A Modular Approach to Oxoindolizino Quinolines: Efficient Synthesis of Mappicine Ketone (Nothapodytine B)

Article abstract of DOI:10.1002/anie.200352094

A general route to oxoindolizino quinolines, such as nothapodytine A, mappicine, camptothecin, and several chemotherapeutic derivatives, is illustrated by the synthesis of the antiviral natural product from Nothapodytes foetida, mappicine ketone (R¹ = R⁴ H, R² = CH₃, R³ = COC₂H₅). A wide range of new camptothecinoids should now be readily available for biological testing.

Full text of DOI:10.1002/anie.200352094

Angewandte
Chemie
Synthesis of Quinoline Alkaloids
A Modular Approach to Oxoindolizino
Quinolines: Efficient Synthesis of Mappicine
Ketone (Nothapodytine B)**
Gajendra B. Raolji, StØphanie Garçon,
Andrew E. Greene,* and Alice Kanazawa*
In memory of Patrick LØon
Scheme 1. Retrosynthesis of oxoindolizino quinolines A.
Oxoindolizino quinolines include the natural products map-
picine ketone (nothapodytine B, 1a),[1] nothapodytine A
(1b),[1] mappicine (1c),[2] and camptothecin (2a),[3] as well
as several chemotherapeutic derivatives of camptothecin,
such as topotecan (2b) and irinotecan (2c).[3] While the
herpes viruses (HSV-1 and HSV-2, including Acyclovir-
resistant forms) and human cytomegalovirus.[9,10]
The synthesis of 1a began with the formation of the
known adduct 4a by cycloaddition of the carbonyl ylide
derived from 3 with methyl acrylate (Scheme 2).[11] This
importance of these and related alkaloids has already fostered
many synthetic approaches, beginning with that by Stork and
Schultz[4] some 30 years ago, additional, and in particular,
efficient and flexible routes remain highly desirable for
discovering derivatives with improved biological profiles.
Our envisioned modular approach to these compounds is
shown in retrosynthetic form in Scheme 1. A Friedländer
condensation, which is ideal for accessing diversely substi-
tuted quinolines, was planned for the formation of the
tetracyclic framework of the oxoindolizino quinolines.[5] The
requisite ketones B were viewed as products of benzylic-type
oxidation of pyridones C, which would originate from various
Claisen and Stille/Suzuki transformations of hydroxypyrido-
nes D.[6] Hydroxypyridones D are easily available through
cycloaddition of the isomünchnone dipoles derived from
diazo imides E.[7]
=
Scheme 2. Synthesis of 1a. a) [Rh(OCOCH3)2]2, H2C CHCO2CH3,
C6H6, 908C, 14 h (81%); b) 48% aq HBr, 1408C, 14 h (82%); c) (E)-
BrCH2CH CHC2H5, Cs2CO3, DMF, 708C, 1 h; d) C6H5Cl, reflux, 24 h
=
(74%, 2 steps); e) C6H5NTf2, N(C2H5)3, CH2Cl2, 0!208C, 18 h (94%);
Sn(CH3)4, [PdCl2{P(C6H5)3}2], LiCl, DMF, 1108C, 2 h (89%); f) RhCl3,
C2H5OH, 1008C, 0.5 h (91%); g) NaHMDS, O2, P(OC2H5)3, THF,
ꢀ788C, 2 h (76%); PDC, 4 Š molecular sieves, CH2Cl2, 08C, 2 h
(81%); h) o-NH2C6H4CHO, p-TsOH, C6H5CH3, reflux, 20 h (73%);
i) O3, CH2Cl2-CH3OH, ꢀ788C; (CH3)2S, ꢀ78!208C, 16 h (60%).
NaHMDS=sodium hexamethyldisilazide, PDC=pyridinium dichro-
mate.
We now illustrate the feasibility of this general strategy by
way of an effective synthesis of mappicine ketone (1a).
Mappicine ketone, present in small amounts in Nothapodytes
foetida (a plant found in India),[1] and formed by thermolysis
of camptothecin,[8] displays strong, selective activity against
multistep sequence proceeded smoothly and in high yield
when catalyzed by rhodium(ii) acetate. Hot aqueous hydro-
bromic acid then effected decarbomethoxylation of 4a to give
4b in 82% yield.[11] Etherification of 4b with commercially
available (E)-1-bromo-2-pentene and cesium carbonate in
dimethylformamide produced the expected substitution prod-
uct, which cleanly underwent Claisen rearrangement[6a] in
refluxing chlorobenzene to afford the desired derivative 5 in
74% overall yield. This transformation is a rare example of a
Claisen rearrangement in a hydroxypyridone system.[12]
The a-hydroxypyridone 5 was converted into its triflate
derivative under standard conditions. This was followed by
Stille coupling[6b] with tetramethyltin to provide a-methyl-
[*] Dr. A. E. Greene, Dr. A. Kanazawa, Dr. G. B. Raolji, S. Garçon
Chimie Recherche (LEDSS)
UniversitØ Joseph Fourier de Grenoble
38041 Grenoble Cedex 9 (France)
Fax: (+33)4-7651-4494
E-mail: andrew.greene@ujf-grenoble.fr
alice.kanazawa@ujf-grenoble.fr
[**] We thank Prof. P. Dumy and Drs. B. Hartmann and J.-P. Vors for
their interest in our work, Ms. B. EscudØ for technical help, and
Aventis and the CNRS (UMR 5616) for financial support.
Angew. Chem. Int. Ed. 2003, 42, 5059 –5061
DOI: 10.1002/anie.200352094
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5059

Communications
J = 7.4 Hz, 2H), 2.30 (q, J = 7.5 Hz, 2H), 2.18–2.08 (m, 2H), 2.02 (s,
3H), 1.72 (d, J = 6.9 Hz, 3H), 0.87 ppm (t, J = 7.5 Hz, 3H); 13C NMR
(CDCl3, 75.5 MHz, major isomer): d = 162.8, 153.1, 145.4, 141.3,
123.2, 120.2, 102.9, 48.8, 31.5, 23.8, 21.7, 13.7, 13.3, 12.5 ppm; HRMS:
calcd for [C14H19NO+H]+: 218.1545; found: 218.1561. 7b: m.p. 70–
pyridone 6 in 84% yield. In the presence of rhodium(iii)
chloride in hot ethanol,[13] 6 rapidly isomerized to olefin 7a
(91%). The success of this key transformation derives from
the carbon symmetry of the b substituent in pyridone 6.
Oxidation[14] of 7a in two steps then selectively generated the
Friedländer substrate 7b, which reacted with o-aminobenzal-
dehyde to give oxoindolizino quinoline 8 in 73% yield.
Pleasingly, ozone in dichloromethane/methanol at ꢀ788C
accomplished selective double-bond cleavage in 8 to provide
mappicine ketone (m.p. 233–2348C), with spectroscopic and
chromatographic properties identical to those of the naturally
derived material (m.p. 231–2328C).[8b]
~
718C; FTIR: n = 1735, 1644, 1603, 1360, 1314, 1267, 1200, 1116, 838,
763, 668 cmꢀ1; 1H NMR (CDCl3, 300 MHz, major isomer): d = 6.68 (s,
1H), 5.32 (q, J = 6.8 Hz, 1H), 4.25 (t, J = 6.9 Hz, 2H), 2.85 (t, J =
6.9 Hz, 2H), 2.34 (q, J = 7.6 Hz, 2H), 2.16 (s, 3H), 1.75 (d, J = 6.8 Hz,
3H), 0.87 ppm (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz,
major isomer): d = 197.2, 162.0, 152.3, 140.0, 135.9, 133.2, 124.9, 105.9,
41.8, 33.8, 23.6, 14.7, 13.3, 12.3 ppm; HRMS: calcd for
[C14H17NO2+H]+: 232.1338; found: 232.1329. 1a: m.p. 233–2348ꢀC1;
~
FTIR: n = 3087, 1702, 1654, 1619, 1599, 1379, 1185, 933, 838, 762 cm
;
1H NMR (CDCl3, 300 MHz, major isomer): d = 8.34 (s, 1H), 8.17 (d,
J = 8.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.79 (m, 1H), 7.62 (m, 1H),
7.22 (s, 1H), 5.27 (s, 2H), 2.88 (q, J = 7.3Hz, 2H), 2.28 (s, 3H),
1.23ppm (t, J = 7.3Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d = 205.5,
161.7, 152.9, 148.8, 148.2, 143.4, 131.0, 130.4, 129.6, 128.6, 128.1, 128.0,
127.7, 127.0, 97.9, 50.2, 36.0, 13.6, 7.8 ppm; HRMS: calcd for
[C19H16N2O2+H]+: 305.1290; found: 305.1313.
In summary, a concise, efficient synthesis of mappicine
ketone has been used to demonstrate a modular approach to
oxoindolizino quinolines. By virtue of the variations that are
possible in the substituents R1–R4 (Scheme 1), a wide range of
new camptothecinoids should be easily available for bio-
logical testing. Continuing efforts are being directed toward
the preparation of irinotecan and derivatives by this
approach.
Received: June 10, 2003[Z52094]
Keywords: cross-coupling · cycloaddition · isomerization ·
.
rearrangement · total synthesis
Experimental Section
8: A mixture of ketone 7b (200 mg, 0.86 mmol), o-aminobenzalde-
hyde (126 mg, 1.04 mmol), and p-toluenesulfonic acid monohydrate
(8 mg, 0.04 mmol) in toluene (10 mL) was refluxed (Dean–Stark trap)
for 20 h. The solvent was then removed under reduced pressure, and
the crude product was purified by column chromatography on silica
[1] T.-S. Wu, Y.-Y. Chan, Y.-L. Leu, C.-Y. Chern, C.-F. Chen,
Phytochemistry 1996, 42, 907 – 908.
[2] T. R. Govindachari, K. R. Ravindranath, N. Viswanathan, J.
Chem. Soc. Perkin Trans. 1 1974, 1215 – 1217.
gel to yield 200 mg (73%) of quinoline 8 as a mixture of E and Z
ꢀ1
~
isomers. FTIR: n = 1650, 1590, 1375, 1226, 968, 834, 755, 725 cm
;
[3] Reviews on camptothecin and derivatives: a) Camptothecins:
New Anticancer Agents (Eds.: M. Potmesil, H. Pinedo), CRC,
Boca Raton, 1995; b) S. Sawada, T. Yokokura, T. Miyasaka,
Curr. Pharm. Des. 1995, 1, 113– 132; c) M. Torck, M. Pinkas, J.
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[4] G. Stork, A. G. Schultz, J. Am. Chem. Soc. 1971, 93, 4074 – 4075.
[5] Review on Friedländer quinoline synthesis: C.-C. Cheng, S. J.
Yan, Org. React. 1982, 28, 37 – 201.
1H NMR (CDCl3, 300 MHz, major isomer): d = 8.31 (s, 1H), 8.16 (d,
J = 8.4 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.76 (m, 1H), 7.59 (m, 1H),
7.12 (s, 1H), 5.41 (q, J = 6.9 Hz, 1H), 5.25 (s, 2H), 2.45 (q, J = 7.6 Hz,
2H), 2.21 (s, 3H), 1.79 (d, J = 6.9 Hz, 3H), 0.94 ppm (t, J = 7.6 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz, major isomer): d = 162.0, 153.7,
153.5, 148.8, 141.5, 140.9, 130.7, 130.2, 129.5, 128.9, 128.1, 127.9, 127.3,
126.8, 124.2, 103.2, 49.8, 23.7, 14.2, 13.3, 12.5 ppm; HRMS calcd for
[C21H20N2O+H]+: 317.1654; found: 317.1661.
~
Selected data for other compounds: 4c: FTIR: n = 1653, 1599,
[6] a) Reviews on the Claisen rearrangement: S. J. Rhoads, N. R.
Raulins, Org. React. 1975, 22, 1 – 252; S. Blechert, Synthesis 1989,
71 – 82; b) Review on Stille coupling: V. Farina, V. Krishnamur-
thy, W. J. Scott, Org. React. 1997, 50, 1 – 652; c) Reviews on
Suzuki coupling: N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95,
2457 – 2483; S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew.
Chem. 2001, 113, 4676 – 4701; Angew. Chem. Int. Ed. 2001, 40,
4544 – 4568.
1
1285, 1248, 1219, 1185, 1054 cmꢀ1; H NMR (CDCl3, 300 MHz): d =
6.60 (d, J = 7.4 Hz, 1H), 5.89 (d, J = 7.4 Hz, 1H), 5.88 ꢀ5.72 (m, 1H),
5.65–5.54 (m, 1H), 4.41 (d, J = 5.9 Hz, 2H), 4.01 (t, J = 7.1 Hz, 2H),
2.93(t, J = 7.7 Hz, 2H), 2.14–2.04 (m, 2H), 2.02–1.98 (m, 2H),
0.92 ppm (t, J = 7.5, 3H); 13C NMR (CDCl3, 75.5 MHz): d = 157.4,
146.7, 140.9, 137.1, 123.5, 116.5, 99.0, 69.7, 48.6, 30.7, 25.1, 22.0,
13.0 ppm; HRMS calcd for [C13H17NO2+H]+: 220.1338; found:
~
220.1319. 5: m.p. 120–1218C; FTIR: n = 3245, 1662, 1634, 1595,
[7] Reviews on carbonyl ylide cycloaddition: a) M. C. McMills, D.
Wright in The Chemistry of Heterocyclic Compounds: Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), Wiley, New York, 2002, pp. 253– 314; b) G. Mehta, S.
Muthusamy, Tetrahedron 2002, 58, 9477 – 9504.
[8] a) J. M. D. Fortunak, A. R. Mastrocola, M. Mellinger, J. L.
Wood, Tetrahedron Lett. 1994, 35, 5763– 5764; b) B. Das, P.
Madhusudhan, A. Kashinatham, Bioorg. Med. Chem. Lett. 1998,
8, 1403– 1406; c) See also W. D. Kingsbury, Tetrahedron Lett.
1988, 29, 6847 – 6850; B. Das, P. Madhusudhan, A. Kashinatham,
Tetrahedron Lett. 1998, 39, 431 – 432.
[9] a) I. Pendrak, S. Barney, R. Wittrock, D. M. Lambert, W. D.
Kingsbury, J. Org. Chem. 1994, 59, 2623– 2625; b) I. Pendrak, R.
Wittrock, W. D. Kingsbury, J. Org. Chem. 1995, 60, 2912 – 2915.
[10] Previous syntheses of mappicine ketone: L. Carles, K. Nar-
kunan, S. Penlou, L. Rousset, D. Bouchu, M. A. Ciufolini, J. Org.
Chem. 2002, 67, 4304 – 4308, and references therein.
1291, 1237 cmꢀ1; 1H NMR (CDCl3, 300 MHz): d = 6.68 (brs, 1H), 5.94
(s, 1H), 5.91–5.82 (m, 1H), 5.09–5.01 (m, 2H), 4.11 (t, J = 7.2 Hz, 2H),
3.55 (q, J = 7.4 Hz, 1H), 2.96 (t, J = 7.6 Hz, 2H), 2.21–2.11 (m, 2H),
1.73–1.55 (m, 2H), 0.85 ppm (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3,
75.5 MHz): d = 157.0, 141.0, 139.7, 138.3, 131.4, 115.0, 100.8, 48.5, 43.9,
30.7, 26.4, 22.3, 11.9 ppm; HRMS calcd for [C13H17NO2+H]+:
~
220.1338; found: 220.1345. 6: m.p. 76–778C; FTIR: n = 1641, 1581,
1537, 1184, 1009, 920, 824, 756, 680 cmꢀ1 1H NMR (CDCl3,
;
300 MHz): d = 5.95 (s, 1H), 5.86–5.74 (m, 1H), 5.09–4.98 (m, 2H),
4.10 (t, J = 7.3 Hz, 2H), 3.38 (q, J = 7.4, 1H), 2.99 (t, J = 7.7 Hz, 2H),
2.17–2.07 (m, 2H), 2.11 (s, 3H), 1.73–1.52 (m, 2H), 0.85 ppm (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3, 75.5 MHz): d = 162.4, 152.0, 145.9,
139.8, 122.6, 115.2, 99.8, 48.7, 47.0, 31.5, 27.0 , 21.5, 11.9, 11.7 ppm;
HRMS: calcd for [C14H19NO+H]+: 218.1545; found: 218.1558. 7a:
~
m.p. 74–758C; FTIR: n = 1646, 1570, 1541, 1314, 1209, 1168, 1050, 947,
834, 772, 665 cmꢀ1; H NMR (CDCl3, 300 MHz, major isomer): d =
1
5.86 (s, 1H), 5.25 (q, J = 6.9 Hz, 1H), 4.10 (t, J = 7.2 Hz, 2H), 2.99 (t,
5060
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[11] A. Padwa, S. M. Sheehan, C. S. Straub, J. Org. Chem. 1999, 64,
8648 – 8659.
[12] Two other examples: a) B. B. Jarvis, C. B. Anderson, J. Hetero-
cycl. Chem. 1983, 20, 471 – 473; b) K. C. Majumdar, A. K.
Kundu, P. Chatterjee, J. Chem. Res. Synop. 1995, 386 – 387.
[13] a) J. Andrieux, D. H. R. Barton, H. Patin, J. Chem. Soc. Perkin
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[14] a) E. J. Corey, H. E. Ensley, J. Am. Chem. Soc. 1975, 97, 6908 –
6909; b) W. Shen, C. A. Coburn, W. G. Bornmann, S. J. Dani-
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