Total synthesis of proposed auranthine

Article abstract of DOI:10.1021/jo100400z

Starting from CBz-protected glutamic anhydride and Boc-protected o-aminobenzyl amine, the first total synthesis of proposed structure of auranthine has been reported. An intramolecular aza-Wittig reaction involving a lactam carbonyl group that delivered the diazepine core unit was the key step in the synthesis.

Full text of DOI:10.1021/jo100400z

pubs.acs.org/joc
Total Synthesis of Proposed Auranthine
Umesh A. Kshirsagar,† Vedavati G. Puranik,‡ and
Narshinha P. Argade*,†
†Division of Organic Chemistry and ‡Centre for Material
Characterization, National Chemical Laboratory (CSIR),
Pune 411 008, India
np.argade@ncl.res.in
Received December 18, 2009
FIGURE 1. Auranthine, (-)-asperlicin, and unstable imide inter-
mediate.
Auranthine is a structurally unique quinazoline alkaloid that
contains an unusually positioned diazepine moiety, a feature
that has largely rendered its total synthesis a challenge to
date.5 On the basis of our continuing interest in the chemistry
of cyclic anhydrides and their applications in natural product
synthesis,6 we herein report a facile synthesis of the target
compound (Scheme 1).
Starting the synthesis of auranthine (1) from CBz-pro-
tected (S)-glutamic anhydride 4, we could foresee that our
major challenges would lie in the following: (i) regioselective
nucleophilic ring-opening of the unsymmetrical anhydride 4
with an aromatic amine, (ii) intramolecular cyclization reac-
tion involving the lactam carbonyl using an aromatic amine/
azide that would deliver the diazepine ring system, and (iii)
the smooth pool of enantiomeric purity throughout the
synthesis. As per the literature reports,7 the nucleophilic
regioselective ring-opening of an anhydride 4 in DMSO with
the amine 3 exclusively furnished the expected anilic acid 5 in
92% yield. Carrying out the reaction in a polar solvent such
as DMSO brings about intermolecular hydrogen bonding of
the hydrogen atom on an amide nitrogen with the solvent,
rather than the five-membered intramolecular hydrogen
bonding with an adjacent carbonyl group of anhydride 4.
The incoming nucleophile, the primary aromatic amine, thus
exclusively attacks on an unhindered carbonyl group of
anhydride 4 to form the product 5. Diazomethane esterifica-
tion of anilic acid 5 provided the methyl ester 6 in 97% yield.
Cleaving the Boc-protection in 6 resulted in instantaneous
intramolcular dehydrative cyclization to 7, which upon an
Starting from CBz-protected glutamic anhydride and
Boc-protected o-aminobenzyl amine, the first total synthe-
sis of proposed structure of auranthine has been reported.
An intramolecular aza-Wittig reaction involving a lactam
carbonyl group that delivered the diazepine core unit was
the key step in the synthesis.
Quinazolinone is a building block for a large number of
structurally diverse alkaloids boasting a wide range of
biological activities, several of which are now in clinical
use.1 In the course of isolating nephrotoxins, a new fungal
metabolite, (-)-auranthine, was isolated from Penicillium
aurantiogriseum but the configuration at the asymmetric
center was not determined.2 Structurally, auranthine bears
a close resemblance to the novel microbial metabolite (-)-
asperlicin, a potent neuropeptide antagonist3 (Figure 1). A
look at the structure of auranthine reveals that (-)-glutamic
acid and anthranilamide could be potential building blocks
for constructing this structurally intriguing alkaloid. How-
ever, studies on the total synthesis of 1 by Bergman and co-
workers indicate that the instability of the potential inter-
mediate 2 and the presence of an active methylene group in
the product were the major impediments in accessing it.4
(5) (a) Tseng, M.-C.; Lai, C.-Y.; Chu, Y.-W.; Chu, Y.-H. Chem. Commun.
2009, 445 and references cited therein. (b) Liu, J.-F.; Kaselj, M.; Isome, Y.;
Chapnick, J.; Zhang, B.; Bi, G.; Yohannes, D.; Yu, L.; Baldino, C. M. J. Org.
Chem. 2005, 70, 10488 and references cited therein. (c) Witt, A.; Bergman, J.
J. Org. Chem. 2001, 66, 2784 and references cited therein.
(6) (a) Kshirsagar, U. A.; Argade, N. P. Tetrahedron 2009, 65, 5244 and
references cited therein. (b) Wakchaure, P. B.; Puranik, V. G.; Argade, N. P.
Tetrahedron: Asymmetry 2009, 20, 220 and references cited therein.
(c) Wakchaure, P. B.; Easwar, S.; Puranik, V. G.; Argade, N. P. Tetrahedron
2008, 64, 1786 and references cited therein. (d) Haval, K. P.; Argade, N. P.
J. Org. Chem. 2008, 73, 6936 and references cited therein. (e) Patel, R. M.;
Argade, N. P. J. Org. Chem. 2007, 72, 4900 and references cited therein.
(7) (a) Huang, X.; Luo, X.; Roupioz, Y.; Keillor, J. W. J. Org. Chem.
1997, 62, 8821. (b) Ksander, G. M.; Yuan, A. M.; Diefenbacher, C. G.;
Stanton, J. L. J. Med. Chem. 1985, 26, 1606. (c) Bergmann, M.; Zervas, L.;
Salzmann, L. Chem. Ber. 1933, 66, 1288.
(1) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009,
48, 348 and references cited therein. (b) Roy, A. D.; Subramanian, A.; Roy,
R. J. Org. Chem. 2006, 71, 382 and references cited therein. (c) Mhaske, S. B.;
Argade, N. P. Tetrahedron 2006, 62, 9787 and references cited therein.
(2) Yeulet, S. E.; Mantle, P. G.; Bilton, J. N.; Rzepa, H. S.; Sheppard,
R. N. J. Chem. Soc., Perkin Trans. 1 1986, 1891.
(3) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417.
(4) Witt, A.; Gustavsson, A.; Bergman, J. J. Heterocycl. Chem. 2003, 40,
29.
2702 J. Org. Chem. 2010, 75, 2702–2705
Published on Web 03/22/2010
DOI: 10.1021/jo100400z
r
2010 American Chemical Society

Kshirsagar et al.
JOCNote
SCHEME 1. Synthesis of Proposed Auranthine via an Intramolecular Aza-Wittig Reaction with the Lactam Carbonyl Groupa
aReagents, conditions, and yields: (i) CH3SOCH3, 25 °C, 30 min (92%); (ii) CH2N2, Et2O, 0 to 25 °C, 30 min (97%); (iii) (a) CF3COOH, CH2Cl2, 25 °C,
8 h, (b) dry toluene, reflux, 8 h (78%); (iv) 30% HBr in AcOH, 25 °C, 2 h (82%); (v) o-azidobenzoic acid, N-ethyl-N0-(3-dimethylaminopropyl)carbodimide
hydrochloride (EDCI), CH2Cl2, 25 °C, 18 h (89%); (vi) sealed tube, n-Bu3P, dry p-xylene, 25 °C, 1 h, then 200 °C, 48 h (74%); (vii) KMnO4, dry acetone,
reflux, 3 h (79%).
immediate refluxing in toluene effected another intramole-
cular cyclization to afford the lactam 8 in 78% yield.6a
Compound 8 on treatment with hydrobromic acid gave the
amine 9, which was used in the next step without further
purification. The EDCI driven dehydrative coupling be-
tween the amine 9 and o-azidobenzoic acid provided the
azido compound 10 in 89% yield. We reduced the azide
group in compound 10 to the corresponding amine using
catalytic hydrogenation and attempted an intramolecular
dehydrative cyclization under a variety of reaction condi-
tions including microwave irradiation, but all our attempts
met with failure. At this stage, we decided to use the
intramolecular aza-Wittig reaction for the transformation
of azide 10 to the potential auranthine precursor 11.8-10
The intramolecular aza-Wittig reaction with triphenylpho-
sphine in refluxing p-xylene, however, was not successful.
Instead, using tributylphosphine-driven aza-Wittig reaction
in refluxing p-xylene gave the required product 11, but in
only 4-5% yield, after 48 h. We were delighted to find that
the same reaction in a sealed tube at 200 °C for 48 h
regioselectively furnished the desired auranthine precursor
11 in 74% yield, however, unfortunately, with the nearly
complete racemization (by specific rotation). The structure
of aza-Wittig product 11 was unambiguously confirmed on
the basis of X-ray crystallographic data. The higher reaction
temperature and the longer reaction time were essential for
the formation of compound 11 in an acceptable yield for two
reasons, viz. (i) the stabilized nitrogen ylide formed is in
conjugation with a suitably ortho-substituted amide carbo-
nyl group and (ii) the nitrogen ylide has to react with the less
reactive lactam carbonyl group to form the seven-membered
cyclized product. Herein, in the conversion of 10 to 11, the
formation of a corresponding four-membered betaine-type
intermediate must be a high-energy process. Hence, during
the course of the reaction, the starting material and/or
product suffer from a thermalracemizationprocess.11 Finally,
the KMnO4-induced12 chemoselective oxidation of the
benzylic methylene group of quinazolinopyridobenzodiaze-
pine 11 to the corresponding carbonyl group, keeping the
allylic methylene group intact, provided auranthine (1), in
79% yield. Starting from anhydride 4, the overall yield of
auranthine (1) in seven steps was 30%. The analytical and
spectral data obtained for tetrahydroquinazolinopyridoben-
zodiazepindione 1 were in complete agreement with those of
the assigned structure.2 Finally, the structure of synthetic
auranthine was unequivocally confirmed on the basis of
1
X-ray crystallographic data. However, the H NMR spec-
trum of synthetic 1 in benzene-d6 was not in agreement with
the 1H NMR spectrum of natural product.2 We were unable
to obtain a 13C NMR spectrum of the synthetic auranthine in
benzene-d6 for comparison due to solubility issues.13 Hence
what we have accomplished is the synthesis of the proposed
structure of auranthine.
In summary, starting from a cyclic anhydride we have
accomplished an efficient total synthesis of the proposed
(8) (a) Hajos, G.; Nagy, I. Curr. Org. Chem. 2008, 12, 39 and references
cited therein. (b) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; Santos,
J. M. Tetrahedron 2007, 63, 523 and references cited therein. (c) Eguchi, S.
ARKIVOC 2005, 2, 98 and references cited therein. (d) Fresneda, P. M.;
Molina, P. Synlett 2004, 1 and references cited therein. (e) Molina, P.;
Vilaplana, M. J. Synthesis 1994, 1197 and references cited therein.
(9) To the best of our knowledge until today only one aza-Wittig reaction
with an amide carbonyl group is reported to design the seven-membered
diazepine nucleus, wherein in the starting material the lone pair on an amide
nitrogen atom is in cross conjugation with an ortho-substituted ester unit.10
(10) Kurita, J.; Iwata, T.; Yasuike, S.; Tsuchiya, T. J. Chem. Soc., Chem.
Commun. 1992, 81 and 970.
ꢀ
(11) (a) Goujon, J.-Y.; Zammattio, F.; Chretien, J.-M.; Beaudet, I.
Tetrahedron 2004, 60, 4037. (b) Martins, J. E. D.; Alifantes, J.; Pohlmann,
A. R.; Costa, V. E. U. Tetrahedron: Asymmetry 2003, 14, 683. (c) Paquette,
L. A.; Branan, B. M.; Friedrich, D.; Edmondson, S. D.; Rogers, R. D. J. Am.
Chem. Soc. 1994, 116, 506. (d) Andrews, L. J.; Hardwicke, J. E. J. Am. Chem.
Soc. 1952, 74, 3582.
(12) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416.
(13) The solubility of synthetic auranthine in benzene-d6 was very weak
(<1 mg/mL), hence we were unable to record the 13C NMR spectrum of 1
even after overnight scanning.
J. Org. Chem. Vol. 75, No. 8, 2010 2703

Kshirsagar et al.
JOCNote
structure of auranthine. The intramolecular aza-Wittig reac-
tion involving a lactam carbonyl group is the key step in
the present synthesis. We strongly believe that the present
approach will be useful to design several desired bioactive
natural and unnatural diazepine analogues and congeners.
Na2SO4. The solvent was removed under reduced pressure, the
resulting crude product was immediately dissolved in dry toluene
(50 mL), and the reaction mixture was refluxed for 8 h under argon
atmosphere. The reaction mixture was allowed to cool to room
temperature and the solvent was removed in vacuo. Silica gel column
chromatographic purification of the resulting residue with petroleum
ether-ethyl acetate (1:1) as an eluent afforded the pure 8 as an
off-white solid (2.18 g, 78%). Mp 145-147 °C; [R]25D -38.7 (c 0.82
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.83 (dq, J = 8 and 4 Hz,
1H), 2.45-2.62(brm, 1H), 2.87(dt, J= 8 and 2 Hz, 1H), 2.97-3.05
(m, 1H), 4.25-4.40 (br m, 1H), 4.73 (d, J= 16 Hz, 1H), 5.05 (d, J=
16 Hz, 1H), 5.14 (s, 2H), 5.75 (br s, 1H), 7.05 (d, J = 8 Hz, 1H),
7.10-7.40(m,8H);13CNMR(CDCl3, 100 MHz) δ25.0(CH2),30.1
(CH2), 42.9 (CH2), 53.0 (CH), 67.1 (CH2), 121.6 (C), 125.5 (CH),
125.7 (CH), 126.9 (CH), 128.1 (2 CH), 128.2 (CH), 128.5 (2 CH),
128.7 (CH), 136.1 (C), 139.0 (C), 150.0 (C), 156.0 (C), 169.2 (C);
ESIMS (m/z) 350 [M þ H]þ, 372 [M þ Na]þ; HRMS (EI) calcd for
C20H19N3O3 349.1426, found 349.1420; IR (Nujol) vmax 3265, 1726,
1679 cm-1. Anal. Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03.
Found: C, 68.46; H, 5.44; N, 11.70.
Experimental Section
(S)-2-(Benzyloxycarbonylamino)-5-(2-((tert-butoxycarbonyl-
amino)methyl)phenylamino)-5-oxopentanoic Acid (5). To a stir-
red solution of anhydride 4 (5.00 g, 19.01 mmol) in DMSO
(25 mL) was added a solution of tert-butyl 2-aminobenzylcar-
bamate 3 (4.60 g, 22.91 mmol) in DMSO (10 mL) in a dropwise
fashion over a period of 5 min and the resulting reaction
mixture was further stirred at room temperature for 25 min.
The reaction mixture was diluted with ethyl acetate (200 mL)
and washed with brine, 1 N HCl, water, and again with brine
and the organic layer was dried over Na2SO4. Concentration
of the organic layer in vacuo followed by silica gel column
chromatographic purification of residue with petroleum ether-
(S)-8-Amino-7,8-dihydro-6H-pyrido[2,1-b]quinazolin-9(11H)-
one (9). Compound 8 (1.00 g, 2.87 mmol) was stirred in 30% HBr
in AcOH (10 mL) at room temperature for 2 h. The reaction
mixture was concentrated under reduced pressure and the
resulting hydrobromide salt was neutralized with a saturated
solution of NaHCO3. The reaction mixture was extracted with
DCM (3 ꢀ 100 mL) and the organic layer was washed with brine
and dried over Na2SO4. Concentration of organic layer in vacuo
afforded the amine 9 as an off-white solid (0.51 g, 82%). The
amine 9 was immediately used for the next step without any
purification. Mp 115-118 °C; [R]25D -27.1 (c 0.42 MeOH); 1H
NMR (CDCl3, 200 MHz) δ 1.70-1.95 (m, 3H), 2.20-2.37 (m,
1H), 2.68-3.08 (m, 2H), 3.58 (dd, J = 12 and 4 Hz, 1H), 4.92 (q,
J = 16 Hz, 2H), 7.00-7.32 (m, 4H); 13C NMR (CDCl3,
50 MHz) δ 26.7 (CH2), 30.5 (CH2), 42.7 (CH2), 52.9 (CH),
121.8 (C), 125.4 (CH), 125.7 (CH), 126.7 (CH), 128.6 (CH),
139.0 (C), 151.2 (C), 173.3 (C); ESIMS (m/z) 216 [M þ H]þ;
HRMS (EI) calcd for C12H13N3O 215.1059, found 215.1073; IR
ethyl acetate (3:7) as an eluent afforded the acid 5 as a white solid
1
(8.49 g, 92%). Mp 93-95 °C; [R]25 þ14.6 (c 0.90 CHCl3); H
D
NMR (CDCl3, 200 MHz) δ 1.39 (s, 9H), 2.19 (br s, 2H), 2.61 (br s,
2H), 4.20 (br d, J = 4 Hz, 2H), 4.39 (br d, J = 2 Hz, 1H), 4.68 (br
s, 1H), 5.06 (s, 2H), 5.27 (br quintet, J = 4 Hz, 1H), 6.10 (br d,
J = 4 Hz, 1H), 6.95-7.45 (m, 8H), 7.95 (br d, J = 6 Hz, 1H), 9.70
1
(br s, 1H); H NMR (CD3OD, 200 MHz) δ 1.41 (s, 9H), 2.03
(sextet, J = 8 Hz, 1H), 2.32 (sextet, J = 8 Hz, 1H), 2.58 (t, J =
8 Hz, 2H), 4.17(s,2H), 4.24 (dd, J = 8 and4 Hz, 1H), 5.08(s, 2H),
7.07-7.40 (m, 8H), 7.58 (d, J = 8 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 28.3 (3 CH3), 29.7 (CH2), 33.1 (CH2), 41.4 (CH2),
53.9 (CH), 66.9 (CH2), 80.7 (C), 123.6 (CH), 124.9 (CH), 127.8
(CH), 128.0 (2 CH), 128.4 (2 CH), 128.7 (CH), 129.7 (C), 130.2
(CH), 135.9 (C), 136.3 (C), 156.4 (C), 157.3 (C), 172.4 (C), 174.9
(C); ESIMS (m/z) 486 [M þ H]þ, 508 [M þ Na]þ, 524 [M þ K]þ;
IR (Nujol) vmax 3330, 1691, 1660 cm-1. Anal. Calcd for
C25H31N3O7: C, 61.84; H, 6.44; N, 8.65. Found: C, 61.96; H,
6.44; N, 8.97.
(neat) vmax 3447, 3358, 1690, 1665, 1620 cm-1
.
(S)-Methyl 2-(Benzyloxycarbonylamino)-5-(2-((tert-butoxy-
carbonylamino)methyl)phenylamino)-5-oxopentanoate (6). An ether
solution of diazomethane was added dropwise to a suspension of
acid 5 (5.00 g, 10.30 mmol) in diethyl ether (50 mL) at 0 °C until the
acid dissolved with persistence of light yellow color and the reaction
mixture was stirred at room temperature for 30 min. The solvent
was removed under reduced pressure and silica gel column chro-
matographic purification of the resulting residue with petroleum
ether-ethyl acetate (6:4) as an eluent afforded the pure ester 6 as a
(S)-2-Azido-N-(9-oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]-
quinazolin-8-yl)benzamide (10). To the stirred mixture of
o-azidobenzoic acid (0.38 g, 2.32 mmol) and EDCI (0.54 g,
2.79 mmol) in DCM (20 mL) was added amine 9 (0.50 g, 2.32
mmol) in DCM (15 mL) and the reaction mixture was further
stirred at room temperature for 18 h. The reaction mixture was
diluted with DCM (100 mL) and washed with water, a satu-
rated solution of NaHCO3, and brine and dried over Na2SO4.
The solvent was removed under reduced pressure and silica gel
column chromatographic purification of the resulting residue
with petroleum ether-ethyl acetate (3:7) as an eluent furnished
the pure azide 10 as an off-white solid (0.76 g, 89%). Mp
white solid (4.99 g, 97%). Mp 71-73 °C; [R]25 þ13.2 (c 1.64
D
CHCl3);1HNMR(CDCl3, 200 MHz) δ1.41(s, 9H), 2.00-2.40 (m,
2H), 2.58 (t, J = 8 Hz, 2H), 3.73 (s, 3H), 4.24 (br s, 2H), 4.44 (br q,
J = 6 Hz, 1H), 5.09 (s, 2H), 5.15 (m, 1H), 5.85 (br d, J = 8 Hz, 1H),
7.04 (t, J = 8 Hz, 1H), 7.13 (dt, J = 8 and 2 Hz, 1H), 7.17-7.42 (m,
6H), 8.15 (d, J = 8 Hz, 1H), 9.54 (br s, 1H); 13C NMR (CDCl3,
50 MHz) δ 27.8 (CH2), 28.2 (3 CH3), 33.1 (CH2), 41.5 (CH2), 52.4
(CH3), 53.7 (CH), 66.9 (CH2), 80.6 (C), 122.6 (CH), 124.2 (CH),
128.0 (2 CH), 128.4 (2 CH), 128.70 (C), 128.73 (CH), 128.8 (CH),
130.3 (CH), 136.2 (C), 136.5 (C), 156.2 (C), 157.3 (C), 171.0 (C),
172.5 (C); ESIMS (m/z) 500 [M þ H]þ, 522 [M þ Na]þ, 538
[M þ K]þ;IR (CHCl3) vmax 3330, 1715, 1683 cm-1. Anal. Calcd for
C26H33N3O7: C, 62.51; H, 6.66; N, 8.41. Found: C, 62.20; H, 6.96;
N, 8.36.
1
177-178 °C; [R]25 þ55.6 (c 0.50 CHCl3); H NMR (CDCl3,
200 MHz) δ 1.70-D2.10 (m, 1H), 2.65-2.80 (m, 1H), 2.85-3.18
(m, 2H), 4.76 (dd, J = 18 and 6 Hz, 1H), 4.80 (d, J = 16 Hz,
1H), 5.12 (d, J = 16 Hz, 1H), 7.04-7.34 (m, 6H), 7.55 (dt, J =
8 and 2 Hz, 1H), 8.20 (dd, J = 8 and 2 Hz, 1H), 8.53 (br d, J =
4 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ 24.7 (CH2), 30.2
(CH2), 42.9 (CH2), 52.6 (CH), 118.5 (CH), 121.6 (C), 124.0 (C),
125.2 (CH), 125.5 (CH), 125.7 (CH), 126.9 (CH), 128.7 (CH),
132.3 (CH), 132.8 (CH), 137.5 (C), 139.0 (C), 150.3 (C), 164.5
(C), 169.6 (C); ESIMS (m/z) 383 [M þ Na]þ; HRMS (EI) calcd
for C19H16N6O2 360.1335, found 360.1338; IR (Nujol) vmax
(S)-Benzyl 9-Oxo-7,8,9,11-tetrahydro-6H-pyrido[2,1-b]quinazolin-
8-ylcarbamate (8). To a stirred solution of ester 6 (4.00 g, 8.02 mmol)
in dry DCM (50 mL) was added trifluoroacetic acid (5.95 mL, 10.00
mmol) and the reaction mixture was stirred at room temperature
for 8 h. The reaction mixture was basified slowly with a saturated
solution of NaHCO3 and extracted with DCM (3 ꢀ 100 mL). The
combined organic layer was washed with brine and dried over
3298, 2127, 1697, 1657, 1620 cm-1
.
6,7,7a,8-Tetrahydro-16H-quinazolino[30,20:1,6]pyrido[2,3-b]-
[1,4]benzodiazepin-9-one (11). To a stirred mixture of com-
pound 10 (0.40 g, 1.11 mmol) in dry p-xylene (5 mL) was
added n-Bu3P (0.33 mL, 1.33 mmol) at room temperature
under argon atmosphere in a sealed tube and the stirring was
2704 J. Org. Chem. Vol. 75, No. 8, 2010

Kshirsagar et al.
JOCNote
continued for 1 h. The reaction mixture was heated at 200 °C in
a sealed tube for 48 h and then allowed to cool to room
temperature. Precipitated product was filtered off and washed
with n-hexane and then recrystalization from DCM afforded
(br s, 1H), 6.95 (t, J = 10 Hz, 2H), 7.07-7.25 (m, 2H), 7.34 (d, J =
10 Hz, 1H), 7.61 (d, J = 10 Hz, 1H), 8.34 (d, J = 10 Hz, 1H), 8.39
(d, J = 10 Hz, 1H); 1H NMR (CDCl3, 400 MHz) δ 2.00 (dq, J =
12 and 4 Hz, 1H), 2.59-2.68 (m, 1H), 2.73 (dt, J = 12, and 4 Hz,
1H), 3.16 (ddd, J = 16, 4, and 4 Hz, 1H), 4.11-4.19 (m, 1H), 7.19
(br d, J = 4 Hz, 1H), 7.38 (t, J = 8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H),
7.50 (t, J = 8 Hz, 1H), 7.60 (dt, J = 8 and 4 Hz, 1H), 7.64 (d, J =
8 Hz, 1H), 7.79 (t, J = 8 Hz, 1H), 8.09 (d, J = 8 Hz, 1H), 8.33 (d,
J = 8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.3 (CH2), 30.2
(CH2), 48.8 (CH), 122.0 (C), 126.0 (C), 126.89 (CH), 126.94 (CH),
127.46 (CH), 127.54 (CH), 128.2 (CH), 130.7 (CH), 132.5 (CH),
135.2 (CH), 143.4 (C), 145.6 (C), 151.2 (C), 152.9 (C), 159.6 (C),
168.6 (C); ESIMS (m/z) 331 [M þ H]þ, 353 [M þ Na]þ, 369
[M þ K]þ; IR (Nujol) vmax 3400, 1716, 1664, 1601 cm-1. Anal.
Calcd for C19H14N4O2: C, 69.08; H, 4.27; N, 16.96. Found: C,
69.02; H, 4.27; N, 16.87.
1
11 as an off-white solid (0.26 g, 74%). Mp 273-275 °C; H
NMR (CDCl3, 200 MHz) δ 1.75-2.14 (m, 1H), 2.15-2.43 (m,
1H), 2.70-2.90 (m, 1H), 3.00-3.20 (m, 1H), 4.07 (q, J = 4 Hz,
1H), 4.88 (d, J = 18 Hz, 1H), 5.33 (d, J = 16 Hz, 1H),
7.08-7.33 (m, 6H), 7.55 (dt, J = 8 and 2 Hz, 1H), 7.99 (dd,
1
J = 8 and 2 Hz, 1H), 8.70 (br d, J = 4 Hz, 1H); H NMR
(DMSO-d6, 400 MHz) δ 1.95-2.05 (m, 1H), 2.14-2.26 (m,
1H), 2.58 (ddd, J = 16, 4, and 4 Hz, 1H), 2.90 (ddd, J = 12, 12,
and 4 Hz, 1H), 4.03 (q, J = 4 Hz, 1H), 4.83 (d, J = 16 Hz, 1H),
5.19 (d, J = 16 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 7.13 (t, J =
8 Hz, 1H), 7.20-7.27 (m, 4H), 7.55 (dt, J = 8 and 2 Hz, 1H),
7.81 (d, J = 8 Hz, 1H), 8.68 (br d, J = 4 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 21.8 (CH2), 28.0 (CH2), 44.1 (CH2), 45.6
(CH), 122.7 (C), 124.2 (CH), 124.7 (CH), 126.0 (CH), 126.2
(CH), 126.6 (C), 126.9 (CH), 128.3 (CH), 130.0 (CH), 131.9
(CH), 139.8 (C), 145.5 (C), 151.8 (C), 156.0 (C), 168.4 (C);
ESIMS (m/z) 317 [M þ H]þ, 339 [M þ Na]þ; HRMS (EI) calcd
for C19H16N4O 316.1324, found 316.1315; IR (Nujol) vmax
Acknowledgment. U.A.K. thanks CSIR, New Delhi for
the award of a research fellowship. N.P.A. thanks the
Department of Science and Technology, New Delhi for
financial support. We are thankful to Professor Peter G.
1
Mantle from UK for the copy of H NMR spectrum of
3435, 1661, 1636, 1612 cm-1
.
natural auranthine. We thank Dr. P. R. Rajmohanan from
our NMR group at NCL for providing the 1H NMR
spectrum of synthetic auranthine in benzene-d6 on the prior-
ity basis. We also thank Dr. Sujata S. Biswas and Mr. B.
Senthilkumar from NCL, Pune for the HRMS data.
6,7,7a,8-Tetrahydroquinazolino[30,20:1,6]pyrido[2,3-b][1,4]benzo-
diazepin-9,16-dione (Auranthine, 1). To a stirred solution of com-
pound 11 (64 mg, 0.20 mmol) in dry acetone (5 mL) was added
KMnO4 (64 mg, 0.40 mmol) and the reaction mixture was refluxed
for 3 h under argon atmosphere. The reaction mixture was allowed
to cool to room temperature and filtered off and the residue was
washed with acetone. Concentration of filtrate in vacuo followed
by silica gel column chromatographic purification of residue with
dichloromethane-methanol (9:1) as an eluent furnished the final
product aurnthine (1) (52 mg, 79%). Mp 188-189 °C (ethyl
acetate); 1H NMR (benzene-d6, 500 MHz) δ 1.40-1.43 (m, 1H),
1.50-1.58 (m, 2H), 2.33-2.39 (m, 1H), 2.98-3.04 (m, 1H), 6.01
Supporting Information Available: 1H NMR, 13C NMR,
and DEPT spectra of compounds 1, 5, 6, and 8-11, 1H NMR
spectrum of natural auranthine, X-ray crystallographic data
(CIF), and the ORTEP diagrams for compounds 11 and 1. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 8, 2010 2705