Total synthesis of (+)-camptothecin via an intramolecular palladium-catalyzed cyclization strategy

Article abstract of DOI:10.1055/s-2007-991054

The novel cascade intramolecular Pd-catalyzed cyclization followed by aromatization for the construction of D ring of (+)-camptothecin as a key step is demonstrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-991054

LETTER
2635
Total Synthesis of (+)-Camptothecin via an Intramolecular Palladium-
Catalyzed Cyclization Strategy
T
otal Synthesi
u
s
of (+)-Cam
b
ptothecin hash P. Chavan,* Ashok B. Pathak, Uttam R. Kalkote
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
E-mail: Sp.chavan@ncl.res.in
Received 1 August 2007
analogues, collectively called camptothecins, which have
been isolated from various botanical species viz. Pyrena-
cantha klaineana2 and roots of Ophiorrhiza pumila,3 dis-
play promising anticancer activity. The structurally
similar nothapodytine A (4) and B (5), recently isolated
from Nothapodytis foetida,4 are the oxidised form of
mappicine (6)5 and show antiviral activity, and foetidine 7
exhibits anti-HIV activity.6 Although camptothecin itself
cannot be used as a drug because of its low solubility,
toxic nature, and unstable lactone ring, two of its
analogues, irinotecan (2) and topotecan (3), were
launched as anticancer drugs and many others are in
different stages of clinical trials (Figure 1).
Abstract: The novel cascade intramolecular Pd-catalyzed cycliza-
tion followed by aromatization for the construction of D ring of
(+)-camptothecin as a key step is demonstrated.
Key words: natural products, alkaloids, antitumor, palladium,
cyclizations
R2
A
R1
R3
O
B
N
C N
D
E
O
OH
To date numerous imaginative syntheses of 1 and its de-
rivatives have been reported by various research groups;7
however, due to its low natural abundance, challenging
structural features, unique mode of action (inhibition of
DNA topoisomerase I), and promising biological activity,
the chemical synthesis of camptothecins remains a
challenge. Our group is also involved in the development
of novel, simple, and practical routes toward campto-
thecins. We have developed various approaches towards
camptothecin and mappicine ketone where the focus was
on the construction of the D ring.8
O
camptothecin (1), R1 , R2 , R3 = H
irinotecan (2), R1 = Et, R2 = H, R3
=
·HCl·3H2O
N
OCON
topotecan (3), R1 = H, R2 = CH2NMe2·HCl, R3 = OH
R
O
N
N
X
Y
As a result of our continuing interest in camptothecin and
its analogues, we report herein a novel and efficient
method for the construction of the D ring of camptothecin
that employs cascade palladium-catalyzed oxidative
cyclization followed by aromatization in one pot as the
key step. The Wacker oxidation is a well-known reaction
for the conversion of olefin into ketone employing PdCl2
as a catalyst and CuCl, CuCl2, p-benzoquinone, or H2O2
as a reoxidant.9,10
nothapodytine A (4), R = OMe, X = Y = O
nothapodytine B (mappicine ketone) (5), R = H, X = Y = O
mappicine (6), X = H, Y = (S)-OH
O
N
OH
N
O
O
HO
O
O
HN
NH
A new synthetic approach towards 1, as depicted in
Scheme 1, was undertaken where (+)-1 could be accessed
from enol ether 28 by Sharpless asymmetric dihydroxyla-
tion followed by oxidation. The enol ether in turn could be
obtained from diester 25 by selective reduction of the het-
eroaromatic ester. The diester 25 could be accessed from
compound 23 by alkylation and carboxylation, compound
23 could be obtained from olefin 22 by Pd-catalyzed cas-
cade cyclization followed by aromatization as a key step.
Olefin 22 can be readily obtained from 21, which in turn
could be readily prepared from keto compound 14 by
Friedländer condensation, which in turn could be prepared
from ethyl ester of glycine Schiff base 8.
foetidine (7)
Figure 1 Camptothecin and its analogues.
The pentacyclic alkaloid camptothecin (CPT, 1), was
isolated in 1966 by Wall and co-worker from Chinese
tree Camptotheca acuminata.1 Camptothecin and its
SYNLETT 2007, No. 17, pp 2635–2638
1
6
.1
0
.
2
0
0
7
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-991054; Art ID: G26507ST
© Georg Thieme Verlag Stuttgart · New York

2636
S. P. Chavan et al.
LETTER
O
O
N
N
(+)-1
N
N
COOEt
COOEt
O
28
25
O
O
N
N
N
COOEt
N
COOEt
23
22
Ph
EtOOC
N
EtOOC
NHCbz
NCbz
NCbz
8
N
O
+
Br
21
14
12
Scheme 1 Retrosynthetic analysis
Accordingly, the synthesis began from simple Schiff base yield after two steps. The compound 17 was subjected to
8, which was converted into allyl ketone 14 following a the Wacker oxidation conditions identical to those of 15.10
sequence of reactions as previously described by us Surprisingly, instead of the expected Wacker product viz.
(Scheme 2).8c The keto compound 14 was protected as ketone 18, it resulted in the formation of a mixture of
ketal to furnish protected compound 15 in 98% yield. cyclized product 19 in 38% yield along with 20 in 43%
With the compound 15 in hand, it was subjected to Wack- yield. Performing this reaction under N2 atmosphere gave
er oxidation using PdCl2 and CuCl2 as a reoxidant in the same result. This indicated that there is no role for O2,
DMF–H2O (3:1) at 95 °C, which resulted in the formation and the ketone 18 could not be detected as an intermedi-
of the anticipated Wacker product 16 in 65% yield.10
ate. This result can be rationalized by invoking the com-
plexation of Pd with the olefin followed by attack of the
malonate carbon as an internal nucleophile, even in the
presence of water nucleophile (Wacker oxidation); after
the b-H elimination, the Pd catalyst is regenerated and
isomerization into internal double bond results in the for-
mation of 19. A competing elimination of H results in the
formation of isomeric olefin 20. The compound 19 is a
key intermediate in Shamma’s approach for campto-
thecin.11 It is pertinent to mention that earlier Hegedus12
and co-workers have observed Pd (II)-catalyzed inter-
molecular alkylation of olefins, and very recently Widen-
hoefer et al. have also observed a similar intramolecular
cyclization where 1,3-diketo and b-keto ester olefins were
used as the substrate in the presence of PdCl2(MeCN)2 as
the catalyst under different reaction conditions.13
After the successful Wacker oxidation on compound 15
(Scheme 2), we then decided to treat compound 17 under
identical conditions (Scheme 3). The compound 17 was
prepared from compound 15 by deprotection of CBz and
further protection with ethyl malonyl chloride in 72%
Ph
Ph
EtOOC
NH2
EtOOC
N
EtOOC
N
a
b
8
9
+
Br
10
11
EtOOC
EtOOC
NHCbz
NCbz
e
c
d
O
O
O
c
N
X
N
NCbz
a, b
O
O
O
12
13
COOEt
COOEt
O
O
O
O
f
g
NCbz
NCbz
NCbz
O
O
15
17
18
O
O
O
O
c
O
O
14
15
16
N
N
O
O
O
+
COOEt
Scheme 2 Reagents and conditions: (a) 10% NaOH (1.2 equiv),
allyl bromide (1.2 equiv), TBAHSO4 (0.1 equiv), CH2Cl2, r.t., 2 h,
96%; (b) 10% HCl (1.2 equiv), r.t., 0.5 h, 95%; (c) K2CO3 (1.2 equiv),
benzylchloroformate (1.1 equiv), anhyd CH2Cl2, 0 °C, 1 h, 94%;
(d) NaH (1.2 equiv), ethyl acrylate (1.2 equiv), C6H6, r.t., 1 h, refluxed
2–3 h; (e) NaCl (4.0 equiv), DMSO–H2O (3:1), 120–130 °C, 6 h,
68%; (f) ethylene glycol (1.2 equiv), PTSA (cat.), anhyd C6H6, reflux,
6 h, 98%; (g) PdCl2 (0.1 equiv), CuCl2 (2.1 equiv), O2, DMF–H2O
(3:1), 95 °C, 8 h, 65%.
COOEt
O
19
20
Scheme 3 Reagents and conditions: (a) KOH (14.0 equiv), EtOH,
reflux, 6–8 h; (b) K2CO3 (1.2 equiv), ethyl malonyl chloride (1.2
equiv), anhyd CH2Cl2, 0 °C, 1 h, 72% over two steps; (c) PdCl2 (0.1
equiv), CuCl2 (2.1 equiv), DMF–H2O (3:1), 95 °C, 7 h, 81% (38% 19
+ 43% 20).
Synlett 2007, No. 17, 2635–2638 © Thieme Stuttgart · New York

LETTER
Total Synthesis of (+)-Camptothecin
2637
O
O
b, c
d
a
NCbz
NCbz
N
N
O
N
N
N
COOEt
COOEt
14
21
22
23
O
O
e
O
f
g
N
N
N
N
N
COOEt
COOEt
COOEt
COOEt
N
CHO
COOEt
24
25
26
h
i
j, k
O
O
O
N
N
N
N
N
N
O
O
O
HO
27
28
(+)-1
OH
O
Scheme 4 Reagents and conditions: (a) N-(o-aminobenzilidine)-p-toluidine (1.2 equiv), PTSA (cat.), anhyd toluene, azeotropic distillation 3–
4 h, 75%; (b) KOH (14.0 equiv), EtOH, reflux, 8 h; (c) K2CO3 (1.2 equiv), ethyl malonyl chloride (1.2 equiv), anhyd CH2Cl2, 0 °C, 1 h, 71%
in two steps; (d) PdCl2 (0.1 equiv), CuCl2 (2.1 equiv), DMF–H2O (3:1), 95 °C, 6 h, 54%; (e) LDA (1.1 equiv), diethyl carbonate (1.0 equiv),
THF, –78 °C, 3–4 h, 70%; (f) NaH (1.1 equiv), EtI (1.1 equiv), anhyd DME, 0 °C to r.t., 3–4 h, 64%; (g) DIBAL-H (3.0 equiv), anhyd THF,
–60 °C, 2 h, 83%; (h) NaBH4 (2.0 equiv), THF–H2O (5:1), 0 °C, 0.5 h, 90%; (i) MsCl (4.0 equiv), Et3N (8.0 equiv), anhyd THF, r.t., 24 h, 92%;
(j) (DHQD)2-py (cat.), OsO4 (cat.), K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO2NH2 (1.0 equiv), t-BuOH–H2O (1:1), 0 °C, 7 h; (k) I2
(12.5 equiv), CaCO3 (12.5 equiv), MeOH–H2O (2:1), r.t., 24 h, 33% in two steps.
By taking advantage of the result obtained (Scheme 3), we yield (92%) via O-mesylation followed by elimination.8e
decided to exploit this result for the synthesis of (+)-1 by It is pertinent to mention that the asymmetric dihydroxy-
employing this methodology on tricyclic compound 22. lation followed by oxidation have also been employed on
The olefin keto ester was synthesized from keto com- DE ring and CDE rings to install the one chiral center of
pound 14, as depicted in Scheme 4, following our camptothecin,17 which leads to solubility problems at ear-
previously established conditions.8c Accordingly, when ly stage and leads to waste of expensive chiral substrate in
compound 22 was subjected to Wacker conditions,10 we subsequent transformations. Since the molecule contains
unexpectedly observed formation of aromatized product only one chiral center, it makes sense to introduce the
23 (54%) as the sole product. This may be ascribed to air- chirality at a late stage or at the end of the synthesis, there-
oxidation of the initially formed tetracyclic dihydro com- by addressing the solubility issues and the loss of chiral
pound under the driving force of aromatization. A note- substrate, and thus maintain chiral economy. According-
worthy feature of this transformation is the Pd-catalyzed ly, we decided to do the Sharpless AD at the last step and
oxidative cyclization followed by concomitant aromatiza- thus, Sharpless asymmetric dihydroxylation followed by
tion in one pot.14 Having secured the tetracyclic rings of oxidation was readily converted into (+)-camptothecin
25
the pentacyclic camptothecin, the last ring (E) was (1), the rotation is [a]D +39 (c 0.142, CHCl3–MeOH,
achieved as follows. The tetracyclic compound 23 was 4:1), lit. +45, (c 0.30 CHCl3–MeOH, 4:1) which was de-
further treated with diethyl carbonate using LDA as the scribed by us earlier8e or most recently by improved pro-
base to furnish compound 24 in 70% yield.15 Compound cedure accomplished by Yao et al.18 The spectroscopic
24 was alkylated with ethyl iodide using sodium hydride data of synthetic (+)-1 was in complete agreement with
as the base, furnishing compound 25 in 64% yield.16 those of the natural compound.
This compound 25 is the same intermediate as described
In summary, we have demonstrated a novel and efficient
Pd-catalyzed oxidative cyclization and aromatization cas-
cade reaction in one pot for the construction of D ring of
camptothecin and its analogues. Thus we have achieved
in our earlier synthesis of camptothecin.8a The diester 25
was converted into (+)-camptothecin (1) as previously
described.8e
Selective reduction of heteroaromatic ester to aldehyde the total synthesis of (+)-camptothecin (1) in sixteen steps
was accomplished using 3 equivalents DIBAL-H in THF in 1.5% overall yield.
at –60 °C and furnished aldehyde 26 in very good yield
(83%). Aldehyde 26 was subjected to 2 equivalents sodi-
um borohydride in a mixture of solvent (THF–H2O, 5:1)
Acknowledgment
A.B.P. thanks CSIR, New Delhi, India, for a fellowship and S.P.C.
acknowledges funding from DST, New Delhi, India.
at 0 °C provided lactol 27 in excellent yield (90%). The
lactol 27 was transformed into enol ether 28 in excellent
Synlett 2007, No. 17, 2635–2638 © Thieme Stuttgart · New York

2638
S. P. Chavan et al.
LETTER
(13) Liu, C.; Wang, X.; Pei, T.; Widenhoefer, R. A. Chem. Eur.
J. 2004, 10, 6343.
(14) Synthesis of Compound 23: Procedure for the Pd-
Catalyzed Cyclization Reaction
References and Notes
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Phytochemistry 1996, 42, 907.
To a stirred solution of compound 22 (0.2 g, 0.61 mmol) in
DMF (3.0 mL) and H2O (1.0 mL) was added PdCl2 (0.007 g,
0.061 mmol) and CuCl2·2H2O (0.22 g, 1.2 mmol). The
resultant dark green solution was heated at 95 °C for 8 h.
After the disappearance of starting material (TLC), the
reaction mixture was cooled to r.t. Then, H2O (10 mL) was
added and extracted with Et2O (3 × 15 mL). The combined
organic layers were washed with H2O (3 × 10 mL), brine (10
mL), dried over anhyd Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatog-
raphy (SiO2) using EtOAc–PE (6:4) as an eluent to furnish
cyclized product 23 as a pale yellow solid in 54% yield, mp
97–100 °C.
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Spectroscopic Data for Compound 23
IR (CHCl3): nmax = 1728, 1658, 1604 cm–1. 1H NMR (400
MHz, CDCl3 and CCl4): d = 1.44 (3 H, t, J = 7.2 Hz), 2.46 (3
H, s), 4.46 (2 H, q, J = 7.2 Hz), 5.27 (2 H, s), 7.21 (1 H, s),
7.66 (1 H, t, J = 8.0 Hz), 7.82 (1 H, t, J = 8.0 Hz), 7.92 (1 H,
d, J = 8.0 Hz), 8.22 (1 H, d, J = 8.0 Hz), 8.37 (1 H, s) ppm.
13C NMR (100 MHz, CDCl3 and CCl4): d = 14.3, 20.4,
50.15, 61.5, 103.5, 124.0, 127.95, 128.1, 129.1, 129.8,
130.5, 131.0, 136.0, 145.7, 148.9, 151.0, 152.4, 158.4, 166.3
ppm. ESI-MS: m/z = 321 [M + H]+, 343 [M + Na]+. Anal.
Calcd (%) for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74.
Found: C, 71.19; H, 5.11; N, 8.69.
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Synlett 2007, No. 17, 2635–2638 © Thieme Stuttgart · New York

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