Regioselective quinazolinone-directed ortho lithiation of quinazolinoylquinoline: Practical synthesis of naturally occurring human DNA topoisomerase I poison luotonin A and luotonins B and E

Article abstract of DOI:10.1021/jo040153v

A regioselective quinazolinone-directed ortho lithiation on an adjacent quinoline moiety has been used as a key step for a short, efficient, and practical synthesis of the human DNA topoisomerase I poison luotonin A and luotonins B and E. The quinazolinoylquinoline 5 on treatment with in situ-generated nonnucleophilic mesityllithium furnished the desired dilithiated intermediate 6, which on treatment with formaldehyde followed by Mitsunobu ring closure reaction gave luotonin A (1a) in very good yield. The reaction of dilithiated intermediate 6 with DMF directly furnished luotonin B (1b) in 81% yield. Luotonin B (1b) on methylation with p-TSA/methanol gave luotonin E (1c) in 82% yield.

Full text of DOI:10.1021/jo040153v

Regioselective Qu in a zolin on e-Dir ected
Or th o Lith ia tion of
Qu in a zolin oylqu in olin e: P r a ctica l
Syn th esis of Na tu r a lly Occu r r in g Hu m a n
DNA Top oisom er a se I P oison Lu oton in A
a n d Lu oton in s B a n d E†
Santosh B. Mhaske and Narshinha P. Argade*
Combi Chem-Bio Resource Center, Division of Organic
Chemistry (Synthesis), National Chemical Laboratory,
Pune 411 008, India
F IGURE 1. Lithiations on substituted quinazolinones.
argade@dalton.ncl.res.in
Received March 16, 2004
Abstr a ct: A regioselective quinazolinone-directed ortho
lithiation on an adjacent quinoline moiety has been used as
a key step for a short, efficient, and practical synthesis of
the human DNA topoisomerase I poison luotonin A and
luotonins B and E. The quinazolinoylquinoline 5 on treat-
ment with in situ-generated nonnucleophilic mesityllithium
furnished the desired dilithiated intermediate 6, which on
treatment with formaldehyde followed by Mitsunobu ring
closure reaction gave luotonin A (1a ) in very good yield. The
reaction of dilithiated intermediate 6 with DMF directly
furnished luotonin B (1b) in 81% yield. Luotonin B (1b) on
methylation with p-TSA/methanol gave luotonin E (1c) in
82% yield.
F IGURE 2. Naturally occurring luotonin alkaloids.
the 2-methyl-/alkyl-substituted quinazolinones are known
to undergo lithiation at the 2-alkyl position.6 However,
to the best of our knowledge, ortho lithiation of aryl and
heteroaryl substituents on quinazolinones have not been
reported in the literature and will be highly useful for
the introduction of ortho substituents for the facile
synthesis of several complex bioactive natural and un-
natural quinazolinones and related compounds (Figures
2 and 3).
Recently, Nomura and co-workers7 isolated six new
alkaloids, luotonins A-F, from aerial parts of the Chinese
medicinal plant Peganum nigellastrum (Figure 2). Luo-
tonin A is cytotoxic toward the murine leukemia P-388
cell line (IC50 1.8 µg/mL).7 Very recently, Hecht et al.8a
have demonstrated that despite the lack of lactone ring
functionality, luotonin A stabilizes the human DNA
topoisomerase I-DNA covalent binary complex and
mediates topoisomerase I-dependent cytotoxicity in intact
cells (IC50 5.7-12.6 µm/mL), like camptothecin and its
analogues8,9 (Figure 3). In a very short span of time (6
years), 11 syntheses of luotonin A have been reported
from different laboratories using a variety of elegant
The use of directing groups to facilitate lithiation,
followed by reaction of the organolithium reagents thus
obtained with electrophiles, has found a wide range of
applications in a variety of synthetic transformations.1
The process of directed ortho metalation using carboxa-
mides, carbamates, carboxylic acids, hydrazides, and
oxazolines as directing groups is one of the better known
methods for introducing various ortho substituents to the
aromatic nucleus.2 Although the great majority of studies
on ortho metalation have been carried out on benzene
rings,3 there are relatively few examples of the use of
group-directed lithiation of more complex heterocyclic
systems.3,4 Quinazolinones are known to undergo selec-
tive lithiation at the 2- and 8-positions5 (Figure 1), and
† NCL Communication No. 6661.
(1) (a) Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059. (b)
El-Hiti, G. A. Heterocycles 2000, 53, 1839. (c) Snieckus, V. Chem. Rev.
1990, 90, 879. (d) Beak, P.; Zajdel, W. J .; Reitz, D. B. Chem. Rev. 1984,
84, 471.
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Chem. 1994, 59, 4042. (b) Fisher, L. E.; Caroon, J . M.; J ahangir, S. S.
R.; Lundberg, S.; Muchowski, J . M. J . Org. Chem. 1993, 58, 3643. (c)
Sibi, M. P.; Snieckus, V. J . Org. Chem. 1983, 48, 1935. (d) Beak, P.;
Brown, R. A. J . Org. Chem. 1982, 47, 34. (e) Slocum, D. W.; J enning,
C. A. J . Org. Chem. 1976, 41, 3653.
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Collect. Czech. Chem. Commun. 1999, 64, 515. (b) Modesta, E. M.;
Avendano, C. J . Org. Chem. 1997, 62, 6424. (c) Rathman, T. L.; Sleevi,
M. C.; Krafft, M. E.; Wolfe, J . F. J . Org. Chem. 1980, 45, 2169. (d)
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1997, 46, 541. (b) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J .
Heterocycles 1999, 51, 1883. (c) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen,
Y.-J . Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1999, 41, 547;
Chem. Abstr. 2000, 132, 234276. (d) Ma, Z.-Z.; Hano, Y.; Nomura, T.;
Chen, Y.-J . Phytochemistry 2000, 53, 1075.
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M. J . Am. Chem. Soc. 2003, 125, 13628. (b) Ma, Z.-Z.; Hano, Y.;
Nomura, T.; Chen, Y.-J . Bioorg. Med. Chem. Lett. 2004, 14, 1193.
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124, 5774. (b) Blagg, B. S. J .; Boger, D. L. Tetrahedron 2002, 58, 6343.
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Nolan, J . M. Org. Lett. 2001, 3, 4255. (e) Toyota, M.; Komori, C.; Ihara,
M. J . Org. Chem. 2000, 65, 7110.
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(4) (a) Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron
2001, 57, 4489. (b) Fukuda, T.; Mine, Y.; Iwao, M. Tetrahedron 2001,
57, 975. (c) Matsuzomo, M.; Fukuda, T.; Iwao, M. Tetrahedron Lett.
2001, 42, 7621. (d) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo,
M. A. J . Org. Chem. 1996, 61, 647 and 656. (e) Siulnier, M. G.; Gribble,
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Asymmetry 1999, 10, 25.
10.1021/jo040153v CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
J . Org. Chem. 2004, 69, 4563-4566
4563

5 in quantitative yield. The 2-quinolinoquinazolinone 5
can undergo lithiation at carbons 8, 3′, and 8′.1 The key
issue of our present approach lies in the dilithiation of
the quinoline-quinazolinone skeleton with high specific-
ity. We reasoned that like carboxamide,14 the amide unit
in quinazolinones will be useful for performing directed
metalation reactions on adjacent 2-aryl/heteroaryl groups.
As expected, the first lithiation of compound 5 would take
place at the 3-position nitrogen atom of quinazolinone
ring, and the monolithiated species formed may direct
the second lithiation at the proximal 3′-position of the
quinoline ring. To perform the quinazolinone-directed
ortho lithiation at the 3′-position of the adjacent quinoline
nucleus with the assistance of the amide moiety in the
quinazolinone skeleton, we tried several reaction condi-
tions. The reaction of 5 with n-BuLi, s-BuLi, and t-BuLi
with or without TMEDA at 0 to -78 °C always led to
the formation of a complex mixture, which was probably
arising from the addition of alkyllithium to the carbon-
nitrogen double bonds1 in 5. The use of LDA also led to
the formation of complex mixtures. Finally, use of 2.2
equiv of in situ-generated nonnucleophilic mesityllithi-
um15 at -20 °C furnished the desired dilithiated species
6 via lithiation of the quinazolinone nitrogen at the
3-position as a first step followed by directed ortho
lithiation at the 3′-position. The reaction of dilithiated
intermediate 6 with formaldehyde exclusively yielded the
desired o-hydroxymethylquinolinoquinazolinone 7 in 86%
yield.16 The Mitsunobu cyclization of 7 furnished the
bioactive natural product luotonin A in 95% yield with
an overall insertion of a methylene group between the
3- and 3′-positions of 5. The reaction of dilithiated species
6 with N,N-dimethylformamide directly furnished luo-
tonin B in 81% yield via intermediate 8 with insertion of
a hydroxymethine group. The PCC oxidation of 7 in DCM
also furnished luotonin B in 61% yield. Luotonin B on
treatment with p-TSA/methanol provided luotonin E in
82% yield. The analytical and spectral data obtained for
all the luotonins were in complete agreement with the
reported data.7,10 We feel that dilithiated species such as
6 can be reacted with several types of electrophiles for
generation of a library of quinazolinone alkaloids.
F IGURE 3. Camptothecin and its analogs.
synthetic strategies.7,10 Out of 11 known syntheses, 10
multistep syntheses of linear pentacyclic luotonin A have
been completed using two suitable building blocks with
construction of ring B or D. Recently, Harayama et al.10k
completed the synthesis of luotonin A with construction
of middle ring C using a Pd-assisted biaryl coupling
reaction. To date, two syntheses of each luotonin C-E
and three syntheses of luotonins B and F are known.7,10
In continuation of our studies10f,11 on total synthesis of
bioactive quinazolinone alkaloids, we herein report the
first regioselective quinazolinone-directed ortho lithiation
of quinazolinoylquinoline 5 to provide a direct and easy
access to naturally occurring luotonins A, B, and E
(Scheme 1).
In conclusion, we have demonstrated a facile quinazoli-
none-directed regioselective ortho lithiation of quinazoli-
noylquinoline and applied it for the short, efficient, and
practical synthesis of naturally occurring promising anti-
cancer agents, luotonins A, B, and E. We feel that our
present approach is general in nature and that such a
regioselective, directed lithiation of aryl- and heteroaryl-
substituted quinazolinone systems will be highly useful
for the synthesis of a large number of desired complex
quinazolinone alkaloids, luotonin, and camptothecin-like
analogues for structure activity relationship studies.
Acylation of anthranilamide (2) with quinaldic acid
chloride12 in the presence of triethylamine furnished the
corresponding diamide 4 in 96% yield. The aqueous
potassium hydroxide-catalyzed dehydrative cyclization13
of diamide 4 in ethanol gave the 2-quinolinoquinazolinone
(10) (a) Wang, H.; Ganesan, A. Tetrahedron Lett. 1998, 39, 9097.
(b) Kelly, T. R.; Chamberland, S.; Silva, R. A. Tetrahedron Lett. 1999,
40, 2723. (c) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J . Heterocycles
1999, 51, 1593. (d) Molina, P.; Tarraga, A.; Gonzalez-Tejero, A.
Synthesis 2000, 1523. (e) Toyota, M.; Komori, C.; Ihara, M. Heterocycles
2002, 56, 101. (f) Mhaske, S. B.; Argade, N. P. Synthesis 2002, 323.
(g) Dallavalle, S.; Merlini, L. Tetrahedron Lett. 2002, 43, 1835. (h)
Yadav, J . S.; Reddy, B. V. S. Tetrahedron Lett. 2002, 43, 1905. (i)
Osborne, D.; Stevenson, P. J . Tetrahedron Lett. 2002, 43, 5469. (j) Lee,
E. S.; Park, J .-G.; J ahng, Y. Tetrahedron Lett. 2003, 44, 1883. (k)
Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.; Takeuchi, Y. Synlett
2003, 847. (l) Witt, A.; Bergman, J . Curr. Org. Chem. 2003, 7, 659.
(m) Toyota, M.; Komori, C.; Ihara, M. ARKIVOC 2003, 15.
Exp er im en ta l Section
Melting points are uncorrected. Column chromatographic
separations were carried out on ACME silica gel (60-120 mesh).
Commercially available anthranilamide, quinolin-2-carboxylic
(14) Nora de Souza, M. V.; Dodd, R. H. Heterocycles 1998, 47, 811.
(15) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29,
773 and refs cited therein.
(16) In both the natural and unnatural quinazolinones, the hydrogen
atom is present on the 3-position nitrogen atom and there is no
noticeable existence of the corresponding tautomeric structure with
the hydrogen atom on the 1-position nitrogen atom.10f,11,13
(11) (a) Mhaske, S. B.; Argade, N. P. J . Org. Chem. 2001, 66, 9038.
(b) Mhaske, S. B.; Argade, N. P. Tetrahedron 2004, 60, 3417.
(12) Norman, M. H.; Navas, F., III; Thompson, J . B.; Rigdon, G. C.
J . Med. Chem. 1996, 39, 4692.
(13) Witt, A.; Bergman, J . Tetrahedron 2000, 56, 7245.
4564 J . Org. Chem., Vol. 69, No. 13, 2004

SCHEME 1a
a
Key: (i) TEA (2 equiv), THF, rt, 3 h (96%). (ii) 5% aq KOH, EtOH, reflux, 5 min (98%). (iiia) mesityllithium (2.2 equiv), -78 °C, 30
min to -20 °C (gradually); (iiib) THF solution of HCHO (5 equiv), - 30 °C, 20 min, saturated aq solution of NH4Cl (86%); (iiic) DMF (5
equiv), - 20 °C, 30 min, saturated aq solution of NH4Cl (81%). (iv) PPh3 (1.3 equiv), DEAD (1.2 equiv), THF, rt, 1 h (95%). (v) PCC (1.2
equiv), powdered 4 Å molecular sieves, DCM, rt, 1 h (61%). (vi) p-TSA (5 equiv), MeOH, reflux, 3 h (82%).
acid, tert-butyllithium, 2-bromomesitylene, PCC, triphenylphos-
phine (TPP), and diethyl azodicarboxylate (DEAD) were used.
2-(2′-Am in oca r bon ylqu in olin yl)ben za m id e (4). 2-Quino-
linecarboxylic acid (2.08 g, 12.00 mmol) and potassium hydroxide
(692 mg, 12.36 mmol) were dissolved in distilled water (20 mL).
The water was removed in vacuo and the resulting white solid
residue was dried under high vacuum. To the resulting potas-
sium salt suspended in benzene (30 mL) was added oxalyl
chloride (1.26 mL, 14.40 mmol) dropwise at 5-10 °C. The
reaction mixture was allowed to warm to room temperature and
slowly heated to a gentle reflux. The resulting wine-red/black
solution was allowed to cool to room temperature and added
dropwise to a solution of anthranilamide (2) (1.63 g, 12.00 mmol)
and triethylamine (3.34 mL, 24.00 mmol) in chloroform (20 mL)
and stirred at room temperature for 3 h. The precipitated solid
was filtered, washed with ethanol to obtain compound 4, and
used for the next step without any further purification. The
analytically pure sample was obtained by recrystalization from
methanol.
146.7, 148.0, 148.9, 149.1, 161.3; IR (Nujol) νmax 3319, 1682, 1605
cm-1. Anal. Calcd for C17H11N3O: C, 74.71; H, 4.06; N, 15.38.
Found: C, 74.83; H, 4.17; N, 15.42.
2-(3′-H yd r oxym e t h yl-2′-q u in olin yl)-3H -q u in a zolin -4-
on e (7). To a solution of t-BuLi (1.5 M in pentane, 2.69 mL,
4.03 mmol) in THF (10 mL) at -78 °C was added a solution of
2-bromomesitylene (0.62 mL, 4.03 mmol) in THF (5 mL) over a
period of 10 min, and the reaction mixture was stirred for 1 h.
To the above reaction mixture was added a solution of quinazoli-
none 5 (500 mg, 1.83 mmol) in THF (30 mL), and then the
mixture was stirred for 30 min at -78 °C. The reaction mixture
turned deep brown in color on gradually warming to -20 °C. A
solution of HCHO (9.16 mmol) in THF (1 mL) (formaldehyde
solution in THF was prepared by thermal cracking of paraform-
aldehyde) was added to the reaction mixture, and stirring was
continued for an additional 20 min at - 20 °C. The reaction was
quenched with a saturated solution of NH4Cl, and the reaction
mixture was extracted with CHCl3 (25 mL x 3). The organic layer
was washed with water and brine and dried over Na2SO4.
Concentration of the organic layer in vacuo followed by silica
gel column chromatographic purification of the residue using a
mixture of ethyl acetate/methanol (9:1) as an eluant furnished
compound 7.
4: 3.35 g (96% yield); mp 269-271 °C (methanol); 1H NMR
(DMSO-d6, 200 MHz) δ 7.21 (t, J ) 8 Hz, 1H), 7.60 (t, J ) 8 Hz,
1H), 7.75 (t, J ) 8 Hz, 1H), 7.82-7.95 (m, 3H), 8.12 (d, J ) 8
Hz, 2H), 8.28 (d, J ) 8 Hz, 1H), 8.33 (bs, 1H), 8.64 (d, J ) 8 Hz,
1H), 8.82 (d, J ) 8 Hz, 1H), 13.55 (s, 1H); 13C NMR (DMSO-d6,
75 MHz) δ 118.7, 120.3, 121.4, 123.0, 128.2, 128.5, 128.8, 129.1,
129.4, 130.7, 132.1, 138.3, 138.9, 146.0, 150.0, 162.9, 170.6; IR
(Nujol) νmax 3360, 3290, 3192, 1688, 1649, 1616 cm-1. Anal. Calcd
for C17H13N3O2: C, 70.09; H, 4.50; N, 14.43. Found: C, 69.89;
H, 4.62; N, 14.39.
2-(2′-Qu in olin yl)-3H -q u in a zolin -4-on e (5). A mixture of
benzamide 4 (2.91 g, 10.00 mmol) in 5% aqueous NaOH (50 mL)
and EtOH (25 mL) was heated to reflux for 5 min. Ethanol was
removed in vacuo, and the aqueous layer was extracted with
chloroform (50 mL x 3). The organic layer was washed with
water and brine and dried over Na2SO4. Concentration of the
organic layer in vacuo followed by silica gel column chromato-
graphic purification of the residue using ethyl acetate as an
eluant gave pure 5.
7: 477 mg (86% yield); mp 212-214 °C (benzene); 1H NMR
(CDCl3, 300 MHz) δ 5.07 (d, J ) 6 Hz, 2H), 6.33 (t, J ) 6 Hz,
1H), 7.54-7.70 (m, 2H), 7.75-7.79 (m, 4H), 8.15 (d, J ) 6 Hz,
1H), 8.28 (s, 1H), 8.39 (d, J ) 6 Hz, 1H), 11.45 (bs, 1H); 13C
NMR (CDCl3, 75 MHz) δ 63.9, 122.5, 126.9, 127.5, 127.7, 128.2,
128.9, 129.0, 129.4, 130.7, 134.1, 134.8, 139.1, 145.9, 146.5, 147.9,
150.1, 160.9; IR (CHCl3) νmax 3747, 3304, 1682, 1638, 1605 cm-1
.
Anal. Calcd for C18H13N3O2: C, 71.28; H, 4.32; N, 13.85. Found:
C, 71.17; H, 4.43; N, 13.96.
Qu in o[2′,3′:3,4]pyr r olo[2,1-b]qu in azolin -11(13H)-on e (Lu -
ot on in A, 1a ). To the solution of compound 7 (200 mg, 0.66
mmol) and TPP (225 mg, 0.86 mmol) in THF (10 mL) was added
solution of DEAD (0.144 mL, 0.79 mmol) in THF (5 mL) dropwise
over a period of 10 min at room temperature and further stirred
for 1 h. The reaction mixture was concentrated in vacuo. The
column chromatographic purification of the residue using ethyl
acetate as an eluant furnished luotonin A (1a ).
5: 2.68 g (98% yield); mp 229-231 °C (ethyl acetate); 1H NMR
(CDCl3, 200 MHz) δ 7.45-7.65 (m, 2H), 7.65-7.90 (m, 4H), 8.12
(d, J ) 8 Hz, 1H), 8.34 (t, J ) 8 Hz, 2H), 8.61 (d, J ) 8 Hz, 1H),
11.19 (bs, 1H); 13C NMR (CDCl3, 75 MHz) δ 118.4, 122.6, 126.7,
127.4, 127.6, 128.2 (2 carbons), 129.2, 129.6, 130.4, 134.4, 137.5,
1a : 179 mg (95% yield); mp 284-285 °C (ethyl acetate) (lit.10k
mp 283-285 °C); 1H NMR (CDCl3, 500 MHz) δ 5.34 (s, 2H), 7.58
(t, J ) 10 Hz, 1H), 7.68 (t, J ) 10 Hz, 1H), 7.84 (t, J ) 10 Hz,
J . Org. Chem, Vol. 69, No. 13, 2004 4565

1H), 7.86 (t, J ) 10 Hz, 1H), 7.94 (d, J ) 10 Hz, 1H), 8.12 (d, J
) 10 Hz, 1H), 8.43 (d, J ) 10 Hz, 1H), 8.44 (s, 1H), 8.47 (d, J )
10 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 47.3, 121.3, 126.4,
127.4, 127.9, 128.5, 128.8 (2 carbons), 129.4, 130.68, 130.71,
131.5, 134.6, 149.35, 149.42, 151.2, 152.5, 160.7; IR (Nujol) νmax
1672, 1628, 1607, 1466 cm-1. Anal. Calcd for C18H11N3O: C,
75.78; H, 3.89; N, 14.73. Found: C, 75.89; H, 3.98; N, 14.61.
Qu in o[2′,3′:3,4]p yr r olo[2,1-b]qu in a zolin -13-h yd r oxy-11-
on e (Lu oton in B, 1b). (A) To a solution of t-BuLi (1.5 M in
pentane, 2.69 mL, 4.03 mmol) in THF (10 mL) at -78 °C was
added a solution of 2-bromomesitylene (0.62 mL, 4.03 mmol) in
THF (5 mL) over a period of 10 min, and the reaction mixture
was stirred for 1 h. To the above reaction mixture was added a
solution of quinazolinone 5 (500 mg, 1.83 mmol) in THF (30 mL),
and then the mixture was stirred for 30 min at -78 °C. The
reaction mixture turned deep brown in color on gradually
warming -20 °C. A solution of DMF (0.71 mL, 9.16 mmol) in
THF (1 mL) was added to the reaction mixture, and stirring was
continued for an additional 30 min at -20 °C. The reaction was
quenched with a saturated solution of NH4Cl, and the reaction
mixture was extracted with CHCl3 (25 mL x 3). The organic layer
was washed with water and brine and dried over Na2SO4.
Concentration of the organic layer in vacuo followed by silica
gel column chromatographic purification of the residue using a
mixture of ethyl acetate/methanol (9:1) as an eluant furnished
luotonin B (1b) (447 mg, 81% yield).
Hz, 1H), 8.41 (d, J ) 10 Hz, 1H), 8.49 (d, J ) 10 Hz, 1H), 8.59
(s, 1H); 13C NMR (CDCl3, 125 MHz) δ 80.9, 121.9, 126.5, 127.9,
128.6, 128.8, 128.9, 129.2, 130.9, 131.0, 131.4, 133.3, 135.1, 149.5,
150.3, 150.4, 150.9, 161.6; IR (CHCl3) νmax 3238, 1686, 1636, 1609
cm-1. Anal. Calcd for C18H11N3O2: C, 71.75; H, 3.68; N, 13.95.
Found: C, 71.66; H, 3.51; N, 14.01.
Qu in o[2′,3′:3,4]p yr r olo[2,1-b]qu in a zolin -13-m eth oxy-11-
on e (Lu oton in E, 1c). The solution of Luotonin B (1b) (350
mg, 1.16 mmol) and p-toluenesulfonic acid (1.11 g, 5.81 mmol)
in methanol (20 mL) was refluxed for 3 h. The reaction mixture
was concentrated in vacuo, and the residue was dissolved in
ethyl acetate (50 mL) and washed with an aqueous solution of
NaHCO3, water, and brine. The ethyl acetate layer was dried
over Na2SO4. Concentration of the organic layer in vacuo
followed by silica gel column chromatographic purification of the
residue using a mixture of ethyl acetate/petroleum ether (1:1)
as an eluant furnished luotonin E (1c).
1c: 300 mg (82% yield); mp 225-227 °C (benzene) (lit.7b mp
222-225 °C); 1H NMR (CDCl3, 500 MHz) δ 3.60 (s, 3H), 6.94 (s,
1H), 7.59 (t, J ) 10 Hz, 1H), 7.71 (t, J ) 10 Hz, 1H), 7.85 (t, J
) 10 Hz, 1H), 7.88 (t, J ) 10 Hz, 1H), 7.99 (d, J ) 10 Hz, 1H),
8.09 (d, J ) 10 Hz, 1H), 8.43 (d, J ) 10 Hz, 1H), 8.48 (d, J ) 10
Hz, 1H), 8.52 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 56.3, 87.0,
122.3, 126.9, 127.9, 128.5, 128.7, 128.88, 128.94, 130.1, 130.8,
131.4, 133.2, 134.9, 149.0, 150.37, 150.43, 151.4, 160.8; IR
(CHCl3) νmax 1686, 1638, 1607 cm-1. Anal. Calcd for C19H13N3O2:
C, 72.37; H, 4.15; N, 13.33. Found: C, 72.43; H, 4.19; N, 13.51.
(B) To the reaction mixture containing powdered 4 Å molec-
ular sieves (200 mg) and compound 7 (100 mg, 0.33 mmol) in
DCM (20 mL) was added PCC (85 mg, 0.40 mmol) in two
portions, and the reaction mixture was stirred for 1 h at room
temperature. The reaction mixture was then diluted with ether
(20 mL) and stirred for another 15 min. The reaction mixture
was then filtered through a bed of celite and silica gel and
washed with ether (15 mL x 3). The filtrate was concentrated
under vacuum, and the residue was purified by using a mixture
of ethyl acetate/methanol (9:1) as an eluant to furnish luotonin
B (1b) (61 mg, 61% yield).
Ack n ow led gm en t. S.B.M. thanks CSIR, New Delhi,
for the award of a research fellowship. N.P.A. thanks
Department of Science and Technology, New Delhi, for
financial support. We thank Dr. K. N. Ganesh, Head,
Division of Organic Chemistry (Synthesis), for constant
encouragement.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of 4, 5, 7, and 1a -c. This material is available
free of charge via the Internet at http://pubs.acs.org.
1b: mp 274-276 °C (ethyl acetate) (lit.10k mp 271-274 °C);
1H NMR (CDCl3, 500 MHz) δ 5.08 (bs, 1H), 7.14 (s, 1H), 7.61 (t,
J ) 10 Hz, 1H), 7.73 (t, J ) 10 Hz, 1H), 7.88 (t, J ) 10 Hz, 1H),
7.90 (d, J ) 10 Hz, 1H), 8.02 (d, J ) 10 Hz, 1H), 8.11 (d, J ) 10
J O040153V
4566 J . Org. Chem., Vol. 69, No. 13, 2004