3 H), 1.76 (m,
4 H), 4.0 (s, 3 H), 4.25 (t, J ) 6.9 Hz, 2 H), 5.23 (d, J ) 16.2
Hz, 1 H), 5.52 (d, J ) 16.2 Hz, 1 H), 7.85 (s, 1 H); 13C NMR
(75 MHz, CDCl3) δ 7.5, 10.3, 21.9, 31.9, 54.1, 65.5, 67.2, 72.7,
114.8, 115.2, 146.0, 148.9, 158.5, 164.5, 173.5; MS (FAB) m/ e
310, ([M + H]+),280, 250, 222, 178, 57. HRMS (FAB) m/ e
calcd for C15H20NO6: ([M + H]+) 310.1290; found: ([M + H]+),
310.1299. Anal. Calcd for C15H19NO6: C, 58.25; H, 6.19; N,
4.53. Found: C, 58.04; H, 6.09; N, 4.59. Chiralpak AD column
(4.6 mm × 25 cm); 90:10 hexane/IPA; 1 mL/min; 295 nm
detector; (S)-24, 17.7 min; (R)-24, 25.0 min.
0.62, CHCl3); lit.6c [R]25D ) +109.7° (c 0.76, CHCl3); lit.32 [R]25
D
) +117.6° (c 0.56, CHCl3)); [R]25 ) +104.56° (c 1.0, 4:1
D
CHCl3-CH3OH); (lit.6a [R]25 ) +96° (c 0.4, 4:1 CHCl3-
D
CH3OH)); IR (KBr) 3424, 1740 cm-1
;
1H NMR (300 MHz,
CDCl3) δ 0.98 (t, J ) 7.5 Hz, 3 H), 1.80 (q, J ) 6.0 Hz, 2 H),
2.96 (m, 2 H), 4.36 (t, J ) 6.0 Hz, 2 H), 5.24 (d, J ) 15.0 Hz,
1
1 H), 5.66 (d, J ) 15.0 Hz, 1 H), 7.27 (s, 1 H); H NMR (300
(S)-4-Eth yl-3,4,7,8-tetr a h yd r o-4-h yd r oxy-3,8-d ioxo-1H-
p yr a n o[3,4-c]p yr id in e-6-ca r b oxylic Acid , P r op yl E st er
(25). Lactone 24 (97.5 g, 0.31 mol) and NaI (94.1 g, 0.62 mol)
were dissolved in 730 mL of acetonitrile and stirred at 0 °C.
TMSCl (79.7 mL, 0.62 mol) was added, and the mixture was
stirred and allowed to warm to rt over 12 h. Additional NaI
(9.4 g, 0.062 mol) and TMSCl (8 mL, 0.062 mol) were added
and stirring was continued for 6 h. 1 N Hydrochloric acid (88
mL), 38% aqueous sodium bisulfite solution (13 mL), saturated
aqueous NaCl solution (195 mL), water (390 mL), and EtOAc
(710 mL) were added, and the mixture was stirred for 30 min.
The phases were separated, and the aqueous phase was
extracted with EtOAc (3 × 310 mL). The combined organic
solutions were stirred with 4.4 g of NaHCO3 and 8.8 mL of
38% aqueous sodium metabisulfite solution in 90 mL of water
for 15 min. The organic phase was removed and washed with
saturated aqueous NaCl solution (2 × 90 mL) and once with
water (90 mL). The EtOAc solution was distilled under
atmospheric pressure to a volume of about 100 mL. MTBE
(100 mL) was added, and the slurry was cooled to 0 °C for 1 h.
The solids were filtered, washed with MTBE (2 × 100 mL),
and dried on a nitrogen press to yield 81.44 g (89%) of 25 as
a light yellow solid: mp 187.6-189 °C; [R]25D ) +95.55° (c 1.0,
MHz, DMSO-d6) δ 0.80 (t, J ) 7.3 Hz, 3 H), 1.81 (m, 2 H),
2.89 (t, J ) 6.3 Hz, 2 H), 4.13 (t, J ) 6.3 Hz, 2 H), 5.34 (d, J
) 17.1 Hz, 1 H), 5.41 (d, J ) 17.1 Hz, 1 H), 6.86 (s, 1 H); 13C
NMR (75 MHz, DMSO-d6) δ 7.5, 30.3, 33.7, 42.6, 65.2, 71.9,
98.5, 123.8, 140.2, 149.0, 157.0, 172.0, 197.9; MS (FAB) m/ e
264, ([M + H]+), 236, 218, 162, 123. Chiralcel OD column (4.6
mm × 25 cm); 65:35 hexane/EtOH + 0.1% TFA; 1 mL/min;
335 nm; (S)-1, 13.2 min; (R)-1, 16.2 min.
Wa r n in g: Irinotecan and SN-38, like camptothecin and
other camptothecin analogs, have cytotoxic properties and are
mutagenic. Appropriate precautions must be taken to avoid
exposure to irinotecan and to waste streams that are gener-
ated. The following procedure was carried out in a class III
glove box.
Ir in oteca n . Ketone 1 (10.0 g, 38.0 mmol), amino ketone
27 (7.0 g, 42 mmol), and p-TSA‚H2O (0.2 g) were mixed with
100 mL of toluene and 100 mL of AcOH and heated for 18 h
at 95-100 °C. Solids gradually precipitated during the course
of the reaction, and the mixture turned black. After 18 h the
toluene and AcOH were distilled under reduced pressure to
yield a black solid mass.
Pyridine (150 mL) was added to the solid (SN-38), and the
mixture was stirred for 15 min at 20-25 °C. A solution of
4-piperidinopiperidinecarbamyl chloride31 (14.0 g, 60.8 mmol)
in 50 mL of CH2Cl2 was added. The mixture was stirred at
20-25 °C for 2 h and then distilled to dryness under reduced
pressure. Toluene (200 mL) was added, and the mixture was
distilled to near dryness under reduced pressure to yield the
crude irinotecan base as a black solid.
The unpurified irinotecan was stirred with 200 mL of
CH2Cl2 and 5 mL of saturated aqueous NaHCO3 solution for
5 min at rt. The phases were allowed to settle, and the CH2Cl2
phase was removed. The aqueous phase was extracted with
100 mL of CH2Cl2. The CH2Cl2 phases were combined and
distilled to yield crude solid irinotecan base.
The crude solid irinotecan base was dissolved in 100 mL of
95:5 CH2Cl2/MeOH and chromatographed on 300 g of silica,
eluting with 95:5 CH2Cl2/MeOH. The product containing
fractions were combined and distilled to a volume of about 100
mL under atmospheric pressure. Some product crystallization
occurred at the end of the distillation. EtOH (150 mL) was
added and the slurry allowed to stand at rt for 24 h. The
product was filtered, washed with 100 mL of EtOH, and dried
to yield 18.03 g (80.9% yield from 1) of irinotecan base as a
pale yellow solid.
Irinotecan base (17.5 g, 29.8 mmol) was suspended in 165
mL of water and heated to 80 °C. A solution of 3 mL of concd
HCl (35.8 mmol) and 10 mL of water was added. The
irinotecan base dissolved to yield a bright yellow solution that
was filtered hot over 5 g of Darco G-60. The filtrate was cooled
and allowed to stand for 24 h at rt. The resulting solids were
filtered, washed with EtOH (2 × 100 mL), and dried under
air to yield 17.2 g (90%, product is the trihydrate) of irinotecan
as pale yellow crystals. Spectroscopic (1H and 13C NMR) and
CHCl3); IR (nujol) 1731 cm-1
1.02 (m, 6 H), 1.80 (m, 4 H), 4.36 (t, J ) 6.0 Hz, 2 H), 5.22 (d,
J ) 16.5 Hz, 1 H), 5.60 (d, J ) 16.5 Hz, 1 H), 7.40 (s, 1 H); 13
;
1H NMR (300 MHz, CDCl3) δ
C
NMR (75 MHz, CDCl3) δ 7.7, 10.3, 21.8, 31.9, 66.1, 68.7, 72.3,
107.1, 124.4, 134.4, 145.0, 159.8, 173.3, 176.6; MS (FAB) m/ e
296, ([M + H]+), 268, 236, 208, 127. HRMS (FAB) m/ e calcd
for C14H18NO6: ([M + H]+) 296.1134; found: ([M + H]+),
296.1132. Anal. Calcd for C14H17NO6: C, 56.94; H, 5.8; N,
4.74. Found: C, 56.75; H, 5.84; N, 4.81. Chiralcel OD-H
column (4.6 mm × 25 cm); 80:20 hexane/EtOH; 1 mL/min; 321
nm detector; (S)-25, 16.7 min; (R)-25, 11.7 min.
(S)-4-Eth yl-3,4,6,7,8,10-h exa h yd r o-4-h yd r oxy-3,6,10-tr i-
oxo-1H-p yr a n o[3,4-f]in d olizin e-7-ca r boxylic Acid , 1,1-
Dim eth yleth yl Ester (26). Pyridone 25 (10.0 g, 0.033 mol),
Cs2CO3 (22.0 g, 0.067 mol), tert-butyl acrylate (50 mL, 0.33
mol), and DMSO (160 mL) were stirred at 47-50 °C for 21 h.
The mixture was cooled to rt, and 20 mL of concd HCl and
200 mL of water were added. The mixture was extracted four
times with a total of 500 mL of 4:1 (v/v) toluene/EtOAc. The
combined extracts were washed with water (3 × 100 mL) and
then evaporated to an oil. Toluene (200 mL) was added, and
the solution was concentrated to yield 11.2 g (74%) of 26 (1:1
toluene solvate) as a light yellow crystalline solid: mp 155.5-
157.9 °C; [R]25D ) +92.88° (c 1.0, CHCl3); IR (KBr) 3528, 1745
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.92 (t, J ) 7.4 Hz, 3 H),
1.50 (s, 9 H), 1.71-1.79 (m, 2 H), 2.28 (s, 3 H), 4.59 (s, 2 H),
5.16 (d, J ) 17.8 Hz, 1 H), 5.61 (d, J ) 17.8 Hz, 1 H), 6.94 (s,
1 H), 7.0-7.2 (m, 5 H); 13C NMR (75 MHz, CDCl3) δ 7.6, 21.4,
28.2, 31.4, 49.3, 66.1, 72.5, 83.5, 97.8, 105.7, 118.6, 125.2, 128.1,
128.9, 137.8, 143.8, 149.5, 156.8, 159.3, 166.0, 173.6; MS (FAB)
m/ e 364, ([M + H]+), 308, 290, 260, 244, 216, 57. HRMS (FAB)
m/ e calcd for C18H21NO7: ([M + H]+) 364.1396; found: ([M +
H]+), 364.1394. Anal. Calcd for C18H21NO7‚C7H8: C, 65.92;
H, 6.42; N, 3.07. Found: C, 65.63; H, 6.38; N, 3.10. ChromTech
AGP column (0.4 mm × 10 cm); 0.05 M pH 5 phosphate buffer;
0.5 mL/min; 355 nm; (S)-26, 13.6 min; (R)-26, 25.8 min.
(31) Prepared from 4-piperidinopiperidine (1. COCl2, toluene, 0 °C;
2. CH2Cl2, K2CO3).
(32) Tagawa, H.; Terasawa, E. U.S. Pat. 4,778,891.

Synthesis of Key Intermediate for Irinotecan Synthesis
J . Org. Chem., Vol. 62, No. 19, 1997 6597
chromatographic properties (reverse phase HPLC and chiral
HPLC) were identical to a sample obtained from Yakult
Honsha: mp 259-260 °C, (lit.1 mp 256.5 °C). Inertsil ODS-2
column (4.6 mm × 25 cm); 70:30 H2O/CH3CN + 0.2% TFA; 1
mL/min; 220 nm; ir in oteca n , 5.23 min; SN-38, 6.74 min.
Chiralpak OD column (4.6 mm × 25 cm); 1:1 hexane/IPA; 1
mL/min; 295 nm detector; (S)-ir in oteca n , 16.7 min; (R)-
ir in oteca n , 11.8 min. Enantiomeric excess of product was
>99.8%; chiral HPLC showed no detectable R enantiomer,
limit of detection 0.1%.
Brad Hewitt and Don Knoechel. Engineering support
was provided by Dae Cha and J ohn Wachter. We thank
Structural and Medicinal Chemistry (Pharmacia &
Upjohn) for microanalyses and high resolution mass
spectra, and Analytical Methods and Services (Phar-
macia & Upjohn) for IR spectra and optical rotations.
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra for compounds 1-6, 8-16, 18-26, and irinotecan.
Chiral HPLC traces for compound 1 (20 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of this journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. We thank Irv O’Leary for de-
velopment and validation of the chiral HPLC assays of
the intermediates, Dale Wieber for chiral HPLC assay
of irinotecan, and Brian Conway for assistance with the
hydrogenations. Process safety evaluation was done by
J O970173F