Total synthesis of camptothecin and SN-38

Article abstract of DOI:10.1021/jo201974f

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 chromatography-free purification was achieved in all steps, which offers an economic industrial process to the camptothecin-family alkaloids.

Full text of DOI:10.1021/jo201974f

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.
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’
method was an efficient route to construct the key core of
CPT-family alkaloids by coupling the A/B ring with the D/E
ring,25−28 but employment of expensive reagents made this
approach unpreferable for application in the industry. In
Comins’ approach, the chiral center of compound 5 was
obtained by the stereoselectively nucleophlic addition of 2-
ketobutyric acid ester with expensively chiral auxiliaries in only
93% ee value.29 Recently, we disclosed a short and efficient
route for producing racemic compound 5,30 in which 2-
chloronicotinic acid was employed as the starting material
(Figure 2). Based on this previous work, we present a scalable
and concise total synthesis of camptothecin (1) and SN-38 (4)
starting from inexpensive and readily available materials.
amptothecin (CPT 1, Figure 1) was first isolated from
Camptothecin acuminata by Wani and Wall in 1966.1 This
C
Figure 1. Camptothecin and two representative derivatives.
natural alkaloid showed potent antitumor activity and a unique
mechanism of action, which selectively inhibits DNA top-
oisomerase I (Topo I), thus attracting intense interest
worldwide as a prominent lead for the development of new
anticancer drugs.2−5 For its good antitumor profiles and unique
mechanism, an amount of camptothecin analogues have been
synthesized and investigated to find better camptothecin
derivatives with reduced toxicity and improved anticancer
activity. To date, two camptothecin analogues, topotecan (2)6
and irinotecan (3),7 have been approved by the FDA to treat
cancers, among which irinotecan (3) turned out to be a more
active metabolite SN-38 (4)8 in vivo. In addition, several others,
such as BNP-1350, silatecan, ST-1481, lurtotecan, and
diflomotecan, are presently in different stages of preclinical
and clinical trials.9
According to our retrosynthesis shown in Figure 2, ring C
was constructed through joining of the A/B ring and the D/E
ring (5) based on our previous work.30 It was obvious that
Since the common drawback of industrial-scale extraction
from the medical plants, development of practical and concise
Received: September 30, 2011
Published: December 13, 2011
© 2011 American Chemical Society
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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%.
With the key intermediate 5 in hand, CPT-family alkaloids
can be obtained by using condensation and Heck reaction with
different A/B fragment.33−36 Here, synthesis of SN-38 (4) as an
example is shown in Scheme 2. Compound 17 was synthesized
by a general procedure which was similar as the synthesis of
unsubstituted A/B ring,33,34 starting from 17a.37 The
condensation of 5 and 17 under basic conditions gave
intermediate 18, which was subjected to Heck reaction to
produce 19. Deprotection of 19 afforded SN-38 (4) in excellent
yield. In addition, camptothecin (1) and 10-hydroxycampto-
thecin were also prepared in this way, and the purity and ee
value for all these CPT-family alkaloids exceeded 99.9%
without column chromatography in all steps. The data for
these synthesized camptothecins were in good agreement with
those of natural products.
Figure 2. Retrosynthesis of camptothecin (1) and SN-38 (4).
asymmetric alcohol 6 was the key fragment in this work. In
2002, Wong’s group31 reported that this S-configuration tertiary
alcohol (9) was constructed by a nucleophilic addition of
lithiated furan and glyceraldehyde derivative (7) in yield of 74%
and de value of 93%, which inspired us that this chiral moiety
could be further converted into the key scaffold, a tertiary
alcohol acid.
Thus, the DE ring (5) was prepared as outlined in Scheme 1.
To facilitate the formation of pyridone (5) in the final step,
commercially available 2-methoxynicotinic acid (8) was chosen
as the starting material, which was lithiated with LTMP (3
equiv compared to 8) and subsequently subjected to a
nucleophilic addition with chiral ketone 732 (3 equiv compared
to 8) at −60 to −78 °C to afford lactone 10 in a yield of 55%.
Fortunately, this lactone 10 could be recrystallized right from
the reaction solution in extraordinarily high purity (chemical
purity >99.9%, de value >99.9%), and its diastereoisomer was
not detected in the LC−MS system. The key intermediate 10
was thus subjected to X-ray crystallography, which confirmed
that the chiral center was the desired S-configuration (Figure 3,
see the Supporting Information). Later, we tried to optimize
the reaction conditions in this step, the molar ratio of
compound 7 to 8 was first reduced to 2:1 from 3:1, but the
In summary, we have succeeded in implementing a practical
and concise total synthesis of camptothecin (1) and SN-38 (11
steps, 14% overall yield, 99.9% ee, and 99.9% purity),
employing an inexpensive and commercial available material
(8) as starting material and compound 7 as asymmetric
inducing reagent. It is worth mentioning that the development
of column chromatography-free purification was achieved in all
steps, which will be valuable as an economical industrial process
of producing camptothecin-family alkaloids.
Scheme 1
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Scheme 2
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
room temperature, and poured into 20 mL water. The solution was
extracted with EA, washed with brine, dried over anhydrous Na2SO4,
and concentrated to afford crude 12, which was further purified by
column chromatography (ethyl acetate/hexane =1:5) to give pure 12
as a colorless liquid (2.8 g, 88% yield). The crude product could be
used in the next step without further purification when in a large scale:
1H NMR (500 MHz, CDCl3) δ 0.85 (t, J = 7.25 Hz, 3H), 1.35 (s, 6H),
2.20 (m, 1H), 2.30 (m, 1H), 3.85 (m, 1H), 3.97(s, 3H), 4.00 (m, 1H),
4.45 (s, 2H), 4.47 (d, J = 9.6 Hz, 1H), 4.68 (m, 2H), 4.79 (t, 1H), 4.87
(d, J = 9.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 7.25−7.36 (m, 10H),
8.10 (d, J = 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 8.6, 14.1,
20.8, 24.5, 25.9, 26.6, 53.6, 60.2, 63.9, 65.4, 65.6, 73.2, 80.4, 82.2,
109.5, 116.4, 119.2, 127.1, 127.3, 128.1, 138.4, 138.9, 146.0, 151.1,
164.3; MS (EI) m/z = 477; HRMS (EI) m/z calcd for C29H35NO5
[M]+ 477.2515, found 477.2508.
(2R,3S)-3-(Benzyloxy)-3-(3-((benzyloxy)methyl)-2-methoxy-
pyridin-4-yl)pentane-1,2-diol (13). To a solution of compound 12
(2.5 g, 5.23 mmol) in methanol (30 mL) was added concentrated HCl
(6 mL) at room temperature and the mixture stirred for another 2 h.
Then the mixture was poured into water (100 mL). The solution was
extracted with CH2Cl2, washed with brine, dried over anhydrous
Na2SO4, and evaporated to dryness to give a viscous solid 13 (2.1 g,
92.1% yield), which was pure enough to use in the next step without
further purification: 1H NMR (500 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz,
3H), 2.16 (m, 1H), 2.30 (s, 1H), 2.45 (m, 1H), 3.31 (m, 1H), 3.54 (m,
1H), 3.93 (s, 3H), 3.99 (s, 1H), 4.11 (m, 1H), 4.35 (d, J = 11.5 Hz,
1H), 4.44 (d, J = 11.5 Hz, 1H), 4.53 (d, J = 10.5 Hz, 1H), 4.67 (d, J =
9.5 Hz, 1H), 4.74 (d, J = 10.5 Hz, 1H), 4.96 (d, J = 9.5 Hz, 1H), 6.88
(d, J = 5.5 Hz, 1H), 7.26−7.42 (m, 10H), 8.09 (d, J = 5.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 7.9, 25.1, 53.7, 63.3, 63.8, 64.9, 72.8, 77.3,
85.0, 116.4, 119.0, 127.4, 127.6, 127.9, 128.3, 137.7, 138.2, 145.7,
151.1, 164.2; MS (ESI) m/z = 438.2 [M + 1]+; FTMS m/z calcd for
C26H32NO5 [M + 1]+ 438.2274, found 438.2275.
EXPERIMENTAL SECTION
■
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-ethyl-4-
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-
idine (14.4 mL, 117.6 mmol) in anhydrous THF (200 mL) at −78 °C
under nitrogen. The mixture was stirred for 30 min before 2-
methoxynicotinic acid (8, 4.84 g, 31.64 mmol) was added. After the
mixture was stirred for 30 min at −78 °C, compound 7 (15.0 g, 94.9
mmol) was added and and the mixture stirred for another 30 min.
Then the mixture was allowed to reach room temperature and
hydrolyzed with 1 N HCl (50 mL). The mixture was extracted with
ethyl acetate, dried over anhydrous Na2SO4, and concentrated to
afford 25.0 g of crude 10, which was further purified by trituration with
petroleun ether (20 mL) to give pure 10 as a white solid (4.7 g, 55%
1
yield). H NMR (500 MHz, CDCl3) δ 0.64 (t, J = 7.5 Hz, 3H), 1.30
(s, 3H), 1.42(s, 3H), 2.06 (m, 1H), 2.22 (m, 1H), 4.04 (m, 2H), 4.14
(s, 3H), 4.16 (m, 1H), 7.04 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 5.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 6.6, 24.5, 24.6, 25.8, 54.3, 64.8,
78.5, 88.2, 109.1, 110.4, 111.0, 152.9, 161.4, 163.4, 167.0; MS (EI) m/
z = 293; HRMS (EI) m/z calcd for C15H19NO5 [M]+ 293.1263, found
293.1264.
(S)-1-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-1-(3-(hydroxy-
methyl)-2-methoxypyridin-4-yl)propan-1-ol (11). A solution of
the compound 10 (5.5 g, 19 mmol) in anhydrous THF (50 mL) was
added slowly to a mixture of LiAH4 (1.3 g, 34 mmol) in anhydrous
THF (30 mL), and then the mixture was stirred for 2 h at the room
temperature, cooled to 0 °C, and quenched with water (2.5 mL). The
mixture was filtered, extracted with ethyl acetate, dried over anhydrous
Na2SO4, and evaporated to dryness to give a white solid 11 (5.4 g,
95.0% yield): 1H NMR (500 MHz, CDCl3) δ 0.78 (t, J = 7.4 Hz, 3H),
1.40 (s, 3H), 1.48 (s, 3H), 2.00 (m, 1H), 2.97 (s, 1H), 3.26 (s, 1H),
3.58 (m, 1H), 3.73 (m, 1H), 3.97 (s, 3H), 4.55 (m, 1H), 4.89 (m, 2H),
6.72 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 5.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 7.7, 25.0, 26.2, 24.1, 53.8, 56.4, 65.5, 78.2, 80.2, 110.0,
114.8, 121.7, 145.4, 150.3, 163.3; MS (EI) m/z = 297; HRMS (EI) m/
z calcd for C15H23NO5 [M]+ 297.1576, found 297.1580.
(S)-2-(Benzyloxy)-2-(3-((benzyloxy)methyl)-2-methoxypyri-
din-4-yl)butanal (14). Sodium periodate (1.2 g, 5.2 mmol) was
added to a solution of compound 13 (1.16 g, 2.65 mmol) in 15 mL of
acetonitrile and 2 mL of water, and then the mixture was stirred for 2 h
4-((S)-1-(Benzyloxy)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-
propyl)-3-((benzyloxy)methyl)-2-methoxypyridine (12). So-
dium hydride (1.1 g, 27 mmol) was added in two portions to a
solution of compound 11 (2.0 g, 6.73 mmol) in 40 mL of anhydrous
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at room temperature and poured into 20 mL water. The solution was
extracted with CH2Cl2, washed with brine, dried over anhydrous
Na2SO4, and evaporated to dryness to give a viscous solid 14 (1.02 g,
anhydrous Na2SO4, and evaporated to dryness give compound 17b
(9.5 g, 81% yield): 1HNMR (CDCl3): δ 11.72 (s, 1 H), 8.62 (d, J = 9
Hz, 1 H), 7.41 (d, J = 3 Hz, 1 H), 7.11 (dd, 1 H), 4.26 (dd, 2 H), 3.84
(s, 3 H), 3.49 (s, 2 H), 3.04 (dd, 2 H), 1.31 (dd, 3 H), 1.22 (dd, 3 H).
Ethyl 4-Ethyl-6-methoxy-2-oxo-1,2-dihydroquinoline-3-car-
boxylate (17c). To a solution of compound 17b (9.5 g, 32.39 mmol)
in MeOH (80 mL) was added NaOMe (5.2 g, 92.26 mmol) at 0 °C.
The mixture was stirred for 1 h and 1 N HCl was added. The solid was
collected, washed with PE/EA (10/1) and dried to give compound
17c (7.5 g, 85% yield): 1H NMR (CDCl3) δ 12.03 (s, 1 H), 7.33 (d, J
= 10 Hz, 1 H), 7.18 (d, J = 10 Hz, 1 H), 7.15 (dd, 1 H), 4.48 (dd, 2
H), 3.87 (s, 3 H), 2.85 (dd, 2 H), 1.44 (t, J = 5 Hz, 3 H), 1.35 (t, J = 5
Hz, 3 H).
1
95% yield), which was used without further purification: H NMR
(500 MHz, CDCl3) δ 0.91 (t, J = 7.0 Hz, 3H), 2.46 (m, 2H), 3.96 (s,
3H), 4.26 (d, J = 11.1 Hz, 1H), 4.33 (d, J = 11.1 Hz, 1H), 4.44 (s, 2H),
4.53 (d, J = 11.1 Hz, 1H), 4.59 (d, J = 11.1 Hz, 1H), 7.11 (d, J = 5.5
Hz, 1H), 7.23−7.35 (m, 10H), 8.16 (d, J = 5.5 Hz, 1H), 9.67 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 7.0, 25.2, 53.7, 65.1, 72.7, 85.5, 116.0,
118.4, 127.1, 127.5, 127.9, 128.0, 137.4, 146.6, 148.0, 163.7, 199.2; MS
(EI) m/z = 405 [M]+; HRMS (EI) m/z calcd for C25H27NO4 [M]+
405.1940, found 405.1944.
(S)-2-(Benzyloxy)-2-(3-((benzyloxy)methyl)-2-methoxypyri-
din-4-yl)butanoic Acid (15). Compound 14 (1.1 g, 2.72 mmol) was
added to a solution of 2-methyl-2-butylene (3 mL) and sodium
dihydrogen phosphate (1.7 g) in 15 mL of acetonitrile and 5 mL of
water. The mixture was stirred for 30 min, and sodium chlorite (1.0 g,
11 mmol) was added at room temperature. Then the mixture was
stirred for 2 h and poured into 15 mL of 1 N HCl solution. The
solution was extracted with CH2Cl2, washed with brine, dried over
anhydrous Na2SO4, and evaporated to dryness give viscous liquid 15
(1.1 g, 96.0% yield), which was pure enough to use in the next step
without further purification: 1H NMR (500 MHz, CDCl3) δ 0.91 (t, J
= 7.0 Hz, 3H), 2.46 (m, 2H), 3.93(s, 3H), 4.30 (m, 3H), 4.45 (d, J =
10.0 Hz, 1H), 4.70 (d, J = 10.5 Hz, 1H), 4.88 (d, J = 10.0 Hz, 1H),
6.99 (d, J = 6.0 Hz, 1H), 7.19−7.37 (m, 10H), 8.15 (d, J = 6.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 7.1, 26.1, 54.0, 62.9, 66.3, 72.8,
84.9, 115.7, 118.8, 127.5, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4,
137.0, 137.6, 146.5, 148.8, 163.9, 173.5; TOF MS (EI) m/z =
421.1904 [M]+; HRMS m/z calcd for C25H27NO5 [M]+ 421.1889,
found 421.1896.
(S)-4-Ethyl-4-hydroxy-8-methoxy-1H-pyrano[3,4-c]pyridin-
3(4H)-one (16). A mixture of compound 15 (1.0 g, 2.37 mmol) and
methanol (30 mL) was hydrogenated at normal pressure and at room
temperature for 12 h with 0.1 g 10% Pd/C. The catalyst was then
filtered off and the filtrate was evaporated to dryness to give crude
compound 16, which was further purified by column chromatography
(ethyl acetate/hexane =1:5) to give pure 16 as a colorless liquid (0.51
g, 85% yield). The crude product could be used in the next step
without purification when in large scale: 1H NMR (500 MHz, CDCl3)
δ 0.95 (t, J = 7.35 Hz, 3H), 1.79 (m, 2H), 3.66 (s, 1H), 3.99 (s, 3H),
5.26 (d, J = 15.6 Hz, 1H), 5.57 (d, J = 15.6 Hz, 1H), 7.15 (d, J = 5.25
Hz, 1H), 8.15 (d, J = 5.25 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
7.4, 31.6, 53.6, 65.5, 72. 8, 111.2, 113.0, 147.1, 148.1, 158.6, 174.0; MS
(EI) m/z = 223 [M]+; HRMS m/z calcd for C11H13NO4 [M]+
223.0845, found 223.0843.
Ethyl 2-Chloro-4-ethyl-6-methoxyquinoline-3-carboxylate
(17d). The solution of compound 17c (1 g, 3.63 mmol) and POCl3
(10 mL) was refluxed 1−3 h. The mixture was quenched by crashed
ice. The solid was collected and dried to give compound 17d (0.7 g,
66% yield): H NMR (CDCl3) δ 7.91 (d, J = 9 Hz, 1 H), 7.38 (q, 1
H), 7.25 (d, J = 4 Hz, 1 H), 4.54 (q, 2 H), 3.98 (s, 3 H), 3.04 (q, 2 H),
1
1.49 (t, J = 7 Hz, 3 H), 1.38 (t, J = 7 Hz, 3 H).
(2-Chloro-4-ethyl-6-methoxyquinolin-3-yl)methanol (17e).
To a solution of compound 17d (2 g, 6.81 mmol) in THF (20 mL)
was added Red-Al (3.5 M, 7.0 mL) at 0 °C. The mixture was stirred for
1 h and poured into 1 N HCl (50 mL). The solid was collected and
1
dried to give compound 17e (1.4 g, 82% yield): H NMR (CDCl3) δ
7.90 (d, J = 9 Hz, 1 H), 7.38 (dd, 1 H), 7.25 (d, J = 9 Hz, 1 H), 4.99
(s, 2 H), 3.96 (s, 3 H), 3.23 (q, 2 H), 2.15 (br, 1 H), 1.35 (t, J = 5 Hz,
3 H).
2-Bromo-3-(bromomethyl)-4-ethyl-6-methoxyquinoline
(17). To a solution of compound 17e (1 g, 3.97 mmol) in CHCl3 (15
mL) was added PBr3 (1 mL). The mixture was refluxed for 12 h and
quenched by water and NaHCO3. The solution was extracted with
CHCl3, washed with brine, dried over anhydrous Na2SO4, and
1
evaporated to dryness give compound 17 (1 g, 70% yield): H NMR
(CDCl3) δ 7.86 (d, J = 9 Hz, 1 H), 7.33 (q, 1 H), 7.17 (d, J = 3 Hz, 1
H), 4.77 (s, 2 H), 3.91 (s, 3 H), 3.15 (q, 2 H), 1.36 (t, J = 8 Hz, 3 H);
13C NMR (CDCl3) δ 158.4, 157.4, 150.9, 143.1, 130.8, 127.2, 126.7,
122.6, 102.6, 61.6, 55.6, 27.5, 22.5, 14.2; MS (EI) m/z = 356 [M]+;
HRMS m/z calcd for C13H13Br2NO [M]+ 356.9364, found 356.8490.
(S)-7-((2-Bromo-4-ethyl-6-methoxyquinolin-3-yl)methyl)-4-
ethyl-4-hydroxy-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione
(18). K2CO3 (2.76 g, 0.02 mol) was added to a solution of compound
17 (3.59 g, 0.01 mol) and compound 5 (2.09 g, 0.01 mol) in DMF (50
mL) under nitrogen. Then the mixture was heated for 4 h at 50 °C,
and poured into 200 mL of 1 N HCl solution, extracted with
dichloromethane, dried with anhydrous Na2SO4, and evaporated to
dryness to afford crude 18, which was further purified by trituration
with petroleum ether/ethyl acetate (15 mL) to give pure 18 as an off-
(S)-4-Ethyl-4-hydroxy-8-methoxy-1H-pyrano[3,4-c]pyridin-
3(4H)-one (5). Compound 16 (16.7 g, 74.9 mmol) was dissolved in 3
N HCl (300 mL) and the solution was heated for 3 h at 100 °C. The
mixture was then cooled to room temperature and evaporated to
dryness to give crude compound 5, which was purified by trituration
with 20 mL anhydrous ethanol affording product 5 (11.72 g, 75%
1
white solid (4.38 g, 90% yield): H NMR (500 MHz, CDCl3) δ 0.95
(t, J = 6.5 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3 H), 1.78 (m, 2 H), 3.09 (m, 2
H), 3.60 (s, 1 H), 3.96 (s, 3 H), 5.23 (d, J = 16.2 Hz, 1 H), 5.54 (m, 2
H), 5.67 (d, J = 16.2 Hz, 1 H), 6.45 (d, J = 7.2 Hz, 1 H), 7.14 (d, J =
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),
7.96 (d, J = 9.2 Hz, 1 H).
yield) as a white solid: [α]D25 = 110.77 (c, 0.30, MeOH); H NMR
1
(500 MHz, DMSO-d6) δ 0.80 (t, J = 7.5 Hz, 3H), 1.75 (m, 2H), 5.22
(s, 2H), 6.25 (s, 1H), 6.35 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 7.0 Hz,
1H), 11.8 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 7.6, 30.4, 65.1,
71.9, 102.1, 119.0, 134.7, 149.9, 158.9, 172.5; MS (EI) m/z = 209
[M]+; HRMS m/z calcd for C10H11NO4 [M]+ 209.0688, found
209.0692. The enantiomeric excess of (S)-5 was determined by HPLC
as 100% [column, CHIRALPAK OD-H (4.6 mm ×250 mm), room
temperature; eluent, hexane-EtOH (90:10); flow rate, 1.0 mL/min;
detect, 300 nm; tR of (S)-5, 24.660 min; tR of (R)-5 (enantiomer of
(S)-5), 17.509 min].
Ethyl 3-((4-Methoxy-2-propionylphenyl)amino)-3-oxopro-
panoate (17b). To a solution of compound 17a37 (7.2 g, 40.17
mmol) in CH2Cl2 (60 mL) and Et3N (17 mL) was added ethyl 3-
chloro-3-oxopropanoate (12.2 g, 81.03 mmol) in 40 mL of CH2Cl2
dropwise over 30 min at 0 °C. The mixture was stirred for further 30
min and water (100 mL) was added at room temperature. The
solution was extracted with CH2Cl2, washed with brine, dried over
(S)-4,11-Diethyl-4-hydroxy-9-methoxy-1H-pyrano[3′,4′:6,7]-
indolizino[1,2-b]quinoline-3,14(4H,12H)-dione (19). A mixture
of bromoquinoline 18 (4.87 g, 0.01 mol), palladium(II) acetate (0.22
g, 1.0 mmol), anhydrous K2CO3 powder (3.46 g, 0.025 mol), and
triphenylphosphine (1.05 g, 4.0 mmol) in 150 mL of toluene was
brought to reflux under nitrogen. As the reflux was continued for 16 h,
the product precipitated. Then the mixture was cooled to room
temperature, and the precipitate was collected, washed with water and
ethyl acetate, and dried to afford a pale yellow solid (2.85 g, 70%
1
yield), which was used without further purification: H NMR (500
MHz, DMSO-d6) δ 0.88 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.5 Hz, 3H),
1.86 (m, 2H), 3.20 (q, J = 7.5 Hz, 2H), 3.99 (s, 3H), 5.30 (s, 2H), 5.42
(s, 2H), 6.52 (s, 1H), 7.27 (s, 1H), 7.52 (m, 2H), 8.08 (d, J = 9.0 Hz,
1H).
7-Ethyl-10-hydroxycamptothecin (SN-38, 4). A mixture of
compound 19 (1.5 g, 3.69 mmol) and HBr solution (150 mL) was
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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
extracted with CHCl3, dried with anhydrous Na2SO4, and evaporated
to dryness to afford crude 4, which was further purified by trituration
with CHCl3/MeOH to give pure 4 as an off-white solid (1.45 g, 87%
(5) Hsiang, Y. H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol. Chem.
1985, 260, 14873.
(6) Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.;
Hecht, S. M.; Gallagher, G.; Caranfa, M. J.; McCabe, F. L.; Faucette, L.
F.; Johnson, R. K. J. Med. Chem. 1991, 34, 98.
(7) Kawato, Y.; Aonuma, M.; Hirota, Y.; Kuga, H.; Sato, K. Cancer
Res. 1991, 51, 4187.
(8) Atsumi, R.; Okazaki, O.; Hakusui, H. Biol. Pharm. Bull. 1995, 18,
1024.
(9) Potmesil, M.; Pinedo, H. Camptothecins: New Anticancer Agents;
CRC Press: Boca Raton, 1995.
(10) Du, W. Tetrahedron 2003, 59, 8649.
1
yield). H NMR (500 MHz, DMSO-d6) δ 0.88 (t, J = 7.25 Hz, 3H),
1.32 (t, J = 7.5 Hz, 3H), 1.87 (m, 2H), 3.10 (q, J = 7.5 Hz, 2H), 5.28
(s, 2H), 5.42 (s, 2H), 6.48(s, 1H), 7.25 (s, 1H), 7.41 (d, J = 10.0 Hz,
2H), 8.03 (d, J = 10.0 Hz, 1H), 10.3 (s, 1H); The enantiomeric excess
of (S)-SN-38 was determined by HPLC as 100% [column,
CHIRALPAK AD-H (4.6 mm × 250 mm), room temperature; eluent,
EtOH; flow rate, 0.4 mL/min; detect, 220 nm; tR of (S)-SN-38, 10.665
min; tR of (R)-SN-38 (enantiomer of (S)-SN-38), 14.906 min].
Camptothecin (1): yield 53% (two steps from 5 and 2-bromo-3-
(bromomethyl)quinoline); [α]D25 = 42.85 (c, 0.40, MeOH/CHCl3);13
1H NMR (500 MHz, DMSO-d6) δ 0.89 (t, J = 7.3 Hz, 3H), 1.88 (m,
2H), 5.27 (s, 2H), 5.43 (s, 2H), 6.52 (s, 1H), 7.35 (s, 1H), 7.71 (t, J =
7.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.16 (d,
J = 8.4 Hz, 1H), 8.68 (s, 1H); MS (ESI): m/z = 349.2 [M + 1]+;
HRMS m/z calcd for C20H17N2O4[M + 1]+ 349.11828, found
349.11877. The enantiomeric excess of (S)-1 was determined by
HPLC as 99.9258% [column, CHIRALPAK OJ-H (4.6 mm × 250
mm), room temperature; eluent, EtOH; flow rate, 0.4 mL/min; detect,
254 nm; tR of (S)-1, 18.835 min; tR of (R)-1 (enantiomer of (S)-1),
15.524 min]. ee = 99.9258%.
10-Hydroxycamptothecin: yield 34.7% (three steps from 5 and
2-bromo-3-(bromomethyl)-6-methoxyquinoline); 1H NMR (500
MHz, DMSO-d6) δ 0.88 (t, J = 7.25 Hz, 3H), 1.86 (m, 2H), 5.23
(s, 2H), 5.41 (s, 2H), 6.50 (s, 1H), 7.27(d, J = 8.0 Hz, 2H), 7.42 (d, J
= 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.45 (s, 1H), 10.3 (s, 1H).
The enantiomeric excess of (S)-10-HCPT was determined by HPLC
as 99.92% [column, CHIRALPAK OJ-Hs (4.6 mm × 250 mm), room
temperature; eluent, MeOH; flow rate, 0.6 mL/min; detect, 220 nm; tR
of (S)-10-HCPT, 10.384 min; tR of (R)-10-HCPT (enantiomer of 10-
HCPT), 8.378 min]. ee = 99.92%.
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ASSOCIATED CONTENT
* Supporting Information
Copy of X-ray structure of the key intermediate 10, copies of
1H and 13C NMR spectra of 10−16, copies of 1H NMR spectra
of 19, 4, 1 and 10-OH-CPT, and copies of HPLC of 4, 1 and
10-OH-CPT. Copies of 1H and 13C NMR spectra of
compound 17. Crystallographic data for 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Comins, D. L.; Saha, J. K. Tetrahedron Lett. 1995, 36, 7995.
(26) Comins, D. L.; Hong, H.; Saha, J. K.; Gao, J. H. J. Org. Chem.
1994, 59, 5120.
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5331.
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114, 10971.
(29) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
(30) Yu, S. B.; Luo, Y.; Liu, H. Y.; Liu, H. M.; Lu, W. Monatsh. Chem.
2010, 245.
■
S
(31) Wong, H. N. C.; Hui, C. W.; Lee, H. K. Tetrahedron Lett. 2002,
43, 123.
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43, 123.
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Biomol. Chem. 2007, 5, 103.
AUTHOR INFORMATION
Corresponding Author
*Email: (Y.L.) yluo@chem.ecnu.edu.cn, (W.L.) wlu@chem.
ecnu.edu.cn.
■
(34) Mekouar, K.; Genisson, Y.; Leue, S.; Greene, A. E. J. Org. Chem.
2000, 65, 5212.
ACKNOWLEDGMENTS
■
This work was supported by grants from the the National
Natural Science Foundation of China (Nos. 81172936 and
21102046), grants from the Shanghai Science and Technology
Mission (10ZR1409600), and grants from the Fundamental
Research Funds for the Central Universities. We also thank the
Laboratory of Organic Functional Molecules, the Sino-French
Institute of ECNU, for support.
(35) Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson, M. R.;
Kang, M. C.; LeHoullier, C. S.; Lewis, G. C.; Lovelace, T. C.; Lowery,
M. W.; McDougald, D. L.; Meerholz, C. A.; Partridge, J. J.; Sharp, M.
J.; Xie, S. P. Tetrahedron 1997, 53, 10953.
(36) Grillet, F.; Baumlova, B.; Prevost, G.; Constant, J. F.;
Chaumeron, S.; Bigg, D. C.; Greene, A. E.; Kanazawa, A. Bioorg.
Med. Chem. Lett. 2008, 18, 2143.
(37) Yu, S. B.; Zhang, L. J.; Luo, Y.; Lu, W. Chin. Chem. Lett. 2011,
22, 1.
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