Note

pubs.acs.org/joc

Total Synthesis of Camptothecin and SN-38

Shanbao Yu,‡ Qing-Qing Huang,† Yu Luo,*,‡ and Wei Lu*,†
†
Institute of Drug Discovery and Development, iAIR, and ‡Department of Chemistry, East China Normal University, Shanghai
200062, China
*
S Supporting Information

ABSTRACT: A new practical and concise total synthesis of

enantiopure camptothecin and SN-38 (14% overall yield, 99.9% ee
and 99.9% purity) was described, starting from inexpensive and
readily available materials. The development of column chromatog-
raphy-free purification was achieved in all steps, which offers an
economic industrial process to the camptothecin-family alkaloids.

C amptothecin (CPT 1, Figure 1) was first isolated from

Camptothecin acuminata by Wani and Wall in 1966.1 This
total synthesis of CPT-family alkaloids has attracted the interest
of both organic and medicinal scientists over the past decades.10
As summarized in Du’s review in 2003,10 the major synthetic
approaches are roughly classified as the C-ring construction
approach, the cascade radical cyclization approach, the broadly
applied Friedlander condensation approach, various Michael
addition approaches, and various Diels−Alder reaction
approaches. Recently, many impressive total syntheses of
camptothecins have been developed in numerous research
groups,11−24 which dramatically advanced the development of
organic synthesis and anticancer medicinal chemistry. Despite
exhaustive attempts to develop a practical synthesis, most
approaches still suffered from infeasibility of column
chromatography, low yields, high cost, or toxic reagents.
Among these reported total synthesis strategies, Comins’
Figure 1. Camptothecin and two representative derivatives. method was an efficient route to construct the key core of
CPT-family alkaloids by coupling the A/B ring with the D/E
natural alkaloid showed potent antitumor activity and a unique ring,25−28 but employment of expensive reagents made this
mechanism of action, which selectively inhibits DNA top- approach unpreferable for application in the industry. In
oisomerase I (Topo I), thus attracting intense interest Comins’ approach, the chiral center of compound 5 was
worldwide as a prominent lead for the development of new obtained by the stereoselectively nucleophlic addition of 2-
anticancer drugs.2−5 For its good antitumor profiles and unique ketobutyric acid ester with expensively chiral auxiliaries in only
mechanism, an amount of camptothecin analogues have been 93% ee value.29 Recently, we disclosed a short and efficient
synthesized and investigated to find better camptothecin route for producing racemic compound 5,30 in which 2-
derivatives with reduced toxicity and improved anticancer chloronicotinic acid was employed as the starting material
activity. To date, two camptothecin analogues, topotecan (2)6 (Figure 2). Based on this previous work, we present a scalable
and irinotecan (3),7 have been approved by the FDA to treat and concise total synthesis of camptothecin (1) and SN-38 (4)
cancers, among which irinotecan (3) turned out to be a more starting from inexpensive and readily available materials.
active metabolite SN-38 (4)8 in vivo. In addition, several others, According to our retrosynthesis shown in Figure 2, ring C
such as BNP-1350, silatecan, ST-1481, lurtotecan, and was constructed through joining of the A/B ring and the D/E
diflomotecan, are presently in different stages of preclinical ring (5) based on our previous work.30 It was obvious that
and clinical trials.9
Since the common drawback of industrial-scale extraction Received: September 30, 2011
from the medical plants, development of practical and concise Published: December 13, 2011

© 2011 American Chemical Society 713 dx.doi.org/10.1021/jo201974f | J. Org. Chem. 2012, 77, 713−717
The Journal of Organic Chemistry Note

yield was very low. Then, replacing LTMP with LDA or

reducing the amount of n-BuLi also decreased the yield
dramatically. Finally, warming the temperature to higher than
−60 °C made the reaction more complex. As all these attempts
were unsuccessful, the aforementioned conditions were thus
considered as the preferred conditions as follows: LTMP was
better than LDA, the molar ratio of compound 8 to 7 should be
1:3, and the temperature should be lower than −60 °C.
Then, compound 10 was reduced with LiAlH4 to give diol 11
in 95% yield. Subsequently, the two hydroxyl groups in 11 were
protected with benzyl to afford 12, which was then hydrolyzed
under acidic condition to give glycol 13 in an excellent yield.
Glycol 13 was subjected to sequent oxidative cleavage and
oxidation to produce acid 15. Hydrogenation proceeded
smoothly to remove the benzyl groups and resulted in ring-
closing product 16, which was hydrolyzed under acidic
conditions to give D/E fragment 5 with >99.5% purity and
>99.8% ee value. The total yield of these eight steps was 25%.
Figure 2. Retrosynthesis of camptothecin (1) and SN-38 (4). With the key intermediate 5 in hand, CPT-family alkaloids
can be obtained by using condensation and Heck reaction with
asymmetric alcohol 6 was the key fragment in this work. In different A/B fragment.33−36 Here, synthesis of SN-38 (4) as an
2002, Wong’s group31 reported that this S-configuration tertiary example is shown in Scheme 2. Compound 17 was synthesized
alcohol (9) was constructed by a nucleophilic addition of by a general procedure which was similar as the synthesis of
lithiated furan and glyceraldehyde derivative (7) in yield of 74% unsubstituted A/B ring, 33,34 starting from 17a.37 The
and de value of 93%, which inspired us that this chiral moiety condensation of 5 and 17 under basic conditions gave
could be further converted into the key scaffold, a tertiary intermediate 18, which was subjected to Heck reaction to
alcohol acid. produce 19. Deprotection of 19 afforded SN-38 (4) in excellent
Thus, the DE ring (5) was prepared as outlined in Scheme 1. yield. In addition, camptothecin (1) and 10-hydroxycampto-
To facilitate the formation of pyridone (5) in the final step, thecin were also prepared in this way, and the purity and ee
commercially available 2-methoxynicotinic acid (8) was chosen value for all these CPT-family alkaloids exceeded 99.9%
as the starting material, which was lithiated with LTMP (3 without column chromatography in all steps. The data for
equiv compared to 8) and subsequently subjected to a these synthesized camptothecins were in good agreement with
nucleophilic addition with chiral ketone 732 (3 equiv compared those of natural products.
to 8) at −60 to −78 °C to afford lactone 10 in a yield of 55%. In summary, we have succeeded in implementing a practical
Fortunately, this lactone 10 could be recrystallized right from and concise total synthesis of camptothecin (1) and SN-38 (11
the reaction solution in extraordinarily high purity (chemical steps, 14% overall yield, 99.9% ee, and 99.9% purity),
purity >99.9%, de value >99.9%), and its diastereoisomer was
employing an inexpensive and commercial available material
not detected in the LC−MS system. The key intermediate 10
was thus subjected to X-ray crystallography, which confirmed (8) as starting material and compound 7 as asymmetric
that the chiral center was the desired S-configuration (Figure 3, inducing reagent. It is worth mentioning that the development
see the Supporting Information). Later, we tried to optimize of column chromatography-free purification was achieved in all
the reaction conditions in this step, the molar ratio of steps, which will be valuable as an economical industrial process
compound 7 to 8 was first reduced to 2:1 from 3:1, but the of producing camptothecin-family alkaloids.

Scheme 1

714 dx.doi.org/10.1021/jo201974f | J. Org. Chem. 2012, 77, 713−717

The Journal of Organic Chemistry Note

Scheme 2

■ EXPERIMENTAL SECTION
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-ethyl-4-
THF at room temperature under nitrogen, the mixture was stirred for
30 min at the same temperature, and then benzyl bromide (3.0 mL, 27
mmol) was added. The mixture was heated for 4 h at 70 °C, cooled to
methoxyfuro[3,4-c]pyridin-3(1H)-one (10). n-BuLi (58.5 mL, 2.5
M in n-hexane) was added to a solution of 2,2,6,6-tetramethylpiper- room temperature, and poured into 20 mL water. The solution was
idine (14.4 mL, 117.6 mmol) in anhydrous THF (200 mL) at −78 °C extracted with EA, washed with brine, dried over anhydrous Na2SO4,
under nitrogen. The mixture was stirred for 30 min before 2- and concentrated to afford crude 12, which was further purified by
methoxynicotinic acid (8, 4.84 g, 31.64 mmol) was added. After the column chromatography (ethyl acetate/hexane =1:5) to give pure 12
mixture was stirred for 30 min at −78 °C, compound 7 (15.0 g, 94.9 as a colorless liquid (2.8 g, 88% yield). The crude product could be
mmol) was added and and the mixture stirred for another 30 min. used in the next step without further purification when in a large scale:
Then the mixture was allowed to reach room temperature and
1
H NMR (500 MHz, CDCl3) δ 0.85 (t, J = 7.25 Hz, 3H), 1.35 (s, 6H),
hydrolyzed with 1 N HCl (50 mL). The mixture was extracted with 2.20 (m, 1H), 2.30 (m, 1H), 3.85 (m, 1H), 3.97(s, 3H), 4.00 (m, 1H),
ethyl acetate, dried over anhydrous Na2SO4, and concentrated to 4.45 (s, 2H), 4.47 (d, J = 9.6 Hz, 1H), 4.68 (m, 2H), 4.79 (t, 1H), 4.87
afford 25.0 g of crude 10, which was further purified by trituration with (d, J = 9.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 7.25−7.36 (m, 10H),
petroleun ether (20 mL) to give pure 10 as a white solid (4.7 g, 55% 8.10 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 8.6, 14.1,
yield). 1H NMR (500 MHz, CDCl3) δ 0.64 (t, J = 7.5 Hz, 3H), 1.30 20.8, 24.5, 25.9, 26.6, 53.6, 60.2, 63.9, 65.4, 65.6, 73.2, 80.4, 82.2,
(s, 3H), 1.42(s, 3H), 2.06 (m, 1H), 2.22 (m, 1H), 4.04 (m, 2H), 4.14 109.5, 116.4, 119.2, 127.1, 127.3, 128.1, 138.4, 138.9, 146.0, 151.1,
(s, 3H), 4.16 (m, 1H), 7.04 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 5.5 Hz, 164.3; MS (EI) m/z = 477; HRMS (EI) m/z calcd for C29H35NO5
1H); 13C NMR (100 MHz, CDCl3) δ 6.6, 24.5, 24.6, 25.8, 54.3, 64.8, [M]+ 477.2515, found 477.2508.
78.5, 88.2, 109.1, 110.4, 111.0, 152.9, 161.4, 163.4, 167.0; MS (EI) m/ (2R,3S)-3-(Benzyloxy)-3-(3-((benzyloxy)methyl)-2-methoxy-
z = 293; HRMS (EI) m/z calcd for C15H19NO5 [M]+ 293.1263, found pyridin-4-yl)pentane-1,2-diol (13). To a solution of compound 12
293.1264. (2.5 g, 5.23 mmol) in methanol (30 mL) was added concentrated HCl
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(3-(hydroxy- (6 mL) at room temperature and the mixture stirred for another 2 h.
methyl)-2-methoxypyridin-4-yl)propan-1-ol (11). A solution of Then the mixture was poured into water (100 mL). The solution was
the compound 10 (5.5 g, 19 mmol) in anhydrous THF (50 mL) was extracted with CH2Cl2, washed with brine, dried over anhydrous
added slowly to a mixture of LiAH4 (1.3 g, 34 mmol) in anhydrous Na2SO4, and evaporated to dryness to give a viscous solid 13 (2.1 g,
THF (30 mL), and then the mixture was stirred for 2 h at the room 92.1% yield), which was pure enough to use in the next step without
temperature, cooled to 0 °C, and quenched with water (2.5 mL). The further purification: 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz,
mixture was filtered, extracted with ethyl acetate, dried over anhydrous 3H), 2.16 (m, 1H), 2.30 (s, 1H), 2.45 (m, 1H), 3.31 (m, 1H), 3.54 (m,
Na2SO4, and evaporated to dryness to give a white solid 11 (5.4 g, 1H), 3.93 (s, 3H), 3.99 (s, 1H), 4.11 (m, 1H), 4.35 (d, J = 11.5 Hz,
95.0% yield): 1H NMR (500 MHz, CDCl3) δ 0.78 (t, J = 7.4 Hz, 3H), 1H), 4.44 (d, J = 11.5 Hz, 1H), 4.53 (d, J = 10.5 Hz, 1H), 4.67 (d, J =
1.40 (s, 3H), 1.48 (s, 3H), 2.00 (m, 1H), 2.97 (s, 1H), 3.26 (s, 1H), 9.5 Hz, 1H), 4.74 (d, J = 10.5 Hz, 1H), 4.96 (d, J = 9.5 Hz, 1H), 6.88
3.58 (m, 1H), 3.73 (m, 1H), 3.97 (s, 3H), 4.55 (m, 1H), 4.89 (m, 2H), (d, J = 5.5 Hz, 1H), 7.26−7.42 (m, 10H), 8.09 (d, J = 5.5 Hz, 1H); 13C
6.72 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 5.5 Hz, 1H); 13C NMR (100 NMR (100 MHz, CDCl3) δ 7.9, 25.1, 53.7, 63.3, 63.8, 64.9, 72.8, 77.3,
MHz, CDCl3) δ 7.7, 25.0, 26.2, 24.1, 53.8, 56.4, 65.5, 78.2, 80.2, 110.0, 85.0, 116.4, 119.0, 127.4, 127.6, 127.9, 128.3, 137.7, 138.2, 145.7,
114.8, 121.7, 145.4, 150.3, 163.3; MS (EI) m/z = 297; HRMS (EI) m/ 151.1, 164.2; MS (ESI) m/z = 438.2 [M + 1]+; FTMS m/z calcd for
z calcd for C15H23NO5 [M]+ 297.1576, found 297.1580. C26H32NO5 [M + 1]+ 438.2274, found 438.2275.
4-((S)-1-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)- (S)-2-(Benzyloxy)-2-(3-((benzyloxy)methyl)-2-methoxypyri-
propyl)-3-((benzyloxy)methyl)-2-methoxypyridine (12). So- din-4-yl)butanal (14). Sodium periodate (1.2 g, 5.2 mmol) was
dium hydride (1.1 g, 27 mmol) was added in two portions to a added to a solution of compound 13 (1.16 g, 2.65 mmol) in 15 mL of
solution of compound 11 (2.0 g, 6.73 mmol) in 40 mL of anhydrous acetonitrile and 2 mL of water, and then the mixture was stirred for 2 h

715 dx.doi.org/10.1021/jo201974f | J. Org. Chem. 2012, 77, 713−717

The Journal of Organic Chemistry Note

at room temperature and poured into 20 mL water. The solution was anhydrous Na2SO4, and evaporated to dryness give compound 17b
extracted with CH2Cl2, washed with brine, dried over anhydrous (9.5 g, 81% yield): 1HNMR (CDCl3): δ 11.72 (s, 1 H), 8.62 (d, J = 9
Na2SO4, and evaporated to dryness to give a viscous solid 14 (1.02 g, Hz, 1 H), 7.41 (d, J = 3 Hz, 1 H), 7.11 (dd, 1 H), 4.26 (dd, 2 H), 3.84
95% yield), which was used without further purification: 1H NMR (s, 3 H), 3.49 (s, 2 H), 3.04 (dd, 2 H), 1.31 (dd, 3 H), 1.22 (dd, 3 H).
(500 MHz, CDCl3) δ 0.91 (t, J = 7.0 Hz, 3H), 2.46 (m, 2H), 3.96 (s, Ethyl 4-Ethyl-6-methoxy-2-oxo-1,2-dihydroquinoline-3-car-
3H), 4.26 (d, J = 11.1 Hz, 1H), 4.33 (d, J = 11.1 Hz, 1H), 4.44 (s, 2H), boxylate (17c). To a solution of compound 17b (9.5 g, 32.39 mmol)
4.53 (d, J = 11.1 Hz, 1H), 4.59 (d, J = 11.1 Hz, 1H), 7.11 (d, J = 5.5 in MeOH (80 mL) was added NaOMe (5.2 g, 92.26 mmol) at 0 °C.
Hz, 1H), 7.23−7.35 (m, 10H), 8.16 (d, J = 5.5 Hz, 1H), 9.67 (s, 1H); The mixture was stirred for 1 h and 1 N HCl was added. The solid was
13
C NMR (100 MHz, CDCl3) δ 7.0, 25.2, 53.7, 65.1, 72.7, 85.5, 116.0, collected, washed with PE/EA (10/1) and dried to give compound
118.4, 127.1, 127.5, 127.9, 128.0, 137.4, 146.6, 148.0, 163.7, 199.2; MS 17c (7.5 g, 85% yield): 1H NMR (CDCl3) δ 12.03 (s, 1 H), 7.33 (d, J
(EI) m/z = 405 [M]+; HRMS (EI) m/z calcd for C25H27NO4 [M]+ = 10 Hz, 1 H), 7.18 (d, J = 10 Hz, 1 H), 7.15 (dd, 1 H), 4.48 (dd, 2
405.1940, found 405.1944. H), 3.87 (s, 3 H), 2.85 (dd, 2 H), 1.44 (t, J = 5 Hz, 3 H), 1.35 (t, J = 5
(S)-2-(Benzyloxy)-2-(3-((benzyloxy)methyl)-2-methoxypyri- Hz, 3 H).
din-4-yl)butanoic Acid (15). Compound 14 (1.1 g, 2.72 mmol) was Ethyl 2-Chloro-4-ethyl-6-methoxyquinoline-3-carboxylate
added to a solution of 2-methyl-2-butylene (3 mL) and sodium (17d). The solution of compound 17c (1 g, 3.63 mmol) and POCl3
dihydrogen phosphate (1.7 g) in 15 mL of acetonitrile and 5 mL of (10 mL) was refluxed 1−3 h. The mixture was quenched by crashed
water. The mixture was stirred for 30 min, and sodium chlorite (1.0 g, ice. The solid was collected and dried to give compound 17d (0.7 g,
11 mmol) was added at room temperature. Then the mixture was 66% yield): 1H NMR (CDCl3) δ 7.91 (d, J = 9 Hz, 1 H), 7.38 (q, 1
stirred for 2 h and poured into 15 mL of 1 N HCl solution. The H), 7.25 (d, J = 4 Hz, 1 H), 4.54 (q, 2 H), 3.98 (s, 3 H), 3.04 (q, 2 H),
solution was extracted with CH2Cl2, washed with brine, dried over 1.49 (t, J = 7 Hz, 3 H), 1.38 (t, J = 7 Hz, 3 H).
anhydrous Na2SO4, and evaporated to dryness give viscous liquid 15 (2-Chloro-4-ethyl-6-methoxyquinolin-3-yl)methanol (17e).
(1.1 g, 96.0% yield), which was pure enough to use in the next step To a solution of compound 17d (2 g, 6.81 mmol) in THF (20 mL)
without further purification: 1H NMR (500 MHz, CDCl3) δ 0.91 (t, J was added Red-Al (3.5 M, 7.0 mL) at 0 °C. The mixture was stirred for
= 7.0 Hz, 3H), 2.46 (m, 2H), 3.93(s, 3H), 4.30 (m, 3H), 4.45 (d, J = 1 h and poured into 1 N HCl (50 mL). The solid was collected and
10.0 Hz, 1H), 4.70 (d, J = 10.5 Hz, 1H), 4.88 (d, J = 10.0 Hz, 1H), dried to give compound 17e (1.4 g, 82% yield): 1H NMR (CDCl3) δ
6.99 (d, J = 6.0 Hz, 1H), 7.19−7.37 (m, 10H), 8.15 (d, J = 6.0 Hz, 7.90 (d, J = 9 Hz, 1 H), 7.38 (dd, 1 H), 7.25 (d, J = 9 Hz, 1 H), 4.99
1H); 13C NMR (100 MHz, CDCl3) δ 7.1, 26.1, 54.0, 62.9, 66.3, 72.8, (s, 2 H), 3.96 (s, 3 H), 3.23 (q, 2 H), 2.15 (br, 1 H), 1.35 (t, J = 5 Hz,
84.9, 115.7, 118.8, 127.5, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 3 H).
137.0, 137.6, 146.5, 148.8, 163.9, 173.5; TOF MS (EI) m/z = 2-Bromo-3-(bromomethyl)-4-ethyl-6-methoxyquinoline
421.1904 [M]+; HRMS m/z calcd for C25H27NO5 [M]+ 421.1889, (17). To a solution of compound 17e (1 g, 3.97 mmol) in CHCl3 (15
found 421.1896. mL) was added PBr3 (1 mL). The mixture was refluxed for 12 h and
(S)-4-Ethyl-4-hydroxy-8-methoxy-1H-pyrano[3,4-c]pyridin- quenched by water and NaHCO3. The solution was extracted with
3(4H)-one (16). A mixture of compound 15 (1.0 g, 2.37 mmol) and CHCl3, washed with brine, dried over anhydrous Na2SO4, and
methanol (30 mL) was hydrogenated at normal pressure and at room evaporated to dryness give compound 17 (1 g, 70% yield): 1H NMR
temperature for 12 h with 0.1 g 10% Pd/C. The catalyst was then (CDCl3) δ 7.86 (d, J = 9 Hz, 1 H), 7.33 (q, 1 H), 7.17 (d, J = 3 Hz, 1
filtered off and the filtrate was evaporated to dryness to give crude H), 4.77 (s, 2 H), 3.91 (s, 3 H), 3.15 (q, 2 H), 1.36 (t, J = 8 Hz, 3 H);
compound 16, which was further purified by column chromatography 13
C NMR (CDCl3) δ 158.4, 157.4, 150.9, 143.1, 130.8, 127.2, 126.7,
(ethyl acetate/hexane =1:5) to give pure 16 as a colorless liquid (0.51 122.6, 102.6, 61.6, 55.6, 27.5, 22.5, 14.2; MS (EI) m/z = 356 [M]+;
g, 85% yield). The crude product could be used in the next step HRMS m/z calcd for C13H13Br2NO [M]+ 356.9364, found 356.8490.
without purification when in large scale: 1H NMR (500 MHz, CDCl3) (S)-7-((2-Bromo-4-ethyl-6-methoxyquinolin-3-yl)methyl)-4-
δ 0.95 (t, J = 7.35 Hz, 3H), 1.79 (m, 2H), 3.66 (s, 1H), 3.99 (s, 3H), ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione
5.26 (d, J = 15.6 Hz, 1H), 5.57 (d, J = 15.6 Hz, 1H), 7.15 (d, J = 5.25 (18). K2CO3 (2.76 g, 0.02 mol) was added to a solution of compound
Hz, 1H), 8.15 (d, J = 5.25 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 17 (3.59 g, 0.01 mol) and compound 5 (2.09 g, 0.01 mol) in DMF (50
7.4, 31.6, 53.6, 65.5, 72. 8, 111.2, 113.0, 147.1, 148.1, 158.6, 174.0; MS mL) under nitrogen. Then the mixture was heated for 4 h at 50 °C,
(EI) m/z = 223 [M]+; HRMS m/z calcd for C11H13NO4 [M]+ and poured into 200 mL of 1 N HCl solution, extracted with
223.0845, found 223.0843. dichloromethane, dried with anhydrous Na2SO4, and evaporated to
(S)-4-Ethyl-4-hydroxy-8-methoxy-1H-pyrano[3,4-c]pyridin- dryness to afford crude 18, which was further purified by trituration
3(4H)-one (5). Compound 16 (16.7 g, 74.9 mmol) was dissolved in 3 with petroleum ether/ethyl acetate (15 mL) to give pure 18 as an off-
N HCl (300 mL) and the solution was heated for 3 h at 100 °C. The white solid (4.38 g, 90% yield): 1H NMR (500 MHz, CDCl3) δ 0.95
mixture was then cooled to room temperature and evaporated to (t, J = 6.5 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3 H), 1.78 (m, 2 H), 3.09 (m, 2
dryness to give crude compound 5, which was purified by trituration H), 3.60 (s, 1 H), 3.96 (s, 3 H), 5.23 (d, J = 16.2 Hz, 1 H), 5.54 (m, 2
with 20 mL anhydrous ethanol affording product 5 (11.72 g, 75% H), 5.67 (d, J = 16.2 Hz, 1 H), 6.45 (d, J = 7.2 Hz, 1 H), 7.14 (d, J =
yield) as a white solid: [α]D25 = 110.77 (c, 0.30, MeOH); 1H NMR 7.2 Hz, 1 H), 7.23 (d, J = 2.3 Hz, 1 H), 7.44 (dd, J = 2.3, 9.2 Hz, 1 H),
(500 MHz, DMSO-d6) δ 0.80 (t, J = 7.5 Hz, 3H), 1.75 (m, 2H), 5.22 7.96 (d, J = 9.2 Hz, 1 H).
(s, 2H), 6.25 (s, 1H), 6.35 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 7.0 Hz, (S)-4,11-Diethyl-4-hydroxy-9-methoxy-1H-pyrano[3′,4′:6,7]-
1H), 11.8 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 7.6, 30.4, 65.1, indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (19). A mixture
71.9, 102.1, 119.0, 134.7, 149.9, 158.9, 172.5; MS (EI) m/z = 209 of bromoquinoline 18 (4.87 g, 0.01 mol), palladium(II) acetate (0.22
[M]+; HRMS m/z calcd for C10H11NO4 [M]+ 209.0688, found g, 1.0 mmol), anhydrous K2CO3 powder (3.46 g, 0.025 mol), and
209.0692. The enantiomeric excess of (S)-5 was determined by HPLC triphenylphosphine (1.05 g, 4.0 mmol) in 150 mL of toluene was
as 100% [column, CHIRALPAK OD-H (4.6 mm ×250 mm), room brought to reflux under nitrogen. As the reflux was continued for 16 h,
temperature; eluent, hexane-EtOH (90:10); flow rate, 1.0 mL/min; the product precipitated. Then the mixture was cooled to room
detect, 300 nm; tR of (S)-5, 24.660 min; tR of (R)-5 (enantiomer of temperature, and the precipitate was collected, washed with water and
(S)-5), 17.509 min]. ethyl acetate, and dried to afford a pale yellow solid (2.85 g, 70%
Ethyl 3-((4-Methoxy-2-propionylphenyl)amino)-3-oxopro- yield), which was used without further purification: 1H NMR (500
panoate (17b). To a solution of compound 17a37 (7.2 g, 40.17 MHz, DMSO-d6) δ 0.88 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.5 Hz, 3H),
mmol) in CH2Cl2 (60 mL) and Et3N (17 mL) was added ethyl 3- 1.86 (m, 2H), 3.20 (q, J = 7.5 Hz, 2H), 3.99 (s, 3H), 5.30 (s, 2H), 5.42
chloro-3-oxopropanoate (12.2 g, 81.03 mmol) in 40 mL of CH2Cl2 (s, 2H), 6.52 (s, 1H), 7.27 (s, 1H), 7.52 (m, 2H), 8.08 (d, J = 9.0 Hz,
dropwise over 30 min at 0 °C. The mixture was stirred for further 30 1H).
min and water (100 mL) was added at room temperature. The 7-Ethyl-10-hydroxycamptothecin (SN-38, 4). A mixture of
solution was extracted with CH2Cl2, washed with brine, dried over compound 19 (1.5 g, 3.69 mmol) and HBr solution (150 mL) was

716 dx.doi.org/10.1021/jo201974f | J. Org. Chem. 2012, 77, 713−717

The Journal of Organic Chemistry Note

refluxed for 2 h. The mixture was cooled to room temperature and (5) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol. Chem.
extracted with CHCl3, dried with anhydrous Na2SO4, and evaporated 1985, 260, 14873.
to dryness to afford crude 4, which was further purified by trituration (6) Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.;
with CHCl3/MeOH to give pure 4 as an off-white solid (1.45 g, 87% Hecht, S. M.; Gallagher, G.; Caranfa, M. J.; McCabe, F. L.; Faucette, L.
yield). 1H NMR (500 MHz, DMSO-d6) δ 0.88 (t, J = 7.25 Hz, 3H), F.; Johnson, R. K. J. Med. Chem. 1991, 34, 98.
1.32 (t, J = 7.5 Hz, 3H), 1.87 (m, 2H), 3.10 (q, J = 7.5 Hz, 2H), 5.28 (7) Kawato, Y.; Aonuma, M.; Hirota, Y.; Kuga, H.; Sato, K. Cancer
(s, 2H), 5.42 (s, 2H), 6.48(s, 1H), 7.25 (s, 1H), 7.41 (d, J = 10.0 Hz, Res. 1991, 51, 4187.
2H), 8.03 (d, J = 10.0 Hz, 1H), 10.3 (s, 1H); The enantiomeric excess (8) Atsumi, R.; Okazaki, O.; Hakusui, H. Biol. Pharm. Bull. 1995, 18,
of (S)-SN-38 was determined by HPLC as 100% [column, 1024.
CHIRALPAK AD-H (4.6 mm × 250 mm), room temperature; eluent, (9) Potmesil, M.; Pinedo, H. Camptothecins: New Anticancer Agents;
EtOH; flow rate, 0.4 mL/min; detect, 220 nm; tR of (S)-SN-38, 10.665 CRC Press: Boca Raton, 1995.
min; tR of (R)-SN-38 (enantiomer of (S)-SN-38), 14.906 min]. (10) Du, W. Tetrahedron 2003, 59, 8649.
Camptothecin (1): yield 53% (two steps from 5 and 2-bromo-3- (11) Peters, R.; Althaus, M.; Nagy, A. L. Org. Biomol. Chem. 2006, 4,
(bromomethyl)quinoline); [α]D25 = 42.85 (c, 0.40, MeOH/CHCl3);13 498.
1
H NMR (500 MHz, DMSO-d6) δ 0.89 (t, J = 7.3 Hz, 3H), 1.88 (m, (12) Tang, C. J.; Babjak, M.; Anderson, R. J.; Greene, A. E.;
2H), 5.27 (s, 2H), 5.43 (s, 2H), 6.52 (s, 1H), 7.35 (s, 1H), 7.71 (t, J = Kanazawa, A. Org. Biomol. Chem. 2006, 4, 3757.
7.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.16 (d, (13) Zhou, H. B.; Liu, G. S.; Yao, Z. J. Org. Lett. 2007, 9, 2003.
J = 8.4 Hz, 1H), 8.68 (s, 1H); MS (ESI): m/z = 349.2 [M + 1]+; (14) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913.
HRMS m/z calcd for C20H17N2O4[M + 1]+ 349.11828, found (15) Anderson, R. J.; Raolji, G. B.; Kanazawa, A.; Greene, A. E. Org.
349.11877. The enantiomeric excess of (S)-1 was determined by Lett. 2005, 7, 2989.
HPLC as 99.9258% [column, CHIRALPAK OJ-H (4.6 mm × 250 (16) Liu, G. S.; Dong, Q. L.; Yao, Y. S.; Yao, Z. J. Org. Lett. 2008, 10,
mm), room temperature; eluent, EtOH; flow rate, 0.4 mL/min; detect, 5393.
254 nm; tR of (S)-1, 18.835 min; tR of (R)-1 (enantiomer of (S)-1), (17) Hiroya, K.; Kawamoto, K.; Sakamoto, T. Synlett 2006, 2636.
15.524 min]. ee = 99.9258%. (18) Chavan, S.; Pathak, A.; Kalkote, U. Synlett 2007, 2635.
10-Hydroxycamptothecin: yield 34.7% (three steps from 5 and (19) Grillet, F.; Sabot, C.; Anderson, R.; Babjak, M.; Greene, A. E.;
2-bromo-3-(bromomethyl)-6-methoxyquinoline); 1H NMR (500 Kanazawa, A. Tetrahedron 2011, 67, 2579.
MHz, DMSO-d6) δ 0.88 (t, J = 7.25 Hz, 3H), 1.86 (m, 2H), 5.23 (20) Yu, J. R.; DePue, J.; Kronenthal, D. Tetrahedron Lett. 2004, 45,
(s, 2H), 5.41 (s, 2H), 6.50 (s, 1H), 7.27(d, J = 8.0 Hz, 2H), 7.42 (d, J 7247.
= 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 10.3 (s, 1H). (21) Chavan, S. P.; Sivappa, R. Tetrahedron Lett. 2004, 45, 3113.
The enantiomeric excess of (S)-10-HCPT was determined by HPLC (22) Chavan, S. P.; Pasupathy, K.; Venkatraman, M. S.; Kale, R. R.
as 99.92% [column, CHIRALPAK OJ-Hs (4.6 mm × 250 mm), room Tetrahedron Lett. 2004, 45, 6879.
temperature; eluent, MeOH; flow rate, 0.6 mL/min; detect, 220 nm; tR (23) Chavan, S. P.; Pathak, A. B.; Kalkote, U. R. Tetrahedron Lett.
of (S)-10-HCPT, 10.384 min; tR of (R)-10-HCPT (enantiomer of 10- 2007, 48, 6561.
HCPT), 8.378 min]. ee = 99.92%.

■
(24) Chavan, S. P.; Dhawane, A. N.; Kalkote, U. R. Tetrahedron Lett.
2010, 51, 3099.
ASSOCIATED CONTENT (25) Comins, D. L.; Saha, J. K. Tetrahedron Lett. 1995, 36, 7995.
*
S Supporting Information (26) Comins, D. L.; Hong, H.; Saha, J. K.; Gao, J. H. J. Org. Chem.
1994, 59, 5120.
Copy of X-ray structure of the key intermediate 10, copies of
1 (27) Comins, D. L.; Hong, H.; Jianhua, G. Tetrahedron Lett. 1994, 35,
H and 13C NMR spectra of 10−16, copies of 1H NMR spectra 5331.
of 19, 4, 1 and 10-OH-CPT, and copies of HPLC of 4, 1 and (28) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992,
10-OH-CPT. Copies of 1H and 13C NMR spectra of 114, 10971.
compound 17. Crystallographic data for 10. This material is (29) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
available free of charge via the Internet at http://pubs.acs.org. (30) Yu, S. B.; Luo, Y.; Liu, H. Y.; Liu, H. M.; Lu, W. Monatsh. Chem.

■
2010, 245.
AUTHOR INFORMATION (31) Wong, H. N. C.; Hui, C. W.; Lee, H. K. Tetrahedron Lett. 2002,
43, 123.
Corresponding Author (32) Hui, C. W.; Lee, H. K.; Wong, H. N. C. Tetrahedron Lett. 2002,
*Email: (Y.L.) [email protected], (W.L.) wlu@chem. 43, 123.
ecnu.edu.cn. (33) Bowman, W. R.; Elsegood, M. R.; Stein, T.; Weaver, G. W. Org.

■ ACKNOWLEDGMENTS
This work was supported by grants from the the National
Biomol. Chem. 2007, 5, 103.
(34) Mekouar, K.; Genisson, Y.; Leue, S.; Greene, A. E. J. Org. Chem.
2000, 65, 5212.
(35) Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson, M. R.;
Natural Science Foundation of China (Nos. 81172936 and Kang, M. C.; LeHoullier, C. S.; Lewis, G. C.; Lovelace, T. C.; Lowery,
21102046), grants from the Shanghai Science and Technology M. W.; McDougald, D. L.; Meerholz, C. A.; Partridge, J. J.; Sharp, M.
Mission (10ZR1409600), and grants from the Fundamental J.; Xie, S. P. Tetrahedron 1997, 53, 10953.
Research Funds for the Central Universities. We also thank the (36) Grillet, F.; Baumlova, B.; Prevost, G.; Constant, J. F.;
Laboratory of Organic Functional Molecules, the Sino-French Chaumeron, S.; Bigg, D. C.; Greene, A. E.; Kanazawa, A. Bioorg.
Institute of ECNU, for support. Med. Chem. Lett. 2008, 18, 2143.

■
(37) Yu, S. B.; Zhang, L. J.; Luo, Y.; Lu, W. Chin. Chem. Lett. 2011,
REFERENCES 22, 1.
(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.
(2) Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Bioorg. Med. Chem.
2004, 12, 1585.
(3) Staker, B. L.; Hjerrild, K.; Feese, M. D.; Behnke, C. A.; Burgin, A.
B. Jr.; Stewart, L. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15387.
(4) Kohn, K. W.; Pommier, Y. Ann. N.Y. Acad. Sci. 2000, 922, 11.

717 dx.doi.org/10.1021/jo201974f | J. Org. Chem. 2012, 77, 713−717