Synthetic studies on camptothecins. Part 1: An improved asymmetric total synthesis of (20S)-camptothecin

Article abstract of DOI:10.1002/hlca.200890218

A six-step asymmetric total synthesis of (20S)-camptothecin (1) has been accomplished in 25% overall yield starting from the known pyridone 3. The key steps in this synthesis are the chemoselective Ni-catalyzed hydrogenation of 3-cyanopyridone 6 to 3-formylpyridone 7 in AcOH/pyridine/H₂O and the Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N-sulfonyloxaziridine into (4′S)-tricyclic hydroxylactone 2.

Full text of DOI:10.1002/hlca.200890218

Helvetica Chimica Acta – Vol. 91 (2008)
2057
Synthetic Studies on Camptothecins
Part 1
An Improved Asymmetric Total Synthesis of (20S)-Camptothecin
a
a
b
a
a b
by Li-Peng Zhang ), Yong Bao ) ), Yun-Yan Kuang ), and Fen-Er Chen* ) )
a) Department of Chemistry, Fudan University, Shanghai, 200433, P. R. China
b) Institute of Biomedical Science, Fudan University, Shanghai, 200032, P. R. China
(
phone/fax: þ 86-21-65643811; e-mail: rfchen@fudan.edu.cn)
A six-step asymmetric total synthesis of (20S)-camptothecin (1) has been accomplished in 25%
overall yield starting from the known pyridone 3. The key steps in this synthesis are the chemoselective
Ni-catalyzed hydrogenation of 3-cyanopyridone 6 to 3-formylpyridone 7 in AcOH/pyridine/H O and the
2
Davis asymmetric hydroxylation of tricyclic lactone 4 utilizing a chiral N-sulfonyloxaziridine into (4’S)-
tricyclic hydroxylactone 2.
Introduction. – Since its first isolation from the Chinese plant Camptotheca
acuminate by Wall and co-workers in 1966 [1], (20S)-Camptothecin (CPT, 1) has
attracted intense interest as a synthetic target over the past decades due to its unique
chemical structure and potent antitumor activity. Although (20S)-camptothecin can not
be used as a drug because of its poor water-solubility and severe side effects, this
alkaloid continues to serve as a very attractive and promising lead compound in the
development of new anticancer (20S)-camptothecins drugs. Accordingly, a number of
strategies have so far been developed for the asymmetric synthesis of 1 [2], and the
Friedlꢀnder approach implying the (4’S)-tricyclic hydroxylactone 2 as a key chiral
building block seems to be most attractive. To date, three approaches have been
disclosed for this chiral intermediate including the use of a chiral auxiliary group [3],
asymmetric dihydroxylation [4], and chemical and enzymatic resolutions [5] as key
steps. However, these methods suffered either from the use of stoichiometric amounts
of expensive chiral auxiliaries, application of highly toxic reagents, or low efficiency of
optical resolution. Therefore, the development of an efficient and practical preparation
of 2 is still in demand. Herein, we describe an efficient asymmetric total synthesis of 1
starting from the known pyridone 3 via the chiral N-sulfonyloxaziridine-mediated
asymmetric hydroxylation [6] of 4 into (4’S)-tricyclic hydroxylactone 2 as the key step.
Results and Discussion. – Our present synthetic route to 1 is outlined in the Scheme.
The known pyridone 3 was prepared in the overall yield of 30.8% from ethyl 2-ethoxy-
4-oxopent-2-enoate following the known protocol [7]. Carbonylation of 3 with diethyl
carbonate in the presence of a catalytic amount of EtONa or MeONa in anhydrous
THF gave the corresponding ester 5 in 90% yield. Although high-yielding ethylation of
5
under Waniꢀs condition (EtI/t-BuOK) [8] was reported, this procedure is impractical
ꢁ
2008 Verlag Helvetica Chimica Acta AG, Zꢂrich

2
058
Helvetica Chimica Acta – Vol. 91 (2008)
for large-scale synthesis due to the low temperature (ꢀ 788). Fortunately, we found that
compound 5 reacted with EtBr and K CO in MeCN under reflux for 3 h to give 3-
2
3
cyanopyridone 6 in 95% yield, which was subjected to Raney-Ni-catalyzed hydro-
genation in AcOH/pyridine/H O (1:1:1) to furnish 3-formylpyridone 7 in 60% yield.
2
Reduction of 7 with NaBH in MeOH at ꢀ 208 for 3 h, followed by lactonization with
4
1
2
0% aqueous HCl at the same temperature for 1 h, then room temperature for another
h led to the racemic tricyclic lactone 4 in 91% yield.
Scheme
a) MeONa, CO(OEt) , THF, reflux, 5 h, 90%. b) EtBr, K CO , MeCN, reflux, 3 h, 95%. c) H , Raney-
2
2
3
2
Ni, AcOH, pyridine, H O, 508, 6 h, 60%. d) 1. NaBH , MeOH, ꢀ 208, 3 h; 2. 10% HCl, ꢀ 208, 1 h, then
2
4
r.t., 2 h, 91%. e) 1. KHMDS, (4aS,7S,8aR)-tetrahydro-8,8-dimethoxy-9,9-dimethyl-4H-4a,7-methanooxa-
zirino[3,2-i][2,1]benzisothiazole 3,3-dioxide, THF, CH Cl , HMPA, ꢀ 788, 12 h; 2. sat. NH Cl soln.,
2
2
4
ꢀ
788, 10 min, 82% (72% ee). f) conc. HCl, EtOH, reflux, 4 h, 66%.
With 4 in hand, our next concern was to assemble the OH group with (S)-
configuration at the C(4’) position in 4 utilizing the Davis asymmetric hydroxylation
protocol [9]. Initially, when 4 was treated with various bases (LHMDS, NHMDS,
KHMDS and LDA) and Davis reagent (¼(4aS,7S,8aR)-tetrahydro-8,8-dimethoxy-9,9-
dimethyl-4H-4a,7-methanooxazirino[3,2-i][2,1]benzisothiazole 3,3-dioxide) [10] in
different solvents (THF, THF/PhMe, THF/HMPA, and THF/PhMe/HMPA), only
4
– 9% of (4’S)-tricyclic hydroxylactone 2 was isolated. Interestingly, treatment of 4
with KHMDS and the above mentioned chiral N-sulfonyloxaziridine in THF/CH Cl /
2
2

Helvetica Chimica Acta – Vol. 91 (2008)
2059
HMPA at ꢀ 788 for 12 h led successfully to 2 in 82% yield (72% ee). Unfortunately, all
attempts to improve the optical purity of 2 by recrystallization from different solvents
were unsuccessful. In the final step, the Friedlꢀnder condensation between 2 and 2-(1,3-
dioxolan-2-yl)aniline in the presence of conc. HCl in EtOH provided (20S)-
camptothecin 1 in 66% yield.
Conclusions. – In conclusion, an improved process for the preparation of (4’S)-
tricyclic hydroxylactone 2 via chiral N-sulfonyloxaziridine-mediated asymmetric
hydroxylation resulted in a short synthesis of (20S)-camptothecin (1) in 25% overall
yield starting from the known pyridone 3. Further studies on asymmetric syntheses of
other camptothecin drugs and their analogues via the key chiral intermediate 2 are
currently underway.
Experimental Part
General. Reagents and chemicals were obtained from commercial suppliers and used without further
purification. THF was distilled from Na/benzophenone. CH Cl and HMPA were distilled from CaH .
2
2
2
AcOEt and petroleum ether (PE) for column chromatography (CC) were distilled before use. M.p.
uncorrected; WRS-1B digital melting-point apparatus. TLC: Aluminium-backed silica gel 60 F254 plates.
HPLC: Shimadzu-LC-10AT liquid chromatograph with Spd-10A UV/VIS detector, working at 270 nm;
Supelco-C18 column (150 ꢁ 4.6 mm), elution with MeCN/H O 50 :50 at a flow rate 1.0 ml/min; Chiralcel
2
OD-H column (250 ꢁ 4.6 mm), elution with hexane/i-PrOH 70 :30 at a flow rate 0.5 ml/min. Optical
1
rotations: Jasco P1020 digital polarimeter. IR Spectra: Jasco FT/IR-4200 spectrometer. H- and
13
1
13
C-NMR spectra: Bruker Avance-400 spectrometer; at 400 ( H) and 100 ( C) MHz; in CDCl or
3
(
D )DMSO with CHCl (d(H) 7.24) or DMSO (d(H) 2.49) and CDCl (d(C) 77.0) or DMSO (d(C) 39.5)
6
3
3
as internal standards; d in ppm, J in Hz. MS: Waters Quattro-Micromass instrument; electrospray
ionization (ESI) techniques; in m/z.
Ethyl (6’-Cyano-2’,3’-dihydro-5’-oxo-5’H-spiro[1,3-dioxolane-2,1’-indolizin]-7’-yl)acetate (5). To a
suspension of MeONa (4.86 g, 90 mmol) in anh. THF (80 ml) was added 3 (4.64 g, 20 mmol) at r.t. (258).
After stirring for 10 min, diethyl carbonate (9.44 g, 80 mmol) was added dropwise within 10 min. The
mixture was refluxed for further 5 h, then cooled to r.t. and poured cautiously into ice-water followed by
addition of 10% aq. HCl (30 ml). The resulting mixture was extracted with CH Cl (3 ꢁ 50 ml) and the
2
2
org. phase was washed with 10% NaCO (3 ꢁ 50 ml) and brine (3 ꢁ 20 ml), and dried (Na SO ).
3
2
4
Evaporation of the solvent under reduced pressure gave the crude product, which was recrystallized from
MeOH to afford pure 5 (5.47 g, 90%) as a pea green solid. M.p. 172 – 1738 ([8]: m.p. 172 – 1738). IR
(
KBr): 2982, 2895, 2220, 1735, 1655, 1600, 1535, 1198, 1094, 1028, 947. 1H-NMR (CDCl ): 6.39 (s,
3
HꢀC(5)); 4.08 – 4.19 (m, 2 CH O, CH N, MeCH O); 3.80 (s, CH CO); 2.36 (t, J ¼ 12, CH CH N); 1.24 (t,
2
2
2
2
2
2
þ
J ¼ 12, Me). ESI-MS: 305 ([M þ H] ).
Ethyl 2-(6’-Cyano-2’,3’-dihydro-5’-oxo-5’H-spiro[1,3-dioxolane-2,1’-indolizin]-7’-yl)butanoate (6). A
mixture of 5 (6.08 g, 20 mmol), K CO (6.90 g, 50 mmol), and EtBr (3.93 g, 36 mmol) in MeCN (100 ml)
2
3
was stirred under reflux for 3 h. After cooling to r.t., the precipitate was filtered and washed with MeCN.
Evaporation of the solvent under reduced pressure gave the crude product 6 (6.30 g, 95%), which could
be directly used for the next step. A small sample was recrystallized from EtOH. M.p. 121 – 1228 ([7b]:
1
m.p. 122 – 1238). IR (KBr): 2964, 2854, 2222, 1732, 1653, 1558, 1458, 1367, 1236, 1093, 945, 845. H-NMR
(
1
CDCl ): 6.33 (s, HꢀC(5)); 4.07 – 4.14 (m, 2 CH O, CH N, MeCH O); 3.85 (t, J ¼ 16, CHCO); 2.33 (t, J ¼
3
2
2
2
þ
2, CH CH N); 1.60 – 1.66, 2.04 – 2.11 (2m, MeCH ); 0.90, 1.19 (2t, 2 Me). ESI-MS: 333 ([M þ H] ).
2
2
2
Ethyl 2-(6’-Formyl-2’,3’-dihydro-5’-oxo-5’H-spiro[1,3-dioxolane-2,1’-indolizin]-7’-yl)butanoate (7).
A soln. of 6 (3.32 g, 10 mmol) in pyridine (15 ml), AcOH (15 ml), and H O (15 ml) was hydrogenated in
2
the presence of Raney-Ni (6.50 g) at 508 under 1 atm for 6 h. The progress of this reaction was followed by
TLC (AcOEt/CH Cl 1:4). The Ni catalyst was removed by filtration, and the solvent was removed
2
2

2
060
Helvetica Chimica Acta – Vol. 91 (2008)
under reduced pressure. The residue was diluted with CH Cl (60 ml) and the org. phase was washed with
2
2
1
0% aq. HCl (3 ꢁ 20 ml), 10% NaCO (3 ꢁ 20 ml), and brine (3 ꢁ 20 ml), and dried (NaSO ).
3
4
Evaporation of the solvent under reduced pressure gave the crude product, which was recrystallized from
EtOH to afford pure 7 (2.00 g, 60%) as a white solid. M.p. 85 – 868. IR (KBr): 2976, 2883, 2844, 1734,
1
1
683, 1648, 1593, 1529, 1440, 1338, 1266, 1189, 1021, 939, 844. H-NMR (CDCl ): 10.50 (s, CHO); 6.36 (s,
3
HꢀC(5)); 5.04 (t, J ¼ 16, CHCO); 4.09 – 4.20 (m, 2 CH O, CH N, MeCH O); 2.41 (t, J ¼ 12, CH CH N);
2
2
2
2
2
1
3
0
6
.91, 1.20 (2t, 2 Me). C-NMR (CDCl ): 191.69; 171.92; 161.86; 157.51; 153.11; 120.98; 112.59; 99.24;
3
þ
5.26; 65.22; 60.46; 46.15; 44.41; 33.11; 25.68; 13.62; 11.44. ESI-MS: 336 ([M þ H] ).
4
’-Ethyl-1’,4’,7’,8’-tetrahydro-3’H,10’H-spiro[1,3-dioxolane-2,6’-pyrano[3,4-f]indolizine]-3’,10’-dione
(
4). To a soln. of 7 (1.68 g, 5 mmol) in MeOH (30 ml) was added slowly NaBH (0.29 g, 7.5 mmol) at
4
ꢀ
208. The mixture was stirred at this temp. for 3 h before adding 10% aq. HCl (8 ml) over a period of
5
min. Stirring was continued at ꢀ 208 for 1 h, then the mixture was gradually warmed to 258 and stirred
for another 2 h. The mixture was evaporated in vacuo and the residue was diluted with CH Cl (30 ml).
2
2
The org. phase was washed with 10% NaCO (3 ꢁ 20 ml) and brine (3 ꢁ 20 ml), and dried (NaSO ).
3
4
Evaporation of the solvent gave the crude product, which was recrystallized from AcOEt/hexane to
afford pure 4 (1.32 g, 91%) as a white solid. M.p. 126 – 1278 ([5a]: m.p. 1308). IR (KBr): 2978, 2896, 1749,
1
1
1
1
663, 1614, 1457, 1306, 1219, 1164, 1062, 937, 822. H-NMR (CDCl ): 6.05 (s, HꢀC(5)); 5.17, 5.40 (2d, J ¼
3
6, CH OCO); 4.04 – 4.14 (m, 2 CH O, CH N); 3.37 (t, J ¼ 16, CHCO); 2.34 (t, J ¼ 12, CH CH N); 1.85 –
2
2
2
2
2
þ
.94 (m, MeCH ); 0.96 (t, J ¼ 12, Me). ESI-MS: 292 ([M þ H] ).
2
(
4’S)-4’-Ethyl-1’,4’,7’,8’-tetrahydro-4’-hydroxy-3’H,10’H-spiro[1,3-dioxolane-2,6’-pyrano[3,4-f]indoli-
zine]-3’,10’-dione (2). Under the atmosphere of Ar, KHMDS (4.50 ml, 3.980 mmol, 0.885m soln. in
toluene) was slowly added to a soln. of 4 (463 mg, 1.591 mmol) in anh. THF (15 ml)/CH Cl (5 ml)/
2
2
HMPA (6 ml) at ꢀ 788. After stirring for 1 h at the same temp., a soln. of (4aS,7S,8aR)-tetrahydro-8,8-
dimethoxy-9,9-dimethyl-4H-4a,7-methanooxazirino[3,2-i][2,1]benzisothiazole 3,3-dioxide (690 mg,
2
.387 mmol) in anh. THF (5 ml) and CH Cl (5 ml) was added into the mixture at ꢀ 788 and stirred
2
2
4
for 12 h at this temp., then a sat. aq. NH Cl soln. (5 ml) was slowly added. After stirring for 10 min, the
mixture was warmed gradually to r.t. and poured into H O (30 ml). The resulting mixture was extracted
2
with CH Cl (2 ꢁ 20 ml), and the combined org. phase was washed with 10% NaHCO (2 ꢁ 20 ml) and
2
2
3
brine (2 ꢁ 20 ml), and dried (Na
2
SO
4
). Evaporation of the solvent gave the crude product, which was
purified by CC (AcOEt/PE, 1:1) to afford 2 (391 mg, 82%, 72% ee) as a white solid. M.p. 163 – 1648.
2
5
25
[
a] ¼ þ76.8 (c ¼ 0.76, CHCl ) ([3]: m.p. 170 – 1718, [a] ¼ þ109.7 (c ¼ 0.76, CHCl )). IR (KBr): 3258,
D
3
D
3
1
2
988, 2969, 1752, 1660, 1594, 1472, 1421, 1377, 1352, 1268, 1115, 1073, 967, 903, 800. H-NMR (CDCl ):
3
6
.58 (s, HꢀC(5)); 5.18, 5.62 (2d, J ¼ 16, CH OCO); 4.13 – 4.21 (m, 2 CH O, CH N); 3.67 (s, OH); 2.43 (t,
2
2
2
þ
J ¼ 12, CH CH N); 1.78 – 1.82 (m, MeCH ); 0.98 (t, J ¼ 12, Me). ESI-MS: 308 ([M þ H] ).
2
2
2
(
20S)-Camptothecin (¼(4S)-4-Ethyl-4-hydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-
3
,14(4H,12H)-dione; 1). A mixture of 2 (0.62 g, 2.0 mmol), 2-(1,3-dioxolan-2-yl)aniline (0.50 g,
3
.0 mmol) and 37% aq. HCl soln. (3.0 ml) in EtOH (30 ml) was stirred under reflux for 4 h. After
cooling to r.t., the precipitate was filtered. Then the filtrate was adjusted to pH ¼ 7 with sat. aq. NaHCO ,
3
condensed to one third of its volume and filtered. The crude product was recrystallized from 80% AcOH
2
5
to afford pure (20S)-camptothecin 1 (0.46 g, 66%) as a yellow solid. M.p. 261 – 2638 (dec.). [a] ¼ þ32.4
D
(
4
c ¼ 0.51, CHCl /MeOH 4 :1) ([3][5a]: m.p. 265 – 2668 (dec.), [a] ¼ þ42.0 (c ¼ 0.51, CHCl /MeOH
3
D
3
:1)).
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[2] C. R. Hutchinson, Tetrahedron 1981, 37, 1047; W. Du, Tetrahedron 2003, 59, 8649.
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Received April 23, 2008