Introduction of the acetate unit to the 2-pyridinone ring system and its application to the synthesis of (20S)-camptothecin DE ring system

Article abstract of DOI:10.1055/s-2006-950433

The DE ring system of (20S)-camptothecin had been prepared from commercially available nicotinic acid in six steps utilizing the nucleophilic addition reaction of the silyl ketene acetal to the pyridinone ring as a key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950433

2636
LETTER
Introduction of the Acetate Unit to the 2-Pyridinone Ring System and Its
Application to the Synthesis of (20S)-Camptothecin DE Ring System
S
ynthesis of (20
S
)
o
-
Camptothe
c
u
inD
E
Ring SystemHiroya,*a Kei Kawamoto,a Takao Sakamotoa,b
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
b
Tohoku University, 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and
Clinical Evaluation’, Sendai 980-8578, Japan
Fax +81(22)7956864; E-mail: hiroya@mail.tains.tohoku.ac.jp
Received 15 July 2006
camptothecin attracted many researchers and a large num-
ber of publications concerning the total synthesis of 414–17
by unique methodologies have resulted. In spite of the fact
that the D ring system of 4 is a substituted 2-pyridinone,
there were no publications describing the straightforward
synthesis of 4 using 2-pyridinone derivatives as the
starting material. Here we report the short and efficient
synthesis of the DE ring system of (20S)-camptothecin, an
important intermediate in the synthesis of 4, utilizing
Lewis acid catalyzed functionalization of 2-pyridinone
derivatives 5 (Figure 1).16,17
Abstract: The DE ring system of (20S)-camptothecin had been
prepared from commercially available nicotinic acid in six steps
utilizing the nucleophilic addition reaction of the silyl ketene acetal
to the pyridinone ring as a key step.
Key words: anti-tumor agents, asymmetric synthesis, Lewis acids,
nucleophilic additions, regioselectivity
The stereoselective construction of multi-functional pipe-
ridine ring systems through the use of pyridinium salts or
dihydropyridine derivatives has been much investigated
recently.1,2 In particular, Comins and co-workers success-
fully applied the chiral 1-acyl-4-alkoxypyridinium salts to
the syntheses of many biologically active natural
products.3 In comparison with the significant work on the
4-alkoxypyridine derivatives, research involving the reac-
tivity of the 2-oxypyridine (2-pyridinone) derivatives has
been limited mainly to Diels–Alder reactions.4,5 To the
best of our knowledge, the introduction of an acetate unit
into oxygenated pyridine derivatives has been reported
only once.6
O
O
OR2
N
O
C
D
E
N
R1
O
B
O
20
OH
5
N
A
(20S)-camptothecin (4)
Figure 1
As part of our continuous program for the development of
new methodologies for heterocyclic compounds,7 we
focused our attention on the utilization of the activated 2-
pyridinone derivatives. We have published the regioselec-
tive functionalization of N-tosyl-2-pyridinone (1)5 with
tert-butyldimethylsilyl ketene acetal 2, activated by a
Lewis acid (Scheme 1).8
O
O
R1
HN
O
D
N
O
E
O
20
O
OH
7
(S)-6
CO2R2
CO2R3
O
O
R1
N
R1
CO2R2
(20S)-Camptothecin (4) is a well-known anti-cancer natu-
ral product that was first isolated from Camptotheca
acuminata in 1966.9,10 The first total synthesis of 4 was re-
ported by Stork’s research group as a racemate in 197111
and the first synthesis of the optically active form was
carried out by Corey.12 After the publication of the
mechanism of the anti-cancer activities of 4, which in-
volved the interaction of 4 with DNA topoisomerase I,13
N
9
8
Figure 2 Retrosynthetic analysis for the preparation of the DE ring
system of (20S)-camptothecin [(S)-6] from 2-pyridinone derivative 9.
Our synthetic strategy is shown in Figure 2. The DE ring
system (S)-6 can be synthesized from 7 by enantioselec-
tive hydroxylation of the lactone, followed by removal
of the protecting group (R1). The lactone 7 can be con-
structed from 8 by the selective reduction of the alkoxy-
carbonyl group. The key reaction of this synthesis is the
introduction of the butyrate unit into the 3-substituted-2-
pyridinone derivative 9.
CO2Et
OTBS
2
10 mol% TBSOTf,
OEt
ClCH2CH2Cl, −78 °C to −20°C
N
O
N
O
24 h, 89%
Ts
1
3
Ts
Scheme 1 Lewis acid catalyzed regioselective nucleophilic
addition of silyl ketene acetal 2 to 2-pyridinone derivative 1.
SYNLETT 2006, No. 16, pp 2636–2640
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-950433; Art ID: U08706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of (20S)-Camptothecin DE Ring System
2637
Table 1 Reaction of 3-Alkoxycarbonyl-2-pyridinone Derivative 10a or 10b with Silyl Ketene Acetal 2
OTBS
CO2Et
CO2R
CO2R
O
CO2R
O
OEt
2
and
Lewis acid
solvent
time, temp
N
N
N
O
EtO2C
Bn
Bn
Bn
10a: R = Me
10b: R = Bn
11a,b
12a,b
Entry Substrate (R) Lewis acid (mol%) Solvent
Temp (°C) Time (h) Yield (%)
11a or 11b (dr)a
15 (13:1)
12a or 12b Recovered 10a or 10b
1
2
3
4
5
10a (Me)
10b (Bn)
TBSOTf (10)
Et2AlCl (110)
Et2AlCl (50)
TBSOTf (15)
Et2AlCl (105)
DCE
–20
–40
–40
–20
–40
38
2
40
11
0
16
31
50
51
0
CH2Cl2
CH2Cl2
DCE
40 (10:1)
13 (14:1)
13 (11:1)
53 (10:1)
12
27
5
36
27
CH2Cl2
a Both 11a and 11b were isolated as a mixture of two inseparable diastereomers; the dr was measured by 1H NMR spectroscopy.
To clarify the reactivity of 3-alkoxycarbonylpyridione was observed for the benzyl ester 10b (Table 1, entries 4
derivatives, the reactions between 10a or 10b and silyl and 5), and the yield for 11b was improved compared with
ketene acetal 2 were examined and the results are summa- the methyl ester 11a (Table 1, entry 2 vs 5).
rized in Table 1.
To apply this methodology to the synthesis of the DE ring
From the results listed in Table 1, it is clear that a single system of camptothecin, the reactions between the TBS
electron-withdrawing group on the ring is enough to per- ketene acetal of ethyl butyrate and 10b in the presence of
form this reaction. The product ratios [11a (C4-adduct) vs either TBSOTf or Et2AlCl were examined (Table 2).
12a (C6-adduct)] were inverted, depending on the Lewis
acid used. Namely, TBSOTf catalyzed the reaction and
gave 12a as the major product (ca. 1:2.7, Table 1, entry 1),
Surprisingly, not only low yields, but also low selectivity
between 14 and 15 and low diastereoselectivity for both
compounds were observed for the addition reaction of
whereas Et2AlCl gave 11a preferentially (ca. 3.6:1,
(E)- and (Z)-TBS ketene acetal toward 10b in the presence
Table 1, entry 2), although a stoichiometric amount of
of TBSOTf (Table 2, entries 1 and 3). On the other hand,
Et2AlCl was required to afford a reasonable yield of 11a
Et2AlCl-mediated reactions were much more successful
than those with TBSOTf, and apparent reversibility of the
(Table 1, entry 2 vs 3). The other Lewis acids did not give
satisfactory results (data not shown). The same tendency
Table 2 Reaction of 3-Alkoxycarbonyl-2-pyridinone Derivative 10b with Silyl Ketene Acetal 13
CO2Et
OTBS
CO2Bn
CO2Bn
O
CO2Bn
13
OEt
and
N
O
Lewis acid
solvent
time, temp
N
N
O
EtO2C
Bn
Bn
10b
Bn
14
15
Entry TBS ketene acetal 13 Lewis acid (mol%) Solvent
Temp (°C) Time (h) Yield (%)
14 (dr)a
15 (dr)a
0
Recovered 10b
1
2
3
4
(E)-13
(Z)-13
TBSOTf (10)
Et2AlCl (105)
TBSOTf (10)
Et2AlCl (105)
DCE
–20
–40
–20
–40
24
2
8 (1.1:1)
68 (2:1)
59
8
CH2Cl2
DCE
11 (1:1.1)
7 (1.7:1)
6b
24
2
10 (1:1.2)
51 (1:4)
73
32
CH2Cl2
a Both 14 and 15 were isolated as a mixture of two inseparable diastereomers; dr was measured by 1H NMR spectroscopy.
b The dr was not determined.
Synlett 2006, No. 16, 2636–2640 © Thieme Stuttgart · New York

2638
K. Hiroya et al.
LETTER
CO2Et
CO2Bn
CO2Et
CO2Bn
diastereomeric ratio for 14 was observed depending on the
geometry of TBS ketene acetal (Table 2, entry 2 vs 4).
These results suggested that the reaction mechanism, es-
pecially the role of the Lewis acid, might differ between
TBSOTf and Et2AlCl. However, the details of the mecha-
nism are not yet clear.
NaH, CuBr2
DMF–DMSO (1:1)
0–50 °C, 28 h, 56%
N
O
N
O
Bn
Bn
11b
17
LiHMDS, EtI
THF, –78 °C to r.t.
11 h, 71%
Consequently, the combination of 10b and (E)-13 as start-
ing materials and Et2AlCl as the Lewis acid afforded 14
with the best result among the tested compounds and
conditions. Although 14 was isolated as a mixture of two
kinds of diastereomers, both compounds are converted to
the same 3,4-disubstituted-2-pyridinone in the next
oxidation step. Thus, 14 was selected for the synthesis of
the camptothecin DE ring system (S)-6.
CO2Et
CO2Bn
CO2Et
CO2Bn
H
SeO2
dioxane, reflux
3 h, 68%
N
O
N
O
Bn
14
Bn
16
Oxidation of 14 by SeO2 in refluxing dioxane gave 16 in
reasonable yield. Compound 16 was also synthesized
from 11b by oxidation with CuBr2 in the presence of
NaH18 (56% yield) followed by alkylation of the lithium
enolate of 17 with EtI in 71% yield. Selective reduction of
the C3-benzyloxycarbonyl group was troublesome; for
example, reduction by NaBH4 gave 18 as the major
product. This problem was finally resolved by employing
the NaBH4/CeCl3·7H2O system, and the lactone 19 was
obtained in 57% yield after treatment with 1 N HCl
(Scheme 2).
O
CO2Et
CO2Bn
NaBH4, CeCl3·7H2O
EtOH, 0 °C, 1.5 h
O
O
then 1 N HCl, r.t., 8 h
57%
N
O
N
18
Bn
Bn
19
Scheme 2 Synthesis of the key intermediate 19 from 4-substituted
lactam derivatives 11b and 14.
Asymmetric hydroxylation of 20-deoxycamptothecin has
been reported by Nagao’s research group (ca. 45% ee).19
They employed chiral N-sulfonyloxaziridine, which was
developed by Davis.20 To improve the optical purity, we
tried the reaction of 19 with modified reagents and
different counter cations (Table 3).
cation of the bis(trimethylsilyl)amide. In the reaction with
20a,20a–c the yield was improved by changing the cation
from Li+ or Na+ to K+, but the ee values were unaccept-
able. Almost no selectivity was observed with 20b20d,21a
for all entries. The best result was obtained using the com-
bination of 20c20c,e,21 and KHMDS; (S)-21 was obtained in
72% ee and 83% chemical yield.22 Interestingly, the ee
was reduced by changes in the size of the acetal moiety
Both the yields and the ee values were highly dependent
on the structure of the reagents and the chosen counter
Table 3 Asymmetric Hydroxylation Reaction of 19 Utilizing Chiral N-Sulfonyloxaziridines
X
O
O
X
N
O
Base,
O
O
O
O
S
HO
S
O
20a–e
O
THF, –78 °C, 5 h
N
N
Bn
Bn
19
(S)-21
Entry Base
(S)-21 (%)
Chiral N-sulfonyloxaziridine
20a (X = H)
20b (X = Br)
20c (X = MeO)
20d (X = EtO) 20e (X = OCH2CH2O)
1
2
3
LiHMDS
Yield
eea
30
23
19
28
84
29
98
19
66
25
65
2
52
38
5
–
–
–
–
NaHMDS
KHMDS
Yield
eea
–
–
39
83
72
–
–
Yield
eea
73
52
54
20
a The ee was determined by chiral HPLC (Daicel, Chiralcel OD-H, i-PrOH–hexane, 1:6).
Synlett 2006, No. 16, 2636–2640 © Thieme Stuttgart · New York

LETTER
Synthesis of (20S)-Camptothecin DE Ring System
Hiroya, K.; Sakamoto, T. Chem. Lett. 2004, 33, 1026.
(d) Hiroya, K.; Itoh, S.; Sakamoto, T. Tetrahedron 2005, 61,
10958. (e) Hiroya, K.; Matsumoto, S.; Ashikawa, M.; Kida,
H.; Sakamoto, T. Tetrahedron 2005, 61, 12330.
(f) Inamoto, K.; Yamamoto, A.; Ohsawa, K.; Hiroya, K.;
Sakamoto, T. Chem. Pharm. Bull. 2005, 53, 1502.
(8) Hiroya, K.; Jouka, R.; Katoh, O.; Sakuma, T.; Anzai, M.;
Sakamoto, T. Arkivoc 2003, (viii), 232.
(9) 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.
2639
(20c: X = MeO, 72% ee vs 20d:21 X = EtO, 52% ee), and
the rigid acetal group caused a serious depression of ee
(20e:21 X = OCH2CH2O, 20% ee). These results suggest-
ed that chelation between the oxygen atom in the substrate
and the reagent (acetal and oxaziridine) is essential for the
high selectivity. Presumably the methyl group in the
acetal moiety is the optimum size, when the reagent and
the substrate form the complex by chelation. Groups that
are bigger or rigid might prevent proper complexation.
Finally, (S)-21 was recrystallized from benzene (91% ee
and 66% yield from 19), and the benzyl group was re-
moved by standard hydrogenolysis conditions to com-
plete the synthesis of the DE ring system of (20S)-
camptothecin (S)-6. All the spectral data were identical to
those reported17 and the specific rotation after recrystalli-
zation {[a]D18+131.1 (c 0.2, CHCl3–MeOH, 4:1), 95%
ee23} was reasonable in comparison with the previously
(10) Camptothecin had been isolated from other sources, see:
(a) Das, B.; Madhusudhan, P.; Reddy, P. V.; Anitha, Y.
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
2001, 40, 453. (b) Kitajima, M.; Yoshida, S.; Yamagata, K.;
Nakamura, M.; Takayama, H.; Saito, K.; Seki, H.; Aimi, N.
Tetrahedron 2002, 58, 9169. (c) Puri, S. C.; Verma, V.;
Amna, T.; Qazi, G. N.; Spiteller, M. J. Nat. Prod. 2005, 68,
1717.
(11) Stork, G.; Schultz, A. G. J. Am. Chem. Soc. 1971, 93, 4074.
(12) Corey, E. J.; Crouse, D. N.; Anderson, J. E. J. Org. Chem.
1975, 40, 2140.
(13) Hsiang, Y.-H.; Hertzberg, R.; Hecht, S.; Liu, L. F. J. Biol.
Chem. 1985, 260, 14873.
(14) For reviews on the synthesis of camptothecin and its
analogues, see: (a) Du, W. Tetrahedron 2003, 59, 8649.
(b) Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Bioorg. Med.
Chem. 2004, 12, 1585.
(15) For the synthesis of camptothecin since the publications of
ref. 14, see: (a) Twin, H.; Batey, R. A. Org. Lett. 2004, 6,
4913. (b) Chavan, S. P.; Pasupathy, K.; Venkatraman, M. S.;
Kale, R. R. Tetrahedron Lett. 2004, 45, 6879. (c) Yu, J. R.;
DePue, J.; Kronenthal, D. Tetrahedron Lett. 2004, 45, 7247.
(d) Chavan, S. P.; Venkatraman, M. S. Arkivoc 2005, (iii),
165. (e) Anderson, R. J.; Raolji, G. B.; Kanazawa, A.;
Greene, A. E. Org. Lett. 2005, 7, 2989.
23
reported data {Lit.16 [a]D +117.0° (c 0.3, CHCl3–
MeOH, 4:1), 93% ee; Scheme 3}.
In conclusion, we have demonstrated the straightforward
synthesis of the DE ring system of (20S)-camptothecin
from cheap and commercially available nicotinic acid in
six steps. The clarification of the reaction mechanism,
especially with regard to diastereoselectivity, is underway
in our laboratory.
O
O
O
O
O
O
HO
HO
H2, Pd(OH)2/C
EtOH, 50 °C, 3 h
N
(16) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
(17) Peters, R.; Althaus, M.; Nagy, A.-L. Org. Biomol. Chem.
2006, 4, 498.
N
H
77% chemical yield
95% ee
Bn
(S)-21
(S)-6
(18) Shi, X.-X.; Dai, L.-X. J. Org. Chem. 1993, 58, 4596.
(19) Tagami, K.; Nakazawa, N.; Sano, S.; Nagao, Y.
Heterocycles 2000, 53, 771.
Scheme 3 Synthesis of the DE ring system of (20S)-camptothecin
(S)-6.
(20) (a) Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Sheppard,
A. C.; Kumar, A.; Davis, F. A. Org. Synth. 1990, 69, 158.
(b) Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55,
3715. (c) Davis, F. A.; Kumar, A.; Chen, B.-C. Tetrahedron
Lett. 1991, 32, 867. (d) Davis, F. A.; Weismiller, M. C.;
Murphy, C. K.; Reddy, R. T.; Chen, B.-C. J. Org. Chem.
1992, 57, 7274. (e) Chen, B.-C.; Murphy, C. K.; Kumar, A.;
Reddy, R. T.; Clark, C.; Zhou, P.; Lewis, B. M.; Gala, D.;
Mergelsberg, I.; Scherer, D.; Buckley, J.; DiBenedetto, D.;
Davis, F. A. Org. Synth. 1996, 73, 159.
References and Notes
(1) (a) Kumar, R.; Chandra, R. In Advances in Heterocyclic
Chemistry, Vol. 78; Katritzky, A. R., Ed.; Academic Press:
San Diego, 2001, 269. (b) Lavilla, R. J. Chem. Soc., Perkin
Trans. 1 2002, 1141.
(2) Comins, D. L.; Joseph, S. P. In Comprehensive Heterocyclic
Chemistry II, Vol. 5; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996, 37.
(3) (a) Kuethe, J. T.; Comins, D. L. J. Org. Chem. 2004, 69,
5219. (b) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227;
and references cited therein.
(4) Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H.
Tetrahedron 1992, 48, 9111.
(5) (a) Posner, G. H.; Switzer, C. J. Org. Chem. 1987, 52, 1642.
(b) Posner, G. H.; Vinader, V.; Afarinkia, K. J. Org. Chem.
1992, 57, 4088. (c) Afarinkia, K.; Mahmood, F.
Tetrahedron Lett. 1998, 39, 493; and references cited
therein.
(6) Kuethe, J. T.; Comins, D. L. Org. Lett. 1999, 1, 1031.
(7) (a) Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.;
Sakamoto, T. Tetrahedron 2001, 57, 9697. (b) Hiroya, K.;
Matsumoto, S.; Sakamoto, T. Org. Lett. 2004, 6, 2953.
(c) Inamoto, K.; Katsuno, M.; Yoshino, T.; Suzuki, I.;
(21) (a) Verfürth, U.; Herrmann, R. J. Chem. Soc., Perkin Trans.
1 1990, 2919. (b) Page, P. C. B.; Heer, J. P.; Bethell, D.;
Lund, A.; Collington, E. W.; Andrews, D. M. J. Org. Chem.
1997, 62, 6093.
(22) Asymmetric Hydroxylation of 19 by 20c (Table 3, entry
3): KHMDS (0.79 mL, 0.59 mmol, 0.75 M solution in
toluene) was slowly added to a solution of 19 (152 mg, 0.536
mmol) in anhyd THF (6.0 mL) at –78 °C. After stirring for
30 min, a solution of 20c (240 mg, 0.829 mmol) in anhyd
THF (6.0 mL) was slowly added to the reaction mixture at
–78 °C and stirred for 5 h at the same temperature. A sat. aq
solution of NH4Cl and THF were added successively to the
mixture and the dry ice–acetone bath was removed. H2O was
added to the mixture and the aqueous phase was extracted
with EtOAc. The combined organic solution was washed
Synlett 2006, No. 16, 2636–2640 © Thieme Stuttgart · New York

2640
K. Hiroya et al.
LETTER
(1 H, d, J = 7.2 Hz), 7.20–7.45 (6 H, m). 13C NMR (100
MHz, CDCl3): d = 7.7, 31.6, 52.3, 66.6, 72.1, 102.9, 119.0,
128.2, 128.3, 128.9, 135.5, 137.4, 148.3, 158.6, 173.7. MS:
m/z (%) = 299 (M+, 88.8), 270 (20.6), 164 (17.8), 91 (100.0).
HRMS: m/z calcd for C17H17NO4: 299.1157; found:
299.1138. Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N,
4.68. Found: C, 68.07; H, 5.79; N, 4.59.
with a sat. aq solution of Na2SO3 and brine, dried over anhyd
MgSO4, and concentrated. The residue was purified by silica
gel chromatography [EtOAc–hexane (2:3)] to afford (S)-21
(133 mg, 83%, 72% ee) as a white solid; mp 140 °C
(benzene); [a]D23 +107.2 (c 1.01, CHCl3, 91% ee). IR (film):
3362, 1747, 1651, 1593, 1564, 1229, 1139, 1047, 880, 748,
702 cm –1. 1H NMR (400 MHz, CDCl3): d = 0.96 (3 H, t,
J = 7.2 Hz), 1.71–1.87 (2 H, m), 3.65 (1 H, s), 5.11 (1 H, d,
J = 14.4 Hz), 5.18 (2 H, m), 5.61 (1 H, d, J = 16.0 Hz), 6.50
(23) The ee was determined by chiral HPLC (Daicel, Chiralcel
OD-H, EtOH–hexane, 1:9).
Synlett 2006, No. 16, 2636–2640 © Thieme Stuttgart · New York