Short and efficient total synthesis of luotonin A and 22-hydroxyacuminatine using a common cascade strategy

Article abstract of DOI:10.1021/jo070837d

(Chemical Equation Presented) Total syntheses of 22-hydroxyacuminatine and luotonin A were achieved in direct fashion and high overall yields (16% in eight steps and 47% in five steps, respectively). A mild cascade methodology was successfully applied in both syntheses as a common strategy. The new approach presents the advantages of short routes, high overall yields, use of stable intermediates, and ease of operations.

Full text of DOI:10.1021/jo070837d

Short and Efficient Total Synthesis of Luotonin A
and 22-Hydroxyacuminatine Using A Common
Cascade Strategy
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 April 21, 2007
FIGURE 1. Structures of camptothecin (1), 22-hydroxyacuminatine
(3), luotonin A, (4), and two representative drugs, 2a and 2b.
some drug candidates5 as well) have emerged from numerous
research groups over the past decades.6 22-Hydroxyacuminatine
(3) is another quinoline alkaloid isolated from Chinese medicinal
plant (Camptotheca acuminate) (in a low isolated yield of
0.000006%) in 1989, showing significant cytotoxic activity
against the murine leukemia P-388 cells (ED50 1.32 µg/mL) and
KB (ED50 0.61 µg/mL) in vitro.7 As the only natural alkaloid
containing a benz[6,7]indolizino[1,2-b]quinolin-11(13H)-one
core, 22-hydroxyacuminatine attracted lots of attention. Three
total syntheses of 22-hydroxyacuminatine have been achieved.8
Luotonin A (4) is one more CPT-family alkaloid isolated from
another Chinese medicinal plant (Peganum nigellastrum) in
1997. Luotonin A also presents potent cytotoxicity against P-388
cells (IC50 1.8 µg/mL).9 Although it lacks the lactone functional-
ity of CPT, luotonin A was recently demonstrated to stabilize
the binary complex between human DNA and topoisomerase I
and mediate topoisomerase I-dependent cytotoxicity in intact
cells (IC50 5.7-12.6 µM).10 Several syntheses of luotonin A
also have been reported.11 Most importantly, Hecht and co-
workers found that 14-azacamptothecin, a hybrid of luotonin
A and CPT, is a water-soluble potent topoisomerase I poison.12
Thus, further development of practical methods and general
strategies for acquiring CPT-family alkaloids, including 22-
Total syntheses of 22-hydroxyacuminatine and luotonin A
were achieved in direct fashion and high overall yields (16%
in eight steps and 47% in five steps, respectively). A mild
cascade methodology was successfully applied in both
syntheses as a common strategy. The new approach presents
the advantages of short routes, high overall yields, use of
stable intermediates, and ease of operations.
The potent antitumor activities and clinical applications of
camptothecin-family alkaloids have attracted intense interest
worldwide. Their parent representative analogue, camptothecin
(CPT, 1), serves as an excellent lead drug in anticancer research
because of its potent antitumor activity (Figure 1).1 The primary
cellular target of CPT and many CPT derivatives 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 analogues (including clinically
used anticancer drugs topotecan (2a)3 and irinotecan (2b)4 and
(4) (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.
(5) (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.
(6) 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, 1998; Vol.
50, Chapter 13, pp 509-520. (c) Hutchinson, C. R. Tetrahedron 1981, 37,
1047-1065. For a related effort on cascade protocol for camptothecin,
see: (d) Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N. J.;
Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett. 1996, 37, 5679-5682.
(7) Lin, L. Z.; Cordell, G. A. Phytochemistry 1989, 28, 1295-1297.
(8) (a) Ma, Z.; Lee, D. Y. W. Tetrahedron Lett. 2004, 45, 6721-6723.
(b) Xiao, X.; Antony, S.; Pommier, Y.; Cushman, M. J. Med. Chem. 2006,
49, 1408-1412. (c) Babjak, M.; Kanazawa, A.; Anderson, R. J.; Greene,
A. E. Org. Biomol. Chem. 2006, 4, 407-409.
† State Key Laboratory of Bioorganic and Natural Products Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ Department of Chemistry, 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. U.S.A.
2002, 99, 15387-15392.
(3) 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.
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46, 541-546.
(10) Cagir, A.; Jones, S. H.; Gao, R.; Eisenhauer, B. M.; Hecht, S. M.
J. Am. Chem. Soc. 2003, 125, 13628-13629.
10.1021/jo070837d CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/04/2007
6270
J. Org. Chem. 2007, 72, 6270-6272

SCHEME 1. Eight-Step Formal Total Synthesis of
22-Hydroxyacuminatine (3)
FIGURE 2. Retrosynthesis of 22-hydroxyacuminatine (3) and luotonin
A (4) using a common cascade strategy.
hydroxyacuminatine (3), luotonin A (4), and other new CPT
derivatives, is of great value.
More recently, we reported a mild cascade methodology to
construct variously substituted indolizino[1,2-b]quinolin-9(11H)-
ones,thetetracyclicA/B/C/D-ringcoreofCPT-familyalkaloids.6d,13
This highly efficient cascade reaction triggered by bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate under mild condi-
tions has been successfully applied in total synthesis of
camptothecin (1).13 In order to examine the power of this
methodology, two additional naturally occurring alkaloids, 22-
hydroxyacuminatine (3) and luotonin A (4) were selected for
its further applications. Both of them are notable with structural
similarities to camptothecin (1) in identical A-C rings. Herein,
we report our results of total syntheses of 22-hydroxyacumi-
natine (3) and luotonin A (4) using the above-mentioned cascade
reaction as a common strategy. These two targets were suc-
cessfully achieved in very short steps and high overall yields.
Figure 2 illustrates their general retrosynthetic analysis. With
the consideration of employing our cascade reaction conditions,
chemically stable amides 5 and 6 have to be prepared at first,
respectively.
Condensation of 2,6-dicyanotoluene 9 with diethyl oxalate in
the presence of potassium tert-butoxide, followed by a basic
treatment, yielded 5-cyano-1-oxo-1,2-dihydroisoquinoline-3-
carboxylic acid (10) in 63% yield.14 Treatment of 10 with oxalyl
chloride followed by reaction with excess methanol afforded
ester 11 (88%). N-Propargylation of 11 was carried out with
propargyl bromide, K2CO3, LiBr, and a catalytic amount of
tetrabutylammonium bromide in toluene, giving a new pyridone
8 in 91% yield.15 Basic hydrolysis of methyl ester 8 afforded
acid 7 in 98% yield. Conversion of acid 7 to its corresponding
acid chloride followed by treatment with aniline afforded amide
5 (70% yield in two steps). Amide precursor 5 was then treated
with bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate
(prepared in situ) at room temperature for half an hour.13 The
known advanced intermediate 128b was finally obtained (91%
yield), containing the whole skeleton of 22-hydroxyacuminatine
(3). Conversion of 12 to 22-hydroxyacuminatine (3) has been
previously carried out by Cushman and co-workers using a two-
step DIBAL-H reduction procedure (51% yield).8b Thus, using
our mild cascade reaction, we accomplished a straightforward
synthesis of the known key intermediate 12 (six steps and 31%
yield) starting from commercially available 2,6-dicyanotoluene
9. This represents a formal total synthesis of 22-hydroxyacumi-
natine (3) in eight steps and 16% overall yield.
Synthesis of 22-hydroxyacuminatine (3) started from the
commercially available 2,6-dicyanotoluene 9 (Scheme 1).
(11) Synthesis of luotonin A: (a) Wang, H.; Ganesan, A. Tetrahedron
Lett. 1998, 39, 9097-9098. (b) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen,
Y.-J. Heterocycles 1999, 51, 1593-1596. (c) Kelly, T. R.; Chamberland,
S.; Silva, R. A. Tetrahedron Lett. 1999, 40, 2723-2724. (d) Molina, P.;
Tarraga, A.; Gonzalez-Tejero, A. Synthesis 2000, 11, 1523-1525. (e)
Toyota, M.; Komori, C.; Ihara, M. Heterocycles 2002, 56, 101-104. (f)
Toyota, M.; Komori, C.; Ihara, M. ARKIVOC 2003, 15-23. (g) Dallavalle,
S.; Merlini, L. Tetrahedron Lett. 2002, 43, 1835-1838. (h) Yadav, J. S.;
Reddy, B. V. S. Tetrahedron Lett. 2002, 43, 1905-1908. (i) Osborne, D.;
Stevenson, P. J. Tetrahedron Lett. 2002, 43, 5469-5470. (j) Lee, E. S.;
Park, J. G.; Jahng, Y. Tetrahedron Lett. 2003, 44, 1883-1886. (k)
Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.; Takeuchi, Y. Synlett
2003, 6, 847-848. (l) Harayama, T.; Hori, A.; Serban, G.; Morikami, Y.;
Matsumoto, T.; Abe, H.; Takeuchi, Y. Tetrahedron 2004, 60, 10645-10650.
(m) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2004, 69, 4563-4566. (n)
Chavan, S. P.; Sivappa, R. Tetrahedron 2004, 60, 9931-9936. (o) Twin,
H.; Batey, R. A. Org. Lett. 2004, 6, 4913-4916. (p) Ma, Z. Z.; Hano, Y.;
Nomura, T. Heterocycles 2005, 65, 2203-2219. (q) Bowman, W. R.;
Cloonan, M. O.; Fletcher, A. J.; Stein, T. Org. Biomol. Chem. 2005, 3,
1460-1467. (r) Tangirala, R.; Antony, S.; Agama, K.; Pommier, Y.; Curran,
D. P. Synlett 2005, 18, 2843-2846. (s) Servais, A.; Azzouz, M.; Lopes,
D.; Courillon, C.; Malacria, M. Angew. Chem., Int. Ed. 2007, 46, 576-
579.
Employing a similar strategy, total synthesis of luotonin A
(4) was accomplished in five steps (Scheme 2). Reaction of the
commercially available anthranilamide 13 with diethyl oxalate
yielded a quinazolinone derivative 14 in 81% yield.16 Ethyl ester
14 was then hydrolyzed with LiOH to give acid 15.17 Conversion
(14) Wenkert, E.; Johnston, D. B. R.; Dave, K. G. J. Org. Chem. 1964,
29, 2534-2542.
(15) (a) Ricoh, I.; Halvorsen, K.; Dubrule, C.; Lattes, A. J. J. Org. Chem.
1994, 59, 415. (b) Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P. Tetrahedron
Lett. 1995, 36, 8917.
(16) Joshi, V.; Chaudhari, R. P. Indian J. Chem. 1987, 26B, 602-604.
(17) Rastogi, R.; Sharma, S. Indian J. Chem. 1982, 21B, 744-746.
(12) (a) Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Thomas, S. J.; Gao,
R.; Hecht, S. M. J. Am. Chem. Soc. 2005, 127, 838-839. (b) Elban, M. A.;
Sun, W.; Eisenhauser, B. M.; Gao, R.; Hecht, S. M. Org. Lett. 2006, 8,
3513-3516.
(13) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003-2006.
J. Org. Chem, Vol. 72, No. 16, 2007 6271

SCHEME 2. Five-Step Total Synthesis of Luotonin A
Experimental Section
7-Cyano-12H-5,11a-diazadibenzo[b,h]fluoren-11-one (12).8b
To a solution of triphenylphosphine oxide (0.77 g, 2.75 mmol) in
dry CH2Cl2 (20 mL) was added trifluoromethanesulfonic anhydride
(0.23 mL, 1.38 mmol) slowly at 0 °C. After the mixture was stirred
at 0 °C for 10 min, amide 5 (0.30 g, 0.92 mmol) was then added
at the same temperature. The reaction was allowed to warm to room
temperature. After 0.5 h, the reaction mixture was quenched by
addition of 10% aqueous NaHCO3 solution. The aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4, filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel to afford 128b (0.26
1
g, 91%). H NMR (CDCl3, 300 MHz): δ 8.77 (1H, d, J ) 8.1
Hz), 8.40 (1H, s), 8.28 (1H, d, J ) 8.4 Hz), 8.09 (1H, d, J ) 7.5
Hz), 8.02 (1H, s), 7.94 (1H, d, J ) 7.8 Hz), 7.85 (1H, t, J ) 7.8
Hz), 7.67 (1H, t, J ) 7.5 Hz), 7.63 (1H, t, J ) 8.0 Hz), 5.41 (2H,
s). HRMS (MALDI, m/z) calcd for C20H11N3O (M+H)+: 310.0980;
found, 310.0975. IR (KBr): 2229, 1664, 1637, 1591, 1550, 1473,
1394, 1377, 1296, 1253, 1205, 868, 816, 760, 705, 599 cm-1. Anal.
calcd for C20H11N3O: C, 77.66; H, 3.58; N, 13.58; found: C, 77.65;
H, 3.58; N, 13.57.
Luotonin A (4).9,11 Compound 4 was prepared by a procedure
similar to that for compound 12, and it was isolated in 99% yield
by column chromatography on silica gel (CH2Cl2/CH3OH, 150:1
to 80:1) as a white solid; mp: 278-280 °C dec. 1H NMR (CDCl3,
500 MHz): δ 8.46 (1H, d, J ) 8.5 Hz), 8.43-8.40 (2H, m), 8.11
(1H, d, J ) 8.1 Hz), 7.92 (1H, d, J ) 8.1 Hz), 7.86 (1H, d, J ) 8.2
Hz), 7.82 (1H, d, J ) 8.2 Hz), 7.66 (1H, t, J ) 7.5 Hz), 7.57 (1H,
t, J ) 7.5 Hz), 5.32 (2H, s). 13C NMR (CDCl3, 125 MHz): δ 160.6,
152.6, 151.2, 149.5, 134.6, 131.5, 130.72, 130.68, 129.5, 128.8 (2C),
128.5, 127.9, 127.4, 126.4, 121.3, 47.3. IR (KBr): 1678, 1630,
1606, 1572, 1467, 1360, 1326, 1237, 769, 690, 604 cm-1. HRMS
(ESI, m/z) calcd for C18H12N3O (M + H)+: 286.0975; found,
286.0990. Anal. calcd for C18H11N3O: C, 75.78; H, 3.89; N, 14.73;
found: C, 75.80; H, 4.10; N, 14.64.
of 15 to its corresponding acid chloride, followed by coupling
with aniline, afforded the amide 16 in 67% yield (from 14).
N-Alkylation of amide 16 with propargyl bromide provided the
precursor amide 6 in 87% yield.15 Finally, the cascade annulation
was carried out by simple treatment of 6 with bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate at room temper-
ature for 1 h, affording luotonin A (4) in 99% yield. This five-
step synthesis of luotonin A represents an efficient overall yield
of 47% from the commercially available 13. To best of our
knowledge, this is the shortest synthesis route for luotonin A.
Compared with a similar strategy previously used by Batey and
Twin,11 our approach presents the advantages of a shorter route,
higher overall yield (especially for the key cascade annulation
step), and the use of the stable amide intermediate.
In conclusion, highly efficient and concise total syntheses of
22-hydroxyacuminatine and luotonin A were accomplished in
direct fashions (eight steps and five steps, respectively) and high
overall yields (16% and 47%, respectively). A mild and efficient
cascade reaction was successfully employed as the common
annulation strategy. Further applications of this useful and highly
efficient cascade annulation protocol to construction of new CPT
derivatives and other structurally related bioactive molecules
are underway in our laboratory, and these results will be reported
in due course.
Acknowledgment. This project is financially supported by
National Natural Science Foundation (20425205, 20621062),
Chinese Academy of Sciences (KGCX2-SW-213, KJCX2-YW-
H08), and the Shanghai Municipal Committee of Science and
Technology (06QH14016, 04DZ14901).
Supporting Information Available: Experimental details and
characterization of new compounds, copies of NMR spectra for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO070837D
6272 J. Org. Chem., Vol. 72, No. 16, 2007