First total synthesis of (-)-auranomide C and its derivatives

Article abstract of DOI:10.1055/s-0033-1338558

The first total synthesis of (-)-auranomide C has been achieved. The short synthetic strategy involves a reductive dehydrocyclization and the nucleophilic ring opening of a fused γ-lactam. The route allows for ease in synthesizing diverse derivatives in the side chain of the natural product.

Full text of DOI:10.1055/s-0033-1338558

PAPER
▌189
paper
First Total Synthesis of (–)-Auranomide C and Its Derivatives
First Total Synthesis of (–)-Auranomide C and Its Derivatives
Kumaraswamy Sorra,*a,b K. Mukkanti,b Srinivas Pusuluria
a
Chemistry Services, GVK Biosciences Private Limited, Plot No.28A, IDA Nacharam, Hyderabad 500076, AP, India
Fax +91(40)66281505; E-mail: kumaraswamy.s@gvkbio.com
b
Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, AP, India
Received: 15.08.2013; Accepted after revision: 24.10.2013
one-pot domino procedure under microwave heating for
the synthesis of racemic quinazolinobenzodiazepine.8 Re-
cently, acid-catalyzed dehydrocyclization9 and copper-
mediated N-arylation methodologies have been reported
for the synthesis of the quinazolinobenzodiazepine skele-
ton.10 Most recently, we reported the synthesis of enantio-
pure pyrroloquinazolino[1,4]benzodiazepine-2,5-diones
employing a palladium-catalyzed amination–cyclization
domino reaction and intended to use this methodology for
the synthesis of auranomide C.11
Abstract: The first total synthesis of (–)-auranomide C has been
achieved. The short synthetic strategy involves a reductive dehydro-
cyclization and the nucleophilic ring opening of a fused γ-lactam.
The route allows for ease in synthesizing diverse derivatives in the
side chain of the natural product.
Key words: auranomide, quinazolinobenzodiazepine, intramolec-
ular cyclization, reductive dehydrocyclization, nucleophilic ring
opening
Auranomide A (1), B (2), and C (3) are a new quinazolin-
4-one derivatives (Figure 1) isolated recently from the
marine-derived fungus Penicillium aurantiogriseum by
Lixin Zhang et al. and their chemical structures were es-
tablished by extensive NMR and MS studies.1 Aurano-
mides A–C exhibit moderate cytotoxic activity against
human tumor cells. The structural similarities of aurano-
mide C with several bioactive quinazolinobenzodiazepine
alkaloids,2–4 such as circumdatins, benzomalvins, asperli-
cins, and sclerotigenin, prompted us to undertake the total
synthesis of auranomide C.
Retrosynthetically, auranomide C (3) could be derived:
(1) from compound 4 and 2-azidobenzoic acid under aza-
Witting conditions, (2) by reductive dehydrocyclization
of compound 4 with 2-nitrobenzoic acid, or (3) from pal-
ladium-catalyzed cyclization of 4 and 2-bromobenzoate
(Scheme 1).
O
O
NH
OH
O
+
3
R
N
H
O
OMe
R = N3, NO2, Br
4
O
NH
R
O
O
NH2
N
O
N
O
N
O
O
H
O
N
+
N
OMe
+H2N
MeO
N
H
O
NH2
5
6
–
1: auranomide A (R = CO2
)
3: auranomide C
2: auranomide B (R = CO2Et)
Scheme 1 Retrosynthetic analysis of (–)-auranomide C
Figure 1 Structures of auranomide A, B, and C
Our synthesis began with the reductive amination of di-
methyl glutamate 6 with benzaldehyde using sodium bo-
rohydride to afford the N-benzyl glutamate 7 (Scheme 2).
To avoid spontaneous cyclization of N-benzyl glutamate
7 into pyroglutamate, the benzyl derivative was instanta-
neously coupled with 2-nitrobenzoyl chloride to afford 8
in 61% yield over two steps.12
Several methods have been reported for the synthesis of
the quinazolinobenzodiazepine skeleton. The Snider,
Thomas, and Eguchi groups separately reported the use of
the intramolecular aza-Wittig tandem reaction for the total
synthesis of sclerotigenin, circumdatin F, asperlicin C,
and benzomalvin A.5 Witt and Bergman reported the total
synthesis of circumdatin F via formation of an iminoben-
zoxazine intermediate.6 The synthesis of asperlicins C and
E was reported by Bock et al following a regioselective
annulation approach.7 Liu and co-workers developed a
It was gratifying to observe that the reduction followed by
concomitant cyclization of 8 furnished 1,4-benzodiaze-
pine-2,5-dione 9 in 82% yield with >99% ee. We intended
to complete the synthesis of 11 via reductive dehydrocy-
clization;9a compound 9 was reacted with 2-nitrobenzoyl
chloride in the presence of triethylamine and 4-(dimethyl-
amino)pyridine in dichloromethane at 0 °C for 30 min-
utes. As the amide 10 was found to be unstable during
SYNTHESIS 2014, 46, 0189–0194
Advanced online publication: 14.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338558; Art ID: SS-2013-N0398-OP
© Georg Thieme Verlag Stuttgart · New York

190
K. Sorra et al.
PAPER
work up, we reduced it with zinc in acetic acid at –20 °C mate 6 in good yield. The intramolecular cyclization of 4
without isolating the amide to obtain quinazolinobenzodi- to the tricyclic intermediate 14 was accomplished by heat-
azepine 11 in 75% yield with complete racemization. Fur- ing in dimethylacetamide (DMA) at 180 °C.13 It was grat-
ther efforts to preserve the enantiopurity of 11 proved to ifying to note that the amidation of compound 14 with 2-
be difficult.
nitrobenzoyl chloride followed by reductive dehydrocy-
clization proceeded smoothly to furnish compound 16 in
good yields and high enantiomeric excess (>98%). The fi-
nal stage, nucleophilic ring opening of fused γ-lactam 16
with ammonia, afforded auranomide C (3) in high yield
with 97.7% ee.14 The spectral and analytical data for syn-
thetic compound 3 were in complete agreement with the
reported data for naturally occurring (–)-auranomide C.4
At this point, we turned to our earlier reported palladium-
catalyzed approach11 and converted the dilactam com-
pound 9 into the mono thiolactam 12 by reacting with 0.6
equivalents of Lawesson’s reagent in 68% yield. The thi-
olactam 12 was treated with ammonia gas in the presence
of mercury(II) chloride to give the cyclic amidine 13 in
good yields. Further, N-arylation and subsequent intramo-
lecular cyclization of 13 with methyl 2-bromobenzoate We conceived that the ring opening of compound 16 with
under palladium-catalyzed conditions resulted again in various amines could give rise to diverse amide analogues
the formation of racemic compound 11 in 66% yield.
of the natural product. Hence, we reacted compound 16
with primary amines 17a,b, secondary amines 17c–e, and
an aromatic amine 17f to obtain the corresponding amides
18–23, respectively, in high yields (Table 1).
At this moment, we planned for an alternate approach to
circumvent the associated problem of racemization and
also to accomplish the synthesis of enantiomerically pure
auranomide C. Hence, we planned to rigidify the key in- In conclusion, we have accomplished the first and effi-
termediate compound by synthesizing the tricyclic com- cient total synthesis of enantioenriched auranomide C and
pound 14 as tricyclic benzodiazepines are well its amido derivatives via reductive dehydrocyclization
documented to retain their chiral integrity during the an- and nucleophilic ring opening. The described short syn-
nulation of benzodiazepinedione (Scheme 3).5,9a,11
thetic strategy is efficient and permits the synthesis of an-
alogues of the natural product.
The dilactam compound 4 was synthesized by the dehy-
drocyclocondensation of isatoic anhydride 5 with gluta-
O
OMe
(i) benzaldehyde, Na2SO4
MeOH, Et3N, r.t., 16 h
(ii) NaBH4, 0 °C, 30 min
2-nitrobenzoyl chloride
K2CO3, Bu4NI, CH2Cl2
0 °C to r.t., 4 h
O
OMe
NO2
O
O
O
OMe
Bn
OMe
N
MeO
OMe
N
H
61%
(over two steps)
+NH3Cl–
Bn
O
O
6
7
8
Zn, NH4Cl, MeOH
r.t., 10 min
O
Cl
NO2
O
Bn
O
O
N
OMe
OMe
O
Et3N, DMAP
CH2Cl2
0 °C, 30 min
Bn
O
N
NH2
O
p-TSA. H2O
N
O
reflux, 16 h
O
N
82%
(over two steps)
O
OMe
N
Bn
H
O
OMe
8′
10
9
O2N
Lawesson's reagent
THF, 75 °C, 1 h
Zn, AcOH
–20 °C, 2 h
–5 °C, 1 h
57%
(over two steps)
O
68%
OMe
O
Br
Bn
O
O
Bn
N
Pd (OAc)2, xantphos
Cs2CO3, 1,4-dioxane
110 °C, 12 h
Bn
NH3, HgCl2, THF
90 °C, 3 h
N
O
N
O
O
OMe
N
N
OMe
74%
66%
N
N
O
H
S
OMe
NH2
12
13
( )-11
Scheme 2 Synthesis of the key intermediate of auranomide C
Synthesis 2014, 46, 189–194
© Georg Thieme Verlag Stuttgart · New York

PAPER
First Total Synthesis of (–)-Auranomide C and Its Derivatives
191
O
O
O
O
DMA
180 °C, 16 h
N
6, pyridine
120 °C, 16 h
NH
O
O
H
76%
N
64%
N
N
H
O
H
O
H
O
OMe
14
4
5
2-nitrobenzoyl chloride
Et3N, DMAP, CH2Cl2
0 °C, 30 min
O
O
O
O
O
Zn, AcOH
–20 °C, 1 h
–5 °C, 1 h
NH3, THF
0 °C to r.t., 16 h
N
NH
N
O
H
55%
(over two steps)
N
92%
N
H
N
O
N
NH2
N
O
O
O
O2N
15
3: (–)-auranomide C
16
Scheme 3 Synthesis of (–)-auranomide C
isolated compounds had purity greater than 98% (area percent) as
judged by HPLC analysis area method.
Table 1 Synthesis of (–)-Auranomide C Derivatives
O
Dimethyl (S)-2-(N-Benzyl-2-nitrobenzamido)pentanedioate (8)
To a mixture of L-glutamic acid dimethyl ester hydrochloride (6, 5
g, 23.69 mmol) and benzaldehyde (2.76 g, 26.06 mmol) in MeOH
(50 mL) was added Et3N (4.0 mL, 28.43 mmol) and anhydrous
Na2SO4 (2 g) at 0 °C; the mixture was stirred at r.t. for 16 h. The
mixture was filtered and the filtrate was concentrated to half its vol-
ume, treated with NaBH4 (1.08 g, 28.43 mmol) at 0 °C and then
stirred at this temperature for 30 min. The mixture was concentrat-
ed; the residue was dissolved in CH2Cl2 and washed with H2O. The
organic layer was dried (Na2SO4) and concentrated to obtain crude
7 (3.5 g). The crude 7 was dissolved in CH2Cl2 (50 mL), K2CO3 (5.2
g, 37.73 mmol) and Bu4NI (2.78 g, 7.54 mmol) were added, the
mixture was cooled to 0 °C and treated with 2-nitrobenzoyl chloride
(2.4 mL, 18.11 mmol), and it was stirred at r.t. for 4 h. The mixture
was quenched with H2O (70 mL) and extracted with CH2Cl2. The
organic layer was dried (Na2SO4) and evaporated. The residue was
purified by column chromatography (silica gel, 100–200 mesh, PE–
EtOAc, 7:3) to afford 8 (6.0 g, 61%) as a white solid; mp 88–89 °C;
[α]D25 –74.0 (c 0.1, DMSO); Rf = 0.50 (PE–EtOAc, 1:1).
NH
O
N
R1R2NH 17a–f
N
R1
THF, 0 °C to r.t., 16 h
N
O
R2
16
18–23
Entry
Amine
R1
R2
Product
Yield
(%)
1
2
3
4
5
6
17a
17b
17c
17d
17e
17f
H
Me
Bn
Me
18
19
20
21
22
23
95
90
90
93
90
95
H
Me
(CH2)4
(CH2)5
H
IR (KBr): 3441, 2951, 1747, 1648, 1524 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.30 (d, J = 7.5 Hz, 1 H), 8.23
(d, J = 8.4 Hz, 1 H), 7.89–7.67 (m, 2 H), 7.52–7.45 (m, 2 H), 7.37–
7.24 (m, 3 H), 4.42 (s, 2 H), 4.15 (m, 1 H), 3.65 (s, 3 H), 3.57 (s, 3
H), 2.50–2.32 (m, 2 H), 2.20–1.98 (m, 2 H).
Ph
13C NMR (75 MHz, DMSO-d6): δ = 172.9, 170.1, 167.6, 144.6,
138.0, 135.5, 135.0, 131.8, 130.6, 130.5, 128.3, 128.1, 127.6, 125.1,
124.8, 57.5, 53.0, 51.9, 51.3, 30.0, 23.6.
MS (APCI): m/z = 415 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C21H23N2O7: 415.1505;
All solvents were purified by standard procedures prior to use and
all commercial chemicals were used as received. TLC analysis:
Merck precoated plates (silica gel 60 F254); melting point: Mel-
temp apparatus (uncorrected); 1H and 13C NMR: Varian Unity
instrument at r.t. at 300 and 400 MHz with reference to internal
solvent; mass spectra: Micro mass QuattroMicroTM API-autospec-
trometer using APCI technique; HRMS TOF-ES: Waters-Alliance
2695 Separation Module/Q-TOF Micromass; IR: Perkin Elmer FT-
IR spectrophotometer; Optical rotations: Jasco P-1030 polarimeter.
Enantiomeric excess was determined by HPLC analysis using
Chiralpak IC column (250 × 4.6 mm, 5 micron), mobile phase: hex-
ane–EtOH (1:1) with 0.1% Et2NH at 1.0mL/min. Petroleum ether
(PE) used refers to the fraction boiling in the 60–80 °C range. All
found: 415.1507.
Methyl (S)-3-(4-Benzyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1,4-
benzodiazepin-3-yl)propanoate (9)
A solution of 8 (5 g, 12.07 mmol) and NH4Cl (3.23 g, 60.38 mmol)
in MeOH (50 mL) was treated with zinc powder (7.85 g, 120.77
mmol) at r.t. After 10 min, the mixture was filtered through a Celite
pad and washed with MeOH. The combined filtrates were concen-
trated to ca. 25 mL; p-TSA·H2O (1.14 g, 6.03 mmol) was added and
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 189–194

192
K. Sorra et al.
PAPER
the mixture refluxed for 16 h, cooled to r.t., and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (silica gel, 100–200 mesh, CHCl3–MeOH, 9.8:0.2) to give 9
(3.5 g, 82%) as a white solid; mp 102–103 °C; [α]D25 –20.0 (c 0.1,
DMSO); Rf = 0.5 (CHCl3–MeOH, 9.5:0.5).
Methyl 3-(6-Benzyl-5,13-dioxo-5,6,7,13-tetrahydro-6,8,13a-tri-
azabenzo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)propanoate
[(±)-11]
Method A: To a solution of 9 (0.5 g, 1.42 mmol), Et3N (0.4 mL, 2.84
mmol), and DMAP (0.07 g, 0.56 mmol) in CH2Cl2 (10 mL) was
added 2-nitrobenzoyl chloride (0.22 mL, 1.70 mmol) at 0 °C and the
mixture was stirred at this temperature for 30 min. The mixture was
cooled to –20 °C, and AcOH (5 mL) and zinc powder (0.92 g, 14.20
mmol) were added. After 2 h, the temperature was slowly warmed
to –5 °C and the mixture was stirred for additional 1 h. The mixture
was filtered through Celite; the filtrate was poured into sat. aq
NaHCO3 (50 mL) and extracted with CH2Cl2. The combined organ-
ic extracts were washed with brine, dried (Na2SO4), and evaporated.
The residue was purified by column chromatography (silica gel,
100–200 mesh, PE–EtOAc, 7:3) to give (±)-11 (0.37 g, 57%).
IR (KBr): 3436, 1747, 1646 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 10.54 (d, J = 18.4 Hz, 1 H),
7.81 (d, J = 7.6 Hz, 1 H), 7.55–7.49 (m, 1 H), 7.35–7.22 (m, 6 H),
7.10 (d, J = 8.0 Hz, 1 H), 5.09 (d, J = 14.8 Hz, 0.5 H), 4.82 (d,
J = 15.6 Hz, 0.5 H), 4.59 (d, J = 15.6 Hz, 0.5 H), 4.48 (d, J = 14.8
Hz, 0.5 H), 4.20–4.12 (m, 1 H), 3.50 (s, 3 H), 2.27–2.19 (m, 2.5 H),
2.0–1.90 (m, 0.5 H), 1.65–1.57 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ (major rotamer) = 171.1, 168.1,
165.3, 138.0, 137.1, 136.6, 135.5, 132.4, 130.8, 128.4, 127.7, 126.6,
125.8, 124.0, 120.6, 63.6, 54.4, 51.4, 29.9, 23.9.
Method B: A solution of compound 13 (0.2 g, 0.57 mmol) and meth-
yl 2-bromobenzoate (0.122 g, 0.57 mmol) in 1,4-dioxane (5 mL)
was degassed and backfilled with argon, followed by the addition of
Pd(OAc)2 (6 mg, 5 mol%), xantphos (22 mg, 10 mol%), and
Cs2CO3 (371 mg, 1.13 mmol). The mixture was heated at 110 °C for
12 h, cooled to r.t., and concentrated. The residue was dissolved in
CHCl3, washed with 10% citric acid solution and then brine, dried
(Na2SO4), and concentrated. The crude compound was purified by
column chromatography to afford (±)-11 (0.17 g, 66%) as a gummy
solid; Rf = 0.4 (PE– EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 6.8 Hz, 1 H), 8.01 (d,
J = 7.2 Hz, 1 H), 7.72 (t, J = 6.8 Hz, 1 H), 7.62–7.48 (m, 5 H), 7.23–
7.21 (m, 2 H), 7.06 (t, J = 7.2 Hz, 2 H), 6.99–6.94 (m, 1 H), 4.94 (d,
J = 16.0, 1 H), 4.70–4.65 (m, 2 H), 3.55 (s, 3 H), 2.78–2.74 (m, 1
H), 2.44–2.22 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 168.1, 161.2, 152.0, 145.7,
137.5, 134.4, 133.1, 131.3, 131.0, 128.9, 128.3 (2 C), 127.7, 127.6,
127.5, 127.5, 127.3, 127.2 (2 C), 127.0, 121.3, 57.4, 51.6, 45.6,
30.5, 22.8.
MS (APCI): m/z = 454 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C27H24N3O4: 454.1767;
MS (APCI): m/z = 353 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C20H21N2O4: 353.1501;
found: 353.1503.
Methyl (S)-3-(4-Benzyl-5-oxo-2-thioxo-2,3,4,5-tetrahydro-1H-
1,4-benzodiazepin-3-yl)propanoate (12)
To a suspension of 9 (3.0 g, 8.52 mmol) in THF (30 mL) was added
Lawesson’s reagent (2.41 g, 5.96 mmol) and the mixture was heated
at 75 °C for 1 h. The mixture was cooled to r.t. and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography (silica gel, 100–200 mesh, PE–EtOAc, 7.5:3.5) to give 12
(1.3 g, 68%) as a yellow solid; mp 126–127 °C; [α]D25 –92.0 (c 0.1,
DMSO); Rf = 0.6 (PE–EtOAc, 1:1).
IR (KBr): 3436, 2946, 1727, 1640 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 12.50 (br s, 1 H), 7.89–7.85
(m, 1 H), 7.64–7.54 (m, 1 H), 7.42–7.23 (m, 7 H), 4.86–4.64 (m, 2
H), 4.44–4.33 (m, 1 H), 3.48 (s, 3 H), 2.44–1.98 (m, 3 H), 1.72–1.52
(m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ (major rotamer) = 200.2, 171.8,
164.7, 136.9, 136.1, 132.5, 131.2, 128.3 (2 C), 127.4, 127.0 (2 C),
126.7, 125.5, 120.5, 70.5, 53.9, 51.3, 29.9, 23.7.
found: 454.1790.
MS (APCI): m/z = 369 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C20H21N2O3S: 369.1273;
Methyl (S)-3-(2,5-Dioxo-2,3,4,5-tetrahydro-1H-1,4-benzodiaze-
pin-3-yl)propanoate (4)
A mixture of isatoic anhydride 5 (3.38 g, 20.85 mmol) and L-glu-
tamic acid dimethyl ester hydrochloride (6, 5 g, 20.85 mmol) in pyr-
idine (50 mL) was heated at 120 °C for 16 h. The mixture was
cooled to r.t. and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 100–200 mesh,
CHCl3–MeOH, 9.5:0.5) to afford 4 (3.5 g, 64%) as an off-white sol-
id; mp 182–183 °C; [α]D25 +332 (c 0.1, DMSO); Rf = 0.4 (CHCl3–
MeOH, 9.5:0.5).
found: 369.1256.
Methyl (S)-3-(2-Amino-4-benzyl-5-oxo-4,5-dihydro-3H-1,4-
benzodiazepin-3-yl)propanoate (13)
A suspension of 12 (2.0 g, 5.43 mmol) and HgCl2 (1.7 g, 6.52
mmol) in dry THF (50 mL) was heated to 90 °C and NH3 gas was
bubbled into the mixture for a period of 2 h at 90 °C. The bubbling
of ammonia gas ceased and the mixture was stirred for an additional
1 h at this temperature. The mixture was filtered through Celite
which was washed (MeOH–THF, 1:1), and the combined filtrates
were concentrated. The residue was washed repetitively with ace-
tone followed by Et2O to give 13 (1.4 g, 74%) as an off-white solid;
IR (KBr): 3173, 2929, 1728, 1678, 1660 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.41 (br s, 1 H), 8.48 (d,
J = 5.4 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.51 (t, J = 7.8 Hz, 1 H),
7.22 (1 H, t, J = 7.5 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 3.74–3.67
(m, 1 H), 3.56 (s, 3 H), 2.47–2.40 (m, 2 H), 2.08–2.00 (m, 1 H),
1.88–1.81 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 172.8, 171.3, 167.7, 136.6,
132.2, 130.4, 126.2, 123.9, 120.9, 51.3, 50.8, 29.6, 23.1.
25
mp 166–167 °C; [α]D –494.0 (c 0.1, DMSO); Rf = 0.3 (CHCl3–
MeOH, 9:1).
IR (KBr): 3368, 1741, 1593, 1470 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.72 (d, J = 8.0 Hz, 1 H), 7.37–
7.26 (m, 5 H), 6.99–6.92 (m, 3 H), 4.84 (d, J = 15.2 Hz, 1 H), 4.57
(d, J = 15.2 Hz, 1 H), 4.14 (t, J = 7.6 Hz, 1 H), 3.46 (s, 3 H), 2.05–
1.90 (m, 2 H), 1.52–1.36 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 171.8, 166.6, 159.6, 147.2,
137.5, 131.6, 130.4, 128.3, 128.2, 127.9 (2 C), 127.2, 126.8, 125.2,
121.1, 59.2, 53.6, 51.3, 29.9, 23.9.
MS (APCI): m/z = 263 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C13H15N2O4: 263.1032;
found: 263.1037.
(S)-1H-Pyrrolo[2,1-c][1,4]benzodiazepine-
3,5,11(2H,10H,11aH)-trione (14)
A solution of 4 (1 g, 3.82 mmol) in DMA (5 mL) was heated to re-
flux for 16 h. The solution was cooled to r.t. and concentrated under
reduced pressure. The residue was suspended with H2O (1 mL) and
stirred for 15 min. The precipitated solid was collected by filtration,
MS (APCI): m/z = 352 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C20H22N3O3: 352.1661;
found: 352.1677.
Synthesis 2014, 46, 189–194
© Georg Thieme Verlag Stuttgart · New York

PAPER
First Total Synthesis of (–)-Auranomide C and Its Derivatives
193
washed with H2O and dried to give pure 14 (0.67 g, 76%) as an off-
white solid; mp 138–139 °C; [α]D25 +498 (c 0.1, DMSO); Rf = 0.50
(CHCl3–MeOH, 9.5:0.5).
IR (KBr): 3510, 2903, 1771, 1681 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.71 (br s, 1 H), 7.85–7.55
(m, 2 H), 7.35–7.20 (m, 2 H), 4.70–4.60 (m, 1 H), 2.95–2.90 (m, 1
H), 2.72–7.80 (m, 1 H), 2.25–2.20 (m, 2 H).
HRMS (TOF ES+): m/z [M + H]+ calcd for C19H17N4O3: 349.1301;
found: 349.1300.
(S)-3-(5,13-Dioxo-5,6,7,13-tetrahydro-6,8,13a-triazaben-
zo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)-N-methylpropan-
amide (18)
Off-white solid; yield: 103 mg (95%); mp 198–199 °C; [α]D25 –36.0
(c 0.1, MeOH); Rf = 0.40 (CHCl3–MeOH, 9:1).
IR (KBr): 3432, 2923, 1646, 1615 cm–1.
13C NMR (100 MHz, DMSO-d6): δ = 173.3, 169.6, 164.0, 136.6,
1H NMR (300 MHz, DMSO-d6): δ = 8.81 (d, J = 6.0 Hz, 1 H), 8.19
(d, J = 8.1 Hz, 1 H), 8.01 (d, J = 5.4 Hz, 1 H), 7.90 (t, J = 8.4 Hz, 1
H), 7.76 (d, J = 6.6 Hz, 2 H), 7.70–7.54 (m, 3 H), 6.64 (d, J = 6.6
Hz, 1 H), 4.10–4.05 (m, 1 H), 2.98 (s, 3 H), 2.20–2.05 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 173.0, 168.8, 161.5, 154.2, 146.8,
145.8, 134.6, 133.3, 131.4, 130.2, 129.4, 128.9, 127.4, 127.1, 121.1,
106.4, 53.6, 39.2, 32.2, 26.2.
133.6, 131.3, 125.8, 124.3, 121.6, 56.0, 30.9, 17.8.
MS (APCI): m/z = 231 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C12H11N2O3: 231.0770;
found: 231.0758.
(2S)-6,14,22-Triazapentacyclo[12.8.0.02,6.08,13.016,21]docosa-
1(22),8,10,12,16(21),17,19-heptaene-5,7,15-trione (16)
To a solution of 14 (1.5 g, 6.52 mmol), Et3N (1.83 mL, 13.04
mmol), and DMAP (0.31 g, 2.60 mmol) in CH2Cl2 (15 mL) was
added 2-nitrobenzoyl chloride (1.03 mL, 7.82 mmol) at 0 °C and the
mixture was stirred at this temperature for 30 min. The mixture was
cooled to –20 °C, and AcOH (15 mL) and zinc powder (4.24 g,
65.21 mmol) were added. After 1 h, the temperature was slowly
warmed to –5 °C and the mixture was stirred for 1 h. The mixture
was filtered through Celite; the filtrate was poured into cold sat. aq
NaHCO3 (100 mL) and extracted with CH2Cl2. The combined or-
ganic extracts were washed with brine, dried (Na2SO4), and evapo-
rated. The crude compound was washed with Et2O to give 16 (1.2
g, 55%) as an off-white solid; mp 261–262 °C; [α]D25 –34.0 (c 0.1,
CHCl3); Rf = 0.70 (CHCl3–MeOH, 9.5:0.5).
MS (APCI): m/z = 363 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C20H19N4O3: 363.1457;
found: 363.1470.
(S)-N-Benzyl-3-(5,13-dioxo-5,6,7,13-tetrahydro-6,8,13a-triaza-
benzo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)propanamide (19)
Off-white solid; yield: 119 mg (90%); mp 153–154 °C; [α]D25 –64.0
(c 0.1, MeOH); Rf = 0.6 (CHCl3–MeOH, 9:1).
IR (KBr): 3431, 2923, 1658, 1617 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.82 (d, J = 6.3 Hz, 1 H), 8.30
(t, J = 6.3 Hz, 1 H), 8.19 (d, J = 6.9 Hz, 1 H), 7.91 (t, J = 8.4 Hz, 1
H), 7.77 (d, J = 6.0 Hz, 2 H), 7.71– 7.58 (m, 3 H), 7.34–7.21 (m, 4
H), 7.16–7.13 (m, 2 H), 4.21–4.16 (m, 3 H), 2.48–2.35 (m, 3 H),
2.27–2.15 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 169.0, 161.4, 154.0, 145.7,
138.2, 134.5, 133.2, 131.3, 130.1, 129.4, 128.9, 128.6, 128.3 (3 C),
127.6, 127.4 (2 C), 127.3, 127.0, 120.9, 53.5, 43.4, 32.4, 25.7.
IR (KBr): 3432, 2923, 1646, 1615 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.18 (d, J = 8.1 Hz, 1 H), 7.93–
7.83 (m, 2 H), 7.77–7.71 (m, 2 H), 7.66–7.58 (m, 3 H), 5.08 (d,
J = 8.1 Hz, 1 H), 2.96–2.73 (m, 2 H), 2.56–2.48 (m, 1 H), 2.34–2.23
(m, 1 H).
MS (APCI): m/z = 439 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C26H23N4O3: 439.1770;
13C NMR (75 MHz, DMSO-d6): δ = 173.1, 163.5, 161.1, 152.6,
145.6, 134.9, 132.7, 131.8, 131.2, 130.2, 129.2, 128.8, 127.6, 127.5,
126.7, 121.5, 58.4, 31.6, 18.9.
MS (APCI): m/z = 332 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C19H14N3O3: 332.1035;
found: 439.1768.
(S)-3-(5,13-Dioxo-5,6,7,13-tetrahydro-6,8,13a-triazaben-
zo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)-N,N-dimethyl-
propanamide (20)
Off-white solid; yield: 102 mg (90%); mp 178–179 °C; [α]D
–110.0 (c 0.1, MeOH); Rf = 0.60 (CHCl3–MeOH, 9:1).
found: 332.1028.
25
Nucleophilic Ring Opening; General Procedure
A solution of 16 (0.1 g, 0.30 mmol) in THF (3 mL) was cooled to 0
°C and saturated THF–NH3 (0.2 mL) was added for the synthesis of
3 or a solution of amine 17a–f (2 equiv) in THF (0.5 mL) for 18–23.
The mixture was allowed to stir at r.t. for 16 h and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography (silica gel, 100–200 mesh, 2–5% MeOH–CHCl3) to obtain
the corresponding amide 3, 18–23.
IR (KBr): 3436, 2923, 1616 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.80 (d, J = 6.3 Hz, 1 H), 8.19
(d, J = 7.5 Hz, 1 H), 7.90 (t, J = 8.1 Hz, 1 H), 7.77 (t, J = 8.7 Hz, 2
H), 7.67– 7.57 (m, 4 H), 4.24–4.22 (m, 1 H), 2.93 (s, 3 H), 2.78 (s,
3 H), 2.39–2.32 (m, 3 H), 2.20–2.14 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.0, 167.7, 161.5, 154.5, 146.1,
134.7, 133.3, 131.1, 130.6, 129.9, 128.8, 128.3, 127.7, 127.5, 127.3,
121.5, 53.9, 37.1, 35.6, 29.3, 24.3.
(S)-3-(5,13-Dioxo-5,6,7,13-tetrahydro-6,8,13a-triazaben-
zo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)propanamide (3,
Auranomide C)
MS (APCI): m/z = 377 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C21H21N4O3: 377.1614;
Off-white solid; yield: 97 mg (92%); mp 263–264 °C; [α]D25 –68.0
(c 0.1, MeOH) [Lit.4 [α]D20 –63.0 (c 0.1, MeOH]; Rf = 0.3 (CHCl3–
MeOH, 9:1).
found: 377.1634.
IR (KBr): 3335, 3198, 2936, 1688, 1646, 1622 cm–1.
(S)-7-[3-Oxo-3-(pyrrolidin-1-yl)propyl]-6,7-dihydro-6,8,13a-
triazabenzo[3,4]cyclohepta[1,2-b]naphthalene-5,13-dione (21)
Off-white solid; yield: 113 mg (93%); mp 146–147 °C; [α]D25 –82.0
(c 0.1, MeOH); Rf = 0.40 (CHCl3–MeOH, 9:1).
1H NMR (300 MHz, DMSO-d6): δ = 8.82 (d, J = 5.7 Hz, 1 H), 8.31
(s, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.90 (t, J = 7.2 Hz, 1 H), 7.77 (t,
J = 7.2 Hz, 1 H), 7.65–7.58 (m, 4 H), 7.25 (br s, 1 H), 6.74 (br s, 1
H), 4.22–4.10 (m, 1 H), 2.35–2.14 (m, 4 H).
IR (KBr): 3436, 2923, 1670, 1616 cm–1.
13C NMR (75 MHz, DMSO-d6): δ = 174.1, 167.3, 161.4, 156.2,
146.3, 135.6, 133.4, 131.7, 131.1, 129.3 (2 C), 129.1, 128.0, 127.9,
127.3, 121.4, 53.6, 31.3, 24.6.
1H NMR (300 MHz, DMSO-d6): δ = 8.81 (d, J = 5.7 Hz, 1 H), 8.19
(d, J = 7.8 Hz, 1 H), 7.90 (t, J = 7.5 Hz, 1 H), 7.77 (t, J = 7.5 Hz, 2
H), 7.67– 7.56 (m, 4 H), 4.24–4.22 (m, 1 H), 3.36 (t, J = 6.6 Hz, 2
H), 3.22 (t, J = 6.9 Hz, 2 H), 2.51–2.33 (m, 3 H), 2.27–2.16 (m, 1
H), 1.90–1.71 (m, 4 H).
MS (APCI): m/z = 349 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 189–194

194
K. Sorra et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 170.6, 167.7, 161.6, 154.5, 146.1,
134.7, 133.3, 131.1, 130.6, 129.9, 128.8, 128.3, 127.6, 127.5, 127.3,
121.5, 53.9, 46.6, 45.8, 30.5, 26.0, 24.4, 24.3.
MS (APCI): m/z = 403 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C23H23N4O3: 403.1770;
References
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Soc. 1998, 120, 6417. (c) Grieder, A.; Thomas, A. W.
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1998, 54, 7997. (e) Eguchi, S. ARKIVOC 2005, (ii), 98.
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found: 403.1750.
(S)-7-[3-Oxo-3-(piperidin-1-yl)propyl]-6,7-dihydro-6,8,13a-tri-
azabenzo[3,4]cyclohepta[1,2-b]naphthalene-5,13-dione (22)
Off-white solid; yield: 113 mg (90%); mp 155–156 °C; [α]D25 –38.0
(c 0.1, MeOH); Rf = 0.50 (CHCl3–MeOH, 9:1).
IR (KBr): 3451, 2926, 1616 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 8.80 (d, J = 6.0 Hz, 1 H), 8.19
(d, J = 8.1 Hz, 1 H), 7.90 (t, J = 8.4 Hz, 1 H), 7.76 (t, J = 8.4 Hz, 2
H), 7.67–7.56 (m, 4 H), 4.22–4.19 (m, 1 H), 3.41–3.39 (m, 4 H),
2.50–2.32 (m, 3 H), 2.20–2.14 (m, 1 H), 1.56–1.30 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 170.2, 167.7, 161.5, 154.4, 146.1,
134.7, 133.3, 131.1, 130.6, 129.8, 128.8, 128.3, 127.6, 127.5, 127.3,
121.4, 54.0, 46.5, 42.9, 29.2, 26.4, 25.4, 24.6, 24.4.
MS (APCI): m/z = 417 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C24H25N4O3: 417.1927;
found: 417.1914.
(S)-3-(5,13-Dioxo-5,6,7,13-tetrahydro-6,8,13a-triazaben-
zo[3,4]cyclohepta[1,2-b]naphthalen-7-yl)-N-phenylpropan-
amide (23)
Off-white solid; yield: 121 mg (95%); mp 171–172 °C; [α]D25 –88.0
(c 0.1, MeOH); Rf = 0.40 (CHCl3–MeOH, 9:1).
IR (KBr): 3434, 2923, 1672, 1617 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 9.84 (s, 1 H), 8.85 (d, J = 6.0
Hz, 1 H), 8.19 (d, J = 8.1 Hz, 1 H), 7.91 (t, J = 7.8 Hz, 1 H), 7.78–
7.75 (m, 2 H), 7.67–7.55 (m, 4 H), 7.50 (d, J = 7.8 Hz, 2 H), 7.25 (t,
J = 7.5 Hz, 2 H), 7.00 (t, J = 7.2 Hz, 1 H), 4.25–4.23 (m, 1 H), 2.59–
2.43 (m, 3 H), 2.30–2.25 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.6, 169.3, 161.5, 154.0, 145.8,
137.9, 134.7, 133.4, 131.6, 130.0, 129.7, 129.0, 128.8 (2 C), 128.4,
127.5 (2 C), 127.1, 124.1, 121.1, 119.9 (2 C), 53.6, 33.6, 25.8.
(8) 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.
MS (APCI): m/z = 425 [M + H]+.
HRMS (TOF ES+): m/z [M + H]+ calcd for C25H21N4O3: 425.1614;
(9) (a) Zhichkin, P. E.; Jin, X.; Zhang, H.; Peterson, L. H.;
Ramirez, C.; Snyder, T. M.; Burton, H. S. Org. Biomol.
Chem. 2010, 8, 1287. (b) Tseng, M. C.; Yang, H. Y.; Chu, Y.
H. Org. Biomol. Chem. 2010, 8, 419.
found: 425.1627.
Acknowledgement
(10) Kshirsagar, U. A.; Argade, N. P. Org. Lett. 2010, 12, 3716.
(11) Kumaraswamy, S.; Mukkanti, K.; Srinivas, P. Tetrahedron
2012, 68, 2001.
The authors are grateful to the GVK Biosciences management for
financial support and encouragement.
(12) Cheng, M.-F.; Yu, H.-M.; Ko, B.-W.; Chang, Y.; Chen, M.-
Y.; Ho, T.-I.; Tsai, Y.-M.; Fang, J.-M. Org. Biomol. Chem.
2006, 4, 510.
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2003, 40, 29.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(14) The enantiomeric purity was determined by comparing
chiral HPLC area method with a racemic compound 3 which
was synthesized similarly from the dimethyl DL-glutamate.
Synthesis 2014, 46, 189–194
© Georg Thieme Verlag Stuttgart · New York