A synthesis of camptothecin

Article abstract of DOI:10.1016/j.tetlet.2004.02.091

A total synthesis of camptothecin has been carried out. Central to our synthesis is the intramolecular condensation of a suitably designed ketol, which in turn was obtained from a tricyclic ABC ring synthon. A tandem reductive amination and Michael additi

Full text of DOI:10.1016/j.tetlet.2004.02.091

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3113–3115
A synthesis of camptothecin
Subhash P. Chavan* and Rasapalli Sivappa
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 16 October 2003; revised 9 February2004; accepted 18 February2004
Abstract—A total synthesis of camptothecin has been carried out. Central to our synthesis is the intramolecular condensation of a
suitably designed ketol, which in turn was obtained from a tricyclic ABC ring synthon. A tandem reductive amination and Michael
addition sequence on an unsaturated quinoline ester was employed for the assembly of the ABC skeleton.
Ó 2004 Elsevier Ltd. All rights reserved.
The isolation and characterization of camptothecin (1,
CPT) as the active component contained in extracts
from the Chinese tree, Camptotheca acuminata, byWani
and co-workers offered hope in 19661 of an antitumor
therapeutic agent and triggered a great deal of interest
among oncologists and synthetic chemists.2 Activityhad
been demonstrated in vivo against leukemia, colon,
mammary, and ovarian tumor models.2b Unfortunately
phase 1 clinical evaluations of CPT revealed dose-lim-
iting toxicities including myelosuppression, severe hem-
orrhagic cystitis, and diarrhea, which halted the clinical
development.3 Later studies pointed to the insolubility
of CPT, which required the drug to be formulated as the
ring-opened seco acid salt, a keyaspect in its clinical
failure.
atives resurface as promising agents for the treatment of
solid tumors by chemotherapy. A variety of total syn-
theses were accomplished involving novel adaptations of
classical reactions as well as new chemistryinspired by
the camptothecin target.5;6 In the light of its impressive
biological activityand the intriguing mode of action
reported for 1, we decided to develop a synthetic route
to camptothecin amenable to the preparation of syn-
thetic analogues.
Earlier,6u we exploited an intramolecular Michael
addition strategyas a keystep for the construction of
ring D.
In this paper we describe a novel approach toward
camptothecin. Central to our approach is the imple-
mentation of an intramolecular aldol reaction of ketol 3
to construct the pyridone D-ring with functionality for
manipulation to the lactone E-ring of the title com-
pounds as shown in our retrosynthetic analysis (Scheme
1). Ketol 3 was to be obtained from the tricyclic synthon
5, the preparation of which we envisaged bya reductive
amination and Michael addition using an a,b-unsatu-
rated ester tethered aldehyde 6.
O
N
N
O
OH O
1
Onlyafter topoisomerase 1 was identified byLiu and
co-workers4 as the cellular target of CPT, did its deriv-
O
CHO
O
O
N
N
NR
COOR
N
1
O
COOEt
N
N
N
N
N
COOR
COOR
O
O
COOR
2
4
3
5
COOEt
OH
COOEt
6
Scheme 1.
Keywords: Camptothecin; Total synthesis; Tandem reductive amination–Michael addition; Ketol.
* Corresponding author. Tel.: +91-20-25893300-2289; fax: +91-20-25893614; e-mail: spchavan@dalton.ncl.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.091

3114
S. P. Chavan, R. Sivappa / Tetrahedron Letters 45 (2004) 3113–3115
CHO
CHO
I
iii
i
ii
NBn
NCbz
COOEt
N
N
N
N
COOEt
COOEt
5
8
6
7
O
O
vi
iv
v
NCbz
N
N
N
N
COOR
N
COOEt
O
COOEt
COOEt
3
9
4
COOEt
OH
O
viii
O
vii
N
N
O
O
N
N
O
2
10
O
COOEt
COOEt
ix
O
O
ref 6a
N
N
O
N
N
O
O
O
1
11
COOEt
OH
Scheme 2. Reagents and conditions: (i) ethyl acrylate, NaOAc, 5 mol % Pd(PPh3)4, DMF, 74%; (ii) (a) BnNH2, MeOH, rt, 1 h, (b) NaBH4, MeOH,
0 °C to rt, 2 h, 91%; (iii) (a) Pd/C–H2, EtOH, (b) CbzCl, DCM, K2CO3, 90%; (iv) (a) DIBAL-H, DCM, (b) ethyl 2-(triphenylphosphoranylid-
ene)butyrate, DCM, 80%; (v) (a) TMSCl, NaI, CH3CN, rt, 1 h, (b) carboethoxyacetyl chloride 68%; (vi) KMnO4, acetone–water, AcOH, 95%; (vii)
NaH, THF, 90%; (viii) DDQ, dioxane, 90%; (ix) 10% Pd/C–H2 (100 psi), EtOH, 88%.
6a
The ketol 3 was prepared from Meth-CohnÕs aldehyde 7
according to Scheme 2.
camptothecin byStork and Schultz. Thus careful
reduction of 2 with 10% Pd–C/H2 provided 11 and this
completed a formal total synthesis of camptothecin.
Thus knowing the reluctance of 2-chloro-3-formylquin-
oline to participate in Heck olefination6r we chose Meth-
CohnÕs 2-iodo-3-formyl quinoline 7 as the substrate,
which underwent facile olefination with ethyl acrylate
with Pd(PPh3)4/base/DMF to give olefin 6 in 74% yield.
Condensation of 6 with benzylamine in methanol at 0 °C
formed the SchiffÕs base that was reduced to a secondary
amine at 0 °C, which subsequentlyunderwent an intra-
molecular Michael addition at room temperature to
form the tricyclic amine 5. N-Debenzylation of 5 under
hydrogenation conditions provided a secondary amine,
which was protected as its benzyloxy carbamate by
condensation with benzyl chloroformate. Careful
reduction of this carbamate 8 with DIBAL-H resulted in
the formation of an aldehyde, which was subjected to
Wittig olefination with ethyl 2-(triphenylphosphoranyl-
idene)butyrate7 to afford the a,b-unsaturated ester 9 in
good yield. Deprotection of the Cbz carbamate with
TMSCl/NaI and condensation with carboethoxyacetyl
chloride afforded amide 4. KMnO4 oxidation of the
olefin8 under acidic conditions furnished ketol 3. Having
obtained a substrate with the functional groups required,
the stage was set to studythe proposed strategy.
In conclusion, we have developed a novel synthetic route
to camptothecin 1 using an intramolecular aldol con-
densation reaction as a keystep. This methodology
could be adapted to the synthesis of analogues and
enantiomericallyenriched camptothecin. These studies
are underwayin our laboratory.
Acknowledgements
R.S. thanks the CSIR, New Delhi, India for financial
support. Funding from DST (SP/S1/G-28/2001) and
CSIR, New Delhi to S.P.C. under YSA scheme is
gratefullyacknowledged.
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