Expeditious total syntheses of camptothecin and 10-hydroxycamptothecin

Article abstract of DOI:10.1021/ol802250y

(Chemical Equation Presented) New expeditious total syntheses of (S)-camptothecin (16% overall yield, 95% ee) and (S)-10-hydroxycamptothecin (14% overall yield, 99% ee) have been accomplished, respectively, starting from readily available and inexpensive materials. Development, optimization, and successful application of the cascade reaction consisting of a pyrrolidine-catalyzed Michael addition, an intramolecular aldol condensation, and an oxidative aromatization, the intramolecular oxa Diels-Alder cycloaddition, and the Sharpless asymmetric dihydroxylation make these two new syntheses more efficient and straightforward.

Full text of DOI:10.1021/ol802250y

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5393-5396
Expeditious Total Syntheses of
Camptothecin and
10-Hydroxycamptothecin
Guan-Sai Liu,†,‡ Qing-Li Dong,† Yuan-Shan Yao,†,‡ and Zhu-Jun Yao*,†,‡
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and Joint Laboratory of Green
Chemistry, Department of Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui 230026, China
yaoz@mail.sioc.ac.cn
Received September 29, 2008
ABSTRACT
New expeditious total syntheses of (S)-camptothecin (16% overall yield, 95% ee) and (S)-10-hydroxycamptothecin (14% overall yield, 99% ee)
have been accomplished, respectively, starting from readily available and inexpensive materials. Development, optimization, and successful
application of the cascade reaction consisting of a pyrrolidine-catalyzed Michael addition, an intramolecular aldol condensation, and an oxidative
aromatization, the intramolecular oxa Diels-Alder cycloaddition, and the Sharpless asymmetric dihydroxylation make these two new syntheses
more efficient and straightforward.
Camptothecin (CPT, 1a, Figure 1), a pentacyclic natural
alkaloid isolated from Camptotheca acuminata (Xi Su,
originated in China) by Wall and co-workers in 1966,1
represents a unique class of complex quinoline cytotoxins
which inhibit the DNA enzyme topoisomerase I (topo I).
Since its isolation and structural elucidation, camptothecin
has attracted considerable attention from both the academic
community and the pharmaceutical industry. However, initial
trials were complicated by its poor solubility and severe and
unpredictable toxicity2 until topoisomerases were discovered
as the biological targets for the anticancer actions of
camptothecin.3 During the past several decades, continuous
research in camptothecin-family alkaloids has led to quite a
number of pharmaceutically useful camptothecin derivatives,
such as topotecan (Hycamtin, 2a, Figure 1) and irinotecan
(Camptosar, 2b).4 Despite the rapid growth of the drug
(2) (a) Moertel, C. G.; Schutt, A. J.; Reitemerier, R. J.; Hahn, R. G.
Cancer Chemother. Rpt. 1972, 56, 95. (b) Gottlieb, J. A.; Luce, J. K. Cancer
Chemother. Rpt. 1972, 56, 103.
(3) (a) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol. Chem.
1985, 260, 14873. (b) Hsiang, Y. H.; Liu, L. F. Cancer. Res. 1988, 48,
1722. (c) Covey, J. M.; Jaxel, C.; Kohn, K. W.; Pommier, Y. Cancer Res.
1989, 49, 5016. (d) Jaxel, C.; Kohn, K. W.; Wani, M. C.; Wall, M. E.;
Pommier, Y. Cancer. Res. 1989, 49, 1465. (e) Kohn, K. W.; Pommier, Y.
Ann. N.Y. Acad. Sci. 2000, 922, 11.
† Shanghai Institute of Organic Chemistry.
‡ University of Science and Technology of China.
(1) 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.
10.1021/ol802250y CCC: $40.75
Published on Web 11/08/2008
2008 American Chemical Society

market, industrial sources of CPT and 10-OH CPT (1c) are
still highly dependent on extraction from the medical plants
C. acuminata and Nothapodytes fetida. As a side result, such
industrial-scale extraction has brought about a shortage of
natural resources and subsequent environmental problems
in some developing countries. Therefore, development of
efficient and economic chemical syntheses of CPT-family
alkaloids, as well as the pharmaceutically useful CPT
derivatives, has been an important task in organic synthesis.
Many impressive total syntheses of CPT and its analogues
have emerged from numerous research groups5,6 since the
first total synthesis of rac-camptothecin by Stock and Schultz
in 1971.7 However, involvement of difficult operations and
high costs make most syntheses very impractical in the
laboratory and commercial process, especially in raising
materials in larger scales. Ecconomic, efficient, and easily
operative syntheses of CPT and its derivatives are of much
urgency and importance.
employed to construct the common key tetracyclic A/B/C/
D-ring core of CPT-family alkaloids in high yield (Figure
1). However, multiple air-sensitive organometallic reagents
were used in the preparation of the key pyridone precursor
(the D/E ring of CPT).9 This is disadvantageous especially
for large-scale synthesis in the future. In order to achieve a
more practical and efficient total synthesis, we herein present
a new expeditious and straightforward route for this family
of biologically important alkaloids. In this synthesis, a
secondary amine-catalyzed cascade reaction was employed
to the preparation of the A/B ring and an inverse electron
demand intramolecular oxa Diels-Alder reaction served as
the protocol for constructing the D/E ring.
In view of the efficiency in constructing a multiring
system, we envisioned that formation of the D/E ring of CPT
(1a) and 10-hydroxycamptothecin (10-OH CPT, 1c) could
be commonly accomplished by an inverse electron demand
intramolecular oxa Diels-Alder reaction in a later stage of
the total synthesis. Such a one-step protocol is novel and
quite different from the literature works in constructing the
D/E ring. More advantageously, such a treatment will avoid
the use of sensitive and expensive organometallic reagents.
In the meantime, synthesis of the A/B ring in this study was
designed to utilize an economic cascade reaction combina-
tion, which consists of a pyrrolidine-catalyzed Michael
addition and an intramolecular aldol condensation and an
oxidative aromatization as the end. According to this
retroanalysis, two simple, inexpensive, and readily available
materials, o-aminobenzaldehyde 7 and R,ꢀ-unsaturated al-
dehyde 8, would serve as the starting materials in this new
total synthesis.
Development and utilization of novel cascade reactions
are a particularly attractive strategy in the synthesis of
complex molecular architectures to achieve the highly
efficient formation of multiple C-C bonds in one opera-
tion.10 In this study, we started our new total syntheses of
CPT and 10-OH CPT from the optimization of an efficient
Michael addition-aldol condensation cascade,11 serving as
a powerful method for construction of the A/B ring of CPT
alkaloids (Scheme 1). In the presence of catalytic amounts
of pyrrolidine (10 mol %) and benzoic acid (10 mol %),
reactions of R,ꢀ-unsaturated aldehyde 8 with 2-aminoben-
zaldehydes 7 could be performed smoothly in dichlo-
romethane at room temperature, affording two inseparable
Figure 1. Camptothecin and representative derivatives, our previ-
ously used methodology, and retrosynthesis in this work.
(5) Representative reviews on camptothecin and its derivatives: (a)
Cuendet, M.; Pezzuto, J. M. In Modern Alkaloids: Structure, Isolation,
Synthesis and Biology; Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiely-
VCH: Weinheim, 2008; Chapter 2, pp 29-33. (b) Thomas, C. J.; Rahier,
N. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 1585. (c) Du, W.
Tetrahedron 2003, 59, 8649. (d) Hutchinson, C. R. Tetrahedron 1981, 37,
1047.
Very recently, our laboratory disclosed a short and efficient
route which is generally applicable to this class of alkaloids
and their analogues.8 In that synthesis, a mild oxodiphos-
phonium-promoted cascade reaction consisting of an imidate
formation, an intramolecular aza-Diels-Alder reaction and
an eliminative aromatization was optimized and successfully
(6) For several recent syntheses of camptothecin, see: (a) Kanazawa,
A.; Muniz, M. N.; Baumlova, B.; Ljungdahl, N.; Greene, A. E. Synlett 2008,
2275. (b) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R. Synlett 2007, 2635.
(c) Peters, R.; Althaus, M.; Nagy, A.-L. Org. Biomol. Chem. 2006, 4, 498.
(d) Chavan, S. P.; Venkatraman, M. S. ARKIVOC 2005, (iii), 165.
(7) Stock, G.; Schultz, A. G. J. Am. Chem. Soc. 1971, 93, 4074.
(8) (a) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003. (b)
Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. J. Org. Chem. 2007, 72, 6270.
(9) Bankston, D.; Fang, F.; Huie, E.; Xie, S. J. Org. Chem. 1999, 64,
3461–3466.
(4) (a) Giovanella, B. C.; Stehlin, J. S.; Wall, M. E.; Wani, M. C.;
Nicholas, A. W.; Liu, L. F.; Silber, R.; Potmesil, M. Science 1989, 246,
1046. (b) Saltz, L. B.; Cox, J. V.; Blanke, C.; Rosen, L. S.; Fehrenbacher,
L.; Moore, M. J.; Maroun, J. A.; Ackland, S. P.; Locker, P. K.; Pirotta, N.;
Elfring, G. L.; Miller, L. L. New Engl. J. Med. 2000, 343, 905. (c) Ozols,
R. F. Int. J. Gynecol. Cancer 2000, 10, 33. (d) Vanhoefer, U.; Harstrick,
A.; Achterrath, W.; Cao, S.; Seeber, S.; Rustum, Y. M. J. Clin. Oncol.
2001, 19, 1501.
(10) For a recent review on domino reactions, see: Enders, D.; Grondal,
C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
5394
Org. Lett., Vol. 10, No. 23, 2008

products. The minor one in the resulting mixture was finally
identified, by careful 1H NMR analysis, as an imine byprod-
uct. This imine was formed by the reaction between the
desired product (benzaldehyde C) and the excess of aniline
reactant 7. Fortunately, the above-mentioned byproduct could
be fully convert to the required aldehyde C by a simple
treatment with silica gel at room temperature. After removal
of silica gel by filtration, the resulting solution was directly
treated with the freshly prepared MnO2 to afford quinolines
6 in satisfactory overall yields (75% for 6a and 72% for 6b).
Using the above mild pyrroline-catalyzed cascade reaction
and subsequent treatment with MnO2, elaboration of the A/B
ring system was efficient accomplished in a short fashion.
The workups involved in the above transformations were
very convenient and practical in laboratory, and only one
chromatographic purification was required.
giving the aminal derivatives 10 (86% for 10a, 84% for 10b,
and 82% for 10c). Acetylation of aminals 10 followed by
treatment with enol silyl ether 1112 in the presence of
BF3·Et2O at -78 °C13 furnished the substrates 12 in
satisfactory yields (65% for 12a, 72% for 12b, and 69% for
12c) for the following oxa Diels-Alder reactions.
Scheme 2. Syntheses of ABC-Ring Intermediates 12
Scheme 1. Construction of Quinoline Precursors 6 by
Pyrrolidine-Catalyzed Michael Addition-Aldol Condensation
Cascade Reaction
The crucial inverse-electron-demand intramolecular oxa-
Diels-Alder reactions were examined in mesitylene at 160
°C in a sealed tube (Table 1).14 Significant electronic effects
of the dienophiles were observed. Using simpler 12a (R4 )
H) as the substrate, all attempts failed including optimizations
in reaction temperatures, solvents, Lewis acids, ultrasound,
neat conditions, etc. Instead, decompositions were frequently
found. Common knowledge in this type of reactions men-
tioned that the substrate modification by tuning the electronic
property of the dienophile would be favorable. Thus, an
electron-donating ethoxyl group was introduced at the
ꢀ-position of unsaturated amide substrate 12 to strengthen
the interactions between the LUMO of the diene and the
HOMO of the dienophile. To our delight, thermal cycload-
dition of the modified substrate 12b (R4 ) OEt) proceeded
smoothly, providing two separable diastereomers (13ba and
13bb, 3:1) in an excellent total yield (83%). This reaction
was surprisingly clean and none other theoretically possible
diastereomeric cycloadducts and byproducts were detected.
The relative configurations of these two products were
determined by NOESY experiments, as well as the X-ray
single crystallography of 13ba (see Supporting Information).
Similarly, substrate 12c also gave two diastereomers 13ca
and 13cb (9:1) in 92% total yield. Both diastereomeric
Sequential three-step treatment (without purification of
intermediates) was adopted to convert the quinolinyl ad-
hedydes 6 into the corresponding amine precursors 5
(Scheme 2). Oximation of the benzaldehydes 6 with NH2OH,
removal of the acetate with K2CO3 in methanol and followed
by hydrogenation (1 atm) of oxime in methanol with 10%
Pd-C at room temperature provided the corresponding
benzylamines 5 in satisfactory yields (79% for 5a and 84%
for 5b). Parallel acylation of amines 5 with acryloyl chloride
or 3-ethoxyacryloyl chloride in DMF yielded the correspond-
ing acrylamides 9 (81% for 9a, 85% for 9b, and 86% for
9c), respectively. MnO2-based oxidation of quinolin-2-
ylmethanols 9 was mildly carried out in dichloromethane,
(11) (a) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876.
(b) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jøgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794. (c) Hayashi, Y.; Gotoh, H.; Hayashi, T.;
Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (d) Chi, Y.; Gellman,
S. H. J. Am. Chem. Soc. 2006, 128, 6804. (e) Wang, W.; Li, H.; Wang, J.;
Zu, L.-S. J. Am. Chem. Soc. 2006, 128, 10354. (f) Zu, L.-S.; Wang, J.; Li,
H.; Xie, H.-X.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036.
(g) Zu, L.-S.; Li, H.; Xie, H.-X.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W.
Angew. Chem., Int. Ed. 2007, 46, 3732. (h) Xie, H.-X.; Zu, L.-S.; Li, H.;
Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886. (i) Wang, J.; Li,
H.; Xie, H.-X.; Zu, L.-S.; Shen, X.; Wang, W. Angew. Chem. Int. Ed. 2007,
46, 9050.
(12) Enol ether 11 was prepared from corresponding unsaturated
aldehyde using TMSOTf and NEt3 in CH2Cl2.
(13) Osante, I.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2004, 45,
1253.
(14) (a) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,
M. P. J. Am. Chem. Soc. 1991, 113, 6161. (b) Ito, M.; Clark, C. W.;
Mortimore, M.; Goh, J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123,
8003.
Org. Lett., Vol. 10, No. 23, 2008
5395

products trans-13(b-c)a and cis-13(b-c)b are eligible for
our following synthesis.
and 3b to camptothecin (1a) and 10-methoxycamptothecin
(1b), respectively. In addition to CPT (83% yield, 95% ee),8a
10-methoxycamptothecin (1b) was afforded in 82% yield and
99% ee (by HPLC, see Supporting Information). Final
demethylation of 1b with 48% aqueous HBr17 in a sealed
tube provided 10-hydroxycamptothecin (1c, 80%, 99% ee
by HPLC), the common industrial material in prodcutions
of anticancer drugs topotecan (2a) and irinotecan (2b). All
aspects of the synthesized camptothecin (1a) and 10-
hydroxycamptothecin (1c) are in well agreement with those
of natural products.
Table 1. Intramolecular Oxa Diels-Alder Reactionsa
In summary, new expeditious total syntheses of (S)-
camptothecin (16% overall yield, 95% ee) and (S)-10-
hydroxycamptothecin (14% overall yield, 99% ee) have been
accomplished, respectively, starting from simple, readily
available, and inexpensive materials. Development, optimiza-
tion, and successful application of the cascade reaction
consisting of a pyrrolidine-catalyzed Michael addition, an
intramolecular aldol condensation, and an oxidative aroma-
tization, the intramoculecular oxa Diels-Alder cycloaddition,
and the Sharpless asymmetric dihydroxylation make these
two new syntheses more efficient and straightforward. Mild
conditions, minimal use of the chromatographic purifications,
and avoiding the use of sensitive organometallic reagents in
many transformations are advantageous and convenient for
construction of the multiple ring system of CPT-family
alkaloids. The achieved syntheses and newly developed
methodologies will be valuable in future endeavors for an
economic industrial process of CPT alkaloids and their
derivatives.
entry
reactant
productsb
yieldc (%)
1
2
3
12a: R1 ) R4 ) H
complicated
13ba:13bb ) 3:1
12b: R1 ) H, R4 ) OEt
83
92
12c: R1 ) OMe, R4 ) OEt 13ca:13cb ) 9:1
a The reactions were performed in mesitylene in a sealed tube at 160
°C. b 13ba was confirmed by single-crystal X-ray crystallography. c Total
isolated yield of both diastereomers.
With the pentacyclic precursors 13 in hand, our endeavor
continued toward the total syntheses of CPT and 10-OH CPT.
Treatment of the mixture of 13ba and 13bb with DDQ and
a catalytic amount of CH3COOH in 1,4-dioxane15 followed
by reductive removal of the ethoxy group16 afforded CPT
precursor 3a in 76% yield (Scheme 3). Accordingly, the other
Scheme 3
.
Completion of Total Syntheses of Camptothecin and
10-Hydroxyoxycamptothecin
Acknowledgment. This work is financially supported by
NSFC (20425205, 20621062) and CAS (KJCX2-YW-H08).
Supporting Information Available: Experimental details
and full characterization of new compounds, copies of NMR
spectra of new compounds, HPLC analyses of synthetic (S)-
1b and (S)-1c), and X-ray crystal data of 13ba.This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802250Y
(15) (a) Chavan, S. P.; Pasupathy, K.; Venkatraman, M. S.; Kale, R. R.
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B. E.; Wang, A. X.; Stashko, M. A.; Lin, C. W.; Tyree, C. M.; Miner,
J. N.; Jacobson, P. B.; Wilcox, D. M.; Lane, B. C. J. Med. Chem. 2001,
44, 4481.
mixture of 13ca and 13cb provided 3b in 81% yield. Further
oxidative transformations (Sharpless asymmemetric dihy-
droxylation followed by I2/CaCO3-based hemiacetal
oxidation)8a successfully converted the cylic enol-ethers 3a
(17) (a) Josien, H.; Ko, S. B.; Bom, D.; Curran, D. P. Chem.sEur. J.
1998, 4, 67. (b) Fortunak, J. M. D.; Kitteringham, J.; Mastrocola, A. R.;
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