Highly efficient and mild cascade reactions triggered by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate and a concise total synthesis of camptothecin

Article abstract of DOI:10.1021/ol0706307

A mild and efficient cascade methodology is reported to construct variously substituted indolizino[1,2-b]quinolin-9(11H)-ones. Efficiently triggered by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate under mild conditions, this cascade achieved significant enhancements in chemical yields. Utilizing this highly efficient domino reaction followed by a Sharpless dihydroxylation, an eight-step total synthesis of camptothecln was accomplished from a known pyridine derivative in direct fashion with an overall yield of 47% and 95% ee.

Full text of DOI:10.1021/ol0706307

ORGANIC
LETTERS
2007
Vol. 9, No. 10
2003-2006
Highly Efficient and Mild Cascade
Reactions Triggered by
Bis(triphenyl)oxodiphosphonium
Trifluoromethanesulfonate and a
Concise Total Synthesis of
Camptothecin
Hai-Bin Zhou,† Guan-Sai Liu,†,‡ and Zhu-Jun Yao*,†,‡
State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China, and Department of Chemistry,
UniVersity of Science and Technology of China, Hefei, Anhui 230026, China
yaoz@mail.sioc.ac.cn
Received March 15, 2007
ABSTRACT
A mild and efficient cascade methodology is reported to construct variously substituted indolizino[1,2-b]quinolin-9(11H)-ones. Efficiently triggered
by bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate under mild conditions, this cascade achieved significant enhancements in chemical
yields. Utilizing this highly efficient domino reaction followed by a Sharpless dihydroxylation, an eight-step total synthesis of camptothecin
was accomplished from a known pyridine derivative in direct fashion with an overall yield of 47% and 95% ee.
The potent antitumor activities and clinical applications of
the camptothecin family of alkaloids have attracted intense
interest worldwide. Camptothecin (CPT, 1, Figure 1) was
isolated from the Chinese plant Camptotheca acuminata in
1966 by Wani and Wall.1 The primary cellular target of CPT
is the covalent binary complex formed between DNA and
topoisomerase I during DNA relaxation, and the stabilization
of this complex by CPT is believed to lead to cell death.2
Many imaginative syntheses of camptothecin and its ana-
logues have emerged from numerous research groups over
† Chinese Academy of Sciences.
‡ University of Science and Technology of China.
(1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A.
T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888-3890.
(2) (a) Hsiang, Y. H.; Hertzberg, R.; Hecht, S. M.; Liu, L. F. J. Biol.
Chem. 1985, 260, 14873-14878. (b) Kohn, K. W.; Pommier, Y. Ann. N.Y.
Acad. Sci. 2000, 922, 11-26. (c) Staker, B. L.; Hjerrild, K.; Feese, M. D.;
Behnke, C. A.; Burgin, A. B., Jr.; Stewart, L. Proc. Natl. Acad. Sci. 2002,
99, 15387-15392.
Figure 1. Camptothecin and two representative derivatives.
10.1021/ol0706307 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/14/2007

the past decades.3 The summit of these efforts occurred when
two camptothecin analogues, topotecan (2a)4 and irinotecan
(2b),5 were approved by the FDA to treat cancers. Addition-
ally, several analogues reached different stages of clinical
trials.6 Thus, development of practical and efficient strategies
for acquiring new CPT derivatives is of great value.
However, to date, the chemical synthesis of camptothecin
remains a challenge since most of the known syntheses are
lengthy, of low overall efficiency, and of high cost as
compared with natural sources.
bond equivalence in aryl ring A, which serves as one 2π
component together with an in situ formed imidate CdN
bond). Consideration of reaction mechanisms indicates that
a critical step to initiate the domino reaction sequence is the
in situ formation of imidates through activation of corre-
sponding chemically stable amides.
To optimize this reaction, we screened a variety of amide-
activating reagents using as substrate amide 3a (see Table
1). With trimethyloxonium fluoroborate (previously used by
By retrosynthetic analysis of CPT, concomitant construc-
tion of the indolizino[1,2-b]quinolin-9(11H)-one B and C
rings by using an intramolecular aza-Diels-Alder reaction3a
could theoretically achieve the highest efficiency (Figure 2).
Table 1. Synthesis of Indolizino[1,2-b]quinolin-9(11H)-ones
with Bis(triphenyl)oxodiphosphonium
Trifluoromethanesulfonate12
entry
1
reactant
product(s)
yield (%)
90
3a: R1 ) R2 ) R4 )
R5 ) H, R3 ) OMe
3b: all R ) H
4a: R1 ) R2 ) R4 )
R5 ) H, R3 ) OMe
4b: all R ) H
2
3
98
3c: R1 ) R2 ) R4 )
R5 ) H, R3 ) NMe2
3d: R1 ) R2 ) R4 )
R5 ) H, R3 ) Me
3e: R1 ) R2 ) R4 )
R5 ) H, R3 ) Br
4c: R1 ) R2 ) R4 )
R5 ) H, R3 ) NMe2
4d: R1 ) R2 ) R4 )
R5 ) H, R3 ) Me
4e: R1 ) R2 ) R4 )
R5 ) H, R3 ) Br
95a
4
5
6
7
8
9
98
95
95
91
99b
3f: R1 ) R2 ) R4 )
R5 ) H, R3 ) F
4f: R1 ) R2 ) R4 )
R5 ) H, R3 ) F
3g: R1 ) R2 ) R4 )
R5 ) H, R3 ) CO2Me
3h, R1 ) R2 ) R4 )
R5 ) H, R3 ) CN
3i: R1 ) R3 ) R4 )
R5 ) H, R2 ) Me
4g: R1 ) R2 ) R4 )
R5 ) H, R3 ) CO2Me
4h, R1 ) R2 ) R4 )
R5 ) H, R3 ) CN
4i: R1 ) R3 ) R4 )
R5 ) H, R2 ) Me
4i′: R1 ) R2 ) R3 )
R5 ) H, R4 ) Me
4j: R2 ) R3 ) R4 )
R5 ) H, R1 ) Me
4k: R1 ) R3 ) R5 )
H, R2 ) R4 ) Me
4l: R1 ) R2 ) R3 )
R4 ) H, R5 ) Et
98
4i:4i′ ) 3:2
10
11
12
3j: R2 ) R3 ) R4 )
R5 ) H, R1 ) Me
3k: R1 ) R3 ) R5 )
H, R2 ) R4 ) Me
3l: R1 ) R2 ) R3 )
R4 ) H, R5 ) Et
94
98
Figure 2. Intramolecular aza-Diels-Alder reaction-based retrosyn-
thesis of the indolizino[1,2-b]quinolin-9(11H)-one core of CPT, and
a previous approach by Fortunak et al. using a cascade reaction.
100
a The yield is based on 55% recovery of 3c. b The yield is based on
63% recovery of 3h.
A previous synthesis by Fortunak and co-workers validated
the practicality of this approach.7 However, Fortunak’s
method has limitations related to chemical yields, byproducts,
and the scope of the reaction. In this intramolecular hetero-
Diels-Alder reaction, an alkyne serves as the dienophile and
an N-arylimidate serves as the diene (presenting a double-
Fortunak et al.7), the expected product 4a was isolated in
only 12% yield, with the concomitant formation of byproduct
5 in 5% yield. The highest yield achieved after optimizations
was only 32% when using dichloromethane as solvent under
reflux. We were not able to achieve the reported yield of
65% for 4a.7 Attempts with other Lewis acids also failed to
give satisfactory results.
(3) For reviews on camptothecin and its derivatives, see: (a) Du, W.
Tetrahedron 2003, 59, 8649-8687. (b) Wall, M. E.; Wani, M. C. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: San Diego, CA, 1998;
Vol. 50, Chapter 13, pp 509-520. (c) Hutchinson, C. R. Tetrahedron 1981,
37, 1047-1065.
(4) 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.; Hertzberg, R. P. J. Med. Chem. 1991, 34, 98-107.
(5) (a) Negoro, S.; Fukuoka, M.; Masuda, N.; Takada, M.; Kusunoki,
Y.; Matsui, K.; Takifuji, N.; Kudoh, S.; Niitani, H.; Taguchi, T. J. Natl.
Cancer Inst. 1991, 83, 1164-1168. (b) Kawato, Y.; Aonuma, M.; Hirota,
Y.; Kuga, H.; Sato, K. Cancer Res. 1991, 51, 4187-4191.
Bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate
(prepared by in situ combination of 1 equiv of Tf2O and 2
equiv of Ph3PO in dichloromethane at 0 °C) has been recently
used for the synthesis of thiazolines and imidazoline-
containing amino acids by Kelly and co-workers.8 According
to the proposed mechanisms, such a reagent should serve as
(6) (a) Cragg, G. M.; Newman, D. J. J. Nat. Prod. 2004, 67, 232-244.
(b) Butler, M. S. Nat. Prod. Rep. 2005, 22, 162-195.
(7) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N. J.;
Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5679-5682.
(8) (a) You, S.-L.; Razavi, H.; Kelly, J. W. Angew. Chem., Int. Ed. 2003,
42, 83-85. (b) You, S.-L.; Kelly, J. W. J. Org. Chem. 2003, 68, 9506-
9509. (c) You, S.-L.; Kelly, J. W. Org. Lett. 2004, 6, 1681-1683.
2004
Org. Lett., Vol. 9, No. 10, 2007

an activator to convert an amide to its corresponding imidate
under mild conditions, and to promote the subsequent
intramolecular aza-Diels-Alder annulation in the desired
direction. To our delight, treatment of amide 3a with bis-
(triphenyl)oxodiphosphonium trifluoromethanesulfonate at
room temperature afforded the desired tetracyclic product
4a in excellent isolated yield (Table 1, entry 1). After
optimization, the best reaction conditions were achieved with
3 equiv of Ph3PO and 1.5 equiv of Tf2O in CH2Cl2 from 0
°C to room temperature. Encouraged by the initial results,
we examined the generality of this reaction. All substrates
(3b-l) were subjected to the optimized conditions and the
reactions proceeded smoothly at ambient temperature, giving
the corresponding indolizino[1,2-b]quinolin-9(11H)-ones (4b-
l) in nearly quantitative yields (Table 1). All the substrates
except 3i afforded single products. In the case of 3i, a mixture
Scheme 1. Eight-Step Total Synthesis of Camptothecin from
Known Pyridine 6
1
of regioisomers 4i and 4i′ (4i:4i′ ) 3:2, measured by H
NMR) was afforded. Thus, the use of Tf2O-2Ph3PO as an
amide activator provides a mild, facile, and general approach
to synthesize variously substituted indolizino[1,2-b]quinolin-
9(11H)-ones through a highly efficient cascade sequence
involving intramolecular aza-Diels-Alder reaction at ambi-
ent temperature.
Total synthesis of camptothecin (1) with this mild and
efficient cascade reaction started from the known chloro-
pyridine 69 (Scheme 1). Carbonylation of 6 was ac-
complished smoothly in methanol under CO atmosphere (120
psig) at 90 °C in the presence of 2 mol % of PdCl2(CH2-
Cl2)dppf and Et3N, affording the methyl ester 7 (97%).
Selective O-demethylation of 7 with iodotrimethylsilane
(generated in situ from TMSCl and sodium iodide) in
acetonitrile afforded pyridone 8 (96%).10 N-Propargylation
of 8 was carried out with propargyl bromide, K2CO3,
tetrabutylammonium bromide, and LiBr in toluene, giving
the new pyridone 9 (70%). Basic hydrolysis of methyl ester
9 gave the corresponding carboxylic acid 10 (94%). Treat-
ment of 10 with oxalyl chloride followed by coupling with
aniline afforded the stable amide precursor 11 (96%).
Employing the newly developed cascade annulation meth-
odology, an advanced intermediate 1211 containing the whole
skeleton of CPT was obtained in 96% yield by simple
treatment of amide 11 with bis(triphenyl)oxodiphosphonium
trifluoromethanesulfonate at room temperature.
chiral HPLC, 99% ee after a simple recrystallization (71%)
from 1,4-dioxane, [R]20D 41.6 (c 0.2, CHCl3-MeOH 4:1)).10
Thus, a short total synthesis of (+)-camptothecin was
accomplished in 8 steps from the known pyridine 6 with an
overall yield of 47% and 95% ee.
In conclusion, reported herein is a concise total synthesis
of camptothecin utilizing a mild and efficient cascade
reaction followed by a highly enantioselective Sharpless
dihydroxylation. This cascade sequence was efficiently
triggered by bis(triphenyl)oxodiphosphonium trifluoromethane-
sulfonate under mild conditions, and achieved significant
enhancements in chemical yields.12 Such a methodology
Transformation of 12 to camptothecin (1) was recently
carried out by a two-step procedure11 involving a Sharpless
asymmetric dihydroxylation and an I2/CaCO3-based hemi-
acetal oxidation in a relatively low yield (33%). Satisfactory
results were finally achieved after our modification of these
two reactions. Optimizing the mixed solvent from 10:1
(MeOH-H2O) to 2:1 (MeOH-H2O) greatly improved the
reaction efficiency and yield in the hemiacetal oxidation. By
using this modified procedure, camptothecin (1) was syn-
thesized in 83% yield (2 steps) and 95% ee (measured by a
(12) Typical procedure for cascade reactions: Trifluoromethanesulfonic
anhydride (0.25 ml, 1.5 mmol) was added slowly to a solution of
triphenylphosphane oxide (0.83 g, 3 mmol) in dry CH2Cl2 (15 mL) at 0
°C. After the mixture was stirred at 0 °C for 10 min, substrate 3 (1 mmol)
was then added at the same temperature. The reaction was allowed to warm
to room temperature and monitored by TLC (it usually completed after 1
h). The reaction mixture was quenched with 10% aqueous NaHCO3 solution.
The aqueous layer was extracted with CH2Cl2, and the combined organic
layers were dried over Na2SO4, filtered, and concentrated. The crude product
was purified by flash chromatography on silica gel to afford pure 4.
(9) Bankston, D.; Fang, F.; Huie, E.; Xie, S. J. Org. Chem. 1999, 64,
3461-3466.
(10) Josien, H.; Ko, S.-B.; Bom, D.; Curran, D. P. Chem. Eur. J. 1998,
4, 67-83.
(11) Chavan, S. P.; Venkatraman, M. S. ARKIVOC 2005, 165-169.
Org. Lett., Vol. 9, No. 10, 2007
2005

should be particularly advantageous for preparing analogues
that would be difficult to derive from natural camptothecin.
It also offers the future possibility of developing an alterna-
tive industrial supply of CPT by chemical synthesis.
(20425205, 20321202), and the Shanghai Municipal Com-
mittee of Science and Technology (06QH14016, 04DZ14901).
Supporting Information Available: Experimental details
1
and characterizations of new compounds, and copies of H
NMR and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This project is financially supported
by CAS (KGCX2-SW-213, KJCX2-YW-H08), NSFC
OL0706307
2006
Org. Lett., Vol. 9, No. 10, 2007